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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

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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

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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

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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

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