Polycystic Ovary Syndrome

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Chapter 15 Polycystic Ovary Syndrome

John K. Park, Tammy L. Loucks, Sarah L. Berga

INTRODUCTION

Polycystic ovary syndrome (PCOS) is a complex, multidimensional disorder resulting in defects in reproduction and metabolism. Although one of the primary characteristic of PCOS is the presence of multiple cysts on the ovaries, this syndrome involves far more than the ovary. The complexity of the syndrome is reflected in the wide range of its clinical manifestations, most notably insulin resistance, obesity, irregular menses, and signs of hyperandrogenism, such as hirsutism and acne.

In 1935, Stein and Leventhal described patients who had a constellation of amenorrhea, infertility, and enlarged, polycystic ovaries.¹ They found that bilateral ovarian wedge resection resulted in regular menses and even pregnancy in some. They reasoned that the thickened tunica was preventing follicles from reaching the surface of the ovary, resulting in the classic appearance of an enlarged ovary with multiple follicles beneath the cortex. Today we know that the mere finding of a polycystic-appearing ovary is not pathognomonic of PCOS, because many females without the disorder will have similar ovarian morphology.^2,³

DIAGNOSTIC CRITERIA

In 1990, a conference on PCOS sponsored by the National Institutes of Health (NIH) led to diagnostic criteria based on a majority opinion of conference participants.⁴ The criteria included: hyperandrogenism and/or hyperandrogenemia, chronic anovulation, and exclusion of other known disorders. In 2003, the European Society of Human Reproduction and Embryology (ESHRE)/American Society of Reproductive Medicine (ASRM)-sponsored PCOS consensus workshop in Rotterdam revised the diagnostic criteria for PCOS.⁵ The revised criteria state that PCOS remains a diagnosis of exclusion, but that two out of the following three criteria must be present: (1) oligo-ovulation or anovulation, (2) hyperandrogenism and/or hyperandrogenemia, and (3) polycystic ovaries.

The differential diagnosis should include other causes of hyperandrogenism and menstrual dysfunction, such as nonclassic congenital adrenal hyperplasia, hypothalamic amenorrhea, Cushing’s syndrome and disease, hyperprolactinemia, thyroid disease, acromegaly, and androgen-secreting neoplasms of the ovary or adrenal gland.

PREVALENCE

The prevalence of PCOS is estimated to be 4% to 12% of reproductive-age women. The largest U.S. study on PCOS prevalence was published in 1998.⁶ Out of 277 women included in the study, 4.0% had PCOS as defined by the 1990 NIH criteria. The prevalence was 4.7% for white women and 3.4% for black women. The inclusion of polycystic ovaries in the 2003 Rotterdam criteria calls for re-evaluation of the prevalence of PCOS, because 21% to 23% of normal women have polycystic-appearing ovaries on ultrasound.^2,³

CLINICAL PRESENTATION

Typical presenting complaints for women with PCOS involve manifestations of hyperandrogenism, menstrual irregularity, and infertility. PCOS is characterized by phenotypic heterogeneity and therefore not all parameters of the syndrome will be found in individual patients.

Hyperandrogenism

Clinical manifestations of hyperandrogenemia include hirsutism, acne, and male pattern alopecia. Hirsutism is defined as the growth of coarse, pigmented hairs in androgen-dependent areas such as the face, chest, back, and lower abdomen. Approximately 80% of hirsute patients will have PCOS.⁷ The modified Ferriman-Gallway scoring system can be used for clinical assessment of hirsutism. This was originally used in the United Kingdom for a population of presumably white women, and scores hair growth in nine body areas from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth).⁸ Sex hair growth differs among various ethnic and genetic groups, being decreased in Asians, even when high androgen levels are present.⁹

Other hyperandrogenic manifestations commonly found in PCOS patients include acne and alopecia.^10,¹¹ Acne is a result of androgen stimulation of the pilosebaceous unit with increased skin oiliness.¹⁰ Cela and colleagues investigated a multiethnic group of 89 women who presented with androgenic alopecia and found that 67% had polycystic ovaries, compared to 27% of controls.¹¹ In addition, women with alopecia had higher androgen levels and a higher prevalence of hirsutism.

Obesity

Obesity is very common in PCOS, with the android pattern present in approximately 44% of women with PCOS.¹² This central obesity is more characteristic of PCOS, because these patients have an increased waist-to-hip ratio compared to obese women without PCOS.¹³ Hyperinsulinemia may stimulate central adiposity, which, in turn, exacerbates underlying or latent insulin resistance.¹⁴ It has been shown that obese women with PCOS have greater insulin resistance than weight-matched controls.¹⁵

Acanthosis Nigricans

Acanthosis nigricans is a dermatologic condition of hyperkeratosis and increased skin pigmentation with raised, symmetric, darkened, velvety plaques that commonly appear on the nape of the neck. It can also be found in the axilla, groin, and other intertriginous areas of the body. This skin finding is a common manifestation of insulin resistance in patients with PCOS. Mor and coworkers found that acanthosis nigricans is more likely to be found in PCOS patients with insulin resistance compared to PCOS patients without insulin resistance (OR = 6.0, P < 0.5).¹⁶ The elevated insulin level has a mitogenic effect on basal cells of the epidermis, making acanthosis nigricans a relatively specific clinical marker of insulin resistance.¹⁷ Other pathologic conditions associated with acanthosis nigricans include insulinoma and malignant disease, especially adenocarcinoma of the stomach.

Reproductive Aberration

Polycystic Ovarian Morphology

The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group included the polycystic morphology of the ovary as one of the diagnostic criteria for the syndrome.⁵ A polycystic ovary is defined as having 12 or more follicles in one ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume of greater than 10 mL, which is the maximum size of a normal ovary³ (Fig. 15-1).

Figure 15-1 The classic image of polycystic ovary syndrome; an enlarged ovary containing an increased number of small follicles around the periphery of the cortex, resembling a string of pearls, along with a bright echogenic stroma.

This definition should not be substituted with a subjective appearance of a polycystic ovary. The classic image is that of an enlarged ovary containing an increased number of small follicles around the periphery of the cortex (i.e., a string of pearls) with a bright echogenic stroma. The characteristic increase in stromal volume differentiates the polycystic ovary from a multifollicular ovary.³

The follicle distribution is omitted from the definition of a polycystic ovary, as well as the increase in stromal echogenicity and volume, but ovarian volume has been shown to be a good surrogate for stromal volume.²⁷ Oral contraceptives modify ovarian morphology; thus the definition of a polycystic ovary does not apply to women taking these medications. When there is a dominant follicle (>10 mm) or a corpus luteum, the ultrasound should be repeated during the early follicular phase of the next cycle.

PATHOGENESIS

Altered Gonadotropin Secretion

One of the well-described features of PCOS is an increase in LH and relative decrease in follicle stimulating hormone (FSH).²⁸ The relative decrease in FSH is the chief cause of anovulation, because increasing FSH will lead to folliculogenesis. The pulsatile secretion of LH from the pituitary is increased in amplitude and frequency in PCOS.²⁹ In addition, the pituitary has a greater LH response to gonadotropin-releasing hormone (GnRH) compared with normal women.^29,³⁰ Elevations in LH could be secondary to increased GnRH pulse frequency, stimulatory factors other than GnRH, or a combination of these effects.

The pulsatile secretion of GnRH cannot be studied in humans, so it must be inferred by detecting peripheral LH patterns. A study of PCOS women by Berga and colleagues found increased pulse frequency and amplitude for LH and α-subunit, providing evidence for aberrant increases in GnRH pulse frequency (Fig. 15-2).²⁹ Furthermore, increased GnRH pulse frequency in rats has been shown to increase LHβ gene expression.³¹ Elevated LH is not caused by altered pituitary sensitivity to GnRH; GnRH receptor blockade resulted in similar LH decreases in PCOS and normal women.³²

Figure 15-2 24-hour concentration profiles of LH (top) and α-subunit (bottom) in an eumenorrheic woman (EW)(left), studied in the follicular phase (day 2) and in a woman with hyperandrogenic anovulation/polycystic ovary syndrome (PCOS, right).

(Data from Berga S, Guzick D, Winters S: Increased luteinizing hormone and α-subunit secretion in women with hyperandrogenic anovulation. J Clin Endocrinol Metab 77:895–901, 1993.)

These findings suggest a derangement of the hypothalamic-pituitary axis, which appears to play a major role; many of the cardinal features of PCOS can be traced to alterations in gonadotropins. The basis for decreased FSH secretion in PCOS has not been determined, although the negative feedback effect of chronic unopposed estrogen secretion in these women has been implicated as a mechanism.³³

Altered GnRH Drive

Neuroanatomic Considerations

The GnRH pulse generator refers to the synchronized pulsatile secretion of GnRH from neurons that are widely distributed in the medial basal hypothalamus. GnRH is synthesized in neuronal cell bodies that have migrated during fetal life from the olfactory placode to the hypothalamus and is secreted from neuroendocrine terminals localized in the median eminence. Knobil conducted experiments with the Rhesus monkey to establish that the GnRH system exhibits rhythmic electrical behavior in the arcuate nucleus of the medial basal hypothalamus.³⁴ There was remarkable synchrony between pulses of GnRH in the portal blood and LH pulses in peripheral blood. This phenomenon was later studied in isolated human medial basal hypothalamus where GnRH pulses were found to occur at a frequency of 60 to 100 minutes.³⁵ Thus, the GnRH neurons per se, with their intrinsic pulsatile secretion, appear to constitute the GnRH pulse generator.

There is compelling evidence that non-neuronal cells, such as glial and endothelial cells, regulate GnRH secretion in the median eminence. Glial processes belonging to either astrocytes or tanycytes separate GnRH nerve endings from the pericapillary space in the median eminence and, through signaling molecules such as nitric oxide, play a role in regulation of GnRH secretion into pituitary portal blood vessels.^36,³⁷ The secretion of GnRH into the portal vasculature also appears to be regulated by dynamic remodeling of GnRH neurovascular junctions. Morphologic plasticity of the median eminence during the menstrual cycle has been demonstrated, where the maximal number of GnRH neurovasculature junctions are found during the LH surge.³⁸

In Vitro GnRH Neuroregulation

Mellon and coworkers developed a cell line of immortalized hypothalamic GnRH neurons (GT1 cells) that were determined to have an inherent ability to secrete GnRH in a pulsatile fashion.⁴⁰ The development of GnRH cell lines, such as the GT1 cells, has permitted numerous studies to identify putative factors that regulate pulsatile GnRH secretion. Substances implicated in the modulation of the GnRH pulse generator include norepinephrine, dopamine, insulin-like growth factor I (IGF-I), γ-aminobutyric acid (GABA), and opioids, among others. There also appears to be an autocrine regulation of GnRH release, because GT1 cells themselves express GnRH receptors. The activation of GnRH receptors enhances action potentials, heightens synchronization of neuronal activities, and results in pulsatile release of GnRH.

In Vivo GnRH Neuroregulation in PCOS

The GnRH pulse generator in PCOS patients is intrinsically faster, and the frequency is less likely to be suppressed with continuous estrogen and progesterone treatment.⁴⁰ A persistently rapid GnRH pulse generator would increase LH secretion and could suppress FSH levels low enough to prevent folliculogenesis.

Increased central adrenergic tone has been implicated as a cause of the aberrations of GnRH and gonadotropin secretion in PCOS. One possible mechanism is the increase in local blood flow and permeability of the portal vascular system, permitting the entry of increased amounts of GnRH.⁴¹ Dopamine injection into the third ventricle led to a rapid increase in GnRH and prolactin inhibitory factor in portal blood, suggesting dopamine-mediated regulation of GnRH and prolactin inhibitory factor.⁴² The identification of β₁-adrenergic and D1-dopaminergic receptors on GT1 GnRH neurons provides a mechanism by which norepinephrine and dopamine could regulate gonadotropin release via direct synapses on GnRH neurons.⁴³

Other studies have examined the effect of dopamine on immunoreactive LH. Dopamine exerts an inhibitory effect on LH secretion in normally cycling women ⁴⁴ and also has been shown to lower circulating LH in PCOS patients.⁴⁵ It has been suggested that an impairment of the dopaminergic inhibitory activity on LH secretion leads to the increased frequency of LH pulses seen in PCOS women.⁴⁶ In fact, the dopamine agonist bromocriptine has been shown to lower circulating LH and improve menstrual function in normoprolactinemic PCOS women.⁴⁷ This finding has not been consistently demonstrated, as Lobo and coworkers did not find an increase in the ratio of bioactive to immunoreactive LH in response to dopamine alone or a dopamine-carbidopa combination, and concluded that dopamine did not play a critical role in LH secretion.⁴⁸

The role of IGF-I in modulation of GnRH cells has also been investigated. IGF-I regulates growth, differentiation, survival, and reproductive function. The IGF receptor is a tyrosine kinase receptor located in the periphery and central nervous system, including the median eminence.⁴⁹ Mouse studies have shown that IGF-I mRNA in the hypothalamus increases through peripubertal and adult development.⁵⁰ IGF-I was found to stimulate GnRH gene expression in postnatal and peripubertal mice.⁵⁰ Another study using the GT1 cell line demonstrated that IGF-I treatment caused a significant increase in GnRH nuclear primary transcript levels and cytoplasmic mRNA.⁵¹ In PCOS women, an increased ratio of IGF-I to IGF binding proteins correlated significantly with increased concentrations of circulating LH.³⁰ These findings suggest that IGF-I can modulate GnRH neurons by inducing gene expression, resulting in more circulating LH.

Other substances found to affect GnRH and LH secretion include GABA and opioids. GABA may tonically inhibit LH secretion, as evidenced by an increase in LH secondary to a GABA-A receptor blocking drug, bicuculline.⁵² Naloxone is an opioid antagonist that has been shown to increase luteal phase LH, suggesting that opiates have an inhibitory effect on pituitary gonadotropins.⁵³

Hyperandrogenemia

Circulating androgens are elevated in PCOS, with contributions from the ovary and adrenal glands. The elevated androgens can only be partially suppressed with combination oral contraceptive therapy. Daniels and Berga treated PCOS women with 3 weeks of combination oral contraceptives and found that androstenedione levels remained significantly higher compared to treated controls.⁴⁰ Pulse frequency of LH was suppressed in both PCOS women and controls, but the frequency remained significantly higher in PCOS patients (Fig. 15-3). This suggests reduced sensitivity of the GnRH pulse generator to suppression by sex steroids. The authors also suggest that the GnRH drive in PCOS women may be intrinsically and irreversibly faster than in eumenorrheic women. GnRH output may be affected by peripheral androgens. Androgen blockade restores hypothalamic sensitivity to feedback inhibition by ovarian steroids.⁵⁴ Administration of estrogen and progesterone to PCOS women and controls pretreated with the anti-androgen flutamide demonstrated similar reductions in LH pulse frequency.

Figure 15-3 Representative 12-hour pulse patterns in two women with polycystic ovary syndrome/hyperandrogenic anovulation are shown on the right side and those from eumenorrheic women on the left. ON means subjects were studied on day 21 of a combination oral contraceptive containing 35 μg of ethinyl estradiol and 1 mg of norethindrone. OFF refers to day 7 after cessation of the combination oral contraceptive.

(Data from Daniels T, Berga S: Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab 82:4179–4183, 1997.)

Theca Cell Function

Ovarian hyperandrogenism is driven by LH acting on theca cells, and the effect is amplified by the increased sensitivity of PCOS theca cells to LH.⁵⁵ Hyperandrogenism may also result from dysregulation of the androgen-producing enzyme P450c17, which has 17α-hydroxylase and 17,20-lyase activity. The dysregulation appears to be an intrinsic abnormality of P450c17, but autocrine/paracrine factors may also be involved.⁵⁶

Insulin and IGF have also been shown to play a role in ovarian androgen production. Receptors for insulin, IGF-I, and IGF-II have been localized to the theca compartment of ovaries from normal and PCOS patients.^57,⁵⁸ When given IGF-I, IGF-II, and insulin, thecal cell cultures from euandrogenic women produced increased androgens, and the effect was potentiated when LH was added.^57,⁵⁹ Ovarian stroma from hyperandrogenic patients also released more androstenedione and testosterone in response to insulin, however, no synergy was found between insulin and LH.⁶⁰

In contrast, in vivo studies do not find significant increases in androgen secretion in PCOS or normal women despite considerable increases in insulin levels. Dunaif and Graf studied PCOS and normal patients undergoing evaluation with the hyperinsulinemic euglycemic clamp, and found that insulin decreased androgens in PCOS women and did not increase androgens in normal women.¹³ This argues against a simple causal relationship between hyperinsulinemia and hyperandrogenism, but a role for insulin is strongly suggested by the observation that reduction of hyperinsulinemia is associated with decreases in serum androgens. Treatment of PCOS patients with metformin, which reduces hepatic glucose production and secondarily lowers insulin, has been shown to decrease levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione.⁶¹

Adrenal Function

Excess adrenal androgen production is seen in PCOS women, with a 48% to 64% increase in DHEAS and 11β-hydroxyandrostenedione.⁹ The underlying cause of elevated adrenal androgens is yet to be elucidated, but PCOS women do not have increased corticotropin levels.⁶² Increased adrenal androgen production in PCOS is likely caused by either altered adrenal responsiveness to corticotropin or abnormal adrenal stimulation by factors other than corticotropin. A recent study by Moran and colleagues found that adrenal androgen excess in PCOS is associated with a greater 17α-hydroxylase activity in response to corticotropin.⁶³ The cytochrome P450c17 (CYP17) gene regulates 17α-hydroxylase and 17,20-lyase activity. A defect in the P450c17 enzyme or in the regulation by autocrine/paracrine factors appears to be involved.⁵⁶

Hyperinsulinemia may also play a role in adrenal androgen production in PCOS. PCOS patients treated with troglitazone experienced improvement in insulin resistance with a concomitant decrease in DHEAS levels, regardless of initial DHEAS levels.⁶⁴ Obese PCOS women treated with pioglitazone had significant improvement in insulin sensitivity with a decrease in corticotropin-stimulated androstenedione levels.⁶⁵ These data support the notion that insulin enhances corticotropin-stimulated steroidogenesis.

Anovulation

The cause of anovulation in PCOS patients has yet to be clarified. However, several observations about granulosa function have been described that may give insight into this process.

Granulosa Cell Function

FSH levels are characteristically low in PCOS women, resulting in arrested follicular development. Insufficient granulosa cell aromatase activity was the basis of earlier studies that tried to explain poor follicular development, because follicular fluid estradiol concentrations were thought to be low. To the contrary, more recent studies found that PCOS granulosa cells are hyperresponsive to FSH in vitro, and estradiol concentrations from PCOS follicles and normal follicles are no different.⁶⁶ A dose–response study in PCOS women demonstrated a significantly greater capacity for estradiol production in response to recombinant human FSH compared with normal women.⁶⁷ The incremental response of serum estradiol was almost two times greater and considerably accelerated compared with that found in normal women.

Van Der Meer and coworkers demonstrated that the accelerated estradiol production may simply be explained by the increased number of follicles.⁶⁸ Another study of granulosa cells from polycystic ovaries discovered that there are more FSH receptors compared with cells from normal ovaries.⁶⁹ Whether the increased estradiol responsiveness to FSH is due to increased number of follicles, increased granulosa cell sensitivity to FSH, or increased FSH receptor binding, women with PCOS appear to be susceptible to ovarian hyperstimulation in response to gonadotropins.

Insulin has been investigated as a modulator of both theca and granulosa cell function. As noted earlier, insulin has been shown to augment the effect of LH on thecal cell androgen secretion. The effects of insulin on granulosa cells are less well known. In vitro studies have shown that insulin augments two actions of FSH on granulosa cells: basal production of estrogen and progesterone and induction of LH responsiveness.^70,⁷¹ The latter effect results in further enhanced LH-stimulated steroid production of estradiol and progesterone. Willis and Franks showed that the effects of insulin were apparent at low concentrations, underscoring the fact that insulin acts via its own receptor and suggesting that the ovary is not insulin resistant.⁷² The premature responsiveness of granulosa cells to LH may lead to untimely differentiation of granulosa cells, resulting in premature arrest of follicular growth. This might explain the presence of the many 5- to 10-mm follicles commonly observed in PCOS ovaries containing steroidogenically active granulosa cells that do not progress spontaneously to the preovulatory stage.

Insulin Resistance

Although 50% to 70% of PCOS patients have insulin resistance,⁷³ it is not one of the diagnostic criteria for PCOS. The topic deservedly receives much attention because many of the clinical signs and symptoms of PCOS may be attributed to excess insulin exposure. The precise molecular basis for insulin resistance is unknown, but it appears to be a postreceptor defect.⁷⁴ There is tissue specificity of insulin resistance in PCOS: muscle and adipose tissue are resistant; the ovaries, adrenals, liver, skin, and hair remain sensitive. The resistance to insulin in skeletal muscle and adipose tissue leads to a metabolic compromise of insulin function and glucose homeostasis, but there is preservation of the mitogenic and steroidogenic function in other tissues. The effect of hyperinsulinemia on the sensitive organs results in the downstream effects seen in PCOS, such as hirsutism,⁷ acanthosis nigricans,¹⁷ obesity,¹⁴ stimulation of androgen synthesis,⁵⁷ increase in bioavailable androgens via decreased sex hormone-binding globulin (SHBG),⁷⁵ and, potentially, modulation of LH secretion.⁶⁰

In 1992, Hales and Barker proposed the concept that the environmental influence of undernutrition in early life increased the risk of type 2 diabetes in adulthood.⁷⁶ They discovered a relationship between low birth weight and type 2 diabetes in men from England. The finding has been replicated in many different populations and ethnic groups, and the relationship has been extended to include the antecedent condition of insulin resistance.⁷⁷ In the thrifty phenotype hypothesis, malnutrition serves as a fetal and infant insult that results in a state of nutritional thrift. The adaptations result in postnatal metabolic changes that prepare the individual for survival under poor nutritional conditions. One advantageous change is the development of insulin resistance in muscle and adipose tissue, with selective protection of brain growth and activity. The adaptations become detrimental when the postnatal environment changes to one of an overabundance of nutrients, resulting in obesity and diabetes.

Recognition of insulin resistance can identify those who are most likely to respond to lifestyle and pharmacologic intervention. Insulin resistance puts patients at increased risk for certain metabolic sequelae, such as diabetes, hypertension, dyslipidemia, and cardiovascular disease.⁷⁸ Insulin resistance is a component of the World Health Organization (WHO) definition of the metabolic syndrome, which is a cluster of risk factors for cardiovascular disease.⁷⁹ The WHO defines the metabolic syndrome as the presence of glucose intolerance or insulin resistance, with at least two of the following: hypertension, dyslipidemia, obesity, and microalbuminuria. Women with PCOS are 4.4 times more likely to have the metabolic syndrome, so it becomes prudent to screen these patients, especially in those with insulin resistance.⁸⁰

LONG-TERM CONSEQUENCES OF PCOS

Metabolic Syndrome

PCOS has many hallmarks of the metabolic syndrome and should no longer be considered a purely gynecologic disorder. However, the gynecologic symptoms may be one of the earliest manifestations of the metabolic syndrome in many young women. The early presentation affords a clinician the opportunity for diagnosis, counseling, and treatment to alter the risk profile for development of the metabolic syndrome or cardiovascular disease and to forestall or ameliorate the development of classical phenotypic features that compromise self-esteem.

Numerous studies have established that there is an increased risk of diabetes and cardiovascular disease in PCOS women. One third of PCOS patients have impaired glucose tolerance, and they also have a fivefold to tenfold greater risk for type 2 diabetes mellitus, regardless of ethnicity.⁷³ By the time these patients reach menopause, they will have significantly more hypertension and diabetes compared to controls.⁸¹ Lipid abnormalities are also more prevalent in PCOS patients. There can be significant increases in total cholesterol, LDL cholesterol, and triglycerides and a decrease in HDL cholesterol compared to weight-matched controls.⁸² The dyslipidemia, impaired glucose intolerance, central obesity, hyperandrogenism, and hypertension seen in PCOS patients greatly increase the risk for cardiovascular disease. Based on this risk profile, women with PCOS have a sevenfold increased risk of myocardial infarction.⁸³

Direct evidence for the increased cardiovascular risk was shown when women in their 40s with a history of PCOS were found to have subclinical atherosclerosis detected by carotid ultrasonography.⁸⁴ PCOS women have also been found to have a higher prevalence of coronary artery and aortic calcification compared to age- and BMI-matched controls.⁸⁰ Women with PCOS also have decreased global fibrinolytic capacity, suggesting the presence of a prothrombotic state, yet another risk for cardiovascular disease.⁸⁵ Whether PCOS itself constitutes a risk factor independent of known risk factors remains to be elucidated. Despite the elevated risk of cardiovascular disease, a large retrospective study of almost 800 PCOS women in the United Kingdom did not find a markedly higher than average mortality from circulatory disease nor increased overall excess mortality.⁸⁶

Cancer

Women with PCOS have unopposed estrogen and are more likely to be obese, which leads to concerns about an increased risk for endometrial hyperplasia or malignancy. One long-term follow-up study of PCOS women in the United Kingdom found a significantly elevated risk of endometrial cancer, but no increased risk of breast cancer.⁸⁷ The elevated risk of endometrial cancer may be a consequence of more than just unopposed estrogen in these patients. Hormone analyses from endometrial cancer patients reveal a 3.6-fold and 2.8-fold increased risk of endometrial cancer among premenopausal and postmenopausal women, respectively, who have high levels of androstenedione.⁸⁸ The elevations in LH may have a role as well, because LH/hCG receptors are overexpressed in endometrial hyperplasia and carcinoma.⁸⁹ The authors concluded that the overexpression of these receptors is a feature of endometrial disease developing in younger anovulatory women, including those with PCOS. An investigation into the possible risk of postmenopausal breast cancer in PCOS women was performed using data from the Iowa Women’s Health Study. This prospective cohort study received completed questionnaires from over 41,000 women aged 55 to 69 and found no increased risk for breast cancer in women with a history of PCOS.⁹⁰

LABORATORY EVALUATION

In addition to confirming elevations of androgens, the laboratory evaluation of PCOS should have the objective of excluding other causes of hyperandrogenic anovulation. Androgen-producing tumors of the ovary and adrenal glands must be excluded. The adrenal glands contribute 98% of circulating DHEAS, whereas both the ovaries and adrenals contribute equal amounts of circulating testosterone and androstenedione. If total testosterone is greater than 200 ng/dL or DHEAS is greater than 7000 ng/dL, magnetic resonance imaging is warranted to identify the hormone-secreting lesion. Measuring 17α-hydroxyprogesterone will screen for 21-hydroxylase deficiency, the most common enzyme deficiency in nonclassic congenital adrenal hyperplasia. A 17-hydroxyprogesterone level of greater than 3 ng/mL is defined as elevated and should be followed by a corticotropin stimulation test, using 250 μg of synthetic corticotropin given intravenously after an overnight fast. A 1-hour increase in 17α-hydroxyprogesterone of more than 10 ng/mL is indicative of an enzyme defect in 21-hydroxylase.

Cushing’s syndrome is extremely rare but may masquerade as PCOS, with hyperandrogenic anovulation and obesity. Those who have additional signs of Cushing’s syndrome, such as a moon facies, buffalo hump, abdominal striae, easy bruising, and proximal myopathy, should undergo screening with a 24-hour urinary free cortisol test. A normal value should be less than 100μg. An abnormal value requires further testing with a dexamethasone suppression test. If suppression of cortisol does not occur, imaging studies should be performed to evaluate for adrenal hyperplasia, adrenal adenoma, or ectopic sources of corticotropin production.

In the workup for anovulation, prolactinoma should be excluded. It is not uncommon to detect mild elevations in prolactin levels in PCOS patients, but high levels deserve magnetic resonance imaging of the pituitary to exclude prolactinoma. Thyroid-stimulating hormone (TSH) should be evaluated to exclude hyperthyroidism or hypothyroidism. Serum LH, FSH, and estradiol levels should be obtained to exclude hypothalamic amenorrhea or premature ovarian failure. A recent study suggested the combination of LH, FSH, and androstenedione levels provide the highest clinical utility in diagnostic sensitivity and specificity for PCOS.⁹¹

Diabetes Screen

The 2003 Rotterdam PCOS consensus group recommends a 2-hour oral glucose tolerance test (OGTT) for obese PCOS patients and nonobese PCOS patients with risk factors for insulin resistance, such as family history of diabetes.⁵ Women with PCOS are at significantly increased risk for impaired glucose tolerance and type 2 diabetes compared to age-, weight-, and ethnicity-matched controls.⁹² The 2-hour OGTT is the preferred method for the detection of diabetes in PCOS patients due to its increased sensitivity over fasting plasma glucose, and it can be used to detect impaired glucose tolerance, an independent risk factor for diabetes that is associated with cardiovascular disease and increased mortality. If either the fasting glucose is 126 mg/dL or more, or the 2-hour level is 200 mg/dL or more, diabetes is detected and should be confirmed with a repeat test. Impaired fasting glucose is defined as a glucose level between 100 mg/dL and 126 mg/dL. Impaired glucose tolerance is defined as a 2-hour glucose level between 140 mg/dL and 200 mg/dL. Both impaired fasting glucose and impaired glucose tolerance are independent risk factors for the future development of diabetes.

Insulin Resistance Evaluation

Defining insulin resistance is difficult because the concept is nebulous with no universally accepted diagnostic strategy. Generally speaking, insulin resistance is defined as “a subnormal biologic response to a given concentration of insulin.”⁹³ The WHO defines insulin resistance as the lowest quartile of measures of insulin sensitivity.⁷⁹ Once the diagnosis of insulin resistance is made, there are many implications given the numerous effects hyperinsulinemia may have on reproduction and metabolism.

The gold standard for the diagnosis of insulin resistance is the hyperinsulinemic euglycemic clamp, which is expensive, time-consuming, labor-intensive, and impractical for clinical use. Alternative tests have been developed and can be grouped by whether they involve insulin infusion, minimal modeling, or fasting. Tests that involve insulin infusion include the clamp techniques, as well as the insulin tolerance test and insulin sensitivity test. The minimal models require intravenous or oral administration of glucose only and include the frequently sampled intravenous glucose tolerance test and the OGTT. Insulin infusion dynamic tests and the frequently sampled glucose tolerance test are feasible only in the research setting due to the time and resources required. Fasting methods to assess insulin sensitivity include the homeostasis model assessment (HOMA), quantitative insulin sensitivity check index, and fasting glucose/insulin (G₀/I₀) ratio.

The G₀/I₀ ratio was first described by Legro and coworkers as a measure of insulin sensitivity in white, obese PCOS women from Pennsylvania. The G₀/I₀ ratio detected insulin resistance with a sensitivity of 95% and specificity of 84% compared to the frequently sampled intravenous glucose tolerance test.⁹⁴ Ducluzeau and coworkers later confirmed that the G₀/I₀ ratio is a predictor of insulin resiatnce in nonobese women as well.⁹⁵ This study sought to identify the best markers of insulin resistance compared to the hyperinsulinemic euglycemic clamp. They measured serum SHBG, leptin, adiponectin, OGTT, and HOMA in addition to the G₀/I₀ ratio. The G₀/I₀ ratio emerged as the strongest independent parameter to appraise insulin resistance. The 2-hour OGTT can also be used to detect insulin resistance, with a 2-hour G₀/I₀ ratio of less than 1.0 suggestive of the diagnosis in the PCOS population.⁹⁴ Correlation of insulin levels to glucose levels from the OGTT reveals how impaired glucose tolerance appears to be the result of decreased insulin sensitivity while impaired fasting glucose is a result of defective insulin secretion.⁹⁶

One must be cognizant that there is considerable ethnic variability when screening for diabetes and insulin resistance. No normative values have been developed that are ethnicity-specific. Kauffman and colleagues studied white and Mexican American women with PCOS and found differing values for G₀/I₀ ratios to detect insulin resistance in the two populations.⁹⁷ A fasting insulin greater than 20 μU/mL and G₀/I₀ ratio less than 7.2 detected insulin resistance in white women; a fasting insulin greater than 23 μU/mL and G₀/I₀ ratio less than 4.0 detected insulin resistance in Mexican American women (Fig. 15-4). In the clinical setting, the 2-hour OGTT that measures both fasting and postprandial glucose and insulin levels will yield the most information about glucose intolerance and hyperinsulinemia. It is recommended that the 2-hour OGTT be used to screen for the metabolic syndrome in obese women with PCOS, as well as any nonobese women with PCOS who have risk factors for insulin resistance.⁹⁸ It is also reasonable to obtain a fasting lipid profile in women suspected of having risk factors for cardiovascular disease.

Figure 15-4 Receiver operating characteristic (ROC) curves for fasting insulin, glucose-to-insulin (G/I) ratio, and homeostasis model assessment (HOMA) values in white and Mexican American populations. If different cutoff values are implemented in each ethnic group, good sensitivity and specificity for each screening test is found. There is no statistical difference among each test of insulin resistance when applied to nonglucose-intolerant populations.

(Data from Kauffman RP, Baker VM, DiMarino P, et al: Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: A comparison of two distinct populations. Am J Obstet Gynecol 187:1362–1369, 2002.)

TREATMENT

There are many considerations when deciding on therapy for PCOS (Fig. 15-5). Identification of patient concerns is necessary when prioritizing goals and formulating a treatment plan. A combination of therapies may be warranted, and the practitioner should appropriately counsel the patient on treatment expectations. Amelioration of long-term health risks should be emphasized regardless of the primary complaints of the patient.

Figure 15-5 Polycystic ovary syndrome treatment algorithm.

(Data from Berga S: The obstetrician-gynecologist’s role in the practical management of polycystic ovary syndrome. Am J Obstet Gynecol 179:109S–113S, 1998.)

Weight Loss

Weight reduction should be a major component of any treatment plan for the overweight patient (BMI 26 or greater). Any sustained improvement in weight should involve diet and exercise, and consultation with a nutritionist may be helpful for those with difficulty achieving weight reduction. Obese PCOS patients who achieve weight loss will have an increase in SHBG, decrease in free testosterone, and improvement in fasting insulin levels.⁹⁹

Oral Contraceptives

Combination oral contraceptives have been the mainstay of PCOS management for the patient not interested in conception. Contraceptives suppress pituitary LH and consequently reduce ovarian androgen secretion, increase SHBG, and reduce free testosterone, while regulating menses and reducing the risk of endometrial hyperplasia or malignancy. However, there may be mild attenuation of insulin sensitivity.

Korytkowski and coworkers have shown that short-term use of combination oral contraceptives in PCOS women results in a small decrease in insulin sensitivity and no change in the baseline elevation in triglyceride levels.¹⁰⁰ However, in normal women, combination oral contraceptives were shown to produce an even more pronounced decline in insulin sensitivity, along with a significant elevation in triglyceride levels. The longer-term effects of combination oral contraceptives on insulin sensitivity and lipoprotein profiles have not been well documented. PCOS women are at greater risk for the development of diabetes and cardiovascular disease, and further investigation into the safety of long-term hormonal therapy is needed.

Antiandrogens

Antiandrogens are commonly used as an adjunct to oral contraceptive therapy for treatment of hirsutism, but they have also been found to improve ovulation and restore regular menses. It is important to remember that all antiandrogens are teratogenic and pose a risk of feminizing a male fetus, and thus should be used along with an effective form of contraception.

Spironolactone is an aldosterone antagonist and is the most commonly used adjunctive agent in the treatment of hirsutism. It competes for testosterone binding sites on the pilosebaceous unit, inhibits 5α-reductase, and inhibits androgen production by interfering with cytochrome P450.¹⁰² The potassium-sparing effect warrants judicious use in the patient on potassium supplementation or with preexisting hypertension.

Flutamide is a nonsteroidal antiandrogen that competes for the androgen receptor. Anovulatory PCOS patients treated with flutamide experienced resumption of ovulation with restoration of normal ovarian appearance with one dominant follicle.¹⁰³ This study also reported a reduction in plasma levels of LH, androstenedione, and testosterone. Liver toxicity is a rare but potentially serious side effect of flutamide.

Finasteride is a potent inhibitor of 5α-reductase used for treatment of prostatic hyperplasia with promising results as a treatment for hirsutism. All antiandrogens should be used along with a form of contraception because they are teratogenic and pose a risk of feminizing a male fetus.

Insulin-Sensitizing Agents

Insulin-sensitizing agents have been shown to improve endocrine and reproductive abnormalities in PCOS. Metformin is the most thoroughly investigated insulin-lowering agent used in PCOS. It is a biguanide that primarily works by suppressing hepatic gluconeogenesis and, to a lesser degree, increasing peripheral insulin sensitivity (Fig. 15-6).¹⁰³ Thiazolidinediones are peroxisome proliferator activating receptor agonists that improve peripheral insulin sensitivity but do not appear to have an effect on hepatic glucose production (see Fig. 15-6).¹⁰³ This class of medications includes troglitazone, pioglitazone, and rosiglitazone.

Figure 15-6 Mean (±SE) percent changes within subjects in endogenous glucose production and the glucose disposal rate under hyperinsulinemic clamp conditions after 3 months of therapy with metformin or troglitazone. NS, not significant.

(From Inzucchi S, Maggs D, Spollett G, et al: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867–872, 1998. Copyright 1998 Massachusetts Medical Society. All rights reserved.)

Troglitazone is the oldest but was removed from the market in 2000 due to hepatotoxicity. Rosiglitazone and pioglitazone are still available and appear to be safer. The role of insulin-sensitizing agents is still an area of active investigation.

Many studies have demonstrated the positive effects of metformin on the reproductive axis of PCOS patients, with one of the most comprehensive studies recently demonstrating a dramatic improvement after 6 months of treatment. Metformin administration to nonobese hyperandrogenic PCOS patients resulted in a reduction of (1) LH pulse amplitude; (2) androstenedione levels; (3) testosterone levels; (4) ovarian volume; and (5) Ferriman-Gallway scores. Menstrual cyclicity was also improved in most patients.¹⁰⁴ The investigators did not determine if metformin increased the likelihood of ovulation or if FSH levels rose. Similarly, troglitazone-treated PCOS patients demonstrated improved ovulation, decreased hirsutism, decreased free testosterone level, and increased SHBG.¹⁰⁵

Insulin-sensitizing agents have a favorable effect on hyperandrogenism by reducing LH secretion, thereby removing the main stimulus for pathologic ovarian and adrenal androgen production. The reduction in insulin levels elevates hepatic SHBG production, decreasing free androgen levels. The concurrent improvement in hyperinsulinemia and hyperandrogenemia conferred by the use of insulin-sensitizing agents may ameliorate hirsutism.

The improvement in ovulation and menstrual cyclicity in patients treated with insulin-sensitizing agents suggests improved fertility. Indeed, spontaneous and clomiphene-induced ovulation rates in metformin-treated PCOS women are increased.¹⁰⁶ Spontaneous ovulation occurred in 34% of those treated with 500 mg of metformin three times daily compared to only 4% in the placebo group. Clomiphene-induced ovulation occurred in 90% of women who received metformin compared to 8% who received placebo. For those who are clomiphene-resistant, significant improvements in ovulation and pregnancy rates were reported in a randomized, double-blind, placebo-controlled trial for women pretreated with metformin.¹⁰⁷ Troglitazone alone and the combination of troglitazone plus clomiphene is also associated with increased rates of ovulation and pregnancy in insulin-resistant women with PCOS.¹⁰⁸

Though metformin is a category B medication, its use throughout pregnancy is becoming more attractive. In one retrospective study, Jakubowicz and colleagues found a significant reduction in the rate of early pregnancy loss for PCOS women who conceived while taking metformin and continued the agent throughout pregnancy. The rate of early pregnancy loss in the metformin group was 8.8% compared to 41.9% in controls. In the women with a prior history of miscarriage, the early loss rate was 11.1% for the metformin group compared with 58.3% in the control group.¹⁰⁹ The efficacy of metformin for pregnancy loss is not yet clear, and safety data for this indication are lacking.

Another possible beneficial effect of metformin administration during pregnancy is the significant reduction in gestational diabetes, as seen in one prospective cohort study.¹¹⁰ Randomized trials are needed before use of metformin is supported to prevent gestational diabetes in PCOS women with insulin resistance.

Metformin should not be given to those with conditions associated with elevated lactate levels, such as renal or hepatic disease, because there is a risk of lactic acidosis with an associated mortality of 50%.¹¹¹ Although most studies of metformin in PCOS used a dose of 500 mg three times daily, no studies have been performed to determine the optimal dosing regimen for improvement in insulin sensitivity, reduction of androgens, and resumption of ovulation. A dose–response study of type 2 diabetic patients demonstrated that the 2000 mg daily dose was optimal for improvement of glucose homeostasis,¹¹² but the relevance of this dose to the PCOS population remains to be investigated.

Metformin should be initiated in a stepwise approach, titrating the dose slowly over several weeks to minimize side effects. Most patients will experience gastrointestinal symptoms such as nausea, diarrhea, indigestion, and abdominal discomfort. Side effects will resolve in several days for most patients, which allow incremental dosing increases on a weekly basis up to a maximum dose of 1000 mg twice a day. Baseline serum creatinine should be obtained with yearly monitoring to avoid lactic acidosis. If metformin is being used to improve reproductive status rather than to correct hyperglycemia, reproductive parameters can be monitored. One would want to employ the lowest dose that results in ovulation for those strictly interested in conceiving. The optimal dose for amelioration of hyperandrogenic phenotype has not been established, and the outcome variables to monitor will be cosmetic sequelae or circulating androgen levels.

There are no guidelines currently on the long-term use of metformin to prevent or improve health outcomes in patients with PCOS. One of the serious reactions to the thiazolidinediones is hepatotoxicity. Initiation of treatment requires baseline liver function studies along with periodic monitoring.

Ovarian Surgery

Ovarian Wedge Resection

Ovarian wedge resection is a surgical procedure that has been found to restore both regular menses and ovulation in the majority of cases when used in PCOS patients. This procedure, originally performed by laparotomy, consists of removing a wedge of ovarian tissue and reconstructing the ovary. In the past, it was recommended for women who remained anovulatory despite therapy with clomiphene citrate, and many of the patients who became ovulatory also achieved pregnancy. Laparoscopic techniques for ovarian wedge resection have been described.

The primary disadvantage of this approach is the formation of significant pelvic adhesions, which occurs in at least one third of the patients. The concern is that these adhesions might actually decrease fertility and increase the risk of pelvic pain. Another concern is that the restoration of ovulation is unlikely to be permanent, because the ovaries are not the causal agents in this complex systemic disorder. However, the actual long-term effectiveness of wedge resection has never been reported.

Ovarian Drilling

A laparoscopic variant with similar results to ovarian wedge resection is called ovarian drilling (see Chapter 37). This procedure involves making multiple punctures in the ovarian cortex and destroying ovarian tissue using unipolar electrosurgery or laser. The results and complications for this approach appear to be similar or slightly less than those for ovarian wedge resection, although a prospective, randomized study has never been done. There are additional concerns about long-term effects of ovarian drilling on ovarian function.