Mini Review - sepeap

J Pediatr Adolesc Gynecol (2007) 20:353e360 

Mini Review 

Adrenarche and Polycystic Ovary Syndrome: 

A Tale of Two Hypotheses 

Shahla Nader, MD 

Departments of Internal Medicine (Endocrinology) and Obstetrics and Gynecology, University of Texas Medical School: 

Houston, Houston, Texas, USA 

Abstract. Polycystic ovary syndrome (PCOS) is an 

extremely common endocrine disorder affecting young 

women, with the potential for both reproductive and nonreproductive 

adverse outcomes. While oligomenorrhea, 

hyperandrogenism, and cystic ovarian morphology are recognized 

characteristics of this syndrome, the origin of these 

disturbances is not always apparent. During normal growth 

and development, adrenarche, the prepubertal onset of adrenal 

androgen secretion, results phenotypically in pubarche. 

Gonadarche, which is the ovarian response to gonadotropin 

releasing hormone-mediated gonadotropin secretion, also 

occurs, leading to reproductive competence, namely the 

establishment of ovulatory cycles, repeatedly. In this 

mini-review, an overview of adrenarche and gonadarche 

are presented, followed by two hypotheses. The first describes 

an evolutionary role for adrenarche: an advantage 

in the attainment of reproductive competence. The second 

proposes that the path to PCOS be viewed from a developmental 

perspective, namely, that PCOS is a maladaptation 

of the processes that lead to reproductive competence in 

women. Its defining characteristics of oligomenorrhea, 

hyperandrogenism, and cystic ovarian morphology are the 

final common pathway of multiple possible derangements. 

Elucidating and understanding these maladaptive processes 

will be the key to future endeavors at prevention and treatment 

of this common reproductive disorder. 

Key Words. Adrenarche—Gonadarche—Hyperandrogenism—Oligomenorrhea—Ovarian 

cysts 

Introduction 

While it is over 70 years since Stein and Levanthal 1 

described the association of amenorrhea, hirsutism, 

Address correspondence to: Shahla Nader, 6431 Fannin Street, Suite 

3604, Houston, Texas, 77030; E-mail: Shahla.Nader-Eftekhari@ 

uth.tmc.edu 

Ó 2007 North American Society for Pediatric and Adolescent Gynecology 

Published by Elsevier Inc. 

and enlarged cystic ovaries, polycystic ovary syndrome 

(PCOS), as it is now called, remains one of 

the enigmas of reproductive endocrinology. 2,3 It is an 

extremely common disorder, affecting approximately 

6% of reproductive age women. 4 In addition, its recognized 

association, over the last few decades, with 

insulin resistance and the metabolic syndrome, 5 has 

added urgency to the quest for its genetic and pathogenic 

underpinnings. Remarkably, the discovery of its 

pediatric antecedents including premature pubarche 

and small for gestational age 6e8 have made this 

syndrome a holy grail for both pediatric and adult 

endocrinologists. 

As is well-known, the clinical manifestations 

include oligomenorrhea and oligo-ovulation, often 

dating from menarche, signs and symptoms of androgen 

excess, such as hirsutism, acne, oily skin and 

alopecia and many, but not all patients, also complain 

of obesity. While not part of the definition (and further 

discussed below), features of insulin resistance, such 

as acanthosis nigricans and skin tags, are often present 

and the obesity is usually abdominal, itself associated 

with insulin resistance. 2 Pathologically, the ovaries 

are often enlarged with a thickened capsule and hyperplastic 

stroma and contain multiple subcortical 

cysts, arranged in rosary-like fashion, some of which 

may enlarge and rupture, causing pain. Biochemically, 

ovarian or adrenal androgen excess, or both, 

may be demonstrated; there may be increased serum 

luteinizing hormone (LH) with low-normal follicle 

stimulating hormone (FSH), hence the high LH/FSH 

ratio, which is classic for this syndrome. In addition, 

serum sex-hormone binding globulin concentrations 

(SHBG) are low, and hence the high free androgens. 

The low SHBG may in part result from the excess 

androgens themselves but, more importantly, it relates 

to the insulin resistance commonly observed in these 

individuals. Biochemical features of insulin resistance 

may also be found: these include increased fasting 

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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


advanced bone age, had augmented LH (and also FSH 

in one of the boys) during sleep at ages 8.5 and 5.5 

years. In the same landmark study 34 quoted above, 

there were nine females with idiopathic sexual precocity 

with onset between the ages of 6e8 years. All had 

Tanner stage 2e3 pubic hair, six had Tanner stage 3 

and three Tanner stage 2 breasts. These nine had advanced 

bone age and significantly greater DHEA-S 

concentrations than chronologic-age-matched controls; 

these concentrations were similar to those of normal 

children matched for bone age. As written by Sklar 

et al., 34 ‘‘These patients exhibited appropriate concordance 

between adrenal androgen and gonadal steroid 

concentrations. At least some of the patients with onset 

of idiopathic precocious puberty between 6 and 8 yr of 

age may represent one end of the normal spectrum of 

puberty development, their precocious puberty being 

part of a more generalized process which includes precocious 

activation of both gonadarche and adrenarche.’’ 

The association between premature pubarche, as 

a result of early or amplified adrenarche, and early 

menarche was clearly demonstrated in a longitudinal 

study of 187 girls with premature pubarche. 43 The authors 

showed that menarche before age 12 was twofold 

more prevalent in these girls than in normal 

controls and was threefold more prevalent in a group 

of girls with both premature pubarche and low birth 

weight. Thus, while adrenarche and gonadarche can 

occur independently, are controlled and initiated by 

separate mechanisms, and have separate pathways, 44 

there appears to be a temporal link between adrenarche 

and gonadarche: early adrenarche is associated 

with earlier gonadarche and conversely delayed or 

inadequate adrenarche with later gonadarche. 

The biochemical evidence supporting a role for 

adrenarche in the onset of gonadarche, that is, a role 

for androgens in the establishment of gonadal axis 

maturation, is circumstantial. The progression of 

changes in neuroendocrine function in normal puberty 

will first be briefly discussed. This topic was elegantly 

reviewed by Blank et al. 45 They stated that the juvenile 

period of childhood is characterized by low levels 

of LH and FSH with approximately one pulse of 

GnRH every 4e6 hours. With the onset of puberty, 

nocturnal sleep-associated increases in LH pulse 

amplitude and frequency occur and precede pubertal 

maturation by about two years. LH pulse frequency 

and amplitude increases four- and nine-fold across pubertal 

maturation in girls. These nocturnal increases 

in LH lead to early morning increase in estradiol, progesterone 

and testosterone. 46,47 It has been proposed 

that, over time, the morning increases in progesterone 

contribute to the reduction in GnRH and LH pulsatility 

the following day, favoring FSH synthesis and thus 

follicular development, progesterone acting either directly 

or indirectly on the GnRH pulse generator. 47 

Androgens have been known to play a role in 

GnRH pulsatility. As previously stated, testosterone 

treatment of adolescent boys with constitutional delay 

has been shown to increase the tempo of testicular enlargement, 

as compared with control subjects. 42 This 

earlier gonadarche can only relate to central axis activation. 

In addition, it has long been known that 

women with PCOS require higher concentrations of 

progesterone to achieve the same degree of suppression 

of GnRH pulsatility as normal ovulatory control 

subjects. 48 This sensitivity is restored by the antiandrogen 

flutamide, implying that decreased progesterone 

sensitivity is secondary to hyperandrogenemia. 49 

Stated differently, androgens seem to be associated 

with a disinhibition of GnRH, with increased GnRH 

pulsatility, this also being a marker of the onset of gonadarche. 

In light of these observations, it is quite 

possible that the gradual increase in androgens characteristic 

of normal puberty 50 could potentially mediate 

this reduction of feedback sensitivity, leading to 

increased GnRH pulsatility, as was suggested by 

Blank et al. 45 In support of this possibility, Blank 

and colleagues performed a study on normal adolescent 

girls given estradiol and progesterone and 

showed that hypothalamic progesterone sensitivity 

(the ability of progesterone to inhibit GnRH pulsatility) 

decreases as puberty progresses, this being coincident 

with a rise in serum testosterone. They also 

showed that hypothalamic progesterone sensitivity is 

further reduced in adolescent girls with androgen 

excess (presented at the 88 th annual meeting of the 

Endocrine Society, Boston, June 2006, p 2-622). 

The hypothesis proposed there is that adrenarche, 

which precedes gonadarche, provides the initial 

source of androgens, leading to the disinhibition of 

GnRH, and hence gonadarche. The progression of 

the gonadal events of puberty, as outlined in the section 

on reproductive competence, and also above, 

would thus naturally follow the production of androgens 

at adrenarche, a harbinger of gonadarche. In 

the absence of adrenarche, as in patients with 

Addison’s disease for example, one would have to 

assume that other mechanisms such as the accrual 

of body fat and leptin activate the hypothalamic pulse 

generator, albeit later. 51,52 

Transition from Adrenarche to Full Reproductive 

Competence 

As outlined in the sections on reproductive competence 

and adrenarche, normal pubertal development starts 

with adrenarche and ends with the attainment of full reproductive 

competence, that is, persistent ovulation, in 

women. In the early phase of puberty, there is relative 

hyperandrogenism, with high levels of androgens relative 

to estrogens, as demonstrated in a study of 56


357 

healthy girls from prepuberty to postmenarche. As Ankarberg 

and Norjavaara stated, ‘‘gonadarche in its earliest 

phase starts in an androgen-dominated state.’’ 50 

There is also increased LH to FSH ratio, with LH hyperpulsatility 

53,54 and a decrease in insulin sensitivity with 

increased insulin secretion. 55,56 Thus, during pubertal 

development, that is, in the transition leading to the attainment 

of full reproductive competence, adolescent 

females have relative androgenemia, insulin resistance, 

and predominantly anovulatory cycles. During this interval, 

ovarian morphology studies, as determined by 

ultrasound, have also shown cystic ovaries. Orsini et 

al 57 studied the ovaries of 114 premenarcheal girls 

and found cystic functional changes after age five. Cohen 

et al 58 determined the prevalence of ovarian cysts in 

101 premenarcheal girls aged 2e12 years. Cysts were 

identified in 68% of ovaries scanned, including a few 

cysts O9mm. Similarly, Buzi et al 59 showed that multicystic 

ovaries, defined as containing $6 follicles with 

diameters 4e9mm, occurred after age 7 in normal girls. 

Using the 1990 National Institutes of Health consensus 

criteria, components of the 2003 Rotterdam 

criteria, 9,10 or the latest criteria from the Androgen 

Excess Society 11 for the definition of PCOS, it 

becomes evident that the transition from adrenarche 

to full reproductive competence is a PCOS-like state. 

So, if pubertal development is PCOS-like in its 

characteristics, then what is PCOS? 

Hypothesis Two: PCOS Is a Developmental 

Maladaptation 

What we recognize as PCOS, namely, persistent anovulation, 

hyperandrogenism, and PCO morphology is 

a maladaptation of the evolutionary phenomenon that 

is adrenarche. In essence, PCOS is when the PCOSlike 

state of the pubertal transition cannot be turned 

off or overcome, as was shown in a prospective study 

of adolescents. 60 This was also proposed by Ankarberg 

and Norjavaara, who stated, ‘‘It is an interesting 

hypothesis that PCOS may develop from abnormal 

pubertal development, and a critical point in pubertal 

development could be in the transition stage from the 

early pubertal androgen-dominated state to the estrogenic 

state later in puberty.’’ 50 In its effect, it is either 

a persistent adrenarche-like state with excess adrenal 

androgen production, 61 or a state of persistent hyperandrogenemia 

resulting from excess stimulation of the 

ovaries by LH and trophic stimuli such as insulin, or, 

it is a combination of the two. 

The path to PCOS is not a single one: numerous 

aberrations can result in this derangement. These 

pathways can be rare or common. They may be purely 

genetic, purely environmental, or a combination. 

They may even relate to programming during intrauterine 

life, resulting from a particular intrauterine 

environment. For example, numerous and sundry 

pathways associated with insulin resistance and hyperinsulinemia 

commonly lead to PCOS. Genetically 

mediated insulin resistance leads to hyperinsulinemia. 

This has a profound effect on androgen production because 

insulin is a trophic hormone that can stimulate 

both ovarian and adrenal androgen secretion. 62e64 Insulin 

resistance itself may be developmental in origin, 

in association with and subsequent to alterations in fuel 

metabolism, as in small-for-gestational-age babies who 

have rapid catch-up growth in infancy. 7,8,65,66 Alternatively, 

the insulin resistance may be secondary to environmental 

factors leading to obesity, especially in 

individuals with the thrifty genotype or a genetic predisposition 

to insulin resistance. For example, peripubertal 

obesity was shown to be a factor in the genesis 

of postpubertal hyperandrogenism 67 and reversibility 

has been demonstrated following weight loss. 68 Clinical 

manifestations of these insulin resistant subjects 

includes premature pubarche, early menarche, and 

adolescent or adult PCOS. 6,43 

However, as well as genes involved in insulin secretion 

and action, there may also be other genetic 

causes of aberrant androgen secretion leading to the 

PCOS phenotype: insulin resistance is not the initiating 

pathophysiology of all cases of PCOS. For example, 

genes involved in steroid metabolism and action 

and gonadotropin activity and regulation have been 

linked to PCOS. 69,70 Genetic variations 71e73 and rare 

disorders of steroidogenesis 74 may lead to the PCOS 

phenotype. Because androgens themselves are associated 

with insulin resistance, any hyperandrogenic 

individual may secondarily have decreased insulin 

sensitivity, as shown in female-to-male transsexuals, 

given androgens. 75 Similarly, puberty itself is a state 

of relative insulin insensitivity and hyperandrogenic 

adolescents may thus be insulin resistant. 76 Even prenatal 

androgen exposure of the female fetus can lead 

to subsequent PCOS, through potentially diverse pathways 

that include central fat accumulation (and insulin 

resistance), and altered target tissue differentiation, 

for example, differentiation of the hypothalamicpituitary 

axis or ovarian theca cells. 77 

Summary and Conclusions 

Adrenarche and PCOS are two sides of a coin representing 

evolutionary advantage (adrenarche) and maladaptation 

(PCOS). In populations that are threatened 

with starvation, disease, and malnutrition, adrenarche 

would be an advantage, promoting earlier gonadarche 

and ensuring survival of the species. Even today, there 

are many who are starving or malnourished. Nearly 

67 million children weigh less than they should for 

their height and 183 million weigh less than they 

should for their age, and the reproductive system is 

very sensitive to external influences. 78 In many


animals, conception is timed to ensure that birth takes 

place in a season when food and climatic conditions 

are appropriate. 79 Women affected by the Dutch famine 

of 1944e45 at ages 3e13 years had a 1.9-fold 

higher risk of having fewer than the desired number 

of children in their lifetime. 80 

Unfortunately, in the western hemisphere, where 

the food supply is plentiful, there is maladaptation. 

This may be exacerbated by an adverse intrauterine 

environment followed by excess catch-up growth, by 

genetic insulin resistance, often compounded by obesity 

or by a thrifty genotype. 78 Under such circumstances, 

early and excessive production of androgens 

from the adrenals promotes growth, development, 

and bone maturation, and leads to excessive LHinduced 

ovarian androgen production. These events 

hasten gonadarche but hinder full gonadal maturation 

and the establishment of ovulatory cycles. This state 

of hyperandrogenism, anovulation, and cystic ovarian 

morphology is what we call PCOS. 

Challenges and Future Directions 

We need to move away from the concept of a single 

path to PCOS toward a broader view of its pathogenesis, 

encompassing multiple derangements. What we 

call PCOS is likely to be a diverse group of disorders 

with similar clinical manifestations and shared biochemical 

features. There will be commonalities and 

differences in these different entities. Should they 

all be called PCOS? For example, non-classic or 

late-onset congenital adrenal hyperplasia is really 

a form of PCOS, with clinical manifestations that are 

virtually identical. The partial deficiency of the 21- 

hydroxylase enzyme responsible for the commonest 

form of this disorder does not manifest itself clinically 

during early childhood. As the zona reticularis develops 

and is stimulated, excessive amounts of adrenal 

androgens are produced. 81 This androgen excess 

not only leads to hirsutism, but hinders the establishment 

of normal ovulatory cycles. We do not call it 

PCOS because we understand its pathophysiology 

and genetics and categorize it as a separate entity. 

Thus it would seem that our task should begin by 

cataloging androgen excess disorders, determining 

their associations, biochemical pathways, and genetics. 

Only by doing so can we rationally approach prevention 

and treatment of this common reproductive 

problem and its many consequences. 

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