The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited

Abstract

Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.

Figure 1.

Depiction of the organization and regulation of the major steroid biosynthetic pathways in the small antral follicle of the ovary according to the 2-gonadotropin, 2-cell model of ovarian steroidogenesis. LH stimulates androgen formation within theca cells via the steroidogenic pathway common to the gonads and adrenal glands. FSH regulates estradiol biosynthesis from androgen by granulosa cells. Long-loop negative feedback of estradiol on gonadotropin secretion does not readily suppress LH at physiologic levels of estradiol and stimulates LH under certain circumstances. Androgen formation in response to LH appears to be modulated by intraovarian feedback at the levels of 17-hydroxylase and 17,20-lyase, both of which are activities of cytochrome P450c17 that is expressed only in theca cells. The relative quantity of androstenedione formation via 17OHP (dotted arrow) in the intact follicle is probably small, as is the amount of progesterone formed from granulosa cell P450scc activity in response to FSH (data not shown). 17βHSD2 activity is minor in the ovary, and estradiol is primarily formed from androstenedione. Androgens and estradiol inhibit (minus signs) and inhibin, insulin, and IGF-1 (IGF) stimulate (plus signs) 17-hydroxylase and 17,20-lyase activities. Pertinent enzyme activities are italicized: the 17-hydroxylase and 17,20-lyase activities of P450c17 are shown, otherwise enzyme abbreviations are as in the text. Modified with permission from Ehrmann et al, Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 1995;16:322–353 (22).

Figure 2.

Depiction of the organization of the major steroid biosynthetic pathways in the adrenal cortex. The top row shows the pathway to aldosterone; the middle row shows the zona fasciculata pathway to cortisol; the lowest, darkly shaded row shows the zona reticularis steps to 17-ketosteroids that are not expressed in the other adrenal zones. Note similarities between the biosynthetic capacities of the zona reticularis and that of ovarian theca cells. Dotted pathways are minor. The zona reticularis is notable for its low 3βHSD2 activity (denoted by small arrow) and unique expression of cytochrome b5, a cofactor which enhances the 17,20-lyase activity of P450c17. Sulfotransferase 2A1 is uniquely expressed in the zona reticularis and rapidly converts DHEA to DHEAS. Compound S (Cpd S), 11-deoxycortisol. Corticosterone and 18-hydroxycorticosterone, the successive intermediates between deoxycorticosterone (DOC) and aldosterone, are not shown. The steroidogenic enzymes are italicized. The clinically relevant electron transfer enzymes also shown are POR and type 1 3′-phosphoadensosine-5′-phosphosulfate synthase (PAPSS). Formation of androstenedione from 17OHP and Cpd S does not seem attributable to CYP450c17. Modified with permission from Rosenfield, Identifying children at risk of polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92:787–796 (431).

Figure 3.

Response to half-maximal hCG stimulation during overnight dexamethasone suppression of normal and PCOS subjects. After bedtime dexamethasone 0.25 mg/m², 500-IU hCG was administered im at 8 am; a basal blood sample was drawn before hCG, and the peak response to hCG was sampled after a repeat dexamethasone dose 24 hours later. Subjects were healthy volunteers with normal ovarian morphology (V-NOMs), PCOS patients with functionally typical FOH (ie, 17OHP hyperresponsiveness to GnRHag; PCOS-T), and PCOS patients with functionally atypical FOH (ie, normal 17OHP responsiveness to GnRHag; PCOS-A). V-NOM had a small but significant rise in serum 17OHP but not in other steroids. PCOS-T had hyperresponsiveness of all steroids. PCOS-A, a heterogenous group, had elevated basal serum free testosterone, but normal hCG-responses of all steroids. To convert to SI units, multiply 17OHP by 0.0303 (nM), androstenedione (A'dione) by 0.0340 (nM), free testosterone by 3.47 (pM), and estradiol by 3.67 (pM). Regraphed from data of Hirshfeld-Cytron et al, Characterization of functionally typical and atypical types of polycystic ovary syndrome. J Clin Endocrinol Metab. 2009;94:1587–1594 (95).

Figure 4.

Scatterplots demonstrating relationships among tests for ovarian hyperandrogenism, PCOM, and serum AMH concentrations. Subjects are patients with PCOS identified by NIH criteria (n = 20 PCOS-A, n = 40 PCOS-T) and age-matched healthy eumenorrheic nonhirsute volunteers with normal or PCOM (V-NOM n = 21, V-PCOM n = 32, respectively). Serum for AMH was available in 92% of PCOS and 82% of these volunteers (39). PCOM was defined according to modified Rotterdam criteria: in adults, it was defined as an ovary more than 10.5 cc (in adolescents, >10.8 cc) using the formula for a prolate ellipsoid and/or more than or equal to 10 follicles 2–9 mm in diameter in the maximum plane (27, 39). Dotted lines show normal ranges for the V-NOM reference group; thus (a) quadrant panels show normal ranges. A, PCOS-T is defined by an elevated 17OHP response to the GnRHag test (c and d). SDAST results correlate with GnRHag results (r = 0.671, P < .0001). SDAST is abnormal in 92.5% of PCOS-T. PCOS-A is defined by lack of 17OHP hyperresponse to GnRHag. The SDAST divides PCOS-A into those with (b) and without (a) ovarian androgenic dysfunction. SDAST indicates that 60% of these PCOS-A cases have atypical FOH (b) and 40% of PCOS-A cases have normal ovarian androgenic function (a). B, SDAST relationship to baseline AMH levels. C, 22% (n = 7) of asymptomatic V-PCOM have baseline hyperandrogenemia (hyperandrogenic PCOM [V-PCOMh]). These all proved to have FOH, as indicated by an abnormal SDAST or GnRHag test (b–d). Adolescent V-PCOM tended to have this asymptomatic FOH less often (1/9) than adult (6/23) V-PCOM. Dysregulated PCOM (V-PCOMd), defined by an abnormal 17OHP response to GnRHag in the absence of baseline hyperandrogenemia (d), was found in 25% (n = 8) V-PCOM. D, Mild AMH elevation was found in V-PCOM independently of hyperandrogenemia. So as to best illustrate differences among groups, very high values (post-SDAST testosterone up to 107 ng/dL and post-GnRHag l7OHP up to 1380 ng/dL) are plotted off-scale. To convert to SI units, multiply total testosterone by 0.0347 (nM), 17OHP by 0.0303 (nM), and AMH by 7.125 (pM). Reproduced with permission from Rosenfield, The polycystic ovary morphology-polycystic ovary syndrome spectrum. J Pediatr Adolesc Gynecol. 2015;28:412–419 (30). Since publication of these data, accumulated evidence suggests that in adolescents mean ovarian volume more than 12 cc is a more appropriate criterion for PCOM than more than 10.8 cc (50, 51). Doing so alters the constitution of the V-NOM and V-PCOM groups. With this adjustment and the addition of data on 4 contemporaneously studied but previously overlooked healthy volunteers, our current upper limits for V-NOM (n = 31) are: baseline-free testosterone 9.3 pg/mL and AMH 6.3 ng/mL; SDAST total testosterone 26 ng/dL; and postdexamethasone GnRHag 17OHP 152 ng/dL (50).

Figure 5.

Relationships among sources of androgen in PCOS. About two-thirds of cases have functionally typical PCOS (PCOS-T) that is due to typical FOH, in which there is hypersensitivity to LH, characterized by hyperresponsiveness of 17OHP to a GnRHag or hCG test. The remaining one-third of PCOS is functionally atypical, lacking 17OHP hyperresponsiveness. This is a heterogeneous group, most of which have atypical FOH, in which ovarian androgen excess is indicated only by a DAST. A small number are due to isolated FAH. About one-quarter of FOH also have FAH. In a minority of cases, the source of androgen cannot be identified as ovarian or adrenal; most of these are associated with obesity. Modified and reproduced with permission from Rosenfield, Polycystic ovary syndrome in adolescents. In: Rose BD, ed. www.uptodate.com. Waltham, MA: UpToDate; 2014.

Figure 6.

Schematic representation of the spectrum of ovarian function found in eumenorrheic nonhirsute V-PCOM (normal-variant PCOM) in relation to that of normal and PCOS women. Approximately 40% of V-PCOM are functionally variations of normal: this group has ovarian function like that of similar V-NOMs. Another 10% of V-PCOM has elevated AMH in the absence of any evidence of ovarian steroidogenic dysfunction, which suggests an isolated increase in folliculogenesis unrelated to ovarian androgenic dysfunction. The remaining half of V-PCOM have some degree of PCOS-related steroidogenic dysregulation, often with AMH elevation. Of these, nearly half (22% of the V-PCOM group) have biochemically hyperandrogenic PCOM, ie, subclinical FOH that suggests ovulatory PCOS. The remainder have isolated dysregulation of ovarian steroidogenesis (ie, isolated in the sense that 17OHP hyperresponsiveness to GnRHag testing occurs in the absence of hyperandrogenemia). Based on data in Figure 4; percentages are averages derived from different denominators for GnRHag test (n = 32) and AMH (n = 28) determinations in V-PCOM.

Figure 7.

Effects of PCOS and sex on response to GnRHag. The early LH responses (1 h after 10-μg/kg GnRHag) of PCOS-T subjects resemble those of normal men (P < .05 vs V-NOM), whereas their surge responses (4 h after GnRHag) resemble those of normal women (P < .001 vs men). The FSH responses of PCOS-T subjects are significantly less than those of V-NOM from 4–24 hours and below those of normal men at 1 and 24 hours after GnRHag (P < .05). PCOS-T and V-NOM are previously reported age-matched groups (47), except NOM in postmenarcheal adolescents has been redefined as mean ovarian volume up to 12.0 cc, consistent with current consensus (30, 51). Adult male data shown for comparison were previously reported using a slightly different GnRHag sampling protocol (407); †, all head-to-head comparisons of normal male and female responses have shown a significant sex difference in the early releasable pool of LH (17, 407).

Figure 8.

Unified minimal model of PCOS pathophysiology. A, Ovarian hyperandrogenism is nearly universal in PCOS and can account for all the cardinal clinical features of the syndrome: hyperandrogenemia, oligo-anovulation, and polycystic ovaries (1). Pituitary LH secretion is necessary to sustain the ovarian androgen excess but is not sufficient to cause it. B, About half of patients with FOH have insulin-resistant hyperinsulinism (2). Insulin-resistant hyperinsulinism acts on theca cells to aggravate hyperandrogenism, synergizes with androgen to prematurely luteinize granulosa cells, and stimulates adipogenesis. The increased hyperandrogenemia provokes LH excess (3), which then acts on both theca and luteinized granulosa cells to worsen hyperandrogenism. LH also stimulates luteinized granulosa cells to secrete estradiol (4), which suppresses FSH secretion. These hyperinsulinism-initiated changes in granulosa cell function further exacerbate PCOM and further hinder ovulation. Obesity increases insulin resistance, and the resultant increased hyperinsulinism further aggravates hyperandrogenism. Heaviness of lines and fonts represents severity. Both FOH and insulin resistance typically have an intrinsic basis. This model does not exclude the possibility that the unknown intrinsic ovarian defects that underpin the ovarian steroidogenic dysfunction also involve granulosa cell folliculogenesis as well. The figure also does not depict other associated defects, such as the FAH that often accompanies the ovarian hyperandrogenism and the contribution of excess adiposity to peripheral androgen production and gonadotropin suppression.