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354 Nader: Adrenarche And Polycystic Ovary Syndrome serum insulin, exaggerated insulin responses to glucose, low glucose to insulin ratios, and occasionally impaired fasting glucose or impaired glucose tolerance. Biochemical features may also include dyslipidemia, with high triglycerides and low HDL, and abnormal adipocytokine profiles, with excess markers of inflammation. 2 While the clinical and/or biochemical features of insulin resistance are very commonly observed, not all patients with PCOS are obese or significantly resistant to insulin. 3 For the most part the patients pose little diagnostic challenge; there is, however, some variability in the clinical, pathologic and biochemical findings and it has proven hard to actually define the syndrome. The 1990 National Institutes of Health consensus criteria required oligo-ovulation and androgen excess. A subsequent consensus conference, held in Rotterdam in 2003, defined the syndrome as two of the following three features: oligo-ovulation, clinical or biochemical evidence of androgen excess and multicystic ovaries. 9 It also required exclusion of late-onset congenital adrenal hyperplasia, Cushing’s syndrome, other causes of androgen excess and hyperprolactinemia. Since its publication, there have been conflicts of opinion regarding this definition: some have supported it while others believe that hyperandrogenism should be an integral part of the definition of this syndrome. 10 These criteria and viewpoints are summarized by Azziz et al, 11 who presented a position statement from the Androgen Excess Society, stating the relevance and importance of hyperandrogenism in the syndrome. We present, both a review and a viewpoint, a broader and developmental view of PCOS is presented, one encompassing multiple possible derangements. The processes leading to reproductive competence are briefly reviewed and two hypotheses are presented. The first relates to adrenarche and proposes a role for this developmental process in the attainment of reproductive competence. The second concerns PCOS and suggests that this syndrome is a maladaptation of the events that lead to reproductive competence in women. Reproductive Competence During fetal life, differentiation of the gonads into ovaries and testes is directed by the sex chromosome complement of the fetus and the hypothalamic-pituitary-gonadal (H-P-G) axis becomes functional in utero. 12 After the neonatal period, the H-P-G axis is suppressed and remains so until the onset of gonadarche, which is manifest as pulsatile release of gonadotropin secretion, initially nocturnal. The precise mechanisms leading to disinhibition of gonadotropin releasing hormone (GnRH) production, and subsequent gonadotropin secretion, remain unknown but include removal of central inhibition, by gammaaminobutyric acid and possibly other neurotransmitters, 12 and as puberty advances, a reduction in sex steroid inhibition of GnRH, 13,14 as will be discussed in a separate section. Release of GnRH allows secretion of the gonadotropins, LH and FSH, leading to ovarian secretion of testosterone and estradiol. Menarche heralds estrogenization of the endometrium sufficient to lead to withdrawal bleeding. Following menarche, ovulatory cycles are not immediately established. A longitudinal study showed that within one and three years of menarche, 10 or more cycles per 12 months occur in 65% and 90% of adolescents respectively. 15 These percentages may overestimate ovulatory cycles, because progesterone concentrations were not determined in the study. The GnRH pulse generator appears to have an intrinsic maximum firing frequency of one pulse per hour after puberty. 16 The frequency of these pulses determines which gonadotropin is preferentially synthesized, rapid pulses favoring LH and slower favoring FSH. 17 During each ovulatory menstrual cycle, follicular growth and ovarian steroidogenesis are stimulated by LH and FSH: while a small amount of LH can lead to sufficient androgen secretion (precursors of estradiol), a finite, threshold concentration of FSH is required for aromatization of androgens (to estradiol) and growth of a mature Graafian follicle. In the late follicular phase, sustained estradiol production, through positive feedback, leads to massive pituitary LH release, that is, to the mid-cycle LH surge. 1e20 The surge is followed by rupture of the follicle and formation of the corpus luteum, which produces progesterone. Progesterone not only prepares the uterus for pregnancy, but slows the GnRH pulse frequency from one pulse per hour to one every 3e4 hours, 16 resulting in preferential synthesis of FSH in late luteal phase, peaking at menses and remaining high during the early follicular phase of the next cycle. This rise in FSH, called the FSH window, allows the next wave of follicular development and dominant follicle selection to occur. 20 Demise of the corpus luteum leads to shedding of the endometrium, marking the beginning of a new cycle. In women, full reproductive competence is achieved with the establishment of ovulatory cycles, occurring repeatedly. Adrenarche After birth the fetal zone of the adrenal gland involutes and there is a paucity of cells resembling zona reticularis. 21 This involution is accompanied by a rapid decline in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S). While in preadrenarcheal children only focal islands
Nader: Adrenarche And Polycystic Ovary Syndrome 355 of zona reticularis can be seen, with adrenarche there is an increase in size of the inner cortical zone, corresponding to increased steroidogenesis. 22 Adrenarche is the prepubertal onset of increased adrenal secretion of 19-carbon steroids, especially DHEA, DHEA-S, and androstenedione and occurs in children at about age 6e8 years. 23 The phenotypic outcome is pubarche, the development of pubic and axillary hair, and this occurs at or after age eight in girls. Serum DHEA and DHEA-S continue to rise in childhood, peaking at age 25e30, followed by slow decline. These C-19 steroids can be converted to testosterone and are called adrenal androgens. The proximal cause of adrenarche is not known with certainty. It has been suggested that the developmentally timed trigger for adrenarche, and its later decline at andropause, may be insulin-like growth factor-1(IGF-1). 24 Prolactin has also been suggested as a trigger for adrenarche. 25 Interestingly, children with isolated growth hormone deficiency 26,27 and Laron dwarfism 28 may have delayed pubertal development, thus supporting a role for IGF-1 in the trigger of adrenarche. Insufficient adrenarche has also been reported in patients with PROP-1 gene defects, who have combined pituitary hormone deficiencies affecting gonadotropins, growth hormone, prolactin and TSH, again supporting roles for IGF-1 and possibly prolactin as initiators of adrenarche. 25,29 Conversely, precocious adrenarche has been demonstrated in pituitary gigantism with increased growth hormone and prolactin secretion. 30 Adrenarche represents an induction of 17, 20 lyase and a decrease in 3-b hydroxysteroid dehydrogenase activity in the zona reticularis. 31,32 Serine phosphorylation of P450c17 and access to cytochrome b5 as a co-factor appear to be necessary steps in this process. 33 No adequate animal model exists for adrenarche; only chimpanzees and gorillas show a pattern of DHEA and DHEA-S characteristic of human adrenarche. The role of adrenarche in human physiology is unknown. 23,24 Neither the gonads nor gonadotropins are required for its onset. A study of 39 patients with gonadal dysgenesis showed age appropriate DHEA-S concentrations. 34 Conversely, gonadarche does not absolutely require the presence of the adrenals. 27 It has been suggested that adrenarche is an example of ongoing evolution and that the failure to identify a clear DHEA deficiency state may indicate that higher primates have not yet evolved efficient ways of using this special hormonal environment. 24 Hypothesis One: A Role for Adrenarche Boyar et al, 35 Sizenko and Paunier, 36 and Ducharme et al 37 have previously suggested that adrenarche may play a role in the maturation of the H-P-G axis. The hypothesis presented in the present paper proposes that adrenarche is a harbinger or promoter of gonadarche, an evolutionary safeguard, ensuring that gonadarche occurs earlier and perhaps with greater certainty than it would otherwise. There is clinical evidence to support this hypothesis. In a study of six girls with Addison’s disease before full pubertal maturation, breast development occurred at age 13.2 with menarche at 15.3 in one; menarche occurred at age 15 in another, a third was prepubertal at 11.4, and two had menarche at ages 12.3 and 13 years. 38 The sixth patient had not menstruated by age 16.3, but she demonstrated both adrenal and theca cell antibodies and had a high FSH, indicative of concomitant ovarian failure. In the same study there were eight boys with a diagnosis of Addison’s; two started puberty at ages 16.2, and 16, another was prepubertal at age 10.9, and four reached pubertal maturity between ages 14e16. One boy with both adrenal and Leydig cell antibodies was prepubertal at age 12.9. Two of the boys were already older than 13 at the time of diagnosis. In another study of seven males with Addison’s disease diagnosed at ages !1 to 11.8 years, onset of puberty, as determined by testicular enlargement O2.4 cm, occurred between 12.2 and 14.9 years as compared with age 11.40.4 for normal American boys. 39 The authors had concluded that the age of onset of gonadal pubertal development was no different in Addisonian patients but they had excluded from analysis two patients with pubertal onset at 14.3 and 14.9 years because the patients exhibited other autoimmune disease (alopecia and hypoparathyroidism) before the onset of puberty. Whether this was a valid reason for exclusion is open to debate. In parallel, lower adrenal androgens have been shown in male patients with constitutionally delayed puberty. 40 In a landmark study of children with pubertal disorders, 29 of 32 patients with constitutionally delayed growth and adolescence had significantly lower DHEA-S concentrations for their chronological age but appropriate for their bone age. 34 While this paper is often quoted to show evidence for the dissociation between adrenarche and gonadarche, as the authors themselves state, ‘‘patients with constitutionally delayed growth and adolescence often exhibit a delay in both adrenarche and gonadarche.’’ It is thus possible that delayed or inadequate adrenarche is the proximal cause of constitutionally delayed puberty and this may have a genetic basis. 41 In support of this possibility, earlier progression into gonadarche has been shown when males with constitutional delay were given androgens. 42 Conversely, premature adrenarche has been linked with premature gonadal development, for example, as evidenced in patients with congenital adrenal hyperplasia. 35 These authors showed that two boys with congenital adrenal hyperplasia, as well as manifesting
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