Polycystic ovary syndrome





Key points





  • Polycystic ovary syndrome (PCOS) is now diagnosed by the Rotterdam criteria, which are clinical end points, and is not a laboratory diagnosis . The diagnosis requires finding any two of the following: menstrual irregularity, hyperandrogenism (clinical or biochemical), or polycystic ovaries on ultrasound.



  • The disorder is heterogeneous and is not a single-gene disorder, although several susceptibility genes have been identified; environmental influences are most likely involved as well.



  • Treatment of women with PCOS should be directed at the specific complaint: menstrual function, skin disorders of androgen excess, or subfertility. Typically more than one complaint exists, and they can be dealt with concomitantly unless the woman is trying to conceive.



  • Weight gain and metabolic concerns (particularly insulin resistance, prediabetes, etc.) are extremely common and should be treated aggressively (usually with lifestyle management), particularly before pregnancy. Evidence suggests that cardiovascular morbidity and mortality are not increased in PCOS unless the woman has obesity and/or diabetes.



  • Long-term consequences of PCOS may include cardiovascular and metabolic concerns and the increased risks of endometrial and ovarian cancer, unless oral contraceptives have been used. With ovarian aging, cycles may become more regular, and some but not all the symptoms of PCOS may disappear as women approach menopause. The age of menopause may be later.



Polycystic ovary syndrome: Definition


Polycystic ovary syndrome (PCOS ) is the most common endocrine disorder in reproductive-age women. It is often misunderstood and may be underdiagnosed in the general population. PCOS, in its most classic sense, was first described in 1935 by Stein and Leventhal as a syndrome consisting of amenorrhea, hirsutism, and obesity in association with enlarged polycystic ovaries ( ). The “classic” features include signs of elevated androgens, such as hirsutism, and oligomenorrhea or amenorrhea and occurs in 3% to 7% of the population ; however, using a broader, now more conventional definition, it is present in as many as 15% to 20% of reproductive-age women ( ). Many of these women may go unddiagnosed because of lack of awareness on the part of a medical provider or because symptoms are relatively mild and are discounted as not being important. The diagnosis is usually made after the exclusion of other causes of irregular cycles and elevated androgens, such as enzymatic disorders (e.g., 21-hydroxylase deficiency), Cushing syndrome, or tumors.


In the United States the diagnosis does not require findings on ultrasound (US) of characteristic polycystic ovaries. This United States–based definition has been referred to as the National Institutes of Health (NIH) consensus definition because it followed an NIH conference in 1989; however, this was not a consensus conference, there was no true consensus among attendees ( ), and two other definitions have been used for PCOS.


In recognition that some women with PCOS may not have menstrual irregularity, and stressing the importance of the US findings, the “Rotterdam” criteria emerged after a European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) conference in 2004 ( ). Menstrual irregularity, symptoms or findings of hyperandrogenism, and polycystic ovaries on US are the three criteria used in the definition , but only two of these three criteria are required for the definition. Thus several phenotypes are possible, including hyperandrogenism and polycystic ovaries in ovulatory women (so-called phenotype C ) and irregular cycles and polycystic ovaries in the absence of documented hyperandrogenism ( phenotype D ). The latter is the most controversial phenotype, and it has been rejected by some investigators in the field. Phenotype A is the classic phenotype, which includes all three criteria with US findings of polycystic ovaries, and phenotype B denotes women with the NIH definition when there are no US findings. In some cases US has not been done, and in others US findings were considered to be normal.


Because hyperandrogenism is deemed to be an important feature of PCOS, the Androgen Excess and Polycystic Ovary Syndrome (AEPCOS) Society has offered a third definition of PCOS, which stresses hyperandrogenism as a key feature and then recognizes that women with PCOS can have polycystic ovaries on US or menstrual irregularity (anovulation) ( ).


A workshop at NIH in December 2012 attempted to draw a consensus among the various definitions. It was concluded among independent panelists that the Rotterdam criteria should be adopted for convention and familiarity (it is the most commonly used definition worldwide) but that it is not ideal and investigators should strive to find a more appropriate name for the disorder ( ). Table 39.1 lists the four definitions with various phenotypes. More recently there was an international workshop for the diagnosis and management of PCOS ( ) and indeed the Rotterdam criteria have now been universally accepted.



TABLE 39.1

Criteria for Diagnosis of Polycystic Ovary Syndrome


















Study * Criteria
National Institute of Child Health and Human Development 1990 Menstrual irregularity
Hyperandrogenism (clinical or biochemical)
ESHRE-ASRM 2003 Rotterdam criteria Menstrual irregularity
Hyperandrogenism (clinical or biochemical)
Polycystic ovaries on ultrasound (two of three required)
AEPCOS Society 2006 Hyperandrogenism (clinical or biochemical) and menstrual irregularity
Polycystic ovaries on ultrasound (either or both of the latter two)
NIH Workshop 2012 Endorsement of Rotterdam criteria, acknowledging its limitations, and suggesting the name PCOS should be changed

AEPCOS , Androgen Excess and PCOS; ASRM , American Society for Reproductive Medicine; ESHRE , European Society of Human Reproduction and Embryology; NIH , National Institutes of Health; PCOS , polycystic ovary syndrome.

* All required the exclusion of other underlying hormonal disorders or tumors.



Clearly the diagnosis of PCOS is made on a clinical basis, and laboratory measurements can be supportive but are not necessary. For example, elevated luteinizing hormone (LH) levels are not a requirement, nor are elevated levels of testosterone or dehydroepiandrosterone sulfate (DHEAS), as long as there are clinical signs of hyperandrogenism such as hirsutism. Acne is much more variable as a complaint, and half the cases of acne are not caused by elevated androgens. Alopecia also is not a reliable manifestation of hyperandrogenism and could have a purely dermatologic cause. Laboratory assays for testosterone and free testosterone have been too insensitive, at least in the past, to be able to discriminate between slightly elevated levels and normal values; thus a normal testosterone level does not exclude the hyperandrogenism criterion for the definition of PCOS as long as hirsutism is present. We now realize that we have not been measuring many of the important androgens in women with PCOS. A class of 11-oxygenated androgens, largely of adrenal origin, are extremely potent and make up more than 50% of circulating androgens but have not been measured until recently by more sophisticated analyses ( ).


Ovarian morphology


Another clinical variable is that of the US feature of polycystic ovaries. The classic definition required 12 or more peripherally oriented cystic structures (2 to 9 mm) in one sonographic plane, and typically the finding in one ovary is sufficient. Figs. 39.1 and 39.2 depict the typical polycystic ovary as seen at surgery and by US; however, the US definition has evolved particularly with the advent of greater resolution of vaginal US and 7- to 9-mHz transducers. Findings now suggest that it is the total follicle count in each ovary that is most diagnostic ( ), and this is more important than the orientation of cystic structures in the ovary or ovarian volume, although ovarian volume is the second most valuable parameter, with a volume of 10 mL or more as being diagnostic. These criteria using follicle number per ovary (FNPO) also present a range for cutoff values. In the 2018 evidence-based guidelines on PCOS ( ) it was suggested that the FNPO should be 19 to 20, whereas our own data have suggested using 22 and that of Christ suggested an FNPO of 28 ( ). Although an antimüllerian hormone (AMH) value greater than 4.7 ng/mL has been useful as a surrogate marker of FNPO for the diagnosis of a polycystic ovary, it is not diagnostic or as valuable as US imaging, and the AMH level varies in different phenotypes, being lower in the milder phenotypes C and D.




Fig. 39.1


Surgical specimen of polycystic ovaries.



Fig. 39.2


Typical color Doppler ultrasound of a polycystic ovary showing increased blood flow.

(From Strauss JF, Barbieri RL, eds. Yen and Jaffe’s Reproductive Endocrinology. 6th ed. Philadelphia: Elsevier; 2009:822.)


It is also important to note that 10% to 25% of the normal reproductive-age population (no symptoms or signs of PCOS) may have polycystic ovaries found on US . These ovaries have been called polycystic-appearing ovaries (PAO) , polycystic ovarian morphology (PCOM), or simply PCO in the literature ( ). This isolated finding should not be confused with the diagnosis of PCOS, but it may be a risk factor for other features of PCOS (e.g., insulin resistance, cardiovascular risk factors) discussed later.


The diagnosis in adolescence


A special category in the definition of PCOS is how it should, or should not, be diagnosed in adolescents. Clearly Rotterdam criteria should not be used . This is because all the three criteria for the diagnosis are in a state of flux and change during adolescents, including the evolution and disappearance of polycystic ovaries. Accordingly PCOS should not be diagnosed unless all three criteria are firmly in place ( ) and at a minimum of 3 years postmenarche ( ). For the ovarian US criterion, because abdominal US is the mainstay, ovarian volumes of 10 mL or greater should be the criterion used; however, it is not necessary to place a label on a teenaged girl who has some findings . It should be suggested that with some features, t he teenager may be at risk and can be reassessed over time, around 8 years postmenarche ( ). A firm diagnosis does not preclude treatment. For example, the provider may prescribe oral contraceptives or progestogens for menstrual irregularity.


Menstrual irregularity


Menstrual irregularity includes oligomenorrhea (cycles longer than 35 days) and a menstrual frequency of every few months and frank amenorrhea (longer than 6 months missed). Although the majority of women with PCOS have irregular cycles, signifying problems with ovulation, patients with the ovulatory phenotype (C) reporting regular cycles occurs with variable frequencies in different populations, from 3% in Korea to 30% in Italy among women diagnosed with PCOS ( ; ). The ovulatory phenotype may have fewer metabolic and cardiovascular risks, as will be discussed later. It has been reported that menstrual irregularity is the best correlate of insulin resistance in women with PCOS ( ; ). Additionally, although the subfertility of women with PCOS is predominantly caused by problems of anovulation, many women with PCOS with ovulatory function will present with subfertility as well.


Androgen excess or hyperandrogenism


Often considered the cardinal feature of women with PCOS, androgen excess may be difficult to diagnose . As discussed in Chapter 38 , production of androgens in excess may emanate from the ovary, the adrenal gland, or the periphery. Although symptoms of androgen excess, particularly of hirsutism, are sufficient for the inclusion of this parameter in the diagnosis of PCOS, blood measurements of testosterone may not always be accurate and often are normal in women with symptoms.


The androgen excess has been implicated in contributing to abnormalities in LH secretion, weight gain and adipose deposition, and the metabolic derangements of PCOS, discussed later. As discussed in Chapter 38 , evidence suggests that 11-oxygenated androgens, derived principally from the adrenal, are quantitatively the most abundant androgens in women with PCOS and may explain many of the symptoms and derangements in metabolism. Adipose tissues also secrete androgen, and this intraadipose androgen source seems to contribute to lipid abnormalities and insulin resistance in women with PCOS ( ).


Characteristic endocrine findings in polycystic ovary syndrome


Characteristic endocrinologic features include abnormal gonadotropin secretion caused by increased gonadotropin-releasing hormone (GnRH) pulse amplitude or increased pituitary sensitivity to GnRH . These abnormalities result in tonically elevated LH levels in approximately two-thirds of the women with this syndrome ( Fig. 39.3 ). After a bolus of GnRH, there is usually an exaggerated response of LH but not of follicle-stimulating hormone (FSH; see Fig. 39.3 ). Because of issues of metabolic clearance, typically the women with PCOS who are more obese will be found to have normal LH levels, whereas women with PCOS who are thin often have elevated levels. The high tonic levels of LH, often referred to as “inappropriate gonadotropin secretion,” are due to elevated androgen and unbound estradiol or hypothalamic/pituitary functional abnormalities related to neurotransmitters such as dopamine.




Fig. 39.3


Comparison of quantitative luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to a single bolus of 150 μg of gonadotropin-releasing hormone (GnRH) in patients with polycystic ovarian syndrome (PCO) and in normal women during low-estrogen (early follicular) and high-estrogen (late follicular) phases of their cycles.

(From Rebar R, Judd HL, Yen SSC, et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome . J Clin Invest. 1976;57(5):1320-1329.)


Because FSH levels in women with PCOS are normal or low, an elevated LH/FSH ratio has been used to diagnose PCOS; however, only 70% of women with a clinical diagnosis of PCOS have an elevated level of immunoreactive LH or an immunologic LH/FSH ratio greater than 3, although almost all women with PCOS had elevated serum levels of biologically active LH ( ) ( Fig. 39.4 ). An elevated LH level or an elevated LH/FSH ratio is neither specific for nor required for the diagnosis of PCOS. These measurements should not be used as diagnostic tools.




Fig. 39.4


Serum measurements of immunoreactive luteinizing hormone (LH), immunoreactive LH–to–follicle-stimulating hormone (FSH) ratios, and bioactive LH in control subjects (C), women with chronic anovulation (CA), and women with polycystic ovary syndrome (PCO). Boxes represent the mean ± 3 standard deviation of control levels.

(From Lobo RA, Kletzky OA, Campeau JD, et al. Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome. Fertil Steril. 1983;39(5):674-678.)


In addition to increased levels of circulatory androgens, women with PCOS have increased levels of biologically active (non–sex hormone-binding globulin [SHBG]–bound) estradiol, although total circulating levels of estradiol are not increased ( Fig. 39.5 ). The increased amount of non–SHBG-bound estradiol is caused by a decrease in SHBG levels, which is brought about by the increased levels of androgens and obesity, with high insulin levels present in many of these women. Estrone is also increased because of increased peripheral (adipose) conversion of androgen. The tonically increased levels of biologically active estradiol may stimulate increased GnRH pulsatility and produce tonically elevated LH levels and anovulation. In addition, the lowered SHBG level increases the biologically active fractions of androgens in the circulation. This relative hyperestrogenism (elevated levels of estrone and non–SHBG-bound estradiol), which is often unopposed by progesterone because of anovulation, increases the risk of endometrial hyperplasia. The risk of hyperplasia or endometrial cancer is enhanced further in some women with PCOS who seem to have progesterone resistance ( ), meaning that progesterone does not work as well in downregulating the actions of estrogen on the endometrium.




Fig. 39.5


Serum estrogen concentrations in 13 patients without polycystic ovary syndrome (PCOS) and 22 patients with PCOS (shaded areas).

(From Lobo RA, Granger L, Goebelsmann U, et al. Elevation in unbound serum estradiol as a possible mechanism for inappropriate gonadotropin secretion in women with PCOS. J Clin Endocrinol Metab. 1981;52(1):156-158.)


Androgens from a variety of sources are elevated in women with PCOS ( Fig. 39.6 ). Serum testosterone levels usually range from 0.55 to 1.2 ng/mL, and androstenedione levels are usually from 3 to 5 ng/mL. In addition, approximately 50% of women with this syndrome have elevated levels of DHEAS, suggesting adrenal androgen involvement. Note the data reviewed earlier and in Chapter 38 on the abundant 11-oxygenated androgens, which are not measured clinically at the present time. Although almost all women with PCOS have elevated levels of circulating androgens, the presence or absence of hirsutism depends on whether those androgens are converted peripherally by 5-alpha-reductase to the more potent androgen dihydrotestosterone (DHT), as reflected by increased circulating levels of 3-alpha-androstanediol glucuronide (3α-diol-G) (see Chapter 38 ). Women with PCOS who are not hirsute have elevated circulatory levels of testosterone, DHEAS, or both, but not 3α-diol-G ( ).




Fig. 39.6


Basal levels of various androgens in hyperandrogenic women with polycystic ovary syndrome versus matched controls. All androgens, including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (A), total testosterone (tT), and unbound testosterone (uT), are significantly elevated.


Approximately 20% to 30% of women with PCOS also have mildly elevated levels of prolactin (20 to 35 ng/mL), possibly related to the increased pulsatility of GnRH, as a result of a relative dopamine deficiency or tonic stimulation from unopposed estrogen. In this setting, if the diagnosis of PCOS is clear, these mild elevations in prolactin level only should be followed.


Insulin resistance


It is well established that some degree of insulin resistance (IR) occurs in most women with PCOS, even in those of normal weight. Insulin and insulin-like growth factor 1 (IGF-1) enhance ovarian androgen production by potentiating the stimulatory action of LH on ovarian androstenedione and testosterone secretion. High levels of insulin bind to the receptor for IGF-1 because of the significant homology of the IGF-1 receptor with the insulin receptor. The granulosa cells also produce IGF-1 and IGF-binding proteins (IGFBPs). This local production of IGF-1 and IGFBP may result in paracrine control and enhancement of LH stimulation and production of androgens by the theca cells in women with PCOS. Because IGFBP levels are lower in women with PCOS, there is increased bioavailable IGF-1, which increases stimulation of the theca cells in combination with LH to produce higher levels of androgen production. In addition, elevated insulin levels (as well as androgen) stimulate adipocyte production of adipokines (adipocytokines), which interfere with the metabolism and breakdown of adipose tissue and further enhance IR ( Fig. 39.7 ). IR in PCOS is primarily characterized by an insulin resistance in peripheral tissues, manifest primarily in muscle and adipose and minimally at the level of ovary or adrenal ( ). Fig. 39.8 reflects these events with the less efficient serine phosphorylation (rather than tyrosine phosphorylation) resulting in less efficient insulin action (metabolic effect) but with no effects on the production of androgens (intact mitogenic effect) ( ).




Fig. 39.7


Diagrammatic depiction of the relationship among androgens, insulin, and body fat (release of adipokines). IL-6, Interleukin 6; TNF α, tumor necrosis factor alpha.

(From Escobar-Morreale HF, San Milan JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab. 2007;18(7):266-272.)



Fig. 39.8


Mechanism of insulin resistance (IR) in women with polycystic ovary syndrome. At specific sites, IR is due to serine (Ser) phosphorylation affecting metabolic, but not mitogenic, actions of insulin. PCOS, polycystic ovary syndrome; Tyr, tyrosine.

(From Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab. 2003;14(8):365-370.)


As part of this feedback loop as noted in Fig. 39.7 , in addition to adipokines produced by adipose tissues, which enhance IR (see Fig. 39.8 ), we now know that androgen produced directly in adipose enhances this effect as well, intensifying the interaction ( ).


The proximate cause of IR in PCOS is unknown ; it is not caused by insulin receptor defects but by signaling abnormalities as noted previously. It is likely that genetic factors contribute to these findings. Most women with PCOS will be found to have euglycemia with peripheral IR; in more severe cases, there is also evidence of beta cell (secretory) dysfunction, which increases the risk of type 2 diabetes. In a prospective evaluation of 254 women with PCOS who had an oral glucose tolerance test, it was found that 31% had impaired glucose tolerance and 7.5% had undiagnosed diabetes. In nonobese women with PCOS, 10% had impaired glucose tolerance and 1.5% had diabetes ( ). Norman and coworkers have shown that over a mean follow-up period of 6.2 years, 9% of women with PCOS in Australia progressed to having impaired glucose tolerance and 8% developed diabetes ( ). Thus the negative effects of obesity and PCOS on insulin resistance are additive. Although clinicians may assume most women with PCOS have some degree of IR, particularly those who are older and who are overweight or obese, it is recommended that testing should be directed at ruling out diabetes and glucose intolerance, rather than diagnosing IR ( ).


Fasting glucose levels are a poor predictor of diabetes in PCOS. A convenient way to assess glucose status is the measurement of the level of hemoglobin A1C. Values greater than 5.8% suggest prediabetes, and values greater than 6% suggest frank diabetes;, but there is still disagreement about the use of A1c as a screening test, and many still advocate performing an oral glucose tolerance test ( ).


Various techniques have been used to diagnose IR in women with PCOS, although it can be argued that women who are overweight or obese with PCOS have IR, and it is not necessary to confirm it. The methods include fairly complicated but more accurate measures used only in a research setting, such as the clamp test, intravenous frequent sampling glucose tolerance test, or insulin tolerance test. Using fasting glucose and insulin measurements and calculating the quantitative insulin sensitivity check index (QUICKI) or homeostasis model assessment of insulin resistance (HOMA-IR) have been useful and correlate well with the more invasive techniques ( Table 39.2 ); however, as stated earlier, it may not be necessary to compute these parameters and clinicians should assume that women who are overweight or obese with PCOS are insulin resistant and an oral glucose tolerance test should be carried out to rule out impaired glucose tolerance or diabetes, which cannot be assumed or discounted. If fasting blood is obtained to detect IR, HOMA or QUICKI are the most valuable parameters ( Fig. 39.9 ) ( ).



TABLE 39.2

Measurements of Insulin Sensitivity



























Test Measurement Normal Value *
Hyperinsulinemic clamp M/1 (mean glucose use/mean plasma insulin concentration) >1.12 × 10 –4
Homeostasis model assessment of insulin resistance (HOMA-IR) (Fasting insulin [μU/mL] × fasting glucose [mmol/L])/ 22.5 <2.77
Glucose-to-insulin ratio Fasting glucose (mg/dL)/fasting insulin (μU/mL) >4.5
Quantitative insulin sensitivity check index (QUICKI) 1/(log fasting insulin [μU/mL] + log + fasting glucose mg/dL]) >0.357
Fasting insulin Assay dependent

* Normal values may vary depending on the insulin assay used.




Fig. 39.9


Percentage of 129 women with obesity and polycystic ovary syndrome (PCOS) with insulin resistance (IR) based on fasting basal insulin (white), glucose/insulin (G/I) ratio (red), homeostasis model assessment of insulin resistance (HOMA) (yellow), or quantitative insulin sensitivity check index (QUICKI) (light blue). * P < .01 compared with G/I ratio.

(From Carmina E, Lobo RA. The use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2004;82(3):661-665.)


Acanthosis nigricans (AN) has been found in approximately 30% of hyperandrogenic women, and it is present in at least 50% of women with PCOS who are hyperandrogenic and obese . This velvety hyperpigmentation is usually found in the nape of the neck, axilla, and vulva regions and is often found if inspected for. The h yper a ndrogenism, IR, and AN (the HAIR-AN syndrome) is a specific disorder associated with insulin receptor antibodies, and presents with very high insulin levels and severe IR. It is distinct from the common findings of most women with PCOS. The combination of increased insulin and IGF-1 in the face of overweight or obese status enhances the development of AN.


Antimüllerian hormone in PCOS


Müllerian-inhibiting substance (MIS) or AMH is a glycoprotein produced by the granulosa cells of preantral follicles. Because of the larger number of preantral follicles in PCOS, the MIS or AMH level is significantly elevated in women with PCOS ( ). Physiologically, AMH attenuates a sensitivity of FSH in stimulating granulosa cells; the levels are higher in clomiphene-resistant women and in those who are chronically anovulatory compared with those with more regular cycles, even as they age (see Fig. 39.10 ) ( ). AMH levels have also been positively correlated with LH levels. It has been suggested that AMH is involved in the pathophysiology of anovulation in PCOS , and recent data have suggested that it may explain some of the hereditary nature of women with PCOS. These data suggest that higher levels of AMH in amniotic fluid program the fetus in utero to have higher LH and androgens and dysregulate the hypothalamic-pituitary-ovarian axis, resulting in the development of PCOS ( ).




Fig. 39.10


Elevated levels of antimüllerian hormone (AMH) in women with polycystic ovary syndrome (PCOS) decrease with time, and levels are lower in ovulatory women. Data are from a 20-year longitudinal study in women with PCOS. **, significant different from controls; [other symbol], significant difference between ovulatory and anovulatory PCOS.

(From Carmina E, Campagna AM, Mansuet P, et al. Does the level of serum antimullerian hormone predict ovulatory function in women with polycystic ovary syndrome with aging? Fertil Steril. 2012;98(4):1043-1046.)


Because AMH correlates with the number of ovarian preantral follicles, it has been suggested that AMH may be used as a blood test to substitute for US findings of a polycystic ovary. A meta-analysis and our own review suggest a cutoff value of 4.7 ng/mL ( ), with values greater than this being consistent with PCOS; however, the degree of overlap in values of AMH between PCOS and normal women precludes its routine use ( ). Our data also suggest that the milder phenotypes such as C and D have lower levels of AMH.


Pathophysiologic considerations


It is clear that there is a genetic predisposition to PCOS; however, it is likely that several genes are involved, and these are susceptibility genes that predispose the women affected to develop PCOS. A review by Kosova and Urbanek pointed out the many difficulties in finding a direct genetic linkage, which are related to the nature of the disorder, its heterogeneity, and the large sample size required to find meaningful associations ( ). There are also multiple family studies of sisters, brothers, and daughters of affected women all showing some traits associated with aspects of PCOS.


Environmental factors are clearly involved as well , based on twin studies, in which PCOS is not always concordant on a genetic basis ( ). Maternal exposure to androgen has been shown in a monkey model to contribute to the development of PCOS ( ). Note the data of Tata and colleagues reviewed earlier, where the pregnancy environment, related to AMH, may also be implicated.


Genome-wide association studies in Han Chinese and European families have pointed out certain susceptibility genes with some consistency. These include loci at 2p16.3, 2p21, and 9q 33.3, involving the LH/human chorionic gonadotropin (HCG) receptor, a thyroid adenoma locus, and DENND1A, potentially affecting function of the endoplasmic reticulum ( ). This was confirmed in subsequent studies with the addition of other potential loci ( ; ) ( Fig. 39.11 ). The 2p16.3 locus was confirmed in a U.S. study ( ). It has been long established that a vicious cycle propagates the disorder in PCOS, regardless of how it begins ( ) ( Fig. 39.12 ). Thus it was attractive to postulate that dopamine deficiency in the hypothalamus might give rise to the exaggerated LH responses in PCOS, and there are several similar hypotheses, although it has been observed that morphologically identifiable polycystic ovaries are seen in children ( ); however, in the adolescent, ovarian morphology has been shown to be variable and can change from being polycystic to normal and vice-versa. This occurrence predicts puberty and other normal endocrinologic events, suggesting a central role for altered PCOM in the disorder.




Fig. 39.11


Genome-wide association studies in 8226 women with polycystic ovary syndrome (PCOS) diagnosed by Rotterdam criteria and 7578 controls, with several loci identified for susceptibility genes of interest.

(From Shi Y, Zhao H, Shi Y, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44(9):1020-1027.)



Fig. 39.12


Pathophysiologic concept of polycystic ovary syndrome (PCOS). Increased luteinizing hormone (LH) secretion, together with enhanced theca cell responsiveness, drives the production of excess ovarian androgen. Increased androgen production may inhibit steroid negative feedback effects on hypothalamic gonadotropin-releasing hormone pulse generation to account for the rapid LH pulse frequency observed in women with PCOS. In addition, increased androgen levels are associated with android obesity, visceral fat deposition, and dyslipidemia, all of which may contribute to insulin resistance. Independently, hyperandrogenemia, obesity, and hyperinsulinemia may decrease sex hormone–binding globulin, thereby increasing bioactive testosterone. Finally, increased androgen may have direct effects on the ovary to increase follicle number and follicle size and possibly enhance granulosa cell responsiveness to follicle-stimulating hormone (FSH). E 2 , Estradiol.

(From Strauss JF, Barbieri RL, eds. Yen and Jaffe’s Reproductive Endocrinology. 6th ed. Philadelphia: WB Saunders; 2009:509.)


Furthermore, not all women with isolated polycystic ovaries have PCOS, as stated earlier. Thus a pathophysiologic model can be put together as follows. An ovary is polycystic in up to 20% of girls, according to data from Bridges and colleagues. Thus the ovary transitions early in life from normal to polycystic appearing (PAO). This influence occurs in a specific way by genetic factors or environmental factors, or it is induced by other endocrine disturbances ( ) ( Fig. 39.13 ). The woman who develops PAO may have normal menses, normal androgen levels, and normal ovulatory function and parity; however, if subjected to various susceptibility factors (likely genetic) or environmental or other challenges or insults, with varying degrees of severity, women with PAO may develop a full-blown syndrome (PCOS) (see Fig. 39.13 ). The syndrome, if full-blown, exhibits the full extent of hyperandrogenism and anovulation, with the most extreme form of this menstrual disturbance being amenorrhea (the type A or B phenotype according to Rotterdam criteria); however, in this spectrum of disorders, the androgen disturbances may also be near normal. Similarly, the menstrual disturbance may be mild.




Fig. 39.13


Pathophysiology of polycystic ovary syndrome (PCOS) showing differences in presentation. PAO, Polycystic-appearing ovaries.


This model requires that normal homeostatic factors may be able to ward off stressors or insults in some women who can go through life without PCOS but have PAO, which does not change morphologically. Alternatively, with varying degrees of success, a woman’s homeostatic mechanisms may at any time, early or later in reproductive life, allow symptoms of PCOS to emerge with varying degrees of severity. Two of the major insults are thought to be weight gain and psychological stress. Therefore the typical teenager born with PAO may develop PCOS fairly quickly, but a PCOS picture may only develop later in life in some women, even after having children, with weight gain, for example.


Consequences of polycystic ovary syndrome


The importance of diagnosing PCOS is that there are known long-term consequences of the diagnosis warranting lifelong surveillance. These include metabolic and cardiovascular risks as well as the risk of certain cancers with aging.


There have been several consensus meetings for the diagnosis and treatment of PCOS, as mentioned earlier. The first two dealt with the diagnosis of PCOS ( ) and the treatment of infertility ( ). The third and most recent of these was held in Amsterdam and addressed the long-term consequences of PCOS ( ). Fig. 39.14 depicts the shift in emphasis with aging, requiring a multidisciplinary approach. With aging, concerns for cardiovascular disease, including hypertension, metabolic syndrome, diabetes, and cancer (endometrial and ovarian), become more prominent.




Fig. 39.14


Schematic representation of the change in emphasis from early-age reproductive disorders to long-term metabolic and cardiovascular health. PCOS, Polycystic ovary syndrome.

(From Fauser B, Tarlatzis B, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28-38.e25.)


Weight gain/obesity and metabolic syndrome


Weight gain as women age is a major predictor of abnormal metabolic findings and the emergence of cardiovascular (CV) disease risks; indeed all the symptoms of PCOS are worse with increasing body weight. The prevalence of obesity varies widely in different countries. It is lowest in countries such as China and Japan (<10%) and highest in the United States and some other Western countries (∼70%). There is increased abdominal and visceral fat in women with PCOS, and this has been correlated to IR and metabolic dysfunction ( ). Therefore lifestyle management has to be a priority for women with PCOS and must be maintained lifelong.


Metabolic syndrome, which is largely driven by obesity and leads to diabetes and CV disease (CVD), has a prevalence during the reproductive years. The prevalence of metabolic syndrome in the United States is approximately 60% in young (20 to 39 years) obese women with PCOS ( ). The diagnosis is made using Adult Treatment Panel III criteria (three of five of the following: waist circumference >88 cm, high-density lipoprotein <50 mg/dL, triglycerides >150 mg/dL; blood pressure >130/85 mm Hg, fasting blood sugar >110 mg/dL). In other countries in which obesity is less prevalent, the prevalence of metabolic syndrome in PCOS is still increased but is much lower (5% to 9%) ( ). The constellation of risk factors that make up metabolic syndrome place women with PCOS at increased risk for CVD and diabetes , but there is nothing specific of more significance regarding metabolic syndrome in PCOS.


Diabetes


Type 2 diabetes mellitus is more prevalent (two to three times higher) in women with PCOS of reproductive age ( ). This is driven by IR, which in turn is worsened by overweight status and menstrual irregularity. In prospective follow-up studies, there is a high conversion rate in women with PCOS from euglycemia toward impaired glucose tolerance, and in women followed for 6 years who had impaired glucose tolerance the conversion rate to frank diabetes was 54% ( ). Thus it is extremely important to screen for diabetes in the overweight population with PCOS; it has been suggested that this is best done with an oral glucose tolerance test ( ). Lack of precision in the screening for diabetes with hemoglobin A1c measurements has precluded the recommendation of using hemoglobin A1c as a screening tool, although it has proven to be useful in the follow-up of women as they are being treated. Diet and exercise remain the mainstays of treatment , and metformin has a significant role to play. In at-risk women and those with glucose intolerance and prediabetes, metformin is often used with doses of 1500 mg/day. Doses are often higher in the presence of diabetes.


Quality-of-life issues


Although the data are not completely consistent, it is generally stated that there is poor quality of life among women with PCOS. This is most likely related to their burden of being overweight, having irregular cycles and decreased fertility, and having skin concerns such as acne and hirsutism, although not all women have the same number or degree of these symptoms. Depression is a factor, which may play a major role in women with PCOS seeking care and being compliant with diet, lifestyle, and various treatments . In a meta-analysis, Dokras found a fourfold increase in the prevalence of depression among women with PCOS ( ). Another meta-analysis showed that in addition to depression, anxiety disorder is also prevalent, with a two- to threefold increase ( ). A strong argument has been made for screening women with PCOS for anxiety and depression. It has also been found that interventions, such as weight loss, are able to improve quality of life ( ).


Cardiovascular concerns


Women with PCOS have characteristic lipid and lipoprotein abnormalities ( ) ( Fig. 39.15 ). These older data have been replicated many times, and abnormal lipoprotein particles are also present, which adds to a long list of abnormalities that tend to increase CV risk. Table 39.3 depicts several CV risk factors, including the development of hypertension and diabetes as women approach menopause. Fig. 39.16 depicts data that have been generated from retrospective observations, and although it is yet not definitively established that these risks pertain to all women with PCOS, it provides evidence suggesting concern ( ). It is unlikely that these risks occur in women with “milder” phenotypes. Data have largely been obtained from women with more classic features of PCOS, particularly in conjunction with presence of obesity. There is evidence that women with the milder phenotypes diagnosed using the Rotterdam criteria have fewer CV risk factors. Fig. 39.17 depicts a hypothetical scheme for increasing CV risk in women with PCOS with various phenotypes ( ).


Aug 8, 2021 | Posted by in GYNECOLOGY | Comments Off on Polycystic ovary syndrome
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