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Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition

Endocrine Research Unit (J.D.V.), Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Department of Pediatrics (J.N.R.), State University of New York at Buffalo, Buffalo, New York 14214-3000; Pediatric Endocrinology (E.J.R.), National Children’s Hospital, San Jose 1000, Costa Rica; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112-2699

Correspondence: Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo Medical School, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: Veldhuis.Johannes{at}mayo.edu

	Abstract

Top Abstract I. Regulation of the... II. Ensemble Regulation of... References

 
Integrative neuroendocrine control of the gonadotropic and somatotropic axes in childhood, puberty, and young adulthood proceeds via multiple convergent and divergent pathways in the human and experimental animal. Emerging ensemble concepts are required to embody independent, parallel, and interacting mechanisms that subserve physiological adaptations and pathological disruption of reproduction and growth. Significant advances in systems biology will be needed to address these challenges.

I. Regulation of the GH and Gonadotropic Axes

A. The somatotropic axis

B. The hypothalamo-pituitary-gonadal axis

II. Ensemble Regulation of GH Secretion

A. Ensemble concept of minimal 5-peptide integration

B. Sexual dimorphism of GH/IGF-I output

C. Self-renewable GH pulsatility

D. Pubertal and gender effects

E. Evaluating pulsatile GH and LH secretion

	I. Regulation of the GH and Gonadotropic Axes

Top Abstract I. Regulation of the... II. Ensemble Regulation of... References

 
A. The somatotropic axis
1. GH
a. Overview of GH neuroregulation.
The principal components of the somatotropic axis comprise hypothalamic regulatory centers, the anterior pituitary gland, peripheral target organs, and cognate binding proteins, receptors, and signaling molecules (1, 2). Ensemble interactions are modulated by neurotransmitters, sex steroids, cortisol, T₄, proteases, metabolites, and acid-base balance. Targets of GH action include the liver, kidney, skeleton, brain, breast, ovary, testis, heart, skeletal muscle, gastrointestinal tract, spleen, thymus, bone marrow, and skin (3, 4). GH stimulates the biosynthesis of IGF-I, which in turn mediates many but not all local growth effects (2, 5). In prechondrocytes and mature adipocytes, GH acts independently of IGF-I production or reception, and in most cells organ-specific hormones also regulate in situ IGF-I gene expression (6).

Hypothalamic GHRH and somatostatin (SS) govern GH secretion by antagonistic and facilitative effects, depending upon the relative timing of their release (1, 7, 8, 9, 10, 11, 12, 13). Ghrelin, an acylated GH-releasing peptide (GHRP) synthesized in the stomach, anterior pituitary gland, hypothalamus, kidney, gonad, and placenta, induces GH secretion via combined hypothalamo-hypophyseal mechanisms, and concomitantly regulates appetite, insulin secretion, fat oxidation, and smooth-muscle contraction (14, 15, 16, 17, 18, 19, 20, 21, 22, 23). The foregoing three (minimal) peptides act as an ensemble, rather than individually, to supervise and respond adaptively to time-varying production of GH and IGF-I (1, 9, 10, 11, 12, 21, 24, 25, 26, 27) (Fig. 1). The stimulatory efficacy of any one of GHRH, GHRP, or L-arginine (to deplete SS) depends upon gender, body composition, age, nutrient status, and underlying disease (1, 27, 28).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Simplified five-peptide model of GH secretion under convergent peptidyl signals SS, GHRH, and GHRP and feedback restraint by GH and IGF-I. Arrows define principal connections among regulatory sites. GH and IGF-I both exert negative feedback via stimulation of SS and inhibition of GHRH secretion. For simplicity, the IGF-I system in the brain is not shown.

Rare mutations of the human GH gene encode dominant-negative proteins that block its processing, release, and/or effects, thereby leading to short stature (34). Biosynthetic analogs of GH have been designed to silence GH-receptor signaling (29, 35). The clinically available antagonist, pegvisomant, harbors 8-amino acid substitutions in high-affinity binding site 1 and one in dimerization site 2, thus disabling intracellular signaling despite binding, dimerizing, and internalizing the receptor (30, 36). Polyethylene glycol residues were affixed to reduce immunogenicity and extend the plasma half-life to 72 h compared with 16 min for native GH (37). Pegvisomant administration in individualized doses normalizes IGF-I concentrations in 95% of patients with acromegaly (38). GH-receptor antagonists also provide probes of the role of GH in physiology and pathophysiology. For example, pegvisomant unleashes GH secretion in young adults by feedback withdrawal without altering GH clearance (37, 39) (Fig. 2). The same agent limits the degree of diabetic glomerulopathy and inhibits growth of colorectal carcinoma in mice (36, 40).

View larger version (22K): [in this window] [in a new window]   FIG. 2. Impact of pegvisomant, a recombinant GH-receptor antagonist peptide, on GH secretion driven by reduced IGF-I negative feedback (A) and GH half-life plotted against the natural logarithm of peak GH concentrations attained after 6-min bolus iv infusion of a 1 µg/kg or 10 µg/kg dose of rhGH (B) in healthy young men and women. Data were obtained 62–72 h after a randomly ordered sc injection of saline or pegvisomant (1 mg/kg). A, Pegvisomant lowered IGF-I concentrations (top left) and elevated basal (top right), pulsatile (bottom left), and total (bottom right) GH secretion, without affecting the half-life of rhGH (B). B, Numerical values are the mean ± SEM for control (top) and pegvisomant (bottom) sessions in relation to a low (left) and higher (right) dose of rhGH. [Adapted with permission from J. D. Veldhuis et al.: J Clin Endocrinol Metab 87:5737–5745, 2002 (37 ); and J. D. Veldhuis et al.: J Clin Endocrinol Metab 86:3304–3310, 2001 (39 ). © The Endocrine Society.]

Rare recessive mutations of the human GH receptor (Laron dwarfism) cause primary insensitivity to GH, IGF-I depletion, growth retardation, and hypersecretion of GH (43). Treatment with recombinant human (rh) IGF-I decreases GH concentrations and ameliorates certain features of the syndrome (44, 45). Perhaps unexpectedly, profound in utero GH deficiency restricts birth size only minimally by reducing longitudinal bone growth in the third trimester (46). Growth continues nearly normally for 6 to 10 months postnatally, and then declines progressively in childhood. Presumptively GH-independent stimuli in prenatal and early neonatal life include IGF-I, IGF-II, insulin, T₄, glucocorticoids, and metabolic substrates (47, 48, 49, 50). Although IGFBP-1, -3, and -5 and novel IGFBP-related peptides that bind insulin both inhibit and stimulate cellular proliferation, their roles in human growth have not been elucidated (6, 51). These issues highlight major knowledge deficits in the GH-independent control of intrauterine and neonatal growth. In relation to this issue, Table 1 outlines inferred differences between GH and IGF-I actions observed experimentally.

2. IGF and IGFBP system
a. Insulinomimetic peptides.
The IGF system comprises insulinomimetic peptides, binding proteins, receptors, and proteases (2, 6, 51, 59, 60, 61). IGF-I and IGF-II exert mitogenic, cytodifferentiative, and antiapoptotic actions in the fetus via receptors designated IGF type I, insulin isoform A, and hybrid IGF-I/insulin isoform A (47, 59, 60). In contrast, IGF type II receptors mediate sequestration, cellular uptake, and degradation of IGF-I and IGF-II. Excessive amounts of soluble IGF-II receptor inhibit hepatocyte proliferation in vitro and bladder smooth-muscle development in vivo (49).

Both GH-dependent and GH-independent (organotypic) mechanisms regulate IGF-I peptide and receptor expression in all major organs (6, 51, 59, 60, 62, 63). Figure 3 illustrates the diversity of organotypic IGF-I regulation. For example, estradiol induces synthesis of IGF-I and cognate receptor in breast, uterus, ovary, pituitary, brain (neurons and glia), and bone; testosterone acts analogously in muscle and bone; PTH does so in bone; LH and FSH in the ovary and testis; and TSH in the thyroid gland (6, 51, 60, 64, 65). The effects of organotypic hormones on local IGF-I availability are not strictly independent of GH, because systemically delivered GH comodulates tissue concentrations of IGF-I, IGFBPs, and proteases.

View larger version (18K): [in this window] [in a new window]   FIG. 3. Illustrative agonist- and tissue-specific control of in situ IGF-I synthesis. Organotypic hormones stimulate local synthesis of IGF-I, which actions are modulated by attendant changes in tissue-specific IGFBPs.

Targeted disruption of hepatic IGF-I gene expression in two murine models reduces systemic IGF-I concentrations by 60–80% and elevates GH concentrations by 2- to 10-fold (68, 69). The transgenic Cre/loxP models exploited postnatal activation of the hepatic albumin and -interferon promoters driving the Cre recombinase enzyme to trigger scission of loxP (P1 bacteriophage) DNA sequences flanking the native IGF-I gene. Despite marked depletion of total IGF-I concentrations, transgenic animals achieve 94% of expected adult size. However, liver and kidney size are increased and decreased, respectively; osteopenia occurs in adulthood; insulin action is impaired in muscle; and hyperlipidemia develops despite decreased total body fat (70). Which of the foregoing outcomes reflect a primary reduction of total IGF-I vis a vis a secondary increase in GH concentrations has not been defined.

Genetic inactivation of either IGFBP-3 or ALS (acid-labile subunit contained in ternary IGF-I/IGFBP-3/ALS) lowers IGF-I concentrations by 65%, yet limits growth minimally and does not amplify GH secretion (71). Normal GH production may reflect the capability of free IGF-I, binary IGF-I/IGFBP-3, and binary IGF-I/IGFBP-1 complexes to undergo capillary endothelial transcytosis into tissues, thereby mediating negative feedback (51, 72). Conversely, overexpression of IGFBP-3, but not of nonlimiting ALS, retards somatic growth putatively by sequestering plasma IGF-I in a stable ternary complex (73) (Table 2).

View larger version (23K): [in this window] [in a new window]   FIG. 4. Schematic depiction of relative roles of IGF-I and IGF-II acting via developmentally regulated receptors.

Disruption of murine genes encoding both type I IGF receptor and IGF-II peptide reduces birthweight by 70% (compared with respective individual reductions of 55 and 40%) (60). Inactivation of the insulin receptor does not decrease live birthweight in this species (81). In contrast, mutation of the human insulin receptor (classical isoform B) is associated with the syndrome of leprechaunism typified by marked insulin resistance, hyperlipidemia, growth impairment, and premature atherosclerosis (82). Combined mutation of the IGF-I and insulin receptors in mice decreases growth by 70% (compared with 50% and no growth failure, respectively) (60, 81). Experiments motivated by this disparity identified a hybrid IGF-I/insulin isoform A receptor, which transduces fetal growth-promoting actions of both IGF-I and IGF-II (47, 81). In mice, insulin-receptor deletion in both ß-cells and hepatocytes or neurons, but not in adipocytes or myocytes individually, impairs adult glucose tolerance, thus indicating partial redundancy in the mechanisms of glucose homeostasis (81, 83).

The type II IGF receptor does not signal growth, but rather directs lysosomal degradation of both IGF-I and IGF-II (84). Silencing the murine IGF-II receptor elevates birthweight by 16% and induces polydactyly, organomegaly, cardiac anomalies, hypoglycemia, edema, and malignancies putatively due to accumulation of insulinomimetic peptides. Severity of the fetal-overgrowth syndrome is ameliorated, but not abolished, by concomitant genetic disruption of either the IGF-I receptor or IGF-II peptide (84) (Table 2).

Transgenic knockout of insulin-receptor substrate (IRS)-1 reduces growth by about 50%, consistent with the fact that IRS-1 transduces cellular signaling by IGF-I, IGF-II, and insulin (81, 85). Significant residual growth motivated the discovery of other related growth factor-receptor signaling messengers, IRS-2, IRS-3, and IRS-4. IRS-2 mediates insulinomimetic peptide drive of satiety and ovarian folliculogenesis (86). In principle, genetic variations in the structure of growth-promoting peptides and their receptor-effector pathways may contribute to currently unexplained growth retardation and populational growth differences in stature (87).

c. Insulinomimetic peptides in puberty.
Isolated hyposomatotropism including GH-resistant Laron syndrome delays the onset and slows the tempo of sexual maturation (43, 44). Although the clinical pathophysiology is not clear, experimental studies indicate that IGF-I administration can: 1) advance the timing of puberty in the female monkey and male or female rat (88, 89, 90); 2) augment secretion by and proliferation of GnRH neurons (91); 3) potentiate GnRH-stimulated LH secretion in vitro (92, 93); 4) synergize with LH and FSH in driving the proliferation and cytodifferentiation of gonadal cells, albeit with wide species differences (94, 95); and 5) enhance human chorionic gonadotropin (hCG)-induced ovulation in the rabbit and oocyte cleavage in the mouse (94). Figure 5 highlights these loci and mechanisms. How such laboratory insights relate to human pubertal development is not established.

View larger version (35K): [in this window] [in a new window]   FIG. 5. Overview of experimentally inferable sites of interaction between local and/or systemic IGF-I and the reproductive system. Species is an important determinant of the particular mechanisms of IGF-I production and action on the gonadotropic axis.

Biological actions of GH and IGF-I differ in several respects (Table 1). For example, both GH and IGF-I increase whole-body protein synthesis and inhibit protein degradation, albeit with different molar efficacies; GH but not IGF-I induces lipoprotein (a), ALS, and IGF-I production; represses muscle IGFBP-4 expression; increases IGFBP-3 protease activity; and stimulates lipolysis; and IGF-I but not GH represses insulin secretion acutely (2, 5, 43, 44, 45, 96, 99, 101).

d. Roles of IGFBP in modulating growth.
Six principal IGFBPs sequester and transport IGF-I and IGF-II and/or stimulate cellular proliferation directly (6, 51). Distinct characteristics confer diversity of control, viz.: 1) IGFBP-1, -2, -3, and -5 bind IGF-I especially, IGFBP-6 binds IGF-II preferentially, and IGFBP-4 binds IGF-I and IGF-II equally; 2) all IGFBPs can block IGF-I actions; 3) IGFBP-1, -3, and -5 stimulate cellular proliferation in vitro; 4) GH induces hepatic and skeletal IGFBP-2, -3, and -5 synthesis, inhibits IGFBP-1 gene transcription, and does not affect IGFBP-4 and -6 concentrations; 5) ovarian and endothelial cells express all except, respectively, IGFBP-6 and IGFBP-1; and 6) IGFBP-1 combines with IGF-I in a high-affinity binary complex, whereas IGFBP-3 and -5 associate with ALS and IGF-I in stable ternary complexes.

The sequestrative effect of IGFBP-3 may have therapeutic implications. An experiment in the ovariectomized rat showed that prolonged administration of binary IGF-I/IGFBP-3 complexes can increase skeletal mass and tensile strength (102); and a short-term clinical study in postmenopausal women reported positive trends in hip bone mineral density (103). Combined peptide injections in patients with type I diabetes mellitus decreased insulin requirements by 50% without increasing hypoglycemia (104). The long-term safety, efficacy, practicability, and indications for combined-protein administration are not known.

IGFBP-1 unlike IGFBP-3 is regulated rapidly (within 1–2 h) by insulin, GH, and glucocorticoids (inhibitory) and estrogen and IGF-I (stimulatory) (51, 105). Posttranslational phosphorylation of IGFBP-1 enhances its affinity for IGF-I and IGF-II, yielding a stable binary complex in plasma. IGFBP-1 reduces dialyzably free IGF-I concentrations in vitro and attenuates hypoglycemia and organ growth in vivo (106). Strongly reciprocal associations between the two proteins are reported in: 1) fetal life, puberty and obesity (low IGFBP-1 and high free IGF-I); and 2) fasting, renal failure, and type I diabetes mellitus (high IGFBP-1 and low free IGF-I). The fact that hyperinsulinemia represses IGFBP-1 production explicates several of the foregoing observations.

IGF-I, IGF-II, and insulin concentrations are also determined by systemic hormones (e.g., testosterone, estradiol, T₄, and glucocorticoids) and nonendocrine factors (e.g., hepatic metabolism, renal filtration, the soluble IGF-II receptor, and endothelial IGFBPs) (107, 108, 109). Pregnancy illustrates such multifactorial control. Maternal concentrations of IGFBP-1 rise, and those of IGFBP-2, -3, -4, -5, and -6 fall, thereby increasing free but not total IGF-I concentrations due to high plasma protease activity, hyperestrogenism, insulin resistance, and secretion of placental variant GH (GH-V), which is a potent somatotropin (6, 51, 61).

e. Sex steroids and the IGF/IGFBP system.
Conjoint activation of the somatotropic and gonadal axes in puberty promotes growth synergistically via independent and concerted mechanisms (1, 27). Sex steroids govern the expression, reception, and degradation of GH and insulinomimetic signals and, conversely, GH and insulinomimetic peptides up-regulate androgen and estrogen receptors (AR and ER) in an organ-specific manner (109, 110) (Table 3). For example, in the rat estradiol 1) induces synthesis of IGF-I and its receptor and alters availability of selected IGFBPs in the central nervous system (CNS), pituitary gland, ovary, breast, uterus, bone, and preadipocytes while inhibiting IGF-I production by the liver; and 2) stimulates the hepatic (subtype 1) GH receptor but represses that in the hypothalamus (62, 64, 65, 111, 112). Testosterone and nonaromatizable androgens induce IGF-I peptide in bone, muscle, and skin, but suppress the type I IGF receptor in fat (109, 112). Thus, the type of sex steroid and the target tissue determine regulation of GH and IGF-I peptides and receptors.

Clinical and research endpoints of GH replacement include linear growth and pubertal progression in childhood; well-being, mood, physical vigor, sexual energy, and sleep quality; lean-body mass and isokinetic or isometric muscle strength; physical endurance and maximal oxygen consumption (aerobic capacity); epiphyseal maturation, bone mineral density, and serum markers of skeletal remodeling; total body fat and regional adiposity; blood pressure, arterial dilatation, cardiac output, and ventricular-wall thickness; extracellular fluid volume, renal size, and glomerular filtration rate; lipoproteins and triglycerides; glycated hemoglobin and glucose; total energy expenditure and basal metabolic rate; TSH, T₄, and T₃ concentrations, because GH facilitates T₄T₃ conversion. The multiplicity of pragmatic and research endpoints underscores the fact that no one biochemical measure is uniquely suited to gauge the full repertoire of GH activity (87, 96, 98, 113, 114).

Linear growth, energy expenditure, body composition, and pubertal development are also influenced by rare mutations and putative polymorphisms of an array of genes variously encoding: 1) receptors for androgen, estrogen, T₄, LH, FSH, glucocorticoid, GH, IGF-I, ACTH, ghrelin, melanocortins, ß-adrenergic agonists, serotonin, insulin, and leptin; and 2) peptides such as GH, IGF-I, LH ß-subunit, ghrelin, leptin, and carboxypeptidase E (1, 115, 116, 117, 118, 119, 120). Thus, precise prediction of growth responses to GH, IGF-I, and/or sex steroids is difficult in individual patients.

B. The hypothalamo-pituitary-gonadal axis
1. In utero
a. Testis.
Human Leydig and Sertoli cells secrete testosterone and inhibin B, respectively, in the second month of fetal life (120). In mice, fetal androgen production is driven by placental hCG acting via Leydig-cell LH receptors, as modulated by insulinomimetic peptides, cytokines, and testis-specific factors (121). Activating mutations of the human LH receptor produce gonadotropin-independent male isosexual precocity, whereas inactivating mutations cause micropenis, hypospadias, genital ambiguity, or severe male pseudohermaphroditism (122, 123). In contrast, silencing the murine LH receptor does not impair prenatal Leydig-cell function (124). The critical role of maternal hCG is affirmed by clinical observations that hypogonadotropic hypogonadism (e.g., Kallmann’s syndrome), mutations of the GnRH receptor or LH ß-subunit gene, pituitary agenesis, and anencephaly do not impair in utero masculinization (120). However, such conditions are associated with a higher incidence of cryptorchidism, putatively due to reduced stimulation of gubernacular muscle by insulin-like 3 (relaxin-like factor) and/or less activation of innervating motoneurons by androgens (125).

Beyond genetic determination of the testis by SRY and SOX9 transcriptional factors (126), gonadal testosterone biosynthesis requires steroidogenic factor 1 (SF-1) and its transcriptional partner DAX (a dosage-sensitive sex-reversal gene product) to induce requisite oxidoreductase enzymes and sterol transport proteins; the Wilm’s tumor suppressor gene and stem-cell factor (c-kit ligand); AR, ER, LH ß-subunit and the LH and peripheral benzodiazepine receptors; selected cytokines and insulinomimetic peptides; and an enlarging array of transcriptional proteins (122, 127, 128, 129, 130, 131). Experimental studies suggest that intragonadal estrogen influences early Leydig-cell development, although this sex steroid inhibits steroidogenesis in the adult animal (132). Transgenic data illustrate that Muellerian-inhibiting substance, signaling via the eponymous Leydig-cell receptor, also modulates steroidogenesis (133).

Concentrations of LH and gonadal steroids in the fetus decline markedly before birth, but are higher in cord blood of boys than girls (120). Male but not female primates exhibit a prominent neonatal surge in LH, FSH, testosterone, and inhibin B production in the presence of a functional AR (134, 135). The surge begins within several hours of birth, peaks at 6 to 8 wk of age, and wanes gradually over 4 to 6 months (134, 136, 137). Testosterone concentrations often exceed 300 ng/dl (10.4 nmol/liter), and LH pulse frequency and amplitude are indistinguishable from values in young men (137) (Fig. 6). The clinical import of this event is not clear.

View larger version (38K): [in this window] [in a new window]   FIG. 6. Pulsatile secretion of LH on the first day of life in a boy. Neonatal activation of the gonadal axis is not evident in girls. [Adapted from Ref. 137 .]

   2. Adrenarche.
Adrenarche is defined phenotypically by the appearance of pubic and axillary hair and increased activity of apocrine sweat glands, and biochemically by increased adrenal synthesis of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione but not cortisol (141, 142, 143). Expression of 3 ß-hydroxysteroid dehydrogenase type II declines in the zona reticularis concomitantly (144). Adrenarche is limited to the primate, thus stymying mechanistic investigations. However, a recent analysis associated mutation of a pituitary-specific transcription factor, PROP-1 (prophet of pit-1), with impaired progression of adrenarche (145).

Adrenarche occurs at or after age 7 yr and 8 yr in African-American and Caucasian girls, respectively, and typically at or after age 9 yr in boys (141, 146). Precocious adrenarche is more common in girls than boys and in Caribbean-Hispanic children. Epidemiological studies associate premature adrenarche with intrauterine growth retardation, prepubertally reduced ovarian volume, peripubertal onset of hyperandrogenism, elevated IGF-I concentrations, and insulin resistance in muscle (147, 148, 149). This constellation mimics features of polycystic ovarian syndrome (POCS). Administration of metformin or a thiazolidenedione in the adolescent and young adult with PCOS ameliorates hyperinsulinism, subfertility, oligo- and amenorrhea, and hyperandrogenism (150, 151). However, the long-term safety of insulin-sensitizing drugs in pubertal girls and the alexiteric impact of these agents on adult cardiovascular events are not known.

Certain polymorphisms of the insulin and insulin-receptor genes predict premature adrenarche and risk of pubertal hyperinsulinism, hyperthecosis, and PCOS (152, 153). Of relevance, IGF-I, insulin, and IGF-II all stimulate adrenal and ovarian androgen secretion in vitro (154, 155, 156). In relation to theca cells, IGF-I or insulin and LH act synergistically (94). Synergy between LH and insulin has import clinically in that hyperinsulinemia coexists with increased pulsatile LH secretion in most patients with PCOS, and in vitro synergism is blocked by troglitazone (156, 157, 158). In one transgenic mouse model, pituitary-directed overexpression of a hybrid LH/hCG gene resulted in persistent anestrus, concomitant adrenal LH-receptor expression, depletion of primordial ovarian follicles, and theca-cell hyperplasia (159). At present, the basic cause of excessive adrenal and ovarian androgen secretion and deficient muscle insulin signaling in PCOS remains undefined.

   3. Gonadarche.
Gonadarche requires orderly activation of the hypothalamo-pituitary-gonadal axis (120, 160, 161). Although the fundamental initiators remain unknown, adrenarche and gonadarche can proceed independently, viz.: 1) adrenarche unfolds in Turner syndrome and under GnRH analog therapy when gonadarche is repressed; and 2) gonadarche progresses with minimal delay in children with adequately treated primary Addison’s disease (141, 142).

Accurate quantitation of gonadal sex-steroid and gonadotropin secretion in childhood requires sensitive assays of estrogen, testosterone, LH, and FSH. A recombinant estradiol receptor-based bioassay documented higher estrogen concentrations in girls than boys prepubertally (162). Ultrasensitive gonadotropin assays have unveiled pulsatile, orderly (low-entropy), and 24-h rhythmic release of LH in prepubertal children (161, 163, 164). In one study, combined application of immunofluorometry, overnight (15-min) blood sampling, and deconvolution analysis disclosed 30-fold amplification of LH secretory-burst mass and 1.8-fold acceleration of LH pulse frequency in late-pubertal compared with prepubertal boys (164). In another analysis, joint use of immunochemiluminometry, daytime (5-min) sampling, and deconvolution analysis delineated 4.2- and 7.5-fold augmentation of LH secretory-burst mass in late- vs. prepubertal boys and girls, respectively, with no detectable increase in LH pulse frequency (163) (Fig. 7). Thus, the amount of LH secreted per burst rather than pulse frequency is the primary locus of pubertal control.

View larger version (15K): [in this window] [in a new window]   FIG. 7. LH secretory-burst mass in normal prepubertal boys and girls and adolescents. Data were obtained by sampling blood every 5 min for 12 h followed by high-sensitivity immunochemiluminometric assay. Median increases were 10-fold and 33-fold in the male and female, respectively. Box-and-whisker plots give the median (center bar), interquartile range (top and bottom lines of box), and absolute extrema (vertical stems). [Derived from Ref. 163 .]

View larger version (25K): [in this window] [in a new window]   FIG. 8. Indirect and direct pathways of selective sex-steroid negative feedback on GnRH neuronal ensemble. KiSS-1 represents an upstream ligand secreted by neurons, which stimulates the GPR54 receptor located upon GnRH-secreting cells. KiSS-1 is under sex-hormone control. (Unpublished schema)

Molecular cloning has identified more than 16 isoforms of GnRH represented among diverse organisms (182). GnRH II (sequenced initially in the chicken) is expressed in the rodent, monkey, and human, and increases in puberty in the primate hypothalamus (183, 184). Transcripts for GnRH-II and cognate receptor are also detected in gonadotropes, the limbic system, ovary, placenta, prostate gland, kidney, and bone marrow (183, 185). GnRH II stimulates LH and FSH secretion in vivo in the primate (186). Actions of GnRH II on limbic neurons may mediate sexual arousal (184, 187, 188), whereas those on granulosa-luteal cells may subserve steroidogenic inhibition (185). GnRH III (first identified in lamprey) may release FSH preferentially over LH in the rat (182).

b. LH secretion in childhood.
In the rodent, sheep, and monkey, hypothalamic GnRH outflow rises in early gonadarche, remains elevated in adulthood, and declines gradually in senescence (166, 174). In the human, LH concentrations reach a nadir at 6 to 8 yr of age before increasing multifold in puberty (161, 163, 164). Postulated bases of developmentally amplified GnRH outflow include the "gonadostat" and "centrally mediated" models.

c. Sex-steroid control of GnRH and LH outflow: gonadostat model.
The gonadostat theory posits that a decline in hypothalamo-pituitary sensitivity to gonadal-steroid negative feedback initiates puberty (Fig. 8). Albeit relevant to the rodent and ruminant, the gonadostat notion does not apply to the monkey and human. In particular, pathological depletion of sex steroids fails to unleash adult castrate-like LH secretion in children with inactivating mutations of LH, FSH, estrogen, or ARs or aromatase or 5 -reductase type 2 enzymes, congenital Leydig-cell agenesis, bilateral anorchia, or gonadal dysgenesis (120, 122, 189, 190, 191). Moreover, in the primate heightened resistance to sex-steroid restraint appears only after the onset of puberty is established (90, 166, 191, 192). The emergence of feedback-induced orderliness of LH secretion after the onset of puberty was verified recently in boys by approximate-entropy analysis (161) (Fig. 9).

View larger version (35K): [in this window] [in a new window]   FIG. 9. Early pubertal gain of synchrony of LH and testosterone (Testo) release in healthy boys, as quantitated via the cross-approximate entropy (X-ApEn) statistic. X-ApEn values (y-axis) are given in relation to clinical pubertal stage (x-axes). Maximal two-hormone synchrony (minimal X-ApEn) emerges in genital stage II (early puberty). Stages IA–IC are prepubertal, and stage IV is the adult male. Increased two-hormone coordination theoretically and empirically signifies enhanced feedback (bottom) and/or reduced feedforward (top) coupling within the gonadotropic axis. Columns with unshared (unique) alphabetic superscripts differ significantly (A differs from B but not from AB). Data are the mean ± SEM. [Adapted with permission from J. D. Veldhuis et al.: J Clin Endocrinol Metab 86:80–89, 2001 (161 ). © The Endocrine Society.]

Molecular studies establish that single GnRH neurons in the adult rodent contain gene transcripts for ER- (>65% of neurons) and ER-ß (>8% of cells) (198). Germ-line mutations of ER- (-ER knockout) or steroid-receptor coactivator proteins (SRC-1 and SRC-3) elevate LH concentrations by 2- to 3-fold in the adult male mouse (202, 203). Inactivation of the murine ER-ß gene does not affect LH concentrations, but impairs fertility due to defective ovulation and obstructed efferent spermatogenic ductules (197). Nonetheless, facile interpretation of LH hypersecretion in the -ER knockout model is confounded by: 1) unabated or amplified production of sex steroids by the gonad, adrenal gland, and CNS; 2) unopposed activities of AR and ER-ß; 3) loss of interactions between ER- and AR- or ER-ß; 4) altered metabolism of sex steroids; and 5) secondary neuronal and glial synaptic changes (189, 193, 194, 196, 204, 205). These issues highlight the challenge of valid clinical integration of multiple mechanisms of in vivo control of GnRH outflow.

d. Neurally mediated (central) hypothesis of gonadarche.
The neurally mediated hypothesis purports that gonad-independent activation of neuronal GnRH outflow initiates puberty (166). The categories of mechanisms thereby subsumed include at least: 1) enhanced coupling among excitable GnRH neurons; 2) potentiation of noradrenergic and excitatory amino acid (e.g., N-methyl-D,L-aspartate, NMDA) drive to GnRH neurons; and 3) muting of GABAergic and neuropeptide Y (NPYergic) inhibition of GnRH neurons (206, 207, 208, 209, 210). In a simplified model, augmented GnRH output would reflect facilitation of GnRH-neuronal coupling, amplification of excitatory inputs, and quenching of inhibitory inputs (Fig. 10).

View larger version (24K): [in this window] [in a new window]   FIG. 10. Selected neurotransmitter signals associated with the transition between prepubertal and adult GnRH outflow. (Unpublished compilation)

GABA and NPY enforce either inhibition or excitation depending upon receptor subtype, neuroanatomic site, species, age, and sex-steroid milieu (206, 207, 209). GABA-A receptors transduce inhibition of the migration and secretion of GnRH neurons in the rat, guinea pig, sheep, and monkey (120, 206, 207, 208, 212). In the rodent and primate, suppressive effects of GABA and NPY recede, whereas excitative actions of the same effectors emerge, in early puberty (206, 208, 209, 210, 212). The fundamental factors that govern this counterpoise in neurotransmitter outflow and action are not established. One swich-like locus is the enzyme glutamic-acid decarboxylase (GAD67), which converts an activating neurotransmitter, glutamic acid, to an inhibitory ligand, GABA (206). Once elevated pubertally, sex steroids modulate GABA, glutamine, and NPYergic signaling (166) (Fig. 10). For example, feedforward by estrogen and progesterone before the LH surge represses, whereas feedback by testosterone in the adult male rat augments, GABA-A inhibition. In some children, anticonvulsant treatment with the GABA-A agonist, valproic acid, is accompanied by delayed puberty or clinical features of PCOS (214, 215). The pathophysiologies underlying these associations are not clear.

Proopiomelanocortin (POMC)-derived peptides, such as ß-endorphin, met-enkephalin, and -MSH, suppress GnRH neurons only in the adult human, monkey, rodent, goat, and sheep. Relief of opiatergic restraint thus does not mediate pubertal onset (216). Testosterone and estradiol enforce POMCergic inhibition of GnRH secretion after puberty, presumptively via ER- expressed in POMC neurons (217).

e. Integrative issues.
GnRH outflow is modulated by an array of countervailing signals, in addition to sex steroids, excitatory amino acids, GABA, NPY, and POMC derivatives. Other effectors include glucose, T₄, glucocorticoids, leptin, ghrelin, TRH, neurotrophic peptides like TGF-, the cocaine and amphetamine-regulated transcript (CART), dopamine, norepinephrine, serotonin, CRH, urocortins, nitrous oxide, melanin-concentrating hormone (MCH), hypocretin (orexin), arginine vasopressin (AVP), vasoactive intestinal polypeptide, galanin, neurotensin, neurokinin B, insulin/IGF-I/IGF-II, ciliary neurotrophic factor, certain cytokines, and prostaglandin E₂ (92, 120, 166, 218, 219, 220, 221). Their aggregate actions have not been parsed. In addition, how a burgeoning repertoire of intrapituitary regulators supervises pubertal development is largely unknown (222).

f. Late puberty and early adulthood.
Menarche occurs at Tanner stage 3 and early stage 4 of breast development in girls of Western European descent, corresponding to a chronological age of approximately 12.7 (± 1.1) yr. Adult reproductive function is not achieved immediately. A recent 4-yr longitudinal study in 112 girls showed that 10 or more ovulatory menstrual cycles per 12 months develop within 1 and 3 yr of menarche in 65 and 90% of adolescents, respectively (223). Normal luteal-phase progesterone concentrations also emerge only several years after onset of menses. Female fecundity and fertility require feedback-sensitive regulation of LH and FSH secretion, cyclical follicular development, surge-like secretion of LH, rupture of a dominant follicle, oocyte maturation, and adequate estradiol and progesterone secretion to ensure endometrial receptivity to blastocyst implantation (165). Given such ensemble complexity, an unresolved question is whether subtle disruption of integrative control underlies the pathophysiology of syndromes like inadequate luteal phase, luteinized unruptured follicle, stress-associated amenorrhea, and hyperandrogenemic oligovulation (37, 224).

Gene-silencing experiments in mice establish that aromatizable androgens imprint adult masculine behavioral traits via ER--dependent pathways, conditional on the SRC-1 and SRC-3 proteins (196, 203). The impact of the neonatal sex-steroid milieu on sexual behavior in humans is far less clear, given the importance of culture-specific psychosocial cues (225, 226). One 46 XY patient with an inactivating mutation of the aromatase enzyme had normal male gender identity and heterosexual orientation (227). Genetic defects in the AR (testicular-feminization syndrome) may alter childhood gender orientation subtly (226). In the Dominican Republic, 46 XY children with 5 -reductase type 2 deficiency, albeit reared as girls due to pseudohermaphroditism, may adopt a male gender role at puberty (225).

g. Timing and tempo of puberty.
An incompletely defined composite of genetic, environmental, nutritional, metabolic, and growth-related factors supervises the onset and progress of puberty. The gradual decline in age of menarche over the last century in the Western hemisphere illustrates such interactions. Observations that nutrient sufficiency allows and caloric deprivation impedes age-specific outflow of reproductive hormones sparked the prediction that somatic signals communicate the status of energy balance (the difference between availability and utilization of metabolic substrates) to integrative CNS loci. Brain signals in turn regulate behavior, appetite, energy expenditure, growth, and sexual maturation (228, 229, 230, 231, 232, 233). The notion is subsumed thematically under the somatometer hypothesis.

h. Somatometer hypothesis: somatic signals trigger pubertal onset.
Somatic inputs to the CNS include (but are not limited to) adipocyte-derived factors, such as leptin (elevated in obesity), adiponectin (reduced in obesity), and perilipin or resistin (antagonists of insulin action); hypothalamo-pituitary-pancreatico enterogastric peptides, such as ghrelin (a potent orexigenic, direct lipotrophic factor, and GH secretagogue), and orexin A (hypocretin-1) (respectively decreased and increased in obesity); glucose, hydrogen ions, branched-chain amino acids, and free fatty acid (FFA); and insulin, IGF-II, and IGF-I (free IGF-I concentrations are higher in puberty and obesity) (228, 230, 231, 232, 234, 235, 236, 237, 238). Intersecting hypothalamic circuits in turn govern appetite, physical activity, sleep, sympathoadrenal outflow, insulin sensitivity, resting energy expenditure, and reproduction (228). An implicit theoretical expectation is that incremental signal exchange must proceed bidirectionally, viz., somaCNS and CNSsoma. The bases for the developmentally defined orchestration of such reciprocity of signaling are only sparingly understood.

i. Critical body weight.
The somatometer conjecture arose from the prescient epidemiological insight that attainment of a so-called critical body mass accompanies the onset of puberty in mammals (239). An important contemporary distinction is that positive energy balance (rather than absolute weight) is necessary but not sufficient for normal onset of puberty (230). Current research further distinguishes whether somatic, metabolic, and/or neural signals: 1) trigger or delay the initiation of puberty; 2) impede ongoing sexual maturation; 3) impair established adult reproductive function; and/or 4) reflect multifactorial effects of type I diabetes mellitus, inanition, systemic inflammation, environmental foxius, sepsis, burns, trauma, surgery, or organ-system failure.

   5. Leptin pathophysiology in the human.
Although facile unification of mechanisms is thwarted by species differences, one uniform inference in mammals is that sustained negativity of energy balance (wherein caloric utilization exceeds availability) inhibits GnRH release, suppresses LH secretion, reduces gonadal steroidogenesis, and impairs fertility (230, 231). The adipocyte-derived glycoprotein, leptin, is one recognized mediator of the effects of caloric extremes on reproduction in the rodent, and constitutes a necessary but not sufficient centrally mediated signal for timely pubertal onset and adult LH pulsatility in the human (238, 240).

In most but not all clinical studies, puberty is associated with higher mean serum leptin concentrations than those in childhood (241, 242, 243, 244). However, causal relevance is difficult to appraise, because no rigorous biochemical markers of the earliest stages of puberty are established to use for comparison of relative timing (1, 3, 160, 165). Moreover, single leptin determinations are confounded by: 1) a strongly positive correlation between leptin and sc adiposity, which also increases in early puberty (3, 245, 246); 2) higher leptin values in the female than male in utero, infancy, childhood, puberty, and adulthood (247, 248); 3) the capability of estradiol to stimulate and testosterone to suppress leptin production in young adults (245, 246); 4) short-term fluctuations in serum leptin concentrations; 5) reduced leptin values during fasting and after fat ingestion (249, 250, 251); and 6) collateral regulation by insulin, cortisol, and cytokines (238).

Inactivating mutations of leptin peptide or receptor in the mouse and human are associated with obesity, insulin resistance, hypertriglyceridemia, hypogonadotropic hypogonadism, low basal oxygen consumption, TSH deficiency, and relative hypothermia (238, 252). Occasional patients have exhibited a less striking phenotype, which receded in adulthood. In a clinical study of three genetically leptin-deficient individuals, administration of rh leptin for 1.5 yr reduced body mass index by about 50%, improved insulin action, decreased hyperlipidemia, and reversed hypogonadism (240). On the other hand, administration of rh leptin in the obese but otherwise normal human reduces weight only initially and modestly (253). Fasting for 3 d reduces pulsatile LH and TSH secretion in healthy young adults, which changes are reversed by leptin injections (250) (Fig. 11). Leptin administration also elevates basal energy expenditure and thyroid-hormone concentrations in subjects with sustained weight reduction (254). Accordingly, leptin availability appears to be necessary but not sufficient to maintain pubertal and young-adult GnRH-LH and TRH-TSH outflow, a nonobese phenotype, and normal insulin sensitivity.

View larger version (37K): [in this window] [in a new window]   FIG. 11. Impact of rh leptin administration on pulsatile LH release in fasting young men. [Adapted from J. L. Chan et al.: J Clin Invest 111:1409–1421, 2003 (250 ) with permission.]

a. Leptinergic impact on appetite and reproduction.
Immunoreactive leptin receptors and gene transcripts abound in cerebral cortex, hippocampus, thalamus, hypothalamus, gonadotropes, somatotropes, and corticotropes (238, 257, 258). Hypothalamic leptin receptors localize on neurons expressing AVP, oxytocin, CRH, NPY/agouti-related protein (AGRP), POMC, GHRH, TRH, neurotensin, dopamine, and MCH, albeit notably not GnRH. Inferentially, therefore, leptin enhances GnRH secretion indirectly. Supplementation with or transgenic knockin of leptin stimulates TRH, GnRH, POMC, MCH, and CART and represses SS, CRH, NPY, and AGRP gene expression in fasting normal or ob/ob (leptin mutation) mice (238, 258, 259) (Table 4). Outcomes encompass increased production of LH, gonadal steroids, TSH, and GH and decreased secretion of ACTH and glucocorticoids (238).

b. Leptinergic adaptations to caloric depletion.
Caloric restriction suppresses leptin synthesis not only in adipose tissue but also in arcuate nuclei (ArC), where the glycoprotein normally reinforces signals that stimulate satiety and repress those that promote appetite (238) (Tables 4 and 5). Thus, in the rodent, nutritional or genetic leptin depletion enhances food intake, depresses LH, GH, and TSH secretion, stimulates ACTH and glucocorticoid output, and enhances oxidation of adipocyte triglycerides (238, 252). Fasting concomitantly augments gastric secretion of ghrelin (20). Ghrelin stimulates GH secretion and potentiates certain metabolic effects of leptin withdrawal, viz. induction of hypothalamic genes encoding NPY, orexin, and AGRP (central appetitive signals) and suppression of SS (an inhibitor of TSH and GH secretion) (264, 265, 266, 267, 268, 269). The reciprocal effects of leptin depletion and ghrelin repletion during nutritional deficiency thus drive food intake and minimize substrate diversion to reproduction and anabolism. The adipostat concept provides a collective term for complex interactions among central and systemic peptides that jointly mediate metabolic adaptations to hypocaloric stress (Fig. 12).

View larger version (34K): [in this window] [in a new window]   FIG. 12. Adipostat concept of a neuropeptidyl signaling ensemble that subserves hypothalamic integration of appetite, body composition, and energy expenditure. In addition to CNS signals, diverse metabolic cues originate from adipocytes (e.g., leptin, adiponectin, resistin), hepatocytes (IGF-I and glucose), gastrointestinal cells (ghrelin), circulating substrates (FFA), and hormones (GH, insulin, sex steroids, glucocorticoids). (Unpublished line drawing)

Leptin induces CART, a potent anorexigenic hypothalamic signal that also stimulates GnRH release (259, 277). CART colocalizes with MCH (satiety factor) and TRH (a thermogenic peptide) in the rat and human ArC, and it promotes satiety even in NPY-infused animals (278, 279). Thus, withdrawal of leptinergic drive to CART during fasting would further reduce GnRH outflow, stimulate food intake, and impair thermogenesis (Table 5 and Fig. 12). CART and GnRH gene transcripts increase in the adult male rodent, suggesting a possible role in pubertal LH secretion.

The POMC gene driven by CRH encodes potent opiatergic peptides, such as enkephalins, -MSH, and ß-endorphin, which diminish feeding behavior via multiple mechanisms (228, 266, 270) (Table 5). Leptin promotes satiety in part by stimulating anorexigenic -MSH, which acts centrally via melanocortin-receptor (MCR) types 3 and 4. Mutations and certain polymorphisms of MCRs are associated with obesity in the human and mouse.

Food restriction elicits CRH-POMC-glucocorticoid outflow (120, 230, 231), inhibits GnRH-LH-androgen production (280), and increases GH secretion in the human, monkey, sheep, and guinea pig (1). In contrast, caloric deprivation suppresses GH secretion via CRH- and leptin-modulated SSergic mechanisms in the rat (238, 281). The tripartite response of elevated glucocorticoids, decreased androgens, and reduced GH/IGF-I in the fasting rodent predicts marked catabolism (238, 282). Catabolism is averted in part in other mammals by increased GH secretion.

   7. Metabolic substrates.
Energy depletion limits GnRH output in the human, monkey, sheep, hamster, mouse, and rat (228, 231, 238, 280, 283, 284). An array of mechanisms pertains. Nutrient restriction accentuates negative feedback by sex steroids in the rodent and ruminant (220, 230, 285). Glucoprivation reduces GnRH secretion via brainstem noradrenergic drive of opiatergic restraint in the rat and sheep and via paraventricular CRH/urocortin and/or AVP-mediated inhibition in the monkey (228, 280). Increased central CRH/POMC outflow rather than the moderate elevation of circulating glucocorticoids in fasting seems to suppress GnRH secretion (231). Augmented ghrelin output associated with caloric restriction may also decrease LH pulsatility via central mechanisms (286, 287).

Food ingestion or infusion of glucose, but not of insulin or IGF-I alone, rapidly reinstates pulsatile GnRH/LH release in the nutrient-depleted animal and human (230, 231, 284, 288). More sustained exposure to insulinomimetic peptides can promote proliferation of immortalized GnRH neurons and enhance GnRH-stimulated LH secretion by pituitary cells (92). In addition, IGF-I supplementation advances the time of first ovulation slightly in the immature female rat and monkey (89, 90). Conversely, transgenic muting of the CNS insulin receptor or insulin-receptor substrate (which mediates actions of both IGF-I and insulin) disrupts murine estrous cyclicity without affecting male reproductive function (81, 86). Thus, insulinomimetic peptides exert long-term trophic effects on GnRH neurons.

	II. Ensemble Regulation of GH Secretion

Top Abstract I. Regulation of the... II. Ensemble Regulation of... References

 
A. Ensemble concept of minimal 5-peptide integration
SS, GHRH and ghrelin/GHRP jointly govern GH and thereby IGF-I secretion via independent and interactive mechanisms (27) (Fig. 1). The result is a complex pattern of GH outflow, defined by pulsatile, nycthemeral (24-h rhythmic), and entropic (degree of orderliness) (Fig. 13A). Interactive control is endowed by mechanistic complementation, which is exemplified by: 1) unique individual properties of GHRH, SS, and GHRP and cognate receptors; 2) partially intersecting cellular signaling systems; 3) reciprocal connectivity among cognate neurons; 4) feedback by GH and IGF-I on peptidergic neurons and receptors; and 5) developmentally timed emergence and quenching of pathways (1, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301). The organized activation of GH/IGF-I production in puberty inferentially requires adaptive control of each of the foregoing relationships.

View larger version (26K): [in this window] [in a new window]   FIG. 13. A, Schematic representation of principal modes of GH secretion, viz., pulsatile (burst-like), nycthemeral (24-h rhythmic or circadian), and entropic (feedback-sensitive). (Unpublished schema) B, Pubertal amplification of the mass of GH secreted per burst (integral of underlying secretory event). Data are presented as described in the legend of Fig. 7. [Adapted with permission from J. D. Veldhuis et al.: J Clin Endocrinol Metab 85:2385–2394, 2000 (316 ). © The Endocrine Society.]

Recent gene-transfer experiments underscore the biological impact of the time-pattern of GH delivery to target tissues. Implantation of human GH-transfected myoblasts stimulates somatic growth in the hypophysectomized but not the intact male mouse, verifying that endogenous GH pulses are more effectual than continuous GH stimulation (307). Conversely, delivery of a muscle-targeted recombinant vector encoding a long-lived GHRH peptide increases lean body mass even in the pituitary-intact adult mouse (308), supporting the capability of constant GHRH stimulation to elicit high-ampitude GH pulses (1, 309).

The male-like pattern of large bursts with intervals of reduced GH concentrations between events obviates response desensitization in target cells; facilitates recycling of membrane GH receptors; and induces STAT5b (signal transducer and activator of transcription) signaling of increased or decreased gene expression (30, 304). The female pattern of nearly constant GH stimulation activates especially STAT5a homodimers, STAT5a/5b heterodimers, and hepatic nuclear factors 4 and 6 (304, 310). Estrogen participates in the sex distinction, because inactivation of -ER in the female animal reduces systemic IGF-I concentrations, up-regulates hepatic STAT5b signaling, and masculinizes liver gene-expression patterns (32, 311). Conversely, germ-cell knockout of STAT5b in the male mouse attenuates somatic growth and feminizes liver gene expression (304). Relevance is suggested clinically by severe growth failure (height –7.5 SD values) in a girl with a STAT5b mutation (312).

2. Human.
The amplitude of peaks in serum GH concentrations reflects secretion, elimination, and basal release (Fig. 13A). Incremental and summed amplitudes predict height velocity in normal, pathological, and induced puberty (313, 314, 315, 316). In adolescents, the mass of GH secreted per burst increases 2- to 10-fold (Fig. 13B). On analytical grounds, GH pulse amplitude also determines interpeak nadir concentrations, which in turn forecast IGF-I concentrations reliably in patients with acromegaly and (in some studies) in pubertal children (313, 316, 317). In this regard, constant infusion of GH in hypopituitary adults elevates IGF-I concentrations more than intermittent injections, whereas bolus infusion of GH stimulates lipolysis more effectively than continuous delivery (318, 319). The hepatic effects of GH are further determined by sex-steroid status, being reduced in estrogen-sufficient individuals (98) (Table 3). A molecular mechanism is that estrogen induces an intracellular suppressor of cytokine synthesis (SOCS-2), which antagonizes GH signaling (31, 111).

Excessive amounts of GH may cause peripheral nerve entrapment, arthralgias, myalgias, fluid retention, gynecomastia, and rarely papilledema, benign intracranial hypertension, or death in intensive care units (87, 320). Therefore, in principle, an idealized GH-repletion regimen would both reproduce physiological signaling mechanisms and preserve negative-feedback control.

C. Self-renewable GH pulsatility
1. GHRH.
Large GH pulses require feedforward (stimulation) by GHRH and feedback (suppression) via SS (reviewed in Refs. 9, 10, 11, 12 and 21) (Fig. 1). The fundamental role of hypothalamic GHRH in driving the amplitude (height or mass) of GH pulses has been established by: 1) passive immunoneutralization; 2) administration of GHRH-receptor antagonists; 3) chemical lesioning of ArC GHRH neurons; 4) loss-of-function mutations of the GHRH receptor in the human (dwarfs of Sindh) and mouse (lit/lit dwarf); and 5) constant and pulsatile infusions of GHRH (1, 7, 13, 321). Figure 14 illustrates profound (> 30-fold) reduction of GH secretory-burst mass and marked disorderliness (ApEn > 5 SD above normal) in a girl and boy with truncational mutation of the human GHRH receptor (13). Because GH pulses emerge at a normal frequency and with diurnal rhythmicity in such patients, the primary pulse-renewal process must not require the GHRH receptor.

View larger version (32K): [in this window] [in a new window]   FIG. 14. Evidence of non-GHRH receptor-dependent timing of pulsatile and 24-h rhythmic GH release in two siblings harboring an inactivating (truncational) mutation of the GHRH receptor. Both patients were unresponsive to an iv GHRH stimulus, exhibited a more than 3-fold response to GHRP-2, and maintained less than 3.5% normal GH pulse size. Twenty-four-hour GH concentration profiles (top) were quantitated in a high-precision, immunofluorometric assay (y-axis scale extends from 0 to 0.5 µg/liter). Increased ApEn SD values denote less orderly GH secretion patterns in patients than controls. Deconvolution analysis was applied to calculate time-varying GH secretion rates (bottom). [Adapted with permission from F. Roelfsema et al.: J Clin Endocrinol Metab 86:2459–2464, 2000 (13 ). © The Endocrine Society.]

View larger version (27K): [in this window] [in a new window]   FIG. 15. Top, GH concentration profiles sampled every 10 min in a healthy postmenopausal woman given an iv infusion of saline (left) and combined rhGHRH-1,44-amide and GHRP-2 (each 1 µg/kg·h) (right) for 24 h beginning at 0800 h (time zero). Bottom, Deconvolution analysis was applied to calculate underlying GH secretion rates (µg/liter/min). Retention of prominent GH pulsatility (120-fold stimulation) over 24 h during dual-secretagogue stimulation indicates that intermittent inputs by endogenous GHRH and GHRP are not required to set the timing of GH secretory bursts.

View larger version (24K): [in this window] [in a new window]   FIG. 16. Illustration of mechanistic contributions to peak and interpulse GH concentrations; viz., decay of antecedent peaks into the sampling window; underlying secretory bursts (hatched region just preceding and concurrent with the GH peak), amplitude (height of unobserved secretory event), and duration (double-headed arrow) of secretory burst; GH half-life (decay rate); and basal (time-invariant) GH secretion. (Unpublished line drawing)

Ghrelin and synthetic congeners exert diverse actions (4) (Table 7). Salient mechanisms and effects include: 1) synergy with GHRH in stimulating GH secretion in vivo, but not in vitro; 2) opposition to the neuronal actions of SS; 3) stimulation of ArC GHRH, NPY, and AGRP and inhibition of leptinergic neurons; 4) induction of the somatotrope pit-1 gene (a pituitary-specific nuclear transcription factor); 5) acute release of prolactin and ACTH; 6) motilin-like prokinetic effects on the gut; 7) osteoblastic proliferation; 8) orexigenesis; 9) cardiotropism; 10) direct inhibition of fat oxidation; 11) suppression of insulin secretion; and 12) repression of GnRH/LH output (4, 14, 15, 18, 19, 20, 21, 23, 24, 26, 27, 238, 268, 269, 287, 337, 338, 339, 340, 341). The aggregate impact is appetitive, trophic, and energy-conserving.

In young adults, iv infusion of ghrelin stimulates GH secretion and increases appetite under double-blind conditions (19). Central pathways mediating appetitive effects of ghrelin in the rodent include stimulation of NPY, AGRP, and orexin (hypocretin) and suppression of leptin and CRHergic neurons, as summarized in Table 7. Fasting enhances ArC neuronal activation by GHRP, possibly by depletion of opposing leptin drive (4, 238, 342). Molecular variants and mutations of ghrelin peptide, and rarely the ghrelin receptor, are associated with obesity in the human (346, 347, 348). Thus, in a simplified view ghrelin and leptin are antipodal signals in maintaining appetite, body weight, growth, and reproduction in the face of a surfeit or deficit in calories (Tables 4 and 5).

Synergism between GHRP/ghrelin and GHRH in driving GH secretion does not occur in static in vitro systems, and requires a functionally intact hypothalamo-pituitary nexus in vivo (15). The mechanisms mediating supraadditive effects may be multifactorial. In particular, ghrelin and congeneric GHRPs are able to: 1) stimulate GHRH release from ArC (325, 349); 2) oppose SSergic inhibition in ArC (24); 3) induce GH gene expression in the immature animal (7); 4) stimulate GH secretion maximally in puberty unlike the peak effect of GHRH in infancy (4, 15, 298); and 5) directly evoke pituitary GH release (14). Conversely, GHRH up-regulates the pituitary GHRP receptor, thus potentially augmenting the effect of ghrelin (324). The collective data allow the provisional model of ghrelin action illustrated in Fig. 17.

View larger version (22K): [in this window] [in a new window]   FIG. 17. Model of primary sites of ghrelin’s inferred interactions with GHRH and SS in the amplification of pulsatile GH secretion. (Unpublished line drawing) AN, Arcuate nucleus.

Recent therapeutic trials in children with idiopathic short stature or organic GH deficiency indicate that administration of synthetic hexapeptides (hexarelin or GHRP-2) intranasally or a nonpeptidyl GHRP mimetic (MK-0677, ipamorelin) orally for 6 months or more increases linear growth velocity to 6.0–8.3 cm/yr (355, 356, 357, 358, 359) (Table 8). GH concentrations rise rapidly (over hours to days), and then decline to a new plateau that is 2-fold above baseline. IGF-I and IGFBP-3 concentrations increase concomitantly and, unlike GH, remain stably elevated. A subset of six children treated for 2 yr continued to respond by way of growth and elevated GH/IGF-I concentrations (355).

View larger version (33K): [in this window] [in a new window]   FIG. 18. Neuroendocrine actions of ghrelin/GHRP. A, Dynamic features of continuous low-dose GHRP-2 stimulation in healthy older men and women mimic those of elevated GH output in normal puberty, consistent with augmented GHRP/ghrelin drive in adolescence. B, Postulated mechanisms underlying sustained GH/IGF-I outflow during continuous low-dose GHRP infusion.

4. SS receptors.
Molecular cloning has identified five distinct SS-receptor subtypes (SSTRs) and a pair of alternative transcripts (SSTR-1A and SSTR-1B), all of which are activated by native SS (364). Each subtype exists in the rat and human anterior pituitary gland (364, 365, 366). SSTR-1, -2, and -5 predominate in somatotropes and mediate inhibition of GH exocytosis. Although octreotide acts principally via SSTR-2, one patient with octreotide-resistant acromegaly harbored an inactivating mutation in SSTR-5 (367). Sex steroids regulate pituitary SSTR genes in a complex manner (Table 9). For example, estrogen induces SSTR-2 and represses SSTR-5. Although androgenic effects are less clear, estrogen administration in the aromatase gene-disabled female mouse reduces transcripts for SSTR-1, -2, -4, and -5 in the pituitary gland (368). This model suggests that aromatization of testosterone to estradiol in the male rodent mediates higher SSTR-2 in this sex (369).

View larger version (27K): [in this window] [in a new window]   FIG. 19. A, Simplified double-oscillator model of time-delayed feedback and feedforward interactions among GH, GHRH, and SS. In this construction, all three signals jointly endow the renewal of GH secretory volleys (cluster of successive pulses). Volleys are separated by quiescent intervolley intervals imposed by GH autofeedback (long-loop slow oscillator, circled number 1). GH pulses act via negative feedback to evoke hypothalamic outflow of SS to GHRH neurons and the pituitary gland. Thus, a given volley unfolds until quenched by intravolley GH-driven SS outflow. Intravolley pulses may reflect either brief cycles of inhibition of GHRH secretion exerted by direct feedback of GH on the brain (short-loop rapid oscillator, circled number 2) or reciprocal signaling between SS and GHRH neurons in the ArC. B, The putative ArC oscillator may be repressed directly (oscillator damped) or indirectly (oscillator shielded) by GH feedback-induced SS outflow from the PeV to GHRH neurons. Ghrelin is viewed 3-fold as an amplifier of GHRH release, inhibitor of neuronal SS actions, and antagonist of pituitary SS effects (Fig. 17). C, Inferred interconnections among GHRH, SS, and GHRP peptides and receptors based upon available data in rodent models.

Concentrations of SS peptide and mRNA increase by 2- to 3-fold in PeV of the male and (in lesser measure) the female rodent in puberty putatively in response to testosterone, which acts via AR expressed in SSergic neurons (374) (Table 10). Estrogen increases ArC SS binding, but does not regulate PeV SS gene expression directly in the adult rat given the absence of estradiol binding, ER immunoreactivity or ER- gene transcripts in these neurons (1, 375). However, there are important species differences, which are highlighted in Table 11.

5. Other GH regulators.
A 5-peptide regulatory model comprising GHRH, SS, GHRP, GH, and IGF-I (Fig. 1) is utilitarian, but incomplete. Putative complementary signals that direct GH synthesis and/or secretion include: 1) other peptides, such as leptin, NPY, galanin, TRH, neurotensin, bombesin, pituitary adenylate-cyclase activating peptide, insulinomimetic peptides, calcitonin, calcitonin-related gene product, opiatergic peptides, CRH, urocortin, cytokines (e.g., TNF-, IL-1/-6); and 2) nonpeptides, such as prostaglandins, catecholamines, cortisol, T₄, glucose, lactic acid, hydrogen ions, potassium, and FFA (1). A daunting unmet challenge is interlinking the full set of physiological signals in a valid fashion across the lifespan.

D. Pubertal and gender effects
1. Developmental regulation of GH outflow.
GH production exhibits profound variations across infancy, childhood, puberty, and young adulthood (316, 360, 380, 381). For example, pulsatile secretion increases markedly just after birth when IGF-I concentrations are reduced (human), and when GHRH induces its own receptor, GHRP stimulates transcription of the GH gene, and the efficacy of SS inhibition falls (rat) (Table 12). Transient postnatal outpouring of GH is quenched presumptively by increased expression of the GH receptor, neonatal estrogen-induced PeV SS outflow, rising IGF-I concentrations, and down-regulation of GHRH receptors, which would collectively potentiate negative feedback (324, 380, 382, 383).

2. Regulation of GH autonegative feedback: gender distinctions.
GH exerts time-delayed reversible feedback via the homonymous CNS receptor (290, 291). In the adult male rat, a pulse of GH: 1) elicits PeV SS release into portal blood within 40–60 min (Fig. 19A); 2) induces PeV SS gene expression; and 3) drives ArC NPY neurons to augment PeV SS release (290, 292, 295, 323) (Table 13). GH-stimulated PeV SSergic neurons also repress GHRH secretion transsynaptically (293, 294, 297) (Fig. 19B). The latter effect is transient, and followed by disinhibition of GHRH and GH release (1, 240, 325). More prolonged elevation of GH concentrations: 1) decreases hypothalamic concentrations of GHRH peptide, GHRP receptor, and GH receptor; 2) reduces the pituitary GHRP receptor, GHRH receptor, and ghrelin; and 3) increases hypothalamic SS and SSTR-1 and pituitary SSTR-5 (290, 291, 295, 299, 370). The ensemble outcomes enforce restraint of GH secretion.

GH feedback is muted in the female compared with the male rodent (1) (Table 13). Putative mechanisms are that: 1) estradiol reduces expression of GHRH peptide and GH receptor in the hypothalamus and GHRH receptor, SSTR-1, and -5 in the pituitary (323, 377, 389, 390, 391); 2) androgen induces PeV SS (374); and 3) the male animal maintains more SSTR-1 in ArC and more SSTR-2 in the pituitary than the female (369) (Table 14). Greater expression of ArC SSTR-1 could accentuate putative oscillations between SS and GHRHergic neurons, whereas increased pituitary SSTR-2 would heighten somatotrope inhibition by secreted SS (11, 12, 371, 392). Conversely, in the female rat, lower ArC SSTR-1 and lesser somatotrope SSTR-2 may restrict GHRH pulse amplitude and disinhibit (elevate) interpulse GH release, respectively, as observed in this sex.

The gender difference in humans is opposite to that in the rodent; i.e., young women maintain 2-fold larger GH secretory bursts and greater feedback responsivity than men (395). Analytical models forecast that higher GH peaks require more prominent cycles of GH feedback, SS outflow, and GHRH disinhibition (9, 10, 11, 12, 21, 396, 397) (Figs. 17 and 19). In relation to such predictions, clinical experiments indicate that an estrogen-rich milieu serves to: 1) accentuate fractional negative feedback by a pulse of rhGH (398); 2) augment SS withdrawal-induced GH secretion (373); 3) facilitative GHRP action (399); 4) enhance the potency of exogenous GHRH pulses (400); 5) reduce pituitary sensitivity to continuously infused SS (378); and 6) oppose feedback of GH on GHRP stimulation (401) (Fig. 20). Important unexplored mechanistic issues include how gender, developmental age, IGF-I, estrogen, and androgen modulate time-varying interactions among SSTR-1, SSTR-2, SS, and GHRH in the hypothalamus. Multidisciplinary approaches involving molecular, cellular, and integrative biology will be required to address these fundamental questions.

View larger version (25K): [in this window] [in a new window]   FIG. 20. Sixfold modulation by estradiol of the neuropeptidyl control of GH secretion, as inferred from clinical studies in postmenopausal individuals. Estrogen supplementation compared with placebo serves to: 1) increase the half-maximally inhibitory dose (ID50) of SS (signifying a reduction in suppressive potency, top left); 2) decrease the half-maximally stimulatory dose (ED50) of GHRH as assessed under L-arginine blockade (denoting enhanced secretagogue potency, top middle); 3) heighten negative feedback by IGF-I on basal GH release (top right); 4) potentiate GH secretion induced by GHRP-2, a synthetic analog of ghrelin (reflecting heightened stimulatory efficacy, bottom left); 5) attenuate GH-dependent negative feedback on GHRP-2-stimulated GH secretion (indicating relief of autoinhibition, bottom middle); and 6) augment post-SS rebound-like GH release (suggesting enhanced outflow of GHRH, bottom right). (Unpublished schema of experimental outcomes reported in Refs. 378 399 and 401 .)

2. Quantitation of secretion and elimination.
Recent advances in deconvolution methods permit quantitating hormone peaks as the tripartite outcome of flexibly shaped (asymmetric or symmetric) secretory bursts, variable basal secretion and subject-specific biexponential kinetics (402, 403, 404, 405) (Fig. 21). Flexible-waveform analyses differ from earlier approaches by way of: 1) primary experimental validation in three mammalian species (405); 2) direct mathematical verification by formal statistical proof (406); and 3) allowance for both deterministic and stochastic (inferably random) variations in hormone secretion and elimination, pulse timing, and sample measurements (405, 406). Such analyses demonstrate that GH secretory-burst mass (amount released per burst per unit distribution volume) is the prime endpoint of neuroendocrine control.

View larger version (33K): [in this window] [in a new window]   FIG. 21. Contemporary methodology of deconvolution analysis to dissect a neurohormone concentration vs. time profile into simultaneously contributing components; viz., A, pulse-onset times; B, secretory-burst waveform (shape) and mass (amount of hormone released within each burst); C, the time integral of the secretory episode (S) or hormone (H) elimination by biexponential kinetics; D, basal (nonpulsatile) secretion; and E, random (stochastic) variability () due to measurement, sampling, and biological nonuniformities. This set of analytical parameters is estimated simultaneously (I, top) by a maximum-likelihood statistical procedure (II, bottom). (Unpublished schema adapted from concepts in Refs. 402 403 404 405 .)

3. Orderliness or regularity of GH secretion patterns.
Quantitation of the orderliness of neurohormone secretion subpatterns via the approximate entropy (ApEn) statistic provides a sensitive (>90%) and specific (>90%) measure of the strength and complexity of unobserved feedforward and feedback signals within an interlinked system (317, 409, 410, 411, 412). Orderliness is thus distinct from but complementary to pulsatile and circadian attributes of neurohormone regulation (Fig. 13A). ApEn analyses document more irregular GH release (less subpattern consistency) in patients with acromegaly compared with healthy subjects, in women compared with men, and in adolescents compared with children and adults (316, 317, 411). Greater irregularity (higher ApEn) signifies deficient feedback restraint and/or enhanced feedforward drive within the interconnected axis (410, 411). ApEn is calculated on a desktop computer as a single number defined by a validated threshold (usually 20% of the SD of the individual series) and template size (usually one or two data points) for appraising subpattern recurrence given serial measurements (13 or more samples at a template size of 1) (317, 411, 412, 413). Testosterone and estradiol (but not DHT) induce irregular GH secretion patterns in children (414, 415). GH release becomes markedly irregular when maximal height velocity is achieved in healthy pubertal boys monitored longitudinally (416) (Fig. 22, A and B). Irregularity is not an artifact of elevated GH concentrations, because ApEn is a scale-invariant measure. In this regard, heightened irregularity occurs in: 1) hypersomatotropic patients with acromegaly; 2) hyposomatotropic subjects with a GHRH-receptor defect; and 3) eusomatotropic women compared with men (13, 316, 317).

View larger version (32K): [in this window] [in a new window]   FIG. 22. A, Relationship between GH ApEn (continuous line) and height velocity (GrVel, interrupted curve) in four boys each studied every 4 months longitudinally (y-axis) at the indicated ages (x-axis) beginning before and continuing throughout normal puberty. Blood was sampled every 20 min for 24 h to create GH concentration profiles. ApEn, a regularity measure, was calculated for each profile. Higher ApEn denotes less orderly secretion patterns (and, conversely, for lower ApEn). GH regularity declines before and concurrently with peak height velocity, which predicts heightened feedforward and/or attenuated feedback signaling within the axis. Regularity then increases in young adulthood. Different tempos of statural growth are evident among the four subjects. [Adapted from Ref. 416 .] B, Irregular patterns of GH release (GH ApEn) emerge in mid-to-late adolescent girls compared with boys or prepubertal children. Higher ApEn values (y-axis) quantitate more disorderly GH secretion, which in turn signifies augmented feedforward and/or reduced feedback within the hypothalamo-pituitary unit in the estrogen-sufficient female compared with male. Different alphabetic superscripts denote significantly different means. Data are presented as described in Fig. 13B. [Adapted from Ref. 316 .]

View larger version (26K): [in this window] [in a new window]   FIG. 23. Feedback inhibition by a single iv pulse of rhGH, when GH release stimulated by saline, GHRH, or GHRP-2 in postmenopausal women. Estradiol (lower panel) compared with placebo (upper panel) relieves autonegative feedback on GHRP-2, but not on saline or GHRH stimulation. [Adapted with permission from S. M. Anderson et al.: J Clin Endocrinol Metab 86:5904–5911, 2001 (401 ). © The Endocrine Society.]

View larger version (28K): [in this window] [in a new window]   FIG. 24. Effects of testosterone, estradiol, or DHT on GHRH and SS peptide and receptor and GHRP-receptor gene expression in the adult rodent. ER- gene transcripts are detectable in the majority of ArC GHRH neurons; and ARs are expressed in periventricular-nuclear SS neurons. In the rat and mouse, estradiol inhibits whereas testosterone enhances GHRH action. Estradiol can induce and repress specific SS receptor subtypes and down-regulate the GHRH receptor in the pituitary gland. Aromatizable androgen up-regulates hypothalamic SS gene expression only in the immature animal (ages 1 to 5 d), whereas nonaromatizable androgen does so in the adult (see text). (Unpublished compilation)

View larger version (25K): [in this window] [in a new window]   FIG. 25. Comparison of the effects of exogenous estradiol and testosterone on the human GH/IGF-I axis. Both sex steroids amplify GH secretory-burst mass and reduce the orderliness of the GH secretory process (elevate ApEn). Neither sex hormone affects GH half-life, GH pulse frequency, or IGFBP-3 concentrations. Testosterone elevates and (exogenous) estrogen lowers total IGF-I concentrations. Estradiol increases IGFBP-1 concentrations, but testosterone has no effect on this endpoint. Both sex steroids increase the GH concentration between successive peaks (i.e., interpulse valley and nadir values). Testosterone also enhances true basal (nonpulsatile) GH secretion. (Unpublished overview of data reported in Refs. 378 399 401 426 and 427 .)

	Acknowledgments

 
The authors thank Ashley Bryant for skillful preparation of the manuscript.

	Footnotes

 
This work was supported in part by National Center for Research Resources Grant MO1 RR00585 to the General Clinical Research Center at the Mayo Clinic and National Institutes of Health/National Institute on Aging Grants AG-014779 and AG-019695.

All authors have nothing to declare.

First Published Online January 24, 2006

Abbreviations: AGRP, Agouti-related protein; ALS, acid-labile subunit; ApEn, approximate entropy; AR, androgen receptor; ArC, arcuate nucleus or nuclei; AVP, arginine vasopressin; CART, cocaine and amphetamine-regulated transcript; CNS, central nervous system; DAX, dosage-sensitive sex-reversal; DHT, 5 -dihydrotestosterone; ER, estrogen receptor; FFA, free fatty acid; GABA, -amino butyric acid; GHBP, GH-binding protein; GHRP, GH-releasing peptide; hCG, human chorionic gonadotropin; IGFBP, IGF-binding protein; IRS, insulin-receptor substrate; LDL, low-density lipoprotein; MCH, melanin-concentrating hormone; MCR, melanocortin receptor; MSH, melanocyte-stimulating hormone; NMDA, N-methyl-D,L-aspartate; NPY, neuropeptide Y; PCOS, polycystic ovarian syndrome; PeV, periventricular nuclei; POMC, proopiomelanocortin; rh, recombinant human; SF-1, steroidogenic factor 1; SOCS, sulfhydryl-containing suppressors of cytokine signaling; SRC, steroid-receptor coactivator; SS, somatostatin; SSTR, SS-receptor subtype; STAT, signal transducer and activator of transcription.

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