This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Terasawa, E. Articles by Fernandez, D. L. Search for Related Content PubMed PubMed Citation Articles by Terasawa, E. Articles by Fernandez, D. L.

Neurobiological Mechanisms of the Onset of Puberty in Primates¹

Department of Pediatrics (E.T.), Wisconsin Regional Primate Research Center (E.T., D.L.F.), and Center for Neuroscience (E.T.), University of Wisconsin-Madison, Madison, Wisconsin 53715-1299

	Abstract

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact, -aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.

I. Introduction

II. Description of Puberty

III. When Does the LHRH Neuronal System Mature?

A. Embryonic and fetal periods

B. Postnatal maturation

IV. What Determines the Timing of Puberty?

A. Hormonal changes during the neonatal and juvenile periods

B. Hormonal changes at the onset of and during puberty

C. Positive feedback effects of estrogen on the LH surge

D. Two hypotheses on the mechanism of the onset of puberty

E. Species differences in the mechanism of the onset of puberty

V. Neurobiology of Puberty

A. Inhibitory neurotransmitters

B. Stimulatory neurotransmitters

C. Role of glia and growth factors

D. Nutritional and metabolic factors

VI. Master Gene(s) Controlling the Onset of Puberty

VII. Summary and Conclusion

	I. Introduction

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
PUBERTY is defined as the transient period between childhood and adulthood during which reproductive function is attained. During this period the secondary sexual characteristics appear, the adolescent growth spurt occurs, the gonads start to produce mature gametes (sperm or oocytes) capable of fertilization, and major psychological changes occur (1). In the last two decades, it has become apparent that puberty begins when the pulsatile release of LH releasing hormone (LHRH, also called GnRH) increases. The hypothalamic decapeptide, LHRH, stimulates pituitary release of LH and FSH, which are essential for the production of mature gametes and gonadal steroid secretion. Thus, the question of "what triggers the onset of puberty?" becomes rather the question of "what triggers the pubertal increase in LHRH release?" Since control of pulsatile LHRH release occurs within the hypothalamus, the answer to the latter question requires a neurobiological approach in animal models. Although many excellent reviews on the mechanism of the onset of puberty are available (2, 3, 4, 5, 6), in this article we will examine the mechanism of puberty from a neurobiological perspective with an emphasis on its developmental aspect. Our discussion will focus on events in the nonhuman primate as a model for humans, but we will review data from other species, particularly from the rat, a common laboratory rodent.

Puberty is also associated with several neurological and reproductive disorders. For example, it has been documented that the onset of schizophrenia occurs during late puberty to early young adulthood (7), precocious puberty is often associated with epilepsy in children (8, 9), and the new onset of epileptic seizures tends to occur early in life as well as during the adolescent period (10). In addition, taking into consideration the recent view that polycystic ovarian syndrome originates during the pubertal stage (11, 12), it is possible that an irregularity of the normal control of pulsatile LHRH release during puberty may be a cause of the polycystic ovarian syndrome, although this is highly speculative at this time. Therefore, it is our hope that this article will be helpful for understanding disorders in humans, including precocious puberty and delayed puberty, and the neuropathogenesis of the clinical disorders associated with puberty.

	II. Description of Puberty

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
Physical and hormonal changes associated with puberty have been used as signs of sexual maturation. First appearance of pubic hair and enlargement of the breasts occurs at 8–10 yr of age (2, 13, 14). Pubic and axillary hair growth is primarily due to a pubertal increase in adrenal androgen (adrenarche), which occurs independently from pituitary-gonadal maturation [gonadarche (15)], whereas breast development is due to an increase in ovarian estrogens (2). Subsequently, menarche occurs at an average age of 11–13 yr due to a further increase in ovarian estrogens (2, 13, 14). Based on development of the breasts and pubic hair, Tanner (16) has developed standards for puberty in girls. Because an increase in estrogen during the early stage of puberty stimulates epiphyseal growth, accelerated growth (the pubertal increase in height velocity) is the first sign of puberty in individual girls (2).

In boys, an increase in testicular size occurs at 9.5–13.5 yr (average 12 yr) of age (17), which is followed by the growth of pubic hair and of the penis (16). Testicular growth is due to a thickening of the seminiferous tubular lining, the formation of a lumen, and the differentiation and growth of Sertoli and Leydig cells, resulting in a volume increase in the Leydig cells. Tanner (16) also has established standards for pubertal development in boys.

In the female rhesus monkey, the first physical signs of puberty are a slight increase in growth velocity and nipple size, and development of perineal sex-skin color, which occurs at 25–28 months of age (18). The increase in nipple size and perineal sex skin development further progresses, and menarche occurs at 28–32 months of age. Several episodes of menstrual cycles occur after menarche (18) without ovulation, and first ovulation occurs at 42–50 months of age (18, 19, 20, 21, 22). After first ovulation, the ovulatory cycles in the rhesus monkey often exhibit a short luteal phase. Previously, we designated the period before any signs of puberty as the prepubertal stage, the period between first signs of puberty and menarche as the early pubertal stage, the period between menarche and first ovulation as the midpubertal stage, and the period between first ovulation and full maturity as the late pubertal stage (18). In female rats, vaginal opening, which occurs around postnatal (P) day 35–37 (P35-P37), and which is usually accompanied by the first ovulation, is a marker of puberty. However, because vaginal opening often occurs without first ovulation under experimental conditions, direct observations of ova in oviducts or corpora lutea formation on the ovary ensure the documentation of true puberty.

In male rhesus monkeys testicular descent into the scrotum occurs slightly after 30 months of age. Subsequently, testicular volume starts to increase. This increase continues until approximately 48 months of age, when full spermatogenesis is observed (3). Male rats become fertile at P42–P45, which is accounted as the time of puberty (4).

	III. When Does the LHRH Neuronal System Mature?

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
A. Embryonic and fetal periods
Studies in the mouse (23, 24), rhesus monkey (25, 26), and human (27) indicate that LHRH neurons originate from the olfactory epithelium during the gestational period. In the rhesus monkey, LHRH cells are found in the olfactory pit as early as at embryonic (E) day 32 (E32) and commonly at E34–E36 (Refs. 25, 26, 28 and Fig. 1). LHRH cells migrate along the nasal septum and terminal nerve, enter the forebrain at E38 (26), and subsequently migrate into the basal hypothalamus of the rhesus monkey by E47 (25). The basic distribution pattern of LHRH neurons in the brain is already established at E55 (25, 26, 29), although LHRH cell migration into the preoptic area (POA) and hypothalamus continues after E55 until the last trimester. The gonadotropes are found in the pituitary at E50 (25), and sex-specific gonadal steroids are detectable in the umbilical cord at E70 (30), suggesting that LHRH cells are functioning at E50–E70. However, activity of LHRH neurons may not be high until close to term; pro-LHRH mRNA is detectable in LHRH cells at E38–E50, but does not increase significantly until E135 (25). Gonadectomy at E98–E104 results in the elevation of LH and FSH in male monkeys, but not in female monkeys (31), indicating that the negative feedback system is operative in the male hypothalamo-pituitary-gonadal axis during the second trimester.

View larger version (19K): [in this window] [in a new window]   Figure 1. Ontogeny of the LHRH-pituitary-gonadal system before birth until after the onset of puberty in female rhesus monkeys (top) and in female humans (bottom). Days and months are used as the scale for the gestational period and after birth in monkeys, respectively, whereas weeks and years are used as the scale in humans. The age of events indicated in this figure is approximate.

FSH and LH are detectable in the human pituitary by E week 10, and their content increases until E week 25–29. The pituitary starts to release gonadotropins into the general circulation by E week 11–12. Circulating gonadotropins reach peak levels at midgestation, and subsequently both LH and FSH levels decline during late gestation (34, 35, 36, 37). The gonadotropes in human fetuses respond to LHRH by releasing LH and FSH both in vivo and in vitro (38, 39, 40, 41). A sex difference in gonadotropin levels is seen during midgestation: pituitary content and circulating concentrations of LH and FSH in female fetuses are higher than those in male fetuses (34, 42, 43, 44). Since circulating testosterone levels are high in male fetuses as compared with circulating estrogen levels in female fetuses during midgestation, both the sex difference in gonadotropin levels and the decrease in gonadotropin levels toward late gestation in fetuses are attributed to the development of the negative feedback mechanism by the gonadal steroid hormones from the fetal gonads as well as from the placenta (2). A report that castration in male rhesus monkeys at E98–104 increases circulating gonadotropins to levels as high as those in female monkeys at similar ages (30, 31) supports this notion. Negative feedback by ovarian steroids is operative in the human female fetus during late gestation when estrogen secretion is elevated (32, 34). In sheep fetuses during late gestation, LH release is pulsatile, and orchidectomy in males, but not ovariectomy in females, results in an increase in the pulse amplitude of LH (45).

B. Postnatal maturation
Although the distribution pattern of LHRH neurons is already established before birth in most species in which it has been studied, the function, morphology, and biosynthesis, as well as synaptic connectivity of LHRH neurons, may not be mature until the time of puberty. In rats it has been shown that the number of LHRH neurons with a wrinkled contour increases, while the number of LHRH neurons with a smooth contour decreases at the age of puberty (46). Further, in rats and mice, LHRH mRNA levels increase gradually with age, and significant increases occur at P15–P30 depending on sex and experimental conditions (47, 48, 49, 50, 51). These observations imply that LHRH neurons in rodents may receive more intensive innervation from other neurons, and that LHRH gene expression matures after birth, but before puberty. In contrast, in primates, available data indicate that LHRH neurons are mature well before the onset of puberty: there are no differences in the number (52) or the shape of LHRH neurons (53) or in the LHRH mRNA levels (54) between juvenile and adult monkeys. Further, we have shown that electrical stimulation of the medial basal hypothalamus (MBH) in prepubertal monkeys, in which basal LHRH release is very low, induces LHRH release similar to that observed in pubertal monkeys (55). However, it is possible that LHRH neurons in primates undergo subtle developmental changes during the juvenile period, as shown by two recent reports: 1) perikarya of LHRH neurons located in the MBH of early pubertal female monkeys are invested with more glial sheathes than in adult cyclic female monkeys (56); and 2) a decrease in the area occupied by synapses onto LHRH neurons occurs in adult castrated male monkeys as compared with prepubertal castrated male monkeys (57), indicating that subtle changes may occur in the innervation pattern of LHRH neurons. Nonetheless, it is problematic to discuss the significance of these discrepancies, because ontogenic changes in morphology and gene expression of LHRH neurons in primates have not been systematically studied, and in both rodents and primates the issue as to how the presence or absence of gonadal steroids affects ontogeny of morphology and gene expression of LHRH neurons has not been assessed.

	IV. What Determines the Timing of Puberty?

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
A. Hormonal changes during the neonatal and juvenile periods
Circulating LH levels in human male neonates abruptly increase within the first few minutes after birth, followed by an increase in serum concentrations of testosterone during the first 3–21 h (58). High levels of LH in the human male infant decline within 6 months and remain low until the beginning of puberty. FSH levels in human males are slightly elevated for the first 3 postnatal months, after which they become low (59, 60). Circulating levels of testosterone are also elevated for 2–4 months postnatally (61). In contrast, in female neonates LH levels are only slightly elevated during the first few months of life, but FSH levels are high for the first 5 months (59, 60). After the first 6 months of life, circulating levels of FSH, LH, and gonadal steroids are all low, and the hypothalamo-pituitary-gonadal system enters a quiescent stage until the time of puberty. Plasma concentrations of LH and FSH in infants with gonadal dysgenesis are strikingly elevated, because of the absence of the negative feedback loop (59, 60, 62, 63). However, the elevated level of gonadotropin in patients with gonadal dysgenesis declines during the juvenile period, as seen in eugonadal children.

In infantile male monkeys, circulating LH and testosterone are elevated during the first 2–3 postnatal months (64, 65), and diurnal variation of testosterone, quantitatively similar to that seen in sexually mature adults, is observed (66). Bilateral orchidectomy at 1 week of age results in an increase in LH and FSH secretion, with a pulse pattern very similar to that in castrated adult males (67). Plant (68) suggests that the hypothalamo-pituitary axis governing testicular function in males is fully mature by the neonatal stage of development. Both LH and FSH levels in male monkeys decrease after 3–4 months of age (69, 70). By contrast, in female monkeys circulating LH is only slightly elevated or not elevated during the first 3 months (65), and the negative feedback mechanism appears to be only partially operative in the late gestational period through the neonatal period. A moderate elevation of estrogen levels is observed during late gestation through the neonatal period in females (65). Ovariectomy in females at 1 week of age induces a truncated and abbreviated elevation of LH release with slower pulse frequency, when compared with those in orchidectomized male infants (71). It is possible that the LHRH neurosecretory system in female monkeys during the neonatal period is less mature than in males (71). Alternatively, in females, central inhibition to the LHRH neurosecretory system (see below) may start earlier than in males and may not be as complete as in males. Nevertheless, at 4–6 months of age, the LHRH neurosecretory system in both sexes enters a quiescent state, which persists until the time of puberty (18, 68, 70, 72).

B. Hormonal changes at the onset of and during puberty
Before the onset of puberty, LH and FSH levels are low, but a highly sensitive assay indicates that circulating LH and FSH levels in prepubertal children are pulsatile, with slightly higher values at night than morning (73, 74, 75, 76, 77, 78, 79, 80). In both boys and girls, preceding the physical signs of puberty, LH and FSH levels become elevated, pulsatility of these hormones becomes more pronounced, and the nocturnal increase in gonadotropin release is enhanced (75, 76, 77, 78, 81, 82). Both pulse frequency and amplitude of LH release increase at this stage as well (77, 78).

Similarly, the first hormonal sign of puberty in female rhesus monkeys appears several months earlier than menarche (18, 83). During the early pubertal period, mean FSH levels increase, followed by an increase in mean LH levels. Basal levels of LH and the amplitude and frequency of pulsatile LH release increase, and a circadian fluctuation (nocturnal increase) of LH emerges. The pubertal increase in gonadotropin release stimulates estrogen secretion from the ovary, resulting in nipple growth, sex skin development, and subsequently menarche (18, 83). Due to an increase in circulating estrogen, FSH levels are suppressed. During the midpubertal period, the nocturnal increase in LH becomes more pronounced, and basal LH levels and the amplitude of LH pulses further increase. A periodic increase in estrogen causes menstrual cycles, although data with laparoscopy indicate that periodic vaginal bleeding is not due to cyclic ovulation (83). Circulating estrogen during this developmental period sometimes reaches the preovulatory level, but there is no LH surge until the time of first ovulation (18). This is called pubescent infertility. After the age of first ovulation, both basal LH levels and LH pulse amplitude decline, and the nocturnal increase in LH release disappears (18).

These changes in the LH release pattern during puberty are the result of developmental changes in pulsatile LHRH release, since pulsatile LHRH release also increases (84). The pulse frequency of LHRH release increases at the onset of puberty and remains elevated throughout the pubertal period (Refs. 84, 85 and Fig. 2), while the pulse amplitude of LHRH release starts to increase at the transition period between prepuberty and puberty and continues to increase throughout puberty until first ovulation occurs (84, 85). The nocturnal increase in LHRH release is readily observed during the early pubertal period and becomes increasingly prominent during the midpubertal period, while during the prepubertal period, nocturnal increases in LHRH release are seldom seen (84, 85). These facts indicate that the hormonal profiles appear as gradual changes throughout puberty and that the development of the LHRH neurosecretory system or its regulatory systems is essential for the onset of puberty.

View larger version (24K): [in this window] [in a new window]   Figure 2. Schematic illustration of postnatal changes in LHRH release and neurotransmitter events that occur in the hypothalamus in association with puberty in nonhuman female primates. The LHRH neurosecretory system appears to be active during the infantile period, but is suppressed by an inhibitory mechanism comprising GABA neurons. At the onset of puberty, a reduction in GABA inhibition and a subsequent increase in glutamate excitation of LHRH neurons result in the pubertal increase in the pulse frequency, pulse amplitude, and baseline levels of LHRH, which trigger puberty. Furthermore, a higher nocturnal level of LHRH release, shown by hatched bars, becomes particularly prominent. After the onset of puberty, other stimulatory neurotransmitters such as NPY and NE take part in control of LHRH neurons, resulting in further increases in the pulse amplitude and baseline level of LHRH release, until the time of first ovulation. The nocturnal increase in LHRH release and LHRH pulse amplitude are reduced to the adult level, perhaps due to participation of inhibitory neurotransmitters, such as opioids. Stippled bars indicate morning levels of LHRH. In males the LHRH neurosecretory system is fully mature during the infantile period, but is suppressed completely during the juvenile period. Recently, it has been hypothesized that NPY is an inhibitory neurotransmitter before puberty in males. (See text for details.)

There is a controversy as to the sites of action of estrogen in nonhuman primates. In a series of studies in adult female monkeys, Knobil and colleagues (104, 105, 106, 107, 108, 109, 110) have shown that the estrogen-induced LH surge does not require the hypothalamus other than as a supply source of pulsatile LHRH release: 1) the positive feedback effects of estrogen occur in monkeys with complete deafferentation or isolation of the MBH (105, 106); 2) whereas lesions of the MBH abolish LH surges (107); 3) pulsatile infusion of LHRH into animals with lesions in the MBH is sufficient to result in the estrogen-induced LH surge (108); and 4) estrogen can induce an LH surge in animals with lesions in the MBH up to 48 h after cessation of pulsatile LHRH infusion (109, 110). In support of the pituitary site of estrogen action in primates, Ferin et al. (111) report that isolation of the pituitary gland from the hypothalamus by stalk section with a Silastic barrier in monkeys fails to block the estrogen-induced LH surge. In contrast, Spies and colleagues (112) report that the hypothalamus is essential for estrogen action in monkeys, based on the observation that stalk section with a Teflon barrier blocks the estrogen-induced LH surge (112), and the estrogen-induced LH surge or the preovulatory LH surge is accompanied by an increase in pulsatile LHRH release (113, 114). The estrogeninduced LHRH increase has also been reported by another group in OVX monkeys (115) as well as by us in pubertal monkeys (99). Without going into further detail on this controversy, it is safe to conclude that, in the rhesus monkey, estrogen stimulates an increase in LHRH release from the hypothalamus, but estrogen also stimulates an LH surge directly from the gonadotropes. Nonetheless, stimulation of pulsatile LHRH release is essential for the functional gonadotropes, and an increase in pulsatile LHRH release triggers puberty; the establishment of the neuronal mechanism responsible for the adult type of pulsatile LHRH release is obligatory to the positive feedback effect of estrogen during the pubertal period.

D. Two hypotheses on the mechanism of the onset of puberty
Two hypotheses have been proposed for the mechanism of the onset of puberty. The first one is commonly called the "gonadostat" hypothesis, or "differential sensitivity to ovarian steroids" hypothesis. More than a half-century ago, this hypothesis was proposed by Dohrn and Hohlweg (117), based on the observation that, compared with adults, in immature rats a smaller dose of estrogen can suppress the castration-induced changes in the gonadotropes. According to this hypothesis, puberty occurs when the regulating system for gonadotropin secretion becomes desensitized to steroid feedback during sexual maturation, and the shift in sensitivity to steroids permits gonadotropin secretion. It has been shown that in rats and sheep, "escape of suppressed LH secretion by gonadal steroids" occurs at the onset of puberty (118, 119), although Ojeda and colleagues (120) argue that the shift in the sensitivity to gonadal steroids does not occur until after the first proestrous surge in rats. Escape from the negative feedback effect of estrogen occurs in monkeys during the midpubertal stage, but not at the onset of puberty (121, 122). Thus, the hypothesis is not applicable to primates (see below), but it appears to be applicable to sheep (see Ref. 5).

The second hypothesis is that sexual quiescence before the onset of puberty is due to central inhibition of LHRH release, independent of the negative feedback of gonadal steroids, and that an increase in pulsatile LHRH release triggers puberty (18, 123, 124). This hypothesis is based on the fact that gonadotropin secretion in gonadectomized monkeys and in human subjects with gonadal dysgenesis is elevated during the neonatal period, but subsequently suppressed until the time of puberty. This hypothesis has been supported by the direct measurement of LHRH in the stalk-median eminence (S-ME) of rhesus monkeys using a push-pull perfusion method. For example, ovariectomy of prepubertal female monkeys fails to stimulate pulsatile LHRH release, whereas ovariectomy of early and midpubertal female monkeys induces the postcastration-induced LHRH release (85). The age of the pubertal increase in LHRH release in OVX monkeys is essentially similar to that in ovarian intact counterparts (85), indicating that the pubertal increase in LHRH release is independent of the ovarian steroids. Therefore, maturational changes in the hypothalamic mechanism that controls pulsatile LHRH release, independent of the negative steroid feedback mechanism, are responsible for the onset of puberty. In addition, estrogen injection in gonadectomized females of pubertal age readily suppresses pulsatile LHRH release, whereas the same treatment does not cause any significant change in LHRH release in gonadectomized females of prepubertal age (125), suggesting that the LHRH neurosecretory system is insensitive to negative feedback effects of estrogen before the onset of puberty. In fact, the LHRH neurosecretory system increases its sensitivity to ovarian steroid feedback after the onset of puberty.

The gonadostat hypothesis is, in part, a historical product of the time during which the brain-pituitary unit had been considered as a "black box." The pubertal increase in release of LH and LHRH can occur independent of the presence or absence of gonadal steroids, as seen in rhesus monkeys. The pubertal increase in LH release can also be influenced by the presence of gonadal steroids, as shown in sheep, although the degree to which the pubertal increase in LHRH release is influenced by the gonadal steroids has not been quantitatively assessed. Perhaps, the term "gonadal steroid-dependent LHRH increase," first introduced by Reiter and Grumbach (123), reflects the gonadostat hypothesis most accurately.

In humans, Grumbach and colleagues (2, 123) suggest that a gonadal steroid-dependent LHRH increase also occurs at the onset of puberty, since smaller amounts of gonadal steroids are effective in suppressing FSH and LH levels in prepubertal children than in adults (126, 127). It is possible during the juvenile period in humans that a small amount of LHRH release from the hypothalamus maintains the minimum levels of gonadotropin secretion, which is susceptible to the negative feedback effect of steroid hormones. In contrast, we observed no changes in either LH or LHRH suppression after estrogen treatments in OVX prepubertal monkeys (99, 128). Therefore, the difference in humans and rhesus monkeys can be attributed to a subtle species difference in the mechanism of the onset of puberty.

E. Species differences in the mechanism of the onset of puberty
An increase in pulsatile LHRH release is essential for the pubertal increase in gonadotropin secretion and subsequent gonadal stimulation. A pulsatile infusion of LHRH into sexually immature monkeys (129) and guinea pigs (130) results in precocious puberty. Further, an increase in pulsatile LHRH release has been shown to occur at the onset of puberty not only in monkeys (84), in which the removal of central inhibition triggers puberty (see below), but also in sheep (5) and rats (131), in which a shift of the sensitivity to ovarian steroids appears to be responsible for the onset of puberty.

Nevertheless, the mechanism initiating puberty appears to differ between primates and other species: 1) in monkeys, castration induces an elevation of gonadotropin release during the neonatal period and after the onset of puberty, but not during the juvenile period before the onset of puberty (3), while in rats and sheep the castration-induced elevation of gonadotropin release occurs from the neonatal period throughout life (4, 5); and 2) the N-methyl-D-aspartic acid (NMDA)-induced precocious puberty in monkeys does not lead to normal reproductive cycles as adults after cessation of the drug infusion (132), while in rats the NMDA-induced precocious puberty continues on to cyclic ovulation (133, 134). However, this may occur because by the time the treatment ends, these animals are near the normal age of puberty and not because of an actual species difference. In primates, LHRH neurons are under tonic central inhibition during the juvenile period, and removal of this inhibition is necessary before the activation of central excitations can allow the initiation of puberty (128, 135). In contrast, in rats, tonic central inhibition, equivalent to that in primates, may not exist, and the establishment of glutamatergic and other facilitatory neuronal systems is required for the onset of puberty (136).

Species differences between the rhesus monkey and rat may also be seen in synaptogenesis. Synaptogenesis in the hypothalamus of the rat increases from the neonatal period to puberty (137, 138, 139, 140) as it does in the cerebral and cerebellar cortices (141, 142, 143), although a part of the pubertal increase in synaptogenesis in rat hypothalamus is probably due to the pubertal increase in estrogen (140), as observed in estrogen-primed OVX rats (144). In contrast, according to the studies by Rakic and colleagues (145, 146, 147, 148), synaptogenesis in the cerebral cortex of rhesus monkeys dramatically increases after birth, reaches a plateau at 2–4 months of age, and declines slightly through the juvenile period followed by a substantial decrease at the age of puberty, to adult levels (145). Interestingly, the developmental changes in synaptogenesis are uniform among the different cortical regions (146) and the dentate gyrus (147) as well as different layers of the neocortex (148). Moreover, the density of neurotransmitter receptors such as dopaminergic, adrenergic, serotoninergic, cholinergic, and -aminobutyric acid (GABA)ergic receptors in the cortex also reaches a maximum level between 2 and 4 months of age and declines thereafter, similar to changes in synaptogenesis (145). These data are interpreted by the authors to indicate that overproduction of synapses and neurotransmitter receptors in the neocortex are eliminated by a gene-regulated mechanism and that this elimination is critical to the establishment of specific cortical functions (145, 149). Although the studies by Rakic and colleagues are primarily focused on the perinatal period, and although synaptogenesis in the hypothalamus with emphasis on the onset of puberty has yet to be investigated, the developmental time course of synaptogenesis in the neocortex is strikingly similar to that of gonadotropin release in the neonatally gonadectomized rhesus monkey. It is possible that a similar decrease in synaptogenesis in the hypothalamus occurs during sexual maturation in primates. If the elimination of predominantly stimulatory synapses to LHRH neurons occurs during the first few months of life, this could lead to the suppression of LHRH release during the first few months of life, and if the elimination of predominantly inhibitory synapses to LHRH neurons occurs before the onset of puberty, this could lead to the pubertal increase in LHRH release. Moreover, a decrease in inhibitory synapses at the onset of puberty may allow the synaptogenesis of facilitatory neurons [e.g., glutamate and norepinephrine (NE)] to establish a specialized function. In support of our view, Perera and Plant (57) reported that a decrease in the area occupied by synapses onto LHRH neurons occurred in adult castrated male monkeys as compared with prepubertal male castrated monkeys, although these authors did not qualify the type of synapses. Nonetheless, the hypothesis that the onset of the pubertal increase in LHRH release is due to the elimination of inhibitory neurons and the subsequent establishment of selective neuronal pathways and/or neuronal networks that are responsible for the adult pattern of LHRH release in primates is yet to be tested. Certainly, it is possible that developmental changes in synaptogenesis in female primates is also influenced by the pubertal increase in estrogen, as recently described in adult OVX monkeys by Horvath and Naftolin and colleagues (150). The degree to which changes in synaptogenesis are attributed to developmental or to the pubertal increase in estrogen should be differentiated.

	V. Neurobiology of Puberty

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
Most neurotransmitters and neuromodulators possess both excitatory and inhibitory properties depending on several factors, such as composition of the neurocircuit, developmental stage, and hormonal environment. Therefore, the classification of inhibitory and stimulatory neurotransmitters in this article is based on the general feature of control of pulsatile LHRH release in the adult, and no neuroactive substance should be confined to a single category.

A. Inhibitory neurotransmitters
In primates, central inhibition of the LHRH neurons is present before the onset of puberty, and the removal or diminution of central inhibition triggers the onset of puberty. This concept is based upon the following: 1) gonadotropin secretion in agonadal humans (62, 63, 151) and neonatally gonadectomized monkeys remains suppressed until the onset of puberty despite the absence of the gonadal steroids (18, 70); and 2) precocious puberty occurs in humans and primates with hypothalamic lesions (see Ref. 83). Therefore, the search for neuronal substrates responsible for inhibition of LHRH release in the prepubertal period has begun. The first neuromodulators that were extensively studied were endogenous opioids, but evidence indicates that these were not likely candidates for the LHRH suppresser before the onset of puberty. Subsequently, the role of GABA was studied.

1. Endogenous opioids. The role of opioids in reproductive function has been well reviewed by others (152, 153, 154, 155, 156, 157). Because opioid substances suppress pulsatile LH release (158, 159, 160), and because the low frequency of LH pulses during the luteal phase, pregnancy, or the negative feedback phase of estrogen can be reversed in adults by the opioid antagonist, naloxone (161, 162, 163, 164, 165, 166, 167), a role for endogenous opioids in puberty has been proposed. In fact, it has been shown that the administration of naloxone stimulates LH release in prepubertal sheep as well as fetal sheep (168, 169, 170). However, a careful study by Foster and colleagues (171) concludes that in sheep the pubertal decrease in sensitivity to inhibitory feedback effects of gonadal steroids before the pubertal increase in LH release is not causally related to opioid inhibition. In addition, both LHRH and ß-endorphin (ß-END) levels in the median eminence of lambs with delayed puberty induced by food restriction are lower than in normal lambs (172), indicating that ß-END is not an inhibitory neurotransmitter responsible for low LHRH release before the onset of puberty.

Similarly, in primates, among possible opioid neurotransmitters, ß-END is an unlikely candidate for the prepubertal inhibition of LHRH release: 1) naloxone, an opioid antagonist, does not increase LH release until after the onset of puberty in chimpanzees (173); 2) effectiveness of naloxone in stimulating LH release increases greatly with the progress of puberty (174); 3) expression of POMC mRNA in the arcuate nucleus increases after puberty (54); and 4) the release of ß-END from the S-ME increases during puberty concomitant with LHRH release (175). It is conceivable that the opioid system may not be active before the pubertal increase in estrogen, since the components of this system, such as the µ-opioid receptor, are activated by estrogen (176, 177). Hence, opioids seem to be a neuronal component controlling LHRH release in mature, but not in immature, animals and humans (Table 1 and Fig. 2).

a. Biochemistry and molecular biology of GABA.

Synthesis of GABA: In presynaptic neurons GABA is synthesized from glutamate by decarboxylation in the presence of glutamic acid decarboxylase (GAD), stored in vesicles, and released by exocytosis upon depolarization in the presence of extracellular Ca²⁺ (179). Although GABA is also synthesized through other pathways, such as putrescine and - hydroxybutyrate, they are considered to play a minor role (see Refs. 180, 181). GABA synthesis occurs in two compartments: 1) GABAergic neuroterminals and 2) perikarya and dendrites. Glia do not synthesize GABA, but play a role in GABA metabolism by providing precursors and by taking up or degrading GABA overflows from the synapse (182). GABA synthesis is controlled by the concentration of glutamate in the GAD-containing cellular compartments, although it is unclear how the glutamate concentration is linked to neuronal activity to control GABA synthesis and maintain the neurotransmitter pool, and how the availability of glutamate regulates physiological GABA synthesis in vivo (180, 181).

Two different forms of proteins have been reported as the GABA-synthetic enzyme GAD. Based on molecular weight they are named GAD67 and GAD65, which are derived from two respective genes (see Refs. 180, 181, 183). The two cDNAs contain no contiguous identical sequences longer than 17 nucleotides (183), and the amino acid sequences of GAD65 and GAD67 from the rat brain are less similar than are sequences of each form in different mammalian species (184). Although both GAD forms are present in most brain regions, the distribution of the two GADs in the brain is not identical (185, 186). Immunocytochemical and in situ hybridization studies suggest that GAD65 is more consistently localized in neuroterminals, whereas GAD67 is found throughout neuronal cells (184, 187). However, recent reports indicating that 1) GAD67 and GAD65 can form a heteromultimer (188); 2) GAD67 may be transported to neuroterminals together with GAD65 (189); and 3) immunoreactive GAD67, but not GAD65, is found in the neuroterminals of hippocampal granular cells (190). The presence of GADs is not limited to the brain. GAD67 mRNA was found in the rat testis, while GAD65 mRNA was found in the rat oviduct (191). Further, both GAD67 and GAD65 are present in pancreatic ß-cells in humans, and a titer of GAD65 antibodies is elevated in patients with insulin-dependent diabetes mellitus (192, 193, 194).

GAD67 and GAD65 exist in the enzymatically active holo form and inactive apo form, and conversion of holo-GAD67 or holo-GAD65 to and from apo-GAD67 or apo-GAD65 is determined by the presence of the cofactor, pyridoxal-5'-phosphate, which is influenced by physiological states as well as by experimental conditions (180, 183).

Recently, it has been hypothesized that vesicular release of GABA may be associated with GAD65, whereas nonvesicular release of GABA, which is mediated by the reversal of GABA transporters (see below), may be associated with GAD67 (199A ).

Reuptake of GABA: Elevated local concentrations of amino acid neurotransmitters in the synaptic cleft are actively removed by specific transporters, located on presynaptic terminals and surrounding glial cells, where the neurotransmitters are recycled. GABA transporters (GAT) are classified in the Na⁺ and Cl^--coupled transporter family. Four GABA transporters (GAT-1, GAT-2, GAT-3, and BGT-1) have been described (195, 196, 197). GAT-1 is the predominant GABA transporter in the mammalian brain (197), and specific GAT-1 antagonists increase extracellular GABA concentration in the rat thalamus (198). Interestingly, the GAT-1 transcript contains an estrogen-responsive element (199). It is possible, therefore, that the reduction of GABA concentration in the S-ME at the onset of puberty might be due to a developmentally regulated increase in GABA transporter activity. At this time there is no information on the role of GAT in puberty.

b. Molecular biology and pharmacology of GABA receptors.
Three GABA receptors, GABA_A, GABA_B, and GABA_C have been identified in the brain. The GABA_A receptor is a pentameric membrane-spanning ligand-gated ion channel that permits Cl^- entry into the cell upon binding with the neurotransmitter GABA (200, 201, 202), whereas the GABA_B receptor is coupled to calcium and potassium channels, as well as an intracellular signaling pathway, via GTP binding proteins (203, 204). The GABA_C receptor is a Cl^- pore and, according to current reports, is found predominantly in the vertebrate retina. GABA_A receptors are modulated by allosteric agonists, benzodiazepines, barbiturates, neurosteroids (primarily metabolites of pregnane steroids), and ethanol, as well as polyvalent cations (205, 206). GABA_A receptors are composed of at least 18 genetically distinct subunits (1–6, ß1–ß4, 1–4, , , 1–2). An -subunit, ß-subunit, and -subunit are all required to form a fully functional GABA_A receptor (207, 208), and the 1ß22 arrangement is the most common in the brain.

The functional and pharmacological characteristics of a GABA_A receptor are determined by the subunit composition (209, 210, 211). The spatial distribution of subunits in the brain differs, and the subunit composition varies from neuron to neuron (209, 210). Further, the pattern of the subunit composition varies during prenatal and postnatal development (212, 213, 214, 215, 216). Since GABA_A receptors mediate GABA inhibition of LHRH release (217), it is particularly important to determine whether the subunit composition in the hypothalamus, especially on LHRH neurons, changes during maturation, related to the onset of puberty. It has been shown that in adult rats some LHRH neurons express the ß₃-, but not ₁- or ß₂-, GABA_A subunits (218), and in peripubertal female rats some LHRH neurons express ₁-, ₂-, ß₃-, and ₂-, but not ₁-subunits (219).

c. Developmental changes in GABA and GABA receptors.
GABA and GAD: The concentration of GABA and the number of GABAergic neurons in the rat spinal cord increase from E13 to the second postnatal week and then decline by the third postnatal week (220). Similarly, GAD67 and GAD65 mRNAs in the rat spinal cord increase exponentially during embryonic development starting on E11 until the first postnatal week, but then decline during the second postnatal week to adult levels (221). In the rat striatum GAD65 mRNA increases until 2 weeks postnatally, and then declines toward adult levels, whereas GAD67 mRNA keeps increasing from 1 week postnatally until adulthood; thus, the ratio of GAD65 to GAD67 mRNAs is high at 1–2 weeks postnatally, and then levels off to the adult ratio by 3 weeks (222). In the mouse cortex, the number of GABA-positive cells decreases postnatally, although the timing of the declining pattern differs depending on the layers of the cortex examined (223). The increase in GAD and GABA concentrations during embryonic development is due to neurogenesis, whereas the postnatal decline is not likely due to cell death (224).

GAD65 and GAD67 mRNA levels and GABA concentrations in the rat POA increase with age between P1 and P15 (225, 226, 227) and increase further between P15 and P35–P40 (228, 229). However, developmental changes in GAD mRNA expression and GABA concentrations within the MBH require additional studies investigating the precise location of GABA neurons and a wider age window. Some reports show that GAD mRNA in the rat arcuate nucleus, but not dorsomedial nucleus, increases with age between P1 and P20 (227), and GABA concentrations in most areas of the brain, including the MBH, caudate-putamen, hippocampus, and amygdala, increase with age (225, 226), whereas other reports indicate GABA concentrations in the rat MBH (229) or in the rat POA/MBH (230) do not change with age between P15–P40.

Developmental changes in GABA and GAD in primates are not well studied, and there are conflicting data from the postnatal period. In the Japanese macaque, GAD concentration in the fetal cerebellum is very low during the second trimester, quickly increases 6.3-fold at full term, and further increases 2.2-fold by adulthood (231). GABA concentrations in the occipital cortex of rhesus monkeys increase 2-fold from the fetal period (E70–E150) to the neonatal period, but do not change further in adults (232). The number of GABA neurons in the visual cortex increases gradually between E110 and P160 in rhesus monkeys, but there are no descriptions at older ages (233, 234). GAD activity in the human neocortex sharply increases at birth and continues to increase until 1 yr of age, after which it declines gradually until pubertal age and then slightly increases at adulthood (235, 236). Recently, Urbanski et al. (237) reported that the distribution pattern and concentration of GAD67 and GAD65 mRNAs in hypothalamic nuclei assessed by in situ hybridization in juvenile (0.6 yr of age) gonadally intact male rhesus monkeys were not different from those in adult (10 yr of age) male monkeys, and a report by Plant and colleagues (238) indicates that GAD mRNA levels in the basal hypothalamus of juvenile castrated male rhesus monkeys did not differ from those in adult castrated male monkeys. Although these data do not appear to support the hypothesis that GAD plays an important role in puberty (see below), more precise developmental studies with the exact regional distribution pattern of GABA neurons in nonhuman primates, including in females, are needed before conclusions can be drawn.

GABA release: GABA release in the POA measured by push-pull perfusion decreases between P26 and P35 in female rats (239). Similarly, in female rhesus monkeys GABA release in the S-ME decreases concomitant with the pubertal increase in LHRH release (217, 240). These findings suggest that elevated GABA in the POA in female rats and in the S-ME in female rhesus monkeys may contribute to the suppression of LHRH release before the onset of puberty.

GABA_A receptors and their subunit composition: Rakic and colleagues (145) report that the density of GABA_A receptors in all five layers of the cerebral cortex of rhesus monkeys increases after birth, reaching a maximum level between 2 and 4 months of age, and then declines gradually to adult levels at 36 months of age. Because similar patterns of developmental changes in the receptor density of ₂- and ß-adrenergic, D₂-dopaminergic, 5HT₂-serotoninergic, and M₁-muscarinic receptors are observed in the cerebral cortex, these authors postulate that synaptic circuitry formation may be orchestrated by a common diffusible factor or a synchronous activation by a common gene.

The developmental pattern of each GABA_A receptor subunit is complex and differs from region to region or neuron to neuron, which ensures the functional heterogeneity of GABA input. Nonetheless, it has been reported consistently that, in general, ₂-subunit expression is very high before birth to shortly after birth, and decreases gradually toward adult levels, whereas ₁ expression is minimal before birth and then gradually increases after birth until adulthood (213, 214, 215, 216, 241). In fact, it appears that GABA_A receptors containing ₁-subunits gradually replace GABA_A receptors containing the ₂-subunit during postnatal maturation in the rat, monkey, and human brain, and that the increase in the ₁-subunit is an indication of brain maturation, i.e., the onset of synaptic GABA inhibition, whereas ß-subunits do not generally undergo developmental changes (213, 214, 241). Recently, changes in subunit composition with functional alteration were demonstrated by using a combination of patch-clamp recording and single cell RT-PCR methods. Brooks-Kayal et al. (242) have shown that changes in GABA_A receptor subunit composition in hippocampal neurons preceded the onset of epilepsy by weeks in epileptic rats. They further hypothesize that retention of an immature pattern of GABA_A receptor subunit composition may be responsible for prolonged childhood epilepsy, which normal children spontaneously outgrow.

It is probable, therefore, that developmental changes in the GABA_A subunit composition in neuronal cells may occur before the onset of puberty. Analysis of the literature provides support for the hypothesis that GABA disinhibition of LHRH neurons through GABA_A receptors at the onset of puberty in female monkeys (217) is due to changes in GABA_A receptor subunit composition. For example, the discrepancy that some LHRH neurons in adult rats express the ß₃-, but not ₁- or ß₂-, GABA_A subunits (218), whereas in peripubertal female rats a subset of LHRH neurons express ₁-, ₂-, ß₃-, and ₂-, but not ₁-subunits (219), may be due to technical differences in the two studies, but it may also be due to developmental changes in subunit composition. In fact, a recent report by Herbison and colleagues (243) using single cell RT-PCR suggest that GABA_A subunit composition in LHRH neurons located in the POA and medial septum of sexually immature mice at neonatal and juvenile ages is more heterogeneous than that in adults, and it becomes homogeneous when the mice mature, supporting this notion. Interestingly, the same authors have reported that sensitivity to GABA in LHRH neurons of juvenile mice is lower than that in adult mice and that the pattern of the dose-response curve to GABA in prepubertal LHRH neurons is more heterogeneous than that in adult LHRH neurons (243). At this time, we have little knowledge of developmental changes in the GABA_A subunit composition of LHRH neurons in nonhuman primates.

d. Direct and indirect control of LHRH neurons by GABA.
GABA input can change activity of LHRH neurons directly. Perikarya of LHRH neurons are innervated by GAD- containing axons (presumably GABA neurons) in rats (244, 245, 246), but not in monkeys (247). LHRH neurons in the POA of adult rats and GT-1 neurons express the GABA_A ß₂/ß₃-subunit (218, 248), and the ₁- subunit colocalizes with LHRH in GT-1 neurons (248, 249). Although abundant distribution of ₂-subunit mRNA in the rat POA has been reported (250), only a small number of LHRH neurons express the ₂-subunit (219). El-Etr et al. (248) report that the GABA_{A 2}-subunit mRNA is not expressed in GT-1 cells. It is, however, possible that the negative data are in part due to technical problems. In fact, a recent study with single cell RT-PCR indicates that GABA_A receptors on the LHRH membrane in adult mice are assembled from ₁-, ₃-, ₅-, ß₁-, and ₂-subunits (243) and 100% of adult mouse LHRH neurons respond to GABA (243).

In primates, direct innervation of LHRH neurons by GABA neurons has not been found (247), although inhibitory synapses on LHRH perikarya, their phenotype yet to be determined, have been reported recently (150). However, GABA inhibition of LHRH neurons could be through glutamatergic neurons, since there is a reciprocal innervation between GABAergic and glutamatergic neurons in monkeys (247). In addition, GABA may alter LHRH release through LHRH neuroterminals or dendritic input, since direct control of oxytocin-vasopressin neuroterminals by GABA has been described (251). Currently, GABA innervation at dendrites and neuroterminals of LHRH neurons in primates has not been investigated. The interaction between GABA neurons and other neurons involved in the control of LHRH release in rats was described in detail by Leranth et al. (252) and Silverman et al. (253).

e. Role of GABA in LHRH release.
The role of GABA in the control of LHRH release appears to be both inhibitory and stimulatory. For example, some early studies indicate that systemic administration or intracerebroventricular infusion of GABA, and application of GABA onto hypothalamic explants, stimulates LHRH and LH release (254, 255, 256), while others show inhibitory or biphasic/triphasic effects (257, 258, 259, 260, 261).

Recent studies using GT-1 cells (249, 262, 263) and LHRH neurons from the mouse olfactory pit (264) suggest that GABA induces excitatory effects on LHRH release, intracellular Ca²⁺ oscillations, and membrane potentials, although the study by Martinez de la Escalera et al. (262) demonstrates that an initial stimulatory effect on LHRH release is followed by prolonged inhibition.

It is possible that GABA is an inhibitory neurotransmitter through GABA_A receptors, whereas it is a stimulatory neurotransmitter through GABA_B receptors for pulsatile LHRH/LH release in adult female animals. GABA release in the medial preoptic area (MPOA) is pulsatile, and a reduction of GABA release precedes an increase in LH release in OVX rats (265, 266). Direct infusion of GABA into the POA suppresses LH release in rats and sheep (267, 268, 269, 270), and GABA and the GABA_A agonist, muscimol, inhibit LH pulses when injected into the third ventricle or the MPOA in rats (257, 271). Similarly, muscimol suppresses, and the GABA_A antagonist bicuculline stimulates, the pulse frequency, but not the pulse amplitude, of LHRH pulse-generator activity, as determined by multiunit activity recording in the hypothalamus of OVX female rats (272). In contrast, infusion of baclofen, a GABA_B agonist, into the arcuate-ventromedial nucleus stimulates LH pulses in castrated rams during the nonbreeding season (268, 273, 274). There are, however, reports indicating that GABA_B receptors are inhibitory for basal LHRH release (258, 260, 261). In addition, the GABA_B agonist baclofen iontophoretically applied to adult LHRH neurons in guinea pigs causes immediate hyperpolarization via opening of potassium channels (274A ), indicating that the direct, GABA_B-mediated action of GABA in these cells is inhibitory.

GABA is also an important inhibitory neurotransmitter before the preovulatory LH surge, and in the positive feedback action of ovarian steroids in females. GABA release as well as GAD67 and GAD65 mRNA levels in the MPOA decrease before the initiation of an estrogen-induced LH surge in OVX female rats and ewes (265, 266, 269, 275, 276, 277, 278) and before the LH surge in female rats (269, 270). The GABA turnover rate also decreases before the estrogen-induced LH surge (276). GABA or muscimol infusion into the third ventricle or MPOA blocks the preovulatory LH surge in female rats and reduces the size of the estrogen-induced LH surge in OVX rats (276, 279, 280, 281), while both intraventricular and intravenous infusions of bicuculline advance the timing of the LH surge in estrogen-primed OVX rats and proestrous rats (271, 282). There is a report, however, that GABA_B, not GABA_A, receptors mediate inhibitory action of GABA during the LHRH surge (274B ).

In males, GABA neurons are involved in the negative feedback effects of testosterone. The GABA turnover rate as well as GAD67 and GAD65 mRNA levels in the MPOA decrease after castration concomitant with an increase in LH release, whereas testosterone administration prevents these changes in adult male rats (283, 284). Moreover, the GABA turnover rate in the MPOA decreases with an increase in LH release after implantation of the androgen receptor antagonist, hydroxyflutamide, into the rostral portion of the MPOA (285).

The conflicting stimulatory and inhibitory roles of GABA in LHRH release may be, in part, explained by the following hypotheses. First, GABA action may differ depending on the receptor subtype. In some studies the receptor subtype is not examined. Second, since GABA effects on LHRH neurons may occur not only directly, but also indirectly through interneurons, results may depend on alterations in the population and/or sensitivity of interneurons, differences in the location of GABA infusion in in vivo studies, and the loss of input from other brain areas in in vitro hypothalamic explant studies. For instance, in in vitro studies Nikolarakis et al. (259) suggest that GABA is inhibitory at LHRH neuroterminals, but stimulatory at LHRH perikarya through inhibitory opioid neurons. GABA input to LHRH neurons in the monkey hypothalamus appears to occur indirectly through glutamate neurons (247, 286).

Third, GABA_A receptor properties may change during maturation, such that GABA is excitatory when LHRHsecreting cells are immature, whereas GABA is inhibitory when LHRH neurons become mature. GABA is stimulatory in immature neurons, such as GT-1 cells and cultured LHRH cells from embryonic mice (249, 263, 264). Similar developmental switches of GABA action have been shown not only in the hypothalamus (287, 288), but also in the spinal cord, hippocampus, cerebellum, cortex, and olfactory bulb (see Refs. 289, 290). So far, two possible mechanisms of developmental changes in GABA_A receptor properties have been shown. 1) Changes in the subunit composition of GABA_A receptors occur during maturation of the brain (215, 241, 291) or under different physiological conditions (292), whereby the response to GABA varies, as discussed in a previous section. A recent report, however, indicates that although the changes in the subunit composition of GABA_A receptors in mouse LHRH neurons occurs between the juvenile and adult stages, GABA input to LHRH neurons is excitatory regardless of the age of mice when tested using pipettes filled with a high chloride solution (243). 2) Changes in the response to GABA could be explained by chloride homeostasis during maturation (290) or some physiological conditions, such as diurnal rhythmicity (293). There is a differential chloride gradient across the neuronal membrane, which is reversed between the immature state and the mature state (294, 295, 296). A recent report further suggests that the neuronal Cl^--extruding K⁺/Cl^- cotransporter, KCC2, responsible for hyperpolarizing postsynaptic inhibition (297), undergoes developmental changes when hippocampal pyramidal neurons developmentally switch GABA_A-mediated responses from the depolarizing state to the hyperpolarizing state (298).

Fourth, interaction with glutamatergic input and/or receptors due to physiological changes, including neuronal maturation, may alter receptor sensitivity to GABA or the relative importance of the inhibitory GABAergic input to the stimulatory glutamatergic input. This was clearly shown in the hippocampus (290) as well as in the POA-hypothalamus (306, 307). Fifth, GABA receptor subunit composition can be altered by the presence of steroid hormones. For example, estrogen injection in OVX rats altered GABA_A receptor subunit composition (250, 299).

GABA neurons or GABA_A receptors seem to mediate progesterone action as follows: 1) Progesterone receptorcontaining neurons in the monkey and rat hypothalamus are GABA neurons (246, 300); and 2) GABA_A receptors contain steroid recognition sites (301), i.e., neurosteroids, which include some progesterone metabolites and derivatives, exert their action through GABA_A receptors located on the cell membrane (301). Recently, Herbison et al. (302) demonstrated that allopregnanolone, a neurosteroid derived from circulating progesterone, directly exerts a facilitatory action on GABA_A receptor-chloride channels in LHRH neurons. GABA neurons also appear to mediate estrogen action. In rats, estrogen-receptive cells in the arcuate nucleus are also GABA neurons (245), and estrogen is necessary for an increase in the number of progesterone receptors in immunostained GABA neurons of OVX monkeys (246, 300). Moreover, the fact that a decline in GABA levels in the MPOA occurs before the estrogen-induced LH surge in rats and sheep (275, 303), while an elevation of GABA levels in the MPOA occurs during the negative feedback action of estrogen in sheep (275), further supports the possible role of GABA neurons in estrogen action. Conversely, estrogen priming in OVX rats increases GABA_A receptor ₂-, and ₁-, but not ß₃-, subunit mRNAs in the POA and bed nucleus of the stria terminalis (250).

f. Role of GABA in puberty.
There are reports that GABA is stimulatory on LH release in male and female rats during the juvenile stage, whereas GABA is inhibitory around the age of puberty (304, 305, 306, 307). Mitsushima and Kimura (308) report that neither bicuculline nor muscimol causes any significant effect on LH release in sexually immature male rats, whereas bicuculline stimulates and muscimol inhibits LH release in pubertal male rats. In contrast, our studies in nonhuman primates using push-pull perfusion suggest that the LHRH neuronal system is tonically inhibited by GABA neurons before the onset of puberty (Fig. 2). First, GABA levels in the S-ME in prepubertal rhesus monkeys are much higher than in midpubertal monkeys (217, 240). Second, bicuculline, a GABA_A antagonist, stimulates LHRH release in prepubertal monkeys by removing endogenous GABA inhibition, whereas exogenous GABA is not effective in suppressing LHRH release until after the onset of puberty, when endogenous GABAergic tone is reduced (217). Third, infusion of antisense oligodeoxynucleotides for GAD67 and GAD65 mRNAs into the S-ME of prepubertal monkeys results in a dramatic increase in LHRH release (309, 310), presumably due to the reduction in GABA synthesis and subsequent release (240, 309). Finally, pulsatile infusion of bicuculline into the third ventricle of prepubertal monkeys results in precocious menarche, which occurs 6–8 weeks after the initiation of bicuculline infusion, and in precocious first ovulation, which occurs by 30 months, the age of menarche in control females (311). However, since the interval between menarche and first ovulation is not shortened by bicuculline infusion, additional mechanisms, such as the establishment of the stimulatory neuronal system for pulsatile LHRH release, are necessary for the pubertal transition in female primates. Nonetheless, disinhibition of LHRH neurons from GABA appears to be critical for the onset of puberty in primates (Table 1).

g. The role of GABA in sexual differentiation in the brain.
Sexual differentiation of the rodent brain is dependent upon exposure to estrogen or testosterone during the perinatal critical period, beginning in late gestation and ending early in neonatal life (312, 313). Sexual dimorphism of the brain, including the male dominant sexually dimorphic nuclei (314, 315), and the female dominant anterior ventral periventricular nucleus [or medial preoptic nucleus (316, 317, 318)], has been extensively described. According to a series of studies by McCarthy, Selmanoff, and colleagues (226, 227, 319), GABA neurons appear to mediate steroid action on the sexual differentiation of the brain during the perinatal period. The GABA turnover rate in the medial preoptic nucleus in the MPOA and ventromedial nucleus of the hypothalamus (VMH) in male rats is 2-fold higher than in female rats (319), and GAD67 and GAD65 mRNA levels in the MPOA and VMH in males are higher than in females on P1, but not on P15 (226, 227). Neonatal castration of male rats results in the female type of GAD mRNA responses, whereas neonatal treatment of female rats with testosterone results in the male type of GAD mRNA responses (227). Further, a higher level of GABA in the VMH and arcuate nucleus in males than in females is observed only during the first few days of life (226), and this dimorphism is lost as GABA levels increase developmentally in both males and females (320). A similar sex difference in GABA concentrations in the MPOA of P10 rats has also been reported by others (225). Since GABA has a potent growth factor-like property for neuronal survival and migration, growth cone guidance, and neurite branching (224, 321, 322, 323, 324, 325, 326, 327, 328), and since GABA is excitatory in the neonatal period, McCarthy and colleagues (328) propose the hypothesis that a rise in GABA release induced by testosterone during the critical period of sexual differentiation permanently alters the structure and function of the POA and hypothalamus.

h. GABA and human diseases associated with puberty.
There is evidence indicating that GABA neurons may be responsible for diseases associated with puberty. First, it has been documented that the onset of schizophrenia often occurs between late puberty and early young adulthood (7). A significant decrease in GAT-1 immunoreactivity on axonal terminals of a subset of GABA neurons that innervate pyramidal cells in the frontal cortex is observed in patients with schizophrenia when compared with normal human subjects (329). Second, the new onset of epileptic seizures tends to occur early in life and during the adolescent period (10). Precocious puberty is often associated with epilepsy in children (8, 9). Furthermore, treatment with sodium valproic acid, a GABA agonist—the mechanism of action has yet to be determined—delays the timing of puberty in children with seizure disorders (330, 331) and in genetically epilepsy-prone mice (332). It is possible that the pubertal increase in gonadal steroids may sensitize neurocircuits involved in epileptic seizures, but it is also possible that there is a common mechanism of developmental deficiency, i.e., weakened GABA inhibition in the LHRH neuronal system resulting in precocious puberty and weakened GABAergic inhibition in the brain at the pubertal age resulting in epilepsy (333). Recently, Bourguignon and colleagues (334) treated an 11-month-old child, who exhibited severe epileptic seizures and precocious puberty, with loreclezole and vigabatrin, GABA agonists. At an earlier stage, traditional treatment for epilepsy with phenobarbital was not effective in this patient. However, treatment with loreclezole followed by vigabatrin not only caused all signs of precocious puberty to regress, but also settled seizure attacks. Finally, a study indicates that treatment with the GABA agonist valproate results in a high rate of polycystic ovaries with elevated serum testosterone concentrations among women with epilepsy, especially if the patients start to receive the valproate treatment before the age of 20 yr (335). Taking into consideration the recent view that polycystic ovarian syndrome originates during the pubertal stage (11, 12), it is possible that an irregularity of the normal control of pulsatile LHRH release by the GABA neurotransmitter system during puberty and/or failure of opioid inhibition during the postpubertal period may be a cause of the polycystic ovarian syndrome, although this is highly speculative.

3. Other inhibitory neuropeptides and neurotransmitters. The neuropeptides, such as vasoactive intestinal peptide (VIP), CRH, and melatonin, are inhibitory to neuronal activity (336, 337) and could be potential inhibitory neurotransmitters before the onset of puberty. However, to date, the role of hypothalamic VIP in puberty has not been systematically studied, and available evidence indicates that changes in CRH are not likely to play a major role in determining the timing of puberty. ß-END, ACTH, and cortisol levels in response to CRH in children and adult humans are independent from age and sexual maturity (338, 339), and there is no evidence for direct inhibitory effects of CRH on LHRH release. Therefore, in this section we will only discuss the role of melatonin in puberty.

a. Melatonin.
Melatonin has been suggested as an inhibitory neurotransmitter for puberty. This is based on the observations that 1) some human patients with pineal tumors exhibit precocious puberty (340); 2) circulating melatonin concentration is elevated in early childhood, declines during late childhood, and remains stable from the early pubertal period to adulthood in humans and monkeys (341, 342, 343, 344, 345); 3) melatonin, which is elevated during the nighttime, is inhibitory for the timing of puberty in hamsters and sheep (346, 347); and 4) circadian melatonin rhythm in blind men differs from normal men (348), and timing of puberty in blind boys is delayed (349), although blind girls with no light perception have earlier onset of menarche than normal girls (350, 351).

However, pineal melatonin is probably not involved in the mechanism of gonadotropin suppression during prepuberty in primates (Table 1). Pineal tumors are often accompanied by lesions in the brain that may be responsible for precocious puberty (352, 353, 354, 355), and the tumor itself may release gonadotropic hormones or substances stimulatory to gonadotropin secretion (356). Further, studies of male patients with LHRH deficiency compared with normal males suggest that a decrease in circulating melatonin before puberty appears to be due to a slight increase in circulating LH which stimulates gonadal steroids (357, 358). Similarly, in female rhesus monkeys, a pubertal increase in LH precedes a decrease in nocturnal melatonin levels by 2 months, and treatment with melatonin for 30 days does not delay pubertal increases in estradiol, insulin-like growth factor I (IGF-I), and perineal coloration (359). Finally and most importantly, pinealectomy during the neonatal period in castrated male rhesus monkeys (360) and at 20–23 months of age in OVX female rhesus monkeys (94) does not alter the pattern of developmental changes in gonadotropin secretion.

Nonetheless, a series of studies by Bellestella and colleagues (see Ref. 361) in blind humans indicate that light signals appear to be important for secretion of LH, FSH, PRL, GH, and TSH. Considering the fact that the nocturnal increase in LH release becomes prominent during the pubertal period in female primates (73, 74), and that in fact this has been used as one of the earliest signs of puberty in female rhesus monkeys in our laboratory (18, 72), circadian rhythms from light signals to the hypothalamus, which may or may not be mediated by melatonin, appear to be important for the mechanism of the onset of puberty. Additional research in this area is urgently needed.

B. Stimulatory neurotransmitters
1. The excitatory amino acid glutamate. Glutamate, L-glutamic acid, is the major excitatory amino acid neurotransmitter in the hypothalamus (362, 363), and LHRH neurons receive direct glutamatergic innervations (247). The role of glutamate in the control of LHRH release has been reviewed extensively (281, 364, 365). Thus, in this article we will focus on the changes in the glutamatergic system during development and the role of glutamate in the mechanism of puberty.

Glutamate is the endogenous ligand for two major excitatory amino acid receptors: 1) ionotropic receptors coupled to ion channels, which are further divided into NMDA, kainite, and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subtypes; and 2) metabotropic receptors coupled to G proteins. All these receptors are present in the hypothalamus (366, 367), and activation of all three ionotropic receptors is stimulatory to LHRH/LH secretion in adult animals (see Ref. 365).

a. Developmental changes in glutamate synthesis and release.
Glutamate synthesis: The availability of releasable glutamate from neuroterminals is essential for stimulation of LHRH release and hence for the control of the onset of puberty. The activity of the enzyme for glutamate synthesis from glutamine, namely glutaminase, is greater after puberty (P50) than before puberty (P15), reflecting an increased glutamatergic input to the LHRH neurons after puberty (368). Bourguignon and colleagues have shown that application of glutamine, a precursor for glutamate synthesis, to hypothalamic explants from P15 and P50 male rats results in LHRH release in a dose-dependent manner, whereas application of the glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), blocks glutamine-induced LHRH release and veratridine-induced LHRH increase, but not glutamate-induced LHRH release (368). Interestingly, inhibition of glutamine-induced and veratridine-induced LHRH increase requires higher concentrations of DON in P50 than P15 hypothalami, indicating that increased activity of glutamate biosynthesis from glutamine occurs at or shortly after the onset of puberty (368). However, this increased glutaminase activity appears to be due to an increase in posttranscriptional changes in gluta-minase mRNA, since mRNA levels increase after birth and reach a maximum by the second week, well before puberty (369), and since glutaminase mRNA levels do not change during pubertal development in the rat hypothalamus (228). The relationship between glutamate synthesis and the onset of puberty in primates has not been studied.

Glutamate release: Since endogenous glutamate exists as four different pools—a transmitter pool, a metabolic pool, a glial pool, and a GABA precursor pool (370)—the role of glutamate in puberty is complex. However, because no literature is available on the developmental context of different pools, we will describe glutamate concentrations as a single entity. Glutamate concentrations in the rat hypothalamus increase with postnatal age (225), reaching a maximum after the onset of puberty (229), and in the rat cortex glutamate levels also continue to increase until adulthood (371). More recent studies indicate that glutamate concentrations in the POA/MBH and release from POA/MBH explants increase between P16 and P30 in female rats (372, 373). In female rhesus monkeys, glutamate release measured by push-pull perfusion in the S-ME is very low during the prepubertal period, increases dramatically during the early pubertal period, and remains high during the midpubertal period, although midpubertal levels decline slightly from early pubertal levels (240). The pubertal elevation of glutamate may occur promptly after GABA reduction before the onset of puberty, since glutamate release increases several hours after the initiation of treatment with antisense GAD67 in prepubertal monkeys, which results in the reduction of GABA release within 3 h of the initiation of the antisense treatment (240).

b. Role of glutamate in puberty.
Glutamate is profoundly involved in pulsatile LHRH release in vivo and in vitro through NMDA and kainate receptors. NMDA stimulates release of LH and LHRH in adult rats and monkeys in vivo (Refs. 374, 375, 376, 384, 385, 386 and Fig. 2), while the NMDA receptor blocker, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), suppresses LHRH pulses as well as the LH surge (365, 381, 382). Glutamate stimulates LHRH release from hypothalamic fragments and GT-1 cells (261, 306, 307, 377, 383), as well as intracellular Ca²⁺ oscillations in GT-1 cells (263). Glutamate depolarizes in LHRH neurons from the mouse olfactory placode, although embryonic LHRH neurons are not responsive to glutamate until cells have been in culture for 10 days (264).

Similarly, glutamate, NMDA, and kainate all stimulate LHRH/LH release in sexually immature monkeys (384, 385, 386), rats (380, 387, 388), sheep (389), and fetal sheep (390) in vitro and in vivo. Moreover, stimulation of NMDA receptors results in precocious puberty in rats and monkeys (132, 133), whereas administration of the NMDA receptor blockers, MK-801 or 2-amino-5-phosphonovaleric acid (AP-5), delays the timing of puberty in rats (382, 391, 392, 393). In contrast, the non-NMDA receptor antagonist, 6,7-dinitro-quinoxaline-2,3-dione (DNQX), fails to change the timing of puberty (364). The excitatory action of glutamate on LHRH release may occur not only through NMDA receptors, but also through metabotropic receptors. Therefore, the developmental changes in NMDA and AMPA receptors are integrated parts of the mechanism of the mechanism of puberty (see below).

c. Sensitivity changes in LHRH response to glutamate during puberty.
Sensitivity to glutamate stimulation temporarily increases during the pubertal period in rats. First, NMDA sensitivity in male rat hypothalamic explants increases from prepubertal levels between P15 and P25, and then decreases at P50 to levels similar to the prepubertal levels (136). Likewise, sensitivity to MK-801 increases between P15 and P25 rats, progressively decreases beginning at P30, and returns to prepubertal levels by P50 (136). Paradoxically, low doses of the NMDA receptor blocker MK-801 (0.1–10 pM) are stimulatory, rather than inhibitory, to LHRH release at P15, but not at P25. However, higher doses of MK-801 (10–100 µM) at P15 suppress LHRH release, and only the highest dose (100 µM) is effective in suppressing LHRH release at P25 (381). Based on these and other data, Bourguignon and colleagues (381) propose that a component of glutamatergic input through NMDA receptors is inhibitory to LHRH release in juvenile rats, and it becomes gradually stimulatory to LHRH release as animals grow. As puberty comes to a close, the disappearance of an inhibitory NMDA system enhances a stimulatory NMDA system, thereby resulting in the increase in NMDA-induced LHRH release. Second, immunostaining for c-fos in the arcuate nucleus after NMDA stimulation is greatest between P15 and P20 and is lower both before and after this period (394). Third, the effectiveness of stimulatory effects of NMDA and kainate on LHRH release from POA/MBH explants of female rats is greater at P30 than at P16 (395, 396), and NMDA enhances the steroid-induced LHRH release from POA/MBH explants at P30, but not at P16 in female rats (395).

In rhesus monkeys as well, sensitivity to glutamatergic stimulation increases at puberty. For example, 1) infusion of NMDA into the S-ME at 10 µM–100 µM stimulates LHRH release in pubertal monkeys, whereas only 100 µM NMDA results in LHRH release in prepubertal monkeys (397); and 2) intravenous injection of NMDA at 10 mg/kg results in LHRH responses with a longer duration in pubertal monkeys than in prepubertal monkeys (397, 398).

d. Developmental changes in NMDA receptors.
The NMDA receptor subunit NR1 is an essential component in the formation of the functional NMDA receptor, which exists as a heteromeric complex consisting of NR1 plus one or more subunits of the NR2 family (399, 400). NR1 immunoreactivity has been reported in most of the hypothalamic nuclei of the rat (for review see Ref. 365), and both NR1 mRNA and protein increase during development. Two phases of developmental increases in NR1 mRNA levels in the POA and the hypothalamus of rodents have been described. The first prominent increase occurs between E18 and P10 during which NR1 mRNA levels in the POA/anterior hypothalamus increase approximately 5-fold in both male and female rats (401, 402). In guinea pigs, as well, MK-801 binding increases from midgestation to late gestation (403). Similarly, immunoreactivity of NMDA-R1 protein increases from P0 through P10 in both male and female rats (401). The second phase of a slight, but significant, increase in NR1 mRNA levels occurs between P10 and P25, approximately 10 days before the onset of puberty in rats (404, 405, 406). Interestingly, there are no further changes in NR1 mRNA levels around the onset of puberty (404, 406), although Nyberg et al. (405) report that NR1 mRNA increases on the first proestrus before first ovulation. Absence of changes in NR1 mRNA levels and NMDA receptor binding after steroid hormone treatments in adult OVX rats has also been reported (364).

In light of the physiological data on the role of NMDA receptors in puberty, colocalization of NMDA receptors in LHRH neurons has been studied extensively. No colocalization of NR1 in LHRH neurons in rats at P0–P14 (401) has been reported, and less than 5% of LHRH neurons contain NR1 mRNA in the POA/hypothalamus of adult rats and hamsters (407, 408, 409). Interestingly, the percentage of LHRH neurons that are double-labeled with NR1 increases from 0% to 5% between prepuberty and postpuberty (404). It is possible, however, that the low percentage of NR1 mRNA containing LHRH neurons may be due to current technical limitations, since high levels of mRNA are required for in situ hybridization studies and clean, highly specific antibodies for NMDA subunits are not available.

Since the combination of different subunits appears to yield differential receptor dynamics, changes in NR2 subunit expression could result in changes in responsiveness to glutamatergic stimulation. For example, it has been reported that LHRH neurons are insensitive to glutamate during the embryonic period (264), but glutamate acting through NMDA receptors is inhibitory to LHRH release during early postnatal development (381), whereas it stimulates the release of LHRH as animals mature (307). Based on an experiment with antisense oligonucleotides for NR2a and NR2c mRNAs in male rat hypothalamic explants, Bourguignon and colleagues (307) further suggest that changes in NMDA receptor subunit composition in relation to LHRH release occur as animals mature, i.e., the NR2c subunit is involved in the inhibitory function of NMDA receptors on LHRH release at P15, but this inhibitory function of NR2c no longer exists at P25. In contrast, the NR2a subunit is involved in the stimulatory function of NMDA receptors on pulsatile LHRH release at both P15 and P25. NR2a levels in male rats increase from undetectable levels between E18 and P15, first becoming detectable at P0, whereas in females NR2a mRNA levels are not detectable until P5 and disappear after P10 (401). NR2b mRNA levels are lower at E18 and P0 than at P5 through P15 in both males and females (401). Eyigor and Jennes (410) report that NR2a subunit mRNA levels colocalizing in LHRH neurons do not change with age between P20 and P50 in female rats. Developmental changes in subunit composition are very important for understanding the role of glutamate. However, since neither changes in mRNA nor receptor numbers alone reflect the state of the receptor function, comprehensive analysis is necessary before conclusions can be made.

e. Developmental changes in non-NMDA receptors.
AMPA receptor subunit GluR1 mRNA levels in the rat POA, measured by quantitative RT-PCR, increase transiently on P20, but the levels at all other ages are comparable, and no change in GluR1 subunit mRNA is seen in the MBH at any time (406). AMPA binding also increases in the hypothalamus of rats from P20 through P33 (1 day before vaginal opening), followed by a return to P20 levels by P35 (406). Sex differences in non-NMDA receptors in neonatal rats have also been reported (411). Thus, it is possible that maturational changes in AMPA receptors are important for the pubertal transition.

The concentration of kainate receptor (KA2) mRNA and the number of LHRH neurons expressing KA2 mRNA increase progressively between P20 and P40, and especially the morning levels of KA2 mRNA are higher than the afternoon levels at P30 and P40 than at P20 in female rats (410). Because first ovulation usually occurs around P35 in female rats, these authors propose that kainate receptors may be involved in the mechanism of the onset of puberty. Further, these authors postulate that a direct signal of excitatory glutamate to LHRH neurons is primarily mediated through kainate receptors, and glutamate signals through NMDA receptors may be mediated by interneurons, based on the fact that a large number of LHRH neurons express KA2 mRNA, but not NR1 mRNA (410). Kainate binding, however, does not change in the hypothalamus during the pubertal transition time (406). Nonetheless, the facts that ovarian steroids increase GluR1 subunit levels (412), that kainate injection advances the onset of puberty by only 1 day, and that DNQX, a non-NMDA receptor blocker, fails to alter the timing of puberty (364) suggest that high GluR1 mRNA levels and AMPA binding property, as well as high KA2 mRNA levels around the age of puberty, may be a consequence of the pubertal increase in steroid hormones, rather than a cause of puberty. At the time of this writing, there are insufficient data on the glutamate receptor subtypes to determine which ones are associated with puberty or to support the hypothesis that non-NMDA receptors play a major role in the onset of puberty. Nonetheless, glutamate neurons are very important for the mechanism of the onset of puberty in many mammalian species (Table 2).

The stimulatory role of catecholamines in puberty was first postulated by Weiner and Ganong (425), based on the observation that treatment with reserpine, a monoamine synthesis blocker, reduces NE in the hypothalamus to only 8% of that of the controls and delays vaginal opening in rats (425). Further, treatment of prepubertal female rats with 6-hydroxydopamine, which selectively lesions catecholaminergic neurons, delays vaginal opening and lowers body weight (426, 427). Inhibition of NE synthesis with bis-(4-methyl-1-homopiperazinil-thiocarbonil) disulfide (FLA-63), which interferes with dopamine-ß-hydroxylase, suppresses the postcastration-induced LH release in rats at all ages examined between P7 and P28 (428), whereas inhibition of NE synthesis with -methyl-paratyrosine (-MPT), which interferes with conversion of L-dopa to the NE precursor dopamine, slightly suppresses the postcastration-induced LH release only in juvenile rats (428). Moreover, diethyldithiocarbamic acid, a dopamine-ß-hydroxylase inhibitor, prevents the progesterone-induced LH surge as well as LHRH mRNA expression in pubertal, OVX, estrogen-primed rats (429). These data indicate that NE is an important neurotransmitter for the pubertal increase in LH/LHRH release. Nonetheless, puberty induced by social cues is not regulated by catecholamines (430).

We have examined the role of the ₁-adrenergic neuronal system in puberty in female rhesus monkeys (431, 432). Prepubertal monkeys exhibit the greatest LHRH increase in response to methoxamine, followed by a moderate increase in early pubertal monkeys, with the lowest LHRH increase in midpubertal monkeys when measured by push-pull perfusion in the S-ME (431). Because NE levels in the S-ME are low in prepubertal and early pubertal monkeys and increase 6-fold in midpubertal monkeys, a larger responsiveness of the LHRH neuronal system to methoxamine stimulation in younger groups is probably due to the absence of high levels of endogenous NE, a situation similar to denervation hypersensitivity (431). Therefore, increase in NE stimulation in early pubertal monkeys may contribute to, rather than be critical for, the increase in LHRH release during pubertal development (Fig. 2). In support of this view, while transplantation of adrenal chromaffin cells, which contain high amounts of catecholamines and neuropeptide Y (NPY), into the third ventricle of three prepubertal monkeys (12–13 months of age) does not alter the timing of menarche, it significantly advances the age of first ovulation (433). In fact, in two of the three monkeys, first ovulation occurred at 30–32 months of age. Since first ovulation at 30–32 months of age was exceptionally early compared with our colony monkeys, we concluded that catecholaminergic neurons as well as other factors in transplants contribute to the facilitation of the onset of puberty (433). However, the fact that first ovulation did not occur until 17–19 months after chromaffin cell transplantation suggests that supplying the stimulatory neurons to the hypothalamus may not be sufficient to result in pubertal activation of LHRH neurons. A GABA mechanism restraining LHRH release is predominant in the immature hypothalamus, and this inhibitory mechanism may need to be removed before a facilitatory mechanism is activated.

In contrast to the prepubertal and peripubertal animal, NE may be inhibitory to LHRH release during embryonic development. Both phenylephrine and clonidine, ₁- and ₂-adrenergic agonists, respectively, suppress LHRH release from primary hypothalamic cell cultures from E16 rat embryos cultured for 12 days (434, 435). On the other hand, prazosin and rauwolscine, ₁- and ₂-adrenergic antagonists, respectively, enhance LHRH release. Treatment with the tyrosine hydroxylase (TH) inhibitor, -MPT, resulted in increased LHRH release. However, since inhibition of TH also interferes with dopamine synthesis, the authors tested the effects of SCH23390 or sulpiride, D₁- and D₂-dopaminergic antagonists, on LHRH release, respectively. Based on the negative results with dopaminergic antagonists, the authors conclude that LHRH release in fetal hypothalamic cell cultures is under the inhibitory control of intrahypothalamic NE. Therefore, a developmental shift of NE action on LHRH release may occur. In support of this notion LHRH release in response to NE does not occur from P9 rat hypothalamic explants, whereas NE stimulates LHRH release from P29 explants, similar to the adult pattern, and this change is steroid independent, because pretreatment with estrogen does not alter LHRH response to NE in either age group (436).

b. Developmental changes in NE neurons.
Noradrenergic neurons in the locus coeruleus of rats are differentiated by E13 (437). Cell bodies in the A11–13 groups (NE neurons) become visible by fluorescent staining for catecholamines during the first week of life (438). Fluorescence intensity as well as cell number of catecholamine-positive cells reaches a maximum between the second and third week after birth and then declines through week 5 when adult levels are attained (438). However, this method measures both NE and dopamine. In contrast, NE levels in the brain of sheep are low during the embryonic period through P5, and the levels in the lateral, dorsomedial, and ventromedial hypothalamic areas then increase at P25 to P30 (439).

Levels of NE in the hypothalamus and brain regions that project to the hypothalamus change from embryonic to adult stages of life. NE concentrations in rat diencephalon increase 9-fold from E15 to birth (440). From P0 to P18, the period that corresponds to the development of noradrenergic innervation of the hypothalamus through the dorsal and ventral noradrenergic bundles, NE concentrations in the diencephalon further increase (440). NE concentrations in the MPOA and hypothalamus then continue to increase to the adult level by no later than 5 to 6 weeks of age (428, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450). NE concentrations in the MPOA increase before the pubertal age in female rats, although a few researchers have noted short-term decreases in NE concentrations at the time of puberty. The discrepancy may be due to differences in methods and sampling locations. Nonetheless, hypothalamic concentrations of NE in female rats with posterior hypothalamic lesions exhibiting precocious puberty and in control rats on the day of vaginal opening are higher than in prepubertal control rats (451), and NE turnover rates in the MPOA increase when estrogen induces an LH surge in P15 female rats (452), similar to those observed with the proestrous surge, indicating that NE may be involved in the first LHRH surge, and hence the onset of puberty in rats (453).

Activity of NE-synthesizing enzymes also changes during the pubertal period. Dopamine-ß-hydroxylase activity in the MPOA and anterior MBH in female rats is highest at P15, decreases significantly between P20 and P35, increases slightly again at P40, and continues to increase to adult levels that are similar to levels seen in P15 animals (456). There is no decrease in dopamine-ß-hydroxylase activity in the posterior MBH and even a slight increase in day 30 and 35 animals, followed by a major increase after puberty to the level seen in adulthood (456).

In rhesus monkeys NE neurons originate from the ventricular zone of the pontine lateral recess of the fourth ventricle at E30–E33, migrate into the locus coeruleus, and differentiate into the cytologically mature form at E50–E70 (454). However, the size of NE cell soma continues to increase until P60 (454). NE levels in the cerebral cortex steadily increase from birth to 36 months of age, at which point adult levels are attained (236, 455). Similarly, NE release in the S-ME is low in prepubertal monkeys (14–18 months) and substantially increases between early pubertal and midpubertal ages (431).

c. Turnover rate.
Because the turnover rate may better reflect neurotransmitter activity than the local concentration, several researchers have measured NE turnover rates in rats. NE turnover is frequently determined by 1) the ratios between NE and its metabolites such as homovanillic acid or 3-methoxy-4-hydroxy-phenolglycol; or 2) inhibiting the synthesis of NE with dopamine-ß-hydroxylase inhibitors and then measuring the levels of NE and its metabolites after a specified period of time. NE turnover rates in the MPOA and MBH increase from low levels at P15 to higher levels at P20, and very high levels at P30–P35 or at first early proestrus, coinciding with the time of puberty in female rats (444, 447, 457, 458). NE turnover rates in the hypothalamus then decline after P35-P40 or at first late proestrus (444, 457, 458). Therefore, NE turnover rates appear to increase before the onset of puberty in rats.

Norepinephrine transporter (NET) is also likely involved in the NE turnover rate. Although the role of NET in control of LHRH release has been studied in adult monkeys (459, 460), its role in puberty has not yet been established.

d. Adrenergic receptors.
The noradrenergic control of LHRH release may occur at the level of the adrenergic receptor. The number of ₁-adrenergic binding sites increases from P0 to P21 in cell membrane preparations from the male and female rat brain (456). In contrast, binding levels of [³H]prazosin, an ₁-adrenergic antagonist, in the MPOA and hypothalamus of female guinea pigs decrease from P0, reaching adult levels by P7 (448). Since lesion of noradrenergic neurons with 6-hydroxydopamine results in increased [³H]prazosin binding in the MPOA and hypothalamus (23% and 35%, respectively), and the difference is due to an increase in receptor number rather than a change in receptor affinity (448), these authors conclude that the developmental increase in noradrenergic neurons decreases ₁-adrenergic binding in the hypothalamus by a decrease in receptor number rather than a change in receptor affinity (448).

e. Possible mechanism of NE action through prostaglandins.
PGE₂ has been shown to mediate NE-induced LHRH release by an intra- and extracellular Ca²⁺-dependent (461, 462), but not calmodulin- and cAMP-dependent, mechanism (463). Treatment with NE induces release of PGE₂ and LHRH in a dose-responsive manner. Moreover, treatment with estradiol results in an increase in sensitivity of both PGE₂ and LHRH response to NE. Since LHRH release from median eminence explants of female rats increases from P22 through P34 in response to PGE₂, and since the LHRH response to PGE₂ stimulation is blocked by ovariectomy on P22, but implantation of an estradiol-containing capsule on P30 restores the LHRH response to PGE₂, the stimulatory action of NE on LHRH release is mediated by an estradiol-sensitive PGE₂ mechanism, which is further accelerated as puberty progresses (464).

Collectively, NE neurons are important for the mechanism of the onset of puberty in rodents, but they appear to play a secondary role in puberty in primates (Table 2).

3. The catecholamine dopamine.
a. Role of dopamine in puberty.
Despite a large amount of literature on the importance of dopamine in the control of LHRH release (for reviews see Ref. 253, 465), the role of dopamine in the onset of puberty has been less well studied. While NE neuroterminals do not form synapses on LHRH neurons (465), dopamine neuroterminals do (253), suggesting that dopamine may play a role in the mechanism of puberty. For example, chronic treatment with pergolide, a dopamine D₁/D₂ receptor agonist, advances the age of vaginal opening in rats (466), but implantation of pimozide, a dopamine antagonist, in the MPOA in female rats also results in a precocious puberty (467, 468). An extensive study with selective lesions of dopamine and NE neurons using neurotoxic agents further indicates that the role of catecholamines in puberty is complex (427). Depletion of dopamine by intracisternal injection of 6-hydroxydopamine with desipramine, which spares NE neurons, on P31, results in delayed vaginal opening compared with the control as well as 6hydroxydopamine alone, and similarly intraventricular treatment with 6-hydroxydopamine and desipramine on P30 decreases LH release induced by PMSG injection, suggesting a stimulatory role of extrahypothalamic dopamine in the mechanism of puberty (427). However, intravenous injection of 6-hydroxydopamine with desipramine on P30 into PMSG-treated rats results in an increase in LH release as well as LHRH release. Because 6-hydroxydopamine, when given intravenously, can only reach the median eminence, which is outside of the blood brain barrier, these results indicate that depletion of dopamine in the median eminence disinhibits LHRH release (427). Therefore, dopamine may have both stimulatory and inhibitory actions on puberty and LHRH release, as has been shown in adult animals.

b. Development of dopamine neurons.
Based on the precise work of Lauder and Bloom (437) using ³H-thymidine labeling, dopamine neurons in the substantia nigra undergo differentiation between E12 and E15 with a peak event occurring on E13. This finding is in good agreement with more recent studies in embryonic rats that dopamine neurons are not seen in the brain or the hypothalamus until E15–E17 (440). There is a very rapid increase in dopamine content in the diencephalon of rats between E15 and E17, followed by a gradual postnatal increase through P18 when adult levels are reached (440). This time period (P0–P18) corresponds to the development of the tubero-infundibular dopaminergic system.

In humans, dopamine neurons first appear in the ventricular floor at E week 6. By E week 8 they start to extend neurites, which reach the striatum at E week 10 (469, 470). In rhesus monkeys dopamine neurons originate from the ventricular zone of the fourth ventricle between E36 and E43 with peak neurogenesis at E38–E40 (454). TH is detected in the mesencephalon and diencephalon at E38, its mRNA in the mesencephalon is observed at E40 (471), and TH immunopositive cells and fibers are present in the substantia nigra and the developing striatum, respectively, at E40–E41 (454, 471). By E60 the size and number of TH immunopositive neurons in the caudal diencephalon and midbrain increase (454, 471), but there are no TH-immunopositive cells in the arcuate nucleus at this age (471). Apparently, arcuate dopamine neurons are also last to develop in rats and sheep (472, 473). The increase in the cell size of dopamine neurons continues until P60 in monkeys (454).

There are gender differences in embryonic development of dopamine neurons. Dopamine-immunopositive neurons from the E14 female rat brain after 3 days in vitro have a morphologically more mature appearance than those from the E14 male brain, and have much higher rates of dopamine reuptake, an indicator of activity and maturity, than male neurons (474). These results indicate that diencephalic dopaminergic neurons in the female mature sooner than in the male and that the differences are not steroid-dependent as the initiation of testosterone secretion does not occur until E17-E18, and incubation of these neurons with androgen or estrogen has no effect on their morphology, development, or activity.

c. Dopamine concentrations and turnover rates.
Earlier data indicate that dopamine levels in the rat brain increase from birth to adulthood (428, 441, 443). However, more recent data show that dopamine concentrations and turnover rates specifically increase before or around the age of puberty. In the MPOA, dopamine concentrations are low in P15 rats and increase from P20 to adult levels by P25 in female rats. In addition, turnover rates of dopamine in the MPOA are low in P15 rats, start to increase at P20 through P25–P35, and then decrease by P40 when turnover rates reach adult levels (444, 457). In the hypothalamus, dopamine levels are significantly higher at P30–P40 than at P10–P30 (450), and dopamine turnover rates increase before first early proestrous but decline at first late proestrus (457). Further, the higher dopamine levels in the hypothalamus in rats with posterior hypothalamic lesions exhibiting precocious puberty and in control rats on the day of vaginal opening compared with prepubertal control rats (451) suggest a role for dopamine in puberty. However, dopamine turnover rates in the MPOA do not change when estrogen induces an LH surge in P15 female rats, unlike increases in NE turnover rates with the same treatments and with the proestrous surge, indicating that dopamine may not be critically involved in the first LHRH surge (453). Rather, it is likely that a developmental increase in turnover rates in prepubertal rats is due to increased levels of circulating PRL (453, 475, 476).

d. The dopamine synthesizing enzyme, TH, and its activity.
TH activity in the MPOA and MBH, including the arcuate nucleus and median eminence, of female rats is low at P5–P10, increases at P15–P20 by 2- to 3-fold, remains stable until P35, and increases further after P40, reaching adult levels (456, 477). TH activity in the MBH does not change after P40 in males (477).

Similar developmental changes in TH mRNA and protein expression in the arcuate nucleus occur in both males and females (477). TH mRNA levels in the arcuate nucleus increase 3.5-fold between P5 and P15 and remain steady between P15 and P35 in both sexes, but a further increase between P35 and P40 occurs in females, but not in males, concomitant with the increase in circulating progesterone. Immunostaining intensity of TH in the arcuate nucleus also undergoes similar developmental changes. TH-containing cells in the zona incerta (A13 cell group) are already present at E16 and E20, and both TH mRNA levels and the intensity of immunostaining for TH in the zona incerta and substantia nigra increase between P5 and P15 in both sexes, with no further increase between P20 and P70 (477).

e. Dopamine receptors.
Although, in rats, dopamine neurons differentiate between E12 and E15, and dopamine appears to be present in the embryonic hypothalamus, dopamine receptors are not functional until somewhat later in development. Moreover, dopamine receptor mRNA is present at a late embryonic stage, yet D_1A dopamine receptor protein synthesis and/or transport to the cell membrane does not occur until a later age. For example, a large group of maturing cells in the intermediate zone of the hypothalamus of E14 rats expresses D_1A dopamine receptor mRNA (478), but there is no apparent binding of the D_1A dopamine receptor agonist [³H]SCH-23390 to any brain tissue at this age or at E16. On E18, D_1A dopamine receptor mRNA is present in the superchiasmatic nucleus and ventromedial hypothalamus, but again no [³H]SCH-23390 binding is seen (478). Similarly, no labeling for dopaminergic D₂ receptors is seen in the hypothalamus between E16 and E18, but by E19–E20, D₂ receptor labeling is seen in the anterior hypothalamic area in rats (435, 479). By E22–P0, the dorsomedial hypothalamus expresses [¹²⁵I]sulfiride labeling, and by P7 the lateral POA begins to exhibit some labeling, although no additional changes occur through P21 (479). D₂-dopamine binding sites in the hypothalamus increase from P5–P15 in rats (480). Neither SCH-23390 nor sulfiride has any effect on LHRH release from primary hypothalamic cells obtained from E16 rat embryos cultured for 12 days in vitro (434). These results indicate that dopamine receptors are not likely involved in LHRH release until after the second week of postnatal life. In support of this view, treatment with pergolide, a D₁ and D₂ agonist, only at P11–P20, but not P1–P10, results in precocious puberty in female rats by desensitization of dopamine receptors (466, 481). With the approach of puberty, changes in dopamine receptors appear to occur. For instance, there is a slight increase in the number of dopamine D₁ and D₂ receptors in the striatum and an increase in D₁ receptors in the nucleus accumbens in female rats between P20 and P40 (482). D₁ receptor numbers in the nucleus accumbens decrease after P40 and through P80, to final adult levels, but there is no change in either D₁ or D₂ receptor numbers in the striatum after the onset of puberty (482). In primates, although the presence of D₁ and D₂ receptors in the fetal brain at E45 in rhesus monkeys and E65–E72 in human has been reported (483, 484), developmental changes in relation to puberty have not been studied.

4. Serotonin. Recently, a classic neurotransmitter, serotonin (5-hydroxytryptamine or 5HT), has drawn special attention because of its role in affective disorders, such as manic depression, which often start during the late pubertal stage in humans. At present, seven distinct subtypes of serotonin receptors, 5-HT₁, (5-HT_1A, 5-HT_1B, 5-HT_ID, 5-HT_1E, 5-HT_1F), 5-HT₂ (5-HT_2A, 5-HT_2B, 5-HT_2C), 5-HT₃ and 5-HT₄ (5-HT_4S, 5-HT_4L), 5-HT₅ (5-HT_5A, 5-HT_5B), 5-HT₆, and 5-HT₇ have been described (485).

Serotonin can be stimulatory or inhibitory to the control of reproductive function (465). A decrease in serotonin synthesis with p-chlorophenylalanine (PCPA) blocks the proestrous LH surge (486), several serotonin antagonists suppress spontaneous ovulation as well as PMSG-induced ovulation in immature rats (487, 488), and lesions of the medial and/or dorsal raphe with the neurotoxin 5,7-dihydroxytryptophan (5,7-DHT) result in blockade of PMSG-induced first ovulation (489) or delay the onset of puberty (490, 491). Elevations of serotonin concentrations in the hypothalamus of female rats and in the median eminence in chicks are associated with the first proestrus and precocious puberty, respectively (487, 492), and serotonin concentrations in the hypothalamus-POA are lower in female rats exhibiting delayed puberty induced by growth deficiency and environmental stress than in normal controls (493). In contrast, the pharmacological elevation of serotonin in the hypothalamus with monoamine oxidase inhibitors suppresses spontaneous ovulation in adult rats (494) and PMSG-induced ovulation in immature female rats (495). Although stimulatory and inhibitory roles of serotonin in gonadotropin secretion and puberty may be attributable to the anatomical differences in two serotoninergic systems, such that the dorsal raphe nucleus plays a stimulatory role and the medial raphe nucleus plays an inhibitory role (496), it is possible that the gonadal state and developmental age may influence serotonin action. In fact, serotonin stimulates LH release in female rats at P16–P20, whereas it does not alter LH release in female rats at P26 (497), and serotonin inhibits LH release in castrated male rats, whereas it stimulates LH release in intact male rats (498).

The role of serotonin in puberty in primates is not well investigated. In adult female rhesus monkeys, however, Bethea and colleagues extensively studied regulation of the serotonin neuronal system by the ovarian steroid hormones (499, 500, 501, 502, 503).

5. Neuropeptide Y (NPY).
NPY, a 36-amino acid peptide, is one of the most abundant peptides found in the mammalian central nervous system and plays several important roles in regulating brain function, including control of reproductive function and food intake behaviors. Physiological roles of NPY in the brain are mediated by NPY receptors that belong to a family of G protein-coupled transmembrane spanning molecules, and at least six receptor subtypes (Y1–Y6) are identified. The Y1, Y2, Y5, and Y6 receptors also mediate the effects of the structurally related peptide YY (PYY). Different classes of receptors have been suggested to be involved in different functions of NPY.

a. Developmental changes in NPY and NPY receptors.
Development of the NPY neuronal system appears to closely parallel the development of the LHRH neuronal system, suggesting a potential interaction between the two neuronal systems (504). For example in the chick, a population of NPY-positive neurons originates beginning at embryonic stage 28 in the olfactory placode, whereas LHRH neurons differentiate at stage 25 (505). A large percentage of NPY neurons coexpressing LHRH migrate into the brain with LHRH neurons (505). However, the majority of NPY neurons originate within the brain. In rats, NPY neurons are already present in the diencephalon and brainstem at E13–E14 (506), the developmental stage during which LHRH neurons are first found in the basal forebrain (507), although NPY neurons are not detectable in the cerebral cortex, hippocampus, and mesencephalon until E16-E19 (506, 508, 509). Concentrations of NPY in these brain areas increase 1.5- to 5-fold at birth with the rate of increase in the diencephalon being the largest.

Biochemical, molecular biological, and neuroanatomical studies show that postnatal development of NPY in the brain either increases or decreases or does not change. NPY contents in the hypothalamus increase during postnatal development in rats (511, 512). NPY concentrations and NPY mRNA levels in the medulla oblongata, cerebral cortex, and hippocampus in rats and in the cortex in monkey also increase postnatally (506, 510, 513). Further, according to Sutton and colleagues (511), NPY levels in the MBH and MPOA increase steadily from birth to P20 in males and from birth to P36 in female rats, and plasma levels of NPY in the hypothalamic-hypophyseal portal circulation collected on the day before vaginal opening are significantly higher than those collected 2 days before vaginal opening, coinciding with the peak of the LH surge. In female rhesus monkeys as well, NPY release in the S-ME increases along with the pubertal increases in LHRH release (514). In contrast, a recent study in male monkeys indicates that NPY concentrations and mRNA levels in the MBH increase between the neonatal and juvenile periods, whereas both decrease between the juvenile period and puberty in male monkeys (238), and expression of NPY mRNA in the arcuate nucleus and VMH also decrease between the juvenile period and puberty (238). Similarly, in rats and pigs, neuroanatomical studies indicate that the number of immunopositive NPY neurons in the hypothalamic nuclei, such as the arcuate nucleus and paraventricular nucleus, as well as cerebral cortex, is largest at birth and declines during postnatal development (508, 509, 515). However, some reports also show that NPY concentrations in the diencephalon and brainstem do not change postnatally (506, 510), and a neuroanatomical report also indicates that no postnatal changes occur in the number of immunopositive NPY neurons in the hypothalamus, including the proportion of neuroendocrine NPY neurons, which send their axoterminals to the median eminence (516). The developmental shift in the distribution pattern of NPY peptide within the neuron is attributable, in part, to biochemical and neuroanatomical discrepancy. The number and distribution of NPY-immunopositive fibers in the hypothalamus and cerebral cortex greatly increase postnatally toward adulthood in rats and monkeys (508, 509, 517): as the animal grows, a higher amount of release occurs from neuroterminals, since the rate of transport of NPY within the neuron increases with age, and a larger amount of NPY peptide is present in fibers and neuroterminals. The reports that immunostaining of NPY perikarya in the adult hypothalamus often requires pretreatment with colchicine, an axonal transport blocker (518, 519), support this speculation. Additional studies are needed to draw a clear developmental profile of NPY neurons.

There are only a few reports on the developmental changes in NPY receptors because of the absence of subtype-specific markers. The NPY Y1 receptor mRNA is expressed as early as E12, while specific [¹²⁵I][Leu31,Pro34]PYY binding is observed by E14 in rats. Thereafter, both signals steadily increase, with Y1 receptor mRNA increasing faster than its translated protein during fetal life. The in situ hybridization signals reach a plateau around P0 and remain high through P14 to display the adult distribution pattern by P21. Similarly, specific [¹²⁵I][Leu31,Pro34]PYY binding constantly increases during brain maturation and reaches a plateau by P21. In some brain areas, such as the cerebral cortex, specific binding declines slightly before attaining its adulthood pattern. Throughout ontogenesis, the profile of both the Y1 receptor mRNA and protein binding is well matched except in hypothalamic areas where relatively higher mRNA signals are observed (520).

In mice, using RNase protection assays, Y1, Y2, and Y5 mRNAs are expressed very early in the developing spinal cord, brain, cerebellum, and dorsal root ganglion and are often down-regulated at times corresponding to their acquisition of the adult function in neurotransmission. In situ hybridization of the adult brain shows that Y1 is widely expressed, Y2 displays a more restricted pattern, Y5 is expressed at very low levels and only in a few brain nuclei, and Y6 is not expressed. Virtually all areas containing neurons positive for Y5 also express Y1, and many Y1-positive cells clearly express Y5. In contrast, Y2 is not expressed by neurons expressing Y1 or Y5. These observations suggest that NPY signaling in the brain can be mediated by simultaneous Y1 and Y5 activation (521).

b. Stimulatory role of NPY in puberty.
The role of NPY in the control of reproduction and LHRH release has been discussed extensively (417, 522, 523, 524). Numerous earlier studies indicate that NPY is inhibitory in OVX rats, rabbits, sheep, and monkeys (525, 526, 527, 528, 529), whereas it is stimulatory in ovarian intact or estrogen-primed adult rats (see Ref. 523). However, in our studies NPY is a stimulatory neuromodulator for LHRH release regardless of the gonadal state of adult female monkeys (Fig. 2). NPY pulses in the S-ME occur with 5 min preceding LHRH pulses (530), and NPY infusion into the S-ME increases LHRH release in a dose-responsive manner (531), whereas infusion of NPY antiserum suppresses LHRH pulses (530). Interestingly, estrogen facilitates NPY action, i.e., the dose-response curve of NPY is left-shifted by estrogen priming (532). The difference between earlier studies in another laboratory (528) and ours was due, perhaps, to technical differences. Since studies in other laboratories examined the effects of NPY with intraventricular (lateral ventricle) infusion, it is possible that NPY might have stimulated neurons inhibitory to LHRH release, such as ß-END neurons, by diffusion through the ventricular system. In fact, recent studies suggest that NPY is stimulatory if it is applied to the median eminence directly in vivo or in vitro in OVX rats and monkeys and GT-1 cells (533, 534, 535, 536). Nonetheless, a more recent study suggests that NPY is obligatory to the full expression of the estrogen-induced LH surge, since the magnitude of the LH surge is significantly less in NPY knockout mice than in normal mice (537).

A line of study indicates that NPY is involved in the mechanism of the onset of puberty in chickens, rats, and monkeys. The hypothalamic content of NPY increases during postnatal development until the age of puberty (511, 512, 517). An increase in NPY mRNA levels and NPY concentrations in the MBH and MPOA occurs in P29 rats treated with estrogen and progesterone, which is followed by a decrease after the LH surge, and the changes in NPY mRNA and NPY concentrations in the MBH and MPOA are parallel to those with LHRH mRNA and LHRH concentrations (538, 539). Intraventricular infusion of a NPY antiserum delays the timing of puberty in female rats (540), whereas a single intraventricular injection of NPY advances vaginal opening followed by first ovulation in female rats (541), and 5-day injection of NPY into the lateral ventricle of chicks induces precocious puberty with an increase in food intake (542). In contrast, chronic infusion of 18 µg NPY into the lateral ventricle starting on P30 delays sexual maturation in female rats with a decrease in food intake, whereas a single injection of 12 µg NPY into the lateral ventricle does not result in any significant effect (543). In food-restricted rats with delayed puberty, NPY injection results in an increase in food intake and rapid restoration of body weight followed by puberty (544). Thus, NPY appears to possess both stimulatory and inhibitory effects, interacting with other neuronal systems, such as leptin neurons, that control food intake behavior and energy balance (545). Because ventricular infusion allows NPY to diffuse elsewhere in the brain, further studies are needed to clarify the inhibitory mechanism of NPY in puberty.

We have also examined the role of NPY in puberty. NPY infusion into the S-ME stimulates LHRH release in pubertal female monkeys, but not in prepubertal monkeys (514). Similarly, NPY antiserum infusion into the S-ME suppresses LHRH release in pubertal monkeys, but not in prepubertal monkeys (514). The mean NPY release is low in prepubertal monkeys, when LHRH release is low, and an increase in NPY occurs along with the pubertal increase in LHRH release (514). Moreover, in a subsequent experiment, a graft of the adrenal medulla, which contains NPY and NE, into the third ventricle of prepubertal female monkeys adjacent to LHRH neurons and their neuroterminals resulted in the advancement of ovulation, but not menarche (433). We have interpreted these results to mean that NPY may be a contributing neuromodulator for puberty, rather than a key factor to trigger the onset of puberty, since neither NPY nor NPY antiserum is effective in altering LHRH release before the onset of puberty (Table 2). However, if NPY is an inhibitory neuromodulator in the prepubertal period as proposed by Plant and colleagues (see below), it is possible that infusion of the NPY antiserum for 10 min in the previous study may not have been sufficient for an increase in LHRH release. The question as to whether NPY is inhibitory to LHRH release before the onset of puberty and reverses its function to stimulatory after the onset of puberty remains to be answered.

c. Inhibitory role of NPY in puberty.
An inhibitory role for NPY has been reported in rats (546). Recently, Plant and colleagues reported that NPY mRNA levels in the hypothalamus, measured by RNase protection assay, decreased at the onset of puberty in male castrated monkeys concomitant with an increase in LHRH mRNA levels (Ref. 238 and Fig. 2). These authors further reported that NPY mRNA expression in neonatal males was lower than in prepubertal juvenile males, although LHRH mRNA expression in neonates was not different from that in prepubertal juveniles (547), and infusion of an NPY antagonist into the ventricle stimulated LH release (238). Similarly, chronic infusion of NPY into the lateral ventricle starting on P30 delays sexual maturation in female rats concomitant with a decrease in food intake (543), which is likely mediated by NPY-Y₅ receptors (548). These observations are particularly interesting, since it has been reported that NPY colocalizes in GABA neurons in the cerebral cortex, hippocampus, suprachiasmatic nucleus, and arcuate nucleus (549, 550, 551). NPY is inhibitory to hippocampal and suprachiasmatic neurons via presynaptic or postsynaptic receptors (552, 553, 554, 555), and studies in NPY knockout mice indicate that NPY is an endogenous antiepileptic agent through presynaptic inhibition of glutamate neurons (556, 557).

Nonetheless, the inhibitory role of NPY in the mechanism of the onset of puberty in rhesus monkeys requires further evaluation: 1) NPY release in the S-ME increases at the onset of puberty in female rhesus monkeys (514), whereas GABA release decreases concomitantly with the pubertal increase in LHRH release in prepubertal females (217, 240); and 2) infusion of an NPY antiserum to the S-ME suppresses LHRH release in pubertal females, but not in prepubertal females (514), whereas the GABA_A antagonist, bicuculline, stimulates LHRH release in prepubertal monkeys (217). Presently, it is unclear whether the discrepancy between female and male monkeys is due to sex differences or to methodological differences. In males, neither developmental changes in release of LHRH and NPY nor the effect of NPY infusion into the S-ME on LHRH release have been investigated; reports from the Plant laboratory have not been confirmed by others. Further, developmental changes in NPY mRNA in the female hypothalamus have not been assessed. If there is any inhibitory role of NPY in puberty (Table 1), the clarification of the issues, such as 1) whether NPY action is direct on LHRH neurons or indirect through interneurons; 2) if it is direct action, whether the site of NPY action is on the LHRH perikarya or their neuroterminals; and 3) whether two subsets of NPY neurons (one is stimulatory and the other is inhibitory to LHRH release), as proposed by Plant and colleagues (558) are present will be critical to understanding its mechanism.

6. Other neuropeptides.
a. Galanin.
Galanin that colocalizes in a subset of LHRH neurons in the rat (559, 560) has been reported to play a role in modulating pulsatile LHRH release and the mechanism of the onset of puberty (561, 562). Galanin concentrations in the hypothalamus increase with precocious puberty induced by PMSG in female rats (563), and galanin mRNA levels in the bed nucleus of the stria terminalis and medial amygdala, and galanin binding levels in the POA increase across puberty in both male and female rats (564, 565, 566). Specifically, galanin mRNA levels in LHRH neurons increase at puberty 8- and 2-fold in female and male rats, respectively, and this increase is due to gonadal steroids (567). Interestingly, perikarya of galanin neurons are innervated by NPY neurons (568). However, galanin neither colocalizes in LHRH neurons nor stimulates LHRH release in monkeys (569) and does not appear to play a significant role in the control of LHRH neurosecretion (570). Therefore, it is not likely that galanin plays any role in puberty in primates.

b. LHRH.
It has been shown that LHRH controls the secretory pattern of LHRH neurons. For instance, GT-1 cells release LHRH into media in a pulsatile manner indicating that LHRH itself may be a regulator of pulsatility. A study using GT-1 cells suggests that LHRH controls the mechanism generating LHRH pulses: exposure to the LHRH agonist analog, des-Gly¹⁰ (D-Ala⁶) LHRH, stimulates the amplitude of intracellular Ca²⁺ oscillations and LHRH pulses in a concentration-related manner, while the frequency of LHRH pulses is reciprocally reduced with an increase in concentrations of the analog (571). The findings that LHRH receptor mRNA containing neurons are distributed in the same area that LHRH neurons are present (572), and that LHRH neurons express LHRH receptors (573), suggest that there is an autocrine mechanism, i.e., that LHRH release is controlled by LHRH itself. Therefore, it is possible that a small increase in LHRH release in the hypothalamus may augment LHRH release further during the progress of puberty. Despite the fact that in-depth discussion on the autocrine action of LHRH is available in reviews by Stojilkovic and colleagues (574, 575), as well as by Terasawa (576), the role of LHRH in the pubertal increase in LHRH release has not been investigated thus far.

C. Role of glia and growth factors
Recently, the role of glia and growth factors from glia has become an important issue in the control of LHRH release and the onset of puberty. Glia can contribute to the control of the pulsatility of LHRH release by 1) modifying the local environment of the release site in the S-ME, where there is an abundance of neuroterminals and glial cells, including tanycytes, but not cell bodies of LHRH neurons (577, 578, 579, 580); 2) producing growth factors (see below); and 3) providing a signaling pathway from other neurons, e.g., the neuroligand, bradykinin, stimulates glutamate release from astrocytes, which in turn appear to signal back to bradykinin neurons (581). In fact, because astrocytes possess a large array of neurotransmitter receptors, and many of the receptors are coupled to second-messenger systems that cause the release of Ca²⁺ from IP₃-sensitive stores, astrocytes can mediate the signal of one neuron to other neurons (582, 583). A critical role of glia in release of oxytocin and vasopressin has been well documented (584, 585, 586).

Astroglia synthesize and release growth factors, such as transforming growth factor- and -ß (TGF and TGFß, respectively). The presence of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I, neuronal cell adhesion molecule (NCAM), cytokines, such as interleukin-1 (IL-1) and IL-6, and diffusible substances such as nitric oxide (NO) have been reported in astrocytes (see Ref. 587), and these substances appear to alter LHRH release. Because several excellent reviews are available on this topic (588, 589, 590, 591, 592, 593), in this article we will only summarize the recent findings.

Expression of TGF mRNA in astrocytes increases with normal puberty as well as precocious puberty induced by hypothalamic lesions in female rats (594, 595). These authors speculate that lesions of the POA-hypothalamus induce astrogliosis, which is responsible for the increase in TGF in the hypothalamus. TGF also stimulates LHRH release and increases glial secretion of PGE₂ (596), which, in turn, mediates the stimulatory effect of NE on LHRH release, as discussed above. Cultured hypothalamic astrocytes treated with estradiol yield a conditioned medium that stimulates the production of PGE₂ receptors on GT1 cells, although there appear to be factors other than astrocytes, as yet unidentified, that enhance LHRH release (597), because the astrocyte-conditioned medium is more effective in inducing LHRH release than simply the addition of PGE₂ to the medium (598). EGF receptors have been shown to mediate the effects of TGF, and EGF receptor mRNA and EGF protein expression appear to decrease before the first preovulatory LHRH surge, indicating a possible role for EGF in the onset of puberty (599). Similarly, TGFß derived from astroglia stimulates LHRH mRNA levels and release from GT1 cells (600, 601). Because astroglia contain LHRH-degrading enzymes as well as a 5-reductase (601), it is possible that they may play a role in mediating steroid action on LHRH release (602).

bFGF is a potent mitogen and neurotropic factor for hypothalamic neurons (594, 603, 604) as well as for GT1 cells stimulating LHRH release (605) in vitro. bFGF alters the secretion of LHRH from GT1 cells by inducing the secretion of intermediate products from the posttranslational processing of LHRH rather than the completely processed decapeptide (606). bFGF mRNA levels in the MBH, but not in the cerebral cortex, significantly decrease with puberty (first ovulation) induced by NMDA or PMSG in female rats, whereas bFGF receptor mRNA levels in the MBH and cortex show no change (607). Further, the number of bFGF-positive cells in the arcuate nucleus is significantly higher in NMDA-treated rats at P29 before puberty as compared with saline-treated controls at the same age, and the number of bFGF-positive cells is significantly lower in NMDA-treated rats at P33 after first ovulation as compared with saline-treated controls at P33 (607).

It is possible that glia also may play a role in the onset of puberty in rhesus monkeys. TGF mRNA in the monkey hypothalamus increases with puberty (608). A larger area of glial ensheathment is present on the perikaryal membrane of LHRH neurons in early pubertal monkeys than in adult monkeys (56). However, additional information is needed to establish the critical involvement of glia in the mechanism of puberty, because it is uncertain whether gliosis occurs in the primate hypothalamus before the onset of spontaneous puberty, and because the anatomical difference seen in prepubertal and adult monkeys could be due to the difference in circulating gonadal steroids, as a similar anatomical difference was observed in gonadectomized monkeys vs. gonadal intact monkeys (579). In addition, the importance of region-specific neuronal networks is not accounted for in the glia hypothesis of puberty. Lesions in two different regions of the hypothalamus induce similar massive gliosis, yet the effects on the timing of puberty are completely different. For instance, lesions in the posterior hypothalamus-premamillary area result in precocious puberty (83, 609), whereas lesions of an area that includes the posterior median eminence and arcuate nucleus delay puberty, even though the LHRH neurosecretory system is spared (610).

Using NLT cell line cells carrying a human LHRH transcript (611), Radovick and colleagues (612) report that LHRH neurons contain IGF-I receptors, and that IGF-I is capable of regulating LHRH mRNA expression directly through the AP-1 transcription factor. Thus, it is plausible that the pubertal increase in IGF-I may directly alter activity of the LHRH neurons, and this mechanism may contribute to the pubertal increase in LHRH release, although it is doubtful that IGF-I plays a role in triggering the onset of puberty.

D. Nutritional and metabolic factors
The timing of puberty is influenced by some metabolic cues. For example, in many species 1) puberty usually occurs at a time when the body is reaching adult proportions; 2) undernutrition can delay the onset of puberty; and 3) chronic undernutrition can cause the adult reproductive axis to return to the prepubertal state (see Ref. 613). Nutritional status, especially energy availability caused by low energy intake or high energy expenditure, has long been known to affect reproductive function (614). Interference with glucose metabolism, whether via food restriction or antagonism of glycolysis, suppresses LH release in adult as well as in sexually immature animals of a variety of species (615, 616, 617, 618, 619, 620). However, little is known about how nutritional status determines the timing of puberty. Because several excellent reviews are available on this subject (545, 614, 621, 622, 623, 624), we will briefly highlight recent key findings.

A series of studies by Cameron and colleagues (614, 625) suggest that in primates there is a dynamic mechanism, sensitive to energy availability, for the control of reproductive function and puberty. Specifically, in male monkeys, missing a single meal results in a suppression of LH and testosterone secretion within the first 4 h, and refeeding immediately restores normal hormone secretions. However, metabolic signals to the hypothalamo-pituitary-gonadal axis are not mediated by circulating hormones such as insulin, cortisol, adrenal corticosterone-stimulating hormone, and endogenous opioids to the hypothalamus (614, 626, 627, 628, 629). They are rather mediated by neuronal input through the nucleus of the solitary tract in the brainstem (614, 630, 631). Further, metabolic signals such as the glucoprivic suppression of LH pulses are mediated by the paraventricular nucleus via NE neurons (620). NE in the paraventricular nucleus increases after injection of the glycolysis inhibitor, 2-deoxyglucose, concomitant with decreases in LH concentrations, whereas injection of the NE synthesis inhibitor -methyl-p-tyrosine prevents these changes (620). Although additional information is required, LHRH neurons are directly or indirectly affected by poor nutrition. Distribution of LHRH neurons in the hypothalamus of food-restricted prepubertal female lambs is different from the distribution of LHRH neurons seen in control females, and the distribution of neurons in the food-restricted lambs more closely resembles that of fetal lambs, while the distribution of neurons in the control lambs is similar to that seen in adult sheep (632).

Recently, it has been suggested that leptin, a peptide synthesized in adipose tissue and secreted into the general circulation, is a key metabolic mediator for the reproductive neuroendocrine axis. Because extensive reviews on the role of leptin in reproduction as well as in puberty are available (633, 634, 635, 636, 637), we will only discuss this topic briefly. Circulating leptin concentration increases and leptin binding activity decreases with puberty (638, 639, 640, 641). Further, leptin induces precocious puberty in mice (642, 643) and prevents the delay in the onset of puberty in underfed female rats (644, 645). Leptin in food-deprived male rhesus monkeys stimulates an increase in LH pulse frequency, amplitude, and mean concentrations (646), indicating that leptin may provide information to the brain about nutritional status. The effect of leptin on LHRH release is indirect through other neurons, as no leptin receptor mRNA is found in LHRH neurons, but it is found in NPY and POMC neurons (646). Since both leptin mRNA and protein are present in neurons in the hypothalamus of rats (647), it is possible that neuronally derived leptin, in addition to transported leptin from peripheral tissues, plays a role in leptin-induced changes in LHRH secretion. Nonetheless, there are a large number of reports indicating that leptin concentration does not change with puberty in monkeys and humans (Refs. 648, 649, 650, 651 , and E. Terasawa, unpublished data), and the timing of puberty is not altered in patients with leptin deficiency who received recombinant leptin (652). Therefore, leptin is an important peripheral signal for the brain, but it may not be critical for the timing of puberty.

In this article we did not discuss the interaction between the pubertal activation of LHRH neurons and somatic growth, which is controlled by GH, and hypothalamic neuropeptides, including GH-releasing hormone (GHRH) and somatostatin. This is due to the complexity of these two systems and also to a relatively unexplored area of research on the control of GH secretion at the onset of puberty.

	VI. Master Gene(s) Controlling the Onset of Puberty

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
The age of puberty is specific to each species during its life span. Further, many genes in the brain are turned on or turned off to establish a complex series of events occurring during puberty. Therefore, it is not unreasonable to propose the hypothesis that a master gene determines the timing of puberty. It is also possible that multiple master genes could be involved in the mechanism of the onset of puberty, or perhaps body clock genes involved in events during the entire life span determine the timing of puberty. Although causes of human clinical cases of precocious or delayed puberty are largely heterogeneous (1, 2), and it may not be feasible to pinpoint the presence of master gene(s) at the present time, evidence to support this concept is just emerging in rodent studies. In light of the tantalizing possibility that a master gene(s) may control puberty, a brief summary of current findings is described below.

A recent study by Ojeda and colleagues (653) suggests that at least the Oct-2 POU domain gene is involved in puberty. Because Oct-2, a POU-II class protein (654), is expressed in the postnatal brain, especially unique in the hypothalamus (654), these authors (653) have examined its role in puberty. Results are summarized thus: 1) three alternatively spliced forms of the Oct-2 gene, Oct-2a, Oct-2b, and Oct-2c, are found in the rat hypothalamus after lesions of the anterior hypothalamus, known to result in precocious puberty; 2) the time course of changes in mRNA levels of each variant after the anterior hypothalamic lesion differs, with expression of Oct-2a mRNA levels being maximal at 8 h after the lesion, Oct-2c transcripts transiently increasing between 48–72 h, and Oct-2b mRNA levels only changing 4–5 days after the lesion; 3) anterior hypothalamic lesion-induced astroglia coexpress both TGFa and Oct-2 proteins; 4) an increase in Oct-2a mRNA levels occurs during the early phase of the onset of puberty, whereas an increase in Oct-2c mRNA levels occurs coinciding with the first LH surge; and 5) infusion of an antisense oligodeoxynucleotide for Oct-2 delays the timing of puberty in female rats. Because the TGF promoter contains an octamer-like motif and a (OCTA-) TAATGARAT motif, the authors speculate that Oct-2a and Oct-2c may trans-activate TGF transcription, leading to puberty. It is possible that Oct-1 and Tst-1/SCIP, POU-II and POU-III class proteins, respectively (654), may be involved in the mechanism of the onset of puberty, since Oct-1 activates the neuron-specific enhancer of the LHRH gene (655), Tst-1/SCIP represses transcriptional activity of the LHRH gene (656), and both mRNAs are present in the adult brain (654). While the results of these studies are exciting and have provided a novel concept on the mechanism of pubertal development, several caveats should be kept in mind. The studies were conducted in rats, in which the mechanism of the onset of puberty differs from that in primates. The results are inconclusive, and these homeobox genes are not necessarily master genes, and further upstream gene(s) may be present. Nonetheless, the search for a master gene(s) that controls the timing of puberty will be a major task in the new century.

	VII. Summary and Conclusions

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 
A summary of the possible mechanism of the onset of puberty in primates is illustrated in Fig. 3. The LHRH pulse-generating system is reasonably mature at birth and is already active during the neonatal period. However, in primates "central inhibition" suppresses pulsatile LHRH release during the juvenile period, whereas central inhibition is not apparent in nonprimates. When approaching puberty, in primates this central inhibition is removed or diminished, and an increase in LHRH release occurs, whereas in nonprimates disinhibition may not be critical for a developmental increase in LHRH release. This pubertal increase in LHRH release results in a cascade of events during puberty, such as increases in synthesis and release of gonadotropins, and increases in steroidogenesis and gametogenesis, followed by the appearance of secondary sexual characteristics. The nature of the central inhibition and neural substrates responsible for central inhibition in primates are still unclear. Recent studies from our laboratory suggest that disinhibition of LHRH neurons from GABA appears to be a critical factor in female rhesus monkeys, although other neural substrates, such as NPY, could be involved in this central inhibition. After the central inhibition is removed, however, increases in stimulatory input from glutamatergic neurons as well as new stimulatory input from NE and NPY neurons and inhibitory input from ß-END neurons to the LHRH neuronal system appear to occur, until the adult type of regulatory mechanism for pulsatile LHRH release is established. Understanding the mechanism of the onset of puberty in detail is very important, because many neurological disorders in humans stem from the changes that occur during the pubertal period. Nonetheless, the most important question still remains: What determines the timing to remove central inhibition? Because many genes in the brain are turned on or turned off to establish a complex series of events occurring during puberty, the timing of spontaneous puberty must be regulated by a master gene or genes, as a part of developmental events. We expect that future studies will include a search for genes determining events to remove central inhibition and master genes that ultimately trigger the onset of puberty in primates.

View larger version (131K): [in this window] [in a new window]   Figure 3. Current understanding of the mechanism of the onset of puberty in nonhuman primates is schematically illustrated in this figure. Predominant GABAergic inhibition on LHRH neurons through GABAA receptors appears to keep LHRH release low in prepubertal monkeys. During the prepubertal stage, GABA release is elevated in the S-ME, because of elevated GABA synthesis and less active GABA transporter (GAT). GABA inhibition on LHRH neurons may be direct or indirect through glutamatergic neurons. At the onset of puberty, decreases in GABA release and an increase in GAT activity in the S-ME result in the dominant state of glutamatergic neurons. Thus, the reduction in GABA and the increase in glutamate induce the pubertal increase in LHRH release, which triggers a cascade of events at puberty, i.e., an increase in gonadotropin secretion, followed by an increase in gonadal steroids, which results in the appearance of secondary sex characteristics. As puberty progresses, other neurotransmitter systems, such as the stimulatory NPY and NE neuronal systems, and the inhibitory opioid neuronal systems participate in the control of LHRH release. During this period, ovarian steroids are also involved in the establishment of the adult type of pulsatile LHRH release. A possible role of glia in puberty is also illustrated (see details in text).

	Acknowledgments

 
The authors thank Kim Keen for her assistance in completing this article, including compiling the references.

	Footnotes

 
Address reprint requests to: Ei Terasawa, Ph.D., Wisconsin Regional Primate Research Center, 1223 Capitol Court, Madison, Wisconsin 53715-1299. E-mail: terasawa{at}primate.wisc.edu

¹ This study (publication number 39–007 from the Wisconsin Regional Primate Research Center) was supported by NIH Grants HD-15433, HD-11533, AG-14972, and RR-00167.

² Present address: California State Polytechnic University, Department of Animal and Veterinary Sciences, Pomona, California 91768.

	References

Top Abstract I. Introduction II. Description of Puberty III. When Does the... IV. What Determines the... V. Neurobiology of Puberty VI. Master Gene(s) Controlling... VII. Summary and Conclusions References

 

1. Grumbach MM 1975 Onset of puberty. In: Berenberg SR (ed) Puberty, Biologic and Social Components. Stenfert Kroese, Leiden, Germany, pp 1–21
2. Grumbach MM, Styne DM 1998 Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds) Williams Textbook of Endocrinology. WB Saunders Co, Philadelphia, pp 1509–1625
3. Plant TM 1994 Puberty in primates. In: Knobil E, Neill JD (eds) The Physiology of Reproduction. Raven Press Ltd, New York, pp 453–485
4. Ojeda SR, Urbanski HF 1994 Puberty in the rat. In: Knobil E, Neill JD (eds) The Physiology of Reproduction. Raven Press Ltd, New York, pp 363–409
5. Foster DL 1994 Puberty in the sheep. In: Knobil E, Neill JD (eds) The Physiology of Reproduction. Raven Press Ltd, New York, pp 411–451
6. Styne DM 1994 Physiology of puberty. Hormone Res 41 [Suppl 2]:3–6
7. Lewis DA 1997 Development of the prefrontal cortex during adolescence-insights into vulnerable neural circuits in schizophrenia. Neuropsycopharmacology 16:385–398[CrossRef][Medline]
8. Lennox WG, Lennox MA 1960 Epilepsy and Related Disorders. Little, Brown and Co, Boston
9. Elian M 1970 EEG, epilepsy and precocious puberty. Electroencephalogr Clin Neurophysiol 28:642[CrossRef]
10. Appleton R, Gibbs J 1998 Epilepsy in Childhood and Adolescence. Martin Dunitz Publishers, London
11. Marshall JC, Eagleson CA 1999 Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin North Am 28:295–324[CrossRef][Medline]
12. Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J 1983 A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N Engl J Med 309:1206–1209[Abstract]
13. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapker MV, Koch GG, Hasemeier CM 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatrics research in office setting network. Pediatrics 99:505–512[Abstract/Free Full Text]
14. Tanner JM, Davies PS 1985 Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 107:317–329[CrossRef][Medline]
15. Cutler Jr GB, Schiebinger RJ, Albertson BD, Cassorla FG, Chrousos GP, Comite F, Booth JD, Levine J, Hobson WC, Loriaux DL 1990 The adrenarche (human and animal). In: Grumbach MM, Sizonenko PC, Aubert ML (eds) Control of the Onset of Puberty. Williams & Wilkins, Baltimore, pp 506–533
16. Tanner JM 1962 Growth at Adolescence. Blackwell Scientific Publications, Oxford, UK
17. Marshall WA 1974 Interrelationships of skeletal maturation, sexual development and somatic growth in man. Ann Hum Biol 1:29–40
18. Terasawa E, Nass TE, Yeoman RR, Loose MD, Schultz NJ 1983 Hypothalamic control of puberty. In: Norman RL (ed) Neuroendocrine Aspects of Reproduction. Academic Press, New York, pp 149–182
19. Rowell TE 1977 Variation in age at puberty in monkeys. Folia Primatol (Basel) 27:284–296[Medline]
20. Foster DL, Rapisarda JJ, Bergman KS, Lemons JA, Jaffee RB, Steiner RA, Wolf RC 1983 Mechanisms limiting initiation of ovulation in the postmenarchial rhesus macaque. In: Norman RL (ed) Neuroendocrine Aspects of Reproduction. Academic Press, New York, pp 103–132
21. Wilson ME, Gordon TP, Blank MS, Collins DC 1984 Timing of sexual maturity in female rhesus monkeys (Macaca mulatta) housed outdoors. J Reprod Fertil 70:625–633[Abstract/Free Full Text]
22. Wilson ME, Gordon TP, Collins DC 1986 Ontogeny of luteinizing hormone secretion and first ovulation in seasonal breeding rhesus monkeys. Endocrinology 118:293–301[Abstract/Free Full Text]
23. Schwanzel-Fukuda M, Pfaff DW 1989 Origin of luteinizing hormone-releasing hormone neurons. Nature 338:161–164[CrossRef][Medline]
24. Wray S, Grant P, Gainer H 1989 Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci USA 86:8132–8136[Abstract/Free Full Text]
25. Ronnekleiv OK, Resko JA 1990 Ontogeny of gonadotropinreleasing hormone-containing neurons in early fetal development of rhesus macaques. Endocrinology 126:498–511[Abstract/Free Full Text]
26. Quanbeck C, Sherwood NM, Millar RP, Terasawa E 1997 Two populations of luteinizing hormone-releasing hormone neurons in the forebrain of the rhesus macaque during embryonic development. J Comp Neurol 380:293–309[CrossRef][Medline]
27. Schwanzel-Fukuda M, Crossin KL, Pfaff DW, Bouloux PM, Hardelin JP, Petit C 1996 Migration of luteinizing hormone-releasing hormone (LHRH) neurons in early human embryos. J Comp Neurol 366:547–557[CrossRef][Medline]
28. Terasawa E, Quanbeck CD, Schulz CA, Burich AJ, Luchansky LL, Claude P 1993 A primary cell culture system of luteinizing hormone releasing hormone neurons derived from embryonic olfactory placode in the rhesus monkey. Endocrinology 133:2379–2390[Abstract/Free Full Text]
29. Terasawa E, Sherwood NM, Millar RP, Jennes L, Glucksman MJThe presence of a luteinizing hormone-releasing hormone (LHRH) fragment in the fetal monkey forebrain. Program of the 79th Annual Meeting of The Endocrine Society, 1997, Minneapolis, MN (Abstract 383)
30. Resko JA, Ellinwood WE, Pasztor LM, Huhl AE 1980 Sex steroids in the umbilical circulation of fetal rhesus monkeys from the time of gonadal differentiation. J Clin Endocrinol Metab 50:900–905[Abstract/Free Full Text]
31. Resko JA, Ellinwood EE 1985 Negative feedback regulation of gonadotropin secretion by androgens in fetal rhesus macaques. Biol Reprod 3:346–352
32. Grumbach MM, Kaplan SL 1990 The neuroendocrinology of human puberty: an ontogenetic perspective. In: Grumbach MM, Sizonenko PC, Aubert ML (eds) Control of the Onset of Puberty. William & Wilkins, Baltimore, pp 1–48
33. Verney C, el Amraoui A, Zecevic N 1996 Comigration of tyrosine hydroxylase- and gonadotropin-releasing hormone-immunoreactive neurons in the nasal area of human embryos. Brain Res Dev Brain Res 97:251–259[CrossRef][Medline]
34. Grumbach MM, Roth JC, Kaplan SL, Kelch RP 1974 Hypothalamic-pituitary regulation of puberty in man: evidence and concepts derived from clinical research. In: Grumbach MM, Grave GD, Mayer FE (eds) Control of the Onset of Puberty. John Wiley & Sons, New York, pp 115–166
35. Kaplan SL, Grumbach MM, Aubert ML 1976 The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent Prog Horm Res 32:161–243
36. Kaplan SL, Grumbach MM 1978 Pituitary and placental gonadotrophins and sex steroids in the human and sub-human primate fetus. Clin Endocrinol Metab 7:487–511[CrossRef][Medline]
37. Clements JA, Reyes FI, Winter JS, Faiman C 1976 Studies on human sexual development. III. Fetal pituitary and serum, and amniotic fluid concentrations of LH, CG, and FSH. J Clin Endocrinol Metab 42:9–19[Abstract/Free Full Text]
38. Grumbach MM 1978 The central nervous system and the onset of puberty. In: Falkner F, Tanner JM (eds) Human Growth. Plenum, New York, pp 215–238
39. Mueller PL, Sklar CA, Gluckman PD, Kaplan SL, Grumbach MM 1981 Hormone ontogeny in the ovine fetus. IX. Luteinizing hormone and follicle-stimulating hormone response to luteinizing hormone-releasing factor in mid- and late gestation and in the neonate. Endocrinology 108:881–886[Abstract/Free Full Text]
40. Matwijiw I, Faiman C 1987 Control of gonadotropin secretion in the ovine fetus: the effects of a specific gonadotropin-releasing hormone antagonist on pulsatile luteinizing hormone secretion. Endocrinology 121:347–351[Abstract/Free Full Text]
41. Dumesic DA, Castillo RH, Bridson WE 1991 Increase in follicle stimulating hormone content occurs in cultured human fetal pituitary cells exposed to gonadotropin-releasing hormone. Life Sci 48:1115–1122[CrossRef][Medline]
42. Castillo RH, Matteri RL, Dumesic DA 1992 Luteinizing hormone synthesis in cultured fetal human pituitary cells exposed to gonadotropin-releasing hormone. J Clin Endocrinol Metab 75:318–322[Abstract]
43. Matwijiw I, Faiman C 1989 Control of gonadotropin secretion in the ovine fetus. II. A sex difference in pulsatile luteinizing hormone secretion after castration. Endocrinology 124:1352–1358[Abstract/Free Full Text]
44. Winter JS, Faiman C, Reyes FI 1977 Sex steroid production by the human fetus: its role in morphogenesis and control by gonadotropins. Birth Defects 13:41–58
45. Mesiano S, Hart CS, Heyer BW, Kaplan SL, Grumbach MM 1991 Hormone ontogeny in the ovine fetus. XXVI. A sex difference in the effect of castration of the hypothalamic-pituitary gonadotropin unit in the ovine fetus. Endocrinology 129:3073–3079[Abstract/Free Full Text]
46. Wray S, Hoffman G 1986 Postnatal morphological changes in rat LHRH neurons correlated with sexual maturation. Neuroendocrinology 43:93–97[Medline]
47. Dutlow CM, Rachman J, Jacobs TW, Millar RP 1992 Prepubertal increases in gonadotropin-releasing hormone mRNA, gonadotropin-releasing hormone precursor, and subsequent maturation of precursor processing in male rats. J Clin Invest 90:2496–2501
48. Jakubowski M, Blum M, Roberts JL 1991 Postnatal development of gonadotropin-releasing hormone and cyclophilin gene expression in the female and male rat brain. Endocrinology 128:2702–2708[Abstract/Free Full Text]
49. Gore AC, Wu TJ, Rosenberg JJ, Roberts JL 1996 Gonadotropin-releasing hormone and NMDA receptor gene expression and colocalization change during puberty in female rats. J Neurosci 16:5281–5289,[Abstract/Free Full Text]
50. Gore AC 1998 Diurnal rhythmicity of gonadotropin-releasing hormone gene expression in the rat. Neuroendocrinology 68:257–263[CrossRef][Medline]
51. Gore AC, Roberts JL, Gibson MJ 1999 Mechanisms for the regulation of gonadotropin-releasing hormone gene expression in the developing mouse. Endocrinology 140:2280–2287[Abstract/Free Full Text]
52. Goldsmith PC, Lambert R, Berizina LR 1983 Gonadotropin-releasing hormone neurons and pathways in the primate hypothalamus and forebrain. In: Norman RL (ed) Neuroendocrine Aspects of Reproduction. Academic Press, New York, pp 7–45
53. Cameron JL, McNeill TJ, Fraser HM, Bremmer WJ, Clifton DK, Steiner RA 1985 The role of endogenous gonadotropin-releasing hormone neurons in the control of luteinizing hormone and testosterone secretion in the juvenile male monkey, Macaca fascicularis. Biol Reprod 33:147–156[Abstract]
54. Vician L, Adams LA, Clifton OK, Steiner RA 1991 Pubertal changes in proopiomelanocortin and gonadotropin-releasing hormone gene expression in the brain of the male monkey. Mol Cell Neurosci 2:31–38
55. Claypool LE, Watanabe G, Terasawa E 1990 Effects of electrical stimulation of medial basal hypothalamus on the in vivo release of luteinizing hormone-releasing hormone in the prepubertal and peripubertal monkey. Endocrinology 127:3014–3022[Abstract/Free Full Text]
56. Witkin JW, O’Sullivan H, Millar R, Ferin M 1997 GnRH perikarya in medial basal hypothalamus of pubertal female rhesus macaque are ensheathed with glia. J Neuroendocrinol 9:881–885[CrossRef][Medline]
57. Perera AD, Plant TM 1997 Ultrastructural studies of neuronal correlates of the pubertal reaugmentation of hypothalamic gonadotropin-releasing hormone (GnRH) release in the rhesus monkey. J Comp Neurol 385:71–82[CrossRef][Medline]
58. Corbier P, Dehennin M, Castanier A, Mebazaa A, Edwards DA, Roffi J 1990 Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J Clin Endocrinol Metab 71:1344–1348[Abstract/Free Full Text]
59. Faiman C, Winter JSD 1974 Gonadotropins and sex hormone patterns in puberty: clinical data. In: Grumbach MM, Grave GD, Mayer FE (eds) The Control of the Onset of Puberty. Wiley and Sons, New York, pp 32–54
60. Winter JS, Faiman C, Hobson WC, Prasad AV, Reyes FI 1975 Pituitary-gonadal relations in infancy. 1. Patterns of serum gonadotropin concentrations from birth to four years of age in man and chimpanzee. J Clin Endocrinol Metab 40:545–551[Abstract/Free Full Text]
61. Andersson AM, Toppari J, Haavisto AM, Petersen JH, Simell T, Simell O, Skakkebaek NE 1998 Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men. J Clin Endocrinol Metab 83:675–681[Abstract/Free Full Text]
62. Conte FA, Grumbach MM, Kaplan SL 1975 A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 40:670–674[Abstract/Free Full Text]
63. Ross JL, Loriaux DL, Cutler Jr GB 1983 Developmental changes in neuroendocrine regulation of gonadotropin secretion in gonadal dysgenesis. J Clin Endocrinol Metab 57:288–293[Abstract/Free Full Text]
64. Frawley LS, Neill JD 1979 Age related changes in serum levels of gonadotropins and testosterone in infantile male rhesus monkeys. Biol Reprod 20:1147–1151[Abstract]
65. Robinson JA, Bridson WE 1978 Neonatal hormone patterns in the macaque. I. Steroids. Biol Reprod 19:773–778[Abstract]
66. Plant TM 1982 Pulsatile luteinizing hormone secretion in the neonatal male rhesus monkey (Macaca mulatta). J Endocrinol 93:71–74[Abstract/Free Full Text]
67. Plant TM 1982 A striking diurnal variation in plasma testosterone concentrations in infantile male rhesus monkeys (Macaca mulatta). Neuroendocrinology 35:370–373[Medline]
68. Plant TM 1988 Neuroendocrine basis of puberty in the rhesus monkey (Macaca mulatta). In: Martini L, Ganong WF (eds) Frontiers in Neuroendocrinology. Raven Press Ltd, New York, pp 215–238
69. Steiner RA, Bremner WJ 1981 Endocrine correlates of sexual development in the male monkey, Macaca fascicularis. Endocrinology 109:914–919[Abstract/Free Full Text]
70. Plant TM 1985 A study of the role of the postnatal testes in determining the ontogeny of gonadotropin secretion in the male rhesus monkey (Macaca mulatta). Endocrinology 116:1341–1350[Abstract/Free Full Text]
71. Plant TM 1986 A striking sex difference in the gonadotropin release to gonadectomy during infantile development in the rhesus monkey (Macaca mulatta). Endocrinology 119:539–545[Abstract/Free Full Text]
72. Terasawa E, Bridson WE, Nass TE, Noonan JJ, Dierschke DJ 1984 Developmental changes in the LH secretory pattern in peripubertal female rhesus monkeys: comparisons between gonadally intact and ovariectomized animals. Endocrinology 115:2233–2240[Abstract/Free Full Text]
73. Boyar RM, Finkelstein JW, Roffwarg H, Kapen S, Weitzman ED, Hellman L 1972 Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med 287:582–586
74. Boyar RM, Finkelstein JW, Roffwarg H, Kapen S, Weitzman D, Hellman L 1973 Twenty-four-hour luteinizing hormone and follicle-stimulating hormone secretory patterns in gonadal dysgenesis. J Clin Endocrinol Metab 37:521–525[Abstract/Free Full Text]
75. Judd HL, Parker DC, Siler TM, Yen SS 1974 The nocturnal rise of plasma testosterone in pubertal boys. J Clin Endocrinol Metab 38:710–713[Abstract/Free Full Text]
76. Jakacki RI, Kelch RP, Sauder SE, Lloyd JS, Hopwood NJ, Marshall JC 1982 Pulsatile secretion of luteinizing hormone in children. J Clin Endocrinol Metab 55:453–458[Abstract/Free Full Text]
77. Wu FCW, Butler GE, Kelnar CJH, Stirling HF, Huhtaniemi I 1991 Patterns of pulsatile luteinizing and follicle stimulating hormone secretion in prepubertal (midchildhood) boys and girls and patients with idiopathic hypogonadotrophic hypogonadism (Kallmann’s syndrome): a study using an ultrasensitive time-resolved immunofluorometric assay. J Clin Endocrinol Metab 72:1229–1237[Abstract/Free Full Text]
78. Wu FCW 1995 GnRH pulse generator activity during human puberty. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 185–197
79. Manasco PK, Umbach DM, Muly SM, Godwin DC, Negro-Vilar A, Culler MD, Underwood LE 1997 Ontogeny of gonadotrophin and inhibin secretion in normal girls through puberty based on overnight serial sampling and a comparison with normal boys. Hum Reprod 12:2108–2114[Abstract/Free Full Text]
80. Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A 1999 Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, and testosterone secretion before the onset of male puberty. J Clin Endorinol Metab 84:29–37[Abstract/Free Full Text]
81. Wennick JMB, Delemarre Van-Der Waal HA, Schoemaker R, Schoemaker H, Schoemaker J 1989 Luteinizing hormone and follicle stimulating hormone secretion patterns in boys throughout puberty measured using highly sensitive immunoradiometric assays. Clin Endocrinol (Oxf) 31:551–564[Medline]
82. Wennick JMB, Delemarre Van-Der Waal HA, Schoemaker R, Schoemaker H, Schoemaker J 1990 Luteinizing hormone and follicle stimulating hormone secretion patterns in girls throughout puberty measured using highly sensitive immunoradiometric assays. Clin Endocrinol (Oxf) 33:333–344[Medline]
83. Terasawa E, Noonan JJ, Nass TE, Loose MD 1984 Posterior hypothalamic lesions advance the onset of puberty in the female rhesus monkey. Endocrinology 115:2241–2250[Abstract/Free Full Text]
84. Watanabe G, Terasawa E 1989 In vivo release of luteinizing hormone-releasing hormone (LHRH) increases with puberty in the female rhesus monkey. Endocrinology 125:92–99[Abstract/Free Full Text]
85. Chongthammakun S, Claypool LE, Terasawa E 1993 Ovariectomy increases in vivo LHRH release in pubertal, but not prepubertal, female rhesus monkeys. J Neuroendocrinol 5:41–50[CrossRef][Medline]
86. Caligaris L, Astrada JJ, Taleisnik S 1972 Influence of age on the release of luteinizing hormone induced by oestrogen and progesterone in immature rats. J Endocrinol 55:97–103[Abstract/Free Full Text]
87. Caligaris L, Astrada JJ, Taleisnik S 1973 Developments of the mechanisms involved in the facilitatory and inhibitory effects of ovarian steroids on the release of follicle stimulating hormone. J Endocrinol 58:547–554[Abstract/Free Full Text]
88. Kronibus J, Wuttke W 1977 Positive feedback action of oestradiol on gonadotrophin release in 15 day old female rats. Acta Endocrinol (Copenh) 86:263–272[Abstract/Free Full Text]
89. Nass TE, Terasawa E, Dierschke DJ 1980 Positive feedback development in immature female rats: possible inhibitory ovarian influence. Biol Reprod [Suppl 1] 22:86A (132)
90. McCormack CE, Meyer RK 1962 Ovulating hormone release in gonadotropin treated immature rats. Proc Soc Exp Biol Med 110:343–346[CrossRef]
91. McCormack CE, Meyer RK 1964 Minimal age for induction of ovulation with progesterone in rats: evidence for neural control. Endocrinology 74:793–799
92. Terasawa E, Timiras PS 1968 Diurnal variation in the effects of progesterone on multiple unit activity in the rat hypothalamus. Exp Neurol 27:359–374
93. Zarrow MX, Wilson ED 1961 The influence of age on superovulation in the immature rat and mouse. Endocrinology 69:851–855
94. Dierschke DJ, Weiss G, Knobil E 1974 Sexual maturation in the rhesus monkey and the development of estrogen-induced gonadotropic hormone release. Endocrinology 94:198–206[Abstract/Free Full Text]
95. Presl J, Horejsi J, Stroufova A, Herzmann J 1976 Sexual maturation in girls and the development of estrogen-induced gonadotropic hormone release. Am Biol Anim 16:377–383
96. Kulin HE 1980 The maturation of ovulatory potential in man. Horm Res 12:46–62[CrossRef][Medline]
97. Terasawa E 1985 Developmental changes in the positive feedback effect of estrogen in ovariectomized female rhesus monkeys. Endocrinology 117:2490–2497[Abstract/Free Full Text]
98. Foster DL, Karsch FJ 1975 Development of the mechanism regulating the preovulatory surge of luteinizing hormone in sheep. Endocrinology 97:1205–1209[Abstract/Free Full Text]
99. Chongthammakun S, Terasawa E Negative and positive feedback effect of estradiol on LHRH release occur in pubertal rhesus monkeys. Program and Abstracts of the 73rd Annual Meeting of The Endocrine Society, Washington, DC, 1991, p 38 (Abstract 33)
100. Karsch FJ 1987 Central actions of ovarian steroids in the feedback regulation of pulsatile secretion of luteinizing hormone. Annu Rev Physiol 49:365–382[CrossRef][Medline]
101. Evans NP, Dahl GE, Mauger DT, Padmanabhan V, Thrun LA, Karsch FJ 1995 Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system. Endocrinology 136:5511–5519[Abstract]
102. Evans NP, Dahl GE, Padmanabhan V, Thrun LA, Karsch FJ 1997 Estradiol requirements for induction and maintenance of the gonadotropin-releasing hormone surge: implications for neuroendocrine processing of the estradiol signal. Endocrinology 138:5408–5414[Abstract/Free Full Text]
103. Caraty A, Fabre-Nys C, Delaleu B, Locatelli A, Bruneau G, Karsch FJ, Herbison A 1998 Evidence that the mediobasal hypothalamus is the primary site of action of estradiol in inducing the preovulatory gonadotropin releasing hormone surge in the ewe. Endocrinology 139:1752–1760[Abstract/Free Full Text]
104. Knobil E 1980 The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53–88
105. Krey LC, Butler WR, Knobil E 1975 Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinology 96:1073–1087[Abstract/Free Full Text]
106. Hess DL, Wilkins RH, Moossy J, Chang JL, Plant TM, McCormack JT, Nakai Y, Knobil E 1977 Estrogen-induced gonadotropin surges in decerebrated female rhesus monkeys with medial basal hypothalamic peninsulae. Endocrinology 101:1264–1271[Abstract/Free Full Text]
107. Plant TM, Moossy J, Hess DL, Nakai Y, McCormack JT, Knobil E 1979 Further studies on the effects of lesions in the rostral hypothalamus on gonadotropin secretion in the female rhesus monkey (Macaca mulatta). Endocrinology 105:465–473[Abstract/Free Full Text]
108. Nakai Y, Plant TM, Hess DL, Keogh EJ, Knobil E 1978 On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102:1008–1014[Abstract/Free Full Text]
109. Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G 1980 Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science 207:1371–1373
110. Wildt L, Hutchison JS, Marshall G, Pohl CR, Knobil E 1981 On the site of action of progesterone in the blockade of the estradiol-induced gonadotropin discharge in the rhesus monkey. Endocrinology 109:1293–1294[Abstract/Free Full Text]
111. Ferin M, Rosenblatt H, Carmel PW, Antunes JL, Vande Wiele RL 1979 Estrogen-induced gonadotropin surges in female rhesus monkeys after pituitary stalk section. Endocrinology 104:50–52[Abstract/Free Full Text]
112. Norman RL, Gliessman P, Lindstrom SA, Hill J, Spies HG 1982 Reinitiation of ovulatory cycles in pituitary stalk-sectioned rhesus monkeys: evidence for a specific hypothalamic message for the preovulatory release of luteinizing hormone. Endocrinology 111:1874–1882[Abstract/Free Full Text]
113. Levine JE, Norman R L Gliessman P M Oyama TT, Bangsberg DR, Spies HG 1985 In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated rhesus macaques. Endocrinology 117:711–721[Abstract/Free Full Text]
114. Pau KY, Berria M, Hess DL, Spies HG 1993 Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. Endocrinology 133:1650–1656[Abstract/Free Full Text]
115. Xia L, Van Vugt D, Alston EJ, Luckhaus J, Ferin M 1992 A surge of gonadotropin-releasing hormone accompanies the estradiolinduced gonadotropin surge in the rhesus monkey. Endocrinology 131:2812–2820[Abstract/Free Full Text]
116. Deleted in proof
117. Dohrn M, Hohlweg W 1931 Hormonale beziehungen zwischen hypohysenvorderlappen und keimdrusen. In: Proceedings of the 2nd International Congress on Sex Research. Oliver and Boyd, Edinburgh, pp 436–442
118. Steele RE, Weisz J 1974 Changes in sensitivity of estradiol-LH feedback system with puberty in the female rat. Endocrinology 95:513–520[Abstract/Free Full Text]
119. Foster DL, Ryan KD 1979 Endocrine mechanisms governing transition into adulthood: a marked decrease in inhibitory feedback action of estradiol on tonic secretion of luteinizing hormone in the lamb during puberty. Endocrinology 105:896–904[Abstract/Free Full Text]
120. Andrews WW, Advis JP, Ojeda SR 1981 The maturation of estradiol-negative feedback in female rats: evidence that the resetting of the hypothalamic "gonadostat" does not precede the first preovulatory surge of gonadotropins. Endocrinology 109:2022–2031[Abstract/Free Full Text]
121. Rapisarda JJ, Bergman KS, Steiner RA, Foster DL 1983 Response to estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey. Endocrinology 112:1172–1179[Abstract/Free Full Text]
122. Wilson ME 1995 IGF-1 administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female monkeys. J Endocrinol 145:121–130[Abstract/Free Full Text]
123. Reiter EO, Grumbach MM 1982 Neuroendocrine control mechanisms and the onset of puberty. Annu Rev Physiol 44:595–613[CrossRef][Medline]
124. Plant TM 1986 Gonadal regulation of hypothalamic gonadotropin-releasing hormone release in primates. Endocr Rev 7:75–88[Abstract/Free Full Text]
125. Chongthammakun S, Terasawa E 1993 Negative feedback effects of estrogen on LHRH release occur in pubertal, but not prepubertal, ovariectomized female rhesus monkeys. Endocrinology 132:735–743[Abstract/Free Full Text]
126. Kulin HE, Grumbach MM, Kaplan SL 1969 Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man. Science 166:1012–1013[Abstract/Free Full Text]
127. Kelch RP, Kaplan SL, Grumbach MM 1973 Suppression of urinary and plasma follicle-stimulating hormone by exogenous estrogens in prepubertal and pubertal children. J Clin Invest 52:1122–1128
128. Terasawa E 1995 Control of luteinizing hormone-releasing hormone pulse generation in nonhuman primates. Cell Mol Neurobiol 15:141–164[CrossRef][Medline]
129. Wildt L, Marshall G, Knobil E 1980 Experimental induction of puberty in the infantile rhesus monkey. Science 207:1373–1375
130. Loose MD, Terasawa E 1985 Pulsatile infusion of LHRH induces precocious puberty (vaginal opening and first ovulation) in the immature female guinea pig. Biol Reprod 33:1084–1093[Abstract]
131. Sisk CL, Shah R, Levine JE Peripubertal patterns of in vivo LHRH release in female rats. Program and Abstracts of the 10th Annual Meeting of the International Congress of Endocrinology, San Francisco, CA, 1996, p 743 (Abstract OR63–3)
132. Plant TM, Gay VL, Marshall GR, Arslan M 1989 Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. Proc Natl Acad Sci USA 86:2506–2510[Abstract/Free Full Text]
133. Urbanski HF, Ojeda SR 1987 Activation of luteinizing hormone-releasing hormone release advances the onset of female puberty. Neuroendocrinology 46:273–276[Medline]
134. Smyth C, Wilkinson M 1994 A critical period for glutamate receptor-mediated induction of precocious puberty in female rats. J Neuroendocrinol 6:275–284[CrossRef][Medline]
135. Terasawa E 1995 Mechanisms controlling the onset of puberty in primates: the role of GABAergic neurons. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 139–151
136. Bourguignon J-P, Gérard A, Mathieu J, Mathieu A, Franchimont P 1990 Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at the onset of puberty. I. Increased activation of N-methyl-D-aspartate receptors. Endocrinology 127:873–881[Abstract/Free Full Text]
137. Matsumoto A, Arai Y 1976 developmental changes in synaptic formation in the hypothalamic arcuate nucleus of female rats. Cell Tissue Res 169:143–156[Medline]
138. Matsumoto A, Arai Y 1977 Precocious puberty and synaptogenesis in the hypothalamic arcuate nucleus in pregnant mare serum gonadotropin (PMSG) treated immature female rats. Brain Res 129:375–378[CrossRef][Medline]
139. Arai Y, Matsumoto A 1978 Synapse formation of the hypothalamic arcuate nucleus during postnatal development in the female rat and its modification by neonatal estrogen treatment. Psychoneuroendocrinology 3:31–45[CrossRef][Medline]
140. Clough RW, Rodriguez-Sierra JF 1983 Synaptic changes in the hypothalamus of the prepubertal female rat administered estrogen. Am J Anat 167:205–214[CrossRef][Medline]
141. Caley DW, Maxwell DS 1968 An electron microscopic study of neurons during postnatal development of the rat cerebral cortex. J Comp Neurol 133:17–44[CrossRef][Medline]
142. Caley DW, Maxwell DS 1968 An electron microscopic study of the neuroglia during postnatal development of the rat cerebrum. J Comp Neurol 133:45–70[CrossRef][Medline]
143. Woodward DJ, Hoffer BJ, Siggins GR, Bloom FE 1971 The ontogenetic development of synaptic junctions, synaptic activation and responsiveness to neurotransmitter substances in rat cerebellar Purkinje cells. Brain Res 34:73–97[CrossRef][Medline]
144. Parducz A, Perez J, Garcia-Segura LM 1993 Estradiol induces plasticity of GABAergic synapses in the hypothalamus. Neuroscience 53:395–401[CrossRef][Medline]
145. Lidow MS, Goldman-Rakic PS, Rakic P 1991 Synchronized overproduction of neurotransmitter receptors in diverse regions of the primate cerebral cortex. Proc Natl Acad Sci USA 88:10218–10221[Abstract/Free Full Text]
146. Rakic P, Bourgeois JP, Eckenhoff MF, Zecevic N, Goldman-Rakic PS 1986 Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232:232–235[Abstract/Free Full Text]
147. Eckenhoff MF, Rakic P 1991 A quantitative analysis of synaptogenesis in the molecular layer of the dentate gyrus in the rhesus monkey. Brain Res Dev Brain Res 64:129–135[CrossRef][Medline]
148. Zecevic N, Bourgeois J-P, Rakic P 1989 Changes in synaptic density on motor cortex of rhesus monkey during fetal and postnatal life. Brain Res Dev Brain Res 50:11–32[CrossRef][Medline]
149. Goldman-Rakic PS 1987 Development of cortical circuitry and cognitive function. Child Dev 58:601–622[CrossRef][Medline]
150. Zsarmovszky A, Horvath TL, Garcia-Segura LM, Horvath B, Naftolin F Plasticity of the hypothalamic GABA system and their relationship with GnRH neurons during positive gonadotropin feedback in non-human primates. Program and Abstracts of the 82nd Annual meeting of The Endocrine Society, Toronto, Ontario, Canada, 2000, p 267 (Abstract 1099)
151. Winter JS, Faiman C 1972 Serum gonadotropin concentrations in agonadal children and adults. J Clin Endocrinol Metab 35:561–564[Abstract/Free Full Text]
152. Goldstein A, Cox BM 1977 Opioid peptides (endorphins) in pituitary and brain. Psychoneuroendocrinology 2:11–16[CrossRef][Medline]
153. McKnight AT, Kosterlitz HW 1980 Opioid peptides and pituitary function. J Reprod Fertil 58:513–519[Abstract/Free Full Text]
154. Ferin M, Van Vugt D, Wardlaw S 1984 The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res 40:441–485
155. Kalra SP 1986 Neural circuitry involved in the control of LHRH secretion: a model for preovulatory LH release. In: Martini L, Ganong WR (eds) Frontiers in Neuroendocrinology. Raven Press, New York, vol 9:31–75
156. Kalra PS, Kalra SP 1986 Steroidal modulation of the regulatory neuropeptides: luteinizing hormone releasing hormone, neuropeptide Y and endogenous opioid peptides. J Steroid Biochem 25:733–740[CrossRef][Medline]
157. Howlett TA, Rees LH 1986 Endogenous opioid peptides and hypothalamo-pituitary function. Annu Rev Physiol 48:527–538[CrossRef][Medline]
158. Ferin M, Wehrenberg WB, Lam NY, Alston EJ, Vande Wiele RL 1982 Effects and site action of morphine on gonadotropin secretion in the female rhesus monkey. Endocrinology 111:1652–1656[Abstract/Free Full Text]
159. Mallory DS, Bona-Gallo A, Gallo RV 1989 Neurotransmitter involvement in naloxone-induced stimulation of pulsatile LH release on day 8 of pregnancy in the rat. Brain Res Bull 22:1015–1021[CrossRef][Medline]
160. Kesner JS, Kaufman JM, Wilson RC, Kuroda G, Knobil E 1986 The effect of morphine on the electrophysiological activity of the hypothalamic luteinizing hormone-releasing hormone pulse generator in the rhesus monkey. Neuroendocrinology 43:686–688[Medline]
161. Van Vugt DA, Lam NY, Ferin M 1984 Reduced frequency of pulsatile luteinizing hormone secretion in the luteal phase of the rhesus monkey. Involvement of endogenous opiates. Endocrinology 115:1095–1101[Abstract/Free Full Text]
162. Orstead KM, Hess DL, Spies HG 1987 Opiatergic inhibition of pulsatile luteinizing hormone release during the menstrual cycle of rhesus macaques. Proc Soc Exp Biol Med 184:312–319[CrossRef][Medline]
163. Devorshak-Harvey E, Bona-Gallo A, Gallo RV 1987 Endogenous opioid peptide regulation of pulsatile luteinizing hormone secretion during pregnancy in the rat. Neuroendocrinology 46:369–378[Medline]
164. Rossmanith WG, Mortola JF, Yen SS 1988 Role of endogenous opioid peptides in the initiation of the midcycle luteinizing hormone surge in normal cycling women. J Clin Endocrinol Metab 67:695–700[Abstract/Free Full Text]
165. Ji WZ, Kaynard AH, Pau KY, Hess DL, Baughman WL, Spies HG 1989 Endogenous opiates regulate the nocturnal reduction in luteinizing hormone pulse frequency during the luteal phase of the macaque menstrual cycle. Biol Reprod 41:1024–1033[Abstract]
166. Evans WS, Weltman ML, Johnson ML, Weltman A, Veldhuis JD, Rogol AD 1992 Effects of opioid receptor blockade on luteinizing hormone (LH) pulses and interpulse LH concentrations in normal women during the early phase of the menstrual cycle. J Endocrinol Invest 15:525–531[Medline]
167. Grosser PM, O’Byrne KT, Williams CL, Thalabard JC, Hotchkiss J, Knobil E 1993 Effects of naloxone on estrogen-induced changes in hypothalamic gonadotropin-releasing hormone pulse generator activity in the rhesus monkey. Neuroendocrinology 57:115–119[Medline]
168. Ebling FJ, Schwartz ML, Foster DL 1989 Endogenous opioid regulation of pulsatile luteinizing hormone secretion during sexual maturation in the female sheep. Endocrinology 125:369–383[Abstract/Free Full Text]
169. Ebling FJ, Foster DL 1989 Seasonal breeding - a model for puberty? In: Delemarre-Van de Waal HA, Plant TM, van Rees GP, Shoemaker J (eds) Control of the Onset of Puberty. Elsevier, Amsterdam, vol 3:253–264
170. Cutler L, Egli CA, Styne DM, Kaplan SL, Grumbach MM 1985 Hormone ontogeny in the ovine fetus. XVIII. The effect of an opioid antagonist on luteinizing hormone secretion. Endocrinology 116:1997–2002[Abstract/Free Full Text]
171. Wood RI, I’Anson H, Ebling FJ, Foster DL 1992 Opioid inhibition of luteinizing hormone secretion compared in developing male and female sheep. Neuroendocrinology 56:822–830[Medline]
172. Prasad BM, Conover CD, Sarkar DK, Rabii J, Advis J-P 1993 Feed restriction in prepubertal lambs: effect on puberty onset and on in vivo release of luteinizing hormone-releasing hormone, neuropeptide Y and ß-endorphin from the posterior-lateral median eminence. Neuroendocrinology 57:1171–1181[Medline]
173. Blank MS, Murphy JR 1991 Luteinizing hormone sensitivity to naloxone in maturing male chimpanzees. Brain Res Bull 27:241–245[CrossRef][Medline]
174. Petraglia F, Bernasconi S, Inghetti L, Loche S, Romanini F, Facchinetti F, Marcellini C, Genazzani AR 1986 Naloxone-induced luteinizing hormone secretion in normal, precocious, and delayed puberty. J Clin Endocrinol Metab 63:1112–1116[Abstract/Free Full Text]
175. Terasawa E, Chongthammakun S Developmental changes in in vivo release of ß-endorphin (ß-END) from the stalk-median eminence (S-ME) in female rhesus monkeys. Proceedings of the 21st Annual Meeting of the Society for Neuroscience, New Orleans, LA, 1991, vol 17:906 (Abstract 361.1)
176. Eckersell CB, Popper P, Micevych PE 1998 Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 18:3967–3976[Abstract/Free Full Text]
177. Quinones-Jenab V, Jenab S, Ogawa S, Inturrisi C, Pfaff DW 1997 Estrogen regulation of mu-opioid receptor mRNA in the forebrain of female rats. Brain Res Mol Brain Res 47:134–138[Medline]
178. Decavel C, van den Pol AN 1990 GABA: a dominant neurotransmitter in the hypothalamus. J Comp Neurol 302:1019–1037[CrossRef][Medline]
179. Rando RR, Bangerter FW, Farb DH 1981 The inactivation of -aminobutyric acid transaminase in dissociated neuronal cultures from spinal cord. J Neurochem 36:985–990[CrossRef][Medline]
180. Martin DL, Rimvall K 1993 Regulation of -aminobutyric acid synthesis in the brain. J Neurochem 60:395–407[Medline]
181. Rimvall K, Martin DL 1994 The level of GAD67 protein is highly sensitive to small increases in intraneuronal -aminobutyric acid levels. J Neurochem 62:1375–1381[Medline]
182. MacGeer PL, MaGeer EG 1989 Amino acid neurotranmitters. In: Siegel G, Agranoff B, Albers RW, Molinoff P (eds) Basic Neurochemistry. Raven Press, New York, pp 311–332
183. Erlander MG, Tobin AJ 1991 The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem Res 16:215–226[CrossRef][Medline]
184. Kaufman DL, Houser CR, Tobin AJ 1991 Two forms of the -aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem 56:720–723[CrossRef][Medline]
185. Sheikh SN, Martin SB, Martin DL 1999 Regional distribution and relative amounts of glutamate decarboxylase isoforms in rat and mouse brain. Neurochem Int 35:73–80[CrossRef][Medline]
186. Lin F-H, Lin S, Wang Y, Hosford DA 1999 Glutamate decarboxylase isoforms in thalamic nuclei in lethargic mouse model of absence seizures. Mol Brain Res 71:127–130[Medline]
187. Esclapez M, Tillakaratne JK, Kaufman DL, Tobin AJ, Houser CR 1994 Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14:1834–1855[Abstract]
188. Sheikh SN, Martin DL 1996 Heteromers of glutamate decarboxylase isoforms occur in rat cerebellum. J Neurochem 66:2082–2090[Medline]
189. Dirkx Jr R, Thomas A, Li L, Lernmark A, Sherwin RS, De Camilli P, Solimena M 1995 Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH₂-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. J Biol Chem 270:2241–2246[Abstract/Free Full Text]
190. Sloviter RS, Dichter MA, Rachinsky TL, Dean E, Goodman JH, Sollas AL, Martin DL 1996 Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol 373:593–618[CrossRef][Medline]
191. Tillakaratne NJ, Erlander MG, Collard MW, Greig KF, Tobin AJ 1992 Glutamate decarboxylases in nonneuronal cells of rat testis and oviduct: differential expression of GAD65 and GAD67. J Neurochem 58:618–627[CrossRef][Medline]
192. Karlsen AE, Hagopian WA, Grubin CE, Dube S, Disteche CM, Adler H, Barmeier S, Mathewes S, Grant F, Foster D 1991 Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci USA 88:8337–8341[Abstract/Free Full Text]
193. Michelson BK, Peterson JS, Boel E, Moldrup A, Dryberg T, Madsen OD 1991 Cloning, characterization, and autoimmune recognition of rat islet glutamic acid decarboxylase in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 88:8754–8758[Abstract/Free Full Text]
194. Lernmark A 1996 Glutamic acid decarboxylase-gene to antigen to disease. J Int Med 240:259–277[CrossRef][Medline]
195. Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI 1990 Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306[Abstract/Free Full Text]
196. Nelson H, Mandiyan S, Nelson N 1990 Cloning of the human brain GABA transporter. FEBS Lett 269:181–184[CrossRef][Medline]
197. Borden LA 1996 GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem Int 29:335–356[CrossRef][Medline]
198. Richards DA, Bowery NG 1996 Comparative effects of the GABA uptake inhibitors, tiagabine and NNC-711, on extracellular GABA levels in the rat ventrolateral thalamus. Neurochem Res 21:135–140[CrossRef][Medline]
199. Herbison AE, Augwood SJ, Simonian SX, Chapman C 1995 Regulation of GABA transporter activity and mRNA expression by estrogen in rat preoptic area. J Neurosci 15:8302–8309[Abstract]
199. Andrade da Costa BL, de Mello FG, Hokoc JN 2000 Transporter-mediated GABA release induced by excitatory amino acid agonist is associated with GAD-67 but not GAD-65 immunoreactive cells of the primate retina. Brain Res 863:132–142[CrossRef][Medline]
200. Barnard EA, Darlison MG, Seeburg P 1987 Molecular biology of the GABA_A receptor: the receptor/channel superfamily. Trends Neurosci 10:502–509[CrossRef]
201. Macdonald RL, Olsen RW 1994 GABA_A-receptor channels. Annu Rev Neurosci 17:569–602[Medline]
202. Rabow LE, Russek SJ, Farb DH 1995 From ion currents to genomic analysis: recent advances in GABA_A receptor research. Synapse 21:189–274[CrossRef][Medline]
203. Bormann J 1988 Electrophysiology of GABA_A and GABA_B receptor subtypes. Trends Neurosci 11:112–116[CrossRef][Medline]
204. Bowery N 1989 GABA_B receptors and their significance in mammalian pharmacology. Trends Pharmacol Sci 10:401–407[CrossRef][Medline]
205. Gee KW, Bolger MB, Brinton RE, Coirini A, McEwen BS 1988 Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action. J Pharmacol Exp Ther 246:803–812[Abstract/Free Full Text]
206. Puia G, Vicini S, Seeburg PH, Costa E 1991 Influence of recombinant -aminobutyric acid_A-receptor subunit composition on the action of allosteric modulators of -aminobutyric acid gated Cl^- currents. Mol Pharmacol 39:691–696[Abstract]
207. Pritchett DB, Luddens H, Seeburg PH 1989 Type I and type II GABA_A-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392[Abstract/Free Full Text]
208. Benke D, Mertens S, Trzeciak A, Gillessen D, Mohler H 1991 GABA_A receptors display association of 2-subunit with 1- and ß2/3-subunits. J Biol Chem 256:4478–4483[Abstract/Free Full Text]
209. Olsen RW, Tobin AJ 1990 Molecular biology of GABA_A-receptors. FASEB J 4:1469–1480[Abstract]
210. Wisden W, Seeberg PH 1992 GABA_A receptor channels: from subunits to functional entities. Curr Opin Neurobiol 2:263–269[CrossRef][Medline]
211. Wisden W, Laurie DJ, Monyer H, Seeberg PH 1992 The distribution of 13 GABA_A receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mensencephalon. J Neurosci 12:1040–1062[Abstract]
212. Tobin AJ, Brecha N, Chiang M-Y, Fundo S, Erlander MG, Feldblum S, Houser CR, Kaufman DL, Khrestchatistky M, Maclennan AJ, Olsen RW, Sternini C, Tillakaratne NJ 1992 Alternative forms of GAD and GABA_A receptors. In: Biggio G, Concas A, Costa E (eds) GABAergic Synaptic Transmission. Raven Press, New York, pp 55–66
213. Brooks-Kayal AR, Pritchett DB 1993 Developmental changes in human -aminobutyric acid A receptor subunit composition. Ann Neurol 34:687–693[CrossRef][Medline]
214. Hendrickson A, March D, Richards G, Erickson A, Shaw C 1994 Coincidental appearance of the 1 subunit of the GABA_A-receptor and the type I benzodiazepine receptor near birth in macaque monkey visual cortex. Int J Dev Neurosci 12:299–314[CrossRef][Medline]
215. Fritschy J-M, Paysan J, Enna A, Mohler H 1994 Switch in the expression of rat GABA_A-receptor subtypes during postnatal development: an immunohistochemical study. J Neurosci 14:5302–5324[Abstract]
216. Fritschy J-M, Mohler H 1995 GABA_A-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol 359:154–194[CrossRef][Medline]
217. Mitsushima D, Hei DL, Terasawa E 1994 GABA is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. Proc Natl Acad Sci USA 91:395–399[Abstract/Free Full Text]
218. Peterson SL, McCrone S, Coy D, Adelman JP, Mahan LC 1993 GABA_A receptor subunit mRNAs in cells of the preoptic area: colocalization with LHRH mRNA using dual-label in situ hybridization histochemistry. Endocr J 1:29–34
219. Jung H, Shannon EM, Fritschy JM, Ojeda SR 1998 Several GABA_A receptor subunits are expressed in LHRH neurons in juvenile female rats. Brain Res 780:218–229[CrossRef][Medline]
220. Schaffner AE, Beher T, Nadi S, Barker JL 1993 Quantitative analysis of transient GABA expression in embryonic and early postnatal rat spinal cord neurons. Brain Res Dev Brain Res 72:265–276[CrossRef][Medline]
221. Somogyi R, Wen X, Ma W, Barker JL 1995 Developmental kinetics of GAD family mRNAs parallel neurogenesis in the rat spinal cord. J Neurosci 15:2575–2591[Abstract]
222. Greif KF, Tillakaratne NJK, Erlander MG, Feldblum S, Tobin AJ 1992 Transient increase in expression of a glutamate decarboxylase (GAD) mRNA during the postnatal development of the rat striatum. Dev Biol 153:158–164[CrossRef][Medline]
223. Del Rio JA, Soriano E, Ferrer I 1992 Development of GABA-Immunoreactivity in the neocortex of mouse. J Comp Neurol 326:501–526[CrossRef][Medline]
224. Barker JL, Behar T, Li YX, Liu QY, Ma W, Maric I, Schaffner AE, Serfini R, Smith SV, Somogyi R, Vautrin JY, Wen XL, Xain H 1998 GABAergic cells and signals in CNS development. Perspect Dev Neurobiol 5:305–322[Medline]
225. Flügge G, Wuttke W, Fuchs E 1986 Postnatal development of transmitter systems: sexual differentiation of the GABAergic system and effects of muscimol. Int J Dev Neurosci 4:319–326[CrossRef][Medline]
226. Davis AM, Ward SC, Selmanoff M, Herbison AE, McCarthy MM 1999 Developmental sex differences in amino acid neurotransmitter levels in hypothalamic and limbic areas of rat brain. Neuroscience 90:1471–1482[CrossRef][Medline]
227. Davis AM, Grattan DR, Selmanoff M, McCarthy MM 1996 Sex differences in glutamic acid decarboxylase mRNA in neonatal rat brain: implications for sexual differentiation. Horm Behav 30:538–552[CrossRef][Medline]
228. Roth C, Leonhardt S, Theiling K, Lakomek M, Jarry H, Wuttke W 1998 Ontogeny of the GnRH-, glutaminase- and glutamate decarboxylase-gene expression in the hypothalamus of female rats. Brain Res Dev Brain Res 110:105–114[CrossRef][Medline]
229. Goroll D, Arias P, Wuttke W 1994 Ontogenic changes in the hypothalamic levels of amino acid neurotransmitters in the female rat. Brain Res Dev Brain Res 77:183–188[CrossRef][Medline]
230. Bonavera JJ, Swerdloff RS, Sinha-Hikim AP, Lue YH, Wang C 1998 Aging results in attenuated gonadotropin releasing hormone-luteinizing hormone axis responsiveness to glutamate receptor agonist N-methyl-D-aspartate. J Neuroendocrinol 10:93–99[CrossRef][Medline]
231. Hayashi M 1987 Ontogeny of glutamic acid decarboxylase, tyrosine hydroxylase, choline acetyltransferase, somatostatin and substance P in monkey cerebellum. Brain Res 429:181–186[Medline]
232. Rassin DK, Sturman JA, Gaull GE 1982 Sulfur amino acid metabolism in the developing rhesus monkey brain. Neurochem Res 7:1107–1118[CrossRef][Medline]
233. Huntley GW, Hendry SH, Killackey HP, Chalupa LM, Jones EG 1988 Temporal sequence of neurotransmitter expression by developing neurons of fetal monkey visual cortex. Brain Res 471:69–96[Medline]
234. Huntley GW, Jones EG 1991 The emergence of architectonic field structure and areal borders in developing monkey sensorimotor cortex. Neuroscience 44:287–310[CrossRef][Medline]
235. Diebler MF, Farkas-Bargeton E, Wehrle R 1979 Developmental changes of enzymes associated with energy metabolism and the synthesis of some neurotransmitters in discrete areas of human neocortex. J Neurochem 32:429–435[CrossRef][Medline]
236. Johnston MV, Coyle JT 1981 Development of central neurotransmitter systems. Ciba Found Symp 86:251–271[Medline]
237. Urbanski HF, Rodrigues SM, Garyfallou VT, Kohama SG 1998 Regional distribution of glutamic acid decarboxylase (GAD65 and GAD67) mRNA in the hypothalamus of male rhesus before and after puberty. Mol Brain Res 57:86–91[Medline]
238. El Majdoubi M, Sahu A, Ramaswamy S, Plant TM 2000 Neuropeptide Y: a hypothalamic brake restraining the onset of puberty in primates. Proc Natl Acad Sci USA 97:6179–6184[Abstract/Free Full Text]
239. Goroll D, Arias P, Wuttke W 1993 Preoptic release of amino acid neurotransmitters evaluated in peripubertal and young adult female rats by push-pull perfusion. Neuroendocrinology 58:11–15[CrossRef][Medline]
240. Terasawa E, Luchansky LL, Kasuya E, Nyberg CL 1999 An increase in glutamate release follows a decrease in -aminobutyric acid and the pubertal increase in luteinizing hormone releasing hormone release in female rhesus monkeys. J Neuroendocrinol 11:275–282[CrossRef][Medline]
241. Laurie DJ, Wisden W, Seeburg PH 1992 The distribution of thirteen GABA_A receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 12:4151–4172[Abstract]
242. Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA 1998 Selective changes in single cell GABA_A receptor subunit expression and function in temporal lobe epilepsy. Nat Med 4:1166–1172[CrossRef][Medline]
243. Sim JA, Skynner MJ, Pape J-R, Herbison AE 2000 Late postnatal reorganization of GABA_A receptor signaling in native GnRH neurons. Eur J Neurosci 12:3497–3504[CrossRef][Medline]
244. Jennes L, Stumpf WE, Tappaz ML 1983 Anatomical relationships of dopaminergic and GABAergic systems with the GnRH-systems in the septo-hypothalamic area. Exp Brain Res 50:91–99[Medline]
245. Leranth C, Maclusky NJ, Sakamoto H, Shanabrough M, Naftolin F 1985 Glutamic acid decarboxylase-containing axons synapse on LHRH neurons in the rat medial preoptic area. Neuroendocrinology 40:536–539[Medline]
246. Leranth C, Maclusky NJ, Brown TJ, Chen EC, Redmond Jr DE, Naftolin F 1992 Transmitter content and afferent connections of estrogen-sensitive progestin receptor-containing neurons in the primate hypothalamus. Neuroendocrinology 55:667–682[Medline]
247. Goldsmith PC, Thind KK 1995 Morphological basis for neuronal control of GnRH secretion in the monkey. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 73–85
248. El-Etr M, Akwa Y, Fiddes RJ, Robel P, Baulieu E-E 1995 A progesterone metabolite stimulates the release of gonadotropinreleasing hormone from GT1–1 hypothalamic neurons via the -aminobutyric acid type A receptor. Proc Natl Acad Sci USA 92:3769–3773[Abstract/Free Full Text]
249. Hales TG, Sanderson MJ, Charles AC 1994 GABA has excitatory actions on GnRH-secreting immortalized hypothalamic (GT1–7) neurons. Neuroendocrinology 59:297–308[CrossRef][Medline]
250. Herbison AE, Fenelon VS 1995 Estrogen regulation of GABA_A-receptor subunit mRNA expression in preoptic area and bed nucleus of the stria terminalis of female rat brain. J Neurosci 15:2328–2337[Abstract]
251. Zhang SJ, Jackson MB 1993 GABA-activated chloride channels in secretory nerve endings. Science 259:531–534[Abstract/Free Full Text]
252. Leranth C, Naftolin F, Shanabrough M, Horvath TL 1995 Neuronal circuits regulating gonadotropin release in the rat. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 55–72
253. Silverman AJ, Livne I, Witkin JW 1994 The gonadotropin-releasing hormone (GnRH) neuronal systems: immunocytochemistry and in situ hybridization. In: Knobil E, Neill JD (eds) The Physiology of Reproduction. Raven Press, New York, pp 1683–1710
254. Ondo JG 1974 -Aminobutyric acid effects on pituitary gonadotropin secretion. Science 186:738–739[Abstract/Free Full Text]
255. Vijayan E, McCann SM 1978 The effects of intraventricular injection of -aminobutyric acid (GABA) on prolactin and gonadotropin release in conscious female rats. Brain Res 155:35–43[CrossRef][Medline]
256. Taleisnik S, Haymal B 1997 Dual effect of electrochemical stimulation of the medial preoptic area on the release of LH: possible neurotransmitter involvement. Neuroendocrinology 66:114–121[Medline]
257. Lamberts R, Vijayan E, Graf M, Mansky T, Wuttke W 1983 Involvement of preoptic-anterior hypothalamic GABA neurons in the regulation of pituitary LH and prolactin release. Exp Brain Res 52:356–362[Medline]
258. Massoto C, Negro-Vilar A 1987 Activation of -aminobutyric acid B-receptors abolishes naloxone-stimulated luteinizing hormone release. Endocrinology 121:2251–2255[Abstract/Free Full Text]
259. Nikolarakis KE, Loeffler JP, Almeida OFX, Herz A 1988 Pre- and postsynaptic actions of GABA on the release of hypothalamic gonadotropin-releasing hormone (GnRH). Brain Res Bull 21:677–683[CrossRef][Medline]
260. Akema T, Kimura F 1992 Modulation of pulsatile LH secretion by baclofen, a selective GABA_B receptor agonist, in ovariectomized rats. Neuroendocrinology 56:141–147[Medline]
261. Donoso AO, Lopez FJ, Negro-Vilar A 1992 Cross-talk between excitatory and inhibitory amino acids in the regulation of luteinizing hormone-releasing hormone secretion. Endocrinology 131:1559–1561[Abstract/Free Full Text]
262. Martinez de la Escalera G, Choi ALH, Weiner RI 1994 Biphasic GABAergic regulation of GnRH secretion in GT1 cells. Neuroendocrinology 59:420–425[Medline]
263. Spergel DJ, Krsmanovic LZ, Stojilkovic SS, Catt KJ 1995 L-type Ca²⁺ channels mediate joint modulation by -aminobutyric acid and glutamate of [Ca^2+]_i and neuropeptide secretion in immortalized gonadotropin-releasing hormone neurons. Neuroendocrinology 61:499–508[Medline]
264. Kusano K, Fueshko SM, Gainer H, Wray S 1995 Electrical and synaptic properties of embryonic luteinizing hormone-releasing hormone neurons in explant cultures. Proc Natl Acad Sci USA 92:3918–3922[Abstract/Free Full Text]
265. Jarry H, Perschl A, Wuttke W 1988 Further evidence that preoptic anterior hypothalamic GABAergic neurons are part of the GnRH pulse and surge generator. Acta Endocrinol (Copenh) 118:573–579[Abstract/Free Full Text]
266. Herbison AE, Augood SJ, McGowan EM 1992 Expression of glutamic acid decarboxylase messenger RNA in rat medial preoptic area neurons during the oestrous cycle and after ovariectomy. Brain Res Mol Brain Res 14:310–316[Medline]
267. Jarry H, Leonhardt S, Wuttke W 1991 -Aminobutyric acid neurones in the preoptic/anterior hypothalamic area synchronized the phasic activity of the gonadotropin-releasing hormone pulse generator in ovariectomized rats. Neuroendocrinology 51:337–344
268. Scott CJ, Clarke IJ 1993 Evidence that changes in the function of the subtypes of the receptors for gamma-amino butyric acid may be involved in the seasonal changes in the negative-feedback effects of estrogen on gonadotropin-releasing hormone secretion and plasma luteinizing hormone levels in the ewe. Endocrinology 133:2904–2912[Abstract/Free Full Text]
269. Herbison AE, Chapman C, Dyer RG 1991 Role of medial preoptic GABA neurones in regulating luteinizing hormone secretion in the ovariectomized rat. Exp Brain Res 87:345–352[Medline]
270. Grattan DR, Rocca MS, Strauss KI, Sagrillo CA, Selmanoff M, McCarthy MM 1996 GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrus. Brain Res 733:46–55[CrossRef][Medline]
271. Akema T, Chiba A, Kimura F 1990 On the relationship between noradrenergic stimulatory and GABAergic inhibitory systems in the control of luteinizing hormone secretion in female rats. Neuroendocrinology 52:566–572[Medline]
272. Kimura F, Sano A, Hiruma H, Funabashi T 1993 Effects of - amino-butyric acid-A receptor antagonist, bicuculline, on the electrical activity of luteinizing hormone-releasing hormone pulse generator in the ovariectomized rat. Neuroendocrinology 57:605–614[Medline]
273. Jackson GL, Wood SG, Kuehl DE 2000 A -aminobutyric acid_B agonist reverses the negative feedback effect of testosterone and luteinizing hormone secretion in the male sheep. Endocrinology 141:3940–3945[Abstract/Free Full Text]
274. Ferreira SA, Scott CJ, Kuehl DE, Jackson GL 1996 Differential regulation of luteinizing hormone release by -aminobutyric acid receptor subtypes in the arcuate-ventromedial region of the castrated ram. Endocrinology 137:3453–3460[Abstract]
274. Lagrange AH, Ronnekleiv OK, Kelley MJ 1995 Estradiol-17ß and µ-opioid peptides rapidly hyperpolarize GnRH neurons: a cellular mechanism of negative feedback? Endocrinology 136:2341–2344[Abstract]
274. Adler BA, Crowley WR 1986 Evidence for gamma-aminobutyric acid modulation of ovarian hormone effects of luteinizing hormone secretion and hypothalamic catecholamine activity in the female rat. Endocrinology 118:91–97[Abstract/Free Full Text]
275. Robinson JE, Kendrick KM, Lambart CE 1991 Changes in the release of -aminobutyric acid and catecholamines in the preoptic/septal area prior to and during the preovulatory surge of luteinizing hormone in the ewe. J Neuroendocrinol 3:393–399
276. Seltzer AM, Donoso AO 1992 Restraining action of GABA on estradiol-induced LH surge in the rat: GABA activity in brain nuclei and effects of GABA mimetics in the medial preoptic nucleus. Neuroendocrinology 55:28–34[CrossRef][Medline]
277. Unda R, Brann DW, Mahesh VB 1995 Progesterone suppression of glutamic acid decarboxylase (GAD₆₇) mRNA levels in the preoptic area: correlation to the luteinizing hormone surge. Neuroendocrinology 62:562–570[Medline]
278. Luine VN, Grattan DR, Selmanoff M 1997 Gonadal hormones alter hypothalamic GABA and glutamate levels. Brain Res 747:165–168[CrossRef][Medline]
279. Morello H, Caligaris L, Haymal B, Taleisnik S 1989 Inhibition of proestrous LH surge and ovulation in rats evoked by stimulation of the medial raphe nucleus involves a GABA-mediated mechanism. Neuroendocrinology 50:81–87[CrossRef][Medline]
280. Herbison AE, Dyer RG 1991 Effect of luteinizing hormone (LH) secretion of GABA receptor modulation in the medial preoptic area at the time of the proestrous LH surge. Neuroendocrinology 53:317–320[Medline]
281. Herbison AE 1998 Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev 19:302–330[Abstract/Free Full Text]
282. Kimura F, Jinnai K 1994 Bicuculline infusions advance the timing of luteinizing hormone surge in proestrous rats: comparisons with naloxone effects. In: Goy RW, Whalen RE (eds) Hormones and Behavior. Academic Press, New York, pp 424–430
283. Grattan DR, Selmanoff M 1994 Castration-induced decrease in the activity of medial preoptic and tuberoinfundibular GABAergic neurons is prevented by testosterone. Neuroendocrinology 60:141–149[Medline]
284. Sagrillo CA, Selmanoff M 1997 Castration decreases single cell levels of mRNA encoding glutamic acid decarboxylase in the diagonal band of broca and the sexually dimorphic nucleus of the preoptic area. J Neuroendocrinol 9:699–706[CrossRef][Medline]
285. Grattan DR, Rocca MS, Sagrillo CA, McCarthy MM, Selmanoff M 1996 Antiandrogen microimplants into the rostral medial preoptic area decrease -aminobutyric acidergic neuronal activity and increase luteinizing hormone secretion in the intact male rat. Endocrinology 137:4167–4173[Abstract]
286. Thind KK, Goldsmith PC 1997 Expression of estrogen and progesterone receptors in glutamate and GABA neurons of the pubertal female monkey hypothalamus. Neuroendocrinology 65:314–324[Medline]
287. Obrietan K, van den Pol AN 1995 GABA neurotransmission in the hypothalamus: developmental reversal from Ca²⁺ elevating to depressing. J Neurosci 15:5065–5077[Abstract]
288. van den Pol AN, Gao X-B, Patrylo PR, Ghosh PK, Obrietan K 1998 Glutamate inhibits GABA excitatory activity in developing neurons. J Neurosci 18:10749–10761[Abstract/Free Full Text]
289. Cherubini E, Gaiarsa JL, Ben-Ari Y 1991 GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14:515–519[CrossRef][Medline]
290. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa J-L 1997 GABA_A, NMDA, and AMPA receptors: a developmentally regulated ‘menage a trois’. Trends Neurosci 20:523–529[CrossRef][Medline]
291. Hornung JP, Fritschy JM 1996 Developmental profile of GABA_A-receptors in the marmoset monkey: expression of distinct subtypes in the pre- and postnatal brain. J Comp Neurol 367:413–430[CrossRef][Medline]
292. Smith SS, Gong QH, Hsu FC, Markowitz RS, French-Mullen JMH, Li X 1998 GABA_A receptor 4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–929[CrossRef][Medline]
293. Wagner S, Castel M, Gainer H, Yarom Y 1997 GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature 387:598–603[CrossRef][Medline]
294. Owens DF, Boyce LH, Davis MBE, Kriegstein AR 1996 Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J Neurosci 16:6414–6423[Abstract/Free Full Text]
295. Rohrbough J, Spitzer NC 1996 Regulation of intracellular Cl^- levels by Na+ -dependent Cl- cotransport distinguishes depolarizing from hyperpolarizing GABA_A receptor-mediated responses in spinal neurons. J Neurosci 16:82–91[Abstract/Free Full Text]
296. Plotkin MD, Snyder EY, Hebert SC, Delpire E 1997 Expression of the Na-K-2Cl cotransporter is developmentally regulated in postnatal rat brains: a possible mechanism underlying GABA’s excitatory role in the immature brain. J Neurobiol 33:781–795[CrossRef][Medline]
297. Payne JA 1997 Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K⁺]_o regulation. Am J Physiol 273:C1516–1525
298. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K 1999 The K⁺/Cl^- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255
299. Herbison AE 1994 Immunocytochemical evidence for oestrogen receptors within GABA neurones located in the perinuclear zone of the supraoptic nucleus and GABA_A receptor ß2/ß3 subunits on supraoptic oxytocin neurones. J Neuroendocrinol 6:5–11[Medline]
300. Leranth C, Shanabrough M, Naftolin F 1991 Estrogen induces ultrastructural changes in progesterone receptor-containing GABA neurons of the primate hypothalamus. Neuroendocrinology 54:571–579[Medline]
301. Paul SM, Purdy RH 1992 Neuroactive steroids. FASEB J 6:2311–2322[Abstract]
302. Herbison AE, Skynnerm MJ, Sim JA Molecular and electrical properties of GnRH neurons revealed through transgenics. Program and Abstracts of the 81st Annual Meeting of The Endocrine Society, 1999, San Diego, CA, p 3 (Abstract S19–3)
303. Demling J, Fuchs E, Baumert M, Wuttke W 1985 Preoptic catecholamine, GABA, and glutamate release in ovariectomized and ovariectomized estrogen-primed rats utilizing a push-pull cannula technique. Neuroendocrinology 41:212–218[Medline]
304. Moguilevsky JA, Carbone S, Szwarcfarb B, Rondina D 1991 Sexual maturation modifies the GABAergic control of gonadotrophin secretion in female rats. Brain Res 563:12–16[CrossRef][Medline]
305. Feleder C, Jarry H, Leonhardt S, Wuttke W, Moguilevsky JA 1996 The GABAergic control of gonadotropin-releasing hormone secretion in male rats during sexual maturation involves effects on hypothalamic excitatory and inhibitory amino acid systems. Neuroendocrinology 64:305–312[CrossRef][Medline]
306. Bourguignon J-P, Gérard A, Purnelle G, Czajkowski V, Yamanaka C, Lemaître M, Rigo J-M, Moonen G, Franchimont P 1997 Duality of glutamatergic and GABAergic control of pulsatile GnRH secretion by rat hypothalamic explants: effects of antisense oligodeoxynucleotides using explants including or excluding the preoptic area. J Neuroendocrinol 9:183–191[CrossRef][Medline]
307. Bourguignon J-P, Gérard A, Purnelle G, Czajkowski V, Yamanaka C, Lemaître M, Rigo J-M, Moonen G, Franchimont P 1997 Duality of glutamatergic and GABAergic control of pulsatile GnRH secretion by rat hypothalamic explants. II. Reduced NR2C- and GABA_A-receptor-mediated inhibition at initiation of sexual maturation. J Neuroendocrinol 9:193–199[CrossRef][Medline]
308. Mitsushima D, Kimura F 1997 The maturation of GABA_A receptor-mediated control of luteinizing hormone secretion in immature male rats. Brain Res 748:258–262[CrossRef][Medline]
309. Mitsushima D, Marzban F, Luchansky LL, Burich AJ, Keen KL, Durning M, Golos TG, Terasawa E 1996 Role of glutamic acid decarboxylase in the prepubertal inhibition of the luteinizing hormone-releasing hormone release in prepubertal female monkeys. J Neurosci 16:2563–2573[Abstract/Free Full Text]
310. Kasuya E, Nyberg CL, Mogi K, Terasawa E 1999 A role of -aminobutyric acid (GABA) and glutamate in control of puberty in female rhesus monkeys: effect of an antisense oligodeoxynucleotide for GAD67 messenger ribonucleic acid and MK801 on luteinizing hormone-releasing hormone release. Endocrinology 140:705–712[Abstract/Free Full Text]
311. Keen KL, Burich AJ, Mitsushima D, Kasuya E, Terasawa E 1999 Effects of pulsatile infusion of the GABA_A receptor blocker bicuculline on the onset of puberty in female rhesus monkeys. Endocrinology 140:5257–5266[Abstract/Free Full Text]
312. Gorski RA, Barraclough CA 1963 Effects of low dosages of androgen on the differentiation of hypothalamic regulatory control of ovulation in the rat. Endocrinology 73:210–216
313. Gorski RA 1971 Steroid hormones and brain function: progress, principles and problems. In: Sawyer CH, Gorski RA (eds) Steroid Hormones and Brain Function. University of California Press, Berkeley, pp 1–26
314. Gorski RA, Harlan RE, Jacobson CD, Shryne JE, Southam AM 1980 Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the rat. J Comp Neurol 193:529–539[CrossRef][Medline]
315. Jacobson CD, Gorski RA 1981 Neurogenesis of the sexually dimorphic nucleus of the preoptic area in the rat. J Comp Neurol 196:519–529[CrossRef][Medline]
316. Bleier R, Byne W, Siggelkow I 1982 Cytoarchitectonic sexual dimorphisms of the medial preoptic and anterior hypothalamic areas in guinea pig, rat, hamster, and mouse. J Comp Neurol 212:118–130[CrossRef][Medline]
317. Simerly RB, Gorski RA, Swanson LW 1986 Neurotransmitter specificity of cells and fibers in the medial preoptic nucleus: an immunohistochemical study in the rat. J Comp Neurol 246:343–363[CrossRef][Medline]
318. Gu G, Varoqueaux F, Simerly RB 1999 Hormonal regulation of glutamate receptor gene expression in the anteroventral periventricular nucleus of the hypothalamus. J Neurosci 19:3213–3222[Abstract/Free Full Text]
319. Grattan DR, Selmanoff M 1997 Sex differences in the activity of -aminobutyric acidergic neurons in the rat hypothalamus. Brain Res 775:244–249[CrossRef][Medline]
320. Davis AM, Ward SC, Selmanoff M, Herbison AE, McCarthy MM 1999 Developmental sex differences in amino acid neurotransmitter levels in hypothalamic and limbic areas of rat brain. Neuroscience 90:1471–1482
321. Meier E, Hansen GH, Schousboe A 1985 The trophic effect of GABA on cerebellar granule cells is mediated by GABA-receptors. Int J Dev Neurosci 3:401–407
322. Barbin G, Pollard H, Gaiarsa JL, Ben-Ari Y 1993 Involvement of GABA_A receptors in the outgrowth of cultured hippocampal neurons. Neurosci Lett 152:150–154[CrossRef][Medline]
323. Behar TN, Li YX, Tran HT, Ma W, Dunlap V, Scott C, Barker JL 1996 GABA stimulates chemotaxis and chemokinesis of embryonic cortical neurons via calcium-dependent mechanisms. J Neurosci 16:1808–1818,[Abstract/Free Full Text]
324. Tobet SA, Chickering TW, King JC, Stopa EG, Kim K, Kuo-Leblank V, Schwarting GA 1996 Expression of -aminobutyric acid and gonadotropin-releasing hormone during neuronal migration through the olfactory system. Endocrinology 137:5415–5420[Abstract]
325. Tobet SA, Bless EP, Schwarting GA Developmental control of gonadotropin-releasing hormone neuronal migration. Program and Abstracts of the 81st Annual Meeting of The Endocrine Society, San Diego, CA, 1999, p 33 (Abstract S19–1)
326. Fueshko SM, Key S, Wray S 1998 Luteinizing hormone releasing hormone (LHRH) neurons maintained in nasal explants decrease LHRH messenger ribonucleic acid levels after activation of GABA(A) receptors. Endocrinology 139:2734–2740[Abstract/Free Full Text]
327. Fueshko SM, Key S, Wray S 1998 GABA inhibits migration of luteinizing hormone-releasing hormone neurons in embryonic olfactory explants. J Neurosci 18:2560–2569[Abstract/Free Full Text]
328. McCarthy MM, Davis AM, Mong JA, Sickel MJ, Auger AP 1998 Mechanisms of steroid-induced brain differentiation. The 14th Tokyo Metropolitan Institute of Neuroscience International Symposium, Tokyo, 1998, pp 26–28
329. Woo TU, Whitehead RE, Melchitzky DS, Lewis DA 1998 A subclass of prefrontal -aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci USA 95:5341–5346[Abstract/Free Full Text]
330. Lundberg B, Nergardh A, Ritzen E, Samuelson K 1986 Influence of valproic acid on the gonadotropin releasing hormone test in puberty. Acta Pediatr Scand 75:787–792[Medline]
331. Cook JS, Bale JF, Hoffman RP 1992 Pubertal arrest associated with valproic acid therapy. Pediatr Neurol 8:229–231[CrossRef][Medline]
332. Snyder PJ, Badura LL 1995 Chronic administration of sodium valproic acid slows pubertal maturation in inbred DBA/2J mice: skeletal, histological and endocrinological evidence. Epilepsy Res 20:203–211[CrossRef][Medline]
333. Olsen RW, Avoli M 1997 GABA and epileptogenesis. Epilepsia 38:399–407[CrossRef][Medline]
334. Bourguignon J-P, Jaeken J, Gérard A, deZegher F 1997 Amino acid neurotransmission and initiation of puberty: evidence from nonketotic hyperglycinemia in a female infant and gonadotropinreleasing hormone secretion by rat hypothalamic explants. J Clin Endocrinol Metab 82:1899–1903[Abstract/Free Full Text]
335. Isojärvi JIT, Laatikainen TJ, Pakarinen AJ, Juntunen KTS, Myllylä VV 1993 Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1381–1388
336. Weick RF, Stobie KM 1995 Role of VIP in the regulation of LH secretion in the female rat. Neurosci Biobehav Rev 19:251–259[CrossRef][Medline]
337. Laatikainen TJ 1991 Corticotropin-releasing hormone and opioid peptides in reproduction and stress. Ann Med 23:489–496[Medline]
338. Ghizzoni L, Virdis R, Ziveri M, Lamborghini A, Alberini A, Volta C, Bernasconi S 1989 Adrenal steroid, cortisol, adrenocorticotropin, and ß-endorphin responses to human corticotropin-releasing hormone stimulation test in normal children and children with premature pubarche. J Clin Endocrinol Metab 69:875–880[Abstract/Free Full Text]
339. Attanasio A, Rosskamp R, Bernasconi S, Terzi C, Ranke MB, Giovanelli G, Gupta D 1987 Plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone response to corticotropin-releasing factor in normal children during pubertal development. Pediatr Res 22:41–44[Medline]
340. Kitay JI, Altshule MD 1954 The Pineal Gland. A Review of the Physiological Literature. Harvard Press, Cambridge, MA
341. Waldhauser F, Weiszenbacher G, Frisch H, Zeitlhuber U, Waldhauser M, Wurtman RJ 1984 Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet 8373:362–365[CrossRef]
342. Waldhauser F, Boepple PA, Schemper M, Mansfeild MJ, Crowley Jr WF 1991 Serum melatonin in central precocious puberty is lower that in age-matched prepubertal children. J Clin Endocrinol Metab 73:793–796[Abstract/Free Full Text]
343. Attanasio A, Borrelli P, Gupta D 1985 Circadian rhythms in serum melatonin from infancy to adolescence. J Clin Endocrinol Metab 61:388–390[Abstract/Free Full Text]
344. Wilson ME, Gordon TP 1989 Nocturnal changes in serum melatonin during female puberty in rhesus monkeys: a longitudinal study. J Endocrinol 121:553–562[Abstract/Free Full Text]
345. Cavallo A, Dolan LM 1996 6-Hydroxymelatonin sulfate excretion in human puberty. J Pineal Res 21:225–230[Medline]
346. Tamarkin L, Westrom WK, Hamill AI, Goldman BD 1976 Effect of melatonin on the reproductive systems in syrian male and female hamsters: a diurnal rhythm in sensitivity to melatonin. Endocrinology 99:1534–1541[Abstract/Free Full Text]
347. Bittman EL, Karsch FJ 1984 Nightly duration of pineal melatonin secretion determines the reproductive response to inhibitory day length in the ewe. Biol Reprod 30:585–593[Abstract]
348. Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H 1992 Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab75:127–134
349. Bellastella A, Criscuolo T, Sinisi AA, Iorio S, Mazzuca A, Parlato F, Perrone L, Faggiano M 1987 Influence of blindness on plasma luteinizing hormone, follicle-stimulating hormone, prolactin, and testosterone levels in prepubertal boys. J Clin Endocrinol Metab 64:862–864[Abstract/Free Full Text]
350. Zachrias L, Wurtman RJ 1964 Blindness: its relation to age of menarche. Science 144:1154–1155[Abstract/Free Full Text]
351. Magee K, Basinska J, Quarrington B, Stancer HC 1970 Blindness and menarche. Life Sci 9:7–12[CrossRef][Medline]
352. Packer RJ, Sutton LN, Rosenstock JG, Rorke LB, Bilaniuk LT, Zimmerman RA, Littman PA, Bruce DA, Schut L 1984 Pineal region tumors of childhood. Pediatrics 74:97–102[Abstract/Free Full Text]
353. Cardinali DP, Vacas MI 1984 Pineal gland, photoperiodic responses, and puberty. J Endocrinol Invest 7:157–165[Medline]
354. Edwards MS, Hudgins RJ, Wilson CB, Levin VA, Wara WM 1988 Pineal region tumors in children. J Neurosurg 68:689–697[Medline]
355. Reiter RJ 1981 Pineal control of reproduction. Prog Clin Biol Res 59B:349–355
356. Siegel-Witchel S 1995 CNS lesions, neurologic disorders, and puberty in man. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 229–239
357. Luboshitzky R, Lavi S, Thuma I, Lavie P 1995 Increased nocturnal melatonin secretion in male patients with hypogonadotropic hypogonadism and delayed puberty. J Clin Endocrinol Metab 80:2144–2148[Abstract]
358. Luboshitzky R, Lavi S, Thuma I, Herer P, Lavie P 1996 Nocturnal secretor patterns of melatonin, luteinizing hormone, prolactin and cortisol in male patients with gonadotropin-releasing hormone deficiency. J Pineal Res 21:49–54[Medline]
359. Wilson ME, Lackey S, Chikazawa K, Gordon TP 1993 The amplitude of nocturnal melatonin concentrations is not decreased by oestradiol and does not alter reproductive function in adolescent or adult female rhesus monkeys. J Endocrinol 137:229–309
360. Plant TM, Zorub DS 1986 Pinealectomy in agonadal infantile male rhesus monkeys (Macaca mulatta) does not interrupt initiation of the prepubertal hiatus in gonadotropin secretion. Endocrinology 118:227–232[Abstract/Free Full Text]
361. Bellastella A, Pisano G, Iorio S, Pasquali D, Orio F, Venditto T, Sinisi AA 1998 Endocrine secretions under abnormal light-dark cycles and in the blind. Horm Res 49:153–157[CrossRef][Medline]
362. van den Pol AN, Trombley PQ 1993 Glutamate neurons in hypothalamus regulate excitatory transmission. J Neurosci 13:2829–2836[Abstract]
363. van den Pol AN, Wuarin J-P, Dudek FE 1990 Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science 250:1276–1278[Abstract/Free Full Text]
364. Brann DW, Mahesh VB 1994 Excitatory amino acids: function and significance in reproduction and neuroendocrine regulation. Front Neuroendocrinol 15:3–49[CrossRef][Medline]
365. Brann DW, Mahesh VB 1997 Excitatory amino acids: evidence for a role in the control of reproduction and anterior pituitary hormone secretion. Endocr Rev 18:678–700[Abstract/Free Full Text]
366. Meeker RB, Greenwood RS, Hayward JN 1994 Glutamate receptors in the rat hypothalamus and pituitary. Endocrinology 134:621–629[Abstract/Free Full Text]
367. van den Pol AN, Kogelman L, Ghost P, Liljelund P, Blackstone C 1994 Developmental regulation of the hypothalamic metatropic glutamate receptor mGluR1. J Neurosci 14:3816–3834[Abstract]
368. Bourguignon J-P, Gérard A, Gonzalez M-LA, Purnelle G, Franchimont P 1995 Endogenous glutamate involvement in pulsatile secretion of gonadotropin-releasing hormone: evidence from the effect of glutamine and developmental changes. Endocrinology 136:911–916[Abstract]
369. Mearow KM, Mill JF, Vitkovic L 1989 The ontogeny and location of glutamine synthase gene expression in rat brain. Mol Brain Res 6:223–232[Medline]
370. Fonnum F 1993 Regulation of the synthesis of the transmitter glutamate pool. Prog Biophys Mol Biol 60:47–57[CrossRef][Medline]
371. Cutler RWP, Dudzinski DS 1974 Regional changes in amino acid content in developing rat brain. J Neurochem 23:1005–1009[CrossRef][Medline]
372. Carbone S, Szwarcfarb B, Otera-Losada M, Moguilevsky JA 1992 Effects of ovarian steroids on the gonadotropin response to N-methyl-D-aspartate and on hypothalamic excitatory amino acid levels during sexual maturation in female rats. Endocrinology 130:1365–1370[Abstract/Free Full Text]
373. Carbone S, Szwarcfarb B, Losada M, Moguilevsky JA 1995 Effects of ovarian hormones on the hypothalamic excitatory amino acid system during sexual maturation in female rats. Neuroendocrinology 61:235–242[Medline]
374. Price MT, Olney JW, Cicero TJ 1978 Acute elevations of serum luteinizing hormone induced by kainic acid, N-methyl-aspartic acid, or homosysteic acid. Neuroendocrinology 26:352–358[Medline]
375. Olney JW, Cicero TJ, Meyer ER, De Gubareff T 1976 Acute glutamate-induced elevations in serum testosterone and luteinizing hormone. Brain Res 12:420–424
376. Wilson RC, Knobil E 1982 Acute effects of N-methyl-DL-aspartate on the release of pituitary gonadotropins and prolactin in the adult female rhesus monkey. Brain Res 248:177–179[CrossRef][Medline]
377. Donoso AO, Lopez FJ, Negro-Vilar A 1990 Glutamate receptors of the non-N-methyl-D-aspartic acid type mediate the increase in luteinizing hormone-releasing hormone release by excitatory amino acids in vitro. Endocrinology 126:414–420[Abstract/Free Full Text]
378. Gore AC, Roberts JL 1994 Regulation of gonadotropin-releasing hormone gene expression by the excitatory amino acids kainic acid and N-methyl-D,L-aspartate in the male rat. Endocrinology 134:2026–2031[Abstract]
379. Gore AC, Roberts JL 1997 Regulation of gonadotropin-releasing hormone gene expression in vivo and in vitro. Front Neuroendocrinol 18:209–245[CrossRef][Medline]
380. Bourguignon J-P, Gérard A, Franchimont P1989 Direct activation of gonadotropin-releasing hormone secretion through different receptors to neuroexcitatory amino acids. Neuroendocrinology 49:402–408
381. Bourguignon J-P, Gérard A, Gonzalez M-LA, Franchimont P 1992 Neuroendocrine mechanism of the onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D- aspartate receptors. J Clin Invest 90:1736–1744
382. Meiji-Roelofs HMA, Kramer P, van Leeuwen ECM 1991 The N-methyl-D-aspartate receptor antagonist MK-801 delays the onset of puberty and may acutely block the first spontaneous LH surge and ovulation in the rat. J Endocrinol 131:435–441[Abstract/Free Full Text]
383. Mahachoklertwuttana P, Sanchez J, Kaplan SL, Grumbach MM 1994 N-Methyl-D-aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) by NMDA in a hypothalamic GnRH neuronal cell line (GT1–1). Endocrinology 134:1023–1030[Abstract/Free Full Text]
384. Gay VL, Plant TM 1987 N-Methyl-D,L-aspartate (NMDA) elicits hypothalamic GnRH release in prepubertal male rhesus monkeys (Macaca mulatta). Endocrinology 120:2289–2296[Abstract/Free Full Text]
385. Medhamurthy R, Dichek HL, Plant TM, Bernardini I, Cutler Jr GB 1990 Stimulation of gonadotropin secretion in prepubertal monkeys after hypothalamic excitation with aspartate and glutamate. J Clin Endocrinol Metab 71:1390–1392[Abstract/Free Full Text]
386. Medhamurthy R, Gay VL, Plant TM 1992 Repetitive injections of L-glutamic acid, in contrast to those of N-methyl-D,L-aspartic acid, fail to elicit sustained hypothalamic GnRH release in the prepubertal male rhesus monkey (Macaca mulatta). Neuroendocrinology 55:660–666[Medline]
387. Brann DW, Mahesh VB 1992 Excitatory amino acid neurotransmission. Evidence for a role in neuroendocrine regulation. Trends Endocrinol Metab 3:122–126
388. Cicero TJ, Meyer ER, Bell RD 1988 Characterization and possible opioid modulation of N-methyl-D-aspartic acid induced increases in serum luteinizing hormone levels in the developing male rat. Life Sci 42:1725–1732[CrossRef][Medline]
389. I’Anson H, Herbosa CG, Ebling FJ, Wood RI, Bucholtz DC, Mieher CD, Foster DL, Padmanabhan V 1993 Hypothalamic vs. pituitary stimulation of luteinizing hormone secretion in the prepubertal female lamb. Neuroendocrinology 57:467–475[Medline]
390. Bettendorf M, de Zegher F, Albers N, Hart CS, Kaplan SL, Grumbach MM 1999 Acute N-methyl-D,L-aspartate administration stimulates the luteinizing hormone releasing hormone pulse generator in the ovine fetus. Horm Res 51:25–30[Medline]
391. Urbanski HF, Ojeda SR 1990 A role for N-methyl-D-aspartate (NMDA) receptors in the control of LH secretion and initiation of female puberty. Endocrinology 126:1774–1776[Abstract/Free Full Text]
392. Wu FCW, Howe DC, Naylor AM 1990 N-Methyl-D-aspartate (NMDA) receptor antagonism by D-2-amino-5-phosphonovaleric acid delays onset of puberty in female rat. J Neuroendocrinol 2:627–631[CrossRef][Medline]
393. MacDonald MC, Wilkinson M 1990 Peripubertal treatment with N-methyl-D-aspartic acid (NMDA) or neonatally with monosodium glutamate (MSG) accelerates sexual maturation in female rats, an effect reversed by MK801. Neuroendocrinology 52:143–149[Medline]
394. MacDonald MC, Robertson HA, Wilkinson M 1993 Age- and dose-related NMDA induction of fos-like immunoreactivity and c-fos mRNA in the arcuate nucleus. Brain Res Dev Brain Res 73:193–198[CrossRef][Medline]
395. Moguilevsky JA, Carbone S, Szwarcfarb DR, Scacchi P 1995 Hypothalamic excitatory amino acid system during sexual maturation in female rats. J Steroid Mol Biochem Mol Biol 53:337–341[CrossRef][Medline]
396. Carbone S, Szwarcfarb B, Rodina D, Feleder C, Moguilevsky JA 1996 Differential effects of the N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors of the excitatory amino acids system on LH and FSH secretion. Its effects on the hypothalamic luteinizing hormone releasing hormone during maturation in male rats. Brain Res 707:139–145[CrossRef][Medline]
397. Claypool LE, Kasuya E, Saitoh Y, Marzban F, Terasawa E 2000 N-methyl-D,L-aspartate (NMA) induces the release of luteinizing hormone-releasing hormone (LHRH) in prepubertal and pubertal female rhesus monkeys as measured by in vivo push-pull perfusion in the stalk-median eminence. Endocrinology 141:219–228[Abstract/Free Full Text]
398. Terasawa E 1998 Hypothalamic control of the onset of puberty. Curr Opin Endocrinol Diabet 6:44–49
399. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH 1992 Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221[Abstract/Free Full Text]
400. Nakanishi S 1992 Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603[Abstract/Free Full Text]
401. Adams MM, Flagg RA, Gore AC 1999 Perinatal changes in hypothalamic N-methyl-D-aspartate receptors and their relationship to gonadotropin-releasing hormone neurons. Endocrinology 140:2288–2296[Abstract/Free Full Text]
402. Pujic Z, Matsumoto I, Wilce PA 1993 Expression of the gene coding for the NR1 subunit of the NMDA receptor during rat brain development. Neurosci Lett 162:67–70[CrossRef][Medline]
403. Mishra OP, Delivoria-Papadopoulos M 1992 Modification of modulatory sites of NMDA receptor in the fetal guinea pig brain during development. Neurochem Res 17:1223–1228[CrossRef][Medline]
404. Gore AC, Wu JT, Rosenberg JJ, Roberts JL 1996 Gonadotropin-releasing hormone and NMDA receptor gene expression and colocalization change during puberty in female rats. J Neurosci 16:5281–5289
405. Nyberg CL, Srivastava V, Hiney JK, Lara F, Dees WL 1995 N-Methyl-D-aspartic acid receptor messenger ribonucleic acid levels and luteinizing hormone release in immature female rats: effects of stage of pubertal development and exposure to ethanol. Endocrinology 136:2874–2880[Abstract]
406. Zamorano PL, Mahesh VB, De Sevilla L, Brann DW 1998 Excitatory amino acid receptors and puberty. Steroids 63:268–270[CrossRef][Medline]
407. Eyigor O, Jennes L 1996 Changes in glutamate receptor subunit mRNAs in gonadotropin-releasing hormone neurons in rat brain. Endocrine 4:133–139
408. Abbud R, Smith MS 1995 Do GnRH neurons express the gene for the NMDA receptor? Brain Res 690:117–120[CrossRef][Medline]
409. Urbanski HF, Garyfallou VT, Kohama SG, Munro G, Lee C Do LHRH neurons of male Siberian hamster express glutamate receptors? Proceedings of the 25th Annual Meeting of the Society for Neuroscience, San Diego, CA, 1995, vol 21:1889 (Abstract 742.12)
410. Eyigor O, Jennes L 1997 Expression of glutamate receptor subunit mRNAs in gonadotropin-releasing hormone neurons during sexual maturation of the female rat. Neuroendocrinology 66:122–129[Medline]
411. McCarthy MM, Chan KYS, Pfaus JG Sex differences in non-NMDA glutamate receptor binding in neonatal rat brain. Proceedings of the 26th Annual Meeting of the Society for Neuroscience, Washington, DC, 1996, vol 22:560 (Abstract 226.12)
412. Brann DW 1995 Glutamate: a major excitatory transmitter in neuroendocrine regulation. Neuroendocrinology 61:213–225[Medline]
413. Sawyer CH 1975 Some recent developments in brain-pituitary-ovarian physiology. Neuroendocrinology 17:97–124[Medline]
414. Barraclough CA, Wise PM, Selmanoff MK 1984 A role for hypothalamic catecholamines in the regulation of gonadotropin secretion. Recent Prog Horm Res 40:487–529
415. Ramirez VD, Feder HH, Sawyer CH 1984 The role of brain catecholamines in the regulation of LH secretion: a critical inquiry. Front Neuroendocrinol 7:27–84
416. Ramirez VD, Kim K, Dluzen D 1985 Progesterone action on the LHRH and the nigrostriatal dopamine neuronal systems: in vitro and in vivo studies. Recent Prog Horm Res 41:421–472
417. Kalra SP, Crowley WR 1992 Neuropeptide Y: a novel neuroendocrine peptide in the control of pituitary hormone secretion, and its relation to luteinizing hormone. Front Neuroendocrinol 13:1–46[Medline]
418. Bhattacharya AN, Dierschke DJ, Yamaji T, Knobil E 1972 The pharmacologic blockade of the circhoral mode of LH secretion in ovariectomized rhesus monkeys. Endocrinology 90:778–786[Abstract/Free Full Text]
419. Plant TM, Nakai Y, Belchetz P Keogh E, Knobil E 1978 The sites of action of estradiol and phentolamine in the inhibition of the pulsatile, circhoral discharges of LH in the rhesus monkey (Macaca mulatta). Endocrinology 102:1015–1018[Abstract/Free Full Text]
420. Kaufman J-M, Kesner JS, Wilson RC, Knobil E 1985 Electrophysiological manifestation of luteinizing hormone-releasing hormone pulse generator activity in the rhesus monkey: influence of -adrenergic blocking agents. Endocrinology 116:1327–1333[Abstract/Free Full Text]
421. Gearing M, Terasawa E 1991 The ₁-adrenergic neuronal system is involved in pulsatile release of luteinizing hormone-releasing hormone (LHRH) in the ovariectomized female monkey. Neuroendocrinology 93:373–381
422. Gearing M, Terasawa E 1991 Suppression of luteinizing hormone (LH) release by the ₁-adrenergic receptor antagonist prazosin in the ovariectomized female rhesus monkey. Am J Primatol 25:23–33
423. Gearing M, Terasawa E 1991 Prostaglandin E₂ mediates the stimulatory effect of methoxamine in in vivo luteinizing hormonereleasing hormone (LHRH) release in the ovariectomized female rhesus monkey. Brain Res 560:276–28l[CrossRef][Medline]
424. Terasawa E, Krook C, Hei DL, Gearing M, Schultz NJ, Davis GA 1988 Norepinephrine is a possible neurotransmitter stimulating pulsatile release of luteinizing hormone releasing hormone in the rhesus monkey. Endocrinology 123:1808–1816[Abstract/Free Full Text]
425. Weiner RI, Ganong WF 1971 Effect of the depletion of brain catecholamines on puberty and the estrous cycle in the rat. Neuroendocrinology 8:125–135[Medline]
426. Ruf KB, Holmes MJ 1974 Delayed vaginal opening in rats after an intraventricular injection of 6-hydroxydopamine. J Endocrinol 60:383–384[Abstract/Free Full Text]
427. Sarkar DK, Smith GC, Fink G 1981 Effect of manipulating central catecholamines on puberty and the surge of luteinizing hormone and gonadotropin releasing hormone induced by pregnant mare serum gonadotropin in female rats. Brain Res 213:335–349[CrossRef][Medline]
428. Cocchi D, Fraschini F, Jalanbo H, Müller EE 1974 Role of brain catecholamines in the postcastration rise in plasma LH of prepubertal rats. Endocrinology 95:1649–1657[Abstract/Free Full Text]
429. Kim K, Lee BJ, Cho RN, Kang SS, Choi WS, Park SD, Lee CC, Cho WK, Wuttke W 1994 Blockade of noradrenergic neurotransmission with diethyldithiocarbamic acid decreases the mRNA level of gonadotropin-releasing hormone in the hypothalamus of ovariectomized, steroid-treated pubertal rats. Neuroendocrinology 59:539–544[Medline]
430. Darney Jr KJ, Goldman JM, Vandenbergh JG 1992 Neuroendocrine responses to social regulation of puberty in the female house mouse. Neuroendocrinology 55:434–443[Medline]
431. Gore AC, Terasawa E 1991 A role for norepinephrine in the control of puberty in the female rhesus monkey, Macaca mulatta. Endocrinology 129:3009–3017[Abstract/Free Full Text]
432. Terasawa E, Gore AC 1992 Regulation of pulsatile LHRH release in primates. In: Crowley Jr WF, Conn PM (eds) Modes of Action of GnRH and GnRH Analogs. Springer-Verlag, New York, pp 256–274
433. Gore AC, Saitoh Y, Terasawa E 1996 Effects of adrenal medulla transplantation into the third ventricle on the onset of puberty in female rhesus monkeys. Exp Neurol 140:172–183[CrossRef][Medline]
434. Héry M, François-Bellan AM, Deprez P, Faudon M, Héry F 1993 Evidence for the presence of noradrenergic neurons and their inhibitory action on luteinizing hormone-releasing hormone release in cultured fetal rat hypothalamic cells. Life Sci 52:2017–2025[CrossRef][Medline]
435. Weiss B, Chen JF, Zhang S, Zhou L-W 1992 Developmental and age-related changes in the D₂ dopamine receptor mRNA subtypes in rat brain. Neurochem Int 20 [Suppl]:49S–58S
436. Clough RW, Hoffman GE, Sladek CD 1988 Peripubertal development of noradrenergic stimulation of luteinizing hormonereleasing hormone neurosecretion in vitro. Brain Res 446:121–132[CrossRef][Medline]
437. Lauder JM, Bloom FE 1974 Ontogeny of monoamine neurons in the locus coeruleus, raphe nuclei and substantia nigra of the rat. I. Cell differentiation. J Comp Neurol 155:469–481[CrossRef][Medline]
438. Loizou LA 1972 The postnatal ontogeny of monoamine-containing neurons in the central nervous system of the albino rat. Brain Res 40:395–418[CrossRef][Medline]
439. Richards GE, Gluckman PD, Ball K, Manneli SC, Kalamaras JA 1990 Expanded ontogeny of neurotransmitters and their metabolites in the brains of fetal and newborn lambs. J Dev Physiol 14:331–336[Medline]
440. Parés-Herbuté N, Tapia-Arancibia L, Astier H 1989 Ontogeny of the metencephalic, mesencephalic and diencephalic content of catecholamines as measured by high performance liquid chromatography with electrochemical detection. Int J Dev Neurosci 7:73–79[CrossRef][Medline]
441. Agrawal HC, Glisson SN, Himwich WA 1966 Changes of monoamines of rat brain during postnatal ontogeny. Biochim Biophys Acta 130:511–513[Medline]
442. Stern WC, Miller M, Forbes WB, Morgane PJ, Resnick O 1975 Ontogeny of the levels of the biogenic amines in various parts of the brain and in peripheral tissues in normal and protein malnourished rats. Exp Neurol 49:314–326[CrossRef][Medline]
443. Gladue BA, Humphrys RR, Debold JF, Clemens LG 1977 Ontogeny of biogenic amine systems and modification of indole levels upon adult sexual behavior in the rat. Pharmacol Biochem Behav 7:253–258[CrossRef][Medline]
444. Höhn K-G, Wuttke W 1979 Ontogeny of catecholamine turnover rates in limbic and hypothalamic structures in relation to serum prolactin and gonadotropin levels. Brain Res 179:281–293[CrossRef][Medline]
445. Weiner RI, Ganong WF 1972 Norepinephrine concentration in the hypothalamus, amygdala, hippocampus, and cerebral cortex during postnatal development and vaginal opening. Neuroendocrinology 9:65–71[CrossRef][Medline]
446. Morris MJ, Dausse J-P, Devynck M-A, Meyer P 1980 Ontogeny of a₁ and a2-adrenoreceptors in rat brain. Brain Res 190:268–271[CrossRef][Medline]
447. Raum WJ, Glass AR, Swerdloff RS 1980 Changes in hypothalamic catecholamine neurotransmitters and pituitary gonadotropins in the immature female rat: relationships to the gonadostat theory of puberty onset. Endocrinology 106:1253–1258[Abstract/Free Full Text]
448. Johnson AE, Renner KJ, Allen D, Luine VN, Nock B, Feder HH 1987 Noradrenergic regulation of a₁-receptors during the postnatal development of the guinea pig. Brain Res Dev Brain Res 32:67–74[CrossRef]
449. Choi S, Kellogg CK 1992 Norepinephrine utilization in the hypothalamus of the male rat during adolescent development. Dev Neurosci 14:369–376[Medline]
450. Ohkura T, Hagino N, Yaoi Y 1995 Changes in monoamine concentrations in developing female rat brains under continuous light. Acta Obstet Gynecol Jpn 47:225–230
451. Ivanisevic-Milanovic OK, Pantic V, Demajo M, Loncar-Stevanovic H 1993 Catecholamines in hypothalamus, ovaries and uteri of rats with precocious puberty. J Endocrinol Invest 16:769–773[Medline]
452. Honma K, Hön KG, Wuttke W 1979 Involvement of catecholamines in electing LH peaks in 15 day old female rats. Acta Endocrinol (Copenh) 86:263–272
453. Wuttke W, Honma K, Lamberts R, Hohn KG 1980 The role of monoamines in female puberty. FASEB J 39:2378–2383
454. Levitt P, Rakic P 1982 The time of genesis, embryonic origin and differentiation of the brain stem monoamine neurons in the rhesus monkey. Dev Brain Res 4:35–57
455. Goldman-Rakic PS, Brown GM 1982 Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Brain Res Dev Brain Res 4:339–349
456. Krieger A, Wuttke W 1980 Ontogeny of tyrosine hydroxylase and dopamine-ß-hydroxylase activity in discrete limbic and hypothalamic structures of female rats. Brain Res 193:181–188[CrossRef][Medline]
457. Donoso AO, Banzan AM 1975 Brain and hypothalamic catecholamine turnover in relation with puberty in the female rat. Acta Physiol Latinoam 25:37–44[Medline]
458. Advis JP, Simpkins JW, Chen HT, Meites J 1978 Relation of biogenic amines to onset of puberty in the female rat. Endocrinology 103:11–16[Abstract/Free Full Text]
459. Pau KYF, Ma YJ, Yu JH, Yang SP, Airhart N, Spies HG 1997 Topographic comparison of the expression of norepinephrine transporter, tyrosine hydroxylase and neuropeptide-Y mRNA in association with dopamine ß-hydroxylase neurons in the rabbit brainstem. Brain Res Mol Brain Res 48:367–381[Medline]
460. Pau KYF, Lee CJ, Cowles A, Yang SP, Hess DL, Spies HG 1998 Possible involvement of norepinephrine transporter activity in the pulsatility of hypothalamic gonadotropin-releasing hormone release: influence of the gonad. J Neuroendocrinol 10:21–29[CrossRef][Medline]
461. Ojeda SR, Negro-Vilar A 1984 Release of prostaglandin E2 from the hypothalamus depends on extracellular Ca²⁺ availability: relation to LHRH release. Neuroendocrinology 39:442–447[Medline]
462. Ojeda SR, Negro-Vilar A 1985 Prostaglandin E2-induced luteinizing hormone-releasing hormone release involves mobilization of intracellular Ca²⁺. Endocrinology 116:1763–1770[Abstract/Free Full Text]
463. Ojeda SR, Urbanski HF, Katz KH, Costa ME 1988 Prostaglandin E₂ releases luteinizing hormone-releasing hormone from the female juvenile hypothalamus through a Ca²⁺-dependent, calmodulin-independent mechanism. Brain Res 441:339–351[CrossRef][Medline]
464. Ojeda SR, Urbanski HF, Katz KH, Costa ME 1986 Activation of estradiol-positive feedback at puberty: estradiol sensitizes the LHRH-releasing system at two different biochemical steps. Neuroendocrinology 43:259–265[Medline]
465. Kordon C, Drouva SV, Martinez de la Escalera G, Weiner RI 1994 Role of classic and peptide neuromodulators in the neuroendocrine regulation of luteinizing hormone and prolactin. In: Knobil E, Neill JD (eds) The Physiology of Reproduction. Raven Press Ltd, New York, pp 1621–1682
466. Lacau de Mengido IM, Becú-Villalobos D, Díaz G, Libertun C 1989 Chronic activation of dopamine receptors in the female infantile rat: effect on hypophyseal hormones and on the onset of puberty. Endocrinology 124:746–753[Abstract/Free Full Text]
467. Döcke F, Rohde W, Oelssner W, Schleussner E, Gutenschwager I, Dörner G 1987 Influence of the medial preoptic dopaminergic activity on the efficiency of the negative estrogen feedback in prepubertal and cyclic female rats. Neuroendocrinology 46:445–452[CrossRef][Medline]
468. Gerber P, Döcke F, Rohde W, Dörner G 1984 Evidence that inhibition of medial preoptic dopaminergic activity may be involved in the prepubertal desensitization to the negative oestrogen feedback in female rats. Exp Clin Endocrinol 84:7–12[Medline]
469. Freeman TB, Spence MS, Boss BD, Spector DH, Strecker RE, Olanow CW, Kordower JH 1991 Development of dopaminergic neurons in the human substantia niagra. Exp Neurol 113:344–353[CrossRef][Medline]
470. Verney C, Zecevic N, Nikolic B, Alvarez C, Berger B 1991 Early evidence of catecholaminergic cell groups in 5- and 6-week old human embryos using tyrosine hydroxylase and dopamine-ß- hydroxylase immunocytochemistry. Neurosci Lett 131:121–124[CrossRef][Medline]
471. Ronnekleiv OK, Naylor BR 1995 Chronic cocaine exposure in the fetal rhesus monkey: consequences for early development of dopamine neurons. J Neurosci 15:7330–7343[Abstract]
472. Daikoku S, Kawano H, Okamura Y, Tokuzen M, Nagatsu I 1986 Ontogenesis of immunoreactive tyrosine hydroxylase-containing neurons in rat hypothalamus. Brain Res 393:85–98[Medline]
473. Tillet Y, Thibault J 1987 Early ontogeny of catecholaminergic structures in the sheep brain. Immunohistochemical study. Anat Embryol (Berl) 177:173–181[CrossRef][Medline]
474. Reisert I, Pilgrim C 1989 Early sexual differentiation of diencephalic dopaminergic neurons of the rat in vitro. Cell Tissue Res 255:411–417[Medline]
475. Olson L, Fuxe K, Hökfelt T 1972 The effect of pituitary transplants on the tubero-infundibular dopamine neurons in various endocrine states. Acta Endocrinol (Copenh) 17:233–244
476. Arbogast LA, Voogt JL 1991 Hyperprolactinemia increases and hypoprolactinemia decreases tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nuclei, but not the substantia nigra or zone incerta. Endocrinology 128:997–1005[Abstract/Free Full Text]
477. Arbogast LA, Voogt JL 1991 Ontogeny of tyrosine hydroxylase mRNA signal levels in central dopaminergic neurons: development of a gender difference in the arcuate nuclei. Brain Res Dev Brain Res 63:151–161[Medline]
478. Schambra UB, Duncan GE, Breese GR, Fornaretto MG, Caron MG, Fremeau Jr RT 1994 Ontogenty of D_1A and D2 dopamine receptor subtypes in rat brain using in situ hybridization and receptor binding. Neuroscience 62:65–85[CrossRef][Medline]
479. Sales N, Martres MP, Bouthenet ML, Schwartz JC 1989 Ontogeny of dopaminergic D-2 receptors in the rat nervous system: characterization and detailed autoradiographic mapping with [¹²⁵I]iodosulpride. Neuroscience 28:673–700[CrossRef][Medline]
480. Murrin LC 1982 In vivo studies of dopamine receptor ontogeny. Life Sci 31:971–980[CrossRef][Medline]
481. Lacau-Mengido IM, Becú-Villalobos D, Thyssen SM, Rey EB, Lux-Lantos VAR, Libertun C 1993 Antidopaminergic-induced hypothalamic LHRH release and pituitary gonadotrophin secretion in 12 day-old female and male rats. J Neuroendocrinol 5:705–709[CrossRef][Medline]
482. Andersen SL, Rutstein M, Benzo JM, Hostetter JC, Teicher MH 1997 Sex differences in dopamine receptor overproduction and elimination. Neuroreport 8:1495–1498[Medline]
483. Choi WS, Ronnekleiv OK 1996 Effects of in utero cocaine exposure on the expression of mRNAS encoding the dopamine transporter and the D1, D2 and D5 dopamine receptor subtypes in fetal rhesus monkey. Brain Res Dev Brain Res 96:249–260[CrossRef][Medline]
484. Unis AS, Roberson MD, Robinette R, Ha J, Dorsa DM 1998 Ontogeny of human brain dopamine receptors. I. Differential expression of [3H]-SCH23390 and [³H]-YM09151–2 specific binding. Brain Res Dev Brain Res 106:109–117[CrossRef][Medline]
485. Peroutka SJ 1995 5-HT receptors: past, present and future. Trends Neurosci 18:68–69[CrossRef][Medline]
486. Héry M, Laplante E, Kordon C 1976 Participation of serotonin in the phasic release of LH. Evidence from pharmacological experiments. Endocrinology 99:496–503[Abstract/Free Full Text]
487. Marco M, Fluckiger E 1980 Role of serotonin in the regulation of ovulation. Neuroendocrinology 30:228–231[Medline]
488. Wilson CA, Horth CE, McNeilly A, McDonald PG 1975 Effect of serotonin and progesterone on induced ovulation in immature rats. J Endocrinol 64:337–347[Abstract/Free Full Text]
489. Meyer DC 1978 Hypothalamic and raphe serotonergic systems in ovulation control. Endocrinology 103:1067–1074[Abstract/Free Full Text]
490. Ayala ME, Rosas P, Dominguez R 1994 Different effects of unilateral and bilateral lesions of the dorsal raphe nucleus on puberty and first ovulation. Brain Res Bull 34:27–30[CrossRef][Medline]
491. Ayala ME, Monroy J, Morales L, Castro ME, Dominguez R 1998 Effects of a lesion in the dorsal raphe nuclei performed during the juvenile period of the female rat, on puberty. Brain Res Bull 47:211–218[CrossRef][Medline]
492. Davidson BA, Kuenzel WJ 1991 Hypothalamic biogenic amine levels in broiler chicks showing advanced sexual maturation. Poult Sci 70:1610–1618[Medline]
493. Antoniou K, Papadopoulou-Daifotis Z, Kanelakis K, Varonos DD, Sfikakis A 1997 Relationship between the thymus and neurochemical changes in the hypothalamus-preoptic area and prefrontal cortex in female rats with delayed puberty. Int J Dev Neurosci 15:911–920[CrossRef][Medline]
494. Cramer OM, Barraclough CA 1978 The actions of serotonin, norepinephrine, and epinephrine on hypothalamic processes leading to adenohypophysial luteinizing hormone release. Endocrinology 103:694–703[Abstract/Free Full Text]
495. Kordon C, Glowinski J 1972 Role of hypothalamic monoaminergic neurons in the gonadotropin release-regulating mechanisms. Neuropharmacology 11:153–162[CrossRef][Medline]
496. Morello H, Taleisnik S 1985 Changes of the release of LH on the day of proestrous after lesions or stimulation of the raphe nuclei in rats. Brain Res 360:311–317[CrossRef][Medline]
497. Moguilevsky JA, Faigon MR, Scacchi P, Szwarcfarb B 1985 Effect of the serotoninergic system on luteinizing hormone secretion in prepubertal female rats. Neuroendocrinology 40:135–138[Medline]
498. Schneider H, McCann S 1970 Monoamine and indolamines and control of LH secretion. Endocrinology 86:1127–1133[Abstract/Free Full Text]
499. Bethea CL, Pecins-Thompson M, Schutzer WE, Gundlah C, Lu ZN 1998 Ovarian steroids and serotonin neural function. Mol Neurobiol 18:87–123[Medline]
500. Gundlah C, Pecins-Thompson M, Schutzer WE, Bethea CL 1999 Ovarian steroid effects on serotonin 1A, 2A and 2C receptor mRNA in macaque hypothalamus. Brain Res Mol Brain Res 63:325–339[Medline]
501. Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL 1996 Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosci 16:7021–7029[Abstract/Free Full Text]
502. Pecins-Thompson M, Brown NA, Bethea CL 1998 Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques. Brain Res Mol Brain Res 53:120–129[Medline]
503. Pecins-Thompson M, Bethea CL 1999 Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience 89:267–277[CrossRef][Medline]
504. Calka J, Majewski M, Kaleczyc J, Lakomy M 1993 Immunocytochemical demonstration of neuropeptide Y and luteinizing hormone-releasing hormone-immunoreactive structures in the organum vasculosum laminae terminalis of juvenile gilts. Neurosci Lett 158:21–24[CrossRef][Medline]
505. Hilal EM, Chen JH, Silverman A-J 1996 Joint migration of gonadotropin-releasing hormone (GnRH) and neuropeptide Y (NPY) neurons from olfactory placode to central nervous system. J Neurobiol 31:487–502[CrossRef][Medline]
506. Allen JM, McGregor GP, Woodhams PL, Polak JM, Bloom SR 1984 Ontogeny of a novel peptide, neuropeptide Y (NPY) in rat brain. Brain Res 303:197–200[CrossRef][Medline]
507. Daikoku S, Koide I 1998 Spatiotemporal appearance of developing LHRH neurons in the rat brain. J Comp Neurol 393:34–47[CrossRef][Medline]
508. Woodhams PL, Allen YS, McGovern J, Allen JM, Bloom SR, Balazs R, Polak JM 1985 Immunohistochemical analysis of the early ontogeny of the neuropeptide Y system in rat brain. Neuroscience 15:173–202[CrossRef][Medline]
509. Kagotani Y, Hashimoto T, Tsuruo Y, Kawano H, Daikoku S, Chihara K 1989 Development of the neuronal system containing neuropeptide Y in the rat hypothalamus. Int J Dev Neurosci 7:359–374[CrossRef][Medline]
510. Higuchi H, Yokokawa K, Iwasa A, Yoshida H, Miki N 1991 Age-dependent increase in neuropeptide Y gene expression in rat adrenal gland and specific brain areas. J Neurochem 57:1840–1847[CrossRef][Medline]
511. Sutton SW, Mitsugi N, Plotsky PM, Sarkar DK 1988 Neuropeptide Y (NPY): a possible role in the initiation of puberty. Endocrinology 123:2152–2154[Abstract/Free Full Text]
512. Corder R, Walker CD, Gaillard RC, Aubert ML 1992 Inhibition of sexual maturation in male rats by melatonin: evidence linking the mechanism of action to changes in the regulation of hypothalamic neuropeptide Y. J Neuroendocrinol 4:1–7
513. Beal MF, Walker LC, Swartz KJ, Casanova MF, Price DL 1988 Developmental changes of neuropeptides and amino acids in baboon cortex. Brain Res Dev Brain Res 44:156–159[CrossRef][Medline]
514. Gore AC, Mitsushima D, Terasawa E 1993 A possible role of neuropeptide Y in the control of the onset of puberty in female rhesus monkeys. Neuroendocrinology 58:23–34[Medline]
515. Pearson PL, Anderson LL, Jacobson CD 1996 The prepubertal ontogeny of neuropeptide Y-like immunoreactivity in the male Meishan pig brain. Brain Res Dev Brain Res 91:41–69[CrossRef][Medline]
516. Thind KK, Boggan JE, Goldsmith PC 1993 Neuropeptide Y system of the female monkey hypothalamus: retrograde tracing and immunostaining. Neuroendocrinology 57:289–298[Medline]
517. McDonald JK, Tigges J, Tigges M, Reich C 1988 Developmental study of neuropeptide Y-like immunoreactivity in the neurohypophysis and intermediate lobe of the rhesus monkey (Macaca mulatta). Cell Tissue Res 254:499–509[Medline]
518. de Quidt ME, Emson PC 1986 Distribution pattern of neuropeptide Y-like immunoreactivity in the rat central nervous system. Neuroscience 18:545–618[CrossRef][Medline]
519. Reuss S, Hurlbut EC, Speh JC, Moore RY 1990 Neuropeptide Y localization in telencephalic diencephalic structures of the ground squirrel brain. Am J Anat 188:163–174[CrossRef][Medline]
520. Tong Y, Dumont Y, Shen SH, Quirion R 1997 Comparative developmental profile of the neuropeptide Y/Y1 receptor gene and protein in the brain. Brain Res Mol Brain Res 48:323–332[Medline]
521. Naveilhan P, Neveu I, Arenas E, Ernfors P 1998 Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience 87:289–302[CrossRef][Medline]
522. Kalra SP 1993 Mandatory neuropeptide-steroid signal for the preovulatory luteinizing hormone-releasing hormone discharge. Endocr Rev 14:507–538[Abstract/Free Full Text]
523. Levine JE, Bauer-Dantoin AC, Besecke LM, Conaghan LA, Legan SJ, Meredith JM, Strobl FJ, Urban JH, Vogelsong KM, Wolfe AM 1991 Neuroendocrine regulation of the luteinizing hormonereleasing hormone pulse generator in the rat. Recent Prog Horm Res 47:97–153
524. Levine JE, Chappell P, Besecke LM, Bauer-Dantoin AC, Wolfe AM, Porkka-Heiskanen T, Urban JH 1995 Amplitude and frequency modulation of pulsatile luteinizing hormone-releasing hormone release. Cell Mol Neurobiol 15:117–139[CrossRef][Medline]
525. Kalra SP, Crowley WR 1984 Norepinephrine-like effects of neuropeptide Y on LH secretion in the rat. Life Sci 35:1173–1176[CrossRef][Medline]
526. McDonald JK, Lumpkin MD, Samson WK, McCann SM 1985 Neuropeptide Y affects secretion of luteinizing hormone and growth hormone in ovariectomized rats. Proc Natl Acad Sci USA 82:561–564[Abstract/Free Full Text]
527. Kohorram O, Pau K-YF, Spies HG 1987 Bimodal effects of neuropeptide Y on hypothalamic release of gonadotropin-releasing hormone in conscious rabbits. Neuroendocrinology 45:290–297[Medline]
528. Kaynard AH, Pau K-YF, Hess DL, Spies HG 1990 Third-ventricular infusion of neuropeptide Y suppresses luteinizing hormone secretion in ovariectomized rhesus macaques. Endocrinology 127:2437–2444[Abstract/Free Full Text]
529. McShane TM, May T, Miner JL, Keisler DH 1992 Central action of neuropeptide-Y may provide a neuromodulatory link between nutrition and reproduction. Biol Reprod 46:1151–1157[Abstract]
530. Woller MJ, McDonald JK, Reboussin DM, Terasawa E 1992 Neuropeptide Y is a neuromodulator of pulsatile luteinizing hormone-releasing hormone release in the gonadectomized rhesus monkey. Endocrinology 130:2333–2342[Abstract/Free Full Text]
531. Woller MJ, Terasawa E 1991 Infusion of neuropeptide Y into the stalk-median eminence stimulates in vivo release of luteinizing hormone-releasing hormone in gonadectomized rhesus monkeys. Endocrinology 128:1144–1150[Abstract/Free Full Text]
532. Woller MJ, Terasawa E 1992 Estradiol enhances the action of neuropeptide Y on in vivo luteinizing hormone-releasing hormone release in the ovariectomized rhesus monkey. Neuroendocrinology 56:921–925[Medline]
533. Besecke LM, Levine JE 1994 Acute increase in responsiveness of luteinizing hormone (LH)-releasing hormone nerve terminals to neuropeptide-Y stimulation before the preovulatory LH surge. Endocrinology 135:63–66[Abstract]
534. Besecke LM, Wolfe AM, Pierce ME, Takahashi JS, Levine JE 1994 Neuropeptide Y stimulates luteinizing hormone-releasing hormone release from superfused hypothalamic GT1–7 cells. Endocrinology 135:1621–1627[Abstract]
535. Pau KYF, Berria M, Hess DL, Spies HG 1995 Hypothalamic site-dependent effects of neuropeptide Y on gonadotropin-releasing hormone secretion in rhesus macaques. J Neuroendocrinol 7:63–67[CrossRef][Medline]
536. Xu B, Pu S, Kalra PS, Hyde JF, Crowley WR, Kalra SP 1996 An interactive physiological role of neuropeptide Y and galanin in pulsatile pituitary luteinizing hormone secretion. Endocrinology 137:5297–5302[Abstract]
537. Xu M, Hill JW, Levine JE 2000 Attenuation of luteinizing hormone (LH) surges in neuropeptides Y-knockout (NPY-KO) mice. Neuroendocrinology 72:263–271[CrossRef][Medline]
538. Brann DW, McDonald JK, Putnam CD, Mahesh VB 1991 Regulation of hypothalamic gonadotropin-releasing hormone and neuropeptide Y concentrations by progesterone and corticosteroids in immature rats: correlation with luteinizing hormone and follicle-stimulating hormone release. Neuroendocrinology 54:425–432[Medline]
539. O’Conner JL, Wade MF, Brann DW, Mahesh VB 1995 Evidence that progesterone modulates anterior pituitary neuropeptide Y levels during the progesterone-induced gonadotropin surge in the estrogen-primed intact immature female rat. J Steroid Biochem 52:497–504
540. Minami S, Frautschy SA, Plotsky PM, Sutton SW, Sarker DK 1990 Facilitatory role of neuropeptide Y on the onset of puberty: effect of immunoneutralization of neuropeptide Y on the release of luteinizing hormone and luteinizing hormone-releasing hormone. Neuroendocrinology 52:112–115[Medline]
541. Minami S, Sarkar DK 1992 Central administration of neuropeptide Y induces precocious puberty in female rats. Neuroendocrinology 56:930–934[Medline]
542. Fraley GS, Kuenzel WJ 1993 Precocious puberty in chicks (Galls domesticus) induced by central injection of neuropeptide Y. Life Sci 52:1649–1656[CrossRef][Medline]
543. Pierroz DD, Gruaz NM, d’Alieves V, Aubert ML 1995 Chronic administration of neuropeptide Y into the lateral ventricle starting at 30 days of life delays sexual maturation in the female rat. Neuroendocrinology 61:293–300[CrossRef][Medline]
544. Gruaz NM, Pierroz DD, Rohner-Jeanenreaud F, Sizonenko PC, Aubert ML 1993 Evidence that neuropeptide Y could represent a neuroendocrine inhibitor of sexual maturation in unfavorable metabolic conditions in the rat. Endocrinology 133:1891–1894[Abstract/Free Full Text]
545. Aubert ML, Pierroz DD, Gruaz NM, d’Alleves V, Vuagnat BA, Pralong FP, Blum WF, Sizonenko PC 1998 Metabolic control of sexual function and growth: role of neuropeptide Y and leptin. Mol Cell Endocrinol 140:107–113[CrossRef][Medline]
546. Aubert ML, Gruaz NM, d’Alleves V, Pierroz DD, Catzeflis C, Sizonenko PC 1995 The control of the onset of puberty in the rat: potential role of neuropeptide Y. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 119–127
547. El Majdoubi M, Sahu A, Plant TM 2000 Changes in hypothalamic gene expression associated with the arrest of pulsatile GnRH release during infancy in the agonadal male rhesus monkey (Macaca mulatta). Endocrinology 141:3273–3277[Abstract/Free Full Text]
548. Raposinho PD, Broqua P, Pierroz DD, Hyward A, Dumont Y, Quirion R, Junien J-L, Aubert ML 1999 Evidence that the inhibition of luteinizing hormone secretion exerted by central administration of neuropeptide Y (NPY) in the rat is predominantly mediated by the NPY-Y₅ receptor subtype. Endocrinology 140:4046–4055[Abstract/Free Full Text]
549. Hendry SHC, Jones EG, DeFelipe J, Schmechel D, Brandon C, Emson PC 1984 Neuropeptide-containing neurons of the cerebral cortex are also GABAergic. Proc Natl Acad Sci USA 81:6526–6530[Abstract/Free Full Text]
550. Francois-Bellan AM, Kachidian P, Dusticier G, Tonon MC, Vaudry H, Bosler O 1990 GABA neurons in the rat suprachiasmatic nucleus: involvement in chemospecific synaptic circuitry and evidence for GAD-peptide colocalization. J Neurocytol 19:937–947[CrossRef][Medline]
551. Horvath TL, Bechman I, Naftolin F, Kalra SP, Leranth C 1997 Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 756:283–286[CrossRef][Medline]
552. Obrietan K, van den Pol AN 1996 Neuropeptide Y depresses GABA-mediated calcium transients in developing suprachiasmatic nucleus neurons: a novel form of calcium long-term depression. J Neurosci 16:3521–3533[Abstract/Free Full Text]
553. van den Pol AN, Obrietan K, Chen G, Belousov AB 1996 Neuropeptide Y-mediated long-term depression of excitatory activity in suprachiasmatic nucleus neurons. J Neurosci 16:5883–5895[Abstract/Free Full Text]
554. Chen G, van den Pol AN 1996 Multiple NPY receptors coexist in pre- and postsynaptic sites: inhibition of GABA release in isolated self-innervating SCN neurons. J Neurosci 16:7711–7724[Abstract/Free Full Text]
555. Qian J, Colmers F, Saggau P 1997 Inhibition of synaptic transmission by neuropeptide Y in rat hippocampal area CA1: modulation of presynaptic Ca²⁺ entry. J Neurosci 17:8169–8177[Abstract/Free Full Text]
556. Erickson JC, Clegg KE, Palmiter RD 1996 Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381:415–418[CrossRef][Medline]
557. Baraban SC, Hollopeter G, Erickson JC, Schwartzkroin PA, Palmiter RD 1997 Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J Neurosci 17:8927–8936[Abstract/Free Full Text]
558. Sahu A, Plant TM 2000 Leptin neuropeptide Y and puberty in nonhuman primates. In: Bourguignon J-P, Plant TM (eds) Control of the Onset of Puberty V. Elsevier, Amsterdam, pp 351–361
559. Lopez FL, Negro-Vilar A 1990 Galanin stimulates luteinizing hormone-releasing hormone secretion from arcuate nucleus-median eminence fragments in vitro involvement of an -adrenergic mechanism. Endocrinology 127:2431–2436[Abstract/Free Full Text]
560. Finn PD, McFall TB, Clifton DK, Steiner RA 1996 Sexual differentiation of galanin gene expression in gonadotropin-releasing hormone neurons. Endocrinology 137:4767–4772[Abstract]
561. Cadd GG, Clifton KK, Steiner RA 1995 Induction of galanin gene expression in GnRH and GHRH neurons: a common motif in pubertal maturation of the growth and reproductive axes. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 73–85
562. Lopez FL, Merchenthaler IJ, Moretto M, Negro-Vilar A 1998 Modulating mechanisms of neuroendocrine cell activity: the LHRH pulse generator. Cell Mol Neurobiol 18:125–146
563. Gabriel SM, Koenig JI, Kaplan LM 1990 Galanin-like immunoreactivity is influenced by estrogen in peripubertal and adult rats. Neuroendocrinology 51:168–173[CrossRef][Medline]
564. Planas B, Kolb PE, Raskind MA, Miller MA 1994 Activation of galanin pathways across puberty in the male rat: assessment of regional densities of galanin binding sites. Neuroscience 63:859–867[CrossRef][Medline]
565. Planas B, Kolb PE, Raskind MA, Miller MA 1994 Activation of galanin pathways across puberty in the male rat: galanin gene expression in the bed nucleus of the stria terminalis and medial amygdala. Neuroscience 63:851–858[CrossRef][Medline]
566. Planas B, Kolb PE, Raskind MA, Miller MA 1994 Galanin in the bed nucleus of the stria terminalis and medial amygdala of the rat: lack of sexual dimorphism despite regulation of gene expression across puberty. Endocrinology 134:1999–2004[Abstract/Free Full Text]
567. Rossmanith WG, Marks DL, Clifton DK, Steiner RA 1994 Induction of galanin gene expression in gonadotropin-releasing hormone neurons with puberty in the rat. Endocrinology 135:1401–1408[Abstract]
568. Horvath TL, Naftolin F, Leranth C, Sahu A, Kalra SP 1996 Morphological and pharmacological evidence for neuropeptide Y-galanin interaction in the rat hypothalamus. Endocrinology 137:3069–3078[Abstract]
569. Finn PD, Pau KYF, Spies HG, Cunningham MJ, Clifton DK, Steiner RA 2000 Galanin’s functional significance in the regulation of the neuroendocrine reproductive axis of the monkey. Neuroendocrinology 71:16–26[CrossRef][Medline]
570. Terasawa E, Nyberg CL 1997 LHRH pulse generation in the monkey: in vivo and in vitro studies. In: Yokoyama A, Maeda K, Tstukamura H (eds) Neuronal Control of Reproduction: Physiology and Behavior. Japan Scientific Society Press, Tokyo, pp 57–70
571. Krsmanovic LZ, Stojilkovic SS, Mertz LM, Tomic M, Catt KJ 1993 Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons. Proc Natl Acad Sci USA 90:3908–3912[Abstract/Free Full Text]
572. Jennes L, Conn PM 1994 Gonadotropin-releasing hormone and its receptors in the rat brain. Front Neuroendocrinol 15:51–77[CrossRef][Medline]
573. Krsmanovic LZ, Martinez-Fuentes AJ, Arora KK, Mores N, Navarro CE, Chen H-C, Stojilkovic SS, Catt K 1999 Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. Endocrinology 140:1423–1431[Abstract/Free Full Text]
574. Stojilkovic SS, Krsmanovic LZ, Spergel DJ, Catt KJ 1994 Gonadotropin-releasing hormone neurons: intrinsic pulsatility and receptor-mediated regulation. Trends Endocrinol Metab 5:201–209
575. Stojilkovic SS, Reinhart J, Catt KJ 1994 Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev 15:462–499[Abstract/Free Full Text]
576. Terasawa ELuteinizing hormone-releasing hormone (LHRH) neurons: mechanism of pulsatile LHRH release. Vitam Horm, in press
577. Kobayashi H, Wada M, Uemura H 1972 The hypothalamic median eminence as a neuroendocrine organ. Med J Osaka Univ 23:43–55[Medline]
578. Kozlowski GP, Coats PW 1985 Ependymoneuronal specializations between LHRH fibers and cells of the cerebroventricular system. Cell Tissue Res 242:301–311[Medline]
579. Witkin JW, Ferin M, Popilskis SJ, Silverman AJ 1991 Effects of gonadal steroids on the ultrastructure of GnRH neurons in the rhesus monkey: synaptic input and glial apposition. Endocrinology 129:1083–1092[Abstract/Free Full Text]
580. King JC, Rubin BS 1994 Dynamic changes in LHRH neurovascular terminals with various endocrine conditions in adults. Horm Behav 28:349–356[CrossRef][Medline]
581. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG 1994 Glutamate-mediated astrocyte-neuron signaling. Nature 369:744–747[CrossRef][Medline]
582. Araque A, Parpura V, Sanzgiri RP, Haydon PG 1999 Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215[CrossRef][Medline]
583. Ma YJ, Hill DF, Creswick KE, Costa ME, Cornea A, Lioubin MN, Plowman GD, Ojeda SR 1999 Neuregulins signaling via a glial erbB-2-erbB-4 receptor complex contribute to the neuroendocrine control of mammalian sexual development. J Neurosci 19:9913–9927[Abstract/Free Full Text]
584. Hatton GI 1985 Reversible synapse formation and modulation of cellular relationships in the adult hypothalamus under physiological conditions. In: Cotman CW (ed) Synaptic Plasticity. Guilford Press, New York, pp 373–404
585. Theodosis DT, Poulain DA 1992 Neuronal-glial and synaptic remodeling in the adult hypothalamus in response to physiological stimuli. Ciba Found Symp 168:209–225[Medline]
586. Boersma CJ, Van Leeuwen FW 1994 Neuron-glia interactions in the release of oxytocin and vasopressin from the rat neural lobe: the role of opioids, other neuropeptides and their receptors. Neuroscience 62:1003–1020[CrossRef][Medline]
587. Ridet JL, Malhorta SK, Privat A, Gage FH 1997 Reactive astrocytes: cellular and molecular cues to biological function. Trend Neurosci 20:570–577[CrossRef][Medline]
588. Ojeda SR, Ma YJ, Rage F 1997 The transforming growth factor gene family is involved in the neuroendocrine control of mammalian puberty. Mol Psychol 2:355–358
589. Ojeda SR, Ma YJ 1998 Epidermal growth factor tyrosine kinase receptors and the neuroendocrine control of mammalian puberty. Mol Cell Endocrinol 140:101–106[CrossRef][Medline]
590. Marchetti B 1997 Cross-talk signals in the CNS: role of neurotrophic and hormonal factors, adhesion molecules and intracellular signaling agents in luteinizing hormone-releasing hormone (LHRH)-astroglial interactive network. Front Biosci 2:d88–d125
591. Marchetti B, Gallo F, Farinella Z, Romeo C, Morale MC 1996 Luteinizing hormone-releasing hormone (LHRH) receptors in the neuroendocrine-immune network. Biochemical bases and implications for reproductive physiopathology. Ann NY Acad Sci 784:209–236[Medline]
592. Garcia-Segura LM, Chowen JA, Duenas M, Parducz A, Naftolin F 1996 Gonadal steroids and astroglial plasticity. Cell Mol Neurobiol 16:225–237[CrossRef][Medline]
593. Martini L, Motta M, Piva F, Zanisi M 1996 LHRF, LHRH, GnRH - What controls the secretion of this hormone. Mol Psych 2:373–376
594. Ojeda SR, Urbanski HF, Costa M, Hill D, Moholt-Siebert M 1990 Involvement of transforming growth factor in the release of LHRH from the developing female hypothalamus. Proc Natl Acad Sci USA 87:9698–9702[Abstract/Free Full Text]
595. Junier M-P, Ma YJ, Costa ME, Hoffman G, Hill DF, Ojeda SR 1991 Transforming growth factor contributes to the mechanism by which hypothalamic injury induces precocious puberty. Proc Natl Acad Sci USA 88:9743–9747[Abstract/Free Full Text]
596. Ojeda SR, Ma YJ 1999 Glial-neuronal interactions in the neuroendocrine control of mammalian puberty: facilitatory effects of gonadal steroids. J Neurobiol 40:528–540[CrossRef][Medline]
597. Rage F, Hill DF, Senaesteves M, Breakefield XO, Coffey RJ, Costa ME, McCann SM, Ojeda SR 1997 Targeting transforming growth factor expression to discrete loci of the neuroendocrine brain induces female sexual precocity. Proc Natl Acad Sci USA 94:2735–2740[Abstract/Free Full Text]
598. Ma YJ, Berg-von der Emde K, Rage F, Wetsel WC, Ojeda SR 1997 Hypothalamic astrocytes respond to transforming growth factor- with the secretion of neuroactive substances that stimulate the release of luteinizing hormone-releasing hormone. Endocrinology 138:19–25[Abstract/Free Full Text]
599. Ma YJ, Hill DF, Junier M, Costa ME, Felder SE, Ojeda SR 1994 Expression of epidermal growth factor receptor changes in the hypothalamus during the onset of female puberty. Mol Cell Neurosci 5:246–262[CrossRef][Medline]
600. Galbiati M, Zanisi E, Messi E, Cavarretta I, Martini L, Melcangi RC 1996 Transforming growth factor-ß and astrocytic conditioned medium influence luteinizing hormone-releasing hormone gene expression in the hypothalamic cell line GT1. Endocrinology 137:5605–5609[Abstract]
601. Melcangi RC, Galbiati M, Messi E, Magnaghi V, Cavarretta I, Riva MA, Zansi M 1997 Astrocyte-neuron interactions in vitro: role of growth factors and steroids on LHRH dynamics. Brain Res Bull 44:465–469[CrossRef][Medline]
602. Fernandez-Galaz MC, Morschl E, Chowen JA, Torres-Aleman I, Naftolin F, Garcia-Segura LM 1997 Role of astroglia and insulin-like growth factor-I in gonadal hormone-dependent synaptic plasticity. Brain Res Bull 44:525–531[CrossRef][Medline]
603. Torres-Aleman I, Naftolin F, Robbins RJ 1990 Trophic effects of basic fibroblast growth factor on fetal rat hypothalamic cells: interactions with insulin-like growth factors I. Brain Res Dev Brain Res 52:253–257[CrossRef][Medline]
604. Ishikawa K, Ohe Y, Okutomi Y, Takeuchi T, Suzuki M 1992 Neurotrophic effects of fibroblast growth factors on peptidecontaining neurons in culture from postnatal rat hypothalamus. Neuroendocrinology 55:193–198[Medline]
605. Tsai P, Werner S, Weiner R 1995 bFGF is a neurotropic factor in GT1 GnRH neuronal cell lines. Endocrinology 136:3831–3838[Abstract]
606. Wetsel WC, Hill DF, Ojeda SR 1996 Basic fibroblast growth factor regulates the conversion of pro-luteinizing hormone (Pro-LHRH) to LHRH in immortalized hypothalamic neurons. Endocrinology 137:2606–2616[Abstract]
607. Smyth C, Knee R, Wilkinson M, Murphy PR 1997 Decline in basic fibroblast growth factor (FGF-2) mRNA expression in female rat hypothalamus at puberty. J Neuroendocrinol 9:151–159[CrossRef][Medline]
608. Ma YJ, Costa ME, Ojeda SR 1994 Developmental expression of the genes encoding transforming growth factor and its receptor in the hypothalamus of female rhesus macaques. Neuroendocrinology 60:346–359[Medline]
609. Schultz NJ, Terasawa E 1988 Posterior hypothalamic lesions advance the time of the pubertal changes in luteinizing hormone release in ovariectomized female rhesus monkeys. Endocrinology 123:445–455[Abstract/Free Full Text]
610. Terasawa E, Claypool L, Gore A, Watanabe G 1989 The timing of the onset of puberty in the female rhesus monkey. In: Delemarre-Van de Waal HA, Plant TM, van Rees GP, Shoemaker J (eds) Control of the Onset of Puberty. Elsevier, Amsterdam, vol 3:123–136
611. Radovick S, Wray S, Lee E, Nicols DK, Nakayama Y, Weintraub BD, Westphal H, Cutler Jr GB, Wondisford FE 1991 Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice. Proc Natl Acad Sci USA 88:3402–3406[Abstract/Free Full Text]
612. Zhen S, Zakaria M, Wolfe A, Radovick S 1997 Regulation of gonadotropin releasing hormone (GnRH) gene expression by insulin-like growth factor I in a cultured GnRH-expressing neuronal cell line. Mol Endocrinol 11:1145–1155[Abstract/Free Full Text]
613. Cameron JL 1991 Metabolic cues for the onset of puberty. Horm Res 36:97–103[Medline]
614. Cameron JL 1996 Nutritional determinants of puberty. Nutr Rev 54:S17–S22
615. Cameron JL, Koerker DJ, Steiner RA 1985 Metabolic changes during maturation of male monkeys: possible signals for onset of puberty. Am J Physiol 249:E385–E391
616. Foster DL, Olster DH 1985 Effect of restricted nutrition on puberty in the lamb: patterns of tonic luteinizing hormone (LH) secretion and competency of the LH surge system. Endocrinology 116:375–381[Abstract/Free Full Text]
617. Dubey AK, Cameron JL, Steiner RA, Plant TM 1986 Inhibition of gonadotropin secretion in castrated male rhesus monkeys (Macaca mulatta) induced by dietary restriction: analogy with the prepubertal hiatus of gonadotropin release. Endocrinology 118:518–525[Abstract/Free Full Text]
618. Foster DL, Ebling FJ, Micka AF, Vannerson LA, Bucholtz DC, Wood RI, Suttie JM, Fenner DE 1989 Metabolic interfaces between growth and reproduction. I. Nutritional modulation of gonadotropin, prolactin. and growth hormone secretion in the growth-limited female lamb. Endocrinology 125:342–350[Abstract/Free Full Text]
619. Bucholtz DC, Vidwans NM, Herbosa CG, Schillo KK, Foster DL 1996 Metabolic interfaces between growth and reproduction. V. Pulsatile luteinizing hormone secretion is dependent on glucose availability. Endocrinology 137:601–607[Abstract]
620. Nagatani S, Tsukamura H, Murahashi K, Bucholtz DC, Foster DL, Maeda K 1996 Paraventricular norepinephrine release mediates glucoprivic suppression of pulsatile luteinizing hormone secretion. Endocrinology 137:3183–3186[Abstract]
621. Cameron JL 1995 Metabolic signals and puberty in primates. In: Plant TM, Lee PA (eds) The Neurobiology of Puberty. Journal of Endocrinology Ltd, Bristol, UK, pp 259–270
622. Foster DL, Nagatani S 1999 Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 60:205–215[Abstract/Free Full Text]
623. Cunningham MJ, Clifton DK, Steiner RA 1999 Leptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 60:216–222[Abstract/Free Full Text]
624. Nazian SJ, Cameron DF 1999 Temporal relation between leptin and various indices of sexual maturation in the male rat. J Androl 20:487–491[Abstract/Free Full Text]
625. Helmreich DL, Cameron JL 1992 Suppression of luteinizing hormone secretion during food restriction in male rhesus monkeys (Macaca Mulatta): failure of naloxone to restore normal pulsatility. Neuroendocrinology 56:464–473[Medline]
626. Cameron JL 1997 Stress and behaviorally induced reproductive dysfunction in primates. Semin Reprod Endocrinol 15:37–45[Medline]
627. Amico JA, Janosky JE, Challinor SM, Cameron JL 1992 Effect of naloxone administration upon the diurnal concentrations of oxytocin in the cerebrospinal fluid of rhesus and cynomolgus monkeys. Horm Res 38:171–176[Medline]
628. Schreihofer DA, Golden GA, Cameron JL 1993 Cholecystokinin (CCK)-induced stimulation of luteinizing hormone(LH) secretion in adult male rhesus monkeys: examination of the role of CCK in nutritional regulation of LH secretion. Endocrinology 132:1553–1560[Abstract/Free Full Text]
629. Williams NI, Lancas MJ, Cameron JL 1996 Stimulation of luteinizing hormone secretion by food intake: evidence against a role for insulin. Endocrinology 137:2565–2571[Abstract]
630. Murahashi K, Bucholtz DC, Nagatani S, Tsukahara S, Tsukamura H, Foster DL, Maeda KI 1996 Suppression of luteinizing hormone pulses by restriction of glucose availability is mediated by sensors in the brain stem. Endocrinology 137:1171–1176[Abstract]
631. Rinaman L, Baker EA, Hoffman GE, Stricker EM, Verbalis JG 1998 Medullary c-Fos activation in rats after ingestion of a satiating meal. Am J Physiol 275:R262–R268
632. I’anson H, Terry SK, Lehman MN, Foster DL 1997 Regional differences in the distribution of gonadotropin-releasing hormone cells between rapidly growing and growth-restricted prepubertal female sheep. Endocrinology 138:230–236[Abstract/Free Full Text]
633. Clarke IJ, Henry BA 1999 Leptin and reproduction. Rev Reprod 4:48–55[Abstract]
634. Kiess W, Reich A, Meyer K, Glasow A, Deutscher J, Klammt J, Yang Y, Muller G, Kratzsch J 1999 A role for leptin in sexual maturation and puberty? Horm Res 51 [Suppl 3]:55–63
635. Foster DL, Nagatani S 1999 Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 60:205–215
636. Ong KK, Ahmed ML, Dunger DB 1999 The role of leptin in human growth and puberty. Acta Paediatr Suppl 88:95–98[CrossRef]
637. Roemmich JN, Rogol AD 1999 Role of leptin during childhood growth and development. Endocrinol Metab Clin North Am 28:749–764[CrossRef][Medline]
638. Ahmed ML, Ong KK, Morrell DJ, Cox L, Perry L, Preece MA, Dunger DB 1999 Longitudinal study of leptin concentrations during puberty: sex differences and relationship to changes in body composition. J Clin Endocrinol Metab 84:899–905[Abstract/Free Full Text]
639. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF 1997 Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab 82:2849–2855[Abstract/Free Full Text]
640. Palmert MR, Radovick S, Boepple PA 1998 Leptin levels in children with central precocious puberty. J Clin Endocrinol Metab 83:2260–2265[Abstract/Free Full Text]
641. Quinton ND, Smith RF, Clayton PE, Gill MS, Shalet S, Justice SK, Simon SA, Walters S, Postel-Vinay MC, Blakemore AI, Ross RJ 1999 Leptin binding activity changes with age: the link between leptin and puberty. J Clin Endocrinol Metab 84:2336–2341[Abstract/Free Full Text]
642. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS 1997 Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391–395[Medline]
643. Chehab FF, Mounzih K, Lu R, Lim ME 1997 Early onset of reproductive function in normal female mice treated with leptin. Science 275:88–90[Abstract/Free Full Text]
644. Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA 1997 Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 138:855–858[Abstract/Free Full Text]
645. Gruaz NM, Lalaoui M, Pierroz DD, Englaro P, Sizonenko PC, Blum WF, Aubert ML 1998 Chronic administration of leptin into the lateral ventricle induces sexual maturation in severely food-restricted female rats. J Neuroendocrinol 10:627–633[CrossRef][Medline]
646. Finn PD, Cunningham MJ, Pau KY, Spies HG, Clifton DK, Steiner RA 1998 The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology 139:4652–4662[Abstract/Free Full Text]
647. Morash B, Li A, Murphy PR, Wilkinson M, Ur E 1999 Leptin gene expression in the brain and pituitary gland. Endocrinology 140:5995–5997[Abstract/Free Full Text]
648. Plant TM, Durrant AR 1997 Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta). Endocrinology 138:4505–4508[Abstract/Free Full Text]
649. Urbanski HF, Pau KY 1998 A biphasic developmental pattern of circulating leptin in the male rhesus macaque (Macaca mulatta). Endocrinology 139:2284–2286[Abstract/Free Full Text]
650. Mann DR, Akinbami MA, Gould KG, Castracane VD 2000 A longitudinal study of leptin during development in the male rhesus monkey: the effect of body composition and season on circulating leptin levels. Biol Reprod 62:285–291[Abstract/Free Full Text]
651. Witchel SF, Arslanian S, Lee PA 1999 Leptin concentrations in precocious puberty or untimely puberty with and without GnRH analogue therapy. J Pediatr Endocrinol Metab 12:839–845[Medline]
652. Farooqi IS, Jebb SA, Langmack G, Lawrence E Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884[Free Full Text]
653. Ojeda SR, Hill J, Hill DF, Costa ME, Tapia V, Cornea A, Ma YJ 1999 The Oct-2 POU domain gene in the neuroendocrine brain: a transcriptional regulator of mammalian puberty. Endocrinology 140:3774–3789[Abstract/Free Full Text]
654. He X, Treacy MN, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG 1989 Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature 340:35–42[CrossRef][Medline]
655. Clark ME, Mellon PL 1995 The POU homeodomain transcription factor Oct-1 is essential for activity of the gonadotropin-releasing hormone neuron-specific enhancer. Mol Cell Biol 15:6169–6177[Abstract]
656. Wierman ME, Xiong X, Kepa JK, Spaulding AJ, Jacobson BM, Fang Z, Nilaver G, Ojeda SR 1997 Repression of gonadotropin-releasing hormone (GnRH) promoter activity by the POU homeodomain transcription factor, SCIP/Oct-6/Tst-1: a regulatory mechanism of phenotype expression? Mol Cell Biol 17:1652–1665[Abstract]

This article has been cited by other articles:

				H. B. Adewale, W. N. Jefferson, R. R. Newbold, and H. B. Patisaul Neonatal Bisphenol-A Exposure Alters Rat Reproductive Development and Ovarian Morphology Without Impairing Activation of Gonadotropin-Releasing Hormone Neurons Biol Reprod, October 1, 2009; 81(4): 690 - 699. [Abstract] [Full Text] [PDF]

				S. K. Blank, C. R. McCartney, S. Chhabra, K. D. Helm, C. A. Eagleson, R. J. Chang, and J. C. Marshall Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls--Implications for Regulation of Pubertal Maturation J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2360 - 2366. [Abstract] [Full Text] [PDF]