Version May 2024
INTRODUCTION — Polycystic ovary syndrome (PCOS) is characterized clinically by menstrual dysfunction, including oligo- or anovulation and signs of hyperandrogenism [1]. This review will describe the abnormalities in steroid hormones that are present in this disorder, including the factors responsible for the increase in androgen production. The clinical manifestations of PCOS are discussed separately. (See "Clinical manifestations of polycystic ovary syndrome in adults".)
ANDROGEN METABOLISM — As a group, women with PCOS have serum concentrations of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS) that are significantly elevated compared with ovulatory, nonhirsute women (figure 1) [1,2]. There is, however, significant individual variation, and some women with PCOS may have normal androgen levels when assayed in a single blood specimen [1].
In women, androgens are produced by the adrenal glands and the ovaries, as well as by conversion of less potent to more potent androgens in the periphery. The source of the major androgens in PCOS is shown in the table (table 1). In PCOS, androstenedione and testosterone are secreted primarily by the ovaries (figure 2) and, to a lesser degree, the adrenals. This pattern differs from that in ovulatory premenopausal women who have approximately equal androstenedione and testosterone production from the ovaries and the adrenals [3].
Testosterone — Testosterone is the most potent circulating androgen. Its biologic activity is determined by three factors: its concentration, the amount of binding to sex hormone-binding globulin (SHBG), as only the free fraction is active, and by the intracellular rate of conversion of testosterone by the 5-alpha reductase enzyme to the potent i androgen, dihydrotestosterone (DHT) (see 'Dihydrotestosterone' below). Unlike testosterone, which is a circulating androgen, dihydrotestosterone is an intracellular androgen. Liver production of SHBG concentrations is regulated by androgens (decrease), estrogens (increase), and insulin (decrease) [4]. Thus, hyperandrogenic women with PCOS, especially if obese or insulin resistant, tend to have low serum SHBG concentrations. When SHBG is low or low-normal, a serum testosterone within the upper end of the normal range may be associated with excess androgen stimulation in target tissues because of elevated free testosterone.
Body mass index (BMI) is positively correlated with serum total testosterone and inversely correlated with SHBG concentrations in women of all reproductive ages regardless of their ovulatory status.
●In a cohort study of 1526 Scandinavian premenopausal women (mean age 31 years), increasing BMI was associated with increased serum testosterone and decreased serum SHBG concentrations in both ovulatory and oligo-ovulatory women [5].
●Similar associations were observed in the Study of Women's Health Across the Nation (SWAN) of 2930 perimenopausal women (mean age 46 years) [6] and in a study of menopausal women [7].
Cigarette smoking is associated with increased serum testosterone concentrations in premenopausal women [6,8]. It is not known if discontinuing smoking is associated with a subsequent decrease in serum testosterone.
Androstenedione — Androstenedione is the immediate precursor to testosterone. Androstenedione is converted to testosterone by the 17-beta-hydroxysteroid dehydrogenase (17-ketosteroid reductase) enzyme, which is present in most tissues. In the ovary of ovulatory women, the theca cells secrete significant quantities of androstenedione, which enters the granulosa cells and is converted to estrone and estradiol. Luteinizing hormone (LH) directly stimulates thecal secretion of androstenedione. In PCOS, LH levels are elevated so the theca secretes increased quantities of androstenedione. In addition, thecal cells from women with PCOS are more sensitive to LH stimulation of androgen production [9]. The androstenedione secreted into the circulation by the ovary and adrenal can be converted to the potent androgen, testosterone, by most peripheral tissues.
Dehydroepiandrosterone sulfate — The majority of DHEAS derives from the adrenal glands, and there is little, if any, sulfotransferase (sulfokinase) activity in the periphery to convert DHEA to DHEAS. As a result, the serum concentration of DHEAS is a good marker of adrenal androgen hypersecretion. In addition, since DHEAS has a long serum half-life, with minimal pulsatile or diurnal variation, a single measurement of serum DHEAS correlates well with integrated measures of DHEAS secretion.
However, some adrenocortical carcinomas have no sulfotransferase activity, and some patients with congenital adrenal hyperplasia have normal DHEAS levels. Thus, normal serum DHEAS concentrations do not necessarily exclude a pathologic adrenal source of excess androgens.
Although DHEA and DHEAS are markers of adrenal androgen production, they have little if any intrinsic androgenic activity. Small amounts are converted to androstenedione and then to testosterone (and to estrogen) in both the adrenal glands and peripheral tissues, including hair follicles and external genitalia. Thus, the hirsutism and virilization that may occur in patients with adrenal hyperandrogenism are caused by androstenedione and testosterone. (See "Adrenal hyperandrogenism".)
Dihydrotestosterone — Testosterone binds to the intracellular androgen receptor with modest affinity. In androgen-responsive tissues, intracellular 5-alpha reductase converts testosterone to DHT. DHT binds to the androgen receptor with an affinity 10 times greater than testosterone. There are multiple subtypes of 5-alpha reductase. In a tissue such as the prostate, the type II isoenzyme predominates, while in the pilosebaceous unit, both the type I and II isoforms are present. Women with PCOS have increased 5-alpha reductase activity [10], resulting in increased activation of the pilosebaceous unit (hair growth, sebum production) with only modest increases in bioavailable testosterone.
Androstanediol — 3-alpha-androstanediol-glucuronide (3aA-G) is derived from the metabolism of the potent intracellular androgen DHT. It can therefore be used as a marker of peripheral androgen metabolism. Serum concentrations of 3aA-G are almost uniformly high in women with hirsutism. Urine concentrations of 3-aA-G are elevated in women with PCOS [11]. Except for research purposes, however, it is probably unnecessary to measure 3aA-G as the presence of hirsutism by definition indicates that androgen activity in the skin is increased.
ESTROGEN METABOLISM — Most women with PCOS have serum estradiol concentrations similar to the early follicular phase of ovulatory women and elevated serum estrone concentrations (figure 3) [1,2]. The serum estrogens in women with PCOS come partly from the multiple small follicles in the polycystic ovaries and partly from aromatization of androgens to estrogens in fat cells.
The net effect is that PCOS is a normoestrogenic state, and estrogen replacement is not required, even in amenorrheic women with PCOS. Women with PCOS are oligo- or anovulatory and do not produce normal quantities of progesterone. Consequently, they are at an increased risk of endometrial hyperplasia and heavy menstrual bleeding. (See "Clinical manifestations of polycystic ovary syndrome in adults".)
CONTROL OF ANDROGEN PRODUCTION — The control of androgen production in women is complex because the androgens are produced in multiple sites. In both the ovaries and adrenal glands, androgen secretion requires the activity of multiple steroidogenic enzymes (figure 4), including:
●Cholesterol synthesis – All gonadal steroid synthesis begins with synthesis of cholesterol and its transport to steroidogenic tissues in lipoproteins. In placebo-controlled trials, the cholesterol synthesis inhibitor atorvastatin (20 mg/day) reduced hyperandrogenemia when administered to women with PCOS [12].
●P450scc (side-chain cleavage) that converts cholesterol to pregnenolone.
●3-beta-hydroxysteroid dehydrogenase that converts steroids such as pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) to progesterone, 17-hydroxyprogesterone, and androstenedione.
●P450c17, which has both 17-hydroxylation and 17,20 lyase functions and, therefore, converts pregnenolone to 17-hydroxypregnenolone and 17-hydroxypregnenolone to DHEA, and progesterone to 17-hydroxyprogesterone and 17-hydroxyprogesterone to androstenedione, respectively.
Ovarian androgen secretion — Ovarian androgens are produced in the theca cells, which respond to luteinizing hormone (LH) [13]. Theca cells synthesize mostly androstenedione and some testosterone, which diffuse across the basement membrane to the granulosa cells. The granulosa cells, in response to stimulation by follicle-stimulating hormone (FSH), produce aromatase, which converts the androgen precursors to estrone and estradiol (figure 5) [13].
In women with PCOS, ovarian androgen production may increase as a result of one or more of the following:
●An increased volume of theca cells.
●Increased LH stimulation of the theca cells. Indirect support for the "excess LH drive" hypothesis derives from transgenic animal studies. Overexpression of human chorionic gonadotropin (hCG) (which binds and activates the same receptor as LH) resulted in mice with large cystic ovaries [14].
●Increased theca cell sensitivity to LH stimulation [9].
●Potentiation of the action of LH by hyperinsulinemia.
●Production of beta subunits of LH that have different biological activity as a result of polymorphism of the gene for the subunit [15]. The more active LH need not be more immunoreactive, so serum LH concentrations as routinely measured might be normal (and often are normal) in these women.
●Increased expression of LH receptor, CYP11A, and CYP17 mRNAs in thecal cells from PCOS follicles versus size-matched control follicles [16]. In addition, theca cells from the ovaries of women with PCOS demonstrate increased CYP17 and 3-beta hydroxysteroid dehydrogenase enzyme activity [16].
Role of insulin — In vitro experiments with human theca cells have demonstrated a synergistic effect of LH and insulin to increase androgen secretion [17]. Several studies in obese women with PCOS are compatible with a contributory role of insulin. As an example, reducing the degree of insulin resistance with metformin [18] or reducing insulin secretion with diazoxide [19] results in a fall in serum androgen concentrations.
The association of insulin resistance with hyperinsulinemia in women with PCOS results in the "insulin paradox" since a resistant organ should not be able to hyper-respond. Several hypotheses have been proposed to explain this paradox:
●The high serum insulin concentrations may activate the homologous receptors for insulin-like growth factors-1 and -2 (IGF-1 and IGF-2). This argument is tenable for women with extreme insulin resistance syndromes who have very high serum insulin concentrations. However, women with PCOS usually have only mildly elevated serum insulin concentrations.
●There may be hybrid receptors in which a half-insulin receptor dimerizes with a half-IGF-1 receptor (figure 6). This hypothesis has not yet been demonstrated in women with PCOS.
Regardless of the mechanism, it appears that some women with PCOS have insulin resistance in muscle, adipose tissue, and liver but demonstrate insulin sensitivity in the ovary. A 1995 report described a woman with PCOS and severe insulin resistance (in terms of glucose metabolism) in whom ovarian insulin sensitivity was normal [20].
Role of anti-müllerian hormone — Anti-müllerian hormone (AMH) circulating levels are increased in women with PCOS [21]. AMH may attenuate FSH stimulation of follicle growth [22] and decrease aromatase enzyme activity, thereby inhibiting estradiol production [23]. Elevated AMH is likely detrimental to the process of follicle development and may contribute to the androgen dominant milieu detected in the follicles of women with PCOS by reducing the rate of conversion of androstenedione and testosterone to estrone and estradiol, respectively.
Other factors — Other factors that can increase ovarian androgen secretion in women with PCOS include:
●Decreased aromatase activity due to decreased FSH secretion.
●A decreased number of maturing follicles to "deactivate" the androgens to estrogens. However, the granulosa cells from the small follicles of PCOS ovaries usually maintain the ability to aromatize androgens to estrogens in response to FSH [24].
●Dysregulated ovarian androgen secretion. An increased serum 17-hydroxyprogesterone response to gonadotropins in hyperandrogenic women suggests that there is dysregulated function of the P450c17 enzyme in the ovaries [25]; the dysfunction may be intrinsic to the thecal cells [26]. In theca cells from women with PCOS, mRNA transcripts for P450c17 have an increased half-life [27]. In addition, these cells appear to have alterations in pathways of mitogen-activated protein kinase and extracellular regulated kinase signaling that enhance P450c17 activity [28].
As noted above, P450c17 catalyzes both 17-hydroxylation and 17,20-lyase reactions; however, it can be selectively induced to increase its 17,20-lyase activity (thereby producing more androgens) by serine phosphorylation [29].
In theca cells from women with PCOS, GATA6, a transcription factor that increases expression of multiple steroidogenic enzymes, has increased activity [30].
Adrenal androgen secretion — Adrenal steroidogenesis is a complex process under the control of corticotropin (ACTH), as well as other factors (figure 4). ACTH has a primary role in controlling the rate-limiting step of adrenal steroidogenesis, the cholesterol side-chain cleavage enzyme, leading to increased secretion of adrenal androgens as well as glucocorticoids and mineralocorticoids.
Over 50 percent of women with PCOS have evidence of increased adrenal androgen secretion including hyper-responsivity of adrenal steroidogenesis to exogenous ACTH administration [31]. This increased adrenal androgen secretion is not due to subtle defects in CYP21 [32]. During the normal aging process in males and females, adrenal androgen secretion decreases. Based on the results from one small study, women with PCOS demonstrate excess adrenal androgen secretion with no age-related decrease into the onset of menopause [33].
Other — There is evidence that other factors can contribute to the regulation of androgen synthesis in PCOS. One important factor may be genetic predisposition. Familial cases of PCOS have been described, although the underlying defect is not known [34,35]. In addition, there is evidence for abnormalities of steroidogenic enzyme function, which may be related to feedback from intraglandular steroid levels, modification of cofactor function, or unknown mechanisms [25,36-39].
In women with PCOS, steroid hormone concentrations may be influenced by genetic traits. For example, the single nucleotide polymorphism (SNP) rs182420 in the DHEA sulfotransferase enzyme (SULT2A1, which converts DHEA to DHEA sulfate [DHEAS]) is associated with increased circulating levels of DHEAS, and the promoter variant 1C in the enzyme CYP3A7, which degrades DHEAS through 16-hydroxylation, is associated with reduced levels of circulating DHEAS [40,41].
In the largest, most comprehensive association study of PCOS genotype, mutations in the region of the FSH-beta gene were identified that positively correlate with an elevation in circulating LH concentration [42]. In turn, elevated LH stimulates ovarian androgen production. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome".)
SUMMARY
●Polycystic ovary syndrome (PCOS) is characterized by excessive secretion of androgens from the ovary and, in many cases, the adrenal gland. Approximately 75 percent of women with PCOS have an elevated concentration of circulating free testosterone, total testosterone, or dehydroepiandrosterone sulfate (DHEAS).
●Women with PCOS typically have elevated pituitary secretion of luteinizing hormone (LH), which stimulates the ovarian theca cells to secrete excess quantities of androstenedione, an androgen precursor that can be metabolized to testosterone, a potent circulating androgen. Circulating testosterone is converted to dihydrotestosterone (DHT), the most potent intracellular androgen, in target tissues.
●Sex hormone-binding globulin (SHBG) is the major high-affinity circulating binding protein for testosterone. Testosterone bound to SHBG is believed to not be bioavailable to tissues. Free testosterone and testosterone weakly bound to albumin are thought to be available to stimulate androgen activity in target tissues such as the hair follicle. In PCOS, hyperandrogenism and hyperinsulinemia due to insulin resistance reduce hepatic production of SHBG and decrease circulating SHBG levels. The decrease in SHBG results in a proportionate increase in free testosterone, increasing testosterone bioactivity, and, at the same time, decreasing total testosterone levels.
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