This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dunaif, A. Search for Related Content PubMed PubMed Citation Articles by Dunaif, A.

Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis¹

Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

	Abstract

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 

I. Introduction

A. Background and historical perspective

B. Definition of PCOS

II. Insulin Action in PCOS

A. Glucose tolerance

B. Insulin action in vivo in PCOS

C. Insulin secretion in PCOS

D. Insulin clearance in PCOS

E. Cellular and molecular mechanisms of insulin resistance

F. Constraints of insulin action studies in PCOS

G. PCOS as a unique NIDDM subphenotype

III. Hypotheses Explaining the Association of Insulin Resistance and PCOS

A. Causal association

B. Possible genetic association of PCOS and insulin resistance

IV. Clinical Implications of Insulin Resistance in PCOS

A. Clinical diagnosis of insulin resistance

B. Other metabolic disorders in PCOS

C. Therapeutic considerations

V. Summary

	I. Introduction

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 
A. Background and historical perspective
POLYCYSTIC ovary syndrome (PCOS) is an exceptionally common disorder of premenopausal women characterized by hyperandrogenism and chronic anovulation (1, 2). Its etiology remains unknown. Although there have been no specific population-based studies, a 5–10% prevalence of this disorder in women of reproductive age is probably a reasonable conservative estimate. This is based as an upper limit on studies of the prevalence of polycystic ovaries, which found that 20% of self-selected normal women had polycystic ovary morphology on ovarian ultrasound (3). Many of these women had subtle endocrine abnormalities (3). The lower estimate is based on the reported 3% prevalence rate of secondary amenorrhea for 3 or more months (4) and the fact that up to 75% of women with secondary amenorrhea will fulfill diagnostic criteria for PCOS (5). PCOS women can also have less profound disturbances in menstrual function (1, 3, 6).

Since the report by Burghen et al. (7) in 1980 that PCOS was associated with hyperinsulinemia, it has become clear that the syndrome has major metabolic as well as reproductive morbidities. The recognition of this association has also instigated extensive investigation of the relationship between insulin and gonadal function (1, 8, 9, 10, 11). This review will summarize our current understanding of insulin action in PCOS, address areas of controversy, and propose several hypotheses for this association. Abnormalities of steroidogenesis and gonadotropin release will not be discussed in detail; these changes have been reviewed recently by Erhmann and colleagues (12) and by Crowley (13), respectively.

The association between a disorder of carbohydrate metabolism and hyperandrogenism was first described in 1921 by Achard and Thiers (14) and was called "the diabetes of bearded women (diabete des femmes a barbe)." The skin lesion, acanthosis nigricans, was reported to occur frequently in women with hyperandrogenism and diabetes mellitus by Kierland et al. (15) in 1947. Brown and Winkelmann (16) noted in 1968 that it was insulin-resistant diabetes mellitus, and a genetic basis was suggested by reports of affected sisters (17), including a pair of identical twins who also had acromegaloid features (18). Several additional syndromes with distinctive phenotypic features, acanthosis nigricans, hyperandrogenism, and insulin-resistant diabetes mellitus have been identified (Table 1). These include the lipoatrophic (total and partial) diabetes syndromes, leprechaunism (intrauterine growth retardation, gonadal enlargement, elfin facies, and failure to thrive), and Rabson-Mendenhall syndrome (unusual facies, pineal hypertrophy, dental precocity, thickened nails, and ovarian enlargement) (8, 19, 20).

In 1980 Burghen and colleagues (7) reported that women with the common hyperandrogenic disorder, PCOS, had basal and glucose-stimulated hyperinsulinemia compared with weight-matched control women, suggesting the presence of insulin resistance. They noted significant positive linear correlations between insulin and androgen levels and suggested that this might have etiological significance. In the mid-1980s several groups noted that acanthosis nigricans occurred frequently in obese hyperandrogenic women (24, 25, 26, 27) (Fig. 1). These women had hyperinsulinemia basally and during an oral glucose tolerance test, compared with appropriately age- and weight-matched control women. The presence of hyperinsulinemia in PCOS women, independent of obesity, was confirmed by a number of groups worldwide (28, 29, 30).

View larger version (91K): [in this window] [in a new window]   Figure 1. A woman with PCOS who has acanthosis nigricans, a cutaneous marker of insulin resistance (panel A). She also has severe hirsutism on her face and chest (panels B and C). [Reproduced from A. Dunaif et al.: Obstet Gynecol 66:545–552, 1985 (25) with permission from The American College of Obstetricians and Gynecologists.]

View larger version (212K): [in this window] [in a new window]   Figure 2. Section of a polycystic ovary with multiple subscapular follicular cysts and stromal hypertrophy (left panel). At higher power (x100) islands of luteinized theca cells are visible in the stroma (right panel). This morphological change is called stromal hyperthecosis and appears to be directly correlated with circulating insulin levels. [Figure is used with permission from A. Dunaif.]

Other nomenclature has been proposed for the syndrome, e.g., chronic hyperandrogenic anovulation (CHA) (1). Many hyperandrogenic anovulatory women have significantly increased ovarian steroidogenic responses to stimulation with GnRH analogs that Rosenfield and colleagues (41) have termed functional ovarian hyperandrogenism (FOH). They have proposed this as an alternative name for PCOS (12). The majority of women who have hyperandrogenemia and chronic anovulation will have polycystic ovary (PCO) on ultrasound and will have responses to GnRH analogs consistent with FOH (1, 2, 12) (Fig. 3). Thus, the terms PCOS, FOH, and CHA define similar groups of women (Fig. 3).

View larger version (70K): [in this window] [in a new window]   Figure 3. The majority of women with CHA will also have polycystic ovary morphology (PCO) and responses to GnRH analogs consistent with FOH. [Figure is used with permission from A. Dunaif.]

It is important to recognize that there is an inherent bias of ascertainment in studies of PCOS that constrains the assessment of the frequency of associated clinical and biochemical findings. Obviously, all women will have polycystic ovaries when this feature is an essential diagnostic criterion. Studies that use an increased LH/FSH ratio as a selection criterion will be biased toward finding increased pulsatile LH release when gonadotropin secretion is examined. The appropriate study would be a population-based one in which clinical and biochemical features were systematically examined in a defined population of women. Until such a study is performed, the prevalence of PCOS and frequency of associated findings will remain subject to debate.

	II. Insulin Action in PCOS

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 
A. Glucose tolerance
Insulin resistance is an important defect in the pathogenesis of noninsulin-dependent diabetes mellitus (NIDDM) (51). Despite the fact that hyperinsulinemia, reflecting some degree of peripheral insulin resistance, was well recognized in PCOS by the mid-1980s (Fig. 4), glucose tolerance was not systematically investigated until our study in 1987 (49). We found that obese PCOS women had significantly increased glucose levels during an oral glucose tolerance test compared with age- and weight-matched ovulatory hyperandrogenic (i.e., elevated plasma androgen levels) and control women (Fig. 4). Twenty percent of the obese PCOS women had impaired glucose tolerance or frank NIDDM by National Diabetes Data Group Criteria (49, 52) (Fig. 4). The women studied ranged in age from 18–36 yr with a mean age of 27 yr for the obese PCOS women. There were no significant differences, however, in glucose levels during the oral glucose tolerance test in the nonobese PCOS women compared with age- and weight-matched control women (Fig. 4).

View larger version (21K): [in this window] [in a new window]   Figure 4. Insulin (panels A and C) and glucose (panels B and D) responses basally and after a 40 g/m2 oral glucose load in obese and lean PCOS women, ovulatory hyperandrogenic women (HA) women, and age- and weight-matched ovulatory control women. Insulin responses are significantly increased only in PCOS women, suggesting that hyperinsulinemia is a unique feature of PCOS and not hyperandrogenic states in general (panels A and B). Glucose responses are significantly increased only in obese PCOS women (C), and 20% of obese PCOS women have impaired glucose tolerance or NIDDM using National Diabetes Data Group Criteria (52). [Derived from Ref. 49.]

B. Insulin action in vivo in PCOS
Although insulin has a number of actions, in addition to those regulating glucose metabolism, such as inhibition of lipolysis and stimulation of amino acid transport (51), the effects of insulin on glucose metabolism are usually examined in studies of insulin resistance (60). This can be studied quantitatively in humans with the euglycemic glucose clamp technique: a desired dose of insulin is administered and euglycemia is maintained by a simultaneous variable glucose infusion whose rate is adjusted based on frequent arterialized blood glucose determinations and a negative feedback principle (60, 61, 62). At steady state, the amount of glucose that is infused equals the amount of glucose taken up by the peripheral tissues and can be used as a measure of peripheral sensitivity to insulin, known as insulin-mediated glucose disposal (IMGD) or M (61, 62). The suppression of hepatic glucose production by insulin can be assessed by the use of a simultaneous infusion of isotopically labeled glucose. Insulin-mediated glucose disposal occurs only in muscle (skeletal and cardiac) and in fat; muscle accounts for about 85% of this (60).

Euglycemic glucose clamp studies have demonstrated significant and substantial decreases in insulin-mediated glucose disposal in PCOS (54, 55) (Fig. 5). This decrease (35–40%) is of a similar magnitude to that seen in NIDDM (Fig. 5). Obesity (fat mass per se), body fat location (upper vs. lower body, e.g., waist to hip girth ratio), and muscle mass all have important independent effects on insulin sensitivity (63, 64, 65, 66). Alterations in any of these parameters could potentially contribute to insulin resistance in PCOS. PCOS women have an increased prevalence of obesity (6, 47), and women with upper, as opposed to lower body, obesity have an increased frequency of hyperandrogenism (66). Since muscle is the major site of insulin-mediated glucose use (60) and androgens can increase muscle mass (67), potential androgen-mediated changes in lean body (primarily muscle) mass must also be controlled for in PCOS (54, 55). Studies in which body composition, assessed by the most precise available method (hydrostatic weighing), has been matched to normal control women, and in which lean PCOS women, who had body composition and waist to hip girth ratios similar to controls, were studied, have confirmed that PCOS women are insulin resistant, independent of those potentially confounding parameters (1, 55, 68). The impact of hyperandrogenism on insulin sensitivity is discussed below, but studies in cultured cells have confirmed the impression from these in vivo studies that an intrinsic defect in insulin action is present in PCOS (69).

View larger version (22K): [in this window] [in a new window]   Figure 5. Insulin-mediated glucose disposal at steady-state insulin levels of 600 pmol/liter (100 µU/ml) is decreased by 35–40% in PCOS women compared with age- and weight-matched control women. This decrease is similar in magnitude to that seen in NIDDM. [Figure is used with permission from A. Dunaif.]

View larger version (25K): [in this window] [in a new window]   Figure 6. Parameters of in vivo insulin action during sequential multiple-dose euglycemic glucose clamp studies in nonobese PCOS women (, Nob PCOS); nonobese normal women (, Nob NL); obese PCOS women (•, Ob PCOS); and obese normal women (, Ob NL). The maximal response in the dose-response curves (top left) for insulin-mediated glucose disposal (IMGD) is significantly decreased in obesity (*P < 0.001) and in PCOS (**P < 0.01). The ED50 insulin IMGD is significantly increased in PCOS women (P < 0.001) and in obese women (P < 0.001) (top right). Basal rates of hepatic glucose production (HGP) are not significantly different in the four groups (bottom left). The statistical interaction is significant between PCOS and obesity on the ED50 insulin for suppression of HGP (bottom right), which is increased significantly in obese PCOS women (*P < 0.001) indicating a synergistic deleterious effect of obesity and PCOS on hepatic insulin sensitivity. [Reproduced with permission by A. Dunaif et al. Diabetes 41:1257–1266, 1992 (55).]

View larger version (22K): [in this window] [in a new window]   Figure 7. The relationship between insulin sensitivity (SI) determined by frequently sampled intravenous glucose tolerance test and first-phase insulin secretion to an intravenous glucose load (AIRg). The majority of PCOS women fall below the normal curve determined in concurrently studied age- and weight-matched control women as well as normative data in the literature. [Derived from Ref. 57.]

D. Insulin clearance in PCOS
Hyperinsulinemia can result from decreases in insulin clearance as well as from increased insulin secretion. Indeed, decreased insulin clearance is usually present in insulin-resistant states since insulin clearance is receptor-mediated, and acquired decreases in receptor number and/or function are often present in insulin resistance secondary to hyperinsulinemia and/or hyperglycemia (78, 79). Thus, PCOS would be expected to be associated with decreases in insulin clearance; however, relatively few studies have examined this question. Direct measurement of posthepatic insulin clearance during euglycemic clamp studies has not been abnormal in PCOS (54, 56). Circulating insulin to C-peptide molar ratios are increased in PCOS, suggesting decreased hepatic extraction of insulin, but such ratios also reflect insulin secretion (28, 80). Direct measurement of hepatic insulin clearance in non-PCOS hyperandrogenic women has found it to be decreased (81). The one study of this question in PCOS found decreased hepatic insulin extraction by model analysis of C-peptide levels (75). Therefore, in PCOS, hyperinsulinemia is probably the result of a combination of increased basal insulin secretion and decreased hepatic insulin clearance.

E. Cellular and molecular mechanisms of insulin resistance
1. Molecular mechanisms of insulin action (Figs. 8 and 9). Insulin acts on cells by binding to its cell surface receptor (51, 82, 83). The insulin receptor is a heterotetramer made up of two ,ß- dimers linked by disulfide bonds (84) (Fig. 8). Each ,ß-dimer is the product of one gene (85, 86). The -subunit is extracellular and contains the ligand-binding domain whereas the ß-subunit spans the membrane, and the cytoplasmic portion contains intrinsic protein tyrosine kinase activity, which is activated further by ligand-mediated autophosphorylation on specific tyrosine residues (87) (Fig. 8). The insulin receptor belongs to a family of protein tyrosine kinase receptors that includes the insulin-like growth factor-I (IGF-I) receptor, with which it shares substantial sequence and structural homology, as well as the epidermal growth factor (EGF), fibroblast growth factor, platelet-derived growth factor, and colony-stimulating factor-1 receptors (88). A number of oncogene products are also protein tyrosine kinases (85, 89).

View larger version (15K): [in this window] [in a new window]   Figure 8. The insulin receptor is a heterotetramer consisting of two ,ß-dimers linked by disulfide bonds. The -subunit contains the ligand-binding site, and the ß-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases the receptor’s tyrosine kinase activity whereas serine phosphorylation inhibits it. [Adapted with permission from C. R. Kahn: Diabetes 43:1066–1084, 1994 (51).]

View larger version (34K): [in this window] [in a new window]   Figure 9. The tyrosine-phosphorylated insulin receptor phosphorylates intracellular substrates, such as insulin receptor substrate (IRS)-1 and IRS-2, initiating signal transduction and the plieotropic actions of insulin. The activation of PI3-K (PI3-kinase) by tyrosine-phosphorylated IRS-1 appears to be the pathway for insulin-mediated glucose transport. The Ras-MAP kinase pathway appears to regulate cell growth and glycogen synthesis. [Adapted with permission from C. R. Kahn: Diabetes 43:1066–1084, 1994 (51).]

Insulin has numerous target tissue actions, such as stimulation of glucose uptake, gene regulation, DNA synthesis, and amino acid uptake (51, 82). The mechanisms of insulin receptor signal specificity are currently a subject of intense investigation. It now appears that the Ras-Raf-MEK pathway is involved in the regulation of cell growth and metabolism whereas the PI3-K pathway is involved in glucose uptake (98, 99, 100, 101). The mechanisms by which the insulin signal is terminated remain incompletely understood. Receptor-mediated endocytosis and recycling are well known to occur and may be important to signal termination (83, 102). Serine phosphorylation has been shown to terminate signaling by the EGF receptor (103, 104), another tyrosine kinase growth factor receptor, and it can be shown under a variety of experimental conditions that insulin receptor serine phosphorylation decreases its tyrosine kinase activity (105, 106, 107, 108). It has been postulated that protein kinase C (PKC)-mediated serine phosphorylation of the insulin receptor is important in the pathogenesis of hyperglycemia-induced insulin resistance (102, 109). Recent evidence suggests that tumor necrosis factor- (TNF-)-mediated serine phosphorylation of IRS-1 inhibits insulin receptor signaling and is the mechanism of TNF--induced insulin resistance (110). Studies addressing this important question have been constrained by a lack of sensitive anti-phosphoserine antibodies. Identification of phosphoserine residues usually requires painstaking phosphoamino acid analysis of ³²P-labeled receptors (111). The use of fluorophore labeling of phosphoserine promises to provide a sensitive methodology for examining in vivo serine phosphorylation events (112).

In summary, insulin action is mediated through a ligand-activated tyrosine kinase receptor, similar to a number of other growth factors. A variety of phosphorylation-dephosphorylation signaling cascades are then activated, leading to the pleiotropic actions of insulin. The mechanisms of signal specificity and termination require further investigation.

2. Molecular insulin action defects in PCOS. Studies in adipocytes, a classic insulin target tissue, have failed to confirm earlier reports in blood cells of decreases in insulin receptor number and/or receptor affinity in PCOS (25, 26, 27, 113) when appropriately weight-matched controls have been included. The one adipocyte study reporting a decrease in insulin receptor number used a control group consisting primarily of lean individuals (114). Studies of insulin action in isolated PCOS adipocytes have revealed marked decreases in insulin sensitivity together with less striking, but significant, decreases in maximal rates of insulin-stimulated glucose transport (55, 115) (Fig. 10). There is evidence for decreases in adipocyte levels of adenosine in PCOS (116), but whether this is a primary defect or secondary to hyperinsulinemia is unclear. The decrease in maximal rates of adipocyte glucose uptake is secondary to a significant decrease in the abundance of GLUT4 glucose transporters (117). Similar defects are present in NIDDM and in obesity but are ameliorated by control of hyperglycemia and hyperinsulinemia as well as by weight reduction, suggesting acquired rather than intrinsic defects (65, 118, 119, 120). In contrast, in PCOS such defects can occur in the absence of obesity, glucose intolerance, or changes in waist to hip girth ratios (55, 117). Moreover, these abnormalities are not significantly correlated with sex hormone levels, suggesting that abnormalities of insulin action in PCOS may be intrinsic (55, 117).

View larger version (24K): [in this window] [in a new window]   Figure 10. Insulin-stimulated adipocyte U-[14C]glucose transport in nonobese PCOS women (, Nob PCOS); nonobese normal women (), Nob NL); obese PCOS women (•, Ob PCOS); and obese normal women (, Ob NL). Basal rates of glucose transport are decreased significantly (*) in PCOS vs. normal women (P < 0.01) and in nonobese vs. obese women (P < 0.001). Maximal insulin-stimulated increments above basal are significantly decreased in PCOS vs. normal women (***, P < 0.01) and in obese vs. nonobese women (**, P < 0.001). The ED50 insulin is increased significantly in PCOS vs. normal and in obese vs. nonobese women (inset). [Reproduced with permission from A. Dunaif et al.: Diabetes 41:1257–1266, 1992 (55).]

View larger version (26K): [in this window] [in a new window]   Figure 11. Representative autoradiograms of autophosphorylated skin fibroblast insulin receptor ß-subunits (top) and phosphoamino acid analysis (bottom) ± 1 µM insulin from a normal (control), a PCOS woman with normal insulin-stimulated tyrosine phosphorylation (PCOS-nl) and a PCOS woman with high basal autophosphorylation on serine residues (PCOS-ser); S-serine, Y-tyrosine. Basal autophosphorylation is increased and there is minimal further insulin-stimulated phosphorylation in the PCOS-ser ß-subunits. The high basal phosphorylation represents phosphoserine, and phosphotyrosine content does not increase in response to insulin in the PCOS-ser ß-subunits. [Reproduced from A. Dunaif et al.: J Clin Invest 96:801–810, 1995 (69) by copyright permission of The American Society for Clinical Investigation.]

View larger version (17K): [in this window] [in a new window]   Figure 12. Phosphorylation of poly GLU4:TYR1 by partially purified skin fibroblast insulin receptors. Skin fibroblast insulin receptors were directly extracted from confluent cell cultures, partially purified, and incubated in the presence of 0–100 nM, and assays of the phosphorylation of poly GLU4:TYR1 were performed. One-way ANOVA, P < 0.005; PCOS-ser < control and PCOS-nl, P < 0.05 Tukey’s test. The values are the mean ± SEM from five PCOS-ser (•), four PCOS-nl (), and four control () subjects. [Reproduced from A. Dunaif et al.: J Clin Invest 96:801–810, 1995 (69) by copyright permission of The American Society for Clinical Investigation.]

Fibroblasts from approximately 50% of PCOS women (PCOS-nl) have no detectable abnormality in insulin receptor phosphorylation (69) (Figs. 11 and 12). Although these women demonstrate the same PCOS phenotype and the same degree of insulin resistance as the PCOS-ser women with abnormal phosphorylation, insulin receptor phosphorylation in fibroblasts and skeletal muscle from these women is similar to that of control women (69). This observation suggests that a defect downstream of insulin receptor signaling, such as phosphorylation of IRS-1 or activation of PI3-K, is responsible for insulin resistance in PCOS-nl women (51, 69, 102). Indeed, our recent human studies demonstrate a significant decrease in muscle PI3-K activation during insulin infusion in PCOS women (121), consistent with a physiologically relevant defect in the early steps of insulin receptor signaling.

We found no insulin receptor mutations in two PCOS-ser women by direct sequencing of genomic DNA (120), and sequence analysis of the tyrosine kinase domain in the ß-subunit of an additional eight PCOS-ser women also revealed no mutations (69). This finding has recently been confirmed by other investigators (122). Immunoprecipitation and mixing experiments suggest that a factor extrinsic to the insulin receptor is responsible for the excessive serine phosphorylation (69). PCOS-ser insulin receptors autophosphorylate normally, if they are first immunoprecipitated from wheat-germ agglutinin (WGA) lectin eluates. Furthermore, mixing control human insulin receptors and WGA eluates from PCOS-ser fibroblasts results in increased insulin-independent serine phosphorylation and decreased insulin-stimulated tyrosine phosphorylation of the normal receptors (69) (Fig. 13). Both experiments suggest that a factor present in WGA eluates is responsible for the abnormal phosphorylation.

View larger version (34K): [in this window] [in a new window]   Figure 13. Phosphoamino acid analysis of immunopurified human insulin receptors (hIR) ß-subunits basally and mixed with WGA-Sepharose eluates from control or PCOS-ser fibroblasts. hIRs were immunopurified from WGA-Sepharose eluates, mixed in a ratio of 10 fmol hIR:1 fmol PCOS-ser or control lectin eluate insulin-binding activity, and autophosphorylation ± 1 µM insulin was examined. Phosphoamino acid analysis revealed a striking increase in phosphoserine content and a marked decrease in insulin-stimulated phosphotyrosine content after mixing hIR with PCOS-ser lectin eluates as compared with mixing hIR with control lectin eluates or in the absence of mixing. [Reproduced from A. Dunaif et al.: J Clin Invest 96: 801–810, 1995 (69) by copyright permission of The American Society for Clinical Investigation.]

Other serine/threonine kinases that might cause the increased serine phosphorylation of PCOS-ser insulin receptors include a casein kinase I-like enzyme and cAMP-dependent protein kinase (125, 126). However, the casein kinase I-like enzyme has been shown to phosphorylate insulin-stimulated insulin receptors twice as well as unstimulated insulin receptors (125). This phosphorylation pattern differs from what we observe with PCOS-ser insulin receptors, namely excessive serine phosphorylation in the absence of insulin. cAMP-dependent protein kinase is a candidate because increases in cAMP cause serine phosphorylation of insulin receptors in cultured lymphocytes (127). However, insulin receptor phosphorylation by cAMP-dependent protein kinase is probably indirect because the human insulin receptor ß-subunit does not contain the amino acid sequences classically recognized by this kinase (128).

Alternatively, a novel serine/threonine kinase or an inhibitor of a serine/threonine phosphatase may be responsible for the abnormal phosphorylation of PCOS-ser insulin receptors (69, 129). Because it is present in WGA eluates, the PCOS-ser factor is either a membrane glycoprotein or a protein associated with a glycoprotein. In some respects, our putative serine phosphorylation factor is similar to a recently identified inhibitor of insulin receptor tyrosine kinase, the membrane glycoprotein PC-1 (130) (Fig. 14). Both factors are extrinsic to the insulin receptor, both are present in WGA eluates from human skin fibroblasts, and both appear to inhibit insulin receptor tyrosine kinase activity. This represents an important new mechanism for human insulin resistance related to factors that modulate the tyrosine kinase activity of the insulin receptor (51) (Fig. 14). The major difference between the two factors is that PC-1 is not associated with increased insulin-independent serine phosphorylation characteristic of the PCOS-ser insulin receptors (69, 130, 131). Recent studies suggest that TNF- produces insulin resistance by a related mechanism: serine phosphorylation of IRS-1, which then inhibits insulin receptor tyrosine kinase activity (Fig. 7). Isolation and characterization of the factor in PCOS-ser fibroblasts are now in progress, as is the mapping of phosphorylated serine residues in PCOS-ser insulin receptors.

View larger version (19K): [in this window] [in a new window]   Figure 14. Insulin resistance in 50% of PCOS women appears to be secondary to a cell membrane-associated factor, presumably a serine/threonine kinase, that serine-phosphorylates the insulin receptor-inhibiting signaling. Serine phosphorylation of IRS-1 appears to be the mechanism for TNF-mediated insulin resistance. The membrane glycoprotein PC-1 also inhibits insulin receptor kinase activity, but it does not cause serine phosphorylation of the receptor. These are examples of a recently appreciated mechanism for insulin resistance secondary to factors regulating the receptor’s tyrosine kinase activity. [Figure used with permission from A. Dunaif.]

F. Constraints of insulin action studies in PCOS
There is general consensus in the literature that obese PCOS women are insulin resistant. Controversy remains as to the pathogenesis of the insulin resistance, and there are studies that suggest that obesity per se or increased central adiposity are responsible for the associated defects in insulin action (135, 136). Many of the conflicting studies can be explained by differing diagnostic criteria for PCOS and by the inclusion of both lean and obese women in the experimental sample. Our studies (49) and those in the United Kingdom (137, 138) strongly suggest that anovulation is associated with insulin resistance. We found insulin resistance only in women with hyperandrogenism and anovulation (Fig. 4). Studies using ovarian morphology to ascertain women have found that only anovulatory women with PCO morphology are insulin resistant (137, 138). Women with regular ovulatory menses and hyperandrogenism [elevated plasma androgen levels (49)] (Fig. 4) or with PCO detected by ovarian ultrasound (137, 138) are not insulin resistant. Therefore, studies that have defined PCOS by PCO morphology without further assessment of ovulation could have included women who were not insulin resistant. Similarly, studies that have included ovulatory hyperandrogenic women will bias the sample with insulin-sensitive subjects.

One reason for the general acceptance of the diagnostic criteria for PCOS of hyperandrogenism and anovulation (1) (Table 2, see above) is that they define the insulin-resistant subset. Even with subjects so identified, not all are insulin resistant, despite using the relatively lenient criterion of 1 SD below the control mean value for insulin action. Moreover, the occasional PCOS woman can have insulin sensitivity more than 2 SDs (95% confidence interval) above the control mean (117). There is clearly heterogeneity in this feature of the syndrome. Obesity is another important factor, and it appears that it has a more pronounced effect on insulin action in PCOS than in control women (71). Ideally, lean and obese PCOS women should be studied separately (30, 49, 54, 55, 68). If groups are pooled, PCOS women should be matched to controls so that the spectrum of body weights are equally represented. This is often not the case so that, although mean body mass may be similar, the PCOS group often contains more obese individuals, thereby skewing the results (114). Moreover, there are very few studies in the literature in which lean PCOS woman have been separately studied (30, 54, 55, 68, 135). There are also major ethnic variations in insulin sensitivity, and this is another less well appreciated potential confounding factor (56). Recent studies from Denmark suggest that adiposity accounts for insulin resistance in their PCOS population in contrast to our US population (135, 136).

We have consistently found significant decreases in insulin-mediated glucose disposal in both lean and obese PCOS women (54, 55, 56). Similarly, our group (57) as well as Yen’s group (68) have found significant decreases in insulin sensitivity (SI) determined by modified frequently sampled intravenous glucose tolerance test with minimal model analysis in such PCOS women (57). Insulin resistance has been found in PCOS women of many racial and ethnic groups including Japanese, Caribbean and Mexican Hispanics, non-Hispanic Whites, and African Americans (55, 56, 139, 140).

G. PCOS as a unique NIDDM subphenotype (Table 3)
Our studies in premenopausal women, extrapolated data based on prevalence estimates of PCOS and glucose intolerance, and studies in postmenopausal women with a history of PCOS all suggest that PCOS-related insulin resistance confers a significantly increased risk for NIDDM (see above). Familial clustering of affected individuals as well as studies in monozygotic twins indicate that NIDDM has an important genetic component (51, 102, 141, 142, 143, 144). Insulin resistance is a major inherited abnormality, but studies in which insulin secretion has been examined in the context of insulin sensitivity demonstrate that ß-cell dysfunction may also be an important contributing factor to the ultimate development of the NIDDM phenotype (51, 145, 146). There is clearly genetic heterogeneity with insulin resistance being absent in some affected individuals (146, 147).

	III. Hypotheses Explaining the Association of Insulin Resistance and PCOS

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 
A. Causal association
1. Do androgens cause insulin resistance? If glucose utilization is expressed as a function of muscle mass rather than total body mass, women do appear to be more insulin sensitive than men (158, 159). Moreover, when isolated fat cells are compared, female adipocytes are more sensitive than male adipocytes to insulin-mediated glucose uptake (160). These are subtle differences, however, and do not approach the degree of impairment in insulin sensitivity observed in PCOS (54, 55). Finally, in the rare syndromes of extreme insulin resistance and hyperandrogenism, specific molecular defects in insulin action have been clearly identified as the cause of insulin resistance (19, 161).

It is possible, however, that androgens may produce mild insulin resistance. Women receiving oral contraceptives containing "androgenic" progestins can experience decompensations in glucose tolerance, as can individuals receiving synthetic anabolic steroids (162, 163). Prolonged testosterone administration to female-to-male transsexuals, which produced circulating testosterone levels in the normal male range, resulted in significant decreases in insulin-mediated glucoses uptake in euglycemic clamp studies (164). These decreases were largest at lower doses of insulin (25% at 300 pM steady-state levels), not significant at moderate insulin doses (1,000 pM steady-state levels), and minimal at higher doses (7% at 5,000 pM steady-state levels) (164) (Fig. 15). Studies in testosterone-treated castrated female rats have suggested that androgen-mediated insulin resistance may be the result of an increase in the number of less insulin-sensitive type II b skeletal muscle fibers (165) and an inhibition of muscle glycogen synthase activity (166).

View larger version (25K): [in this window] [in a new window]   Figure 15. Hyperinsulinemic euglycemic clamp studies basally and during treatment with virilizing doses of testosterone in 13 female-to-male transsexuals. Insulin-mediated glucose disposal decreased significantly at low and at high doses of insulin. [Reproduced with permission from K. H. Polderman et al.: J Clin Endocrinol Metab 79:265–271, 1994 (164). © The Endocrine Society.]

View larger version (33K): [in this window] [in a new window]   Figure 16. Basal and insulin-mediated glucose disposal in 43 hyperandrogenic women and 12 control women. The hyperandrogenic women were studied before and after 3–4 months of antiandrogen therapy with spironolactone, flutamide, or Buserelin. Insulin-mediated glucose disposal increased significantly during treatment (P < 0.01). [Adapted with permission from P. Moghetti et al.: J Clin Endocrinol Metab 81:952–960, 1996 (170). © The Endocrine Society.]

In summary, the modest hyperandrogenism characteristic of PCOS may contribute to the associated insulin resistance. Additional factors are necessary to explain the insulin resistance, since suppressing androgen levels does not completely restore normal insulin sensitivity (167, 170). Further, androgen administration does not produce insulin resistance of the same magnitude as that seen in PCOS (54, 55, 164). Finally, there are clearly defects in insulin action that persist in cultured PCOS skin fibroblasts removed from the hormonal milieu for generations (see above) (69).

2. Does hyperinsulinemia cause hyperandrogenism? The syndromes of extreme insulin resistance are commonly associated with hyperandrogenism when they occur in premenopausal women (19, 20) (Table 1). The cellular mechanisms of insulin resistance in these conditions range from antibodies that block insulin binding to its receptor (type B syndrome) to genetic defects in the receptor resulting in decreased numbers and/or depressed function of the receptor (type A syndrome, leprechaunism); the common biochemical feature is profound hyperinsulinemia (19, 20) (Table 1). Accordingly, it has been proposed that hyperinsulinemia causes hyperandrogenism. Insulin can be shown experimentally to have a variety of direct actions on steroidogenesis in humans (1, 9, 20). Insulin can stimulate ovarian estrogen, androgen, and progesterone secretion in vitro (1, 20, 176). Although some of these actions have been observed at physiological insulin concentrations, most actions have been observed at higher concentrations (1, 20).

The presence of insulin receptors in crude ovarian membranes does not necessarily indicate a physiological role for insulin in the regulation of steroidogenesis since such receptors are widely distributed through the body (51, 83). Insulin is present in human follicular fluid but in concentrations most likely representing an ultrafiltrate of plasma rather than local production (177). In contrast, IGF-I is produced by human ovarian tissue, and IGF-I receptors are present in the ovary (178, 179). IGF-I and its receptor share considerable sequence, structural, and functional homology with insulin and its receptor, respectively (180). The IGF-I receptor is a heterotetramer with two ,ß-dimers assembled analogous to the insulin receptor (85, 88, 181, 182, 183) (see above). Insulin can bind to the ligand-binding domain of the IGF-I receptor and activate the tyrosine kinase activity of the ß-subunit and the intracellular events normally mediated by IGF-I (85, 88, 180, 181). IGF-I can bind to and activate the insulin receptor, resulting in rapid effects on glucose metabolism (85, 88, 181). In general, the affinity of the IGF-I receptor for insulin is considerably less than it is for IGF-I and vice versa (181). However, this varies by tissue; thus data on receptor affinity cannot be extrapolated from one tissue to another. There are also so-called "atypical" IGF-I receptors that bind IGF-I and insulin with similar affinity (184, 185). ,ß-Dimers of the insulin and IGF-I receptor can assemble together to form hybrid heterotetramers (11, 182, 186, 187).

Insulin-like growth factor-binding proteins (IGFBPs) are major regulators of IGF action. IGFBPs can specifically bind IGF-I and modulate its cellular actions by altering its bioavailability (182, 188). Insulin decreases hepatic production of IGFBP-1 and may, thus, make IGF-I more biologically available (182). Growth factor regulation of ovarian steroidogenesis appears to be primarily a paracrine system with locally produced IGF-I and IGFBPs acting on neighboring cells in concert with gonadotropins (1, 178, 179, 189). A number of other growth factors, including IGF-II, EGF, and transforming growth factor- and -ß, appear to have a role in the regulation (both stimulatory and inhibitory) of ovarian steroidogenesis (1, 188, 190). Insulin cannot interact directly with the receptors for these hormones (84, 88, 181, 182). However, the receptors for some of these growth factors, such as the EGF receptor (which binds both EGF and transforming growth factor-), are also protein kinases (1, 84, 88). Thus the potential exists for communication between the insulin-IGF-I system and the other protein kinase growth factor systems through receptor "cross-talk" and/or by shared kinases or phosphatases that may regulate all of these receptors (51, 191). For example, serine phosphorylation of the EGF receptor also decreases its tyrosine kinase activity (103, 104). In rodents, hyperinsulinemia can result in up-regulation of ovarian IGF-I-binding sites, and this may provide yet another mechanism by which insulin can modulate growth factor action (192).

Insulin in high concentrations can mimic IGF-I actions by occupancy of the IGF-I receptor (1, 181, 182), and this has been a proposed mechanism for insulin-mediated hyperandrogenism (8, 9, 10). However, it has recently been shown that insulin has specific actions on steroidogenesis acting through its own receptor (193). Moreover, these actions appear to be preserved in insulin-resistant states (193, 194), presumably because of differences in receptor sensitivity to this insulin action or because of differential regulation of the receptor in this tissue. Our studies in cultured skin fibroblasts suggest that a mechanism for this may be selective defects in insulin action. Both insulin- and IGF-I-stimulated glycogen synthesis are significantly decreased in PCOS fibroblasts whereas thymidine incorporation is similar to control fibroblasts (Fig. 17) (195). Thus only the signaling pathways regulating carbohydrate metabolism may be impaired in PCOS, while those involved in steroidogenesis are preserved. This would explain the paradox of persistent insulin-stimulated androgen production in insulin-resistant PCOS women. Insulin decreases hepatic IGFBP-1 production, the major circulating IGF-I-binding protein (183). Thus, bioavailable IGF-I levels are increased in insulin-resistant PCOS women, and this may contribute to the ovarian steroidogenic abnormalities via activation of the IGF-I receptor (68). In lean PCOS women, increases in GH release may also affect ovarian steroidogenesis (68).

View larger version (12K): [in this window] [in a new window]   Figure 17. Dose-response curves for insulin-stimulated glycogen synthesis (left panel) and thymidine incorporation (right panel) in confluent skin fibroblasts from PCOS (•) and control (, NL) women. Maximal responses for insulin-stimulated glycogen synthesis were significantly decreased (P < 0.001). There were no significant differences in thymidine incorporation in the PCOS fibroblasts (right panel). The dose-response curves for IGF-I were similar to those for insulin (data not shown). [Reproduced with permission from A. Dunaif (195).]

Studies in which insulin levels have been lowered for prolonged periods have been much more informative. This has been accomplished for 7 days to 3 months with agents that either decrease insulin secretion, diazoxide (199) or somatostatin (200), or that improve insulin sensitivity, metformin (201) or troglitazone (202). Circulating androgen levels have decreased significantly in women with PCOS in these studies. Sex hormone binding globulin (SHBG) levels have increased (199, 202), compatible with a major role for insulin in regulating hepatic production of this protein (203, 204). Abnormalities in apparent 17,20-lyase activity have improved in parallel with reduced circulating insulin levels consistent with insulin-mediated stimulation of this enzyme (205). However, estrogen levels also decreased significantly, suggesting that insulin has diffuse effects on steroidogenesis (202). Changes in estrogen levels were seen only when insulin levels were lowered with troglitazone and thus, alternatively, these changes might be the result of troglitazone-mediated increases in sex steroid metabolism, a recently reported action of this agent (Rezulin Package Insert, Parke-Davis, Morris Plains, NJ). It is also possible that troglitazone has direct effects on steroidogenesis. Indeed, the thiazolidinediones have been shown to have such effects on granulosa cell steroidogenesis (206).

Most of the reported actions of insulin on steroidogenesis are observed only in women with PCOS (197, 198) and are greatly enhanced by the addition of gonadotropins when measured in in vitro experiments (1, 20, 176, 190, 207). In the one study in normal women in which insulin levels were lowered by diazoxide administration, no significant changes in androgen levels were noted (208). These observations suggest that, if insulin is to produce ovarian hyperandrogenism in women, polycystic ovarian changes (e.g., theca cell hyperplasia) must be present that predispose the ovaries to secrete excess androgens. In normal women insulin does not appear to have any acute effects on ovarian function under physiological circumstances (196, 197, 208).

Although insulin has been shown to stimulate gonadotropin release in isolated rat pituitary cells (209), human studies of insulin action on gonadotropin release have yielded conflicting results. Acute insulin infusion has not changed pulsatile LH or FSH release or gonadotrope sensitivity to GnRH in normal or in PCOS women, despite direct effects on gonadal steroidogenesis in PCOS women (197). Long-term suppression of insulin levels with diazoxide, which resulted in decreases in circulating testosterone levels, did not alter circulating LH levels (199). In contrast, decreases in LH levels were observed after 7 days of somatostatin-mediated insulin lowering (201), after metformin for 8 weeks (205), or after troglitazone for 3 months (202). It is possible that insulin-mediated changes in gonadotropin release contribute to the changes of steroidogenesis produced by insulin in humans (Fig. 18).

View larger version (18K): [in this window] [in a new window]   Figure 18. Studies in which insulin levels have been lowered with the insulin-sensitizing agent, troglitazone, suggest that insulin is a general augmentor of steroidogenesis and LH release. [Figure is used with permission from A. Dunaif.]

In summary, studies in which insulin levels have been lowered by a variety of modalities indicate that hyperinsulinemia augments androgen production in PCOS (Fig. 18). Moreover, this action appears to be directly mediated by insulin acting through its cognate receptor rather than by spillover occupancy of the IGF-I receptor. Intrinsic abnormalities in steroidogenesis appear to be necessary for this insulin action to be manifested since lowering insulin levels does not affect circulating androgen levels in normal women. Further, in many PCOS women, lowering insulin levels ameliorates but does not abolish hyperandrogenism.

B. Possible genetic association of PCOS and insulin resistance
1. Family studies of PCOS. Familial aggregation of PCOS suggesting a genetic etiology has been clearly established (1, 212, 213, 214). Cooper et al. (212) reported that a history of oligomenorrhea was more common in the mothers and sisters of PCOS women than in controls. Probands reported that male relatives had increased "pilosity" (212). The proposed mechanism of inheritance was autosomal dominant with decreased penetrance. Givens and colleagues have reported multiple kindreds showing affected women in several generations and have examined some males in considerable detail (1, 215). Diagnostic criteria for PCOS were hirsutism and enlarged ovaries. There was a high frequency of metabolic disorders, such as NIDDM and hyperlipidemia, in both male and female pedigree members. In one kindred there were several males with oligospermia and one with Klinefelter’s syndrome (47, XXY). Elevated LH/FSH ratios were present in some males and 89% of their daughters had PCOS. This would suggest inheritance in either an autosomal or X-linked dominant manner.

Ferriman and Purdie (216) studied 700 women; affected status was assigned on the basis of hirsutism and enlarged ovaries (assessed by gynecography). The frequency of various abnormalities in relatives was determined by history provided by the proband; no relatives were examined. Oligomenorrhea and infertility were most common in women who had both hirsutism and enlarged ovaries. Forty-six percent of female relatives were reported to be similarly affected. There was an increased incidence of baldness reported in male relatives. Similar results were found in a study of 132 Norwegian PCOS probands identified by ovarian wedge resection (217). Information on pedigree members was obtained by questionnaire. Female first-degree relatives had a significantly increased frequency of PCOS symptoms (i.e., hirsutism, oligomenorrhea, infertility), and male first-degree relatives had a significantly increased frequency of early baldness or "excessive hairiness" compared with controls. Human leukocyte antigen typing in PCOS has had conflicting results; an initial report showed no human leukocyte antigen association, whereas a follow-up study reported an association with DQA1¹0501 (218, 219). There have been case reports of polyploidies and X-chromosome aneuploidies in PCOS (220, 221). Larger studies, however, have found normal karyotypes (222).

Studies from the United Kingdom have phenotyped women on the basis of polycystic ovarian morphology detected by ultrasound (223). Familial polycystic ovary morphology was observed in 51 of 62 pedigrees (92%). The proportion of females affected in all sibships was 80.5% (107 of 133), which would exceed the expected ratios for either an autosomal dominant or an X-linked dominant mode of inheritance. However, not all women in each kindred were examined and, thus, an accurate ratio of affected to unaffected women could not be established for segregation analysis. Further, the male phenotype was not sought.

A more recent study prospectively examined the families of probands consecutively identified on the basis of polycystic ovarian morphology on ultrasound (224). The first-degree relatives in 10 families were evaluated by history, measurement of physical indices, and hirsutism as well as serum levels of androgens, 17-hydroxyprogesterone, gonadotropins, and PRL. Transabdominal ultrasound was performed in female first-degree relatives. Only 54% of women with polycystic ovaries had an elevated total testosterone or LH level consistent with the endocrine syndrome. Glucose and insulin levels were assessed in obese but not lean probands. Twenty-two males were screened; eight had premature (before age 30 yr) fronto-parietal hair loss, 10 did not, and four were too young to assess. Female affected status was assigned on the basis of ultrasound evidence of polycystic ovaries. If male affected status was considered to be premature balding, and a history of menstrual irregularity was used to assign postmenopausal affected status, the segregation ratio for affected families, excluding the proband, was 51.4%, consistent with an autosomal dominant mode of inheritance with complete penetrance (224). Studies in monozygotic twins, however, have not found complete concordance of polycystic ovary morphology, arguing against this mode of inheritance (133). The study contained only 19 pairs of monozygotic twins as well as a sample of 15 dizygotic twins. The prevalence of polycystic ovary morphology was 50% in these twins, who were recruited from a twin registry, which was twice the prevalence reported in other randomly selected groups of women (3). This raises concern about the accuracy of the detection of polycystic ovaries.

Family studies have been constrained by small sample sizes and/or failure to examine all available family members. In several studies, PCOS affected status has been assigned on the basis of ovarian morphology rather than hormonal abnormalities. Only one study has proposed a male phenotype on the basis of examination of male relatives, and this study was constrained by a small sample size (224). Nevertheless, these studies strongly suggest that PCOS has a genetic component, most likely with an autosomal dominant mode of transmission (220, 224). If this is true, are there other phenotypes in affected kindreds? The studies cited above have suggested that premature male balding may be a male phenotype (216, 224). This finding could be an artifact, since it is also possible that bald men choose to marry hirsute women. Recent studies in these families, however, suggesting linkage of this phenotype with a candidate gene in the steroidogenic enzyme pathway (Ref. 225; see below), if verified, would confirm genetically that this is a male phenotype.

Our studies have suggested that insulin resistance may be an additional male phenotype as well as a prepubertal and postmenopausal female phenotype (132, 220) (Table 4). This has been also reported recently in a series of Australian PCOS kindreds. In the small number of families that we have studied (132, 220), when women of reproductive age are insulin resistant, they usually have possessed the other endocrine features of PCOS. The one insulin-resistant prepubertal girl was also hyperandrogenic and developed chronic anovulation after menarche consistent with the diagnosis of PCOS (132). That insulin resistance and hyperandrogenism may be a prepubertal phenotype is supported by recent studies suggesting that PCOS develops in insulin-resistant girls with premature adrenarche (58, 226, 227) (Table 4). Our studies suggest that hyperandrogenism without insulin resistance is another phenotype in female PCOS kindred members of reproductive age (228) (Table 4). Finally, we have found postmenopausal hyperandrogenic female family members with normal insulin sensitivity, which may represent an additional postmenopausal phenotype (132) (Table 4). This possibility is supported by the study of Dahlgren and colleagues (53), which found that postmenopausal women with a history of PCOS had higher androgen levels than age-matched control women. We have found that hyperandrogenism and insulin resistance can segregate independently in PCOS kindreds (132). It is not yet possible to determine whether this reflects separate genetic traits or variable penetrance of a single defect. These studies also indicate that there is considerable phenotypic variation, even within kindreds.

The insulin resistance in PCOS is secondary to a postbinding defect in insulin receptor signaling, as discussed above (69). In 50% of PCOS women studied, the abnormality appears to be in an enzyme regulating insulin receptor tyrosine kinase activity (69). When this enzyme is identified, it will make an excellent candidate gene for insulin resistance in PCOS. This enzyme may also be responsible for altering P450c17 activity that results in hyperandrogenism and the PCOS reproductive phenotype (231). It appears that at least 50% of PCOS women do not have this defect in insulin action and, thus, any factor regulating insulin receptor signaling is a potential candidate gene for insulin resistance in such women (51, 82, 102).

Polymorphisms in the P450c17 gene itself were found not to cosegregate with the polycystic ovary-premature balding phenotypes in the families reported by Carey et al. (224, 232). However, the polymorphism did affect the promoter region of the gene, and the frequency of the polymorphism was significantly increased in PCOS, suggesting that it might play a role in modifying the phenotype (232). Further candidate gene searches in these families suggest a linkage with the steroid synthesis gene CYP11a, and an association study indicated a significant increase in a CYP11a polymorphism in hirsute PCOS women (225). The polymorphism was also significantly associated with elevated testosterone levels. These investigators have recently reported that an insulin gene VNTR-regulatory polymorphism was significantly associated with PCO in the same families (233). Case-control studies suggested that the polymorphism was associated with anovulation and higher insulin levels (233), women who would be considered to have the endocrine syndrome. This observation suggests that there may be a genetic basis for the finding of insulin resistance only in anovulatory women with hyperandrogenism or the PCO morphology. This insulin gene VNTR has been associated with decreased levels of islet cell insulin RNA and may thus result in decreased insulin secretion. The mechanism by which this might cause hyperinsulinemia and insulin resistance is unknown. Polymorphisms in the dopamine and androgen receptors have not been significantly associated with PCOS (220, 234, 235). There have been no mutations in the coding portions of the insulin receptor gene detected in PCOS (69, 120, 122).

Extreme caution must be exercised, however, in the interpretation of both linkage and association studies. Case-control association studies can give false-positive results because of subtle genetic differences between the populations (236). This appears to have occurred in the association studies of the polymorphism in the P450c17 gene promoter with PCO (232). Subsequent larger studies by these investigators failed to confirm the finding (232a). Linkage studies of many candidate genes in the same families must have the level of significance for positive results adjusted for multiple tests. Thus log of odds scores greater than the traditional threshold of 3 must be used to prove linkage (236). Such log of odds scores have not been achieved in the reported studies in PCOS (225, 233).

3. Does insulin resistance produce PCOS in women with PCO? The polycystic ovary morphology (detected by ultrasonography) has been reported to be inherited as an autosomal dominant, if premature balding is used as the male phenotype (224) (see above). We have found that Caribbean Hispanic women have twice the prevalence of PCOS compared with other ethnic groups (56). Brothers, as well as sisters, of PCOS women can be insulin resistant (132, 134). The insulin-resistant sisters usually also have PCOS (132). Finally, in 50% of PCOS women, defects in insulin receptor phosphorylation (PCOS-ser, see above) persist in cultured cells (69). All of these observations support the hypothesis that there is a genetic component to PCOS and the insulin resistance associated with it. Caribbean Hispanic women are also significantly more insulin resistant than non-Hispanic White women by euglycemic clamp determination of insulin-mediated glucose disposal (56). PCOS independently further decreases insulin action. Non-Hispanic White PCOS women have similar degrees of insulin resistance to Caribbean Hispanic normal ovulatory women (56). These findings suggest that the increased prevalence of PCOS in this ethnic group may be secondary to an increased prevalence of insulin resistance.

Hyperinsulinemia resulting from a spectrum of defects in insulin action, at least some of which are genetic, may play a permissive role in the development of PCOS in genetically susceptible women (Fig. 19). Polycystic ovaries may secrete excessive androgens when hyperinsulinemia and/or insulin resistance are also present. This hypothesis is supported by the finding of the full-blown polycystic ovary syndrome (hyperandrogenism and anovulation) primarily in women with polycystic ovaries who are also hyperinsulinemic (137, 138).

View larger version (22K): [in this window] [in a new window]   Figure 19. A proposed schema for the association of insulin resistance and PCOS. A single factor that causes serine phosphorylation of the insulin receptor and serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis, could produce both the insulin resistance and the hyperandrogenism characteristic of PCOS. It is also possible that the insulin resistance and the reproductive abnormalities reflect separate genetic defects and that the insulin resistance unmasks the syndrome in genetically susceptible women. Recent studies suggest that insulin acting through its own receptor augments steroidogenesis and LH release. Androgens amplify the associated insulin resistance. [Figure is used with permission from A. Dunaif.]

	IV. Clinical Implications of Insulin Resistance in PCOS

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 
A. Clinical diagnosis of insulin resistance
Making a diagnosis of insulin resistance in an individual is problematic. First, there is a wide range of insulin sensitivities in normal individuals such that 25% of normal subjects have insulin action values that overlap with those from insulin-resistant individuals (238) (Fig. 20). Second, clinically available measures of insulin action, such as fasting or glucose-stimulated insulin values (239), do not correlate well with more detailed measurements of insulin sensitivity in research settings (62). In view of these constraints, it is prudent to consider all PCOS women at risk for insulin resistance and the associated metabolic abnormalities of the insulin resistance syndrome: dyslipidemia, coronary artery disease, and hypertension. Lipid and lipoprotein levels should be obtained on all PCOS women, and obese PCOS women should also have fasting and 2-h post-75 g glucose load glucose levels as a screen for glucose intolerance. The WHO criteria (52) for glucose intolerance can be applied to the 2-h glucose value: <140 mg/dl normal; 140–199 mg/dl impaired; 200 mg/dl NIDDM (Table 5). The criterion for the diagnosis of diabetes mellitus based on fasting glucose values is currently being revised downward from the old criterion of 140 mg/dl to 126 mg/dl (7 mM).

View larger version (13K): [in this window] [in a new window]   Figure 20. Individual values for fasting and 2-h post-75 g oral glucose load insulin levels are shown in PCOS and in weight-matched control women. Although the means differ significantly, there is substantial overlap such that an individual value in a PCOS woman may not fall outside the normal range. [Figure is used with permission from A. Dunaif.]

There are several intriguing cross-sectional studies that suggest that PCOS women may indeed be at increased risk for cardiovascular disease. Women coming to cardiac catheterization who have a history of symptoms of hyperandrogenism have an increased prevalence of coronary artery disease (249). Postmenopausal women with a history of ovarian wedge resection for PCOS have a significantly increased frequency of cardiovascular events compared with age-matched control women (250). Women with PCO detected by ovarian ultrasound have more extensive coronary artery disease by angiography than women with sonographically normal ovaries (251). The women with PCO also have higher free testosterone, triglyceride, and C-peptide levels and lower LDL levels than the women with normal ovaries, suggesting that they have both the endocrine and the metabolic derangements of PCOS (251). Finally, increased carotid wall thickness measured by ultrasonography was found in PCOS women compared with case-controls (252). The carotid wall thickness was significantly positively correlated with fasting insulin levels and body mass index, after adjustment for possible confounding variables (252). However, since the PCOS women were significantly heavier than the controls, it was not possible to determine the independent impact of obesity on these findings (252).

As with studies of insulin action, studies of lipid metabolism in PCOS have been confounded by differences in body weight and ethnicity between patient and control groups. Inconsistencies in diagnostic criteria, in particular, basing the diagnosis on ultrasound morphology rather than hormonal parameters, have resulted in heterogenous patient populations that have included women with regular ovulation and normal insulin sensitivity (241, 242, 243). Some investigators have found that LDL and HDL changes in PCOS can be accounted for by obesity and that only modest increases in total triglyceride levels appear secondary to PCOS-related insulin resistance (138, 253, 254). A recent case control study does suggest that there are lipid abnormalities in PCOS after statistical adjustments for obesity (242). However, Legro and colleagues (255) found atherogenic alterations in lipoprotein levels in normal Hispanic women that did not differ further in Hispanic PCOS women. Thus, there appear to be important additional genetic and environmental factors influencing lipid metabolism in PCOS.

2. Hypertension. It has been suggested that insulin resistance causes hypertension; thus PCOS women would be expected to be hypertensive (240). Significant increases in systolic blood pressure, albeit within the normal range, have been reported in obese PCOS women, but this study did not include a weight-matched control group (243). Moreover, lean PCOS women in the study were not hypertensive, consistent with an effect of obesity rather than PCOS on blood pressure. Careful studies of 24-h blood pressures and left ventricular mass have failed to find evidence for hypertension in PCOS women in their second to fourth decades of life (256). This has been confirmed in another recent study (138). The studies discussed above in postmenopausal PCOS women, however, have found a significant increase in prevalence of hypertension (53). It may be that hypertension is not manifested until later in life in PCOS women. Conversely, it remains possible that the association between insulin resistance and hypertension does not exist in PCOS, analogous to observations in African Americans and in Pima Indians (257).

3. Gestational diabetes mellitus (GDM). Women with a history of GDM are insulin resistant, at increased risk to develop NIDDM, and have defects in the ß-cell function that can be detected in the absence of glucose tolerance (258, 259). PCOS women share these traits, and it would be expected that they would be at increased risk to develop GDM, if GDM is yet another manifestation of insulin resistance. Two small studies of this have yielded conflicting results: one study found no increase in GDM while another detected an increased risk for GDM in PCOS women (260, 261). A large prospective study in PCOS women containing appropriately matched control women is required to address this issue. Until such a study has been completed, it is prudent to advise PCOS women contemplating pregnancy that they may be at increased risk to develop GDM.

4. Leptin in PCOS. Leptin, the recently identified product of the ob gene (262), has been investigated in PCOS. Since leptin is a fat cell product that acts on the hypothalamus (263), it could link the metabolic and neuroendocrine derangements characteristic of PCOS. Leptin production is regulated by insulin and could be modulated in insulin-resistant PCOS women via this mechanism (263). An initial report suggested that leptin levels were elevated in some PCOS women (264). However, in this study the confounding effects of differences in body weight were not adjusted for appropriately. Subsequent studies in PCOS that have contained appropriately weight- (265) or fat mass-matched (266) control women have not found significant differences in leptin levels in PCOS women.

C. Therapeutic considerations
Agents that exacerbate insulin resistance should probably be avoided in PCOS, particularly in women who are also obese. Oral contraceptives are widely used in PCOS to control menstrual irregularities and hyperandrogenism. Most oral contraceptive agents have been demonstrated to produce insulin resistance in normal women (162), and one study (267) found a worsening of insulin resistance during therapy with a combination oral contraceptive containing triphasic progestin (Novum 7/7/7, Ortho Pharmaceutical Corp, Raritan, NJ). Norethindrone-only containing contraceptives do not cause insulin resistance in normal women (162) and, thus, may provide an alternative agent for PCOS women. Specific studies should be performed, however, to verify this hypothesis.

Glucocorticoids can exacerbate insulin resistance and should be avoided in PCOS. Fortunately, there are several therapeutic agents for hyperandrogenism that do not worsen and may even improve insulin sensitivity in PCOS (Fig. 16). These are spironolactone, GnRH analogs, and flutamide (169, 170). Although medroxyprogesterone acetate does decrease insulin sensitivity in normal women (268), intermittent progestin withdrawal with this agent in the minimally effective dose (i.e., 5 mg daily for 13 days monthly or every other month) would be preferable to continuous oral contraceptive therapy for endometrial protection.

Weight loss is well known to decrease androgen levels and restore ovulation in PCOS (269). As little as a 7% reduction in body weight can restore fertility in obese PCOS women (270), and this should be encouraged in all overweight PCOS women. It now appears that a reduction in circulating insulin levels is the mechanism for weight loss-associated reproductive benefits (270, 271), since lowering insulin levels by other modalities has similar results (199, 202, 205). Indeed, agents that lower insulin levels by improving insulin sensitivity may provide a new therapeutic modality for PCOS. Metformin acts mainly by suppressing hepatic glucose production, and its insulin-sensitizing actions are primarily mediated through the weight loss that frequently occurs during therapy (272, 273, 274, 275). In two studies in PCOS, both from Venezuela, metformin therapy resulted in significant decreases in insulin and androgen levels (201, 205). In one study (201) this was also associated with weight loss, whereas in the other it was not (205). Weight loss accounted for metformin effects on sex hormone levels in the study of Crave et al. (275). Metformin has not altered androgen levels (276) or insulin action (277) in PCOS in other studies. In contrast, the thiazolidenedione troglitazone improves insulin sensitivity without altering body weight and lowers circulating androgen, estrogen, and LH levels in PCOS (202) (Fig. 18). Further studies are in progress to determine the role for troglitazone as a therapeutic agent for PCOS.

	V. Summary

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 
It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

	Footnotes

 
Address reprint requests to: Andrea Dunaif, M.D., Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.

¹ Supported by Public Health Service Grants RO1 DK-40605 and MO1 RR-10732 as well as grants from the American Diabetes Association and Parke-Davis Pharmaceutical Research.

	References

Top Abstract I. Introduction II. Insulin Action in... III. Hypotheses Explaining the... IV. Clinical Implications of... V. Summary References

 

1. Dunaif A, Givens JR, Haseltine F, Merriam GR (eds) 1992 The Polycystic Ovary Syndrome. Blackwell Scientific, Cambridge, MA
2. Franks S 1995 Polycystic ovary syndrome. N Engl J Med 333:853–861[Free Full Text]
3. Polson DW, Wadsworth J, Adams J, Franks S 1988 Polycystic ovaries — a common finding in normal women. Lancet 1:870–872[CrossRef][Medline]
4. Pettersson F, Fries H, Nillius SJ 1973 Epidemiology of secondary amenorrhea. Am J Obstet Gynecol 117:80–86[Medline]
5. Hull MGR 1987 Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1:235–245[Medline]
6. Goldzieher JW, Green JA 1962 The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 22:325–338
7. Burghen GA, Givens JR, Kitabchi AE 1980 Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113–116[Abstract/Free Full Text]
8. Dunaif A, Hoffman AR 1988 Insulin resistance and hyperandrogenism: clinical syndromes and possible mechanisms. In: Pancheri P, Zichella L (eds) Biorhythms and Stress in the Physiopathology of Reproduction. Hemisphere Publishing Co, Washington, DC, pp 293–317
9. Barbieri RL, Ryan KJ 1983 Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 147:90[Medline]
10. Poretsky L, Kalin MF 1987 The gonadotropic function of insulin. Endocr Rev 8:132–141[Abstract/Free Full Text]
11. Poretsky L 1991 On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev 12:3–13[Abstract/Free Full Text]
12. Ehrmann DA, Barnes RB, Rosenfield RL 1995 Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16:322–353[Abstract/Free Full Text]
13. Crowley WF 1996 New tools for pituitary-gonadal assessment. In: Filicori M, Flagmini C (eds) The Ovary: Regulation, Dysfunction and Treatment. Elsevier, Amsterdam, pp 287–293
14. Achard C, Thiers J 1921 Le virilisme pilaire et son association a l’insuffisance glycolytique (diabete des femmes a barb). Bull Acad Natl Med 86:51–64
15. Kierland RR, Lakatos I, Szijarto L 1947 Acanthosis nigricans: An analysis of data in twenty-two cases and a study of its frequency in necropsy material. J Invest Dermatol 9:299–305[Medline]
16. Brown J, Winkelmann RK 1968 Acanthosis nigricans: a study of 90 cases. Medicine 47:33–51[Medline]
17. Barnes ND, Palumbo PJ, Hayles AM, Folgar H 1974 Insulin resistance, skin changes and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction. Diabetologia 10:284–289
18. Colle M, Doyard P, Chaussain J, Battin J, Job J 1979 Acanthosis nigricans, hirsutisme et diabete insulin-resistant. Arch Fr Pediatr 36:518–523[Medline]
19. Taylor SI, Cama A, Accili D, Barbetti F, Quon J, Sierra MDLL, Suzuki Y, Koller E, Levy-Toledano R, Wertheimer E, Moncada VY, Kadowaki H, Kadowaki T 1992 Mutations in the insulin receptor gene. Endocr Rev 13:566–595[Abstract/Free Full Text]
20. Dunaif A 1992 Insulin resistance and ovarian hyperandrogenism. The Endocrinologist 2:248–260
21. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J 1976 The syndromes of insulin resistance and acanthosis nigricans. N Engl J Med 294:739–745[Abstract]
22. Flier JS, Kahn R, Roth J, Bar RS 1975 Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 190:63–65[Abstract/Free Full Text]
23. O’Rahilly S, Woong HC, Patel P, Turner RC, Flier JS, Moller DE 1991 Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms. Diabetes 40:777–782[Abstract]
24. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW 1985 Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the Type A and B syndromes. Diabetes 34:101–107[Abstract]
25. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C, Levy LJ, Crowley Jr WF 1985 The clinical, biochemical and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet Gynecol 66:545–552[Medline]
26. Stuart CA, Peters EJ, Prince MJ, Richards G, Cavallo A, Meyer WJ 1986 Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess. Metabolism 35:197–205[CrossRef][Medline]
27. Peters EJ, Stuart CA, Prince MJ 1986 Acanthosis nigricans and obesity: acquired and intrinsic defects in insulin action. Metabolism 35:807–813[CrossRef][Medline]
28. Pasquali R, Venturoli S, Paradisi R, Capelli M, Parenti N, Melchionda N 1982 Insulin and C-peptide levels in obese patients with polycystic ovaries. Horm Metab Res 14:284–287[Medline]
29. Shoupe D, Kumar DD, Lobo RA 1983 Insulin resistance in polycystic ovary syndrome. Am J Obstet Gynecol 147:588–592[Medline]
30. Chang RJ, Nakamura RM, Judd HL, Kaplan SA 1983 Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356–359[Abstract/Free Full Text]
31. Judd HL, Scully RE, Herbst AL, Yen SSC, Ingersol FM, Kliman B 1973 Familial hyperthecosis: comparison of endocrinologic and histologic findings with polycystic ovarian disease. Am J Obstet Gynecol 117:976–982[Medline]
32. Hughesdon PE 1982 Morphology and morphogenesis of the stein-leventhal ovary and of so-called "hyperthecosis." Obstet Gynecol Surv 37:59–77[Medline]
33. Nagamani M, Dinh TV, Kelver ME 1986 Hyperinsulinemia in hyperthecosis of the ovaries. Am J Obstet Gynecol 154:384–389[Medline]
34. Keettel WC, Bradbury JT, Stoddard FJ 1957 Observations on the PCO syndrome. Am J Obstet Gynecol 73:954–65
35. Yen SSC, Vela P, Rankin J 1970 Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab 30:435–442[Abstract/Free Full Text]
36. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F 1976 Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 57:1320–9
37. Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley Jr WF 1988 Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 66:165–172[Abstract/Free Full Text]
38. Dunaif A, Anderson R, Chapin D, Scully RE, Crowley Jr WF 1984 The effects of continuous androgen secretion upon the hypothalamic-pituitary-axis in women: evidence from a luteinized thecoma of the ovary. J Clin Endocrinol Metab 59:389–393[Abstract/Free Full Text]
39. Lobo RA, Goebelsmann U 1980 Adult manifestation of congenital adrenal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease. Am J Obstet Gynecol 138:720–726[Medline]
40. Santen RJ, Bardin CW 1973 Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52:2617–28
41. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z 1992 Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 327:157–162[Abstract]
42. Yen SSC 1980 The polycystic ovary syndrome. Clin Endocrinol (Oxf) 12:177–208[Medline]
43. McKenna TJ, Moore A, Magee F, Cunningham S 1983 Amenorrhea with cryptic hyperandrogenemia. J Clin Endocrinol Metab 56:893–896[Abstract/Free Full Text]
44. Mechanick J, Dunaif A 1990 Masculinization: a clinical approach to the diagnosis and treatment of hyperandrogenic women. In: Mazzaferri E (ed) Advances in Endocrinology and Metabolism. Mosley Year Book, Inc, Chicago, IL, pp 129–173
45. Futterweit W, Dunaif A, Yeh H, Kingsley P 1988 The prevalence of hyperandrogenism in 109 consecutive women presenting with diffuse alopecia. J Am Acad Dermatol 19:831–836[Medline]
46. Lobo RA, Goebelsmann U, Horton R 1983 Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 57:393–397[Abstract/Free Full Text]
47. Dunaif A 1992 Polycystic ovary syndrome and obesity. In: Bjorntorp P, Brodoff BN (eds) Obesity. J.B. Lippincott Co., Philadelphia, pp 594–605
48. Quintana B, Chinchilli V, Sieber J, Fultz P, George N, Dunaif A High risk of glucose intolerance (GI) in women with oligomenorrhea (oligo) or with polycystic ovary syndrome (PCOS). Program of the 77th Annual Meeting of The Endocrine Society, Washington DC, 1995 (Abstract OR3–5:50)
49. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A 1987 Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499–507[Abstract/Free Full Text]
50. Dunaif A, Green G, Phelps RG, Lebwohl M, Futterweit W, Lewy L 1991 Acanthosis nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings. J Clin Endocrinol Metab 73:590–595[Abstract/Free Full Text]
51. Kahn CR 1994 Insulin action, diabetogenes, and the cause of Type II diabetes. Diabetes 43:1066–1084[Medline]
52. Modan M, Harris MI, Halkin H 1989 Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Diabetes 38:1603–1635
53. Dahlgren E, Johansson S, Lindstedt G, Knutsson F, Oden A, Janson PO, Mattson L, Crona N, Lundberg P 1992 Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 57:505–513[Medline]
54. Dunaif A, Futterweit W, Segal KR, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
55. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T 1992 Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257–1266[Abstract]
56. Dunaif A, Sorbara L, Delson R, Green G 1993 Ethnicity and polycystic ovary syndrome are associated with independent and additive decreases in insulin action in Caribbean Hispanic women. Diabetes 42:1462–1468[Abstract]
57. Dunaif A, Finegood DT 1996 ß-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942–947[Abstract]
58. Apter D, Butzow T, Laughlin GA, Yen SSC 1995 Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism. J Clin Endocrinol Metab 80:2966–2973[Abstract/Free Full Text]
59. Harris MI, Hadden WC, Knowler WC, Bennett PH 1987 Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20–74 yr. Diabetes 36:523–534[Abstract]
60. DeFronzo RA 1988 The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667–687[Medline]
61. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
62. Bergman RN, Hope ID, Yang YJ, Watanabe RM, Meador MA, Youn JH, Ader M 1989 Assessment of insulin sensitivity in vivo: a critical review. Diabetes Metab Rev 5:411–429[Medline]
63. Yki-Jarvinen H, Koivisto VA 1983 Effects of body composition on insulin sensitivity. Diabetes 32:965–969[Abstract]
64. Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G 1985 Relationship between degree of obesity and in vivo insulin action in man. Am J Physiol 248:E286–E291
65. Caro JF, Dohm LG, Pories WJ, Sinha MK 1989 Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and Type II diabetes. Diabetes Metab Rev 5:665–689[Medline]
66. Kissebah AH, Peiris AN 1989 Biology of regional body fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5:83–109[Medline]
67. Bagatell CJ, Bremner WJ 1996 Androgens in men — uses and abuses. N Engl J Med 334:707–714[Free Full Text]
68. Morales AJ, Laughlin GA, Bützow T, Maheshwari H, Baumann G, Yen SSC 1996 Insulin, somatotropic, and luteinizing hormones axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 81:2854–2864[Abstract/Free Full Text]
69. Dunaif A, Xia J, Book C, Schenker E, Tang Z 1995 Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle: a potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 96:801–810
70. Dunaif A 1995 Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of NIDDM. Am J Med 98:33–39[CrossRef]
71. Holte J, Bergh T, Berne C, Berglund L, Lithell H 1994 Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J Clin Endocrinol Metab 78:1052–1058[Abstract]
72. Bergman RN, Phillips LS, Cobelli C 1981 Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1456–1467
73. Bergman RN 1989 Toward physiological understanding of glucose tolerance. Minimal model approach. Diabetes 38:1512–1527[Abstract]
74. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte Jr D 1993 Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Diabetes 42:1663–1672[Abstract]
75. O’Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, Polonsky KS 1993 Defects in ß-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1241–1247[Abstract]
76. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonksy KS 1995 Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 96:520–527
77. Weber RFA, Pache TD, Jacobs ML, Docter R, Loriaux DL, Fauser BCJM, Birkenhager JC 1993 The relation between clinical manifestations of polycystic ovary syndrome and beta-cell function. Clin Endocrinol (Oxf) 38:295–300[Medline]
78. Flier JS, Minaker KL, Landsberg L, Young JB, Pallotta J, Rowe JW 1982 Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin. Diabetes 31:132–135[Abstract]
79. Marshall S 1985 Kinetics of insulin receptor internalization and recycling in adipocytes. Shunting of receptors to a degradative pathway by inhibitors of recycling. J Biol Chem 260:4136–4144[Abstract/Free Full Text]
80. Mahabeer S, Jialal I, Norman RJ, Naidoo C, Reddi K, Joubert SM 1989 Insulin and C-peptide secretion in non-obese patients with polycystic ovarian disease. Horm Metab Res 21:502–506[Medline]
81. Peiris AN, Mueller RA, Struve MF, Smith GA, Kissebah AH 1987 Relationship of androgenic activity to splanchnic insulin metabolism and peripheral glucose utilization in premenopausal women. J Clin Endocrinol Metab 64:162–169[Abstract/Free Full Text]
82. Cheatham B, Kahn CR 1995 Insulin action and the insulin signaling network. Endocr Rev 16:117–142[Abstract/Free Full Text]
83. Kahn CR 1985 The molecular mechanism of insulin action. Annu Rev Med 36:429–451[CrossRef][Medline]
84. Kasuga M, Hedo JA, Yamada KM, Kahn CR 1982 The structure of the insulin receptor and its subunits: evidence for multiple non-reduced forms and a 210 kD possible proreceptor. J Biol Chem 257:10392–10399[Abstract/Free Full Text]
85. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J 1985 Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761[CrossRef][Medline]
86. Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou J, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ 1985 The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell 40:747–758[CrossRef][Medline]
87. Kasuga M, Karlsson FA, Kahn CR 1982 Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–187[Abstract/Free Full Text]
88. Ullrich A, Schlessinger J 1990 Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212[CrossRef][Medline]
89. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S 1991 Oncogenes and signal transduction. Cell 64:281–302 [published erratum appears in Cell 1991 May 31; 65(5): following 914][CrossRef][Medline]
90. Cobb MH, Sang BC, Gonzalez R, Goldsmith E, Ellis L 1989 Autophosphorylation activates the soluble cytoplasmic domain of the insulin receptor in an intermolecular reaction. J Biol Chem 264:18701–18706[Abstract/Free Full Text]
91. Shoelson SE, Boni-Schnetzler M, Pilch PF, Kahn CR 1991 Autophosphorylation within insulin receptor ß-subunits can occur as an intramolecular process. Biochemistry 30:7740–7746[CrossRef][Medline]
92. Frattali AL, Treadway JL, Pessin JE 1992 Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular ß subunit trans- and cis-autophosphorylation and substrate kinase activation. J Biol Chem 267:19521–19528[Abstract/Free Full Text]
93. Myers Jr MG, Sun XJ, White MF 1994 The IRS-1 signaling system. Trends Biochem Sci 19:289–293[CrossRef][Medline]
94. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF 1991 Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77[CrossRef][Medline]
95. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers Jr MG, Glasheen E, Lane WS, Pierce JH, White MF 1995 Role of IRS-2 in insulin and cytokine signalling. Nature 377:173–177[CrossRef][Medline]
96. Patti ME, Sun XJ, Bruening JC, Araki E, Lipes MA, White MF, Kahn CR 1995 4PS/insulin receptor substrate (IRS)-2 is the alternative substrate of the insulin receptor in IRS-1-deficient mice. J Biol Chem 270:24670–24673[Abstract/Free Full Text]
97. Sasaoka T, Rose DW, Jhun BH, Saltiel AR, Draznin B, Olefsky JM 1995 Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-1, and epidermal growth factor. J Biol Chem 269:13689–13694[Abstract/Free Full Text]
98. Rose DW, Saltiel AR, Majumdar M, Decker SJ 1994 Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction. Proc Natl Acad Sci USA 91:797–801[Abstract/Free Full Text]
99. Waters SB, Yamauchi K, Pessin JE 1993 Functional expression of insulin receptor substrate-1 is required for insulin-stimulated mitogenic signaling. J Biol Chem 268:22231–22234[Abstract/Free Full Text]
100. Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M 1994 Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. J Biol Chem 269:3568–3573[Abstract/Free Full Text]
101. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR 1994 Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis and glucose transporter translocation. Mol Cell Biol 14:4902–4911[Abstract/Free Full Text]
102. Kruszynska YT, Olefsky JM 1996 Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. J Invest Med 44:413–428[Medline]
103. Theroux SJ, Latour DA, Stanley K, Raden DL, Davis RJ 1992 Signal transduction by the epidermal growth factor receptor is attenuated by a COOH-terminal domain serine phosphorylation site. J Biol Chem 267:16620–16626[Abstract/Free Full Text]
104. Cochet C, Gill GN, Meisenhelder J, Cooper JA, Hunter T 1984 C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259:2553–2558[Abstract/Free Full Text]
105. Bollage GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland Jr DE 1986 Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA 83:5822–5824[Abstract/Free Full Text]
106. Takayama S, White MF, Kahn CR 1988 Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem 263:3440–3447[Abstract/Free Full Text]
107. Karasik A, Rothenberg PL, Yamada K, White MF, Kahn CR 1990 Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. J Biol Chem 265:10226–10230[Abstract/Free Full Text]
108. Chin JE, Liu F, Roth RA 1994 Activation of protein kinase C inhibits insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. Mol Endocrinol 8:51–58[Abstract/Free Full Text]
109. Muller HK, Kellerer M, Ermel B, Muhlhofer A, Obermaier-Kusser B, Vogt B, Haring HU 1991 Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. Diabetes 40:1440–1448[Abstract]
110. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-- and obesity-induced insulin resistance. Science 271:665–668[Abstract]
111. Boyle WJ, van der Geer P, Hunter T 1991 Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol 201:110–149[Medline]
112. Fadden P, Haystead TAJ 1995 Quantitative and selective fluorophore labeling of phosphoserine on peptides and proteins: characterization at the attomole level by capillary electrophoresis and laser-induced fluorescence. Anal Biochem 225:81–88[CrossRef][Medline]
113. Jialal I, Naiker P, Reddi K, Moodley J, Joubert SM 1987 Evidence for insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 64:1066–1069[Abstract/Free Full Text]
114. Marsden PJ, Murdoch A, Taylor R 1994 Severe impairment of insulin action in adipocytes from amenorrheic subjects with polycystic ovary syndrome. Metabolism 43:1536–1542[CrossRef][Medline]
115. Ciaraldi TP, El-Roeiy A, Madar Z, Reichart D, Olefsky JM, Yen SSC 1992 Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 75:577–583[Abstract]
116. Ciaraldi TP, Morales AJ, Hickman MG, Odom-Ford R, Olefsky JM, Yen SSC 1997 Cellular insulin resistance in adipocytes from obese polycystic ovary syndrome subjects involves adenosine modulation of insulin sensitivity. J Clin Endocrinol Metab 82:1421–1425[Abstract/Free Full Text]
117. Rosenbaum D, Haber RS, Dunaif A 1993 Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. Am J Physiol 264:E197–E202
118. Caro JF 1991 Clinical Review 26. Insulin resistance in obese and nonobese man. J Clin Endocrinol Metab 73:691–695[Abstract/Free Full Text]
119. Freidenberg GR, Reichart D, Olefsky JM, Henry RR 1988 Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. J Clin Invest 82:1398–1406
120. Sorbara LR, Tang Z, Cama A, Xia J, Schenker E, Kohanski RA, Poretsky L, Koller E, Taylor SI, Dunaif A 1994 Absence of insulin receptor gene mutations in three women with the polycystic ovary syndrome. Metabolism 43:1568–1574[CrossRef][Medline]
121. Dunaif A, Diamanti E Defective insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Program of the 57th Annual Scientific Meeting of the American Diabetes Association, Boston, MA, 1997 (Abstract 91)
122. Talbot JA, Bicknell EJ, Rajkhowa M, Krook A, O’Rahilly S, Clayton RN 1996 Molecular scanning of the insulin receptor gene in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 81:1979–1983[Abstract]
123. Lewis RL, Cao L, Perregaux D, Czech MP 1990 Threonine 1336 of the human insulin receptor is a major target for phosphorylation by protein kinase C. Biochemistry 29:1807–1813[CrossRef][Medline]
124. Pillay TS, Whittaker J, Lammers P, Ullrich A, Siddle K 1991 Multisite serine phosphorylation of the insulin and IGF-1 receptors in transfected cells. FEBS Lett 288:206–211[CrossRef][Medline]
125. Rapuano M, Rosen OM 1991 Phosphorylation of the insulin receptor by a casein kinase I-like enzyme. J Biol Chem 266:12902–12907[Abstract/Free Full Text]
126. Roth RA, Beaudoin J 1987 Phosphorylation of purified insulin receptor by cAMP kinase. Diabetes 36:123–126[Abstract]
127. Stadtmaurer L, Rosen OM 1986 Increasing the cAMP content of IM-9 cells alters the phosphorylation state and protein kinase activity of the insulin receptor. J Biol Chem 261:3402–3407[Abstract/Free Full Text]
128. Kemp BE, Graves DJ, Benjamin E, Krebs EG 1977 Role of multiple basic residues in determining the substrate specificity of cyclic AMP-dependent protein kinase. J Biol Chem 252:4888–4893[Free Full Text]
129. Guo H, Damuni Z 1993 Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A. Proc Natl Acad Sci USA 90:2500–2504[Abstract/Free Full Text]
130. Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA, Reaven GM, Goldfine ID 1995 Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373:448–451[CrossRef][Medline]
131. Sbraccia P, Goodman PA, Maddux BA, Wong KY, Chen YI, Reaven GM, Goldfine ID 1991 Production of inhibitor of insulin-receptor tyrosine kinase in fibroblasts from patient with insulin resistance and NIDDM. Diabetes 40:295–299[Abstract]
132. Legro RS, Fox J, Dunaif A Insulin resistance is a potential phenotypic marker for familial polycystic ovary syndrome (PCOS). Proceedings of the 50th Annual Meeting of the American Fertility Society, San Antonio, TX, 1994 (Abstract)
133. Jahanfar S, Eden JA, Warren P, Seppala M, Nguyen TV 1995 A twin study of polycystic ovary syndrome. Fertil Steril 63:478–486[Medline]
134. Norman RJ, Masters S, Hague W 1996 Hyperinsulinemia is common in family members of women with polycystic ovary syndrome. Fertil Steril 66:942–947[Medline]
135. Ovesen P, Moller J, Ingerslev HJ, Jorgensen JOL, Mengel A, Schmitz O, George K, Alberti MM, Moller N 1993 Normal basal and insulin-stimulated fuel metabolism in lean women with the polycystic ovary syndrome. J Clin Endocrinol Metab 77:1636–1640[Abstract]
136. Holte J, Bergh T, Berne C, Wide L, Lithell H 1995 Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:2586–2593[Abstract]
137. Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, Johnston DG, Franks S 1993 The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39:351–355[Medline]
138. Sampson M, Kong C, Patel A, Unwin R, Jacobs HS 1996 Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome. Clin Endocrinol (Oxf) 45:623–629[CrossRef][Medline]
139. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA 1992 Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807–1812[Medline]
140. Norman RJ, Mahabeer S, Masters S 1995 Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome. Fertil Steril 63:58–62[Medline]
141. Tattersall RB, Fajans SS 1975 A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24:44–53[Abstract]
142. Ghosh S, Schork NJ 1996 Genetic analysis of NIDDM. The study of quantitative traits. Diabetes 45:1–14[Abstract]
143. Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WGH, Knowler WC, Bennett PH, Moll P, Bogardus C 1987 In vivo insulin action is familial characteristic in nondiabetic Pima indians. Diabetes 36:1329–1335[Abstract]
144. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Con-cannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Lindner T, Mereu LE, Wang YQ, Xiang K, Yamagata K, Yang Y, Bell GI 1996 A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166[CrossRef][Medline]
145. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR 1990 Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909–915
146. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J 1992 Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29[Abstract]
147. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J 1995 Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA 273:1855–1861[Abstract/Free Full Text]
148. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, Permutt MA, Beckmann JS, Bell GI, Cohen D 1993 Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328:697–702[Abstract/Free Full Text]
149. Gerbitz K, Gempel K, Brdiczka D 1996 Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45:113–126[Abstract]
150. Pillay TS, Langlois WJ, Olefsky JM 1995 The genetics of non-insulin-dependent diabetes mellitus. Adv Genet 32:51–98[Medline]
151. Beck-Nielsen H 1989 Insulin resistance in skeletal muscles of patients with diabetes mellitus. Diabetes Metab Rev 5:487–493[Medline]
152. Unger RH 1995 Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870[Abstract]
153. Wells AM, Sutcliffe IC, Johnson AB, Taylor R 1993 Abnormal activation of glycogen synthesis in fibroblasts from NIDDM subjects. Diabetes 42:583–89[Abstract]
154. Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI 1995 Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 92:983–987[Abstract/Free Full Text]
155. Price TB, Perseghin G, Duleba A, Chen W, Chase J, Rothman DL, Shulman RG, Shulman GI 1996 NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise. Proc Natl Acad Sci USA 93:5329–5334[Abstract/Free Full Text]
156. Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, Rothman DL, Shulman GI 1996 Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335:1357–1362[Abstract/Free Full Text]
157. Cox NJ, Xiang K, Fajans SS, Bell GI 1992 Mapping diabetes-susceptibility genes. Lessons learned from search for DNA marker for maturity-onset diabetes of the young. Diabetes 41:401–407[Abstract]
158. Yki-Jarvinen H 1984 Sex and insulin sensitivity. Metabolism 33:1011–1015[CrossRef][Medline]
159. Nuutila P, Knuuti MJ, Maki M, Laine H, Ruotsalainen U, Teras M, Haaparanta M, Solin O, Yki-Jarvinen H 1995 Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes 44:31–36[Abstract]
160. Foley JE, Kashiwagi A, Chang H, Huecksteadt TP, Lillioja S, Verso MA, Reaven G 1984 Sex differences in insulin-stimulated glucose transport in rat and human adipocytes. Am J Physiol 246:E211–E215
161. Moller DE, Flier JS 1991 Insulin resistance-mechanisms, syndromes, and implications. N Engl J Med 325:938–948[Medline]
162. Godsland IF, Walton C, Felton C, Proudler A, Patel A, Wynn V 1992 Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab 74:64–70[Abstract]
163. Speiser PW, Serrat J, New MI, Gertner JM 1992 Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 75:1421–1424[Abstract]
164. Polderman KH, Gooren JG, Asscherman H, Bakker A, Heine RJ 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265–271[Abstract]
165. Holmang A, Larsson BM, Brzezinska Z, Bjorntorp P 1992 Effects of short-term testosterone exposure on insulin sensitivity of muscles in female rats. Am J Physiol 262:E851–E855
166. Rincon J, Holmang A, Wahlstrom EO, Lonnroth P, Bjorntorp P, Zierath JR, Wallberg-Henriksson H 1996 Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 45:615–621[Abstract]
167. Dunaif A, Green G, Futterweit W, Dobrjansky A 1990 Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 70:699–704[Abstract/Free Full Text]
168. Diamanti-Kandarakis E, Mitrakou A, Hennes MMI, Platanissiotis D, Kaklas N, Spina J, Georgiadou E, Hoffmann RG, Kissebah AH, Raptis S 1995 Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism 44:525–531[CrossRef][Medline]
169. Elkind-Hirsch KE, Valdes CT, Malinak LR 1993 Insulin resistance improves in hyperandrogenic women treated with Lupron. Fertil Steril 60:634–641[Medline]
170. Moghetti P, Tosi F, Castello R, Magnani CM, Negri C, Brun E, Furlani L, Caputo M, Muggeo M 1996 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 81:952–960[Abstract]
171. Marin P, Krotkiewski M, Bjorntorp P 1992 Androgen treatment of middle-aged, obese men: Effects on metabolism, muscle and adipose tissues. Eur J Med 6:329–336
172. Buffington CK, Givens JR, Kitabchi AE 1991 Opposing actions of dehydroepiandrosterone and testosterone on insulin sensitivity. Diabetes 40:693–700[Abstract]
173. Mortola JF, Yen SSC 1990 The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 71:696–704[Abstract/Free Full Text]
174. Nestler JE, Barlascini CO, Clore JN, Blackard WG 1988 Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 66:57–61[Abstract/Free Full Text]
175. Rittmaster RS, Deshwal N, Lehman L 1993 The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome. J Clin Endocrinol Metab 76:1295–1300[Abstract]
176. Nestler JE, Strauss III JF 1991 Insulin as an effector of human ovarian and adrenal steroid metabolism. Endocrinol Metab Clin North Am 20:807–823[Medline]
177. Diamond MP, Webster BW, Carr RK, Wentz AC, Osteen KG 1985 Human follicular fluid insulin concentrations. J Clin Endocrinol Metab 61:990–992[Abstract/Free Full Text]
178. el-Roeiy A, Chen X, Roberts VJ, LeRoith D, Roberts Jr CT, Yen SSC 1993 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 77:1411–1418[Abstract]
179. el-Roeiy A, Chen X, Roberts VJ, Shimasakai S, Ling N, LeRoith D, Roberts Jr CT, Yen SSC 1994 Expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin receptors, and IGF-binding proteins-1–6 and the localization of their gene products in normal and polycystic ovary syndrome ovaries. J Clin Endocrinol Metab 78:1488–1496[Abstract]
180. Czech MP 1982 Structural and functional homologies in the receptors for insulin and the insulin-like growth factors. Cell 31:8–10[CrossRef][Medline]
181. Froesch ER, Zapf J 1985 Insulin-like growth factors and insulin: comparative aspects. Diabetologia 28:485–493[Medline]
182. Leroith D, Werner H, Beitner-Johnson D, Roberts Jr CT 1995 Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143–163[Abstract/Free Full Text]
183. Bach LA, Rechler MM 1995 Insulin-like growth factor binding proteins. Diabetes Rev 3:38–61
184. Hintz RL, Thorsson AV, Enberg G, Hall K 1984 IGF-II binding on human lymphoid cells: demonstration of a common high affinity receptor for insulin like peptides. Biochem Biophys Res Commun 118:774–782[CrossRef][Medline]
185. Jonas HA, Cox AJ, Harrison LC 1989 Delineation of atypical insulin receptors from classical insulin and type I insulin-like growth factor receptors in human placenta. Biochem J 257:101–107[Medline]
186. Moxham CP, Duronio V, Jacobs S 1989 Insulin-like growth factor I receptor ß-subunit heterogeneity. J Biol Chem 264:13238–13244[Abstract/Free Full Text]
187. Moxham CP, Jacobs S 1992 Insulin/IGF-1 receptor hybrids: a mechanism for increasing receptor diversity. J Cell Biochem 48:136–140[CrossRef][Medline]
188. Erickson GF 1995 The ovarian connection. In: Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive Endocrinology, Surgery, and Technology. Raven Press, New York, pp 1141–1160
189. Mason HD, Cwyfan-Hughes SC, Heinrich G, Franks S, Holly JMP 1996 Insulin-like growth factor (IGF) I and II, IGF-binding proteins, and IGF-binding protein proteases are produced by theca and stroma of normal and polycystic human ovaries. J Clin Endocrinol Metab 81:276–284[Abstract]
190. Mason HD, Margara R, Winston RML, Beard RW, Reed MJ, Franks S 1990 Inhibition of oestradiol production by epidermal growth factor in human granulosa cells of normal and polycystic ovaries. Clin Endocrinol (Oxf) 33:404–410
191. Ballotti R, Lammers R, Scimeca J 1989 Intermolecular transphosphorylation between insulin receptors and EGF-insulin receptor chimerae. EMBO J 8:3303–3309[Medline]
192. Poretsky L, Glover B, Laumas V, Kalin M, Dunaif A 1988 The effects of experimental hyperinsulinemia on steroid secretion, ovarian insulin receptors, and ovarian type I insulin-like-growth-factor receptors in the rat. Endocrinology 122:581–585[Abstract/Free Full Text]
193. Willis D, Franks S 1995 Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the Type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 80:3788–3790[Abstract]
194. Willis D, Mason H, Gilling-Smith C, Franks S 1996 Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 81:302–309[Abstract]
195. Dunaif A, Book C-B Selective intrinsic defects in insulin and IGF-1 action in polycystic ovary syndrome (PCOS) in skin fibroblasts. Program of the 56th Annual Meeting of The American Diabetes Association, San Francisco, CA, 1996 (Abstract 317)
196. Fox JH, Licholai T, Green G, Dunaif A 1993 Differential effects of oral glucose-mediated vs. intravenous hyperinsulinemia on circulating androgen levels in women. Fertil Steril 60:994–1000[Medline]
197. Dunaif A, Graf M 1989 Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23–29
198. Micic D, Popovic V, Nesovic M, Sumarac M, Dragasevic M, Kendereski A, Markovic D, Djordjevic P, Manojlovic D, Micic J 1988 Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease. J Steroid Biochem 31:995–999[CrossRef][Medline]
199. Nestler JE, Barlascini CO, Matt DW 1989 Suppression of serum insulin by diazoxide reduced serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 68:1027[Abstract/Free Full Text]
200. Prelevic GM, Wurzburger MI, Balint-Peric L, Nesic JS 1990 Inhibitory effect of sandostatin on secretion of luteinizing hormone, ovarian steroids in polycystic ovary syndrome. Lancet 336:900–903[CrossRef][Medline]
201. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ 1994 Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654[CrossRef][Medline]
202. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996 The insulin sensitizing agent troglitazone: a novel therapy for the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299–3306[Abstract]
203. Plymate SR, Matej LA, Jones RE 1988 Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460–464[Abstract/Free Full Text]
204. Nestler JE 1993 Sex hormone-binding globulin: a marker for hyperinsulinemia and/or insulin resistance? J Clin Endocrinol Metab 76:273–274[CrossRef][Medline]
205. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450c17 activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623[Abstract/Free Full Text]
206. Gasic S, Bodenburg YH, Nagamani M, Green A, Urban RJ Troglitazone inhibits progesterone production in porcine granulosa cells. Program of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997 (Abstract P2–416)
207. Franks S, Mason H, White D, Willis D 1996 Mechanisms of anovulation in polycystic ovary syndrome. In: Filicori M, Flamigni C (eds) The Ovary: Regulation, Dysfunction and Treatment. Elsevier, Amsterdam, pp 183–186
208. Nestler JE, Singh R, Matt DW, Clore JN, Blackard WG 1990 Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women. Am J Obstet Gynecol 163:1243–1246[Medline]
209. Adashi EY, Hsueh AJW, Yen SSC 1981 Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 108:1441–1449[Abstract/Free Full Text]
210. Beer NA, Jakubowicz DJ, Beer RM, Nestler JE 1994 Disparate effects of insulin reduction with diltiazem on serum dehydroepiandrosterone sulfate levels in obese hypertensive men and women. J Clin Endocrinol Metab 79:1077–1081[Abstract]
211. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, Balducci R, Toscano V, Muggeo M 1996 Insulin infusion amplifies 17 -hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab 81:881–886[Abstract]
212. Cooper HE, Spellacy WN, Prem KA, Cohen WD 1968 Hereditary factors in Stein-Leventhal syndrome. Am J Obstet Gynecol 100:371–387[Medline]
213. Givens JR 1971 Familial ovarian hyperthecosis: a study of two families. Am J Obstet Gynecol 11:959–972
214. Wilroy RS, Givens JR, Weser WL, Coleman SA, Andersen RN, Fish SA 1975 Hyperthecosis — an inheritable form of polycystic ovarian disease. Birth Defects 11:81–85
215. Givens JR 1988 Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 17:1–17
216. Ferriman D, Purdie AW 1979 The inheritance of polycystic ovarian disease and possible relationship to premature balding. Clin Endocrinol (Oxf) 1:291–299
217. Lunde O, Magnus P, Sandvik L, Hoglo S 1989 Familial clustering in the polycystic ovarian syndrome. Gynecol Obstet Invest 28:23–30[Medline]
218. Mandel FP, Chang RJ, Dupont B, Pollack MS, Levine LS, New MI, Lu JKH, Judd HL 1983 HLA genotyping in family members and patients with familial polycystic ovarian disease. J Clin Endocrinol Metab 56:862–864[Abstract/Free Full Text]
219. Ober C, Weil S, Steck T, Billstrand C, Levrant S, Barnes R 1992 Increased risk for polycystic ovary syndrome associated with human leukocyte antigen DQA1*0501. Am J Obstet Gynecol 167:1803–1806[Medline]
220. Legro RS 1995 The genetics of polycystic ovary syndrome. Am J Med 98:9S–16S
221. Rojanasakul A, Gustavson KH, Lithell H, Nillius SJ 1985 Tetraploidy in two sisters with the polycystic ovary syndrome. Clin Genet 27:167–174[Medline]
222. Stenchever MA, Macintyre MN, Jarvis JA, Hempel JM 1968 Cytogenic evaluation of 41 patients with Stein-Leventhal syndrome. Obstet Gynecol 32:794–801[Medline]
223. Hague WM, Adams J, Reeders ST, Peto TEA, Jacobs HS 1988 Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf) 29:593–605[Medline]
224. Carey AH, Chan KL, Short F, White DM, Williamson R, Franks S 1993 Evidence for a single gene effect in polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 38:653–658[Medline]
225. Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R 1997 Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6:307–403
226. Ibanez L, Potau N, Zampolli M, Prat N, Virdis R, Vicens-Calvet E, Carrascosa A 1996 Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 81:1237–1243[Abstract]
227. Oppenheimer E, Linder B, DiMartino-Nardi J 1995 Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J Clin Endocrinol Metab 80:614–618[Abstract]
228. Legro RS, Fox J, Dunaif A Hyperandrogenic, cycling, insulin sensitive sisters: an additional familial PCOS phenotype. Program of the 10th International Congress of Endocrinology, San Francisco, 1996 (Abstract OR26–6)
229. Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER 1994 A syndrome of female pseudohermaphroditism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 78:1287–1292[Abstract]
230. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nelson JH 1995 Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci USA 92:1322–1326[Abstract/Free Full Text]
231. Zhang L, Rodriquez H, Ohno S, Miller WL 1995 Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 92:10619–10623[Abstract/Free Full Text]
232. Carey AH, Waterworth D, Patel K, White D, Little J, Novelli P, Franks S, Williamson R 1994 Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 3:1873–1876[Abstract/Free Full Text]
232. Gharani N, Waterworth DM, Williamson R, Franks S1996 5' Polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries. J Clin Endocrinol Metab 81:4174
233. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R 1997 Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986–990[CrossRef][Medline]
234. Legro RS, Muhleman DR, Comings DE, Lobo RA, Kovacs BW 1995 A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics. Fertil Steril 63:779–784[Medline]
235. Legro RS, Shahbahrami B, Lobo RA, Kovacs BW 1995 Size polymorphisms of the androgen receptor among female hispanics and correlation with androgenic characteristics. Obstet Gynecol 83:701–706[CrossRef]
236. Lander E, Kruglyak L 1995 Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247[CrossRef][Medline]
237. Barbieri RL, Gao X, Frost RA 1994 Phosphorylation of 17B-hydroxysteroid dehydrogenase in BeWo choriocarcinoma cells. Am J Obstet Gynecol 171:223–230[Medline]
238. Hollenbeck C, Reaven GM 1987 Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab 64:1169–1173[Abstract/Free Full Text]
239. Laakso M 1993 How good a marker is insulin level for insulin resistance? Am J Epidemiol 137:959–965[Abstract/Free Full Text]
240. DeFronzo RA, Ferrannini E 1991 Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173–194[Abstract]
241. Wild RA 1995 Obesity, lipids, cardiovascular risk, and androgen excess. Am J Med 98:27S–32S
242. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L 1995 Coronary heart disease risk factors in women with polycystic ovary syndrome. Arter Throm Vas Biol 15:821–826
243. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS 1992 Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 37:119–125[Medline]
244. Wild RA, Bartholomew MJ 1988 The influence of body weight on lipoprotein lipids on patients with polycystic ovary syndrome. Am J Obstet Gynecol 159:423–427[Medline]
245. Wild RA, Alaupovic P, Parker IJ 1992 Lipid and apolipoprotein abnormalities in hirsute women. Am J Obstet Gynecol 166:1191–1197[Medline]
246. Andersen P, Seljeflot I, Abdelnoor M, Arnesen H, Dale PO, Lovik A, Birkeland K 1995 Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 44:611–616[CrossRef][Medline]
247. Sobel BE 1996 Altered fibrinolysis and platelet function in the development of vascular complications of diabetes. Curr Opin Endocrinol Diabetes 3:355–360
248. Ehrmann DE, Schneider DJ, Sobel BE, Cavaghan JI, Rosenfield RL, Polonsky KS 1997 Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2108–2116[Abstract/Free Full Text]
249. Wild RA, Grubb BG, Hartz A, VanNort JJ, Bachman W, Bartholomew M 1990 Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril 54:255–259[Medline]
250. Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A 1992 Polycystic ovary syndrome and risk for myocardial infarction. Acta Obstet Gynecol Scand 71:599–603[Medline]
251. Birdsall MA, Farquhar CM, White HD 1997 Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med 126:32–35[Abstract/Free Full Text]
252. Guzick DS, Talbott EO, Sutton-Tyrrell K, Herzog HC, Kuller LH, Wolfson SK 1996 Carotid atherosclerosis in women with polycystic ovary syndrome: initial results from a case-control study. Am J Obstet Gynecol 174:1224–32[CrossRef][Medline]
253. Graf M, Brown V, Richards C, Meissner L, Dunaif A 1990 The independent effects of hyperandrogenemia, hyperinsulinemia, and obesity on lipid and lipoprotein profiles in women. Clin Endocrinol (Oxf) 33:119–131[Medline]
254. Holte J, Bergh T, Berne C, Lithell H 1994 Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables. Clin Endocrinol (Oxf) 41:463–471[Medline]
255. Legro RS, Blanche P, Krauss RM, Lobo RA Alterations in atherogenic lipoproteins among hyperandrogenic women: influence of insulin and genetic factors. Program of the 40th Annual Meeting of the Society for Gynecologic Investigation, 1993 (Abstract P355:360)
256. Zimmerman S, Phillips RA, Wikenfeld C, Dunaif A, Finegood D, Ardeljan M, Wallenstein S, Gorlin R, Krakoff L 1992 Polycystic ovary syndrome: lack of hypertension despite insulin resistance. J Clin Endocrinol Metab 75:508–513[Abstract]
257. Saad MF, Lillioja S, Nyomba BL 1991 Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med 324:733–739[Abstract]
258. Ryan EA, O’Sullivan MJ, Skyler JS 1985 Insulin action during pregnancy: studies with the euglycemic clamp technique. Diabetes 34:380–389[Abstract]
259. Ryan EA, Imes S, Dating L, McManus R, Finegood DT, Polonsky KS, Sturis J 1995 Defects in insulin secretion and action in women with a history of gestational diabetes. Diabetes 44:506–512[Abstract]
260. Wortsman J, de Angeles S, Futterweit W, Singh KB, Kaufmann RC 1991 Gestational diabetes and neonatal macrosomia in the polycystic ovary syndrome. J Reprod Med 36:659–661[Medline]
261. Lanzone A, Caruso A, DiSimone N, DeCarolis S, Fulghesu AM, Mancuso S 1995 Polycystic ovary disease. A risk factor for gestational diabetes? J Reprod Med 40:312–316[Medline]
262. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432[CrossRef][Medline]
263. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV 1996 Leptin: the tale of an obesity gene. Diabetes 45:1455–1462[Medline]
264. Brzechffa PR, Jakimiuk AJ, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA 1996 Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab 81:4166–4169[Abstract/Free Full Text]
265. Mantzoros CS, Dunaif A, Flier JS 1997 Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 82:1687–1691[Abstract/Free Full Text]
266. Laughlin GA, Morales AJ, Yen SSC 1997 Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab 82:1692–1696[Abstract/Free Full Text]
267. Korytkowski MT, Mokan M, Horwitz MJ, Berga SL 1995 Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J Clin Endocrinol Metab 80:3327–3334[Abstract]
268. Elkind-Hirsch KE, Sherman LD, Malinak R 1993 Hormone replacement therapy alters insulin sensitivity in young women with premature ovarian failure. J Clin Endocrinol Metab 76:472–475[Abstract]
269. Bates G, Whitworth MS 1982 Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 38:406–409[Medline]
270. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S 1992 Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 36:105–111[Medline]
271. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ 1994 Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 61:598–604[Medline]
272. DeFronzo RA, Barzilai N, Simonson DC 1991 Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 73:1294–1301[Abstract/Free Full Text]
273. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE 1995 Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333:550–554[Abstract/Free Full Text]
274. DeFronzo RA, Goodman AM 1995 Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333:541–549[Abstract/Free Full Text]
275. Crave J, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M 1995 Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab 80:2057–2062[Abstract]
276. Acbay Ö, Gündogdu S 1996 Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 65:946–949[Medline]
277. Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS 1997 Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:524–530[Abstract/Free Full Text]

This article has been cited by other articles:

				A. Mueller, C. Schofl, R. Dittrich, S. Cupisti, P.G. Oppelt, R.L. Schild, M.W. Beckmann, and L. Haberle Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome Hum. Reprod., November 1, 2009; 24(11): 2924 - 2930. [Abstract] [Full Text] [PDF]

				F. de Zegher and L. Ibanez Early Origins of Polycystic Ovary Syndrome: Hypotheses May Change without Notice J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3682 - 3685. [Full Text] [PDF]

				E Wehr, S Pilz, N Schweighofer, A Giuliani, D Kopera, T R Pieber, and B Obermayer-Pietsch Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome Eur. J. Endocrinol., October 1, 2009; 161(4): 575 - 582. [Abstract] [Full Text] [PDF]

				S. Franks Do Animal Models of Polycystic Ovary Syndrome Help to Understand Its Pathogenesis and Management? Yes, but Their Limitations Should be Recognized Endocrinology, September 1, 2009; 150(9): 3983 - 3985. [Full Text] [PDF]

				V. M. Victor, M. Rocha, C. Banuls, M. Sanchez-Serrano, E. Sola, M. Gomez, and A. Hernandez-Mijares Mitochondrial Complex I Impairment in Leukocytes from Polycystic Ovary Syndrome Patients with Insulin Resistance J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3505 - 3512. [Abstract] [Full Text] [PDF]

				D. Shi, M. K. Dyck, R. R. E. Uwiera, J. C. Russell, S. D. Proctor, and D. F. Vine A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome Endocrinology, September 1, 2009; 150(9): 4425 - 4436. [Abstract] [Full Text] [PDF]

				B. K. Tan, J. Chen, S. Farhatullah, R. Adya, J. Kaur, D. Heutling, K. C. Lewandowski, J. P. O'Hare, H. Lehnert, and H. S. Randeva Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin Diabetes, September 1, 2009; 58(9): 1971 - 1977. [Abstract] [Full Text] [PDF]

				V. Koika, D. J Marioli, A. D Saltamavros, V. Vervita, K. D Koufogiannis, G. Adonakis, G. Decavalas, and N. A Georgopoulos Association of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor {gamma}2 with decreased basic metabolic rate in women with polycystic ovary syndrome Eur. J. Endocrinol., August 1, 2009; 161(2): 317 - 322. [Abstract] [Full Text] [PDF]

				K.-M. Seow, Y.-L. Tsai, J.-L. Hwang, W.-Y. Hsu, L.-T. Ho, and C.-C. Juan Omental adipose tissue overexpression of fatty acid transporter CD36 and decreased expression of hormone-sensitive lipase in insulin-resistant women with polycystic ovary syndrome Hum. Reprod., August 1, 2009; 24(8): 1982 - 1988. [Abstract] [Full Text] [PDF]

				B. K. Tan, R. Adya, J. Chen, S. Farhatullah, D. Heutling, D. Mitchell, H. Lehnert, and H. S. Randeva Metformin decreases angiogenesis via NF-{kappa}B and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1 Cardiovasc Res, August 1, 2009; 83(3): 566 - 574. [Abstract] [Full Text] [PDF]

				S. K. Blank, C. R. McCartney, S. Chhabra, K. D. Helm, C. A. Eagleson, R. J. Chang, and J. C. Marshall Modulation of Gonadotropin-Releasing Hormone Pulse Generator Sensitivity to Progesterone Inhibition in Hyperandrogenic Adolescent Girls--Implications for Regulation of Pubertal Maturation J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2360 - 2366. [Abstract] [Full Text] [PDF]

				V. Padmanabhan Polycystic Ovary Syndrome -- "A Riddle Wrapped in a Mystery inside an Enigma" J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1883 - 1885. [Full Text] [PDF]

				T. Sir-Petermann, E. Codner, V. Perez, B. Echiburu, M. Maliqueo, A. Ladron de Guevara, J. Preisler, N. Crisosto, F. Sanchez, F. Cassorla, et al. Metabolic and Reproductive Features before and during Puberty in Daughters of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1923 - 1930. [Abstract] [Full Text] [PDF]

				A. Iwase, M. Goto, T. Harata, S. Takigawa, T. Nakahara, K. Suzuki, S. Manabe, and F. Kikkawa Insulin Attenuates the Insulin-Like Growth Factor-I (IGF-I)-Akt Pathway, not IGF-I-Extracellularly Regulated Kinase Pathway, in Luteinized Granulosa Cells with an Increase in PTEN J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 2184 - 2191. [Abstract] [Full Text] [PDF]

				L. W. Cho, V Jayagopal, E S Kilpatrick, and S L Atkin The mean and the biological variation of insulin resistance does not differ between polycystic ovary syndrome and type 2 diabetes Ann Clin Biochem, May 1, 2009; 46(3): 218 - 221. [Abstract] [Full Text] [PDF]

				E. Diamanti-Kandarakis, A. Piouka, S. Livadas, C. Piperi, I. Katsikis, A. G Papavassiliou, and D. Panidis Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome Eur. J. Endocrinol., May 1, 2009; 160(5): 847 - 853. [Abstract] [Full Text] [PDF]

				S. Mukherjee, N. Shaikh, S. Khavale, G. Shinde, P. Meherji, N. Shah, and A. Maitra Genetic variation in exon 17 of INSR is associated with insulin resistance and hyperandrogenemia among lean Indian women with polycystic ovary syndrome Eur. J. Endocrinol., May 1, 2009; 160(5): 855 - 862. [Abstract] [Full Text] [PDF]

				J. Hirshfeld-Cytron, R. B. Barnes, D. A. Ehrmann, A. Caruso, M. M. Mortensen, and R. L. Rosenfield Characterization of Functionally Typical and Atypical Types of Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1587 - 1594. [Abstract] [Full Text] [PDF]

				H. H Ortega, N. R Salvetti, and V. Padmanabhan Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance Reproduction, May 1, 2009; 137(5): 865 - 877. [Abstract] [Full Text] [PDF]

				A. Balen, R. Homburg, and S. Franks Defining polycystic ovary syndrome BMJ, February 13, 2009; 338(feb13_2): a2968 - a2968. [Full Text]

				S. Palomba, A. Falbo, F. Zullo, and F. Orio Jr. Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review Endocr. Rev., February 1, 2009; 30(1): 1 - 50. [Abstract] [Full Text] [PDF]

				M. C. Richardson, S. Ingamells, C. D. Simonis, I. T. Cameron, R. Sreekumar, A. Vijendren, L. Sellahewa, S. Coakley, and C. D. Byrne Stimulation of Lactate Production in Human Granulosa Cells by Metformin and Potential Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 670 - 677. [Abstract] [Full Text] [PDF]

				K. Wang, L. Wang, Y. Zhao, Y. Shi, L. Wang, and Z.-J. Chen No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene and polycystic ovary syndrome Hum. Reprod., February 1, 2009; 24(2): 485 - 490. [Abstract] [Full Text] [PDF]

				M A Velazquez, J Zaraza, A Oropeza, R Webb, and H Niemann The role of IGF1 in the in vivo production of bovine embryos from superovulated donors Reproduction, February 1, 2009; 137(2): 161 - 180. [Abstract] [Full Text] [PDF]

				A. Piouka, D. Farmakiotis, I. Katsikis, D. Macut, S. Gerou, and D. Panidis Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E238 - E243. [Abstract] [Full Text] [PDF]

				M. Dorfman, V. D. Ramirez, E. Stener-Victorin, and H. E. Lara Chronic-Intermittent Cold Stress in Rats Induces Selective Ovarian Insulin Resistance Biol Reprod, February 1, 2009; 80(2): 264 - 271. [Abstract] [Full Text] [PDF]

				N. Sattar Review: PCOS, insulin resistance and long-term risks for diabetes and vascular disease The British Journal of Diabetes & Vascular Disease, January 1, 2009; 9(1): 15 - 18. [Abstract] [PDF]

				S. M Nelson Obesity, insulin resistance and assisted conception The British Journal of Diabetes & Vascular Disease, January 1, 2009; 9(1): 23 - 26. [Abstract] [PDF]

				A.E. Nieuwenhuis-Ruifrok, W.K.H. Kuchenbecker, A. Hoek, P. Middleton, and R.J. Norman Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis Hum. Reprod. Update, January 1, 2009; 15(1): 57 - 68. [Abstract] [Full Text] [PDF]

				B. Rossi, S. Sukalich, J. Droz, A. Griffin, S. Cook, A. Blumkin, D. S. Guzick, and K. M. Hoeger Prevalence of Metabolic Syndrome and Related Characteristics in Obese Adolescents with and without Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4780 - 4786. [Abstract] [Full Text] [PDF]

				Y. Zhang, E. Calvo, C. Martel, V. Luu-The, F. Labrie, and A. Tchernof Response of the adipose tissue transcriptome to dihydrotestosterone in mice Physiol Genomics, November 12, 2008; 35(3): 254 - 261. [Abstract] [Full Text] [PDF]

				E. Tasali, E. Van Cauter, L. Hoffman, and D. A. Ehrmann Impact of Obstructive Sleep Apnea on Insulin Resistance and Glucose Tolerance in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3878 - 3884. [Abstract] [Full Text] [PDF]

				K. Mai, T. Bobbert, F. Reinecke, J. Andres, C. Maser-Gluth, S. A. Wudy, M. Mohlig, M. O. Weickert, M. F. Hartmann, H. M. Schulte, et al. Intravenous Lipid and Heparin Infusion-Induced Elevation in Free Fatty Acids and Triglycerides Modifies Circulating Androgen Levels in Women: A Randomized, Controlled Trial J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3900 - 3906. [Abstract] [Full Text] [PDF]

				A Gambineri, R K Semple, G Forlani, S Genghini, I Grassi, C S S Hyden, U Pagotto, S O'Rahilly, and R Pasquali Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin Eur. J. Endocrinol., September 1, 2008; 159(3): 347 - 353. [Abstract] [Full Text] [PDF]

				E. Moll, J.C. Korevaar, P.M.M. Bossuyt, and F. van der Veen Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Hum. Reprod., August 1, 2008; 23(8): 1830 - 1834. [Abstract] [Full Text] [PDF]

				M. Demissie, M. Lazic, E. M. Foecking, F. Aird, A. Dunaif, and J. E. Levine Transient prenatal androgen exposure produces metabolic syndrome in adult female rats Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E262 - E268. [Abstract] [Full Text] [PDF]

				T. M. Barber, M. Hazell, C. Christodoulides, S. J. Golding, C. Alvey, K. Burling, A. Vidal-Puig, N. P. Groome, J. A. H. Wass, S. Franks, et al. Serum Levels of Retinol-Binding Protein 4 and Adiponectin in Women with Polycystic Ovary Syndrome: Associations with Visceral Fat But No Evidence for Fat Mass-Independent Effects on Pathogenesis in This Condition J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2859 - 2865. [Abstract] [Full Text] [PDF]

				K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, and R. Bhushan Comparison of Single and Combined Treatment with Exenatide and Metformin on Menstrual Cyclicity in Overweight Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2670 - 2678. [Abstract] [Full Text] [PDF]

				S. M. Fenkci, V. Fenkci, O. Oztekin, S. Rota, and N. Karagenc Serum total L-carnitine levels in non-obese women with polycystic ovary syndrome Hum. Reprod., July 1, 2008; 23(7): 1602 - 1606. [Abstract] [Full Text] [PDF]

				M. Jensterle, A. Janez, B. Mlinar, J. Marc, J. Prezelj, and M. Pfeifer Impact of metformin and rosiglitazone treatment on glucose transporter 4 mRNA expression in women with polycystic ovary syndrome. Eur. J. Endocrinol., June 1, 2008; 158(6): 793 - 801. [Abstract] [Full Text] [PDF]

				M. Rachmiel, S. Kives, E. Atenafu, and J. Hamilton Primary Amenorrhea as a Manifestation of Polycystic Ovarian Syndrome in Adolescents: A Unique Subgroup? Arch Pediatr Adolesc Med, June 1, 2008; 162(6): 521 - 525. [Abstract] [Full Text] [PDF]

				L.P. Cheung, R.C.W. Ma, P.M. Lam, I.H. Lok, C.J. Haines, W.Y. So, P.C.Y. Tong, C.S. Cockram, C.C. Chow, and W.B. Goggins Cardiovascular risks and metabolic syndrome in Hong Kong Chinese women with polycystic ovary syndrome Hum. Reprod., June 1, 2008; 23(6): 1431 - 1438. [Abstract] [Full Text] [PDF]

				B. K. Tan, D. Heutling, J. Chen, S. Farhatullah, R. Adya, S. D. Keay, C. R. Kennedy, H. Lehnert, and H. S. Randeva Metformin Decreases the Adipokine Vaspin in Overweight Women With Polycystic Ovary Syndrome Concomitant With Improvement in Insulin Sensitivity and a Decrease in Insulin Resistance Diabetes, June 1, 2008; 57(6): 1501 - 1507. [Abstract] [Full Text] [PDF]

				S. Franks, J. Stark, and K. Hardy Follicle dynamics and anovulation in polycystic ovary syndrome Hum. Reprod. Update, May 22, 2008; (2008) dmn015v1. [Abstract] [Full Text] [PDF]

				S Cupisti, N Kajaia, R Dittrich, H Duezenli, M W Beckmann, and A Mueller Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome Eur. J. Endocrinol., May 1, 2008; 158(5): 711 - 719. [Abstract] [Full Text] [PDF]

				S. E. Recabarren, R. Smith, R. Rios, M. Maliqueo, B. Echiburu, E. Codner, F. Cassorla, P. Rojas, and T. Sir-Petermann Metabolic Profile in Sons of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1820 - 1826. [Abstract] [Full Text] [PDF]

				M. Mohlig, M. O Weickert, E. Ghadamgahi, A. M Arafat, J. Spranger, A. F H Pfeiffer, and C. Schofl Retinol-binding protein 4 is associated with insulin resistance, but appears unsuited for metabolic screening in women with polycystic ovary syndrome. Eur. J. Endocrinol., April 1, 2008; 158(4): 517 - 523. [Abstract] [Full Text] [PDF]

				E. Diamanti-Kandarakis, S. Livadas, S. A Kandarakis, A. Margeli, and I. Papassotiriou Serum concentrations of atherogenic proteins neutrophil gelatinase-associated lipocalin and its complex with matrix metalloproteinase-9 are significantly lower in women with polycystic ovary syndrome: hint of a protective mechanism? Eur. J. Endocrinol., April 1, 2008; 158(4): 525 - 531. [Abstract] [Full Text] [PDF]

				B. K. Tan, R. Adya, S. Farhatullah, K. C. Lewandowski, P. O'Hare, H. Lehnert, and H. S. Randeva Omentin-1, a Novel Adipokine, Is Decreased in Overweight Insulin-Resistant Women With Polycystic Ovary Syndrome: Ex Vivo and In Vivo Regulation of Omentin-1 by Insulin and Glucose Diabetes, April 1, 2008; 57(4): 801 - 808. [Abstract] [Full Text] [PDF]

				S. Chakrabarty and M. Nagamani Peripubertal Hyperinsulinemia Upregulates Phosphatidylinositol 3-Kinase/Akt Pathway in Rat Ovaries Reproductive Sciences, March 1, 2008; 15(3): 274 - 284. [Abstract] [PDF]

				T. M. Barber, S. J. Golding, C. Alvey, J. A. H. Wass, F. Karpe, S. Franks, and M. I. McCarthy Global Adiposity Rather Than Abnormal Regional Fat Distribution Characterizes Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 999 - 1004. [Abstract] [Full Text] [PDF]

				D. Heutling, H. Schulz, I. Nickel, J. Kleinstein, P. Kaltwasser, S. Westphal, F. Mittermayer, M. Wolzt, K. Krzyzanowska, H. Randeva, et al. Asymmetrical Dimethylarginine, Inflammatory and Metabolic Parameters in Women with Polycystic Ovary Syndrome before and after Metformin Treatment J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 82 - 90. [Abstract] [Full Text] [PDF]

				L. J Moran, M. Noakes, P. M Clifton, G. A Wittert, C. W Le Roux, M. A Ghatei, S. R Bloom, and R. J Norman Postprandial ghrelin, cholecystokinin, peptide YY, and appetite before and after weight loss in overweight women with and without polycystic ovary syndrome Am. J. Clinical Nutrition, December 1, 2007; 86(6): 1603 - 1610. [Abstract] [Full Text] [PDF]

				C. Roberge, A. C. Carpentier, M.-F. Langlois, J.-P. Baillargeon, J.-L. Ardilouze, P. Maheux, and N. Gallo-Payet Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1465 - E1478. [Abstract] [Full Text] [PDF]

				P. Vigil, P. Contreras, J. L. Alvarado, A. Godoy, A. M. Salgado, and M. E. Cortes Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome Hum. Reprod., November 1, 2007; 22(11): 2974 - 2980. [Abstract] [Full Text] [PDF]

				N. Kajaia, H. Binder, R. Dittrich, P. G Oppelt, B. Flor, S. Cupisti, M. W Beckmann, and A. Mueller Low sex hormone-binding globulin as a predictive marker for insulin resistance in women with hyperandrogenic syndrome Eur. J. Endocrinol., October 1, 2007; 157(4): 499 - 507. [Abstract] [Full Text] [PDF]

				V. Skov, D. Glintborg, S. Knudsen, T. Jensen, T. A. Kruse, Q. Tan, K. Brusgaard, H. Beck-Nielsen, and K. Hojlund Reduced Expression of Nuclear-Encoded Genes Involved in Mitochondrial Oxidative Metabolism in Skeletal Muscle of Insulin-Resistant Women With Polycystic Ovary Syndrome Diabetes, September 1, 2007; 56(9): 2349 - 2355. [Abstract] [Full Text] [PDF]

				M. Mohlig, M. O Weickert, E. Ghadamgadai, A. Machlitt, B. Pfuller, A. M Arafat, A. F H Pfeiffer, and C. Schofl Adipocyte fatty acid-binding protein is associated with markers of obesity, but is an unlikely link between obesity, insulin resistance, and hyperandrogenism in polycystic ovary syndrome women Eur. J. Endocrinol., August 1, 2007; 157(2): 195 - 200. [Abstract] [Full Text] [PDF]

				L. J. Moran, M. Noakes, P. M. Clifton, G. A. Wittert, D. P. Belobrajdic, and R. J. Norman C-Reactive Protein before and after Weight Loss in Overweight Women with and without Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2944 - 2951. [Abstract] [Full Text] [PDF]

				S. Palomba, A. Falbo, T. Russo, F. Manguso, A. Tolino, F. Zullo, P. De Feo, and F. Orio Jr. Insulin Sensitivity after Metformin Suspension in Normal-Weight Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3128 - 3135. [Abstract] [Full Text] [PDF]

				X. Ma, L. Fan, Y. Meng, Z. Hou, Y.-D. Mao, W. Wang, W. Ding, and J.-Y. Liu Proteomic analysis of human ovaries from normal and polycystic ovarian syndrome Mol. Hum. Reprod., August 1, 2007; 13(8): 527 - 535. [Abstract] [Full Text] [PDF]

				E. Carmina, S. Bucchieri, A. Esposito, A. Del Puente, P. Mansueto, F. Orio, G. Di Fede, and G. Rini Abdominal Fat Quantity and Distribution in Women with Polycystic Ovary Syndrome and Extent of Its Relation to Insulin Resistance J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2500 - 2505. [Abstract] [Full Text] [PDF]

				M. Luque-Ramirez, F. Alvarez-Blasco, J. I. Botella-Carretero, E. Martinez-Bermejo, M. A. Lasuncion, and H. F. Escobar-Morreale Comparison of Ethinyl-Estradiol Plus Cyproterone Acetate Versus Metformin Effects on Classic Metabolic Cardiovascular Risk Factors in Women with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2453 - 2461. [Abstract] [Full Text] [PDF]

				B. K. Tan, J. Chen, H. Lehnert, R. Kennedy, and H. S. Randeva Raised Serum, Adipocyte, and Adipose Tissue Retinol-Binding Protein 4 in Overweight Women with Polycystic Ovary Syndrome: Effects of Gonadal and Adrenal Steroids J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2764 - 2772. [Abstract] [Full Text] [PDF]

				T. Sir-Petermann, B. Echiburu, M M. Maliqueo, N. Crisosto, F. Sanchez, C. Hitschfeld, M. Carcamo, P. Amigo, and F. Perez-Bravo Serum adiponectin and lipid concentrations in pregnant women with polycystic ovary syndrome Hum. Reprod., July 1, 2007; 22(7): 1830 - 1836. [Abstract] [Full Text] [PDF]

				M. Luque-Ramirez, F. Alvarez-Blasco, C. Mendieta-Azcona, J. I. Botella-Carretero, and H. F. Escobar-Morreale Obesity Is the Major Determinant of the Abnormalities in Blood Pressure Found in Young Women with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2141 - 2148. [Abstract] [Full Text] [PDF]

				M.L. Hendriks, J.C.F. Ket, P.G.A. Hompes, R. Homburg, and C.B. Lambalk Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome Hum. Reprod. Update, May 1, 2007; 13(3): 249 - 264. [Abstract] [Full Text] [PDF]

				E. Codner and H. F. Escobar-Morreale Hyperandrogenism and Polycystic Ovary Syndrome in Women with Type 1 Diabetes Mellitus J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1209 - 1216. [Abstract] [Full Text] [PDF]

				K.-M. Seow, C.-C. Juan, Y.-P. Hsu, J.-L. Hwang, L.-W. Huang, and L.-T. Ho Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery Hum. Reprod., April 1, 2007; 22(4): 1003 - 1010. [Abstract] [Full Text] [PDF]

				K.-M. Seow, C.-C. Juan, L.-T. Ho, Y.-P. Hsu, Y.-H. Lin, L.-W. Huang, and J.-L. Hwang Adipocyte resistin mRNA levels are down-regulated by laparoscopic ovarian electrocautery in both obese and lean women with polycystic ovary syndrome Hum. Reprod., April 1, 2007; 22(4): 1100 - 1106. [Abstract] [Full Text] [PDF]

				S. E Kasim-Karakas, W. M Cunningham, and A. Tsodikov Relation of nutrients and hormones in polycystic ovary syndrome Am. J. Clinical Nutrition, March 1, 2007; 85(3): 688 - 694. [Abstract] [Full Text] [PDF]

				A Corbould Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women J. Endocrinol., March 1, 2007; 192(3): 585 - 594. [Abstract] [Full Text] [PDF]

				R. S. Legro A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome JAMA, February 7, 2007; 297(5): 509 - 519. [Abstract] [Full Text] [PDF]

				B. K. Tan, J. Chen, J. E. Digby, S. D. Keay, C. R. Kennedy, and H. S. Randeva Increased Visfatin Messenger Ribonucleic Acid and Protein Levels in Adipose Tissue and Adipocytes in Women with Polycystic Ovary Syndrome: Parallel Increase in Plasma Visfatin J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5022 - 5028. [Abstract] [Full Text] [PDF]

				C. Li, E. S. Ford, L. C. McGuire, A. H. Mokdad, R. R. Little, and G. M. Reaven Trends in hyperinsulinemia among nondiabetic adults in the u.s. Diabetes Care, November 1, 2006; 29(11): 2396 - 2402. [Abstract] [Full Text] [PDF]

				F. Alvarez-Blasco, J. I. Botella-Carretero, J. L. San Millan, and H. F. Escobar-Morreale Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med, October 23, 2006; 166(19): 2081 - 2086. [Abstract] [Full Text] [PDF]

				A. G. Hoppin, E. S. Katz, L. M. Kaplan, and G. Y. Lauwers Case 31-2006 -- A 15-Year-Old Girl with Severe Obesity. N. Engl. J. Med., October 12, 2006; 355(15): 1593 - 1602. [Full Text] [PDF]

				D. R. Stewart, B. A. Dombroski, M. Urbanek, W. Ankener, K. G. Ewens, J. R. Wood, R. S. Legro, J. F. Strauss III, A. Dunaif, and R. S. Spielman Fine Mapping of Genetic Susceptibility to Polycystic Ovary Syndrome on Chromosome 19p13.2 and Tests for Regulatory Activity J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4112 - 4117. [Abstract] [Full Text] [PDF]

				H.F. Escobar-Morreale, G. Villuendas, J.I. Botella-Carretero, F. Alvarez-Blasco, R. Sanchon, M. Luque-Ramirez, and J.L. San Millan Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study Hum. Reprod., September 1, 2006; 21(9): 2257 - 2265. [Abstract] [Full Text] [PDF]

				M. H M Lima, L. C Souza, L. C Caperuto, E. Bevilacqua, A. L Gasparetti, R. Zanuto, M. J A Saad, and C. R O Carvalho Up-regulation of the phosphatidylinositol 3-kinase/protein kinase B pathway in the ovary of rats by chronic treatment with hCG and insulin. J. Endocrinol., August 1, 2006; 190(2): 451 - 459. [Abstract] [Full Text] [PDF]

				J. C. Lo, S. L. Feigenbaum, G. J. Escobar, J. Yang, Y. M. Crites, and A. Ferrara Increased Prevalence of Gestational Diabetes Mellitus Among Women With Diagnosed Polycystic Ovary Syndrome: A population-based study Diabetes Care, August 1, 2006; 29(8): 1915 - 1917. [Full Text] [PDF]

				M. Mohlig, A. Jurgens, J. Spranger, K. Hoffmann, M. O Weickert, H. W Schlosser, T. Schill, G. Brabant, A. Schuring, A. F H Pfeiffer, et al. The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome. Eur. J. Endocrinol., July 1, 2006; 155(1): 127 - 130. [Abstract] [Full Text] [PDF]

				S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]

				E. Moll, P. M M Bossuyt, J. C Korevaar, C. B Lambalk, and F. van der Veen Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial BMJ, June 24, 2006; 332(7556): 1485. [Abstract] [Full Text] [PDF]

				R. Pasquali and A. Gambineri Insulin-sensitizing agents in polycystic ovary syndrome. Eur. J. Endocrinol., June 1, 2006; 154(6): 763 - 775. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dunaif, A. Search for Related Content PubMed PubMed Citation Articles by Dunaif, A.