Polycystic Ovary Syndrome
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Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting approximately 5–10 % of reproductive-age women. PCOS is considered the most common cause of anovulatory infertility. PCOS is widely accepted as a combination of ovulatory dysfunction, androgen excess, and polycystic ovaries with the exclusion of specific disorders that may lead to similar phenotypes. Genetic variants have also been identified which result in PCOS. PCOS is associated with insulin resistance, type 2 diabetes mellitus, dyslipidemia, and visceral obesity. The treatment of PCOS is multifaceted, including the use of oral contraceptives, insulin sensitizers, antiandrogen agents, and other medications; PCOS therapy is tailored to patient-specific physiological conditions and treatment goals.
KeywordsPOLYCYSTIC OVARY SYNDROME INSULIN RESISTANCE OLIGOMENORRHEA HIRSUTISM ANDROGENS
Definition, Clinical Manifestations, and Prevalence
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 most recent 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 [3, 4].
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 [6, 7]. 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.
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.”  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
Genes implicated in polycystic ovary syndrome and linked to insulin signaling pathway or insulin resistance
Insulin action and secretion
Insulin (VNTR polymorphism)
Insulin receptor substrate (IRS-1 or IRS-2)
Thyroid adenoma associated (THADA)
Leptin gene and receptor
PPAR-γ (Pro12Ala polymorphism)
DENN/MADD domain-containing protein 1A (DENND1A)
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 (described in detail in the chapter “Syndromes of Extreme Insulin Resistance”) 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 [22, 23, 24].
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 vs. 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 [28, 29, 30]. 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 [31, 32]. Elevated circulating levels of FFA and TNF-α have been reported in PCOS patients [33, 34, 35].
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 [36, 37, 38] 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 [41, 42].
Role of Insulin in Ovarian Function
Despite Joslin’s early observations of abnormal ovarian function in women with type 1 diabetes mellitus , insulin was not thought to play a significant role in ovarian function until the late 1970s, when patients with extreme forms of insulin resistance were described [22, 23]. Manifestations of ovarian hypofunction (primary amenorrhea, late menarche, anovulation, and premature ovarian failure) in untreated type 1 diabetes mellitus can be understood if it is accepted that insulin is necessary for the ovary to reach its full steroidogenic and ovulatory potential. Thus, patients with insulin deficiency commonly exhibit hypothalamic-pituitary and ovulatory defects but not hyperandrogenism [20, 44]. On the other end of the clinical spectrum, women with syndromes of severe insulin resistance and consequent hyperinsulinemia exhibit anovulation associated with hyperandrogenism, as discussed above.
If insulin is capable of stimulating ovarian androgen production in insulin-resistant patients, one has to postulate that ovarian sensitivity to insulin in these patients is preserved, even in the presence of severe insulin resistance in the classical target organs, such as liver, muscle, and fat . To explain this paradox, we will briefly review cellular mechanisms of insulin action in the ovary and the relationships between insulin, insulin-like growth factors (IGFs), and their receptors.
Insulin receptors are widely distributed in the ovaries. These ovarian insulin receptors are structurally and functionally similar to insulin receptors found in other organs. Regulation of insulin receptor expression, however, may be somewhat different in the ovaries compared to other target tissues. While in classical target tissues insulin receptors are downregulated by hyperinsulinemia, there is evidence that circulating factors other than insulin may regulate insulin receptor expression in the ovaries of premenopausal women [45, 46]. These factors may include sex steroids, gonadotropins, IGFs, and IGFBPs. The phenomenon of differential regulation of ovarian insulin receptors, with their preservation on cell membrane in spite of hyperinsulinemia, may provide one explanation for the ovarian responsiveness to insulin in premenopausal women with insulin resistance in peripheral target organs .
The ovarian insulin receptors have heterotetrameric α2β2 structure, possess tyrosine kinase activity, and may stimulate the generation of inositolglycans. After insulin binds to the α-subunits of the insulin receptor, the β-subunits are activated via phosphorylation of the tyrosine residues and acquire tyrosine kinase activity, e.g., the ability to promote phosphorylation of other intracellular proteins. The intracellular proteins phosphorylated under the influence of the insulin receptor tyrosine kinase are the insulin receptor substrates (IRS).
The insulin receptor activation and IRS phosphorylation result in the activation of phosphatidylinositol-3 kinase (PI-3-kinase). This activation is necessary for transmembrane glucose transport. Mitogen-activated protein kinase (MAPK), responsible for DNA synthesis and gene expression, is also activated by insulin; MAPK activation does not require activation of PI-3-kinase.
Finally, the ovaries may remain sensitive to the actions of insulin in the presence of insulin resistance because, as mentioned above, insulin, when present in high concentration, can activate type 1 IGF receptors. This pathway of insulin action may be operative in patients with syndromes of extreme insulin resistance whose insulin receptors are rendered inactive by a mutation or by anti-insulin receptor antibodies. There is evidence that type 1 IGF receptors may be upregulated in the presence of hyperinsulinemia both in animal models and in women with PCOS [50, 51, 52].
Effects of TZDs related to ovarian function (Adapted with permission from Seto-Young et al. )
Can be observed in vitro, may be present in vivo
Observed in vivo; are due to systemic insulin-sensitizing action and reduction of hyperinsulinemia
↑ Progesterone production
↓ Testosterone production
↓ Estradiol production
↑ IGFBP-1 production in the absence of insulin
↓ Testosterone production
↓ Estradiol production
↑ IGFBP-1 production
↑ SHBG ↓free T
B. Insulin sensitizing (enhanced insulin effect)
↓ IGFBP-1 production
↑ Estradiol production (in vivo, in a setting of high-dose insulin infusion)
Possible mechanisms of preserved ovarian sensitivity to insulin in insulin resistant states
Differential regulation of ovarian insulin receptors in premenopausal women
Activation of alternative insulin signaling pathways (MAP-kinase and inositolglycan), rather than PI-3 kinase pathway of glucose transport
Activation of type 1 IGF receptors which may be up-regulated by hyperinsulinemia
Activation of PPAR-γ
Insulin Effects Related to Ovarian Function
Insulin effects related to ovarian function
Directly stimulates steroidogenesis
Acts synergistically with LH and FSH to stimulate steroidogenesis
Stimulates 17 α-hydroxylase
Stimulates or inhibits aromatase
Ovary, adipose tissue
Up-regulates LH receptors
Promotes ovarian growth and cyst formation synergistically with LH/hCG
Down-regulates insulin receptors
Up-regulates type I IGF receptors or hybrid insulin/type I IGF receptors
Inhibits IGFBP-I production
Potentiates the effect of GnRH on LH and FSH
Inhibits SHBG production
Activates StAR protein
Effects on steroidogenesis . In vitro, insulin acts on the granulosa and thecal cells to increase production of androgens , estrogens, and progesterone. This action is likely mediated by the interaction of insulin with its receptors. Several in vitro studies, however, have demonstrated that supraphysiological concentrations of insulin are needed to achieve this steroidogenic effect on the ovary, suggesting that, under some circumstances, insulin action may be mediated via the type 1 IGF receptor [20, 42].
Studies that attempted to determine whether insulin stimulates or inhibits aromatase or 17-α-hydroxylase have resulted in contradictory conclusions. For example, Nestler et al. reported that 17-α-hydroxylase activity appears to be stimulated by insulin , but Sahin et al. in a later study found no relation between insulin levels and 17-hydroxyprogesterone (17-OHP) after treatment with GnRH agonist . One study showed that, after gonadotropin infusion, hyperinsulinemic women with PCOS had an increased estradiol/androstenedione ratio compared with women with PCOS and normal insulin levels , thus suggesting insulin’s stimulatory effect on aromatase. However, in other studies increased circulating levels of androstenedione were found during insulin infusions, suggesting that insulin inhibits aromatase [59, 60].
Ovarian androgen production in response to insulin has also been extensively studied in vivo both directly, in the course of insulin infusions, and indirectly, after a reduction of insulin levels by insulin sensitizers or other agents, such as diazoxide. While insulin infusion studies did not produce consistent evidence of increased androgen production, reduction of insulin levels has consistently resulted in decreased androgen levels .
Synergism with LH and FSH on the stimulation of steroidogenesis. At the ovarian level, insulin has been demonstrated to potentiate the steroidogenic response to gonadotropins [20, 52]. This effect is possibly caused by an increase in the number of LH receptors that occurs under the influence of hyperinsulinemia [20, 61].
Enhancement of pituitary responsiveness to GnRH . Another area of uncertainty is whether insulin enhances the sensitivity of gonadotropes to GnRH in the pituitary. Several investigators have demonstrated increased responsiveness of gonadotropes to GnRH in the presence of insulin in cultured pituitary cells [62, 63]. Nestler and Jakubowicz showed decreased circulating levels of LH in patients treated with insulin sensitizers . But in another study, gonadotropin responsiveness to GnRH did not change after insulin infusion . Similarly, in rats with experimentally produced hyperinsulinemia, response of gonadotropins to GnRH does not appear to be altered .
The effect on SHBG . Insulin has been shown to suppress hepatic production of sex hormone-binding globulin (SHBG) [66, 67, 68, 69]. Lower levels of SHBG result in increased serum levels of unbound steroid hormones, such as free testosterone. In PCOS and other hyperinsulinemic insulin-resistant states, insulin may increase circulating levels of free testosterone by inhibiting SHBG production. When insulin sensitizers are used, SHBG levels rise, thereby decreasing free steroid hormone levels .
The effect on IGFBP-1 . Insulin has been found to regulate insulin-like growth factor-binding protein-1 (IGFBP-1) levels. In both liver and ovarian granulosa cells, insulin inhibits IGFBP-1 production [41, 70, 71]. Lower circulating and intraovarian IGFBP-1 concentrations result in higher circulating and intraovarian levels of free IGFs that may contribute to increased ovarian and adrenal steroid secretion [15, 72].
Type 1 IGF receptor . Insulin increases ovarian IGF-I binding in rats, suggesting an increase in the expression of ovarian type 1 IGF receptors or hybrid insulin/type 1 IGF receptors . In these studies, ovarian type 1 IGF receptors are upregulated even though insulin receptors are either downregulated or preserved. Studies in women with PCOS appear to confirm this phenomenon [51, 73].
In summary, in a number of in vitro animal and human ovarian cell systems and in vivo experiments in animals and in women a variety of insulin effects related to ovarian function have been demonstrated. These effects can account for many features of PCOS in hyperinsulinemic insulin-resistant women . Insulin effects related to ovarian function are summarized in Table 4.
Risk of Diabetes Mellitus; Prevention of Diabetes
A major risk factor for the development of type 2 diabetes mellitus in PCOS is insulin resistance. However, a defect in pancreatic β-cell function resulting in deficient insulin secretion has also been reported in PCOS patients .
The prevalence and predictors of risk for type 2 diabetes mellitus have been studied in PCOS women. In prospective studies of glucose tolerance in women with hyperandrogenism and chronic anovulation, the prevalence of undiagnosed diabetes mellitus was 7.5 % and that of impaired glucose tolerance (IGT) was 31.1 %. Further analysis of the nonobese subgroup demonstrated that the risk for diabetes decreased to 1.5 % and for IGT to 10.3 %. However, these rates were still significantly increased compared to a population-based study of age-matched women in the United States in whom the prevalence rate of undiagnosed diabetes mellitus was 1.0 % and that of IGT was 7.8 % .
A study of women with previous history of gestational diabetes revealed a greater prevalence of polycystic ovaries (PCO) compared to controls (39.4 % vs. 16.7 %), higher serum levels of adrenal androgens, and significantly impaired glucose tolerance. Oral glucose tolerance testing in these women uncovered a decreased early phase insulin response while euglycemic clamp studies demonstrated impaired insulin sensitivity. The investigators theorized that a dual component of insulin resistance plus impaired pancreatic insulin secretion could explain the vulnerability of PCOS patients to diabetes .
PCOS, and not PCO (in which the polycystic ovarian morphology is not associated with hyperandrogenism or anovulation), has been found to be a substantially more significant risk factor for diabetes mellitus than race or ethnicity . Factoring in obesity, age, family history of diabetes, and waist/hip ratios, the prevalence of glucose intolerance increases. This suggests that the pathogenesis of diabetes mellitus in PCOS is a result of underlying genetic defects, resulting in insulin resistance and pancreatic β-cell dysfunction, and an interplay of various environmental factors.
Primary prevention of type 2 diabetes mellitus was the focus of the Diabetes Prevention Program (DPP). The DPP, a National Institutes of Health-sponsored clinical study, targeted preventive measures at specific individuals or groups at high risk for the future development of type 2 diabetes. The study interventions included intensive lifestyle modification or pharmacological intervention versus placebo. The primary outcome was the development of diabetes mellitus in these high-risk groups. The results of this study showed that both lifestyle modification and treatment with metformin prevented or delayed the onset of type 2 diabetes in individuals with impaired glucose tolerance (IGT) [83, 84]. Thus, specific interventions may be implemented at an early enough time period to prevent the development of diabetes mellitus and its accompanying complications in high-risk individuals. PCOS, with its dual defect of insulin resistance and β-cell dysfunction, is a significant risk factor for diabetes mellitus. When effective protocols for prevention of diabetes mellitus are established, PCOS patients may become one target group for such measures.
Treatment for PCOS; Role of Insulin Sensitizers
There are numerous treatment modalities for the signs and symptoms of PCOS; treatment plans should be tailored to the specific concerns and presentation of the affected patient. In women not seeking fertility, traditional approaches such as oral contraceptives and antiandrogens may regulate menstrual cycles and improve hirsutism, however they do not address insulin resistance.
Hyperandrogenism is a key feature of PCOS which presents with hirsutism, acne, androgenic alopecia, infertility, and virilization. Biochemically, hyperandrogenemia is characterized by elevated serum testosterone concentrations (total and free circulating) as well as elevated levels of adrenal androgens , primarily dehydroepiandrosterone sulfate (DHEAS) . Androgen levels are highest in women ages 18–44 with PCOS; levels decline after menopause but remain higher when compared to postmenopausal women without PCOS . Hirsutism can be treated with depilatories, shaving, waxing, electrolysis, or laser therapy. Oral contraceptives and antiandrogen medications, such as spironolactone  or cyproterone acetate , may be used to reduce androgen levels and manifestations of hyperandrogenism.
Oral contraceptive (OC) pills are a mainstay of therapy in women with PCOS who are not seeking fertility and are often used as monotherapy in women with PCOS who lack the metabolic phenotype of insulin resistance, dyslipidemia, and overweight or obesity. OCs regulate menstrual cycles and decrease androgen levels by inhibiting the synthesis of GnRH at the level of the hypothalamus . Estrogens suppress FSH and thus prevent the selection of a dominant follicle. Progestins suppress the LH surge and thus inhibit ovulation; they also serve to increase the viscosity of the cervical mucus which prevents sperm from penetrating the cervix. Long-term OC use is associated with decreased risk of ovarian and endometrial cancer. Weight gain due to OC use is unclear; controlled clinical trials have failed to show any association between low dose OCs and weight gain though there may be central redistribution of fat in young women with PCOS . The benefits of OC must be weighed against the risk of use, particularly with respect to the increased risk of venous thromboembolism (VTE) which has been reported consistently. Potential adverse cardiometabolic effects of OCs are of concern given long-term use. The metabolic effects of estrogen in OCs are modulated by the type of progestin included. OCs containing newer progestins as well as drospirenone and cyproterone acetate have reduced metabolic side effects compared to OCs containing more androgenic progestins . Available data in a healthy population do not support a significant influence of OCs on glucose and insulin homeostasis . A meta-analysis of 35 observational studies and cohorts from randomized controlled trials showed that OC use was not associated with significant change in fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance, or euglycemic hyperinsulinemic clamp-glucose disposal rate in women with PCOS on OC therapy .
Weight loss , when successful, is a very effective measure which addresses insulin-related abnormalities of PCOS by decreasing insulin resistance and circulating insulin levels. One report studied 18 obese women who were hyperandrogenic and insulin resistant. A weight reduction diet resulted in a decrease in plasma androstenedione and testosterone levels . Pasquali et al. found decreased concentrations of LH, fasting insulin, and testosterone levels after weight loss in 20 obese women with hyperandrogenism and oligo-ovulation . In another study, 67 obese anovulatory women were treated with weight reduction. Sixty of these women ovulated and eighteen became pregnant .
When weight loss is not achieved, insulin resistance can be reduced with the help of insulin sensitizers, such as biguanides, thiazolidinediones, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and myoinositol (MI). The goal of these approaches is to decrease the amount of circulating insulin, thereby decreasing insulin’s stimulatory effect on androgen production and gonadotropin secretion. Circulating levels of SHBG and IGFBP-1 are increased, leading to clinical improvement via mechanisms described above .
Metformin decreases hepatic gluconeogenesis and increases fat and muscle sensitivity to insulin. There are many reports showing meformin’s efficacy in PCOS; however, most of the studies have been short term only. One long-term study followed women with PCOS treated with metformin (500 mg tid) for 6–26 months. These women not only had a reduction in insulin and androgen levels, independent of any change in weight, but also a sustained increase in menstrual regularity .
Nestler and coworkers showed that when insulin secretion is decreased by metformin administration either alone or in combination with clomiphene in obese women with PCOS, the ovulatory response is increased . In an analysis of 14 studies of metformin treatment of PCOS, 57 % of women had ovulatory improvement with metformin . The improvement in ovulation may have been only due to weight loss. However, lean women with PCOS, who had increased P450c17-alpha activity and whose circulating insulin levels were reduced while on metformin, experienced a decline in P450c17-alpha activity and improvement in hyperandrogenism . In another study, women with PCOS who were given metformin demonstrated decreased circulating levels of LH, free testosterone, and a decreased LH/FSH ratio, as well as a reduced body mass index (BMI) .
In one study of women with PCOS given metformin, improved endometrial function and intrauterine environment were found. This observation suggests that metformin can be used to improve implantation and pregnancy maintenance in women with PCOS . Treatment of infertility using either metformin or clomiphene citrate in anovulatory PCOS women has been successful. In the study by Legro et al. clomiphene was shown to be superior to metformin in achieving live births . Later in a smaller study by Palomba et al., both agents have been found to be equally effective .
A thiazolidinedione (TZD) troglitazone, an insulin-sensitizing agent, was the first in its class shown to improve insulin action in patients with PCOS . Studies with troglitazone in patients with PCOS showed improvements in ovulation, insulin resistance, hyperandrogenemia, and hirsutism . However, troglitazone was taken off the market because of hepatotoxicity. Since other members of TZD family (rosiglitazone and pioglitazone) became available, multiple studies evaluating their efficacy in PCOS patients have been published. Studies of overweight and nonobese females treated with rosiglitazone showed an improvement in ovulation, glucose tolerance, insulin sensitivity, hirsutism , and a decrease in hyperinsulinemia and androgen levels, as well as a small increase in BMI [101, 102]. Pioglitazone in PCOS patients showed similar effects (increased insulin sensitivity, ovulation rate, and SHBG levels and decreased insulin secretion and free androgen index) but BMI remained unchanged [103, 104]. While assessing the effects of TZDs in such studies, it is important to remember that TZDs exhibit both systemic insulin-sensitizing action and direct insulin-independent effects in the ovary (Table 2) .
Some of the medications were evaluated in a head-to-head comparison to determine the best therapy of PCOS. When metformin was compared with spironolactone, both medications increased frequency of menstrual cycles and decreased testosterone, DHEA-S, and hirsutism score. Spironolactone produced more significant changes, but metformin improved glucose tolerance and insulin sensitivity . In another study, metformin was compared with rosiglitazone in obese and lean women with PCOS . Women taking these agents exhibited decrease in insulin resistance and increase in insulin sensitivity but only rosiglitazone group showed significant reduction in androgen levels as well as small but significant increase in BMI (metformin had significant decrease in BMI). Pioglitazone was compared with metformin in yet another study . Both medications were equally effective in improving insulin sensitivity and hyperandrogenism (hirsutism and androgen levels) despite an increase in BMI in pioglitazone group.
Single medication therapy (monotherapy) sometimes is not sufficient to ameliorate the symptoms of PCOS. Various studies have explored the effects of combination therapies. One study involved combination therapy of metformin and oral contraceptive pills (OCPs). When a combination of metformin and OCP (ethinyl estradiol-cyproterone acetate) was compared to OCP alone, the group using combination therapy had more dramatic reduction in androstenedione and increase in SHBG [108, 109]. This group, unlike OCP group, also had significant decrease in BMI, waist-to-hip ratio, and fasting insulin level; however, these differences between the groups did not reach statistical significance. There was significant increase in total cholesterol in OCP group, while the rest of the lipid panel remained unchanged in both groups. Elter et al. suggested that insulin sensitivity (glucose-to-insulin ratio) improved in combination therapy group but these results were not supported by the study of Cibula et al. which used more definitive testing (euglycaemic hyperinsulinaemic clamp). Another combination therapy that has been studied involved rosiglitazone with OCP. In the study by Lemay et al. overweight women with PCOS and insulin resistance were divided into two groups to receive either rosiglitazone or ethinyl estradiol/cyproterone acetate for the first 6 months and then a combination therapy for an additional 6 months . Women receiving combination therapy had greater reduction in androgens and increase in SHBG and HDL than either agent alone. Improved insulin sensitivity and increased triglycerides were found in only one of the two combination groups. In summary, combination therapies of oral contraceptives and insulin sensitizers have small but beneficial effect on androgen levels.
Glucagon-like peptide-1 receptor agonists (GLP-1 RA ) are widely used in the treatment of diabetes mellitus (DM). They improve glucose homeostasis and reduce body weight, in part, through a direct hypothalamic effect which reduces food intake. GLP-1 RAs delay gastric emptying as well. When used in obese patients with or without diabetes mellitus, clinically relevant and sustained weight loss is observed . The GLP-1 RAs exenatide and liraglutide have been studied as treatments in PCOS. Studies show that combination therapy with GLP-1 RA and metformin is superior to monotherapy with either agent in women with PCOS with regard to weight loss. Across several studies, liraglutide combined with metformin resulted in an average weight loss of 6.5 to 9.0 kg [113, 114].
Inositols (INS) and their derivatives are incorporated into cell membranes as phosphatidyl-myo-inositol; its derivatives are second messengers, regulating the activities of several hormones such as FSH, TSH, and insulin. Inositols are found in many foods such as fruits and beans. Inositol was once considered a member of the vitamin B complex, however it is not considered a “true” nutrient because it can be synthesized from glucose . Myo-inositol (MI) is thought to play an important role in the fertility process, specifically in oocyte and spermatozoa development. INS has been proposed as a novel treatment for women with PCOS. MI has been shown to significantly improve features of dysmetabolic syndrome including insulin sensitivity, impaired glucose tolerance, lipid levels, and diastolic blood pressure. Six randomized control trials have examined the role of MI in over 300 PCOS patients: MI supplementation improves insulin sensitivity, restores ovulation, improves oocyte quality, and reduces clinical and biochemical hyperandrogenism and dyslipidemia by reducing plasma insulin levels . Further study is needed to fully assess the effect of different methods of INS supplementation on ovarian function.
Patients and physicians should be aware that at this time there is no medical therapy which is approved by the Food and Drug Administration for the treatment of PCOS. Women with PCOS often presume their condition leads to infertility; thus, it is imperative to discuss contraception before prescribing insulin sensitizers when pregnancy is to be avoided. Women with PCOS who think that they are infertile and therefore do not use contraception may become pregnant. Thus, it is important to discuss contraception before prescribing any of these medications.
PCOS is a compilation of multiple endocrine and metabolic abnormalities. The main features of PCOS include chronic anovulation, hyperandrogenemia, and polycystic ovaries. Many patients have insulin resistance and hyperinsulinemia of unknown etiology, although often related to obesity. Besides the hirsutism, acne, and infertility, these women are at an increased risk for diabetes.
New therapeutic strategies addressing insulin resistance in PCOS are developing. As research elucidates specific ovarian effects of insulin and specific pathways of insulin signaling in the ovary, new targets will be identified for emerging therapies.
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