Pathogenesis of polycystic ovary syndrome: What is the role of obesity?
Source:
http://www2.us.elsevierhealth.com/sc...26049503004979
Abstract TOP
Both obesity and the polycystic ovary syndrome (PCOS) are commonly seen in women of reproductive age. Fifty percent of all patients with PCOS are obese, and the presence of obesity affects the clinical manifestations of PCOS. The underlying pathogenetic mechanisms appear to involve insulin resistance and hyperinsulinemia, the magnitude of which is greater in obese than in non-obese women with PCOS. Specific effects of obesity on the manifestations of PCOS, underlying mechanisms of the interactions between obesity and PCOS, and therapeutic implications of these interactions are discussed in this article.
POLYCYSTIC OVARY syndrome (PCOS) is the most common endocrinological disorder of reproductive age women. Although its etiology remains unknown and the pathogenesis is unclear, a variety of theories have been proposed to explain the development of PCOS. These theories classically included the “central hypothesis,” which postulated a primary defect at the level of the hypothalamus/pituitary, and an “ovarian hypothesis,” which proposed a primary defect of steroidogenesis in the ovary.
The most recent theories of the pathogenesis of PCOS have focused also on the role of insulin resistance and hyperinsulinemia. It has been proposed that, by a variety of mechanisms, hyperinsulinemia increases ovarian androgen production and contributes to the development of the hallmark abnormality of PCOS-anovulation. The insights into the role of hyperinsulinemia in the development of PCOS brought into focus the role of obesity, which is present in about 50% of patients with PCOS and which magnifies hyperinsulinemia observed in PCOS patients. In addition to enhanced hyperinsulinemia, other potential contributions of obesity to the development of PCOS involve a recently discovered hormone, leptin, produced in adipose tissue, and the enzymatic activity of adipose tissue as it relates to steroid hormone metabolism (eg, aromatase and 11- hydroxysteroid dehydrogenase [11-HSD]).
In the course of this article, we will first review current theories of the development of PCOS and then focus on the role of obesity in its pathogenesis. Specifically, we will review the contributions of insulin resistance/hyperinsulinemia, leptin, and adipose tissue steroid hormone metabolism to the development of PCOS. We will then examine differences between clinical presentations of PCOS in obese and non-obese women. We will conclude the article by discussing therapeutic approaches to PCOS, focusing, in particular, on therapeutic modalities which address pathogenetic contributions of obesity to the development of this common disorder.
Definition, genetics, and epidemiology of PCOS TOP
In their original description of the syndrome, Stein and Leventhal1 reported the condition characterized by enlarged ovaries, which contained multiple small subcapsular cysts and were associated with amenorrhea and hirsutism. PCOS, as it is understood today, is a disorder of unknown and probably heterogeneous etiology, which is characterized by chronic anovulation, menstrual irregularities, evidence of hyperandrogenism (either clinical, manifested as hirsutism, acne, male pattern balding, or biochemical, manifested by elevated serum adrenal and/or ovarian androgen concentration), and exclusion of other etiologic factors (nonclassical congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, thyroid disease, and androgen-producing tumors).2 These diagnostic criteria, adopted by the 1990 National Institutes of Health consensus conference on PCOS, do not require pelvic ultrasonography to evaluate ovarian morphology.
Demonstration of polycystic ovaries on ultrasound is not required for diagnosis of PCOS because, with the introduction of high-resolution ultrasonography, it became apparent that 20% of healthy women have morphologic features of polycystic ovaries, and only some of them have symptoms of hyperandrogenemia.3 Furthermore, while 80% to 100% of women with PCOS have polycystic ovaries (which are defined sonographically by the presence of 8 or more small 4 to 8 mm follicles in each ovary in subcapsular location) so do many women with idiopathic hirsutism and other hyperandrogenic disorders.4 Finally, ovarian vein catheterization studies proved that ovarian hyperandrogenism may be present with and without polycystic ovaries.5
Although the etiology of PCOS remains unclear, there is increasing evidence for a genetic component. Givens et al6 were among the first to describe a familial presentation of this disease. The specific genetic defect, if any, causing familial PCOS is unknown. Autosomal dominant type of inheritance has been suggested by familial clustering of cases and high prevalence of PCOS (close to 50%) among siblings.7,8
PCOS is the most common endocrinopathy in women of reproductive age with a probable prevalence of 5% to 10%. Available data on the prevalence of PCOS are variable, in part due to ethnic differences and lack of consistent criteria for diagnosis. By the end of the 20th century, the prevalence of PCOS had ranged from 2% to 20% in general population studies.9–11 In 1998, a prospective study that used the above criteria reported 3.4% prevalence of PCOS in African American and 4.7% in Caucasian women who presented for a routine pre-employment history and physical examination in the United States.10 A survey in Greece reported 6.8% prevalence of PCOS, similar to that seen in the United States.11 In some genetically homogeneous groups, such as, for example, the Pima Indians, who also have a very high prevalence of obesity and diabetes (the latter approaching 50%), the prevalence of PCOS has been reported as high as 21%.12
Obesity, insulin resistance, and hyperinsulinemia TOP
Women with PCOS are often insulin resistant and hyperinsulinemic.13 Both insulin resistance and hyperinsulinemia are magnified in the presence of obesity, which is defined by body mass index (BMI = body weight in kilograms divided by height in meters2) of 30 kg/m2 or more. BMI of 25 to 29.9 kg/m2 is defined as ‘overweight’, while BMI of less than 25 kg/m2 is considered normal.14
Rabinowitz and Zierler15 were among the first to demonstrate the presence of insulin resistance in obese individuals. Obesity in PCOS is usually of the central variety. Central obesity (also called visceral, android, abdominal, or male-type) can be diagnosed clinically by measuring the waist circumference (WC) or waist-to-hip circumference ratio (WHR).14 WC larger than 102 cm for men and 88 cm for women or WHR greater than 0.95 in men and 0.85 in women confer high risk for metabolic complications in obese individuals with BMI between 25.0 and 34.9 kg/m2.16 Studies have shown that excess fat in the upper part of the body is associated with increased risk for diabetes, hyperlipidemia, hypertension, atherosclerosis, and insulin resistance17 more often than peripheral fat excess (gynoid, female-type, or peripheral obesity).18–21 Buffington and Kitabchi22 studied insulin clearance in obese PCOS patients and concluded that the hyperinsulinemia may be due, in part, to defects in insulin clearance and peripheral tissue insulin degradation. Thus, in addition to its association with insulin resistance, fat localized in the upper body is correlated with significantly reduced overall clearance of insulin, which contributes to hyperinsulinemia.23
Although the mechanisms by which obesity causes insulin resistance are not fully understood, the 2 main pathogenetic hypotheses that have been proposed focus on the roles of free fatty acids (FFAs) and tumor necrosis factor- (TNF-).
FFAs, which are released from adipose tissue triglycerides via lipolysis, are the key mediators of impaired insulin sensitivity. Elevated circulating levels of FFA have been reported in PCOS patients,24 and Ek et al25 showed that visceral adipocytes in PCOS women exhibit significantly increased cathecholamine-induced lipolysis in vitro.
Whether visceral adipose tissue differs from subcutaneous adipose tissue in the magnitude of FFA flux into liver is not quite clear. FFA released from the splanchnic bed account for only about 10% of the FFA reaching the liver.26 Recent studies using catheterization of the hepatic vein to determine the maximal contribution of visceral and mesenteric fat depots to the increased fatty acid release in women with upper body obesity have concluded that the major source of FFA in circulation is not the visceral depot, but rather upper body nonsplanchnic subcutaneous adipose tissue.27
Increased FFA flux into the liver, irrespective of its source, decreases hepatic insulin extraction, increases gluconeogenesis, and produces hyperinsulinemia.28,29 Additionally, high circulating FFA concentrations lead to peripheral insulin resistance by reducing glucose uptake by the skeletal muscle.29,30
TNF- is produced by adipose tissue and leads to insulin resistance by stimulating the phosphorylation of serine residues of the insulin receptor substrate-1 (IRS-1). Consequently, tyrosine kinase activity of the insulin receptor -subunit, the rate-limiting component of the insulin receptor signaling cascade, is inhibited.31,32 Serum TNF- concentrations have been reported to be high in hyperandrogenic women,33 including women with PCOS.33 The nature of the direct effects of TNF- on ovarian cells, if any, is not understood. TNF- was shown to enhance the proliferative actions of insulin and insulin-like growth factor-I (IGF-I) in rat ovarian theca cells,34 but, on the other hand, it inhibited gonadotropin-stimulated steroidogenesis.35
In summary, regardless of its pathogenesis, insulin resistance is commonly present in obesity, particularly in its central or android form, which is the characteristic form of obesity in PCOS. As will be discussed later in this article (in the section comparing obese and non-obese women with PCOS), obesity magnifies insulin resistance and hyperinsulinemia in PCOS patients.
Endocrine abnormalities in PCOS: the role of obesity TOP
Based on the putative primary abnormality, 3 major hypotheses of the pathogenesis of PCOS have been proposed. They are the central (luteinizing hormone [LH]) hypothesis, the peripheral (ovarian or adrenal) hypothesis, and the insulin hypothesis (Table 1).
--------------------------------------------------------------------------------
Table 1.Theories of the Pathogenesis of PCOS
--------------------------------------------------------------------------------
Theory Primary Defect Origin of Abnormality Mechanism
Central (LH) hypothesis Increased LH pulse amplitude and frequency; elevated LH/FSH ratio. ?Primary abnormality in GnRH pulsatility36 (rapid pulse generation). -Increased LH secretion leading to hyperandrogenism.
?Sensitization of GnRH receptor to GnRH by endogenous opioids.38,43
?Reduced dopaminergic inhibition of LH release.43
Peripheral (ovarian or adrenal) hypotheses54,55 1. Intrinsic ovarian or adrenal defect leading to overproduction of androgens and anovulation. Ovarian theca cell hypertrophy.52 Steroidogenic and mitogenic abnormalities of granulosa cells.40 -Dysregulated function of the p450 C17-alpha in the ovaries and adrenal glands;54–56,152 autocrine and paracrine local defects as well as blocked FSH activity at the ovarian level.40
2. Inhibin B deficiency. Product of granulosa cells, inhibin B locally enhances follicular development.211 -Deficiency of inhibin results in anovulation.211
Insulin/IGF hypothesis Insulin resistance and hyperinsulinemia. Postreceptor defect in insulin signaling. -Hyperinsulinemia leads to inhibition of SHBG secretion and increase in free fraction of androgens.40
-Direct stimulation of ovarian steroidogenesis by hyperinsulinemia.152
-Synergism of insulin with LH leads to stimulation of theca cells, hyperandrogenism59 and large cystic ovaries.210
Increase in free IGF-I and IGF-II.212 Systemic and local excess of free IGFs. -Potentiate LH-stimulated androgen synthesis in theca cells.153
-Supresses IGFBP-1 synthesis.159,160
--------------------------------------------------------------------------------
Gonadotropins and the central hypothesis
In 1970 Yen et al36 reported that increased serum luteinizing hormone (LH) concentration or increased LH to follicle-stimulating hormone (FSH) ratio were characteristic of the syndrome. The increased LH/FSH ratio became a commonly used diagnostic criterion in association with a biopsy confirming polycystic ovarian morphology.
While serum concentrations of FSH in anovulatory women with the PCOS are similar to those in the midfollicular phase of normal cycle, approximately 75% of women with PCOS exhibit elevated pooled LH serum concentrations compared with ovulatory control women.37 The prevalence of this abnormality has ranged from 30% to 90%, depending on gonadotropin assays used and timing of sampling.38 Gonadotropin-releasing hormone (GnRH) pulse amplitude and frequency determine the preferential gonadotropin secretion, slower pulses favoring FSH release, while more rapid pulses favoring increased LH secretion. Abnormally rapid GnRH pulse generation is assumed to underlie abnormal LH secretion in PCOS.36 Studies addressing the response of gonadotropins to GnRH have demonstrated an increased LH responsiveness,39 with no differences in FSH response in PCOS patients when compared with normal women. This preferential LH responsiveness may be related to the elevated circulating concentrations of estrone, which, as will be discussed below, are commonly present in PCOS women. Conversely, selective suppressive effects on FSH response may be related to the effects of estradiol and inhibins, although the role of inhibins in decreased FSH responsiveness has not been clearly demonstrated in PCOS women.38
Whether the hypothalamic defect, manifested by rapid GnRH pulse generation, is the primary cause of PCOS or whether this abnormality is secondary to other hormonal phenomena, such as hyperinsulinemia, remains to be determined. It has been shown that insulin augments the effect of GnRH on gonadotropin secretion in vitro.40 However, the ability of either insulin or IGFs to enhance gonadotrope sensitivity to GnRH-releasing hormone has not been consistently demonstrated in vivo.40–42
In addition to abnormal GnRH function, other central mechanisms involved in the pathogenesis of PCOS may include abnormalities of neuroendocrine modulators, such as endogenous opioids and dopamine.38,43 There is evidence suggesting that endogenous opioid excess may play a role in sensitization of the gonadotrope to GnRH and that decreased dopaminergic inhibition, leading to increased prolactin and LH secretion, is present in women with this disorder.43 Further, B-endorphin administration increases insulin secretion in humans, and opioid antagonists suppress glucose-stimulated insulin secretion, particularly in patients with central obesity.44 Thus, in obese PCOS women, excessive activation of the opioid system may contribute to a higher degree of hyperinsulinemia than in non-obese patients.
Two studies by Arroyo et al45 and Morales et al46 addressed the role of obesity in the abnormalities of the gonadotropin axis in PCOS and reported consistent results: accelerated LH pulse frequency is seen in many patients with PCOS, regardless of body weight, but obese patients exhibit lower LH pulse amplitude and mean circulating LH values than lean patients. Factors proposed to account for these differences include variations of insulin and leptin levels, as well as differences in cathecholamine and endorphine metabolism. The exact mechanism, however, remains unclear.
Today, an increased LH/FSH ratio is not required for diagnosis of PCOS, because this ratio can be elevated in women without identifiable ovarian pathology,3 as well as in women with other hyperandrogenic disorders, such as, for example, congenital adrenal hyperplasia.47
Regardless of the cause, LH hypersecretion, when present, is thought to contribute to stromal and thecal stimulation with a resultant increase in ovarian andogen secretion in PCOS.
Ovarian androgens and the ovarian hypothesis
Evidence suggesting a primary ovarian role in androgen excess in PCOS women includes the following observations: increased synthesis of testosterone and androstenedione by the ovaries, documented by direct sampling of ovarian and adrenal venous blood48,49; suppression of serum testosterone and androstenedione concentrations in PCOS women treated with GnRH agonists, whereas dehydroepiandrosterone concentrations remains unaltered50; decreased serum androgen concentrations after ablation of ovarian interstitial tissue.51
An intrinsic ovarian defect has been postulated as a primary cause of PCOS. Thecal hypertrophy and overproduction of androgens are characteristic of the PCOS ovary.52 Women with PCOS exhibit increased circulating levels of 17-OH progesterone, as well as increased ovarian 17-OH-progesterone response to stimulation with GnRH, GnRH-agonists, or human chorionic gonadotropin (hCG).53 This exaggerated response suggests a dysregulated function of ovarian P450c-17--hydroxylase, an enzyme with 17-hydroxylase and 17,20-lyase functions. P450c-17--hydroxylase can be selectively induced to increase 17,20-lyase activity (leading to excessive androgen production) by serine phosphorylation.54–56 Interestingly, almost 50% of women with PCOS have been reported to have an abnormally high level of serine phosphorylation of the insulin receptor -subunit13; such insulin-receptor serine phosphorylation inhibits insulin receptor signaling. Thus, an abnormality of serine phosphorylation may account for both insulin resistance and excess androgen prodution in some women with PCOS.
Possibly because of increased 17-hydroxylase activity and reduced aromatase activity (the latter abnormality will be discussed in more detail later in the article), serum concentrations of ovarian androgens (testosterone and androstenedione) are 50% to 150% higher in PCOS women than in control populations.57–59 Further, serum concentration of sex hormone-binding globulin (SHBG) is decreased because of the inhibitory effect of hyperinsulinemia on SHBG production.60 As a result, free testosterone concentration is increased out of proportion to total testosterone in women with PCOS.40
In a study performed in the United Kingdom, total testosterone and androstenedione concentrations in serum were similar in obese and non-obese women with PCOS, but serum SHBG concentrations were significantly lower and circulating free testosterone levels higher in obese compared with lean subjects. In addition, circulating concentrations of androsterone glucuronide, a marker of peripheral 5-reductase activity, were higher in obese than in non-obese women.60 These abnormalities may be due to hyperinsulinemia, which is more pronounced in the presence of obesity.
Adrenal androgens and cortisol
Many studies have demonstrated adrenocortical hyperfunction in PCOS. Adrenal uptake of I-131-iodocholesterol and serum concentration of dehydroepiandrosterone sulfate (DHEAS) are increased in 20% of women with PCOS.61–63 The most common adrenocortical disturbance in this syndrome, present in about 50% of women with PCOS, is excessive DHEAS response to adrenocorticotrophic hormone (ACTH) stimulation.63 Adrenal glands may also contribute to the excess of testosterone and androstenedione in PCOS, because administration of metyrapone to women with PCOS causes an excessive increase in serum levels of these hormones.64
One of the theories of the pathogenesis of PCOS involves a hypothesis that increased cortisol metabolism leads to a compensatory increase in corticotropin secretion, in order to maintain normal circulating cortisol concentrations. Increased corticotropin secretion, in turn, leads to increased adrenal production of androgens.65 In support of this hypothesis, increased mean serum concentrations and pulse frequency and amplitude of both ACTH and cortisol during daytime were noted in PCOS patients.66
Some investigators have proposed that cortisol metabolism may be affected in patients with PCOS because of abnormal activity of 11-HSD. 11-HSD exists in 2 isoforms: type 1 is expressed in liver, gonads, and adipose tissue and in vivo acts as a reductase generating active cortisol from inactive cortisone. The type 2 11-HSD is predominantly present in mineralocorticoid target tissues, such as placenta and kidney, and converts active cortisol to the inactive compound cortisone. In a study by Rodin et al,67 oxidized cortisol metabolites were increased in patients with PCOS when compared with control subjects, suggesting dysregulation and increased activity of type 2 11-HSD, possibly leading to excess adrenal androgen production via the increase in corticotropin activity. When adjusted for BMI, however, no significant differences were found in the level of cortisol metabolites among obese compared with nonobese PCOS patients.
Plasma cortisol concentrations in obese subjects have often been found to be lower than in lean individuals.68,69 However, investigators have not been able to find consistently any difference between obese and non-obese subjects in cortisol response either to ACTH stimulation70 or to hypoglycemia.71 The number and affinity of glucocorticoid receptors on mononuclear leukocytes in women with PCOS, obese or non-obese, does not differ from that in control women.72
In summary, although the circulating levels of adrenal androgen dehydroepiandrosterone sulfate (DHEAS) in patients with PCOS are often increased, the reason for this abnormality and the contribution of obesity, if any, to its development remain unclear. There is no clear-cut evidence that abnormal cortisol metabolism is present in either obese or non-obese PCOS women.
Estrogen and progesterone
Progesterone deficiency and acyclical and continuous estrogen production are typical of PCOS.73 Women with PCOS exhibit chronic anovulation, and plasma levels of progesterone are low. Progesterone acts as an inhibitor of GnRH pulse frequency, and low circulating levels of progesterone in PCOS women may contribute to rapid LH pulse frequency and elevated serum LH concentrations.73 Reduction in LH pulse frequency has been demonstrated in PCOS patients given a vaginal progesterone compound74 or estrogen-progesterone containing contraceptives.75 LH pulse frequency was decreased to a greater degree in normal women compared with PCOS women, suggesting reduced hypothalamic sensitivity to ovarian steroid hormones in PCOS.76
Estrogen production in the ovary requires both theca and granulosa cells. Testosterone and androstenedione produced by theca cells are converted to estradiol and estrone by P450arom activity in granulosa cells. Aromatase cytochrome P450 (P450arom) is a unique member of a superfamily of microsomal enzymes that catalyze the rate-limiting step in the conversion of C19 androgens (testosterone and androstenedione) into C18 estrogens (estradiol and estrone) in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue.
Aromatase activity of granulosa cells is a function of follicular size.77 PCOS ovaries are characterized by multiple small follicles, which enter developmental arrest before selection of a dominant follicle.40 Because of the lower activity of aromatase in smaller follicles, follicular fluid from ovaries of women with PCOS is characterized by low concentration of estradiol.78 In rats with experimentally-induced hyperinsulinemia, however, systemic aromatase activity appears to be increased.79 Therefore, low aromatase activity in ovarian cells of PCOS women suggests the presence of a local aromatase inhibitor that counteracts the stimulatory effect of insulin. Insulin-like growth factor-binding proteins (IGFBPs), among other molecules, have been proposed as candidates for the role of ovarian aromatase inhibitors.40
It has been suggested that reduced aromatase activity may be responsible for hyperandrogenism in PCOS women.80 Aromatase knockout (ArKO) mice (both female and male) develop intra-abdominal obesity due to increased adipocyte size and number. Moreover, these mice exhibit lower lean body mass, hyperinsulinemia, and fatty liver.81,82 These features, however, have not been consistently observed in humans with aromatase gene mutation,83,84 a rare disorder characterized in females by pubertal virilization and multicystic ovaries.85
There are conflicting observations concerning the etiologic role of reduced aromatase activity in hyperandrogenism. For example, both troglitazone and meformin inhibit aromatase activity, but also reduce systemic hyperandrogenism.86,87 Further, aromatase inhibitors have been used to induce ovulation in anovulatory women, including women with PCOS.88 Thus, the role of reduced aromatase activity in the development of hyperandrogenism in PCOS remains controversial.
It has been demonstrated in both in vivo and in vitro studies that peripheral aromatase activity is positively correlated with adiposity.89,90 Adipocytes exhibit variable levels of P450arom activity, depending on their location. The highest level of activity is present in the buttocks, next highest in the thighs, and the lowest in the subcutaneous abdominal tissue.91 Aromatase activity is higher in women with lower body obesity than in those with upper body obesity.92
An increased peripheral conversion of androgens to estrogens, combined with decreased SHBG levels, results in increased circulating bioactive estrogen levels in obesity. These factors contribute to a state of functional hyperestrogenism in obese compared with lean PCOS patients.93 High estrogenic activity, mostly due to elevated levels of estrone, may contribute to positive feedback on LH secretion, leading to enhanced stimulation of androgen production in obese PCOS patients.94 This issue is controversial, however, given the lower mean LH serum concentrations in obese compared with lean PCOS women reported in some studies.45,46
In summary, peripheral aromatase activity in obese PCOS women may be increased, contributing to the hyperestrogenic state. On the other hand, reduction in ovarian aromatase activity in PCOS may contribute to hyperandrogenism. Further studies are needed to clarify the role of aromatase in the pathogenesis of PCOS in both obese and non-obese women.
Leptin
Several decades ago, investigators at The Jackson Laboratory postulated the presence of recessive mutations in obese (ob/ob) and diabetes (db/db) mice, which exhibited hyperphagia, morbid obesity, insulin resistance, hypercortisolism, and infertility.95 Subsequently, Coleman et al,96 through cross-circulation studies, demonstrated that the ob gene encoded a factor that decreased appetite and increased metabolism, while the db gene encoded a receptor for this factor. These observations were confirmed with the discovery of the ob gene through positional cloning in 1994.97 The ob gene encodes a 167-amino acid protein that acts as a circulating feedback signal to the brain to regulate adipose mass. Based on its ability to reduce the body weight, ob gene product was named “leptin” (from the Greek root “leptos,” meaning “thin”). The human ob gene is located on chromosome 7q32 and consists of 3 exons and 2 introns.97
Leptin is synthesized in adipose tissue. Its synthesis is regulated by many factors, including the state of nutrition and a variety of hormonal influences.95,98 Leptin circulates in plasma in free and bound form. It can be bound to plasma proteins (5% to 20%) or to complexes with soluble leptin receptors (Ob-R).95 Multiple variants of Ob-R mRNA, encoding at least 6 different leptin receptor isoforms, have been identified. All Ob-R isoforms share an identical extracellular ligand-binding domain at the N-terminus, but differ at the C terminus. Ob-Rb, the long receptor isoform, is the only receptor isoform that is able to activate janus kinase signal transduction and translation (JAK/STAT) pathway, the signaling system for the intracellular portion of the leptin receptor.95
Obesity in animals defective in leptin or leptin-receptor genes (ob,db, fa, and cp rodents) resembles hypothalamic obesity induced by ventromedial lesions,99,100 suggesting that the anorexic actions of leptin are exerted mainly at the level of the hypothalamus.
In common forms of human obesity (unlike in leptin-deficient ob/ob mouse), leptin mRNA and circulating protein levels are high, indicating leptin resistance in obese subjects.101–103 Leptin resistance may be secondary to defects in leptin transport or abnormalities in leptin signaling.104 Excessive amounts of insulin or high-fat diets may cause leptin resistance.105,106 An acute increase in caloric intake causes an increase of circulating leptin up to 40% over baseline levels within 12 hours, without any change in BMI.107 Starvation-induced reduction of circulating leptin levels has been reported as well.108 Insulin, glucocorticoids, and TNF- stimulate leptin secretion.95 The stimulatory effect of insulin on leptin synthesis, however, is seen only long-term.109 It appears that under steady-state energy balance conditions circulating leptin concentrations reflect the amount of triglyceride stored in adipocytes, while in nonsteady-state conditions, leptin acts as a sensor of energy balance.95
Almost a century ago, Marshall and Peel110 observed that “over-fat” animals were sterile. The sterility was reversible with starvation.110 In 1922, Evans and Bishop111 reported that inadequate nutrition also affected reproduction. Frisch112 observed that menarche occurs only when a certain “critical” mass of body weight is reached. The mechanism of the relationship between reproduction and body weight was a mystery until the discovery of leptin. Leptin treatment reverses the hypogonadism in ob/ob mouse independently of the effect on body weight.113 Similarly, leptin ameliorates starvation-induced hypogonadism.114 Moreover, leptin accelerates puberty in normal mice115 and its circulating levels increase before puberty.116–118 Thus, it has been proposed that leptin acts as a signal from adipose tissue to the brain indicating that the critical amount of fat mass necessary for initiation of puberty and maintenance of reproductive function has been reached. Although Ob-Rs have been found in the ovaries and the testes, it remains unknown whether the effect of leptin on reproduction is mediated by its central action (on hypothalamus), peripheral action (on gonads), or both.
Most studies have shown that serum leptin concentrations in women with PCOS do not differ from those in normal women with similar adiposity.119–122 Besides, serum leptin concentrations did not correlate with circulating androgen levels in most studies.119,120 Studies of the relationship between leptin and circulating insulin concentrations produced variable results, from no correlation120,123 to positive correlation.119,121 The same lack of consistency was seen in studies that examined correlation between leptin and circulating LH levels.119–121,123
Insulin sensitizers seem to have no effect on circulating leptin levels in women with PCOS if the weight of the subject remains stable. For example, troglitazone treatment did not affect the level of leptin in PCOS patients.120 Metformin therapy reduced the level of leptin in both control women and in PCOS patients in some studies, but the values of circulating leptin levels in these studies were not corrected for weight reduction.124,125
In summary, the circulating concentrations of leptin in women with PCOS do not appear to differ from those in weight-matched, normal women. Thus, the role of leptin in PCOS and, particularly, in the development of hyperandrogenism in PCOS remains under debate.
Insulin and the IGF system
Endogenous insulin has a circulatory half-life of 3 to 5 minutes. The normal circulating concentration of insulin ranges from approximately 10 µU/mL in the fasting state to approximately 50 µU/mL postprandially. In insulin-resistant conditions, such as PCOS or type 2 diabetes, circulating insulin concentrations can be as high as 35 µU/mL in a fasting state and 180 µU/mL postprandially. In syndromes of extreme insulin resistance caused, for example, by a mutation in the insulin receptor gene, circulating insulin levels can be increased many-fold.40
Insulin action is initiated by insulin binding to its receptor on the surface membrane of target cells. Insulin receptors are heterotetrameric glycoproteins composed of 4 subunits. Two larger -subunits are extracellular and bind the insulin molecule, while two smaller -subunits are mainly cytoplasmic and contain a tyrosine kinase, the main signaling component of the insulin receptor. Tyrosine kinase becomes activated following insulin binding to the -subunits. A cascade of intracellular protein phosphorylation, beginning with two members of the insulin receptor substrate (IRS) protein family (IRS-1 and -2), is then initiated. Subsequent activation of phosphatidylinositol-3-kinase (PI-3 kinase) leads to increased glucose transport by glucose transporter-4 (GLUT-4) proteins.
Some actions of insulin may involve inositol-glycan second messengers, which are produced by the insulin-sensitive hydrolysis of a glycolipid in the plasma membrane. The inositol-glycan pathway may participate in the mediation of insulin effects on ovarian steroidogenesis40,126 (Fig 1).
As mentioned above, many women with PCOS are insulin resistant and therefore exhibit compensatory hyperinsulinemia.127 The etiology of insulin resistance in PCOS is not completely understood.
Fig 1. Insulin receptor and its signaling pathways. See text for details. (Adapted and reprinted from Poretsky et al40 with permission. © The Endocrine Society.)
Click on Image to view full size
The defect of insulin receptor action appears to be at postbinding level and to involve a unique abnormality of postreceptor insulin signaling and glucose transport, distinct from that seen in patients with type 2 diabetes.128
Several molecular mechanisms have been suggested to explain the origin of insulin resistance in PCOS: lower content of GLUT4 glucose transporter,129 excessive phosphorylation of insulin receptor on serine residues (which reduces signal transduction), or depletion of cellular adenosine.130 Dunaif et al130 demonstrated that many obese women with PCOS have defect in tyrosine autophosphorylation of the insulin receptor. It appears that the basal unstimulated phosphorylation is occurring on serine, rather than tyrosine residues, and that the tyrosine phosphorylation is decreased.128
Archard and Thiers131 original description of “diabetes of bearded women” in the 1920s suggested a link between insulin and ovarian function. In one of the first studies addressing the relationship between insulin resistance and hyperandrogenism, Burghen et al132 observed that circulating insulin levels correlated with circulating testosterone levels in obese women with PCOS. Kitabchi et al133 later found that the direct correlation between hyperinsulinemia and gonadal hyperandrogenemia might be a race-related phenomenon, possibly limited to African American women with PCOS.
The hypothesis suggesting that hyperandrogenism causes significant insulin resistance has been proposed. Indeed, chronic excessive use of androgen in powerlifters134 or in female-to-male transsexuals135 has been shown to decrease insulin sensitivity. A study involving use of oxymetholone, a testosterone-like compound, has demonstrated a positive correlation between its use and the presence of insulin resistance.136 However, oophorectomy,137,138 GnRH agonists,139,140 or antiandrogenic agents141 do not produce a significant change in insulin sensitivity in most studies despite eliminating hyperandrogenism in PCOS patients. Further, the degree of insulin resistance produced by androgens appears to be much less severe than that seen, for example, in women with hyperandrogenemia associated with syndromes of insulin resistance and acanthosis nigricans.142,143 Finally, some PCOS women do not exhibit insulin resistance despite hyperandrogenism.144
Evidence of possible salutary effects of hyperandrogenism of adrenal origin, as opposed to ovarian origin, on insulin sensitivity was developed by Schriock et al.145 Their study evaluated the insulin response to standard oral glucose tolerance test (OGTT) in 26 women, finding divergent correlations of circulating DHEAS and testosterone with insulin levels and insulin receptor binding to erythrocytes. The investigators concluded that, unlike testosterone, DHEAS might enhance insulin binding and action.
Thus, it appears that hyperandrogenism of ovarian origin may produce mild reduction of insulin sensitivity and may contribute to the development of insulin resistance in PCOS. However, because significant hyperandrogenism develops in women whose insulin resistance is clearly a primary phenomenon, for example, in women with mutations of insulin receptor or with insulin-receptor antibodies,143,146 the hypothesis proposing that hyperinsulinemia may affect ovarian function has been developed.142 Insulin receptors and IGF receptors are expressed in all types of ovarian cells, and multiple theories of effects of insulin and IGFs in the ovary have been proposed.147,148
In early studies, Channing et al149 examined the effects of insulin on porcine granulosa cells. They found increased responsiveness of granulosa cells to gonadotropin stimulation in the presence of insulin. Other investigators have reported insulin-induced stimulation of androgen, estrogen, and progesterone production by both granulosa and theca cells.150,151 In vitro, insulin directly stimulates ovarian androgen secretion via its effects on 17--hydroxylase, 17,20-lyase, and p450 enzymes.152 Insulin also directly stimulates LH secretion from cultured pituitary cells and sensitizes gonadotrophs to GnRH stimulation.59,153
Despite the in vitro evidence that insulin can stimulate ovarian steroidogenesis, in vivo studies which examined the effects of acute administration of insulin on androgen production in normal women and in PCOS patients have rendered conflicting results (ranging from increased circulating androgen levels to no change to a decline in circulating androgens).40 On the other hand, studies in which reduction of circulating insulin levels was achieved (such as those involving weight loss, metformin, thiazolidinediones, or diazoxide) have consistently reported a reduction in circulating androgen levels.40
The fact that supraphysiologic concentrations of insulin, often many-fold higher than found in PCOS individuals, are required in some in vitro studies to stimulate ovarian steroidogenesis, suggested that insulin may cross-react with type 1 IGF receptor to activate steroidogenesis in ovarian cells. Studies using anti-insulin receptor and anti-IGF-1 receptor antibodies, however, have demonstrated that insulin action in ovarian cells from both normal and PCOS women is usually mediated by the insulin receptor,40,126 although nonclassical insulin receptor signaling mechanisms can be involved in the ovarian effects of insulin.154 For example, PI-3 kinase, an enzyme whose activation is crucial for glucose transport, may not be needed for insulin-induced stimulation of progesterone synthesis or for inhibition of IGFBP-1 production in human ovarian cells.154 Activation of mitogen-activated protein kinase (MAPK), another key enzyme which is phosphorylated following insulin receptor activation and which is responsible for the growth-promoting effects of insulin,155 may not be necessary for some of the ovarian effects of insulin. In support of this hypothesis, a recent study addressing insulin and IGF-I signaling pathways involving MAPK, demonstrated that while MAPK participated in IGF-I-induced progesterone synthesis and inhibition of IGFBP-1 production in human granulosa cells, insulin-induced stimulation of progesterone or inhibition of IGFBP-1 did not require MAPK activation.156 Involvement of alternate pathways of insulin action, as well as insulin activation of type I IGF-I receptor in cases of extreme hyperinsulinemia, explains why the ovary may remain sensitive to insulin, while classical organs for insulin action (liver, fat, and muscle) are insulin resistant.157,158
The IGF-system is closely related to insulin and participates in the regulation of ovarian function. In vitro studies have shown that IGF-I, a 70-amino acid polypeptide homologous with proinsulin, affects ovarian function in animal and human cells.79 IGF-II, a 67-amino acid polypeptide with 70% homology with IGF-I and 50% homology with proinsulin, appears to be the principal IGF peptide in the human ovary, with effects similar to those of IGF-I. It appears that the effects of both IGF peptides (IGF-I and IGF-II) in the ovary are mediated by the type 1 IGF receptor.40 Hyperinsulinemia may enhance IGF action in the ovary by upregulating ovarian type 1 IGF receptors.40,79
The activity of IGFs is modulated by low-molecular weight-binding proteins, called IGFBPs, which bind IGFs with high affinity. Synthesis of one of these proteins, IGFBP-1, is inhibited by insulin.159 Hyperinsulinemia may contribute to hyperandrogenism through inhibition of ovarian IGFBP-1 synthesis,160 because low intrafollicular levels of IGFBP-1 may lead to increased intraovarian concentration of unbound IGFs. Because circulating IGFBP-1 is derived from the liver, where its production is also under inhibitory control of insulin, serum IGFBP-1 levels are negatively correlated with insulin in PCOS patients.161. Thus, in the presence of hyperinsulinemia, both circulating and intraovarian concentrations of bioavailable IGFs are increased, possibly contributing to stimulation of steroidogenesis.40
Body weight affects the growth hormone (GH)/IGF-I system in PCOS patients. In non-obese PCOS patients (whose insulin resistance, although present, is not as significant as in obese PCOS women) IGF bioavailability seems to be increased, not only as a result of insulin-induced IGFBP-1 suppression, but also because of excessive GH-induced stimulation of hepatic IGF-I production.40,162 Indeed, increased GH pulse amplitude has been found in lean PCOS women.46 On the other hand, in obese patients, reduced GH pulse amplitude and 24-hour mean circulating GH levels have been reported.94 This decrease in circulating GH levels is probably caused by decreased pituitary responsiveness to growth hormone-releasing hormone (GHRH) in obese PCOS patients.46 The reduced circulating GH concentrations in obese PCOS women are probably related to obesity itself, as demonstrated by studies in obese patients without PCOS.163 Further, increased GH clearance in obese subjects contributes to the decreased GH/IGF system activity.164
These findings have led to a hypothesis proposing that, although both hyperinsulinemia and excessively activated IGF system participate in the development of PCOS in non-obese and obese women, the IGF system is more important in the pathogenesis of PCOS in non-obese women, while hyperinsulinemia is more important for the development of PCOS in the presence of obesity94 (Table 2).
--------------------------------------------------------------------------------
Table 2.Insulin Effects Related to Ovarian Function
--------------------------------------------------------------------------------
Insulin Effect Organ
Directly stimulates steroidogenesis Ovary
Acts synergistically with LH and FSH to stimulate steroidogenesis Ovary
Stimulates 17--hydroxylase Ovary
Stimulates or inhibits aromatase Ovary, adipose tissue
Upregulates LH receptors Ovary
Promotes ovarian growth and cyst formation (synergistically with LH and hCG) Ovary
Downregulates insulin receptors Ovary
Upregulates type 1 IGF receptors or hybrid insulin/type 1 IGF receptors Ovary
Inhibits IGFBP-1 production Ovary, liver
Inhibits SHBG production Liver
Potentiates the effect of GnRH on LH and FSH Hypothalanmus, pituitary
Adapted and reprinted from Poretsky et al.40 © The Endocrine Society.
--------------------------------------------------------------------------------
Obese and non-obese PCOS patients: differences in clinical manifestations TOP
Onset of clinical symptoms in PCOS usually occurs perimenarcheally, often in association with obesity. Women with PCOS have a wide range of phenotypic manifestations, most likely because of underlying genetic differences in etiology.
A hallmark feature of PCOS is irregular, infrequent, and unpredictable uterine bleeding. Some patients experience bleeding less than 6 times per year, while in others, it may occur monthly, but with lack of ovulation.
The most common symptom in young women is excessive facial hair growth (hirsutism), followed by acne. These symptoms are present in about 80% of patients. The Ferriman-Gallwey score can be used to assess the degree of hirsutism (Fig 2). 165
Many patients present with infertility due to anovulation.1 Recent evidence suggests that there is increased prevalence of miscarriage among patients with PCOS.166,167 In addition, the rate of pregnancy is lower than the rate of ovulation induction, which may be a reflection of inefficient fertilization in PCOS.168
Overall, approximately 50% of women with PCOS are obese.169,170 As discussed above, obese women with PCOS typically exhibit an increased WHR characteristic of an android or central pattern of obesity.171
The prevalence of obesity in PCOS varies between studies and between ethnic groups.
Fig 2. Grading the severity of hirsutism. Grade 1, minimal; grade 4, virilization. (Adapted and reprinted with permission.58)
Click on Image to view full size
A prospective study from Spain, for example, reported that the prevalence of PCOS in Spain was similar to that in the US population, but the prevalence of obesity in Spanish PCOS women was considerably lower than in most studies from North America, with a mean BMI in Spanish patients of 23 kg/m2.172 Asian PCOS patients exhibit less obesity and hirsutism than their US counterparts, even though the prevalence of biochemical hyperandrogenism is similar in these 2 groups.173
Distinct clinical presentations observed in different ethnic groups of PCOS patients are sometimes attributed to the differences in the prevalence of obesity among populations. For example, a high prevalence of obesity in Pima Indians may produce features of PCOS in this population that are different from those of a lean Japanese population. A recent study concluded that both the prevalence and the degree of insulin resistance were higher in Mexican American women with PCOS than in Caucasian PCOS patients.174
The differences in biochemical and clinical features between obese and non-obese PCOS patients allow to determine, to some degree, the contributions of obesity to the clinical manifestations of PCOS (Table 3).
Differences in menstrual function have been reported, with obese patients exhibiting a greater prevalence of oligoamenorrhea and anovulation than non-obese women.94
In a large study of 1,741 patients by Balen et al,175 the presence of obesity was associated with an increased prevalence of infertility.
--------------------------------------------------------------------------------
Table 3.Clinical and Biochemical Features of Obese Versus Non-Obese Patients With PCOS
--------------------------------------------------------------------------------
Features Obese PCOS Lean PCOS
Hirsutism60 ++ +
Total testosterone/androstenedione ratio60
Sex hormone-binding globulin60 Normal
Free testosterone60
Androsterone glucuronide60
Oligomenorrhea/anovulation94 ++ +
Infertility175 ++ +
Acanthosis nigricans169,178 ++ +
Insulin resistance171 ++ +
IGT/diabetes mellitus169,179 ++ +
Hyperlipidemia180 + –
Hypertension169,181 + (?) –
Cardiovascular risk182 ++ (?) + (?)
Endometrial carcinoma risk9 ++ +
--------------------------------------------------------------------------------
This finding is consistent with the results of a recent study by Gill et al,176 who reported higher rates of successful ovulation in response to pulsatile GnRH administration among lean PCOS patients than among obese PCOS subjects.
It is known that obesity has a direct relationship with the degree of hirsutism in PCOS patients. In a study performed in the United Kingdom in 1990, for example, obese women with PCOS had a greater prevalence of hirsutism than non-obese patients (73% compared with 56%).60
Stuart et al177 found significant correlations between hyperandrogenism, insulin resistance, and the presence of acanthosis nigricans. On physical examination, acanthosis nigricans is found with greater frequency in obese than in non-obese patients with PCOS,169,178 probably reflecting a higher prevalence and magnitude of insulin resistance among obese PCOS patients.
As discussed above, women with the PCOS have a higher prevalence and degree of both hyperinsulinemia and insulin resistance than weight-matched controls. Both lean and obese women with the syndrome have evidence of reduced insulin sensitivity, but insulin resistance is most marked when obesity is present.171 Impaired glucose tolerance and type 2 diabetes mellitus are more prevalent in PCOS patients compared with weight-matched controls, with the highest risk in obese PCOS patients.169 In a prospective study that included 254 PCOS patients, 31% of obese subjects had impaired glucose tolerance, and 7.5% had overt diabetes. By comparison, 10% of non-obese PCOS patients had impaired glucose tolerance, and 1.5% had diabetes, prevalence rates still 3 times higher than in an age-matched control population.179
Along with the increased risk for diabetes mellitus, the prevalence of dyslipidemia is increased in women with the syndrome. Elevated circulating levels of triglycerides, very-low-density lipoprotein (VLDL), and total cholesterol, accompanied by low levels of high-density lipoprotein (HDL), have been reported in PCOS. Dyslipidemia is present in both obese and non-obese patients, but higher BMI correlates with higher triglyceride levels.180
The association of PCOS with hypertension has not been firmly established. Initial studies noted higher blood pressure among PCOS patients, but the difference was not statistically significant after adjustment for BMI.169 A cross-sectional study involving non-obese PCOS patients undergoing ambulatory blood pressure monitoring demonstrated no increase in the prevalence of hypertension.181 Thus, the available evidence suggests that hypertension in patients with PCOS is related to obesity rather than to PCOS itself.
Overall, given the prevalence of risk factors for atherosclerosis in women with PCOS, a higher prevalence of cardiovascular events in these patients can be expected. Some studies suggest that this might be true,182 but definitive, prospective studies are lacking. Recent studies have demonstrated higher plasma homocysteine and tissue plasminogen activator (t-PA) concentrations44,183 in PCOS subjects, suggesting that early development of atherosclerosis in this syndrome may not depend exclusively on abnormal lipid levels.
With obesity being a risk factor for endometrial carcinoma, obese PCOS patients have higher prevalence of this malignancy than non-obese PCOS women.9 Anovulation, unopposed estrogen stimulation, and hyperinsulinemia may play a role in the increased risk of this gynecologic carcinoma in PCOS patients. The data for other malignancies in PCOS are less conclusive.
Recently, an association of PCOS with obstructive sleep apnea has been reported.184 Even in lean PCOS subjects, the prevalence of obstructive sleep apnea was higher than in weight-matched controls. Obese PCOS patients had a higher prevalence of sleep apnea than non-obese patients (19% v 8%). The reason for the association between sleep apnea and PCOS remains unknown.184
The clinical course of pregnancy in PCOS patients is affected by the presence of obesity. Gjonnaess et al185 and Urman et al186 studied PCOS patients who conceived after ovarian electrocautery; an 8% prevalence of gestational diabetes was found, higher than the 2% to 5% seen in control populations. This increased prevalence of gestational diabetes was found only in overweight PCOS women, but not among non-obese PCOS patients.185,186
Obesity itself is a risk factor for preeclampsia and gestational non-proteinuric hypertension.187 In the study by Gjonnaess mentioned above, an increased risk of preeclampsia was found among obese PCOS patients, but not among lean women with PCOS. On the contrary, in a retrospective analysis of 81 pregnant PCOS patients in the Netherlands, De Vries et al188 found that an increased risk of preeclampsia was present even after adjustment for BMI. Thus, the respective roles of BMI and PCOS in the development of hypertension during pregnancy remain unclear.
In summary, the presence of obesity in PCOS has implications for some of the clinical features and biochemical abnormalities of the disease. Specifically, obesity appears to play a role in the prevalence of hirsutism, hyperandrogenism, menstrual irregularities and infertility, glucose intolerance and overt diabetes mellitus, endometrial carcinoma, the level of bioactive estrogen activity, and hypertension. In other areas, such as hyperlipidemia and pregnancy, the role of obesity is less clear. Prospective studies are needed to clarify whether the presence of PCOS, with or without obesity, represents a cardiovascular risk factor.
Therapy of PCOS: impact of obesity (Table 4) TOP
Weight loss
There have been numerous studies of the effects of weight loss in obese women with PCOS. Many of these studies, however, were uncontrolled, had a small sample size, and were conducted over a short period of time. Even with these limitations, the studies showed fairly consistently that weight loss resulted in the improvement of hormonal and menstrual parameters in obese PCOS patients. These benefits appear to be related to the improvement in insulin sensitivity that occurs with weight loss.
Huber-Buchholz et al189 found a 71% improvement in insulin sensitivity index and a 33% reduction in fasting circulating insulin concentration in anovulatory obese PCOS women who responded to weight loss with ovulation. Kiddy et al190 found a reduction in fasting circulating insulin concentrations in patients who achieved greater than 5% weight loss. Guzick et al191 randomized 12 obese PCOS women to 12 weeks of treatment with a weight-reduction diet or to 12 weeks with weight-maintaining diet. Fasting insulin levels declined markedly in the weight-loss group; there was no change of circulatory insulin concentrations in the control group.191 Thus, the above studies demonstrated that calorie restriction leading to weight loss produces a reduction in circulating insulin levels in obese women with PCOS, suggesting an improvement in insulin sensitivity.
Improved insulin sensitivity is associated with reduction of hyperandrogenism. Kiddy et al190 evaluated the effects of long-term calorie restriction in 24 obese PCOS women. Thirteen women who had lost more than 5% of weight had an increase in circulating concentrations of SHBG and a decrease in circulating free testosterone compared with 11 women who lost less than 5% of weight; the latter group exhibited no significant changes in these values.190
Confirming that weight loss is necessary to achieve an improvement in hyperandrogenism, Huber-Buchholz et al190 evaluated obese women with PCOS who were treated with diet and exercise, but achieved no significant weight loss. The investigators found no statistically significant changes in the circulating concentrations of SHBG and free testosterone in these women.189
Nevertheless, hypocaloric diet, with or without weight loss, appears to be associated with an improvement of menstrual function in women with PCOS. In a study by Huber-Buchholz et al,189 after a 6-month diet and exercise program that promoted a healthy lifestyle, but produced no rapid weight loss, 9 of 18 obese PCOS patients ovulated; of these, 2 became pregnant. In a study by Kiddy et al,190 9 of 11 patients who had lost at least 5% of weight had improvement in menstrual function, manifested by regular menstrual periods and conception. Guzick et al191 evaluated serum progesterone values to assess ovulation in 6 obese PCOS women treated with weight reduction. Four of these women acheived ovulatory circulating progesterone levels compared with only 1 of 6 obese PCOS patients with no weight loss.191
Several groups of investigators have studied the effects of weight loss on serum LH concentrations and found inconsistent responses. Some studies showed no changes in either basal LH levels or in LH pulse frequency or amplitude,190,191 even with improvement in reproductive function.190 Alternatively, a 39% decline in circulating LH levels in obese PCOS women who responded to weight loss with ovulation was reported; women who did not resume ovulation did not exhibit significant changes in circulating LH concentration.189
In summary, most studies show that weight loss in obese women with PCOS leads to hormonal, menstrual, and metabolic improvement. Weight loss, especially more than 5% of the baseline weight, is associated with increased serum concentrations of SHBG and reduced serum concentrations of free testosterone in obese women with PCOS. The mechanism by which weight loss leads to a reduction of hyperandrogenism appears to involve improved insulin sensitivity with a resultant decline in circulating insulin levels. Exercise, even in the absence of weight loss, also has some beneficial effects, probably because of associated reduction in insulin resistance. Exercise may lead to changes in body fat distribution, with a decrease in abdominal fat and an increase in lean muscle mass, but with no change in weight.
Insulin sensitizers
Metformin
Metformin, which belongs to the biguanide class of oral antihyperglycemic agents, has been shown to improve the metabolic, hormonal, and menstrual parameters in obese women with PCOS.
In the first major study of metformin in obese PCOS women, Velazquez et al192 followed for 8 weeks 26 women with PCOS who had mean BMI of 29 kg/m2. The women received 1,500 mg metformin daily. The effect of metformin on insulin secretion and glucose metabolism was assessed by an OGTT. After 8 weeks of treatment, there was no significant change in the area under the glucose curve, but there was a 35% decrease in the area under the insulin curve. The insulin area to glucose area ratio decreased by 31%, demonstrating an improvement in insulin sensitivity with metformin.192 In a study by Arslanian et al,193 15 obese adolescents with PCOS and impaired glucose tolerance, diagnosed using an OGTT, were treated with 850 mg metformin twice a day for 3 months. After this course of treatment, OGTT parameters improved in 8 patients. The glucose area under the curve and the insulin area under the curve declined, but there were no differences in steady-state circulating glucose or insulin concentrations before and after treatment.193 In a study of obese PCOS women treated with metformin, Nestler and Jacubowicz152 demonstrated a reduction of the mean area under the insulin curve after oral glucose challenge.
Not all studies have shown consistent improvement of insulin sensitivity with metformin therapy. In a double-blind study by Moghetti et al,194 23 women were randomly assigned to treatment with metformin (1,500 mg/d) or placebo for 6 months. Eighteen of these patients and 14 additional patients were subsequently given metformin in an open trial for 11 months. The mean BMI was 30 kg/m2. At baseline, both groups had similar fasting glucose and insulin plasma concentrations. After 6 months of metformin therapy, fasting plasma insulin concentration decreased in the metformin-treated group; there were no changes in the placebo group. Insulin sensitivity, assessed by a euglycemic-hyperinsulinemic glucose clamp, improved. There was, however, no statistically significant difference between circulating glucose or insulin levels before and after treatment when the patients underwent 2-hour OGTT.194 Acbay and Gundogdu195 followed 16 women with PCOS who were treated with placebo for 8 weeks followed by metformin for 10 weeks. Insulin sensitivity was assessed by an intravenous insulin tolerance test. There was no difference in BMI or in the areas under the curve for insulin or glucose in metformin versus placebo groups.196
As with weight loss, the reduction in insulin resistance achieved with metformin in most studies was associated with improved hormonal and menstrual parameters,193,194 In the study by Velazquez et al,192 at baseline, all patients had abnormal menstrual cycles, 90% exhibited hirsutism, and 85% had elevated circulating concentration of free testosterone. After treatment with metformin, mean circulating levels of free testosterone declined by 52%, total testosterone declined by 44%, androstenedione declined by 29%, DHEAS declined by 21%, free androgen index was reduced by 49%, and LH declined by 35%. Concurrently, circulating SHBG concentration increased by 33% and FSH increased by 95%. Three patients became pregnant.192
Adrenal steroidogenesis can also be affected by metformin, suggesting that hyperinsulinemia may contribute to the increased adrenal androgen production in PCOS. In a study by Nestler et al,152 12 women with PCOS were randomly assigned to receive metformin, while 13 received placebo. In the metformin group, mean basal serum concentration of 17--hydroxyprogesterone decreased by 51% and peak 17--hydroxyprogesterone serum concentration after leuprolide injection decreased by 38%; no changes were observed in the placebo group.152 After 3 months of metformin treatment, Arslanian et al193 reported significantly lower plasma concentrations of androstenedione, 17-hydroxyprogesterone, and 17-hydroxypregnenelone in response to ACTH stimulation in women with PCOS.
Studies of the combined effects of metformin and hypocaloric diets leading to weight loss have been performed. Pasquali et al124 evaluated the effects of combined hypocaloric diet and metformin in 40 obese PCOS patients. All patients followed a low-calorie diet for 1 month prior to being randomized to metformin or placebo in a double-blind design for 6 months. The metformin-treated group demonstrated improvement in menstrual cycles and hirsutism compared with the placebo group. Fasting plasma insulin concentrations declined significantly in both treatment arms, but glucose-stimulated insulin secretion decreased only in patients treated with metformin. The area under the curve for insulin decreased in PCOS patients treated with metformin, but not in the placebo arm. There were no changes in LH, FSH, DHEAS, or progesterone, but a decline in circulating total testosterone concentration in the PCOS patients treated with metformin was observed. Circulating leptin levels also decreased in patients treated with metformin in contrast to the placebo group.124
Kowalska et al125 examined the combined effects of a hypocaloric diet and metformin in 23 obese PCOS patients, 19 obese patients without PCOS, and 11 normal-weight healthy women. The obese patients were treated with a hypocaloric diet and metformin for 4 to 5 months. Fasting insulin, LH, and testosterone serum concentrations decreased significantly only in obese PCOS patients treated with diet and metformin. Circulating leptin levels declined in both groups of PCOS patients, but not in normal-weight healthy women. Six of the 11 obese PCOS patients developed more regular menstrual cycles, and 2 patients conceived.125 Both of these studies demonstrated that metformin therapy, combined with weight loss, could improve insulin sensitivity, hyperandrogenism, and menstrual irregularity in patients with PCOS.
In summary, treatment with metformin in most studies was associated with an improvement in insulin sensitivity. Improved insulin sensitivity, in turn, was associated with a reduction in circulating androgen levels and improvement in menstrual and ovulatory symptoms. However, not all studies have shown consistent results, with a few showing no improvement in insulin sensitivity with metformin treatment. Possible explanations for this discrepancy may be the variability in the doses of metformin and the effect of metformin on BMI. Metformin, used in conjuction with weight loss, appears to produce a more consistent effect on insulin sensitivity and androgen profile than metformin without weight loss.
Thiazolidinediones
The thiazoledinediones are a group of insulin-sensitizing medications commonly used in the treatment of type 2 diabetes mellitus. The effects of one thiazolidinedione, troglitazone, have been studied in PCOS patients. A study by Dunaif et al,196 in which 25 women with PCOS were randomized to receive either 200 mg or 400 mg troglitazone and were compared with 12 normal (control) women, reported an improvement in insulin sensitivity and reduction in circulating DHEAS and estrone levels in the groups that received 200 mg or 400 mg troglitazone daily. The group that received 400 mg troglitazone daily also exhibited a decline in circulating free testosterone, androstenedione, and LH concentrations and an increase in circulating SHBG levels. In 2 patients, ovulatory menses resumed.196 In a study of 13 obese women with PCOS who were treated with 400 mg troglitazone for 12 weeks, Ehrmann et al197 reported a significant decrease in fasting and 2-hour plasma glucose concentration during OGTT, improvement in insulin sensitivity, and a decrease in total and free serum testosterone concentrations. Leuprolide-stimulated serum levels of 17-OH progesterone, androstenedione, and total testosterone were also significantly reduced with treatment.198
In a randomized, double-blind, controlled study of rosiglitazone and metformin in lean patients with PCOS, preliminary results showed a greater increase in ovulation with metformin alone versus rosiglitazone alone, and no greater benefit with combination therapy. Serum free testosterone decreased in the metformin group and also in the rosiglitazone group.198 Mercado-Asis et al199 reported that patients previously treated with troglitazone maintained normal menses when their therapy was changed to rosiglitazone, and newly diagnosed patients treated with rosiglitazone also had restoration of menses within 6 weeks of initiating treatment. In a preliminary report of a randomized, double-blind, placebo-controlled trial of 40 women with PCOS, administration of 30 mg pioglitazone for 3 months resulted in a reduction of fasting serum insulin levels, increased insulin sensitivity, reduction in free androgen index, increase in SHBG, and resumption of ovulatory function.200
It appears, therefore, that troglitazone has beneficial effects in obese PCOS women. Since troglitazone has been removed from the market because of liver toxicity, definitive studies with other thiazolidinediones need to be completed.
D-chiro-inositol
Inositol-phosphoglycans are involved in mediating insulin action.202 It has been proposed that, at least in some patients, insulin resistance in PCOS may be due to a deficiency of D-chiro-inositol-phosphoglycan mediators.201, 202 Nestler et al202 hypothesized that repletion of D-chiro-inositol stores would lead to improved insulin sensitivity. Forty-four obese women with PCOS were given either 1,200 mg D-chiro-inositol daily or placebo for 6 to 8 weeks. The treatment group demonstrated a significant reduction in the mean area under the insulin curve after oral glucose load, a 55% decrease in free testosterone, a 47% reduction in DHEAS, and reduction in circulating triglyceride levels; an increase in circulating SHBG concentrations was also observed. The placebo group demonstrated none of these changes. There were no changes seen in basal LH concentrations in either group. Nineteen of the 22 women treated with D-chiro-inositol ovulated versus only 6 of the 22 patients in the placebo group.202 Thus, D-chiro-inositol holds promise for the treatment of insulin resistance and hyperandrogenism in patients with PCOS.
Antiandrogens
Antiandrogens, such as flutamide or spironlactone, are beneficial in the treatment of the hyperandrogenism associated with PCOS and may improve insulin sensitivity. In a study of 8 teenagers given flutamide for 6 months, De Leo et al203 reported significant reductions in circulating levels of LH, androstenedione, and free and total testosterone, an increase in serum SHBG, and resumption of regular menses. In a study by Diamanti-Kandarakis et al,204 10 obese and 8 lean PCOS women and 13 lean control women were treated with flutamide, 250 mg/d, for 3 months. Patients in the flutamide-treated group exhibited significant improvement in hirsutism and reduction in circulating androstenedione and DHEAS levels, in contrast to the control group. There were no changes in circulating free testosterone levels and no improvement in insulin sensitivity in either group.204 In a study of hyperandrogenic patients treated with anyone of 3 agents (spironolactone, flutamide, or buserelin) Moghetti et al205 found an improvement in insulin sensitivity, with lean patients responding better than obese patients.
Oral contraceptive agents
Oral contraceptive agents have been used extensively in the treatment of PCOS. Pasquali et al206 studied 37 obese patients with PCOS approximately 10 years after their initial evaluation. Sixteen women took estrogen-progesterone combination and 21 women did not. In the treatment group, circulating basal insulin levels and fasting C-peptide levels decreased, but no change was found in the insulin area under the curve during OGTT in comparison to baseline. The control group exhibited no changes in basal insulin levels, but demonstrated an increase in the insulin area under the curve and in both fasting and stimulated C-peptide levels compared with baseline. Serum SHBG concentrations increased only in the estrogen-progesterone group, but there were no changes in total testosterone in either group. Thus, this study demonstrated that estrogen-progesterone combination can enhance insulin sensitivity and that, if left untreated, insulin resistance in obese PCOS patients tends to progress.206 In a comparison of combined oral contraceptives in lean versus obese PCOS women, Cibula et al207 found significant improvements in hyperandrogenism in lean PCOS patients with only a moderate improvement in the obese PCOS patients.
Estrogen has been combined with the antiandrogen cyproterone acetate. Dahlgren et al208 compared the effects of ethinylestradiol plus cyproterone versus the antiandrogen goserelin in 32 women with PCOS over a 6-month period. In the ethinylestradiol-cyproterone-treated group, serum androgen concentrations decreased and hirsutism improved, but there was a reduction in insulin sensitivity. Patients treated with goserelin had an improvement in both circulating androgen levels and insulin sensitivity. The investigators speculated that the estrogen component of the combined therapeutic regimen was responsible for the reduction in insulin sensitivity.208
In a study comparing metformin versus ethinylestradiol plus cyproterone in obese PCOS women, Morin-Papunen et al209 reported a reduction in circulating insulin concentrations, improvement in glucose utilization, and improvement in insulin sensitivity in the metformin-treated group, in contrast to an increase in the glucose area under the curve and no improvement in insulin sensitivity in the ethinylestradiol-cyproterone-treated group.
Thus, oral contraceptives may improve the androgen profile of PCOS patients, with a greater benefit in lean than obese PCOS patients; their effects on insulin sensitivity are controversial.
Summary
In summary, many studies assessing the role of diet, exercise, and multiple therapeutic agents in the treatment of PCOS have been published (Table 4). Although many of these studies are not double-blind, randomized, or long-term, they show benefits of treating obese women with PCOS with a variety of approaches.
--------------------------------------------------------------------------------
Table 4.Selected Studies of Therapeutic Modalities and Their Effects in Obese Women With PCOS
--------------------------------------------------------------------------------
Therapeutic Modality/References Year Insulin Sensitivity T Free T SHBG Other
Weight loss
Kiddy et al190 1992
Guzick et al191 1994
Huber-Buchholz et al189 1999 LH
Metformin
Velazquez et al192 1994 LH
Acbay et al195 1996
Nestler et al152 1996 LH
Moghetti et al194 2000 NS
Pasquali et al124 2000 Leptin
Arslanian et al193 2002
Troglitazone
Dunaif et al196 1996 LH
Ehrmann et al197 1997
Antiandrogens
Diamanti-Kandarakis204 1995 NS DHEAS
De Leo et al203 1998 LH
Oral contraceptive agents
Pasquali et al206 1999 NS
Cibula et al207 2001 NS
Abbreviations: NS, not studied; , increase; , decline; , no change.
--------------------------------------------------------------------------------
Because insulin resistance and hyperinsulinemia may contribute to the pathogenesis of PCOS, weight loss as first-line therapy will benefit obese patients with PCOS by reducing circulating insulin concentration and, consequently, androgen levels, and producing a resumption of regular ovulatory periods. Metformin can be suggested as a second-line treatment for most obese women with PCOS. Further studies of D-chiro-inositol in PCOS women will demonstrate whether this agent is safe and effective for the treatment of insulin resistance and hyperandrogenism in PCOS patients. Antiandrogens and oral contraceptives are effective in reducing androgen levels, but their effects on insulin sensitivity are inconsistent. The effects of rosiglitazone, pioglitazone, and other thiazolidinediones in PCOS patients need to be studied in detail.
Conclusions TOP
PCOS is a common disorder, which, in all likelihood, is etiologically diverse. Obesity is present in approximately 50% of PCOS patients. The differences in clinical manifestations between obese and non-obese PCOS patients are mostly quantitative in nature. Although obese PCOS patients do not exhibit manifestations that are not seen in non-obese women with PCOS, obesity contributes to the manifestations of PCOS by increasing the magnitude of hyperandrogenism and by increasing the rates of anovulatory cycles and infertility.
The pathophysiologic mechanisms by which obesity makes these contributions to the clinical picture of PCOS appear to be related to hyperinsulinemia which, in turn, is induced by insulin resistance. Although insulin resistance is present in both obese and non-obese PCOS patients, the magnitude of both insulin resistance and hyperinsulinemia is greater in obese than in non-obese women with PCOS. Hyperinsulinemia impacts ovarian function and morphology not only by stimulating androgen production directly and in synergism with gonadotropins, but also by activating the ovarian IGF-system (specifically by inducing expression of ovarian-type 1 IGF receptors and by inhibiting IGFBP-1 production in both liver and ovary), by inhibiting SHBG production in the liver, and by contributing to ovarian growth and cyst formation.40,210 Therapeutic modalities directed at the reduction of hyperinsulinemia (weight loss or insulin-sensitizing agents) appear to ameliorate symptoms of PCOS and restore normal ovarian function in obese women with PCOS.
Acknowledgements
We thank Dr Barnett Zumoff for his helpful comments.
References TOP
1. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935;29:181-191.
2. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In Polycystic Ovary Syndrome. Current Issues in Endocrinology and Metabolism, eds Dunaif A, Givens JR and Hasetline FP. Blackwell Scientific, Boston, MA 1992, 377-384.
3. Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries—a common finding in normal women. Lancet 1988;1:870-872.MEDLINE
4. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 1986;293:355-359.MEDLINE
5. Wentz AC, White RI, Migeon CJ, et al. Differential ovarian and adrenal vein catheterization. Am J Obstet Gynecol 1976;125:1000-1007.MEDLINE
6. Givens JR, Wiser WL, Coleman SA, et al. Familial ovarian hyperthecosis: A study of two families. Am J Obstet Gynecol 1971;11:959.
7. Simpson JL. Elucidating the genetics of polycystic ovary syndrome. In Polycystic Ovary Syndrome. Current Issues in Endocrinology and Metabolism, eds Dunaif A, Givens JR, Hasetline FP et al. Blackwell Scientific, Boston, MA 1992, 59-69.
8. Govind A, Obhrai MS, Clayton RN. Polycystic ovaries are inherited as an autosomal dominant trait: Analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab 1999;84:38-43.MEDLINE
9. Solomon CG. The epidemiology of polycystic ovary syndrome. Prevalence and associated disease risks. Endocrinol Metab Clin North Am 1999;28:247-263.MEDLINE
10. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. J Clin Endocrinol Metab 1998;83:3078-3082.MEDLINE
11. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A survey of polycystic ovary syndrome in the Greek island of Lesbos: Hormonal and metabolic profile. J Clin Endocrinol Metab 1999;84:4006-4011.MEDLINE
12. Roumain J, Charles MA, de Courten MP, et al. The relationship of menstrual irregularity to type 2 diabetes in Pima Indian women. Diabetes Care 1998;21:346-349.MEDLINE
13. Chang RJ, Nakamura RM, Judd HL, et al. Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983;57:356-359.MEDLINE
14. Klein S, Romijin JA. Obesity. In Williams Textbook of Endocrinology, eds Larsen PR, Kronenberg HM and Melmed S. Saunders, Philadelphia, PA 2002, 1619-1641.
15. Rabinowitz D, Zierler KL. Forearm metabolism in obesity and its response to intraarterial insulin. Characterization of insulin resistance and evidence for adaptative hyperinsulinism. J Clin Invest 1962;12:2173-2181.
16. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: Evidence in support of current National Institutes of Health guidelines. Arch Intern Med 2002;162:2074-2079.MEDLINE
17. Kissebah AH, Vydelingum N, Murray R, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982;54:254-260.MEDLINE
18. Larsson B, Svärdsudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and death: 13 year follow-up of participants in the study of men born in 1913. BMJ 1984;288:1401-1404.MEDLINE
19. Lapidus L, Bengtsson C, Larsson B, et al. Distribution of adipose tissue and risk of cardiovascular disease and death: A 12 year follow-up of participants in the population study of women in Gothenburg, Sweden. BMJ 1984;289:1257-1261.MEDLINE
20. Stokes J III, Garrison RJ, Kannel WB. The independent contributions of various indices of obesity to the 22-year incidence of coronary heart disease: The Framingham Heart Study. In Metabolic Complications of Human Obesities, eds Vague J, Björntorp P and Guy-Grand B. Elsevier, Amsterdam, The Netherlands 1985, 49-57.
21. Ross R, Freeman J, Hudson R, et al. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. J Clin Endocrinol Metab 2002;87:5044-5051.MEDLINE
22. Buffington CK, Kitabchi AE. Evidence for a defect in insulin metabolism in hyperandrogenic women with polycystic ovary syndrome. Metabolism 1994;43:1367-1372.MEDLINE
23. Peiris AN, Struve MF, Kissebah AH. Relationship of body fat distribution to the metabolic clearance of insulin in premenopausal women. Int J Obes 1987;11:581-589.MEDLINE
24. 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 (Oxf) 1994;41:463-471.MEDLINE
25. 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;51:484-492.MEDLINE
26. Havel RJ, Kane JP, Balasse EO, et al. Splanchnic metabolism of free fatty acids and production of triglyserides of very low-density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest 1970;49:2017-2035.MEDLINE
27. Basu A, Basu R, Shah P, et al. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J Physiol 2001;280:E1000-E1006.
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;39:570-574.MEDLINE
29. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIIDM. Diabetes 1997;46:3-10.MEDLINE
30. Kelley DE. Skeletal muscle triglycerides: An aspect of regional adiposity and insulin resistance. Ann N Y Acad Sci 2002;967:135-145.MEDLINE
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;271:665-668.MEDLINE
32. Hrebicek A, Rypka M, Chmela Z, et al. Tumor necrosis factor alpha in various tissues of insulin-resistant obese Koletsky rats: Relations to insulin receptor characteristics. Physiol Res 1999;48:83-86.MEDLINE
33. Escobar-Morreale HF, Calvo RM, Sancho J, et al. TNF-alpha and hyperandrogenism: A clinical, biochemical, and molecular genetic study. J Clin Endocrinol Metab 2001;86:3761-3767.MEDLINE
34. Gonzalez F, Thusu K, Abdel-Rahman E, et al. Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 1999;48:437-441.MEDLINE
35. Spaczynski RZ, Arici A, Duleba AJ. Tumor necrosis factor- stimulates proliferation of rat ovarian theca-interstitial cells. Biol Reprod 1999;61:993-998.MEDLINE
36. Yen SSC, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 1970;30:435-442.MEDLINE
37. Taylor AE, McCourt B, Martin KA, et al. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2248-2256.MEDLINE
38. Marshall JC, Eagleson CA. Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:295-324.MEDLINE
39. Yen SSC, Chaney C, Judd HL. Functional aberrations of the hypohalamic-pituitary system in PCOS—a consideration of pathogenesis, in Endocrine Function of the Human Ovary. Academic, New York, NY 1976, 273.
40. Poretsky L, Cataldo N, Rosenwaks Z, et al. The insulin-related ovarian regulatory system in health and disease. Endocr Rev 1999;20:535-582.MEDLINE
41. Hashizume T, Kumahara A, Fujino M, et al. Insulin-like growth factor I enhances gonadotropin-releasing hormone-stimulated luteinizing hormone release from bovine anterior pituitary cells. Anim Reprod Sci 2002;70:13-21.MEDLINE
42. Kovacs P, Parlow AF, Karkanias GB. Effect of centrally administered insulin on gonadotropin-releasing hormone neuron activity and luteinizing hormone surge in the diabetic female rat. Neuroendocrinology 2002;76:357-365.MEDLINE
43. Barnes RB. Central opioid activity in polycystic ovary syndrome with and without dopaminergic inhibition. J Clin Endocrinol Metab 1985;61:779-782.MEDLINE
44. Loverro G, Lorusso F, Mei L, et al. The plasma homocysteine levels are increased in polycystic ovary syndrome. Gynecol Obstet Invest 2002;53:157-162.MEDLINE
45. Arroyo A, Laughlin GA, Morales AJ. Inappropriate gonadotropin secretion in polycystic ovary syndrome: Influence of adiposity. J Clin Endocrinol Metab 1997;82:3728-3733.MEDLINE
46. Morales AJ, Laughlin GA, Butzow T. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: Common and distinct features. J Clin Endocrinol Metab 1996;81:2854-2864.MEDLINE
47. Levin JH, Carmina E, Lobo RA. Is the inappropriate gonadotropin secretion of patients with polycystic ovarian syndrome similar to that of patients with adult onset congenital adrenal hyperplasia?. Fertil Steril 1991;56:635-640.MEDLINE
48. Wajchenberg BL, Achando SS, Okada H, et al. Determination of the sources of androgen overproduction in hirsutism associated with polycystic ovarian syndrome by simultaneous adrenal and ovarian venous cathetherization: Comparison with the dexamethasone suppression test. J Clin Endocrinol Metab 1986;63:1204-1210.MEDLINE
49. Kirschner MA, Jacobs JB. Combined ovarian and adrenal vein cathetherization to determine the sites of androgen overproduction in hirsute women. J Clin Endocrinol Metab 1971;33:199-209.MEDLINE
50. Chang RJ, Laufer LR, Meldrum DR, et al. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1983;56. 997-903.
51. Gadir AA, Khatim MS, Mowafi RS, et al. Hormonal changes in patients with polycystic ovarian disease after ovarian electrocautery or pituitary desensitation. Clin Endocrinol (Oxf) 1990;32:749-754.MEDLINE
52. Rosenfield RL. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:265-293.MEDLINE
53. Rosenfield RL. Studies of the nature of 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1994;79:1686-1692.MEDLINE
54. Rosenfeld Rl, Barnes RB, Cara JF, et al. Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil Steril 1990;53:785-791.MEDLINE
55. Ehrmann DA, Rosenfeld RL, Barnes RB, et al. Detection of functional ovarian hyperandrogenism in women with androgen axis. N Engl J Med 1992;327:157-162.MEDLINE
56. Zhang LH, Rodriguez H, Ohno S, et al. Serine phosphorilation of human p450c17 alpha increases 17,20-lyase activity; implications for adrenarche and PCOS. Proc Natl Acad Sci USA 1995;92:10619-10623.MEDLINE
57. DeVane GW, Czekala NM, Judd HL, et al. Circulating gonadotropins, estrogens, and androgens in polycystic ovarian disease. Am J Obstet Gynecol 1975;121:496-500.MEDLINE
58. Hatch R, Rosenfield RL, Kim MH, et al. Hirsutism: Implications, etiology, and management. Am J Obstet Gynecol 1981;140:815-830.MEDLINE
59. Yen SSC. The polycystic ovary syndrome. Clin Endocrinol (Oxf) 1980;12:177-207.MEDLINE
60. Kiddy DS, Sharp PS, White DM, et al. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: An analysis of 263 consecutive cases. Clin Endocrinol 1990;32:213-220.
61. Lobo RA, Paul WL, Goebelsmann U. Dehydroepiandrosterone sulfate as an indicator of adrenal androgen function. Obstet Gynecol 1981;57:69-73.MEDLINE
62. Gross MD, Wortsman J, Shapiro B, et al. Scintigraphic evidence of adrenal cortical dysfunction in the polycystic ovary syndrome. J Clin Endocrinol Metab 1986;62:197-201.MEDLINE
63. Ehrmann DA, Rosenfield RL, Barnes RB. Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J of Med 1992;327:157-162.
64. Bardin CW, Hembree WC, Lipsett MB. Suppression of testosterone and androstenedione production rates with dexamethasone in women with idiopathic hirsutism and polycystic ovaries. J Clin Endocrinol Metab 1968;28:1300-1306.MEDLINE
65. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 2000;24:S47-49.MEDLINE
66. Invitti C, De Martin M, Delitala G. Altered morning and nighttime pulsatile corticotropin and cortisol release in polycystic ovary syndrome. Metabolism 1998;47:143-148.MEDLINE
67. Rodin A, Thakkar H, Taylor N, et al. Hyperandrogenism in polycystic ovary syndrome-evidence of dysregulation of 11-hydroxysteroid dehydrogenase. N Engl J Med 1994;330:460-465.MEDLINE
68. Jessop DS, Dallman MF, Fleming D, et al. Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab 2001;86:4109-4114.MEDLINE
69. Strain GW, Zumoff B, Kream J, et al. Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 1982;31:209-212.MEDLINE
70. Chin D, Shackleton C, Prasad VK. Increased 5 alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome. J Pediatr Endocrinol Metab 2000;13:253-259.MEDLINE
71. Gennarelli G, Holte J, Stridsberg M, et al. Response of the pituitary-adrenal axis to hypoglycemic stress in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1999;84:76-81.MEDLINE
72. Guven M, Acbay O, Sultuybek G. Glucocorticoid receptors on mononuclear leukocytes in polycystic ovary syndrome. Int J Gynaecol Obstet 1998;63:33-37.MEDLINE
73. Dunaif A. Preface, polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:11A-12A.
74. Christman GM, Randolph JF, Kelch RP, et al. Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease. J Clin Endocrinol Metab 1991;72:1278-1285.MEDLINE
75. Pastor CL, Griffin-Korf ML, Aloi JA, et al. Polycystic ovarian syndome—evidence for reduced sensitivity of the GnRH pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 1987;88:582-590.
76. Daniels TL, Berga SL. Resistance of GnRH drive to sex steroid induced suppression in hyperandrogenemic anovulation. J Clin Endocrinol Metab 1997;82:4179-4183.MEDLINE
77. Jakimiuk AJ, Weitsman SR, Brzechffa PR, et al. Aromatase mRNA expression in individual follicles from polycystic ovaries. Mol Hum Reprod 1998;4:1-8.MEDLINE
78. Erickson GF, Hsueh AJ, Quigley ME, et al. Functional studies of aromatase activity in human granulosa cells from normal and polycystic ovaries. J Clin Endocrinol Metab 1979;49:514-519.MEDLINE
79. Poretsky L, Glover B, Laumas V, et al. 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;122:581-585.MEDLINE
80. Gabrielove JL. The pathogenesis of the polycystic ovary syndrome: A hypothesis. Endocr Practice 2002;8:127-132.
81. Jones ME, Thoburn AW, Britt KL. Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. J Steroid Biochem Mol Biol 2001;79:3-9.MEDLINE
82. Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 2000;97:12735-12740.MEDLINE
83. Morishima A, Grumbach MM, Simpson ER, et al. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995;80:3689-3698.MEDLINE
84. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91-95.MEDLINE
85. MacGillivray MH, Morishima A, Conte F, et al. Pediatric endocrinology update: An overview. The essential roles of estrogens in pubertal growth, epiphyseal fusion and bone turnover: Lessons from mutations in the genes for aromatase and estrogen receptor. Horm Res 1998;49:2-8.MEDLINE
86. Mu YM, Yanase T, Nishi Y, et al. Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells. Biochem Biophys Res Commun 2000;271:710-713.MEDLINE
87. Vrbikova J, Hill M, Starka L, et al. The effects of long-term metformin treatment on adrenal and ovarian steroidogenesis in women with polycystic ovary syndrome. Eur J Endocrinol 2001;144:619-628.MEDLINE
88. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305-309.MEDLINE
89. Cleland WH, Mendelson CR, Simpson ER. Effects of aging and obesity on aromatase activity of human adipose cells. J Clin Endocrinol Metab 1985;60:174-177.MEDLINE
90. Longcope C, Baker R, Johnston CC Jr. Androgen and estrogen metabolism: Relationship to obesity. Metabolism 1986;35:235-237.MEDLINE
91. Bulun SE, Simpson ER. Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab 1994;78:428-432.MEDLINE
92. Kirschner MA, Samojlik E, Drejka M, et al. Androgen-estrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab 1990;70:473-479.MEDLINE
93. Pasquali R, Casimirri F. The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women. Clin Endocrinol 1993;39:1-16.
94. Gambineri A, Pelusi C, Vicennati V, et al. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord 2002;26:883-896.MEDLINE
95. Ahima RS, Flier JS. Leptin. In Endocrinology, eds DeGroot LJ, Jameson JL, Burger HG et al. Saunders, Philadelphia, PA 2001, 605-615.
96. Coleman DL. Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14:141-148.MEDLINE
97. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.MEDLINE
98. Boden G, Chen X, Mozzoli M, et al. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 1996;81:3419-3423.MEDLINE
99. Bray GA, York DA. The MONA LISA hypothesis in the time of leptin. Recent Prog Horm Res 1998;53:95-117.MEDLINE
100. Dube MG, Xu B, Kalra PS, et al. Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats. Brain Res 1999;816:38-46.MEDLINE
101. Frederich RC, Lollmann B, Hamann A, et al. Expression of ob mRNA and its encoded protein in rodents: Impact of nutrition and obesity. J Clin Invest 1995;96:1658-1663.MEDLINE
102. Maffei M, Halaas J, Ravussin E. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155-1161.MEDLINE
103. Frederich RC, Hamann A, Anderson S, et al. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nat Med 1995;1:1311-1314.MEDLINE
104. Caro JF, Kolaczynski JW, Nyce MR, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: A possible mechanism for leptin resistance. Lancet 1996;348:159-161.MEDLINE
105. Lin L, Martin R, Schaffhauser AO. Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol 2001;280:R504-R509.
106. Friedman JM, Halaas JL. Leptin and regulation of body weight in mammals. Nature 1998;395:763-770.MEDLINE
107. Kolaczynski JW, Ohannesian JP, Considine RV, et al. Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endocrinol Metab 1996;81:4162-4165.MEDLINE
108. Caro JF, Sinha MK, Kolaczynski JW, et al. Leptin: The tale of an obesity gene. Diabetes 1996;45:1455-1462.MEDLINE
109. Poretsky L, Lesser M, Brillon D. Lack of postprandial leptin peaks in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2001;3:105-111.MEDLINE
110. Marshall FHA, Peel WR. “Fatness” as a cause of sterility. J Agric Sci (Cambridge) 1908;3:383-389.
111. Evans HM, Bishop KS. On the relations between fertility and nutrition. II. The ovulation rhythm in the rat on inadequate nutritional regimes. J Metab Res 1922;1:335-356.
112. Frisch RE. Body fat, menarche, fitness and fertility. Adipose Tissue and Reproduction. Progress in Reproductive Biology and Medicine, ed Frisch RE. Karger Basel, Cambridge, MA 1990, 1-26.
113. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996;12:318-320.MEDLINE
114. Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250-252.MEDLINE
115. Ahima RS, Dushay J, Flier SN. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997;99:391-395.MEDLINE
116. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. J Clin Endocrinol Metab 1997;82:1066-1070.MEDLINE
117. Clayton PE, Gill MS, Hall CM, et al. Serum leptin through childhood and adolescence. Clin Endocrinol (Oxf) 1997;46:727-733.MEDLINE
118. Blum WF, Englaro P, Hanitsch S, et al. Plasma leptin levels in healthy children and adolescents: Dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 1997;82:2904-2910.MEDLINE
119. Laughlin GA, Morales AJ, Yen SSC. Serum leptin levels in women with polycystic ovary syndrome: The role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 1997;82:1692-1696.MEDLINE
120. Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:1687-1697.MEDLINE
121. Carmina E, Ferin M, Gonzalez F, et al. Evidence that insulin and androgens may participate in the regulation of serum leptin levels in women. Fertil Steril 1999;72:926-931.MEDLINE
122. Pirwany IR, Fleming R, Sattar N, et al. Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. Eur J Endocrinol 2001;145:289-294.MEDLINE
123. Spritzer PM, Poy M, Wiltgen D, et al. Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: Influence on LH and relationship with hormonal, metabolic, and anthropometrics measurements. Hum Reprod 2001;16:1340-1346.MEDLINE
124. Pasquali R, Gambineri A, Biscotti D, et al. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen ad insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:2767-2774.MEDLINE
125. Kowalska I, Kinalski M, Straczkowski M. Insulin, leptin, IGF-I and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome. Eur J Endocrinol 2001;144:509-515.MEDLINE
126. Nestler JE, Jakubowicz DJ, De Vargas AF, et al. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998;83:2001-2005.MEDLINE
127. Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocr Rev 1997;18:774-800.MEDLINE
128. Ciaraldi TP, El-Roeiy A, Madar Z, et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 1992;75:577-583.MEDLINE
129. Rosenbaum D, Haber RS, Dunaif A. Insulin resistance in polycystic ovary syndrome: Decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 1993;264:E197-E202.MEDLINE
130. Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: A potential mechanism of insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96. 81–10.
131. Archard C, Thiers J. Le virilisme pilaire et son association a l’insuffisance glycolytique (diabetes des femmes a barbe). Bull Acad Natl Med 1921;86:51.
132. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113-116.MEDLINE
133. Kitabchi AE, Imseis RE, Bush AJ, et al. Racial differences in the correlation between gonadal androgens and serum insulin levels. Diabetes Care 1999;22:1524-1529.MEDLINE
134. Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 1987;64:960-963.MEDLINE
135. Polderman KH, Gooren JG, Asscherman H. Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 1994;79:265-271.MEDLINE
136. Woodard TL, Burghen GA, Kitabchi AE. Glucose intolerance and insulin resistance in aplastic anemia treated with oxymetholone. J Clin Endocrinol Metab 1981;53:905-908.MEDLINE
137. Lemieux S, Lewis GF, Ben-Chetrit A. Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels. J Clin Endocrinol Metab 1999;84:4278-4282.MEDLINE
138. Nagamani M, Van Dinh T, Kelver ME. Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 1986;154:384-389.MEDLINE
139. Dunaif A, Green G, Futterweit W. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1990;70:699-704.MEDLINE
140. Geffner ME, Kaplan SA, Bersch N. Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril 1986;45:327-333.MEDLINE
141. Ibanez L, Potau N, Marcos MV. Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: Effect of flutamide. J Clin Endocrinol Metab 2000;85:3251-3255.MEDLINE
142. Taylor SI, Dons RF, Hernandez E. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med 1982;97:851-855.MEDLINE
143. Kahn CR, Flier RS, Archer JA, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 1976;294:739-745.MEDLINE
144. Ovesen P, Moller J, Ingerslev HJ. Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1993;77:1636-1640.MEDLINE
145. Shriock ED, Buffington CK, Hubert GD. Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metabol 1988;66:1329-1331.
146. Flier JS, Kahn CR, Roth J, et al. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 1975;190:63-65.MEDLINE
147. El-Roeiy A, Chen X, Roberts VJ, et al. Expression of insulin-like growth factor-I (IGF-I) and IGF-II and the IGF-I, IGF-II, and insulin receptor genes and localization of the gene products in the human ovary. J Clin Endocrinol Metab 1993;77:1411-1414.MEDLINE
148. Hernandez ER, Hurwitz A, Vera A, et al. Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary. J Clin Endocrinol Metab 1992;74:419-425.MEDLINE
149. Channing CP, Tsai V, Sachs D. Role of insulin, thyroxin and cortisol in luteinization of porcine granulosa cells grown in chemically defined media. Biol Reprod 1976;15:235-247.MEDLINE
150. Veldhuis JD, Furlanetto RW. Trophic actions of human somatomedin C/insulin-like growth factor I on ovarian cells: In vitro studies with swine granulosa cells. Endocrinology 1985;116:1235-1242.MEDLINE
151. Adashi EY, Resnick CE, Svoboda ME, et al. Somatomedin-C synergizes with follicle-stimulating hormone in the acquisition of progestin biosynthetic capacity by cultured rat granulosa cells. Endocrinology 1985;116:2135-2142.MEDLINE
152. Nestler JE, Jacubowicz 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;335:617-623.MEDLINE
153. Antilla L, Ding YQ, Ruutainen K, et al. Clinical features and circulating gonadotropin, insulin and androgen interactions in women with polycystic ovarian disease. Fertil Steril 1991;55:1057-1061.MEDLINE
154. 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;86:3115-3119.MEDLINE
155. White MF, Kahn CR. Mechanisms of insulin action. In Insulin Resistance, ed Moller DE. Wiley, New York, NY 1991, 9-47.
156. Seto-Young D, Zajac J, Hung-Ching L, et al. The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. J Clin Endocrinol Metab 2003;88:3385-3391.MEDLINE
157. Poretsky L, Grigorescu F, Seibel M, et al. Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary. J Clin Endocrinol Metab 1985;61:728-734.MEDLINE
158. Poretsky L, Bhargava G, Kalin MF, et al. Regulation of insulin receptors in the human ovary: In vitro studies. J Clin Endocrinol Metab 1988;67:774-778.MEDLINE
159. Suikkari AM, Koivisto VA, Rutanen EM, et al. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 1988;66:266-272.MEDLINE
160. Poretsky L, Chandrasekher YA, Bai C, et al. Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-I, on IGF binding protein 1 (IGFBP-1) production in human granulosa cells. J Clin Endocrinol Metab 1996;81:493-496.MEDLINE
161. Buyalos RP, Pekonen F, Halme JK, et al. The relationship between circulating androgens, obesity, and hyperinsulinemia on serum insulin-like growth factor binding protein-1 in the polycystic ovarian syndrome. Am J Obstet Gynecol 1995;172:932-939.MEDLINE
ABSTRACT
FULL TEXT
162. Garcia-Rudaz MC. Amplified and orderly growth hormone secretion characterizes lean adolescents with polycystic ovary syndrome. Eur J Endocrinol 2002;147:207-216.MEDLINE
163. Slowinska-Srzednicka J, Zgliczynski W, Makowska A, et al. An abnormality of the growth hormone/insulin-like growth factor-1 axis in women with polycystic ovarian syndrome with coexisting obesity. J Clin Endocrinol Metab 1992;74:1432-1435.MEDLINE
164. Veldhuis JD, Iranmanesh A, Ho KKY, et al. Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatropinism of obesity in man. J Clin Endocrinol Metab 1991;72:51-59.MEDLINE
165. Ferriman D, Galleway JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440-1447.MEDLINE
166. Balen AH, Tan SL, MacDougall J, et al. Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 1993;8:959-964.MEDLINE
167. Wiegerinck M. Early pregnancy loss in chronic hyperandrogenic anovulation. In Chronic Hyperandrogenic Anovulation, ed Coelingh-Bennink HJT. Parthenon, London, UK 1991, 169.
168. White DM. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: An analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996;81:3821-3824.MEDLINE
169. Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499-507.MEDLINE
170. Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995;15:821-826.MEDLINE
171. Franks S. Medical progress: Polycystic ovary syndrome. N Engl J Med 1995;333:853-861.MEDLINE
172. Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000;85:2434-2438.MEDLINE
173. Carmina E, Koyama T, Chang L, et al. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome?. Am J Obstet Gynecol 1992;167:1807-1812.MEDLINE
174. Kauffman RP, Baker VM, Dimarino P, et al. Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: A comparison of two distinct populations. Am J Obstet Gynecol 2002;187:1362-1369.MEDLINE
ABSTRACT
FULL TEXT
175. Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary syndrome: The spectrum of the disorder in 1741 patients. Hum Reprod 1995;10:2107-2111.MEDLINE
176. Gill S, Taylor AE, Martin KA, et al. Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome. J Clin Endocrinol Metab 2001;86:2428-2436.MEDLINE
177. Stuart CA, Peters EJ, Prince MJ, et al. Insulin resistance with acanthosis nigricans: The roles of obesity and androgen excess. Metabolism 1986;35:197-205.MEDLINE
178. Conway GS, Jacobs HS. Acanthosis nigricans in obese women with the polycystic ovary syndrome: Disease spectrum not distinct entity. Postgrad Med J 1990;66:536-538.MEDLINE
179. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk of 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;84:165-169.MEDLINE
180. Conway GS, Agrawal R, Betteridge DJ, et al. Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992;37:119-125.
181. Sampson M, Kong C, Patel A, et al. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol 1996;45:623-629.
182. Wild RA, Grubb B, Hartz A, et al. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 1990;54:255-259.MEDLINE
183. Kelly CJ, Lyall H, Petrie JR, et al. A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001;87:3287-3290.
184. Vgontzas AN, Legro RS, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance. J Clin Endocrinol Metab 2001;86:517-520.MEDLINE
185. Gjonnaess H. The course and outcome of pregnancy after ovarian electrocautery in women with polycystic ovarian syndrome: The influence of body-weight. Br J Obstet Gynaecol 1989;96:714-719.MEDLINE
186. Urman B, Sarac E, Dogan L, et al. Pregnancy in infertile PCOD patients. Complications and outcome. J Reprod Med 1997;42:501-505.MEDLINE
187. Thadhani R, Stampfer MJ, Hunter DJ, et al. High body mass index and hypercholesterolemia: Risk of hypertensive disorders of pregnancy. Obstet Gynecol 1999;94:543-550.MEDLINE
188. De Vries MJ, Dekker GA, Schoemaker J. Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study. Eur J Obstet Gynecol Reprod Biol 1998;76:91-95.MEDLINE
189. Huber-Buchholz MM, Carey DGP, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470-1474.MEDLINE
190. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 1992;38:105-111.
191. Guzick DS, Berga SL, Wing R, et al. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61:598-604.MEDLINE
192. Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647-654.MEDLINE
193. Arslanian SA, Lewy V, Danadian K. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: Amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002;87:1555-1559.MEDLINE
194. 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;85:139-146.MEDLINE
195. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome?. Fertil Steril 1996;65:946-949.MEDLINE
196. Dunaif A, Scott D, Finegood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299-3306.MEDLINE
197. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2108-2116.MEDLINE
198. Baillargeon JP, Jakubowicz DJ, Iuorno MJ, et al. Effects of metformin and rosiglitazone, alone and in combination, in lean women with polycystic ovary syndrome and normal indices of insulin sensitivity. Proceedings of the 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19–22. 2000. (abstr OR10-1).
199. Mercado-Asis LB, Faller TM, Mercado AB. Long term follow-up of Filipino patients with polycystic ovary syndrome (PCOS) with insulin sensitizer: From troglitazone to rosiglitazone. Proceedings of the 84th Annual Meeting of the Endocrine Society, San Francisco, CA, June 19–22. 2000. (abstr P1–57).
200. Brettenthaler N, De Geyter C, Huber P, et al. Effect of the insulin sensitizer pioglitazone on insulin resistance and hyperandrogenaemia in women with polycystic ovary syndrome: A placebo controlled double blind randomised trial. Diabetes 2003;52:A140.
201. Bloomgarden ZT, Futterweit W, Poretsky L. Use of insulin-sensitizing agents in patients with polycystic ovary syndrome. Endocr Practice 2001;7:279-286.
202. Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 1999;340:1314-1320.MEDLINE
203. De Leo V, Lanzetta D, D’Antona D, et al. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:99-102.MEDLINE
204. Diamanti-Kandarakis E, Mitrakou A, Hennes MM, et al. Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism 1995;44:525-531.MEDLINE
205. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: Evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 2000;81:952-960.
206. Pasquali R, Gambineri A, Anconetani B, et al. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf) 1999;50:517-527.MEDLINE
207. Cibula D, Hill M, Fanta M, et al. Does obesity diminish the positive effect of oral contraceptive treatment on hyperandrogenism in women with polycystic ovarian syndrome?. Hum Reprod 2001;16:940-944.MEDLINE
208. Dahlgren E, Landin K, Krotkiewski M, et al. Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 1998;13:2706-2711.MEDLINE
209. Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: A randomized study. J Clin Endocrinol Metab 2000;85:3161-3168.MEDLINE
210. Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic onadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism 1992;41:903-910.MEDLINE
211. Welt CK, Taylor AE, Martin KA, et al. Serum inhibin B in polycystic ovary syndrome: Regulation by insulin and luteinizing hormone. J Clin Endocrinol Metab 2002;87:5559-5565.MEDLINE
212. Singh A, Hamilton-Fairley D, Koistinen R, et al. Effect of insulin-like growth factor-type I (IGF-I) and insulin on the secretion of sex hormone binding globulin and IGF-I binding protein (IBP-I) by human hepatoma cells. J Endocrinol 1990;124:R1-R3.MEDLINE
Publishing and Reprint Information TOP
aDivision of Endocrinology and Metabolism, Department of Medicine, Beth Israel Medical Center and Albert Einstein College of Medicine, New York, NY, USA
Supported in part by Dr Gerald G. and Dorothy Friedman and Pharmacia foundations and by Grant No. R01MH60563 from the National Institutes of Health.
1M.S. and R.B-V. contributed equally to this work.
*Address reprint requests to Leonid Poretsky, MD, Division of Endocrinology and Metabolism, Beth Israel Medical Center, 317 East 17th St, New York, NY 10003, USA
Submitted May 19, 2003.
Accepted on October 29, 2003.
Copyright © 2004 by Elsevier Inc.
doi:10.1016/j.metabol.2003.10.005
Pathogenesis of polycystic ovary syndrome: What is the role of obesity? 
