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Initial and Cyclic Recruitment of Ovarian Follicles¹

Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California 94305-5317 USA

	Abstract

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 
Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive senescence. Each follicle develops to either ovulate or, more likely, to undergo degeneration. The dynamics of ovarian follicle development have interested endocrinologists and developmental biologists for many years. With the advent of assisted reproductive techniques in humans, the possibility of regulating follicle development in vivo and in vitro has gained clinical relevance. In this review, we focus upon key branching points during the development of ovarian follicles as well as factors involved in determining the eventual destiny of individual follicles. We discuss inconsistencies in the literature regarding the definitions of follicle recruitment and selection and propose to name the two major steps of follicle development as initial and cyclic recruitment, respectively. Because some of these disparities have arisen due to differences in the animal systems studied, we also compare the development of the ovarian follicles of both humans and rats. We also review the status of knowledge of several puzzling clinical issues that may provide important clues toward unlocking the mechanisms of follicle development.

I. Life History of Ovarian Follicles

A. Follicle endowment, growth, demise, and ovulation

B. Initial vs. cyclic recruitment

C. Negative and positive selection leading to dominance

D. Chronicle of early follicle development in humans

E. Chronicle of early follicle development in rodents

II. Initial Recruitment of Follicles and Regulation of Early Follicle Growth

A. Initial recruitment of follicles from the resting pool

B. Role of gonadotropins, intraovarian factors, and the oocyte in primary follicle growth

C. Preantral follicle growth and differentiation

D. Preantral follicles are gonadotropin responsive

III. Cyclic Recruitment of Follicles to Escape from Atresia

A. FSH is the survival factor for antral follicles

B. Intrafollicular hormonal mechanisms to ensure survival of preovulatory follicles

IV. Dynamics of the Follicle Pool: Puzzles and Unanswered Questions

A. Does early onset of menarche lead to a corresponding younger age at menopause?

B. Do women of reproductive age who have undergone unilateral ovariectomy or chemotherapy have an earlier onset of menopause?

C. Do women who have used steroidal contraceptives have delayed menopause?

D. Do women with increased parity have delayed menopause?

E. Do women with dizygotic twins have an earlier onset of menopause?

F. Do women who have undergone repeated cycles of controlled ovarian hyperstimulation with gonadotropins have an earlier onset of menopause?

V. Conclusions

	I. Life History of Ovarian Follicles

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 
A. Follicle endowment, growth, demise, and ovulation
THE MAJOR function of the female gonad is the differentiation and release of the mature oocyte for fertilization and successful propagation of the species. Additionally, the ovary produces steroids that allow the development of female secondary sexual characteristics and support pregnancy. In mammalian ovaries the individual follicles consist of an innermost oocyte, surrounding granulosa cells, and outer layers of thecal cells. The fate of each follicle is controlled by endocrine as well as paracrine factors (1 2 3 4 5 ). The follicles develop through primordial, primary, and secondary stages before acquiring an antral cavity. At the antral stage, most follicles undergo atretic degeneration, whereas a few of them, under the cyclic gonadotropin stimulation that occurs after puberty, reach the preovulatory stage (1 2 ). These Graafian follicles are the major source of the cyclic secretion of ovarian estrogens in women of reproductive age. In response to preovulatory gonadotropin surges during each reproductive cycle, the dominant Graafian follicle ovulates to release the mature oocyte for fertilization, whereas the remaining theca and granulosa cells undergo transformation to become the corpus luteum (6 ). The pool of oocytes in the mammalian ovary becomes fixed early in life; thus, ovarian senescence is linked to the dwindling supply and eventual exhaustion of the pool of primordial follicles (Fig. 1).

View larger version (31K): [in this window] [in a new window]   Figure 1. Life history of ovarian follicles: endowment and maintenance, initial recruitment, maturation, atresia or cyclic recruitment, ovulation, and exhaustion. A fixed number of primordial follicles are endowed during early life, and most of them are maintained in a resting state. Growth of some of these dormant follicles is initiated before and throughout reproductive life (Initial recruitment). Follicles develop through primordial, primary, and secondary stages before acquiring an antral cavity. At the antral stage most follicles undergo atresia; however, under optimal gonadotropin stimulation that occurs after puberty, a few of them are rescued (Cyclic recruitment) to reach the preovulatory stage. Eventually, depletion of the pool of resting follicles leads to ovarian follicle exhaustion and senescence.

In contrast, cyclic recruitment starts after pubertal onset and is the result of the increase in circulating FSH during each reproductive cycle that rescues a cohort of antral follicles from atresia. In rodents, the recruitable early antral follicles are 0.2–0.4 mm in diameter, whereas human follicles at the comparable stage are larger (2–5 mm in diameter) and have acquired antrum for some time. During cyclic recruitment, only a limited number of follicles survive, and the default pathway is to undergo atresia. Oocytes in these follicles have already completed their growth, acquired a zona pellucida, and are competent to resume meiosis (11 12 ).

C. Negative and positive selection leading to dominance
Similar to the confusion associated with two distinct stages of follicle recruitment, the FSH-initiated cyclic recruitment step is sometimes described interchangeably with the process of follicle selection (9 10 13 ). Cyclic recruitment and selection of follicles represent a continuous process, eventually leading to the emergence of the preovulatory follicle(s). Cyclic recruitment and final follicle selection are most clearly illustrated during the human menstrual cycle (Fig. 2). After increases in circulating FSH during the perimenstrual period, a cohort of antral follicles escapes apoptosis due to the survival action of FSH. Among this group of about 10 antral follicles (found in young adults), one of the leading follicles grows faster than the rest of the cohort and produces higher levels of estrogens and inhibins (4 ). Although the exact reasons why one follicle emerges as dominant are unclear, this follicle is likely to be more sensitive to FSH (6 ), perhaps because of enhanced FSH and/or LH receptor expression or increases in local growth factors that augment FSH responsiveness as suggested by bovine studies (14 15 16 ). Estrogens and inhibins produced by the largest follicle suppress pituitary FSH released during the midfollicular phase. As a result, the remaining growing antral follicles are deprived of adequate FSH stimulation required for survival (17 ). In monkeys, it has been elegantly demonstrated that immunoneutralization of the actions of circulating estrogens during the midfollicular phase leads to sustained elevation of circulating FSH, thus allowing the development of multiple preovulatory follicles (18 ). Furthermore, administration of exogenous estrogens suppresses follicle development in women (19 20 ), whereas treatment with high levels of exogenous gonadotropins during ovulation induction in women is widely known to stimulate the growth of multiple preovulatory follicles (6 ).

View larger version (30K): [in this window] [in a new window]   Figure 2. Duration of follicle recruitment and selection in human and rat ovaries. Primordial follicles undergo initial recruitment to enter the growing pool of primary follicles. Due to its protracted nature, the duration required for this step is unknown. In the human ovary, greater than 120 days are required for the primary follicles to reach the secondary follicle stage, whereas 71 days are needed to grow from the secondary to the early antral stage. During cyclic recruitment, increases in circulating FSH allow a cohort of antral follicles (2–5 mm in diameter) to escape apoptotic demise. Among this cohort, a leading follicle emerges as dominant by secreting high levels of estrogens and inhibins to suppress pituitary FSH release. The result is a negative selection of the remaining cohort, leading to its ultimate demise. Concomitantly, increases in local growth factors and vasculature allow a positive selection of the dominant follicle, thus ensuring its final growth and eventual ovulation. After cyclic recruitment, it takes only 2 weeks for an antral follicle to become a dominant Graafian follicle. In the rat, the duration of follicle development is much shorter than that needed for human follicles. The time required between the initial recruitment of a primordial follicle and its growth to the secondary stage is more than 30 days, whereas the time for a secondary follicle to reach the early antral stage is about 28 days. Once reaching the early antral stage (0.2–0.4 in diameter), the follicles are subjected to cyclic recruitment, and only 2–3 days are needed for them to grow into preovulatory follicles.

Cyclic recruitment of early antral follicles and selection of dominant follicles in rodents is similar to that of the primates with the major exception that multiple follicles become dominant during each estrous cycle. Monoovulatory and polyovulatory species likely differ in the threshold (or set point) for negative feedback signals, presumably a genetically determined trait (27 28 ). The law of follicular constancy proposed by Lipschutz (29 ) emphasizes that the ovulatory number remains constant in a given species even when a single ovary or a large portion of the remaining ovary is removed. Thus, findings of compensatory ovulation (30 ) underline the importance of the putative central set point within a given species. In several high fecundity strains of sheep, the follicular negative feedback signals (estrogens and inhibins) secreted by each individual follicle are decreased, thus allowing the selection of more preovulatory follicles (31 ). In general, the preovulatory dominant follicles in these animals are of a smaller size than those found in the low fecundity strain (32 33 34 ). Furthermore, species and strain differences in follicular responsiveness to FSH (35 ), or the available number of growing antral follicles, may also play a role in determining the number of preovulatory-size follicles.

D. Chronicle of early follicle development in humans
In humans, primordial germ cells arrive in the gonadal ridge from the yolk sac endoderm by the seventh week of gestation to become oogonia, which proliferate by mitosis before differentiating into primary oocytes. Some oogonia begin transformation into primary oocytes and enter the first stages of meiosis at around 11–12 weeks of gestation (Fig. 3). The total germ cell number peaks at 20 weeks. After this time, the rate of oogonial division declines. Primordial follicle formation begins around midgestation when a single layer of pregranulosa cells surround each oocyte and continues until just after birth (36 ). After oocytes are within the primordial follicles, they remain arrested in the dictyate stage of meiosis I. From a peak of 6 to 7 million at 20 weeks of gestation, the oocyte number falls dramatically so that at birth, there are only 300,000 to 400,000 remaining (37 38 ). Oocytes not surrounded by granulosa cells to form primordial follicles are lost, probably via apoptosis (39 40 41 ). Meanwhile, some primordial follicles leave the resting pool by initiating growth (Fig. 2; initial recruitment). Once entering the growing pool, most growing follicles progress to the antral stage, at which point they inevitably undergo atresia. After pubertal onset, a small number of the antral follicles can be rescued by gonadotropins to continue growth (Fig. 2; cyclic recruitment), and normally one Graafian follicle is formed each month in preparation for ovulation. Antral follicles (2–5 mm in diameter) develop into Graafian follicles in only 14 days during the follicular phase of the menstrual cycle, although more than 85 days are needed for late secondary follicles to grow into preovulatory follicles (1 ) (Fig. 2). In addition, it has been estimated that more than 120 days are needed for primary follicles to grow into the secondary stage and even longer for the development of primordial follicles into primary follicles (1 42 ). Thus, the entire growth phase of a follicle is much greater than 220 days or eight menstrual cycles.

View larger version (17K): [in this window] [in a new window]   Figure 3. Landmarks of follicular development during fetal and neonatal life in humans and rodents. In the human ovary, primordial follicles are present by 20 weeks of fetal life, whereas primary follicles are found by 24 weeks. By 26 weeks, some follicles have progressed to the secondary stage. Antral follicles develop in the third trimester and are also seen postnatally when FSH levels are elevated. After puberty, cyclic increases in serum gonadotropins stimulate the antral follicles to become preovulatory follicles during each menstrual cycle. In the rat ovary, primordial follicles are formed by 3 days after birth when the first wave of follicles begins growth. These follicles progress to the early antral stage during the third week of life when serum gonadotropin levels are elevated. After early antral follicles are formed, ovarian cell apoptosis increases. FSH receptors are found by day 7 of age, when secondary follicles are present, followed closely by the formation of LH receptors in the thecal cells. Cyclic ovarian function begins around day 35 of age. The neonatal rodent model allows analysis of early follicle development in a synchronized population of growing follicles. Pmd follicles, Primordial follicles.

E. Chronicle of early follicle development in rodents
Important landmarks of ovarian development in rats are similar to those in the human; however, the timing is greatly compressed. Primordial germ cells migrate to the gonadal ridge late in embryonic development to become oogonia. At birth, the rat ovary consists of cords and oogonia (Fig. 3). Primordial follicles are formed by day 3 of age, and the first wave of follicles develops into antral follicles over the next 3 weeks (49 50 51 52 53 ). Well developed secondary follicles are found by day 7 of age. Minimal ovarian cell apoptosis can be found until day 18 when early antral follicles are apparent (54 55 ). Puberty or first estrus occurs around day 34. The regular estrous cycles continue until around 10–12 months of age when the cycles become prolonged and irregular (56 57 ). By age 12–15 months, animals enter persistent estrus, and this is followed by persistent diestrus and ultimately anestrus (58 59 ).

The timing of follicle growth has been meticulously evaluated in adult rats (2 ). The follicle grows from about 25 µm in diameter (primordial follicles) to 500–800 µm in diameter (preovulatory follicles) over a period of greater than 60 days (or about 15 estrous cycles) (Fig. 2). The time for primordial follicles to grow to the secondary follicle stage may be more than 30 days or comparable to the time (28 plus 2–3 days) to grow from the secondary stage to ovulation. Thus, as in the human, early follicle growth in rodents is very protracted. Of interest, the rate of development of the first wave of follicles in juvenile rats (Fig. 3) is more rapid than that in adult cycling animals (60 ) (Fig. 2).

	II. Initial Recruitment of Follicles and Regulation of Early Follicle Growth

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 
A. Initial recruitment of follicles from the resting pool
Mechanisms controlling the initiation of follicle growth have been difficult to investigate because initial follicle recruitment represents a protracted process characterized by the slow growth of a substantial number of small follicles over a prolonged period of time (49 ). Most investigators have monitored changes in the number of primordial and/or primary follicles that remain in the ovary at any given time, the supposition being that the decline of follicle numbers in this category is due to follicles leaving the resting pool to enter the growing pool. Because of the difficulties involved in distinguishing between nongrowing and growing follicles, primordial and primary follicles have often been considered a contiguous group (1 61 62 63 ), although primary follicles have been shown to be growing (49 ).

By counting follicles of different categories in ovarian sections, rates of follicle progression and loss have been estimated (1 2 5 45 61 62 63 ). Despite the limitations of this approach, several useful models have been formulated to describe the dynamics of initial recruitment of follicles. Although a radioactive decay model proposed a constant loss of a fixed number of resting follicles from the original pool over time (61 64 ), some studies suggested a decreasing number of follicles initiate growth as the ovary ages, in proportion to the number of remaining follicles in the diminishing supply (65 ). Morphometric studies further suggested that follicles initiate growth based upon the order in which they were formed (2 ).

The decay model proposed to account for the baseline rate of the initial recruitment of follicles has been further modified based on observed variations in the rate of follicle loss from the resting pool over the reproductive life span. An accelerated loss of follicles from the resting pool has been found during the initial waves of follicle growth in infantile rodents (66 ). In addition, morphometric studies have demonstrated that an increasing percentage of follicles is lost in the perimenopausal years in humans (44 46 ). In both of these situations, serum gonadotropins are elevated compared with those during the peak reproductive years. The accelerated rate of loss of follicles in infantile rodents has been attributed both to a lack of mature follicles that might exert a negative effect on initial recruitment and to qualitative differences in the first groups of growing follicles (5 61 ). Likewise, the accelerated follicle loss in perimenopausal women may reflect intrinsic differences in their remaining follicles. Although the observed follicle depletion may be due to increasing serum gonadotropin levels, changes in gonadotropin secretion could also be the result of diminishing inhibitory influences from a lower number of growing follicles.

B. Role of gonadotropins, intraovarian factors, and the oocyte in primary follicle growth
Resting follicles are likely to be under constant inhibitory influences of systemic and/or local origins to remain dormant (67 ). A decrease of inhibitory influences and/or an increase of stimulatory factors allow the initiation of follicle growth. In hypophysectomized rodents, decreased initial recruitment of follicles is evidenced by a larger resting pool as compared with nonoperated controls (61 68 ). Elevated serum FSH levels are associated with accelerated initial recruitment found in both the early and late stages of reproductive life, as mentioned earlier. High tonic LH/human CG (hCG) levels may also reduce the number of resting follicles. In transgenic mice overexpressing a long-acting LH, primordial follicles are lost from the resting pool more rapidly than controls (69 ). However, FSH and LH are unlikely to exert direct actions on primordial follicles because functional gonadotropin receptors have not yet developed in them (70 71 72 73 74 ). Instead, the ability of FSH to accelerate the development of preantral follicles, as described in the following section, may indirectly increase the loss of resting follicles from the dormant pool. Other factors, such as elevated steroid levels and mediation by paracrine factors, may also have a role in the loss of follicles from the transgenic animals.

Although follicles do not have functional FSH receptors until the secondary stage, pregranulosa cells and primordial follicles respond to activators of the cAMP pathways (e.g., forskolin and cAMP analogs) with increased expression of aromatase and FSH receptors (75 ). It has been proposed that endogenous activators of cAMP may play a role in the differentiation of follicles after their initial recruitment (76 ). Treatment of ovarian explants from neonatal rats with vasoactive intestinal peptide or norepinephrine increases cAMP production and accelerates early follicle development. Because the first follicles that grow in the rat ovary are in the highly innervated corticomedullary junction, the first wave of follicle growth may be facilitated by these local neurotransmitters.

The role of the oocyte in the initial recruitment of follicles has been considered. During development, granulosa cells of primordial follicles start to divide (49 ), followed by morphological changes to the cuboidal shape characteristic of primary follicles. Because an increase in oocyte size is not evident until formation of the primary follicle, a passive role of the oocyte in initial recruitment has been suggested (12 ). Based on the observation that the number of chiasmata, or crossing-over events, in ovulated oocytes decreases with the increasing age of an animal, it was proposed that the order of follicle recruitment is related to the order in which the oocytes entered meiosis during development (61 ). This "production line" hypothesis predicts that the first oocytes entering meiosis are the first ones maturing and ovulating. In addition, Hirshfield (2 ) has demonstrated that rapidly progressing oocytes located near the corticomedullary junction of the ovary begin growth earlier and are enclosed into follicles that initiate growth during the neonatal and infantile period, a time of accelerated follicle loss. In contrast, oocytes that undergo slower meiotic progression are located closer to the cortex and are enclosed in follicles that grow later in life. Meiotic competence of human follicles declines with age (77 ), and this finding has been used in support of the production line hypothesis. However, the reduction of oocyte quality could be due to poorer conditions present during folliculogenesis after age 35. These issues have yet to be resolved.

Factors involved in oocyte-granulosa cell communication in early follicles have also been proposed to have a role in initial recruitment. The Steel factor or kit ligand is expressed by granulosa cells of growing follicles whereas c-kit, a tyrosine kinase receptor of the platelet-derived growth factor receptor family, is located on oocytes and theca cells. Mutations in mice that prevent the production of the soluble form of the kit ligand lead to failure of follicular growth beyond the primary stage (78 79 80 ) (Table 2). Less severe mutations that result in reduced production of the soluble ligand allow a few follicles to grow to the antral stage. These animals ovulate sporadically and show limited fertility. Of interest, treatment of neonatal mice with a neutralizing antibody against the c-kit receptor caused apparent disturbances in initial follicle recruitment, primary follicle growth, and antrum formation in larger follicles (81 ). Mutations affecting the function of c-kit in humans, however, do not seem to affect female fertility (82 ). The role of c-kit in human ovarian function requires further study.

Although these studies provide insight into the growth process of very early follicles, the exact mechanisms propelling the primordial follicles to leave the resting pool remain elusive. Of importance, both kit ligand and GDF-9 are first found in primary follicles and their role in primordial follicle activation remains to be established. Further studies are needed to reveal potential inhibitory factors and/or intraovarian-stimulating factors that are involved in the initial stage of follicle recruitment. Recent establishment of a serum-free culture of baboon primordial follicles capable of initiating growth in vitro (92 ) could provide further insight into the mechanisms of initial follicle recruitment.

C. Preantral follicle growth and differentiation
Compared with the initial recruitment process, substantially more is known about the regulation of subsequent follicle differentiation and growth. After initial recruitment, granulosa cells in primary follicles undergo profound changes, progressively acquiring the differentiated characteristics of epithelial cells found in secondary follicles. The oocyte continues to grow, the zona pellucida is formed, theca condenses around the preantral follicle, and the vascular supply develops.

In vitro studies have shown that granulosa-oocyte communication is essential for normal oocyte growth in early follicles. Immature oocytes separated from granulosa cells do not grow, but oocytes allowed to maintain gap junctions with granulosa cells grow at a near-normal rate (12 ). In mice, a gap junction protein, connexin 37, is expressed at the oocyte-granulosa cell junction by the time follicles have developed to the secondary stage, whereas follicles of mice that lack connexin 37 do not progress normally (93 ) (Table 2). These defective follicles contain normal zona pellucida and granulosa cell processes but lack oocyte-granulosa gap junctions and have impaired oocyte-granulosa communication. They progress normally to the late secondary stage and form a limited number of small antral follicles. The oocytes do not reach full size and are not competent to undergo meiosis. Several studies have further demonstrated that oocytes secrete factors to regulate granulosa cell functions (94 ), including granulosa cell division (95 ), LH receptor formation (96 ), and steroidogenesis (97 98 ) as well as cumulus cell expansion (85 ). These studies underscore the concept that granulosa-oocyte communication is important for normal preantral follicle development.

Because preantral follicle development proceeds much slower than that of larger antral follicles, it is possible that ovarian growth and differentiation genes are suppressed during early follicle development. High levels of the Wilms’ tumor gene, WT1, are expressed in the granulosa cells of primary follicles in rats with lower levels in secondary follicles and negligible levels in antral and preovulatory follicles (99 ). Recent studies extend the finding of restricted WT1 expression in immature follicles to diverse avian (chicken) and mammalian (porcine and monkey) species and over the reproductive life span in rats (100 ). WT1, a transcription factor with zinc finger domains (101 ), suppresses the expression of several growth factors and their receptors in different cell types. Furthermore, in vitro studies demonstrated that WT1 represses activities of the promoters for inhibin- and FSH receptor, marker genes essential for follicle development. In gel retardation assays, recombinant WT1 proteins interact directly with consensus DNA sequences in the inhibin- gene promoter (100 ). Thus, WT1 may act as a stasis factor on smaller follicles, and falling levels of WT1 allow the progression of early follicle development. Mutant mice with deletion of the WT1 gene die during embryonic development, thus preventing analysis of ovarian follicle development. In human males with inactivating mutations of WT1, gonadal dysgenesis is prominent (102 ); but detailed analysis of ovarian phenotypes in human females with WT1 mutations (103 ) remains to be performed. Further studies are needed to elucidate the regulation of WT1 expression in human follicles as well as the interaction of WT1 with other genes involved in follicle development.

Granulosa-theca cell interactions may also have a role in the development of early follicles. Although the role of sex steroids in preantral follicle development is still unclear, a recent study suggested that androgen treatment in intact monkeys increases the number of preantral and small antral follicles up to 1 mm in diameter through androgen receptors (104 105 106 ). In cultured mouse preantral follicles, androgen treatment also augments follicle growth (107 ).

Rat preantral follicles have been shown to secrete proteins that enhance the growth and differentiation of theca cells before their expression of LH receptors (51 ). Likewise, cocultures of theca and granulosa cells enhance proliferation and steroidogenesis of both cell types (108 ). The observed interactions between granulosa and theca cells are probably mediated by paracrine growth factors. Recent studies indicated that keratinocyte growth factor, or fibroblast growth factor-7, a paracrine hormone secreted by theca cells (109 ), enhances the growth of preantral rat follicles in culture (110 ).

Treatment of dissociated ovarian cells from juvenile rats with activin and FSH enhances formation and growth of follicular structure (111 ). Activin treatment also enhances FSH-stimulated inhibin production in dispersed ovarian cells from neonatal rats (112 ). In mice, cultured preantral follicles secrete activin, and treatment with recombinant activin enhances FSH-stimulated inhibin and estrogen production (113 ). Furthermore, studies using cocultures of mouse follicles at different stages of development suggested that activin secreted from secondary follicles causes small preantral follicles to remain dormant (114 115 ). The exact stage-dependent effects of activin in early follicle development remain to be elucidated.

High levels of IGF-I and IGF receptors have been found in postnatal rats during preantral follicle development (116 ). However, follicles seem to develop relatively normally to the early antral stage in mutant mice lacking IGF-I, although numerical morphometrics were not performed (117 ). Studies using these mutant mice further suggested that ovarian IGF-I expression serves to enhance granulosa cell FSH responsiveness by augmenting FSH receptor expression (118 ). A large body of data exists on the effects of growth factors on monolayer cultures of granulosa and theca-interstitial cells as well as on cultures of antral and preovulatory follicles (5 24 119 120 ). It is clear that paracrine growth factors are also involved in preantral follicle development. With recent advances in transgenic technology, more than 30 mouse models with ovarian defects at different stages of follicle development have been described (reviewed in Ref. 121 ). Derivation of additional mutant mice with ovarian phenotypes will further enhance our understanding of early follicle development.

D. Preantral follicles are gonadotropin responsive
Several recent studies investigated the role of FSH on follicle development based on mutant mice with a defective FSH-ß or FSH receptor gene (122 123 ) and in patients with loss-of-function FSH receptors (124 ). Although the growth of preantral follicles has been considered to be gonadotropin independent because follicles can develop to the antral stage in animals or humans with minimal circulating FSH or defective FSH receptors (6 122 124 125 126 127 ), studies in rodents have suggested that the development of early follicles is under the influence of gonadotropins. During the first 3 weeks of life in rats, the first wave of follicles begins to grow, corresponding to events found during fetal life in the human ovary (Fig. 3). Functional FSH and LH receptors are present when well developed secondary follicles are found by day 7 of age. In addition, serum FSH levels are elevated between days 11 and 19, a time of rapid follicle growth (128 129 130 ). Treatment with dihydrotestosterone propionate during the first week of life decreases serum gonadotropins and leads to a delay in ovarian FSH receptor acquisition (131 ). Conversely, treatment of infantile rats with PMSG increases ovarian weight (132 ), whereas treatment of neonatal rats with a GnRH antagonist reduces the number of growing ovarian follicles found at puberty (7 ).

Taking advantage of the relatively uniform development of the first wave of follicles in the postnatal rat ovary, the role of endogenous and exogenous gonadotropins on preantral follicle development was evaluated (50 ). Reduction of the high levels of gonadotropins present in juvenile rats by either hypophysectomy or GnRH antagonist treatment decreases ovarian weight at day 19 of age and reduces the number of developing follicles together with increasing atresia of the remaining ones. In contrast, treatment with FSH in intact, hypophysectomized, or GnRH antagonist-treated juvenile rats increases ovarian weight and preantral follicle development (50 ). In vitro studies on the role of FSH in preantral follicle development have been conflicting. In one model, FSH treatment promotes the progression of cultured rat follicles to the antral stage (133 ). In another study, FSH treatment alone does not enhance granulosa cell division or steroidogenesis (111 ). In mice, FSH treatment enhances antral formation without increasing granulosa cell numbers in cultured follicles (134 ) whereas, in cultured hamster follicles, FSH treatment increases granulosa cell division (135 ). Using a cGMP analog to suppress apoptosis in preantral rat follicles in serum-free cultures, it was demonstrated that FSH treatment increases both follicle size and cell number (54 ).

Recently, FSH has been shown to stimulate the expression of cyclin D2, a cell cycle protein important in the G₁ phase of cell division. Mice lacking cyclin D2 are infertile, and granulosa cell replication is impaired as early as the secondary follicle stage (136 ) (Table 2). The paucity of granulosa cells results in the formation of small atypical antral follicles that cannot ovulate properly.

Thus, these results demonstrate that preantral follicles respond to gonadotropins with cell division and differentiation. However, as discussed earlier, follicles can progress to the antral stage in the absence of gonadotropins. In hypogonadal mice (127 ) or hypophysectomized rats (137 ), ovarian follicles can develop to the secondary and early antral stages, but more slowly and in fewer numbers. In individuals with hypogonadotropic hypogonadism, treatment with exogenous gonadotropins leads to the development of preovulatory follicles within 2 weeks, suggesting that antral follicles are present and available for cyclic recruitment (138 ). Clearly, continued development of antral and larger follicles is dependent on the presence of FSH, but gonadotropin responsiveness may occur earlier in follicle development (139 ) than is widely believed (Fig. 4). This concept is further supported by studies on human early follicles in ovarian xenografts transplanted into the kidney capsule of immunodeficient and hypogonadal mice (140 ). In this model, FSH was shown to be required for the growth of follicles beyond the two-layer granulosa cell stage. Therefore, gonadotropin fluctuations during the estrous cycle in the rodent may not only advance the development of antral follicles but may also affect smaller growing follicles that are several cycles away from becoming the leading cohort. In humans, exogenous gonadotropins could have an effect on follicle development for several months after a controlled ovarian hyperstimulation cycle, although the exact role of gonadotropins remains to be elucidated.

View larger version (24K): [in this window] [in a new window]   Figure 4. Follicle mountain: stage-specific hormonal factors are involved in the survival and development of rodent follicles. Studies in rodents indicated that the development of follicles from the smallest primordial and primary follicles to the largest preovulatory follicles requires different stimulatory and survival factors that are stage dependent. Although the exact mechanisms for the initial recruitment of follicles from the dormant primordial follicle pool are still unclear, FSH, activin, and GDF-9 have been shown to stimulate the growth and differentiation of primary and/or secondary follicles. In addition, unknown ligand(s) activating through the cGMP pathway could serve as survival factors for preantral follicles. FSH is the major survival factor to rescue early antral follicles from apoptotic demise during cyclic recruitment. Once the follicles reach antral and larger sizes, multiple intrafollicular factors are produced locally to ensure successful maturation and ovulation. Although it is known that the growth of antral and preovulatory follicles is dependent on adequate gonadotropin stimulation, recent in vitro and in vivo studies indicated that the growth of preantral follicles could also be enhanced by endogenous and exogenous gonadotropins. Thus, the development of follicles can be divided into gonadotropin-dependent and gonadotropin-responsive stages. During treatment with exogenous gonadotropins, it is likely that both large antral follicles and smaller preantral follicles are stimulated to grow.

	III. Cyclic Recruitment Of Follicles to Escape from Atresia

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

FSH and LH are important trophic factors for the proliferation and survival of follicular somatic cells and the cyclic recruitment of antral follicles. Suppression of serum gonadotropins after hypophysectomy leads to atresia and apoptosis of developing follicles (147 ), whereas FSH treatment of cultured early antral follicles prevents the spontaneous onset of follicular apoptosis (148 ). However, LH/hCG treatment alone is ineffective, suggesting that FSH is the predominant survival factor at this stage of follicle development (148 ). In rats, estrogens are potent antiapoptotic hormones in early antral follicles (149 ), although the role of estrogen in human follicles is still unclear. Follicular estrogen production is dependent upon both FSH stimulation of aromatase in the granulosa cells and LH stimulation of androstenedione production by the theca (24 ). Therefore, both gonadotropins play a role in the continued survival of growing follicles, but the cellular mechanism by which FSH or estrogen ensures the survival of early antral follicles is unknown.

B. Intrafollicular hormonal mechanisms to ensure survival of preovulatory follicles
It is becoming evident that survival factors are needed to sustain folliculogenesis during the progression of follicle development (Fig. 4). Recent rodent studies indicate that preantral follicles in serum-free cultures undergo apoptosis despite exposure to gonadotropins or cAMP analogs (54 ), suggesting that gonadotropins are probably not survival factors at early stages of folliculogenesis. As discussed above, FSH seems to be the most important survival factor for early antral follicles. However, in preovulatory follicles, numerous factors promote follicle cell survival (142 150 151 152 ), indicating that overlapping hormonal cascades are involved in maintaining follicles that develop to this stage. The differential responsiveness of follicles to hormonal signals at different developmental stages may ensure a staggered supply of maturing follicles during reproductive life.

An elaborate intrafollicular control mechanism ensures the survival of preovulatory follicles (153 ). The onset of apoptosis in preovulatory follicles in a serum-free culture is prevented by treatment with FSH and LH (150 ). In addition, treatment with GH (151 ) or local factors including IGF-I, epidermal growth factor, TGF, and fibroblast growth factor-2, likewise suppresses follicle cell apoptosis (150 154 ). Interleukin-1ß is also a survival factor for preovulatory follicles, and the action of interleukin-1ß is mediated through increases in the production of nitric oxide, which, in turn, activates soluble guanyl cyclase (152 ). Although gonadotropins are the most important survival factors for preovulatory follicles, this array of extracellular signals acting through endocrine, paracrine, autocrine, or juxtacrine mechanisms, ensures their survival for ovulation.

	IV. Dynamics of the Follicle Pool: Puzzles and Unanswered Questions

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 
Analysis of the basic mechanisms of follicle recruitment and selection has important clinical implications. Although the exact mechanisms underlying initial recruitment of follicles is still unclear, hormonal mechanisms underlying cyclic recruitment have been better elucidated. In the following section, several puzzling clinical issues related to altered follicle development and menopausal timing are discussed. Menopause is linked to the exhaustion of the primordial follicle reserve. Because all primordial follicles initiated to grow are programmed to undergo apoptosis unless rescued by FSH, depletion of the follicle pool results from initial, but not cyclic, recruitment of follicles (Fig. 1). However, some factors that are well known regulators of cyclic recruitment may also affect the less characterized process of initial recruitment. Much of the current human data are based on epidemiological analysis. Although these studies can provide valuable clues regarding the mechanisms of altered physiological processes, they are sometimes complicated by compounding variables.

A. Does early onset of menarche lead to a corresponding younger age at menopause?
No. Despite a substantial decrease in the age of menarche in women during the last century, a corresponding change of the menopausal age has not been detected (48 ). As discussed, initial follicle recruitment and follicle loss from the resting pool begins long before pubertal onset. Changes in the age of menarche as the result of environmental, nutritional, or pathophysiological factors (such as in women with central precocious puberty) allow an earlier onset of cyclic follicle recruitment but should not affect the timing of follicle pool depletion.

B. Do women of reproductive age who have undergone unilateral ovariectomy or chemotherapy have an earlier onset of menopause?
Yes, but it is dependent on the timing of the procedure. Unilateral oophorectomy or chemotherapy, which reduces the pool of resting follicles, shortens the reproductive life span. Although removal of up to 95% of ovarian tissue in monkeys does not affect subsequent reproductive cycles for up to 1 yr (155 ), the size of the resting follicle pool is a major determinant of ovarian senescence. Thus, unilateral oophorectomy can accelerate reproductive aging. If unilateral oophorectomy is performed in the later part of the human reproductive years when the resting pool is smaller, substantial advancement in menopausal age occurs (45 46 ). However, when the same procedure is performed early in life, the menopausal age is less affected, suggesting that a compensatory mechanism in initial follicle recruitment might allow a lower number of follicles to initiate growth (156 ).

In rodent studies, removal of one ovary accelerates follicle loss in the remaining ovary (30 ), but halving the total follicle number only results in the loss of a quarter of expected cycles (157 ). Furthermore, unilateral oophorectomy increases the loss of remaining primordial follicles in middle-aged rats but not in young rats operated on at 30 days of age (158 ). Likewise, treatment with a chemotherapy agent, busulfan, decreases the resting follicle pool by more than 90% in rats and substantially accelerates follicle depletion (159 ). Conversely, mutant mice deficient in a proapoptotic gene, Bax, maintain a larger resting pool of follicles later into adult life (160 ).

In humans, exposure to alkylating agents is associated with premature ovarian failure (161 ), and the degree of ovarian dysfunction seems to be inversely related to the age of drug exposure (162 ). Some reports suggest that treatment with GnRH agonist protects against chemotherapy-induced ovarian damage, possibly by reducing the rate of primordial follicle attrition (163 164 ). However, recent studies do not show a protective effect of GnRH agonist treatment on radiation-induced follicular injury (165 ). Given the increased survival rates of patients from cancers of childhood and early adulthood, more studies on potential protective measures of the follicle pool are greatly needed.

C. Do women who have used steroidal contraceptives have delayed menopause?
Probably no. Prolonged exposure to steroidal contraceptive pills mainly affects the ovulatory surges of circulating gonadotropins during the fertile period. Thus, ovulation is suppressed, but follicles continue to grow to the antral stage (6 ). It would seem likely that neither initial nor cyclic recruitment of follicles would be affected. However, since the advent of the oral contraceptive pill in the 1950s, the first generation of pill takers have reached menopause, and epidemiological studies have suggested that menopausal age may be slightly delayed (166 167 ). Further studies of subsequent generations of pill takers are needed to rule out compounding variables in the population of "pill pioneers" (167 ).

D. Do women with increased parity have delayed menopause?
Yes. Epidemiological studies indicate that women with increased parity show a delay in menopausal onset (166 168 169 ). Prolonged elevation of circulating progesterone during pregnancy may suppress initial follicle recruitment, thus maintaining a larger follicle pool size. Early studies in pregnant mice indicated that fewer follicles start growth per unit time (170 ). Indeed, middle-aged rats treated with progesterone implants or allowed to undergo multiple pregnancies show a delay in reproductive aging (171 ). Furthermore, prolonged treatment of young rats with a progesterone implant is associated with the conservation of follicle reserve in aging animals (172 ). One is unable to distinguish, however, between a direct action of progesterone on resting follicles and an indirect effect of progesterone mediated by changes in gonadotropin secretion. Additional pregnancy-related factors may also override the facilitatory effect of hCG on follicle exhaustion (69 ) and could result in the protection of the follicle pool. It would be interesting to determine whether users of levenorgestrel implants or injectable medroxyprogesterone acetate showed any change in menopausal timing.

E. Do women with dizygotic twins have an earlier onset of menopause?
Maybe not. The exact mechanism of dizygotic twining is still uncertain, although increased numbers of large antral follicles have been found in mothers of dizygotic twins during the follicular phase of their cycle (173 ). Assuming the increases in preovulatory follicles found in these individuals are due to elevated gonadotropins during the early follicular phase of their menstrual cycle (174 175 176 ), this condition is likely due to enhanced cyclic recruitment of follicles and should not alter initial recruitment and menopausal age. However, some epidemiological studies have suggested that mothers of twins have an earlier menopause (177 178 ), although this may be related to other variables such as cigarette smoking which was not evaluated. Also, women who are carriers of the Fragile X syndrome show increased incidence of dizygotic twinning and an earlier onset of menopause (179 ). The relationship between the defective FMR-1 (Fragile X Mental Retardation) protein found in these patients, twinning, and ovarian senescence awaits further analysis.

F. Do women who have undergone repeated cycles of controlled ovarian hyperstimulation with gonadotropins have an earlier onset of menopause?
A qualified no because exogenous gonadotropins are believed to act mainly on antral follicles to start cyclic recruitment. Although an accelerated decrease of the follicle pool size before menopause is associated with increases in circulating FSH, it is still unclear whether the premenopausal increase in FSH is the result or the cause of follicle pool depletion. There is no doubt that initial recruitment of follicles can proceed without gonadotropins, but it is unclear whether repeated exogenous gonadotropin treatment might accelerate follicle loss by an indirect action mediated through gonadotropin-responsive preantral follicles. Due to the possibility of underlying ovarian disorders in women who undergo gonadotropin stimulation for infertility, analysis of this issue may be difficult. Women who are egg donors would be an interesting group to evaluate in this regard.

	V. Conclusions

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 
Advances in ovarian endocrinology, molecular biology, and transgenic technology provide new perspectives on factors controlling the life history of ovarian follicles and new tools with which to investigate normal and abnormal follicle development. Understanding the hormonal and molecular mechanisms of the initial and cyclic recruitment of follicles, as well as the factors regulating follicle maturation, atretic degeneration, and ovulation, will facilitate 1) the design of new contraceptives, 2) the refinement of culture conditions for the generation of fertilizable eggs (11 ), and 3) the manipulation of the female reproductive life span and treatment of infertility associated with abnormal follicle development. It is becoming evident that the design of noninvasive methods to monitor the pool size of primordial and primary follicles could be useful in determining the follicular reserve (180 ). Elucidation of factors involved in the initial recruitment of follicles could provide new treatments for patients with premature ovarian failure. The possibility of suppressing initial recruitment and preventing the growth of resting follicles could be the basis for designing treatments that would preserve the resting follicle pool, thus extending the female fertile period and delaying menopause. Although prolonging cyclic ovarian function minimizes the need for hormonal replacement therapy, age-related increases in chromosomal defects in the oocyte should be considered. Future advances in the elucidation of the regulatory mechanisms underlying cyclic recruitment are essential for understanding the pathophysiology of polycystic ovarian syndrome (181 ). The combination of basic and clinical approaches to issues associated with follicle dynamics will facilitate the understanding of mechanisms of follicle development and improve clinical practice.

	Acknowledgments

 
We thank Drs. Bart Fauser, Jock Findlay, Linda Giudice, Roger Gosden, Nanette Santoro, Alex Tsafriri, and Tony Zeleznik for helpful comments on the manuscript.

	Footnotes

 
Address reprint requests to: Aaron J. W. Hsueh, Ph.D., Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University, 300 Pasteur Drive, Room A344, Stanford, California 94305-5317 USA.

¹ Supported by NIH Grant HD-31398, Specialized Cooperative Centers Program in Reproduction Research, and K12-HD084908 cofunded by the American Society for Reproductive Medicine through the Reproductive Scientist Development Program.

² Fellow of the Reproductive Scientist Development Program. Present address: Department of Obstetrics and Gynecology, University of Kentucky, Lexington, Kentucky 40536-0293 USA.

	References

Top Abstract I. Life History of... II. Initial Recruitment of... III. Cyclic Recruitment Of... IV. Dynamics of the... V. Conclusions References

 

1. Gougeon A 1996 Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev 17:121–155[Abstract/Free Full Text]
2. Hirshfield AN 1991 Development of follicles in the mammalian ovary. Int Rev Cytol 124:43–101[Medline]
3. Richards JS, Fitzpatrick SL, Clemens JW, Morris JK, Alliston T, Sirois J 1995 Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes. Recent Prog Horm Res 50:223–254
4. Zeleznik AJ, Benyo DF 1994 Control of follicular development, corpus luteum function, and the recognition of pregnancy in higher primates. In: Knobil E, Neill J (eds) The Physiology of Reproduction. Raven Press, New York, pp 751–782
5. Greenwald G, Roy SY 1994 Follicle development and its control. In: Knobil E, Neill J (eds) The Physiology of Reproduction. Raven Press, New York, pp 629–724
6. Fauser BC, Van Heusden AM 1997 Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev 18:71–106[Abstract/Free Full Text]
7. Meijs-Roelofs HM, van Cappellen WA, van Leeuwen EC, Kramer P 1990 Short- and long-term effects of an LHRH antagonist given during the prepubertal period on follicle dynamics in the rat. J Endocrinol 124:247–253[Abstract/Free Full Text]
8. Gosden RG, Laing SC, Felicio LS, Nelson JF, Finch CE 1983 Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol Reprod 28:255–260[Abstract]
9. Gougeon A, Testart J 1990 Influence of human menopausal gonadotropin on the recruitment of human ovarian follicles. Fertil Steril 54:848–852[Medline]
10. Rombauts L, Suikkari AM, MacLachlan V, Trounson AO, Healy DL 1998 Recruitment of follicles by recombinant human follicle-stimulating hormone commencing in the luteal phase of the ovarian cycle. Fertil Steril 69:665–669[CrossRef][Medline]
11. Trounson A, Anderiesz C, Jones GM, Kausche A, Lolatgis N, Wood C 1998 Oocyte maturation. Hum Reprod 3:52–62
12. Tsafriri A 1997 Follicular development: impact on oocyte quality. In: Fauser BCJM (ed) FSH Action and Intraovarian Regulation. Parthenon Press, New York, pp 83–105
13. Scheele F, Schoemaker J 1996 The role of follicle-stimulating hormone in the selection of follicles in human ovaries: a survey of the literature and a proposed model. Gynecol Endocrinol 10:55–66[Medline]
14. Evans AC, Fortune JE 1997 Selection of the dominant follicle in cattle occurs in the absence of differences in the expression of messenger ribonucleic acid for gonadotropin receptors. Endocrinology 138:2963–2971[Abstract/Free Full Text]
15. Bao B, Garverick HA, Smith GW, Smith MF, Salfen BE, Youngquist RS 1997 Changes in messenger ribonucleic acid encoding luteinizing hormone receptor, cytochrome P450-side chain cleavage, and aromatase are associated with recruitment and selection of bovine ovarian follicles. Biol Reprod 56:1158–1168[Abstract]
16. Xu Z, Garverick HA, Smith GW, Smith MF, Hamilton SA, Youngquist RS 1995 Expression of follicle-stimulating hormone and luteinizing hormone receptor messenger ribonucleic acids in bovine follicles during the first follicular wave. Biol Reprod 53:951–957[Abstract]
17. diZerega GS, Hodgen GD 1981 Folliculogenesis in the primate ovarian cycle. Endocr Rev 2:27–49[Abstract/Free Full Text]
18. Zeleznik AJ, Hutchinson JS, Schuler HM 1987 Passive immunization with anti-oestradiol antibodies during the luteal phase of the menstrual cycle potentiates the perimenstrual rise in serum gonadotrophin concentrations and stimulates follicular growth in the cynomolgus monkey (Macaca fascicularis). J Reprod Fertil 80:403–410[Abstract/Free Full Text]
19. Tsai CC, Yen SS 1971 The effect of ethinyl estradiol administration during early follicular phase of the cycle on the gonadotropin levels and ovarian function. J Clin Endocrinol Metab 33:917–923[Abstract/Free Full Text]
20. Vaitukaitis JL, Bermudez JA, Cargille CM, Lipsett MB, Ross GT 1971 New evidence for an anti-estrogenic action of clomiphene citrate in women. J Clin Endocrinol Metab 32:503–508[Abstract/Free Full Text]
21. Adashi EY 1995 Insulin-like growth factors as determinants of follicular fate. J Soc Gynecol Invest 2:721–726[CrossRef][Medline]
22. Giudice LC 1992 Insulin-like growth factors and ovarian follicular development. Endocr Rev 13:641–669[Abstract/Free Full Text]
23. diZerega GS, Hodgen GD 1980 The primate ovarian cycle: suppression of human menopausal gonadotropin-induced follicular growth in the presence of the dominant follicle. J Clin Endocrinol Metab 50:819–825[Abstract/Free Full Text]
24. Hsueh AJW, Adashi EY, Jones PB, Welsh Jr TH 1984 Hormonal regulation of the differentiation of cultured ovarian granulosa cells. Endocr Rev 5:76–127[Abstract/Free Full Text]
25. Harlow CR, Shaw HJ, Hillier SG, Hodges JK 1988 Factors influencing follicle-stimulating hormone-responsive steroidogenesis in marmoset granulosa cells: effects of androgens and the stage of follicular maturity. Endocrinology 122:2780–2787[Abstract/Free Full Text]
26. Gore MA, Nayudu PL, Vlaisavljevic V 1997 Attaining dominance in vivo: distinguishing dominant from challenger follicles in humans. Hum Reprod 12:2741–2747[Abstract/Free Full Text]
27. McNatty KP, Lun S, Heath DA, Ball K, Smith P, Hudson NL, McDiarmid J, Gibb M, Henderson KM 1986 Differences in ovarian activity between booroola x merino ewes which were homozygous, heterozygous and non-carriers of a major gene influencing their ovulation rate. J Reprod Fertil 77:193–205[Abstract/Free Full Text]
28. Spearow JL 1986 Changes in the kinetics of follicular growth in response to selection for large litter size in mice. Biol Reprod 35:1175–1186[Abstract]
29. Lipschutz A 1928 New developments in ovarian dynamics and the law of follicular constancy. Br J Exp Biol 5:283–291
30. Baker TG, Challoner S, Burgoyne PS 1980 The number of oocytes and the rate of atresia in unilaterally ovariectomized mice up to 8 months after surgery. J Reprod Fertil 60:449–456[Abstract/Free Full Text]
31. Montgomery GW, McNatty KP, Davis GH 1992 Physiology and molecular genetics of mutations that increase ovulation rate in sheep. Endocr Rev 13:309–328[Abstract/Free Full Text]
32. Cahill LP, Saumande J, Ravault JP, Blanc M, Thimonier J, Mariana JC, Mauleon P 1981 Hormonal and follicular relationships in ewes of high and low ovulation rates. J Reprod Fertil 62:141–150[Abstract/Free Full Text]
33. Driancourt MA, Hermier D, Hanrahan JP 1996 Alterations in follicular function associated with selection on ovulation rate in Finn ewes. J Anim Sci 74:199–210[Abstract]
34. Baird DT, Campbell BK 1998 Follicle selection in sheep with breed differences in ovulation rate. Mol Cell Endocrinol 145:89–95[CrossRef][Medline]
35. Abdennebi L, Monget P, Pisselet C, Remy JJ, Salesse R, Monniaux D 1999 Comparative expression of luteinizing hormone and follicle-stimulating hormone receptors in ovarian follicles from high and low prolific sheep breeds. Biol Reprod 60:845–854[Abstract/Free Full Text]
36. Van Wagenen G, Simpson ME 1965 Embryology of the Ovary and Testis; Homo sapiens and Macaca mulatta. Yale University Press, New Haven, CT
37. Block E 1953 A quantitative morphological investigations of the follicular system in newborn female infants. Acta Anat (Basel) 17:201–206
38. Forabosco A, Sforza C, De Pol A, Vizzotto L, Marzona L, Ferrario VF 1991 Morphometric study of the human neonatal ovary. Anat Rec 231:201–208[CrossRef][Medline]
39. Coucouvanis EC, Sherwood SW, Carswell-Crumpton C, Spack EG, Jones PP 1993 Evidence that the mechanism of prenatal germ cell death in the mouse is apoptosis. Exp Cell Res 209:238–247[CrossRef][Medline]
40. Pesce M, De Felici M 1994 Apoptosis in mouse primordial germ cells: a study by transmission and scanning electron microscope. Anat Embryol (Berl) 189:435–440[Medline]
41. De Pol A, Vaccina F, Forabosco A, Cavazzuti E, Marzona L 1997 Apoptosis of germ cells during human prenatal oogenesis. Hum Reprod 12:2235–2241[Abstract/Free Full Text]
42. Gougeon A 1986 Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1:81–87[Abstract/Free Full Text]
43. Block E 1952 Quantitative morphological investigations of the follicular system in women. Variations at different ages. Acta Anat (Basel) 14:108–123
44. Richardson SJ, Senikas V, Nelson JF 1987 Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 65:1231–1237[Abstract/Free Full Text]
45. Faddy MJ, Gosden RG 1996 A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 11:1484–1486[Abstract/Free Full Text]
46. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF 1992 Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 7:1342–1346[Abstract/Free Full Text]
47. Gougeon A, Echochard R, Thalabard JC 1994 Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod 50:653–663[Abstract]
48. Makinoda S, Uno Y, Kikuchi T, Tanaka T, Ichinoe K, Fujimoto S, Aging of human granulosa cells. Program of the Satellite Symposium of the 8th International Congress of Endocrinology, Sapporo, Japan, 1988, pp 201–213
49. Hirshfield AN 1989 Granulosa cell proliferation in very small follicles of cycling rats studied by long-term continuous tritiated-thymidine infusion. Biol Reprod 41:309–316[Abstract]
50. McGee EA, Perlas E, LaPolt PS, Tsafriri A, Hsueh AJW 1997 Follicle-stimulating hormone enhances the development of preantral follicles in juvenile rats. Biol Reprod 57:990–998[Abstract]
51. Gelety TJ, Magoffin DA 1997 Ontogeny of steroidogenic enzyme gene expression in ovarian theca-interstitial cells in the rat: regulation by a paracrine theca-differentiating factor prior to achieving luteinizing hormone responsiveness. Biol Reprod 56:938–945[Abstract]
52. Rajah R, Glaser EM, Hirshfield AN 1992 The changing architecture of the neonatal rat ovary during histogenesis. Dev Dyn 194:177–192[Medline]
53. Malamed S, Gibney JA, Ojeda SR 1992 Ovarian innervation develops before initiation of folliculogenesis in the rat. Cell Tissue Res 270:87–93[CrossRef][Medline]
54. McGee E, Spears N, Minami S, Hsu SY, Chun SY, Billig H, Hsueh AJW 1997 Preantral ovarian follicles in serum-free culture: suppression of apoptosis after activation of the cyclic guanosine 3',5'-monophosphate pathway and stimulation of growth and differentiation by follicle-stimulating hormone. Endocrinology 138:2417–2424[Abstract/Free Full Text]
55. McGee EA, Hsu SY, Kaipia A, Hsueh AJW 1998 Cell death and survival during ovarian follicle development. Mol Cell Endocrinol 140:15–18[CrossRef][Medline]
56. McPherson III JC, Costoff A, Mahesh VB 1977 Effects of aging on the hypothalamic-hypophyseal-gonadal axis in female rats. Fertil Steril 28:1365–1370[Medline]
57. Wise PM 1982 Alterations in proestrous LH, FSH, and prolactin surges in middle-aged rats. Proc Soc Exp Biol Med 169:348–354[CrossRef][Medline]
58. Dudley SD 1982 Responsiveness to estradiol in central nervous system of aging female rats. Neurosci Biobehav Rev 6:39–45[CrossRef][Medline]
59. Huang HH, Steger RW, Bruni JF, Meites J 1978 Patterns of sex steroid and gonadotropin secretion in aging female rats. Endocrinology 103:1855–1859[Abstract/Free Full Text]
60. Hirshfield AN, DeSanti AM 1995 Patterns of ovarian cell proliferation in rats during the embryonic period and the first three weeks postpartum. Biol Reprod 53:1208–1221[Abstract]
61. Edwards RG, Fowler RE, Gore-Langton RE, Gosden RG, Jones EC, Readhead C, Steptoe PC 1977 Normal and abnormal follicular growth in mouse, rat and human ovaries. J Reprod Fertil 51:237–263[Abstract/Free Full Text]
62. van Wezel IL, Rodgers RJ 1996 Morphological characterization of bovine primordial follicles and their environment in vivo. Biol Reprod 55:1003–1011[Abstract]
63. Pedersen T, Peters H 1968 Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil 17:555–557[Abstract/Free Full Text]
64. Mandl AM, Zucherman S 1951 The relation of age to numbers of oocytes. J Endocrinol 7:190–193[Abstract/Free Full Text]
65. Jones EC, Krohn PL 1961 The relationships between age, numbers of oocytes and fertility in virgin and multiparous mice. J Endocrinol 21:469–495
66. Hage AJ, Groen-Klevant AC, Welschen R 1978 Follicle growth in the immature rat ovary. Acta Endocrinol (Copenh) 88:375–382[Abstract/Free Full Text]
67. Wandji SA, Srsen V, Voss AK, Eppig JJ, Fortune JE 1996 Initiation in vitro of growth of bovine primordial follicles. Biol Reprod 55:942–948[Abstract]
68. Wang XN, Greenwald GS 1993 Hypophysectomy of the cyclic mouse. I. Effects on folliculogenesis, oocyte growth, and follicle-stimulating hormone and human chorionic gonadotropin receptors. Biol Reprod 48:585–594[Abstract]
69. Flaws JA, Abbud R, Mann RJ, Nilson JH, Hirshfield AN 1997 Chronically elevated luteinizing hormone depletes primordial follicles in the mouse ovary. Biol Reprod 57:1233–1237[Abstract]
70. Rannikki AS, Zhang FP, Huhtaniemi IT 1995 Ontogeny of follicle-stimulating hormone receptor gene expression in the rat testis and ovary. Mol Cell Endocrinol 107:199–208[CrossRef][Medline]
71. Sokka T, Huhtaniemi I 1990 Ontogeny of gonadotrophin receptors and gonadotrophin-stimulated cyclic AMP production in the neonatal rat ovary. J Endocrinol 127:297–303[Abstract/Free Full Text]
72. Dunkel L, Tilly JL, Shikone T, Nishimori K, Hsueh AJW 1994 Follicle-stimulating hormone receptor expression in the rat ovary: increases during prepubertal development and regulation by the opposing actions of transforming growth factors ß and . Biol Reprod 50:940–948[Abstract]
73. O’Shaughnessy PJ, McLelland D, McBride MW 1997 Regulation of luteinizing hormone-receptor and follicle-stimulating hormone-receptor messenger ribonucleic acid levels during development in the neonatal mouse ovary. Biol Reprod 57:602–608[Abstract]
74. Oktay K, Briggs D, Gosden RG 1997 Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab 82:3748–3751[Abstract/Free Full Text]
75. Ahmed CE, Dees WL, Ojeda SR 1986 The immature rat ovary is innervated by vasoactive intestinal peptide (VIP)-containing fibers and responds to VIP with steroid secretion. Endocrinology 118:1682–1689[Abstract/Free Full Text]
76. Mayerhofer A, Dissen GA, Costa ME, Ojeda SR 1997 A role for neurotransmitters in early follicular development: induction of functional follicle-stimulating hormone receptors in newly formed follicles of the rat ovary. Endocrinology 138:3320–3329[Abstract/Free Full Text]
77. Volarcik K, Sheean L, Goldfarb J, Woods L, Abdul-Karim FW, Hunt P 1998 The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 13:154–160[Abstract/Free Full Text]
78. Kuroda H, Terada N, Nakayama H, Matsumoto K, Kitamura Y 1988 Infertility due to growth arrest of ovarian follicles in Sl/Slt mice. Dev Biol 126:71–79[CrossRef][Medline]
79. Huang EJ, Manova K, Packer AI, Sanchez S, Bachvarova RF, Besmer P 1993 The murine steel panda mutation affects kit ligand expression and growth of early ovarian follicles. Dev Biol 157:100–109[CrossRef][Medline]
80. Bedell MA, Brannan CI, Evans EP, Copeland NG, Jenkins NA, Donovan PJ 1995 DNA rearrangements located over 100 kb 5' of the Steel (Sl)-coding region in Steel-panda and Steel-contrasted mice deregulate Sl expression and cause female sterility by disrupting ovarian follicle development. Genes Dev 9:455–470[Abstract/Free Full Text]
81. Yoshida H, Takakura N, Kataoka H, Kunisada T, Okamura H, Nishikawa SI 1997 Stepwise requirement of c-kit tyrosine kinase in mouse ovarian follicle development. Dev Biol 184:122–137[CrossRef][Medline]
82. Ezoe K, Holmes SA, Ho L, Bennett CP, Bolognia JL, Brueton L, Burn J, Falabella R, Gatto EM, Ishii N, Moss C, Pittelkow MR 1995 Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. Am J Hum Genet 56:58–66[Medline]
83. McGrath SA, Esquela AF, Lee SJ 1995 Oocyte-specific expression of growth/differentiation factor-9. Mol Endocrinol 9:131–136[Abstract/Free Full Text]
84. Hayashi M, McGee EA, Min G, Klein C, Rose UM, van Duin M, Hsueh AJW 1999 Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles. Endocrinology 140:1236–1244[Abstract/Free Full Text]
85. Elvin JA, Clark AT, Wang P, Wolfman NM, Matzuk MM 1999 Paracrine actions of growth differentiation factor-9 in the mammalian ovary. Mol Endocrinol 13:1035–1048[Abstract/Free Full Text]
86. Aaltonen J, Laitinen MP, Vuojolainen K, Jaatinen R, Horelli-Kuitunen N, Seppa L, Louhio H, Tuuri T, Sjoberg J, Butzow R, Hovata O, Dale L, Ritvos O 1999 Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. J Clin Endocrinol Metab 84:2744–2750[Abstract/Free Full Text]
87. Bodensteiner KJ, Clay CM, Moeller CL, Sawyer HR 1999 Molecular cloning of the ovine growth/differentiation factor-9 gene and expression of growth/differentiation factor-9 in ovine and bovine ovaries. Biol Reprod 60:381–386[Abstract/Free Full Text]
88. Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM 1996 Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383:531–535[CrossRef][Medline]
89. Elvin JA, Yan C, Wang P, Nishimori K, Matzuk MM 1999 Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary. Mol Endocrinol 13:1018–1034[Abstract/Free Full Text]
90. Laitinen M, Vuojolainen K, Jaatinen R, Ketola I, Aaltonen J, Lehtonen E, Heikinheimo M, Ritvos O 1998 A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis. Mech Dev 78:135–140[CrossRef][Medline]
91. Dube JL, Wang P, Elvin J, Lyons KM, Celeste AJ, Matzuk MM 1998 The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes. Mol Endocrinol 12:1809–1817[Abstract/Free Full Text]
92. Wandji SA, Srsen V, Nathanielsz PW, Eppig JJ, Fortune JE 1997 Initiation of growth of baboon primordial follicles in vitro. Hum Reprod 12:1993–2001[Abstract/Free Full Text]
93. Simon AM, Goodenough DA, Li E, Paul DL 1997 Female infertility in mice lacking connexin 37. Nature 385:525–529[CrossRef][Medline]
94. Eppig JJ, Chesnel F, Hirao Y, O’Brien MJ, Pendola FL, Watanabe S, Wigglesworth K 1997 Oocyte control of granulosa cell development: how and why. Hum Reprod 12:127–132[Medline]
95. Vanderhyden BC, Telfer EE, Eppig JJ 1992 Mouse oocytes promote proliferation of granulosa cells from preantral and antral follicles in vitro. Biol Reprod 46:1196–1204[Abstract]
96. Eppig JJ, Pendola FL, Wigglesworth K 1998 Mouse oocytes suppress cAMP-induced expression of LH receptor mRNA by granulosa cells in vitro. Mol Reprod Dev 49:327–332[CrossRef][Medline]
97. Nekola MV, Nalbandov AV 1971 Morphological changes of rat follicular cells as influenced by oocytes. Biol Reprod 4:154–160[Abstract]
98. Vanderhyden BC, Macdonald EA 1998 Mouse oocytes regulate granulosa cell steroidogenesis throughout follicular development. Biol Reprod 59:1296–1301[Abstract/Free Full Text]
99. Hsu SY, Kubo M, Chun SY, Haluska FG, Housman DE, Hsueh AJW 1995 Wilms’ tumor protein WT1 as an ovarian transcription factor: decreases in expression during follicle development and repression of inhibin- gene promoter. Mol Endocrinol 9:1356–1366[Abstract/Free Full Text]
100. Chun SY, McGee EA, Hsu SY, Minami S, LaPolt PS, Yao HH, Bahr JM, Gougeon A, Schomberg DW, Hsueh AJW 1999 Restricted expression of WT1 messenger ribonucleic acid in immature ovarian follicles: uniformity in mammalian and avian species and maintenance during reproductive senescence. Biol Reprod 60:365–373[Abstract/Free Full Text]
101. Rauscher FJ 1993 The WT1 Wilms’ tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J 7:896–903[Abstract]
102. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN 1991 Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447[CrossRef][Medline]
103. Henry I, Hoovers J, Barichard F, Bertheas MF, Puech A, Prieur F, Gessler M, Bruns G, Mannens M, Junien C 1993 Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family. Genes Chromosom Cancer 7:57–62[Medline]
104. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, Bondy CA 1998 Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 83:2479–2485[Abstract/Free Full Text]
105. Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA 1998 Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 101:2622–2629[Medline]
106. Hillier SG, Tetsuka M, Fraser HM 1997 Location and developmental regulation of androgen receptor in primate ovary. Hum Reprod 12:107–111[CrossRef][Medline]
107. Murray AA, Gosden RG, Allison V, Spears N 1998 Effect of androgens on the development of mouse follicles growing in vitro. J Reprod Fertil 113:27–33[Abstract/Free Full Text]
108. Kotsuji F, Tominaga T 1994 The role of granulosa and theca cell interactions in ovarian structure and function. Microsc Res Tech 27:97–107[CrossRef][Medline]
109. Parrott JA, Skinner MK 1998 Thecal cell-granulosa cell interactions involve a positive feedback loop among keratinocyte growth factor, hepatocyte growth factor, and Kit ligand during ovarian follicular development. Endocrinology 139:2240–2245[Abstract/Free Full Text]
110. McGee EA, Chun SY, Lai S, He Y, Hsueh AJW 1999 Keratinocyte growth factor promotes the survival, growth, and differentiation of preantral ovarian follicles. Fertil Steril 71:732–738[CrossRef][Medline]
111. Li R, Phillips DM, Mather JP 1995 Activin promotes ovarian follicle development in vitro. Endocrinology 136:849–856[Abstract]
112. Drummond AE, Dyson M, Mercer JE, Findlay JK 1996 Differential responses of post-natal rat ovarian cells to FSH and activin. Mol Cell Endocrinol 122:21–32[CrossRef][Medline]
113. Smitz J, Cortvrindt R, Hu Y, Vanderstichele H 1998 Effects of recombinant activin A on in vitro culture of mouse preantral follicles. Mol Reprod Dev 50:294–304[CrossRef][Medline]
114. Mizunuma H, Liu X, Andoh K, Abe Y, Kobayashi J, Yamada K, Yokota H, Ibuki Y, Hasegawa Y 1999 Activin from secondary follicles causes small preantral follicles to remain dormant at the resting stage. Endocrinology 140:37–42[Abstract/Free Full Text]
115. Liu X, Andoh K, Yokota H, Kobayashi J, Abe Y, Yamada K, Mizunuma H, Ibuki Y 1998 Effects of growth hormone, activin, and follistatin on the development of preantral follicle from immature female mice. Endocrinology 139:2342–2347[Abstract/Free Full Text]
116. Levy MJ, Hernandez ER, Adashi EY, Stillman RJ, Roberts Jr CT, LeRoith D 1992 Expression of the insulin-like growth factor (IGF)-I and -II and the IGF-I and -II receptor genes during postnatal development of the rat ovary. Endocrinology 131:1202–1206[Abstract/Free Full Text]
117. Baker J, Hardy MP, Zhou J, Bondy C, Lupu F, Bellve AR, Efstratiadis A 1996 Effects of an IGF1 gene null mutation on mouse reproduction. Mol Endocrinol 10:903–918[Abstract/Free Full Text]
118. Zhou J, Kumar TR, Matzuk MM, Bondy C 1997 Insulin-like growth factor I regulates gonadotropin responsiveness in the murine ovary. Mol Endocrinol 11:1924–1933[Abstract/Free Full Text]
119. Kol S, Adashi EY 1995 Intraovarian factors regulating ovarian function. Curr Opin Obstet Gynecol 7:209–213[Medline]
120. Findlay JK, Drummond AC, Fry RC 1996 Intragonadal regulation of follicular development and ovulation. Anim Reprod Sci 42:321–331[CrossRef]
121. Elvin JA, Matzuk MM 1998 Mouse models of ovarian failure. Rev Reprod 3:183–195[Abstract]
122. Kumar TR, Wang Y, Lu N, Matzuk MM 1997 Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 15:201–204[CrossRef][Medline]
123. Dierich A, Sairam MR, Monaco L, Fimia GM, Gansmuller A, LeMeur M, Sassone-Corsi P 1998 Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612–13617[Abstract/Free Full Text]
124. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehvaslaiho H, Engel AR 1995 Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959–968[CrossRef][Medline]
125. Gulyas BJ, Hodgen GD, Tullner WW, Ross GT 1977 Effects of fetal or maternal hypophysectomy on endocrine organs and body weight in infant rhesus monkeys (Macaca mulatta): with particular emphasis on oogenesis. Biol Reprod 16:216–227[Abstract]
126. Hillier SG 1994 Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis. Hum Reprod 9:188–191[Abstract/Free Full Text]
127. Halpin DM, Jones A, Fink G, Charlton HM 1986 Postnatal ovarian follicle development in hypogonadal (hpg) and normal mice and associated changes in the hypothalamic-pituitary ovarian axis. J Reprod Fertil 77:287–296[Abstract/Free Full Text]
128. Dohler KD, Wuttke W 1975 Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology 97:898–907[Abstract/Free Full Text]
129. Kamberi IA, de Vellis J, Bacleon ES, Inglish D 1980 Hormonal patterns of the hypothalamo-pituitary-gonadal axis in the rat during postnatal development and sexual maturation. Endokrinologie 75:129–140[Medline]
130. Dahl KD, Jia XC, Hsueh AJW 1988 Bioactive follicle-stimulating hormone levels in serum and urine of male and female rats from birth to prepubertal period. Biol Reprod 39:32–38[Abstract]
131. Smith SS, Ojeda SR 1986 Neonatal release of gonadotropins is essential for development of ovarian follicle-stimulating hormone receptors. Biol Reprod 34:219–227[Abstract]
132. Goldenberg RL, Reiter EO, Ross GT 1973 Follicle response to exogenous gonadotropins: an estrogen-mediated phenomenon. Fertil Steril 24:121–125[Medline]
133. Cain L, Chatterjee S, Collins TJ 1995 In vitro folliculogenesis of rat preantral follicles. Endocrinology 136:3369–3377[Abstract]
134. Boland NI, Humpherson PG, Leese HJ, Gosden RG 1993 Pattern of lactate production and steroidogenesis during growth and maturation of mouse ovarian follicles in vitro. Biol Reprod 48:798–806[Abstract]
135. Roy SK, Greenwald GS 1989 Hormonal requirements for the growth and differentiation of hamster preantral follicles in long-term culture. J Reprod Fertil 87:103–114[Abstract/Free Full Text]
136. Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA 1996 Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384:470–474[CrossRef][Medline]
137. Hirshfield AN 1985 Comparison of granulosa cell proliferation in small follicles of hypophysectomized, prepubertal, and mature rats. Biol Reprod 32:979–987[Abstract]
138. Santen RJ, Paulsen CA 1973 Hypogonadotropic eunuchoidism. II. Gonadal responsiveness to exogenous gonadotropins. J Clin Endocrinol Metab 36:55–63[Abstract/Free Full Text]
139. Scaramuzzi RJ, Adams NR, Baird DT, Campbell BK, Downing JA, Findlay JK, Henderson KM, Martin GB, McNatty KP, McNeilly AS, Tsonis CG 1993 A model for follicle selection and the determination of ovulation rate in the ewe. Reprod Fertil Dev 5:459–478[CrossRef][Medline]
140. Oktay K, Newton H, Mullan J, Gosden RG 1998 Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle-stimulating hormone. Hum Reprod 13:1133–1138[Abstract/Free Full Text]
141. Flemming W 1885 Ueber die bildung von richtungsfiguren in saugethiereiern beim untergang graafscher follikel. Arch Anat Physiol Jahrgang 221–224
142. Hsueh AJW, Billig H, Tsafriri A 1994 Ovarian follicle atresia: a hormonally controlled apoptotic process. Endocr Rev 15:707–724[Abstract/Free Full Text]
143. Morita Y, Tilly JL 1999 Oocyte apoptosis: like sand through an hourglass. Dev Biol 213:1–17[CrossRef][Medline]
144. Yuan W, Giudice LC 1997 Programmed cell death in human ovary is a function of follicle and corpus luteum status. J Clin Endocrinol Metab 82:3148–3155[Abstract/Free Full Text]
145. Shikone T, Kokawa K, Yamoto M, Nakano R 1997 Apoptosis of human ovary and uterine endometrium during the menstrual cycle. Horm Res 48:27–34
146. Fukaya T, Funayama Y, Muakami T, Sugawara J, Yajima A 1997 Does apoptosis contribute follicular atresia and luteal regression in human ovary? Horm Res 48:20–26
147. Nahum R, Beyth Y, Chun SY, Hsueh AJW, Tsafriri A 1996 Early onset of deoxyribonucleic acid fragmentation during atresia of preovulatory ovarian follicles in rats. Biol Reprod 55:1075–1080[Abstract]
148. Chun SY, Eisenhauer KM, Minami S, Billig H, Perlas E, Hsueh AJW 1996 Hormonal regulation of apoptosis in early antral follicles: follicle-stimulating hormone as a major survival factor. Endocrinology 137:1447–1456[Abstract]
149. Billig H, Furuta I, Hsueh AJW 1993 Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology 133:2204–2212[Abstract/Free Full Text]
150. Chun SY, Billig H, Tilly JL, Furuta I, Tsafriri A, Hsueh AJW 1994 Gonadotropin suppression of apoptosis in cultured preovulatory follicles: mediatory role of endogenous insulin-like growth factor I. Endocrinology 135:1845–1853[Abstract]
151. Eisenhauer KM, Chun SY, Billig H, Hsueh AJW 1995 Growth hormone suppression of apoptosis in preovulatory rat follicles and partial neutralization by insulin-like growth factor binding protein. Biol Reprod 53:13–20[Abstract]
152. Chun SY, Eisenhauer KM, Kubo M, Hsueh AJW 1995 Interleukin-1ß suppresses apoptosis in rat ovarian follicles by increasing nitric oxide production. Endocrinology 136:3120–3127[Abstract]
153. Hsueh AJW, Eisenhauer K, Chun SY, Hsu SY, Billig H 1996 Gonadal cell apoptosis. Recent Prog Horm Res 51:433–455
154. Tilly JL, Billig H, Kowalski KI, Hsueh AJW 1992 Epidermal growth factor and basic fibroblast growth factor suppress the spontaneous onset of apoptosis in cultured rat ovarian granulosa cells and follicles by a tyrosine kinase-dependent mechanism. Mol Endocrinol 6:1942–1950[Abstract/Free Full Text]
155. Danforth DR, Chillik CF, Hertz R, Hodgen GD 1989 Effects of ovarian tissue reduction on the menstrual cycle: persistent normalcy after near-total oophorectomy. Biol Reprod 41:355–360[Abstract]
156. Gosden RG, Faddy MJ 1994 Ovarian aging, follicular depletion, and steroidogenesis. Exp Gerontol 29:265–274[CrossRef][Medline]
157. Gosden RG, Telfer E, Faddy MJ, Brook DJ 1989 Ovarian cyclicity and follicular recruitment in unilaterally ovariectomized mice. J Reprod Fertil 87:257–264[Abstract/Free Full Text]
158. Meredith S, Dudenhoeffer G, Butcher RL, Lerner SP, Walls T 1992 Unilateral ovariectomy increases loss of primordial follicles and is associated with increased metestrous concentration of follicle-stimulating hormone in old rats. Biol Reprod 47:162–168[Abstract]
159. Hirshfield AN 1994 Relationship between the supply of primordial follicles and the onset of follicular growth in rats. Biol Reprod 50:421–428[Abstract]
160. Perez GI, Robles R, Knudson CM, Flaws JA, Korsmeyer SJ, Tilly JL 1999 Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 21:200–203[CrossRef][Medline]
161. Apperley JF, Reddy N 1995 Mechanism and management of treatment-related gonadal failure in recipients of high dose chemoradiotherapy. Blood Rev 9:93–116[CrossRef][Medline]
162. Byrne J, Mulvihill JJ, Myers MH, Connelly RR, Naughton MD, Krauss MR, Steinhorn SC, Hassinger DD, Austin DF, Bragg K, Holmes GF, Holmes FF, Latourette HB, Weyer PJ, Meigs JW, Teta MJ, Cook JW, Strong LC 1987 Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer. N Engl J Med 317:1315–1321[Abstract]
163. Blumenfeld Z, Avivi I, Linn S, Epelbaum R, Ben-Shahar M, Haim N 1996 Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 11:1620–1626[Abstract/Free Full Text]
164. Ataya KM, McKanna JA, Weintraub AM, Clark MR, LeMaire WJ 1985 A luteinizing hormone-releasing hormone agonist for the prevention of chemotherapy-induced ovarian follicular loss in rats. Cancer Res 45:3651–3656[Abstract/Free Full Text]
165. Gosden RG, Wade JC, Fraser HM, Sandow J, Faddy MJ 1997 Impact of congenital or experimental hypogonadotrophism on the radiation sensitivity of the mouse ovary. Hum Reprod 12:2483–2488[Abstract/Free Full Text]
166. Cramer DW, Xu H, Harlow BL 1995 Does "incessant" ovulation increase risk for early menopause? Am J Obstet Gynecol 172:568–573[CrossRef][Medline]
167. van Noord PA, Dubas JS, Dorland M, Boersma H, te Velde E 1997 Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil Steril 68:95–102[CrossRef][Medline]
168. Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R 1987 Factors influencing the age at natural menopause. J Chronic Dis 40:995–1002[CrossRef][Medline]
169. Whelan EA, Sandler DP, McConnaughey DR, Weinberg CR 1990 Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol 131:625–632[Abstract/Free Full Text]
170. Pedersen T, Peters H 1971 Follicle growth and cell dynamics in the mouse ovary during pregnancy. Fertil Steril 22:42–52[Medline]
171. Lapolt PS, Yu SM, Lu JK 1988 Early treatment of young female rats with progesterone delays the aging-associated reproductive decline: a counteraction by estradiol. Biol Reprod 38:987–995[Abstract]
172. LaPolt PS, Matt DW, Lu JK 1998 Progesterone implants delay age-related declines in regular estrous cyclicity and the ovarian follicular reserve in Long-Evans rats. Biol Reprod 59:197–201[Abstract/Free Full Text]
173. Martin NG, Shanley S, Butt K, Osborne J, O’Brien G 1991 Excessive follicular recruitment and growth in mothers of spontaneous dizygotic twins. Acta Genet Med Gemellol (Roma) 40:291–301[Medline]
174. Martin NG, Olsen ME, Theile H, El Beaini JL, Handelsman D, Bhatnagar AS 1984 Pituitary-ovarian function in mothers who have had two sets of dizygotic twins. Fertil Steril 41:878–880[Medline]
175. Martin NG, Robertson DM, Chenevix-Trench G, de Kretser DM, Osborne J, Burger HG 1991 Elevation of follicular phase inhibin and luteinizing hormone levels in mothers of dizygotic twins suggests nonovarian control of human multiple ovulation. Fertil Steril 56:469–474[Medline]
176. Thomas HV, Murphy MF, Key TJ, Fentiman IS, Allen DS, Kinlen LJ 1998 Pregnancy and menstrual hormone levels in mothers of twins compared to mothers of singletons. Ann Hum Biol 25:69–75[CrossRef][Medline]
177. Wyshak G 1975 Twinning rates among women at the end of their reproductive span and their relation to age at menopause. Am J Epidemiol 102:170–178[Abstract/Free Full Text]
178. Murphy M, Allen D, Key T, Thomas HV, Fentiman IS, Wang DY 1998 Social, biological and reproductive characteristics of mothers of twins: implications for breast cancer risk. Ann Hum Biol 25:77–85[CrossRef][Medline]
179. Turner G, Robinson H, Wake S, Martin N 1994 Dizygous twinning and premature menopause in fragile X syndrome. Lancet 344:1500
180. Broekmans FJ, Scheffer GJ, Bancsi LF, Dorland M, Blankenstein MA, te Velde ER 1998 Ovarian reserve tests in infertility practice and normal fertile women. Maturitas 30:205–214[CrossRef][Medline]
181. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss JF, 3rd Spielman RS, Dunaif A 1999 Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci USA 96:8573–8578 [Abstract/Free Full Text]

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				T. D. Gallardo, G. B. John, K. Bradshaw, C. Welt, R. Reijo-Pera, P. H. Vogt, P. Touraine, S. Bione, D. Toniolo, L. M. Nelson, et al. Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea Hum. Reprod., January 1, 2008; 23(1): 216 - 221. [Abstract] [Full Text] [PDF]

				S. Rajareddy, P. Reddy, C. Du, L. Liu, K. Jagarlamudi, W. Tang, Y. Shen, C. Berthet, S. L. Peng, P. Kaldis, et al. p27kip1 (Cyclin-Dependent Kinase Inhibitor 1B) Controls Ovarian Development by Suppressing Follicle Endowment and Activation and Promoting Follicle Atresia in Mice Mol. Endocrinol., September 1, 2007; 21(9): 2189 - 2202. [Abstract] [Full Text] [PDF]

				K. J. McTavish, M. Jimenez, K. A. Walters, J. Spaliviero, N. P. Groome, A. P. Themmen, J. A. Visser, D. J. Handelsman, and C. M. Allan Rising Follicle-Stimulating Hormone Levels with Age Accelerate Female Reproductive Failure Endocrinology, September 1, 2007; 148(9): 4432 - 4439. [Abstract] [Full Text] [PDF]

				A. Sen, A. Bettegowda, F. Jimenez-Krassel, J. J. Ireland, and G. W. Smith Cocaine- and Amphetamine-Regulated Transcript Regulation of Follicle-Stimulating Hormone Signal Transduction in Bovine Granulosa Cells Endocrinology, September 1, 2007; 148(9): 4400 - 4410. [Abstract] [Full Text] [PDF]

				M. E. Kevenaar, A. P.N. Themmen, F. Rivadeneira, A. G. Uitterlinden, J. S.E. Laven, N. M. van Schoor, P. Lips, H. A.P. Pols, and J. A. Visser A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity Hum. Reprod., September 1, 2007; 22(9): 2382 - 2388. [Abstract] [Full Text] [PDF]

				T. D. Gallardo, G. B. John, L. Shirley, C. M. Contreras, E. A. Akbay, J. M. Haynie, S. E. Ward, M. J. Shidler, and D. H. Castrillon Genomewide Discovery and Classification of Candidate Ovarian Fertility Genes in the Mouse Genetics, September 1, 2007; 177(1): 179 - 194. [Abstract] [Full Text] [PDF]

				Y. Wang, J. Li, C. Ying Wang, A. H. Yan Kwok, and F. C. Leung Epidermal Growth Factor (EGF) Receptor Ligands in the Chicken Ovary: I. Evidence for Heparin-Binding EGF-Like Growth Factor (HB-EGF) as a Potential Oocyte-Derived Signal to Control Granulosa Cell Proliferation and HB-EGF and Kit Ligand Expression Endocrinology, July 1, 2007; 148(7): 3426 - 3440. [Abstract] [Full Text] [PDF]

				S. Tsepelidis, F. Devreker, I. Demeestere, A. Flahaut, Ch. Gervy, and Y. Englert Stable serum levels of anti-Mullerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women Hum. Reprod., July 1, 2007; 22(7): 1837 - 1840. [Abstract] [Full Text] [PDF]

				M. E. Kevenaar, A. P.N. Themmen, J. S.E. Laven, B. Sonntag, S. L. Fong, A. G. Uitterlinden, F. H. de Jong, H. A.P. Pols, M. Simoni, and J. A. Visser Anti-Mullerian hormone and anti-Mullerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women Hum. Reprod., June 1, 2007; 22(6): 1547 - 1554. [Abstract] [Full Text] [PDF]

				G. B John, L. J Shirley, T. D Gallardo, and D. H Castrillon Specificity of the requirement for Foxo3 in primordial follicle activation Reproduction, May 1, 2007; 133(5): 855 - 863. [Abstract] [Full Text] [PDF]

				P M. Lokman, K. A N George, S. L Divers, M. Algie, and G. Young 11-Ketotestosterone and IGF-I increase the size of previtellogenic oocytes from shortfinned eel, Anguilla australis, in vitro Reproduction, May 1, 2007; 133(5): 955 - 967. [Abstract] [Full Text] [PDF]

				J. A. Visser, A. L. L. Durlinger, I. J. J. Peters, E. R. van den Heuvel, U. M. Rose, P. Kramer, F. H. de Jong, and A. P. N. Themmen Increased Oocyte Degeneration and Follicular Atresia during the Estrous Cycle in Anti-Mullerian Hormone Null Mice Endocrinology, May 1, 2007; 148(5): 2301 - 2308. [Abstract] [Full Text] [PDF]

				L. S. Sleer and C. C. Taylor Cell-Type Localization of Platelet-Derived Growth Factors and Receptors in the Postnatal Rat Ovary and Follicle Biol Reprod, March 1, 2007; 76(3): 379 - 390. [Abstract] [Full Text] [PDF]

				A. E. Roberts, L. K. Arbogast, C. I. Friedman, D. E. Cohn, P. T. Kaumaya, and D. R. Danforth Neutralization of Endogenous Vascular Endothelial Growth Factor Depletes Primordial Follicles in the Mouse Ovary Biol Reprod, February 1, 2007; 76(2): 218 - 223. [Abstract] [Full Text] [PDF]

				L. Liu, S. Rajareddy, P. Reddy, K. Jagarlamudi, C. Du, Y. Shen, Y. Guo, K. Boman, E. Lundin, U. Ottander, et al. Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development J. Mol. Endocrinol., January 1, 2007; 38(1): 137 - 146. [Abstract] [Full Text] [PDF]

				C. R Greenfeld, J. K Babus, P. A Furth, S. Marion, P. B Hoyer, and J. A Flaws BAX is involved in regulating follicular growth, but is dispensable for follicle atresia in adult mouse ovaries Reproduction, January 1, 2007; 133(1): 107 - 116. [Abstract] [Full Text] [PDF]

				L. Liu, S. Rajareddy, P. Reddy, C. Du, K. Jagarlamudi, Y. Shen, D. Gunnarsson, G. Selstam, K. Boman, and K. Liu Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a Development, January 1, 2007; 134(1): 199 - 209. [Abstract] [Full Text] [PDF]

				M. Orisaka, K. Tajima, T. Mizutani, K. Miyamoto, B. K. Tsang, S. Fukuda, Y. Yoshida, and F. Kotsuji Granulosa Cells Promote Differentiation of Cortical Stromal Cells into Theca Cells in the Bovine Ovary Biol Reprod, November 1, 2006; 75(5): 734 - 740. [Abstract] [Full Text] [PDF]

				M. Orisaka, S. Orisaka, J.-Y. Jiang, J. Craig, Y. Wang, F. Kotsuji, and B. K. Tsang Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage Mol. Endocrinol., October 1, 2006; 20(10): 2456 - 2468. [Abstract] [Full Text] [PDF]

				D. Modi, D. Bhartiya, and C. Puri Developmental expression and cellular distribution of Mullerian inhibiting substance in the primate ovary. Reproduction, September 1, 2006; 132(3): 443 - 453. [Abstract] [Full Text] [PDF]

				K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]

				B. Campbell, J. Dickey, B. Beckman, G. Young, A. Pierce, H. Fukada, and P. Swanson Previtellogenic Oocyte Growth in Salmon: Relationships among Body Growth, Plasma Insulin-Like Growth Factor-1, Estradiol-17beta, Follicle-Stimulating Hormone and Expression of Ovarian Genes for Insulin-Like Growth Factors, Steroidogenic-Acute Regulatory Protein and Receptors for Gonadotropins, Growth Hormone, and Somatolactin Biol Reprod, July 1, 2006; 75(1): 34 - 44. [Abstract] [Full Text] [PDF]

				M. P. Del Borgo, R. A. Hughes, R. A. D. Bathgate, F. Lin, K. Kawamura, and J. D. Wade Analogs of Insulin-like Peptide 3 (INSL3) B-chain Are LGR8 Antagonists in Vitro and in Vivo J. Biol. Chem., May 12, 2006; 281(19): 13068 - 13074. [Abstract] [Full Text] [PDF]

				L J Spicer, P Y Aad, D Allen, S Mazerbourg, and A J Hsueh Growth differentiation factor-9 has divergent effects on proliferation and steroidogenesis of bovine granulosa cells. J. Endocrinol., May 1, 2006; 189(2): 329 - 339. [Abstract] [Full Text] [PDF]

				N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M. Fauser The Science behind 25 Years of Ovarian Stimulation for in Vitro Fertilization Endocr. Rev., April 1, 2006; 27(2): 170 - 207. [Abstract] [Full Text] [PDF]

				C M Allan, Y Wang, M Jimenez, B Marshan, J Spaliviero, P Illingworth, and D J Handelsman Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice. J. Endocrinol., March 1, 2006; 188(3): 549 - 557. [Abstract] [Full Text] [PDF]

				K. A Slot, J. Kastelijn, A. Bachelot, P. A Kelly, N. Binart, and K. J Teerds Reduced recruitment and survival of primordial and growing follicles in GH receptor-deficient mice. Reproduction, March 1, 2006; 131(3): 525 - 532. [Abstract] [Full Text] [PDF]

				C. J. Guigon and S. Magre Contribution of Germ Cells to the Differentiation and Maturation of the Ovary: Insights from Models of Germ Cell Depletion Biol Reprod, March 1, 2006; 74(3): 450 - 458. [Abstract] [Full Text] [PDF]

				K. A Slot, M. Voorendt, M. de Boer-Brouwer, H. H van Vugt, and K. J Teerds Estrous cycle dependent changes in expression and distribution of Fas, Fas ligand, Bcl-2, Bax, and pro- and active caspase-3 in the rat ovary J. Endocrinol., February 1, 2006; 188(2): 179 - 192. [Abstract] [Full Text] [PDF]

				J. A Visser, F. H de Jong, J. S E Laven, and A. P N Themmen Anti-Mullerian hormone: a new marker for ovarian function Reproduction, January 1, 2006; 131(1): 1 - 9. [Abstract] [Full Text] [PDF]

				A. Navarro, R. Torrejon, M. J. Bandez, J. M. Lopez-Cepero, and A. Boveris Mitochondrial function and mitochondria-induced apoptosis in an overstimulated rat ovarian cycle Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1101 - E1109. [Abstract] [Full Text] [PDF]

				E. H. Y. Ng, O. S. Tang, C. C. W. Chan, and P. C. Ho Ovarian stromal blood flow in the prediction of ovarian response during in vitro fertilization treatment Hum. Reprod., November 1, 2005; 20(11): 3147 - 3151. [Abstract] [Full Text] [PDF]

				P. K. Kreeger, N. N. Fernandes, T. K. Woodruff, and L. D. Shea Regulation of Mouse Follicle Development by Follicle-Stimulating Hormone in a Three-Dimensional In Vitro Culture System Is Dependent on Follicle Stage and Dose Biol Reprod, November 1, 2005; 73(5): 942 - 950. [Abstract] [Full Text] [PDF]

				P. Su, J. C. Wu, J. R. Sommer, A. J. Gore, R. M. Petters, and W. L. Miller Conditional Induction of Ovulation in Mice Biol Reprod, October 1, 2005; 73(4): 681 - 687. [Abstract] [Full Text] [PDF]

				M. K. Skinner Regulation of primordial follicle assembly and development Hum. Reprod. Update, September 1, 2005; 11(5): 461 - 471. [Abstract] [Full Text] [PDF]

				R. R. Greb, K. Grieshaber, J. Gromoll, B. Sonntag, E. Nieschlag, L. Kiesel, and M. Simoni A Common Single Nucleotide Polymorphism in Exon 10 of the Human Follicle Stimulating Hormone Receptor Is a Major Determinant of Length and Hormonal Dynamics of the Menstrual Cycle J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4866 - 4872. [Abstract] [Full Text] [PDF]

				E. H. Y. Ng, C. C. W. Chan, W. S. B. Yeung, and P. C. Ho Comparison of ovarian stromal blood flow between fertile women with normal ovaries and infertile women with polycystic ovary syndrome Hum. Reprod., July 1, 2005; 20(7): 1881 - 1886. [Abstract] [Full Text] [PDF]

				ESHRE Capri Workshop Group Fertility and ageing Hum. Reprod. Update, May 1, 2005; 11(3): 261 - 276. [Abstract] [Full Text] [PDF]

				Y. Park, E. T. Maizels, Z. J. Feiger, H. Alam, C. A. Peters, T. K. Woodruff, T. G. Unterman, E. J. Lee, J. L. Jameson, and M. Hunzicker-Dunn Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad J. Biol. Chem., March 11, 2005; 280(10): 9135 - 9148. [Abstract] [Full Text] [PDF]

				M. R. Hussein Apoptosis in the ovary: molecular mechanisms Hum. Reprod. Update, March 1, 2005; 11(2): 162 - 178. [Abstract] [Full Text] [PDF]

				A. P. N. Themmen Anti-Mullerian Hormone: Its Role in Follicular Growth Initiation and Survival and as an Ovarian Reserve Marker J Natl Cancer Inst Monographs, March 1, 2005; 2005(34): 18 - 21. [Abstract] [Full Text] [PDF]

				F. Parborell, G. Irusta, A. Vitale, O. Gonzalez, A. Pecci, and M. Tesone Gonadotropin-Releasing Hormone Antagonist Antide Inhibits Apoptosis of Preovulatory Follicle Cells in Rat Ovary Biol Reprod, March 1, 2005; 72(3): 659 - 666. [Abstract] [Full Text] [PDF]

				H. M. Fraser, H. Wilson, J. S. Rudge, and S. J. Wiegand Single Injections of Vascular Endothelial Growth Factor Trap Block Ovulation in the Macaque and Produce a Prolonged, Dose-Related Suppression of Ovarian Function J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1114 - 1122. [Abstract] [Full Text] [PDF]

				N. Kaivo-Oja, D. G. Mottershead, S. Mazerbourg, S. Myllymaa, S. Duprat, R. B. Gilchrist, N. P. Groome, A. J. Hsueh, and O. Ritvos Adenoviral Gene Transfer Allows Smad-Responsive Gene Promoter Analyses and Delineation of Type I Receptor Usage of Transforming Growth Factor-{beta} Family Ligands in Cultured Human Granulosa Luteal Cells J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 271 - 278. [Abstract] [Full Text] [PDF]

				S. Jonard, P. Pigny, L. Jacquesson, C. Demerle-Roux, Y. Robert, and D. Dewailly The ovarian markers of the FSH insufficiency in functional hypothalamic amenorrhoea Hum. Reprod., January 1, 2005; 20(1): 101 - 107. [Abstract] [Full Text] [PDF]

				H. Jiang, K. M. Whitworth, N. J. Bivens, J. E. Ries, R. J. Woods, L. J. Forrester, G. K. Springer, N. Mathialagan, C. Agca, R. S. Prather, et al. Large-Scale Generation and Analysis of Expressed Sequence Tags from Porcine Ovary Biol Reprod, December 1, 2004; 71(6): 1991 - 2002. [Abstract] [Full Text] [PDF]

				T. Shimizu, Y. Miyahayashi, M. Yokoo, Y. Hoshino, H. Sasada, and E. Sato Molecular cloning of porcine growth differentiation factor 9 (GDF-9) cDNA and its role in early folliculogenesis: direct ovarian injection of GDF-9 gene fragments promotes early folliculogenesis Reproduction, November 1, 2004; 128(5): 537 - 543. [Abstract] [Full Text] [PDF]

				S. Lenie, R. Cortvrindt, T. Adriaenssens, and J. Smitz A Reproducible Two-Step Culture System for Isolated Primary Mouse Ovarian Follicles as Single Functional Units Biol Reprod, November 1, 2004; 71(5): 1730 - 1738. [Abstract] [Full Text] [PDF]

				L. J. Clark, H. F. Irving-Rodgers, A. M. Dharmarajan, and R. J. Rodgers Theca Interna: The Other Side of Bovine Follicular Atresia Biol Reprod, October 1, 2004; 71(4): 1071 - 1078. [Abstract] [Full Text] [PDF]

				E. H. Y. Ng, C. C. W. Chan, W. S. B. Yeung, and P. C. Ho Effect of age on ovarian stromal flow measured by three-dimensional ultrasound with power Doppler in Chinese women with proven fertility Hum. Reprod., September 1, 2004; 19(9): 2132 - 2137. [Abstract] [Full Text] [PDF]

				Y. Wang and W. Ge Cloning of Epidermal Growth Factor (EGF) and EGF Receptor from the Zebrafish Ovary: Evidence for EGF as a Potential Paracrine Factor from the Oocyte to Regulate Activin/Follistatin System in the Follicle Cells Biol Reprod, September 1, 2004; 71(3): 749 - 760. [Abstract] [Full Text] [PDF]

				Y.-C. Hu, P.-H. Wang, S. Yeh, R.-S. Wang, C. Xie, Q. Xu, X. Zhou, H.-T. Chao, M.-Y. Tsai, and C. Chang Subfertility and defective folliculogenesis in female mice lacking androgen receptor PNAS, August 3, 2004; 101(31): 11209 - 11214. [Abstract] [Full Text] [PDF]

				C.-W. Luo, K. Kawamura, C. Klein, and A. J. W. Hsueh Paracrine Regulation of Ovarian Granulosa Cell Differentiation by Stanniocalcin (STC) 1: Mediation through Specific STC1 Receptors Mol. Endocrinol., August 1, 2004; 18(8): 2085 - 2096. [Abstract] [Full Text] [PDF]

				F. Miro, S. W. Parker, L. J. Aspinall, J. Coley, P. W. Perry, and J. E. Ellis Relationship between Follicle-Stimulating Hormone Levels at the Beginning of the Human Menstrual Cycle, Length of the Follicular Phase and Excreted Estrogens: The FREEDOM Study J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3270 - 3275. [Abstract] [Full Text] [PDF]

				M. A. Cunningham, Q. Zhu, and J. M. Hammond FoxO1a Can Alter Cell Cycle Progression by Regulating the Nuclear Localization of p27kip in Granulosa Cells Mol. Endocrinol., July 1, 2004; 18(7): 1756 - 1767. [Abstract] [Full Text] [PDF]

				L. M. Salvador, M. P. Flynn, J. Avila, S. Reierstad, E. T. Maizels, H. Alam, Y. Park, J. D. Scott, D. W. Carr, and M. Hunzicker-Dunn Neuronal Microtubule-associated Protein 2D Is a Dual A-kinase Anchoring Protein Expressed in Rat Ovarian Granulosa Cells J. Biol. Chem., June 25, 2004; 279(26): 27621 - 27632. [Abstract] [Full Text] [PDF]

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