Polycystic Ovary Syndrome

  • Minisha Sood
  • Susan B. Zweig
  • Marsha C. Tolentino
  • Marina Strizhevsky
  • Leonid PoretskyEmail author
Living reference work entry


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.



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 [1]. 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 [2]. 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 [5]. 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.

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 [9]. 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 [10].

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) [11]. Reports of elevated circulating androgen levels followed [12].

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 PCOS is a complex genetic trait in which other comorbid conditions and environmental factors interact with any number of genetic variants to result in the syndrome. Familial aggregation of PCOS phenotypes has been reported in as early as the 1960s [13]. 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; androgen biosynthesis and action; and energy homeostasis [14]. Over 100 genes have been examined as candidate genes. Several 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). The first genome-wide association (GWAS) conducted in Chinese Han women [111] demonstrated loci significantly associated with PCOS: LHCGR (chromosome 2p16.3 which contains a gene for the LH/hCG receptor); THADA (chromosome 2p21) in the gene coding for thyroid adenoma associated protein and impaired beta cell function; and DENND1A (chromosome 9p33.3), a gene coding for a protein that binds endoplasmic reticulum aminopeptidase 1 (ERAP1). Increased ERAP1 levels are linked to PCOS in the setting of obesity. DENND1A and THADA were also found to increase the risk for PCOS in a cohort of women in Europe [112] (Table 1).
Table 1

Genes implicated in polycystic ovary syndrome and linked to insulin signaling pathway or insulin resistance



Insulin action and secretion

Insulin (VNTR polymorphism)

Insulin receptor

Insulin receptor substrate (IRS-1 or IRS-2)

Thyroid adenoma associated (THADA)

Energy homeostasis

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 [15].

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 [16]. 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 [17]. 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 [15]. 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 [18].

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 [19].

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 [20].

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 [21]. 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 [25].

Insulin sensitivity is affected by several independent parameters, including obesity, muscle mass, and the site of body fat deposition (central vs. peripheral obesity) [25]. 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 [26]. The etiology of insulin resistance in polycystic ovary syndrome is unknown, although abnormalities of insulin receptor signaling have been reported in some patients [27].

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 [39]. 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 [40]. 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 [43], 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 [42]. 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.

The term “insulin-related ovarian regulatory system ” has been proposed to describe a complex system of ovarian regulation by insulin and IGFs [15]. The components of this system include insulin, insulin receptors, insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), type 1 IGF receptors, type 2 IGF receptors, IGF binding proteins (IGFBPs) 1-6, and IGFBP proteases. The relationships among the various components of this system are illustrated in Fig. 1 and are discussed in detail in Poretsky et al. [15].
Fig. 1

The relationships among the various components of the insulin-related ovarian regulatory system. Insulin, IGF-I, and IGF-II, acting through insulin receptors or type I IGF receptors, increase pituitary responsiveness to GnRH; stimulate gonadotropin secretion directly; stimulate ovarian steroidogenesis; inhibit IGFBP-1 and SHBG production; and act synergistically with gonadotropins to promote ovarian growth and cyst formation (Adapted, with permission, from L. Poretsky et al. [15] ©The Endocrine Society)

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 [46].

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.

Tyrosine kinase activation is the earliest postbinding event and is necessary for many of the effects of insulin. Although it is believed to be the main signaling mechanism of the insulin receptor, an alternative-signaling pathway involving the generation of inositolglycan second messengers has been described [47, 48] (see Fig. 2). This alternative pathway has been found to mediate several of the effects of insulin, including, possibly, ovarian steroid production. Thus, activation of MAP-kinase and inositolglycan signaling cascades follows pathways that are distinct from those involved in glucose transport. This phenomenon of postreceptor divergence of insulin signaling pathways helps explain how some of the effects of insulin may be normally preserved, or even overexpressed, in the presence of hyperinsulinemia observed in insulin-resistant states. In fact, it has been demonstrated that some of the ovarian effects of insulin are PI-3-kinase independent [49].
Fig. 2

Insulin receptor, its signaling pathways for glucose transport, and hypothetical mechanisms of stimulation or inhibition of steroidogenesis. The main pathways for the propagation of the insulin signal include the following events: after insulin binds to the insulin receptor α-subunits, the β-subunit tyrosine kinase is activated; IRS-1 and -2 are phosphorylated; PI-3 kinase is activated; GLUT glucose transporters are translocated to the cell membrane, and glucose uptake is stimulated. An alternative-signaling system may involve generation of inositolglycans at the cell membrane after insulin binding to its receptor. This inositolglycan signaling system may mediate insulin modulation of steroidogenic enzymes (Adapted, with permission, from L. Poretsky et al. [15] ©The Endocrine Society)

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].

Recent studies suggested yet another pathway which explains preserved insulin sensitivity in the ovary by invoking insulin-induced activation of PPAR-γ gene. This activation was shown to have direct and indirect effects in the ovary (Table 2). Activation of PPAR-γ by PPAR-γ agonists, thiazolidinediones (TZD) (rosiglitazone or pioglitazone), has been shown to produce direct effects in the ovary, which can be both insulin independent and insulin sensitizing [53]. Another study demonstrated an interaction between PPAR-γ and insulin signaling pathways with steroidogenic acute regulatory (StAR) protein, thus suggesting that PPAR-γ may represent a novel human ovarian regulatory system [54].
Table 2

Effects of TZDs related to ovarian function (Adapted with permission from Seto-Young et al. [53])

1. Direct

Can be observed in vitro, may be present in vivo

2. Indirect

Observed in vivo; are due to systemic insulin-sensitizing action and reduction of hyperinsulinemia

A. Insulin-independent

↑ 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)

In summary, the paradox of preserved ovarian sensitivity to insulin in insulin-resistant states can be explained by differential regulation of insulin receptors in the ovaries of premenopausal women; by activation of signaling pathways distinct from those involved in glucose transport (inositolglycan and MAP-kinase pathways, rather than tyrosine kinase and PI-3 kinase pathways); by the activation of type 1 IGF receptors which may be upregulated in the presence of hyperinsulinemia; and by activation of PPAR-γ gene leading to improvement in insulin sensitivity either by direct or indirect effects in the ovary (Table 3). In conclusion, in PCOS patients, ovarian sensitivity to insulin appears to be preserved and the insulin signaling pathways do not exhibit hypersensitivity [55].
Table 3

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

Potential mechanisms underlying the gonadotropic activity of insulin include direct effects on steroidogenic enzymes, synergism with FSH and LH, enhancement of pituitary responsiveness to GnRH, and effects on SHBG and on the IGF/IGFBP systems (see Table 4). Investigations focused on these mechanisms have provided insights not only into normal ovarian physiology but also into the pathogenesis of ovarian dysfunction in a wide spectrum of clinical entities, such as obesity, diabetes mellitus, PCOS, and syndromes of extreme insulin resistance.
Table 4

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

Ovary, liver

Potentiates the effect of GnRH on LH and FSH


Inhibits SHBG production


Up-regulates PPAR-γ


Activates StAR protein


Adapted, with permission, from L. Poretsky et al. [15] ©The Endocrine Society

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 [56], but Sahin et al. in a later study found no relation between insulin levels and 17-hydroxyprogesterone (17-OHP) after treatment with GnRH agonist [57]. 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 [58], 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 [15].

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 [64]. But in another study, gonadotropin responsiveness to GnRH did not change after insulin infusion [65]. Similarly, in rats with experimentally produced hyperinsulinemia, response of gonadotropins to GnRH does not appear to be altered [50].

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 [64].

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 [37]. 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].

PPAR-γ . Insulin increases expression of PPAR-γ in vitro in human ovarian cells. Activation of PPAR-γ enhances steroidogenesis via activation of StAR protein (Fig. 3) [54].
Fig. 3

Proposed interactions among PPAR-γ, insulin receptor (IR), IRS-1, and StAR protein in human ovarian cells. Both insulin (by activating primarily insulin receptor) and TZDs (by activating primarily PPAR-γ) lead to stimulation of StAR protein expression. In addition TZDs activate insulin receptor expression while insulin activates expression of PPAR-γ, thus, further enhancing StAR protein expression and stimulating steroidogenesis. Both insulin and TZDs activate a downstream component of insulin signaling pathway, IRS-1. This effect of TZDs may be mediated with or without activation of the insulin receptor (Adapted with permission from Seto-Young et al. [54])

StAR protein . In addition to being activated through PPAR-γ, StAR protein can be also activated by insulin directly via insulin signaling pathway (Fig. 3) [54].

Ovarian growth and cyst formation . It has been shown that insulin enhances theca-interstitial cell proliferation in both human and rat ovaries [74, 75, 76, 77, 78]. In a report of a patient with the type B syndrome of insulin resistance, infusion of insulin resulted in a significant increase of ovarian volume with sonogram demonstrating that the ovaries doubled in size [79]. Experimental hyperinsulinemia in synergism with hCG produces significant increase in ovarian size and development of polycystic ovaries in rats (Fig. 4).
Fig. 4

The effects of 23 days of daily injections of normal saline (control), hCG, insulin, or insulin plus hCG and GnRHant on gross ovarian morphology in rats. Female Sprague–Dawley rats were randomized into the following treatment groups: vehicle; high-fat diet (to control for the effects of weight gain); insulin; hCG; GnRH antagonist (to control for possible central effects of insulin vs. direct effects on the ovary); GnRHant and hCG; insulin and GnRHant; insulin and hCG; insulin, hCG, and GnRHant. Ovarian morphology in the group treated with insulin and hCG (not shown) did not differ from that seen in the group treated with insulin, hCG, and GnRHant (shown above) (Reproduced with permission from L. Poretsky et al. [40] ©W.B. Saunders Co.)

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 [15]. 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 [80].

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 % [81].

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 [82].

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 [81]. 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) [117]. 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 [117]. Hirsutism can be treated with depilatories, shaving, waxing, electrolysis, or laser therapy. Oral contraceptives and antiandrogen medications, such as spironolactone [85] or cyproterone acetate [86], 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 [87]. 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 [118]. 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 [119]. Available data in a healthy population do not support a significant influence of OCs on glucose and insulin homeostasis [120]. 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 [121].

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 [88]. 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 [89]. In another study, 67 obese anovulatory women were treated with weight reduction. Sixty of these women ovulated and eighteen became pregnant [90].

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 [91].

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 [92].

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 [93]. In an analysis of 14 studies of metformin treatment of PCOS, 57 % of women had ovulatory improvement with metformin [94]. 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 [56]. 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) [95].

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 [96]. 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 [97]. Later in a smaller study by Palomba et al., both agents have been found to be equally effective [98].

A thiazolidinedione (TZD) troglitazone, an insulin-sensitizing agent, was the first in its class shown to improve insulin action in patients with PCOS [99]. Studies with troglitazone in patients with PCOS showed improvements in ovulation, insulin resistance, hyperandrogenemia, and hirsutism [100]. 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 [100], 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) [53].

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 [105]. In another study, metformin was compared with rosiglitazone in obese and lean women with PCOS [106]. 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 [107]. 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 [110]. 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 [113]. 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 [115]. 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 [116]. 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.


  1. 1.
    Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovarian syndrome in unselected black and white women of the Southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83:3078–82.PubMedGoogle Scholar
  2. 2.
    Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, editor. Polycystic ovary syndrome. Boston: Blackwell Scientific; 1995. p. 337–84.Google Scholar
  3. 3.
    Rotterdam ESHRE/ASRM – Sponsored PCOS Concensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary disease. Fertil Steril. 2004;81:19–25.Google Scholar
  4. 4.
    Rotterdam ESHRE/ASRM – Sponsored PCOS Concensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary disease. Hum Reprod. 2004;19:41–7.CrossRefGoogle Scholar
  5. 5.
    Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med. 1995;98(Suppl):33S–9S.PubMedCrossRefGoogle Scholar
  6. 6.
    Legro RS. Polycystic ovary syndrome and cardiovascular disease: premature association? Endocr Rev. 2003;24:302–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Hardiman P, Pillay OS, Atiomo W. Polycystic ovary syndrome and endometrial carcinoma. Lancet. 2003;361:1810–2.PubMedCrossRefGoogle Scholar
  8. 8.
    Chereau A. Mémoires pour servir a l’étude des maladies des ovaries. Paris: Fortin, Masson and Cie; 1844.Google Scholar
  9. 9.
    Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181–6.CrossRefGoogle Scholar
  10. 10.
    Culiner A, Shippel S. Virilism and thecal cell hyperplasia of the ovary syndrome. J Obstet Gynaecol Br Commonw. 1949;56:439–45.CrossRefGoogle Scholar
  11. 11.
    McArthur JW, Ingersoll FW, Worcester J. The urinary excretion of interstitial-cell and follicle-stimulating hormone activity by women with diseases of the reproductive system. J Clin Endocrinol Metab. 1958;18:1202–15.PubMedCrossRefGoogle Scholar
  12. 12.
    De Vane GW, Czekala NM, Judd HL, Yen SS. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol. 1975;121:496–500.Google Scholar
  13. 13.
    Cooper H, Spellacy W, Prem K, Cohen W. Hereditary factors in the Stein-Leventhal syndrome. Am J Obstet Gynecol. 1968;100:371–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Unluturk U, Harmanci A, Kocaefe C, Yildiz B. The genetic basis of the polycystic ovary syndrome: a literature review including discussion of PPAR-g. PPAR Res. 2007;2007:49109.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Poretsky L, Cataldo N, Rosenwaks Z, Giudice L. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999;20:535–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J. A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycystic-ovary syndrome. N Engl J Med. 1983;309:1206–9.PubMedCrossRefGoogle Scholar
  17. 17.
    McLachlan RI, Healy DL, Burger HG. The ovary. In: Felig P, Baxter JD, Broadus AE, Frohman LA, editors. Endocrinology and metabolism. 2nd ed. New York: McGraw-Hill Book; 1987. p. 951–83.Google Scholar
  18. 18.
    Pang S, Softness B, Sweeney WJ, New MI. Hirsutism, polycystic ovarian disease, and ovarian 17-ketosteroid reductase deficiency. N Engl J Med. 1987;316:1295–301.PubMedCrossRefGoogle Scholar
  19. 19.
    Nelson VL, Qin K-N, Rosenfeld RL, et al. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:5925–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Poretsky L, Kalin M. The gonadotropic function of insulin. Endocr Rev. 1987;8:132–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Archard C, Thiers J. Le virilisme pilaire et son association a l’insuffisance glycolytique (diabete des femmes a barbe). Bull Acad Natl Med. 1921;86:51.Google Scholar
  22. 22.
    Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med. 1976;294:739–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science. 1975;190:63–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Taylor SI, Moller DE. Mutations of the insulin receptor gene. In: Moller DE, editor. Insulin resistance. New York: Wiley; 1993. p. 83–121.Google Scholar
  25. 25.
    Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774–800.PubMedGoogle Scholar
  26. 26.
    Salehi M, Bravo-Vera R, Sheikh A, Gouller A, Poretsky L. Pathogenesis of polycystic ovary syndrome: what is the role of obesity? Metabolism. 2004;53:358–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Dunaif A, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96:801–10.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Svedberg J, Bjorntorp P, Smith U, et al. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes. 1990;39:570–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIIDM. Diabetes. 1997;46:3–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Kelley DE. Skeletal muscle triglycerides: an aspect of regional adiposity and insulin resistance. Ann N Y Acad Sci. 2002;967:135–45.PubMedCrossRefGoogle Scholar
  31. 31.
    Hotamisligil GS, Peraldi P, Budavari A. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha and obesity-induced insulin resistance. Science. 1996;271:665–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Hrebicek A, Rypka M, Chmela Z, et al. Tumor necrosis factor alpha in various tissues and of insulin-resistant obese Koletsky rats: relations to insulin receptor characteristics. Physiol Res. 1999;48:83–6.PubMedGoogle Scholar
  33. 33.
    Holte J, Bergh T, Berne C, et al. Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol. 1994;41:463–71.CrossRefGoogle Scholar
  34. 34.
    Ek I, Arner P, Ryden M, et al. A unique defect in the regulation of visceral fat cell lipolysis in the polycystic ovary syndrome as an early link to insulin resistance. Diabetes. 2002;51:484–92.PubMedCrossRefGoogle Scholar
  35. 35.
    Escobar-Morreale HF, Calvo RM, Sancho J, et al. TNF-alpha hyperandrogenism: a clinical, biochemical, and molecular genetic study. J Clin Endocrinol Metab. 2001;86:3761–7.PubMedGoogle Scholar
  36. 36.
    Poretsky L, Smith D, Seibel M, Pazianos A, Moses AC, Flier JS. Specific insulin binding sites in the human ovary. J Clin Endocrinol Metab. 1984;59:809–11.PubMedCrossRefGoogle Scholar
  37. 37.
    Poretsky L, Grigorescu F, Seibel M, Moses AC, Flier JS. Distribution and characterization of the insulin and IGF-I receptors in the normal human ovary. J Clin Endocrinol Metab. 1985;61:728–34.PubMedCrossRefGoogle Scholar
  38. 38.
    El-Roeiy A, Chen X, Roberts VJ, et al. Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins 1-6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries. J Clin Endocrinol Metab. 1994;78:1488–96.PubMedGoogle Scholar
  39. 39.
    Barbieri RL, Makris A, Ryan KJ. Effects of insulin on steroidogenesis in cultured porcine ovarian theca. Fertil Steril. 1983;40:237–41.PubMedGoogle Scholar
  40. 40.
    Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41:903–10.PubMedCrossRefGoogle Scholar
  41. 41.
    Poretsky L, Chandrasekher YA, Bai C, Liu HC, Rosenwaks Z, Giudice L. Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-1, on binding protein 1 (IGFBP-1) production in human granulosa cells. J Clin Endocrinol Metab. 1996;81:493–6.PubMedGoogle Scholar
  42. 42.
    Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Joslin EP, Root HF, White P. The growth, development and prognosis of diabetic children. J Am Med Assoc. 1925;85:420–2.CrossRefGoogle Scholar
  44. 44.
    Zumoff B, Miller L, Poretsky L, et al. Subnormal follicular-phase serum progesterone levels and elevated follicular-phase serum estradiol levels in young women with insulin-dependent diabetes. Steroids. 1990;55:560–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Poretsky L, Bhargava G, Kalin MF, Wolf SA. Regulation of insulin receptors in the human ovary: in vitro studies. J Clin Endocrinol Metab. 1988;67:774–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Poretsky L, Bhargava G, Saketos M, Dunaif A. Regulation of human ovarian insulin receptors in vivo. Metabolism. 1990;39:161–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Saltiel AR. Second messengers of insulin action. Diabetes Care. 1990;13:244–56.PubMedCrossRefGoogle Scholar
  48. 48.
    Nestler JE, Jakubowicz DJ, De Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovarian syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83:2001–5.PubMedGoogle Scholar
  49. 49.
    Poretsky L, Seto-Young D, Shrestha A, et al. Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. J Clin Endocrinol Metab. 2001;86:3115–9.PubMedGoogle Scholar
  50. 50.
    Poretsky L, Glover B, Laumas V, Kalin M, Dunaif A. The effects of experimental hyperinsulinemia on steroid secretion, ovarian [125I] insulin binding, and ovarian [125I] insulin-like growth factor I binding in the rat. Endocrinology. 1988;122:581–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Samoto T, Maruo T, Matsuo H, Katayama K, Barnea ER, Mochizuki M. Altered expression of insulin and insulin-like growth factor-I receptors in follicular and stromal compartments of polycystic ovarian ovaries. Endocr J. 1993;40:413–24.PubMedCrossRefGoogle Scholar
  52. 52.
    Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab. 1996;81:302–9.PubMedGoogle Scholar
  53. 53.
    Seto-Young D, Paliou M, Schlosser J, et al. Thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production. J Clin Endocrinol Metab. 2005;90:6099–105.PubMedCrossRefGoogle Scholar
  54. 54.
    Seto-Young D, Avtanski D, Strizhevsky M, et al. Interactions among peroxisome proliferators activated receptor-g, insulin signaling pathways, and steroidogenic acute regulatory protein in human ovarian cells. J Clin Endocrinol Metab. 2007;92:2232–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Poretsky L. Commentary: polycystic ovary syndrome-increased or preserved ovarian sensitivity to insulin? J Clin Endocrinol Metab. 2006;91:2859–60.PubMedCrossRefGoogle Scholar
  56. 56.
    Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335:617–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Sahin Y, Ayata D, Kelestimur F. Lack of relationship between 17-hydroxyprogesterone response to buserelin testing and hyperinsulinemia in polycystic ovary syndrome. Eur J Endocrinol. 1997;136:410–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Fulghesu AM, Villa P, Pavone V, et al. The impact of insulin secretion on the ovarian response to exogenous gonadotropins in polycystic ovarian syndrome. J Clin Endocrinol Metab. 1997;82:644–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Stuart CA, Nagamani M. Acute augmentation of plasma androstenedione and dehydroepiandrosterone by euglycemic insulin infusion: evidence for a direct effect of insulin on ovarian steroidogenesis. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, editors. Polycystic ovary syndrome. Boston: Blackwell Scientific Publications; 1992. p. 279–88.Google Scholar
  60. 60.
    Stuart CA, Prince MJ, Peters EJ, Meyer WJ. Hyperinsulinemia and hyperandrogenemia: in vivo androgen response to insulin infusion. Obstet Gynecol. 1987;69:921–5.PubMedGoogle Scholar
  61. 61.
    Poretsky L, Piper B. Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome. Obstet Gynecol. 1994;84:613–21.PubMedGoogle Scholar
  62. 62.
    Adashi EY, Hsueh AJW, Yen SSC. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981;108:1441–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Soldani R, Cagnacci A, Yen SS. Insulin, insulin-like growth factor I (IGF I) and IGF-II enhance basal and gonadotropin-releasing hormone-stimulated luteinizing hormone release from rat anterior pituitary cells in vitro. Eur J Endocrinol. 1994;131:641–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075–9.PubMedGoogle Scholar
  65. 65.
    Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with polycystic ovary syndrome. J Clin Invest. 1989;83:23–9.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (HepG2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 1988;67:460–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Peiris AN, Stagner JL, Plymate SR, Vogel RL, Heck M, Samols E. Relationship of insulin secretory pulses to sex hormone-binding globulin production in normal men. J Clin Endocrinol Metab. 1993;76:279–82.PubMedGoogle Scholar
  68. 68.
    Fendri S, Arlot S, Marcelli JM, Dubreuil A, Lalau JD. Relationship between insulin sensitivity and circulating sex hormone-binding globulin levels in hyperandrogenic obese women. Int J Obes Relat Metab Disord. 1994;18:755–9.PubMedGoogle Scholar
  69. 69.
    Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Pao CI, Farmer PK, Begovic S, et al. Regulation of insulin-like growth factor-I (IGF I) and IGF-binding protein I gene transcription by hormones and provision of amino acids in rat hepatocytes. Mol Endocrinol. 1993;7:1561–8.PubMedGoogle Scholar
  71. 71.
    Lee PD, Giudice LC, Conover CA, Powell DR. Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med. 1997;216:319–57.PubMedCrossRefGoogle Scholar
  72. 72.
    Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev. 1992;13:641–69.PubMedGoogle Scholar
  73. 73.
    Nagami M, Stuart CA. Specific binding sites for insulin-like growth factor I in the ovarian stroma of women with polycystic ovarian disease and stromal hyperthecosis. Am J Obstet Gynecol. 1990;163:1992–7.CrossRefGoogle Scholar
  74. 74.
    Duleba AJ, Spaczynski RZ, Olive DL, Behrman HR. Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells. Biol Reprod. 1997;56:891–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Duleba AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells. Fertil Steril. 1998;69:335–40.PubMedCrossRefGoogle Scholar
  76. 76.
    Watson H, Willis D, Mason H, Modgil G, Wright C, Franks S. The effects of ovarian steroids, epidermal growth factor (EGF), insulin (I), and insulin-like growth factor-1 (IGF-I), on ovarian stromal cell growth. Program of the 79th Annual Meeting of the Endocrine Society, Minneapolis, (Abstract 389); 1997.Google Scholar
  77. 77.
    Bogovich K, Clemons J, Poretsky L. Insulin has a biphasic effects on the ability of human chorionic gonadotropin to induce ovarian cysts in the rat. Metabolism. 1999;48:995–1002.PubMedCrossRefGoogle Scholar
  78. 78.
    Damario M, Bogovich K, Liu HC, Rosenwaks Z, Poretsky L. Synergistic effects of IGF-I and human chorionic gonadotropin in the rat ovary. Metabolism. 2000;49:314–20.PubMedCrossRefGoogle Scholar
  79. 79.
    De Clue TJ, Shah SC, Marchese M, Malone JI. Insulin resistance and hyperinsulinemia induce hyperandrogenism in a young type B insulin-resistant female. J Clin Endocrinol Metab. 1991;72:1308–11.CrossRefGoogle Scholar
  80. 80.
    Dunaif A, Finegood DT. Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:942–7.PubMedGoogle Scholar
  81. 81.
    Legro R, Kunselman A, Dodson W, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165–9.PubMedGoogle Scholar
  82. 82.
    Koivunen RM, et al. Metabolic and steroidogenic alterations related to increased frequency of polycystic ovaries in women with a history of gestational diabetes. J Clin Endocrinol Metab. 2001;86:2591–9.PubMedGoogle Scholar
  83. 83.
    The Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care. 2000;23(11):1619–29.PubMedCentralCrossRefGoogle Scholar
  84. 84.
    Fujimoto W. Background and recruitment data for the U.S. Diabetes Prevention Program. Diabetes Care. 2000;23:B11–3.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Board JA, Rosenberg SM, Smeltzer JS. Spironolactone and estrogen-progestin therapy for hirsuitism. South Med J. 1987;80:483–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Falsetti L, Gamera A, Tisi G. Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome. Hum Reprod. 2001;16:36–42.PubMedCrossRefGoogle Scholar
  87. 87.
    Dewis P, Petsos P, Newman M, Anderson DC. The treatment of hirsuitism with a combination of desogestrel and ethinyl oestradiol. Clin Endocrinol. 1985;22:29–36.CrossRefGoogle Scholar
  88. 88.
    Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese infertile women. Fertil Steril. 1982;38:406–9.PubMedGoogle Scholar
  89. 89.
    Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, et al. Clinical and hormonal characteristics of obese and amenorrheic women before and after weight loss. J Clin Endocrinol Metab. 1989;68:173–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod. 1998;13:1502–5.PubMedCrossRefGoogle Scholar
  91. 91.
    Crave JC, Fimbel S, Lejeune H, Cugnardey N, DeChaud H, Pugeat M. Effects of diet and metformin administration on sex hormone-binding globuliln, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab. 1995;80:2057–62.PubMedGoogle Scholar
  92. 92.
    Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000;85:139–46.PubMedGoogle Scholar
  93. 93.
    Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338:1876–80.PubMedCrossRefGoogle Scholar
  94. 94.
    Bloomgarden ZT, Futterwiet W, Poretsky L. The use of insulin-sensitizing agents in patients with polycystic ovary syndrome. Endocr Pract. 2001;7:279–86.PubMedCrossRefGoogle Scholar
  95. 95.
    Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90:392–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Jakubowicz DJ, Seppala M, Jakubowicz S, et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:1126–33.PubMedGoogle Scholar
  97. 97.
    Legro R, Barnhart H, Schlaff W, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.PubMedCrossRefGoogle Scholar
  98. 98.
    Palomba S, Orio F, Falbo A, Russo T, Tolino A, Zullo F. Clomiphene citrate versus metformin as first-line approach for the treatment of infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92:3498–503.PubMedCrossRefGoogle Scholar
  99. 99.
    Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81:3299–306.PubMedGoogle Scholar
  100. 100.
    Azziz R, Ehrmann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2001;86:1626–32.PubMedGoogle Scholar
  101. 101.
    Dereli D, Dereli T, Bayraktar F, Ozgen A, Yilmaz C. Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease. Endocr J. 2005;52:299–308.PubMedCrossRefGoogle Scholar
  102. 102.
    Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen LC. Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo-controlled study. Hum Reprod. 2006;21:1400–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Brettenthaler N, De Geyter C, Huber P, Keller U. Effect of insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:3835–40.PubMedCrossRefGoogle Scholar
  104. 104.
    Garmes H, Tambascia M, Zantut-Wittmann D. Endocrine-metabolic effects of the treatment with pioglitazone in obese patients with polycystic ovary syndrome. Gynecol Endocrinol. 2005;21:317–23.PubMedCrossRefGoogle Scholar
  105. 105.
    Ashraf Ganie M, Khurana M, Eunice M, Gulati M, Dwivedi S, Ammini A. Comparison of the efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study. J Clin Endocrinol Metab. 2004;89:2756–62.PubMedCrossRefGoogle Scholar
  106. 106.
    Yilmaz M, et al. The effect of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with PCOS. J Endocrinol Invest. 2005;29:1003–9.CrossRefGoogle Scholar
  107. 107.
    Ortega-Gonzalez C, Luna S, Hernandez L, et al. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:1360–5.PubMedCrossRefGoogle Scholar
  108. 108.
    Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradio-cyproterone acetate in non-obese women with polycystic ovary syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729–37.PubMedCrossRefGoogle Scholar
  109. 109.
    Cibula D, Fanta M, Vrbikova J, et al. The effect of combination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hyperandrogenaemia, SHBG and lipids in PCOS patients. Hum Reprod. 2005;20:180–4.PubMedCrossRefGoogle Scholar
  110. 110.
    Lemay A, Dodin S, Turcot L, Dechene F, Forest J-C. Rosiglitazone and ethinyl estradiol/cyproterone acetate as single and combined treatment of overweight women with polycystic ovary syndrome and insulin resistance. Hum Reprod. 2006;21:121–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Chen ZJ, Zhao H, He L, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011;45:55.CrossRefGoogle Scholar
  112. 112.
    Goodarzi MO, Jones MR, Li X, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012;49:90.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Jensterle Sever M, Kocjan T, Pfeifer M, Aleksandra Kravos N, Janez A. Short-tem combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycycstic ovary syndrome and previous poor response to metformin. Eur J Endocrinol. 2014;170:451–9.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Rasmussen C, Lindenberg S. The effect of liraglutide on weight loss in women with polycystic ovary syndrome: an observational study. Front Endocrinol. 2014;5:1–6.CrossRefGoogle Scholar
  115. 115.
    Dinicola S, Chiu T, Unfer V, Carlomagno G, Bizzarri M. The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. J Clin Pharmacol. 2014;54(10):1079–92.PubMedCrossRefGoogle Scholar
  116. 116.
    Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myoinositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol. 2012;28(7):509–15.PubMedCrossRefGoogle Scholar
  117. 117.
    Pinola P, Piltonene TT, Puurunen J, Vanky E, Sundstrom-Poromaa I, Stener-Victorin E, Ruokonen A, Puukka K, Tapanainen J, Morin-Papunen LC. Androgen profile through life in women with PCO: a Nordic multicenter collaboration study. J Clin Endocrinol Metab. 2015;100(9):3400–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Yildiz BO. Approach to the patient: contraception in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2015;100(3):794–802.PubMedCrossRefGoogle Scholar
  119. 119.
    Sitruk-Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Pract Res Clin Endocrinol Metab. 2013;27:13–24.PubMedCrossRefGoogle Scholar
  120. 120.
    Troisi RJ, Cowie CC, Harris MI. Oral contraceptive use and glucose metabolism in a national sample of women in the United States. Am J Obstet Gynecol. 2000;183:389–95.PubMedCrossRefGoogle Scholar
  121. 121.
    Halperin IJ, Kumar SS, Stroup DF, Laredo SE. The association between the combined oral contraceptive pill and insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of observational studies. Hum Reprod. 2011;26:191–201.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Minisha Sood
    • 1
  • Susan B. Zweig
    • 2
  • Marsha C. Tolentino
    • 3
  • Marina Strizhevsky
    • 4
  • Leonid Poretsky
    • 1
    Email author
  1. 1.Division of EndocrinologyLenox Hill Hospital, Northwell HealthNew YorkUSA
  2. 2.Division of EndocrinologyNYU Langone Medical CenterNew YorkUSA
  3. 3.Perpetual Succour Hospital and Cebu Doctors’ University HospitalCebuPhilippines
  4. 4.Barnabas Health Medical GroupCliftonUSA

Personalised recommendations