Polycystic ovary syndrome (PCOS) is a common disorder affecting (depending on the population studied and the definition of the syndrome) between 5 and 20% of reproductive age women. If the middle of this range is considered as a realistic prevalence, then PCOS may be the most prevalent endocrine disorder in women. In spite of the widespread presence of PCOS, its precise definition still eludes both investigators and practitioners.
Most consensus definitions describe PCOS as a disorder characterized by chronic anovulation and the presence of some degree of hyperandrogenism, with the exclusion of specific disorders that may lead to similar phenotypes, particularly, 21-hydroxylase deficiency and other forms of congenital adrenal hyperplasia. The definition proposed in 1990 by the National Institutes of Health Conference on PCOS requires a minimum of two criteria: menstrual abnormalities due to oligo- or anovulation, and hyperandrogenism of ovarian origin. Other disorders, such as 21-hydroxylase deficiency, androgen secreting tumors, hypothyroidism, Cushing’s syndrome, and hyperprolactinemia, must be excluded. In 2003 in Rotterdam a revised consensus on the diagnosis of PCOS was proposed. The new criteria require two out of the three following features once exclusion of other causes of hyperandrogenism has been made: oligo- or amenorrhea, hyperandrogenism (clinical or biochemical), and polycystic ovary morphology on ultrasound.
Clinical manifestations vary widely among women with this disorder. Chronic anovulation may present as infertility or some form of menstrual irregularity, such as amenorrhea, oligomenorrhea, or dysfunctional uterine bleeding. Signs of hyperandrogenism include hirsutism, seborrhea, acne, and alopecia. Evidence of virilization, including clitoromegaly, may be present in severe cases. Obesity and acanthosis nigricans are clinical features that are commonly seen in PCOS women and are associated with insulin resistance.
Epidemiological data and prospective controlled studies have reported an increased prevalence of insulin resistance, impaired glucose tolerance, and undiagnosed type 2 diabetes mellitus in these women. Increased risk for dyslipidemia, cardiovascular disease, and endometrial carcinoma has also been observed in this population.In this chapter, we will discuss the role of insulin resistance in the pathogenesis of PCOS, the risk of diabetes mellitus in this population and the role of insulin-sensitizing agents, oral contraceptive pills and antiandrogens in treating patients with polycystic ovary syndrome.
Stein–Leventhal Syndrome
Although reports of disorders resembling PCOS date prior to the seventeenth century, the first clear description belongs to Chereau, who in 1844 described “sclerocystic degeneration of the ovaries.”8 The modern era of PCOS began with a report by two gynecologists, Irving F. Stein and Michael L. Leventhal, who in 1935 described a syndrome of amenorrhea, hirsutism, and enlarged polycystic ovaries in anovulatory women. After observing the restoration of menstruation following ovarian biopsies in patients with this syndrome, Stein and Leventhal performed one-half to three-fourths wedge resection of each ovary in seven women. During the operation the ovarian cortex containing the cysts was removed. All of the patients who underwent wedge resection in Stein and Leventhal’s series experienced the return of their menses and two became pregnant. Stein and Leventhal established both the term “polycystic ovary syndrome” and the theory attributing the origin of this disorder to endocrine abnormalities.
In 1949, Culiner and Shippel coined the term “hyperthecosis ovarii” for polycystic ovaries comprised of nests of theca cells. Wedge resection performed in patients with this condition did not result in amelioration of hyperandrogenism. These women were masculinized, and often had diabetes and hypertension. The hyperthecosis ovarii was characterized by familial clustering. The polycystic ovaries in these patients were found to have not only hyperplasia of the theca cells but also atretic follicles. Hormonal studies in PCOS women were performed only after the clinical manifestations and anatomical abnormalities of this disorder were well reported. In one of the first studies that measured hormone levels in PCOS patients, McArthur et al., in 1958, reported increased urinary levels of luteinizing hormone (LH). Reports of elevated circulating androgen levels followed. During the last two decades PCOS has been identified as a metabolic disorder in which underlying insulin resistance and consequent hyperinsulinemia contribute to hyperandrogenism.
Genetics in PCOS
It has been proposed that the development of PCOS is dependent on the combination of both genetic and environmental factors. Familial aggregation of PCOS phenotypes has been reported in as early as the1960s. Multiple studies have evaluated the association of various genes and PCOS. Some of these studies support the association while others do not. The genes that have been evaluated can be divided into those involved in adrenal or ovarian steroidogenesis; gonadotropin action and regulation; insulin action and secretion; chronic inflammation; and energy homeostasis. The genes which are potential candidates for the pathogenesis of PCOS are CYP 11a, CYP 17, sex hormone-binding globulin (SHBG), insulin (with variable tandem repeats [VNTR] polymorphism), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and plasminogen activator inhibitor-1 (PAI-1). In summary, studies evaluating the genetic association of PCOS, have presented conflicting results. Further research is required to have a more conclusive proof of the relationship between genetic inheritance and PCOS (Table 33.1).
Table 33.1 Genes implicated in polycystic ovary syndrome and linked to insulin signaling pathway or insulin resistance
Mechanisms Genes
Insulin action and secretion Insulin (VNTR polymorphism)
Insulin receptor
Insulin receptor substrate (IRS-1 or IRS-2)
Energy homeostasis Leptin gene and receptor
Adiponectin
PPAR-γ (Pro12Ala polymorphism)
Main Hormonal Abnormalities
The two main endocrine theories of PCOS attribute its pathogenesis to the primary role of either central (hypothalamic, pituitary) or ovarian hormonal abnormalities. The central theory proposes that the initial pathogenic event is an abnormally increased pulsatile secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus that causes a tonically increased secretion of LH instead of the normal pulsatile pattern with a surge during ovulation. It has been proposed that LH levels may rise further because of hyperandrogenism: after androstenedione is converted in the peripheral fat to estrone by aromatase, estrone enhances LH secretion by increasing LH-producing gonadotroph sensitivity to GnRH. In response to increased LH, ovarian thecal cells undergo hypertrophy and their androgen secretion is further increased, thus establishing a vicious cycle. On the contrary, follicle stimulating hormone (FSH) secretion is normal or decreased due to negative feedback from increased estrogen levels produced through aromatization of androgens.
Thus, the LH:FSH ratio is often increased. The ovarian theory attributes primary pathogenic role in the development of PCOS to the ovary, where the production of androgens is increased. According to this theory, dysregulation of the enzyme cytochrome P450c17-alpha, which comprises 17-hydroxylase and 17/20 lyase activities, results in increased amount of androgens. Increased levels of androstenedione and estrone could also be secondary to reduced levels of the enzyme 17-ketosteroid reductase, which converts androstenedione to testosterone and estrone to estradiol. When ovarian theca cells from women with PCOS were propagated in vitro, it was shown that the activity of 17 α-hydroxylase/C17,20 lyase and 3β-hydroxysteroid dehydrogenase levels were elevated. This results in increased production of testosterone precursors, and, ultimately, causes increased testosterone production. Thus, thecal cells from PCOS patients, when cultured in vitro, possess intrinsic ability to produce increased amounts of testosterone. In summary, main hormonal abnormalities in PCOS include elevated androgen and estrogen levels and commonly, although not always, an elevated LH:FSH ratio. Hyperinsulinemia, commonly observed in patients with PCOS, contributes to the development of these hormonal abnormalities.
Insulin Resistance in PCOS
In 1921, Archard and Thiers described “the diabetes of bearded women,” the first reference to an association between abnormal carbohydrate metabolism and hyperandrogenism. Since then, several syndromes of extreme insulin resistance have been described in patients with distinctive phenotypes which include acanthosis nigricans, hyperandrogenism, polycystic ovaries, or ovarian hyperthecosis and, sometimes, diabetes mellitus. These syndromes are rare and include leprechaunism, type A and B syndromes of insulin resistance, lipoatrophic diabetes and, Rabson–Mendenhall syndrome. Severe insulin resistance observed in these rare syndromes can be due to a mutation of the insulin receptor gene or other genetic defects in insulin action. In the type B syndrome of insulin resistance, anti-insulin receptor autoantibodies have been identified as a cause of severe insulin resistance.
Euglycemic hyperinsulinemic glucose/insulin clamp studies are used to quantify insulin resistance. After a priming dose of insulin, euglycemia is maintained by a constant dose of insulin infusion and simultaneous glucose infusion, the rate of which is adjusted to achieve normal circulating glucose levels. When stable glucose levels are achieved, the rate of peripheral glucose utilization, measured in grams glucose/m2 of body surface area, is equal to the rate of glucose infusion. Insulin clamp studies in PCOS subjects have demonstrated significant reduction in insulin-mediated glucose disposal similar to that seen in type 2 diabetes mellitus, thus proving that many patients with PCOS are insulin resistant. Insulin sensitivity is affected by several independent parameters, including obesity, muscle mass, and the site of body fat deposition (central versus peripheral obesity). When insulin clamp studies are performed in PCOS women who are matched to non-PCOS controls for body mass index and body composition, insulin resistance is demonstrated in PCOS women independent of these parameters.
Thus, lean PCOS women are more insulin resistant than lean controls. However, body fat does have a synergistically negative effect on insulin sensitivity in PCOS, so that lean PCOS women are usually less insulin resistant than the obese PCOS subjects. Central obesity is the characteristic form of obesity in PCOS and it magnifies insulin resistance and hyperinsulinemia in PCOS patients. The etiology of insulin resistance in polycystic ovary syndrome is unknown, although abnormalities of insulin receptor signaling have been reported in some patients. Two theories of the pathogenesis of insulin resistance, one involving free fatty acids (FFAs) and another involving tumor necrosis factor-α (TNF-α) have been proposed. First, increased FFA flux into the liver decreases hepatic insulin extraction, increases gluconeogenesis, produces hyperinsulinemia, and reduces glucose uptake by the skeletal muscle. Second, TNF-α, produced by adipose tissue, leads to insulin resistance by stimulating phosphorylation of serine residues of the insulin receptor substrate-1 (IRS-1), which leads to the inhibition of insulin receptor cascade. Elevated circulating levels of FFA and TNF-α have been reported in PCOS patients.
It has been hypothesized that elevated serum insulin levels in patients with PCOS result in excessive ovarian androgen production, as well as ovarian growth and cyst formation. Several in vitro studies have demonstrated the presence of insulin receptors in the ovary and the stimulation of androgen production in ovarian cells by insulin. Continuous stimulation of the ovary by hyperinsulinemia in synergism with LH over a prolonged period of time may produce morphological changes in the ovary, such as ovarian growth and cyst formation. The effects of insulin on the ovary can be mediated by the binding of insulin to its own receptor or to the type 1 IGF receptor in what is known as the “specificity spillover” phenomenon. The latter could be an important mechanism in cases of extreme insulin resistance with severe hyperinsulinemia.
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