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ß-Cell Function: A Key Pathological Determinant in Polycystic Ovary Syndrome

Division of Endocrinology, Diabetes, and Hypertension (M.O.G., S.G.K.), Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095; Division of Endocrinology, Diabetes, and Metabolism and Department of Obstetrics and Gynecology (M.O.G.), Cedars-Sinai Medical Center, Los Angeles, California 90048; and Department of Statistics (S.E., S.C.P., R.I.J.), University of California, Los Angeles, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Mark O. Goodarzi, M.D., Ph.D., Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes, and Metabolism, 8700 Beverly Boulevard, Becker B-128, Los Angeles, California 90048. E-mail: mark.goodarzi{at}cshs.org.

	Abstract

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We report data from 60 patients with polycystic ovary syndrome (PCOS) who had undergone assessment of insulin resistance, pancreatic ß-cell function, obesity, and androgen levels to elucidate the complex relationships among these traits. Homeostasis model assessment was used to quantify insulin resistance and ß-cell function. A reference population was derived from the National Health and Nutrition Examination Study (NHANES III, 1988–1994). Indices of insulin resistance, insulin secretion, bioavailable testosterone, and body mass index all exhibited significant pairwise correlations. Multiple regression analysis clarified the phenotypic relationships, demonstrating that insulin resistance and bioavailable testosterone were independent predictors of ß-cell function; ß-cell function and obesity were independent predictors of insulin resistance; and ß-cell function was an independent predictor of bioavailable testosterone. Of note, comparison with normal women from NHANES revealed a significantly stronger relationship between ß-cell function and insulin resistance in PCOS, raising the possibility of an intrinsic defect in ß-cell function whereby increasing insulin resistance leads to a greater insulin response in PCOS than normal. The altered relationship of ß-cell function and insulin resistance coupled with the fact that ß-cell function, not insulin resistance, was a predictor of hyperandrogenemia suggests that ß-cell dysfunction may be a key pathogenic determinant in PCOS.

	Introduction

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POLYCYSTIC OVARY SYNDROME (PCOS) is found in 4–7% of women of reproductive age, making it the most common endocrine disorder in women (1, 2). For many years, obesity has been an important feature of the syndrome. More recently, investigators recognized insulin resistance, which characterizes 50–90% of PCOS women (3, 4, 5), as a central component of PCOS, possibly playing an underlying pathogenic role (6). PCOS, in turn, may confer a risk of insulin resistance in addition to that caused by obesity (7, 8). However, it is not clear whether insulin resistance itself or the resultant compensatory hyperinsulinemia leads to the hormonal abnormalities in PCOS. Of the handful of studies that address insulin secretion in PCOS, some describe increased insulin secretion (9, 10, 11, 12, 13, 14, 15, 16), although others suggest decreased insulin secretion (17, 18, 19).

For these reasons we sought to better understand the role of pancreatic insulin secretion in PCOS, in particular to place it in the context of insulin resistance, hyperandrogenemia, and obesity. To achieve this goal, we analyzed a cohort of PCOS patients who had undergone detailed characterization of these phenotypes and compared it with a matched normal population. Simple correlation and multiple regression analyses were used to describe the relationships among these traits. We found an altered relationship between ß-cell function and insulin resistance in PCOS compared with normal women.

	Subjects and Methods

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We conducted an Institutional Review Board-approved retrospective chart review of patients presenting to S.G.K.’s university-based (David Geffen School of Medicine at UCLA) reproductive endocrinology clinic with chief complaints of hirsutism, alopecia, acne, or weight gain. Criteria defining PCOS were those of the 1990 National Institute of Child Health and Human Development Consensus Conference (20), namely that there was evidence of hyperandrogenism and oligo-ovulation with exclusion of other disorders known to result in a hyperandrogenic syndrome, such as Cushing’s disease or congenital adrenal hyperplasia. Hyperandrogenism was either clinical in the form of hirsutism, acne, or alopecia, or biochemical in the form of an elevated serum androgen level. Clinical assessment was made by the same physician in all cases. Oligo-ovulation was considered to be present if the patient gave a history of a reduced frequency of menses (missed periods or secondary amenorrhea) or if anovulation was demonstrated by luteal phase progesterone measurement.

Exclusion criteria included a hyperandrogenic disorder other than PCOS, such as Cushing’s syndrome, 21-hydroxylase deficiency, or hyperandrogenic insulin resistance acanthosis nigricans syndrome. 21-Hydroxylase deficiency presenting as adult-onset (nonclassical) adrenal hyperplasia was diagnosed using standard criteria (21, 22). Also excluded were patients who at presentation were receiving medications that could alter the endocrine and metabolic parameters under investigation, because we wanted to characterize PCOS as it affects women before treatment. Such medications included oral contraceptives, metformin, glucocorticoids, and dexamethasone. Patients were also excluded if they had impaired fasting glucose, diabetes mellitus, anorexia nervosa, hypopituitarism, prolactinoma, or active thyroid disease, with the latter assessed by prolactin and TSH measurements. Hypopituitarism was excluded biochemically when a suggestive history or physical exam findings were present. In light of the above entry and exclusion criteria, 60 cases of PCOS (of 143 charts reviewed) were deemed appropriate for inclusion in this study.

Anthropometric and laboratory data were always measured during initial evaluation, before institution of therapy. A clinic nurse obtained the weight, height, and blood pressure of each subject. Age was determined at time of presentation. Body mass index (BMI) was calculated as kg/m². All 60 had a morning fasting glucose, insulin, and total and bioavailable [non-sex-hormone-binding globulin (non-SHBG)-bound] testosterone, as previously described (23). The laboratory performing the blood tests (Quest Diagnostics, San Juan Capistrano, CA, for hormonal measurements) provided normal values; all other tests were done at the University of California, Los Angeles, Clinical Laboratory.

The homeostasis model assessment (HOMA) was used to calculate indices of insulin resistance and insulin secretion for each patient (24, 25). The computer-based HOMA calculator (available at www.dtu.ox.ac.uk/homa) uses fasting glucose and insulin to generate the index of insulin resistance, HOMA-IR, and the index of ß-cell function, HOMA-%B. An ideal, normal-weight person less than 35 yr of age has a HOMA-IR of 1 and HOMA-%B of 100% (26).

Data from the National Health and Nutrition Examination Study (NHANES III) (27) were used to obtain a population of normal women for comparison with women with PCOS. Subjects from NHANES III who had glucose and insulin levels obtained after at least 8 h fasting were selected to match the age, BMI, and racial/ethnic distribution of the PCOS group. Thus, the groups were comparable in age (NHANES mean age, 27.8 yr with a range of 15–39 yr; PCOS mean age, 26.2 yr with a range of 13–46 yr) and BMI (NHANES mean BMI, 30.0 kg/m² with a range of 24–69 kg/m²; PCOS mean BMI, 30.6 kg/m² with a range of 19–64 kg/m²). Both populations had equal proportions of Caucasian subjects (64%), Mexican-Americans (11%), African-Americans (9%), and other ethnic groups (16%). We excluded participants who were using insulin or who had a fasting glucose greater than 110 mg/dl (6.1 mmol/liter) or a glycosylated hemoglobin greater than 6% to remove individuals with glucose intolerance or diabetes, yielding 486 subjects for analysis. The methods used for glucose, insulin, and lipid levels are detailed in the NHANES report (27).

Statistical analysis

Parameters that had a skewed distribution (weight, BMI, insulin, HOMA-IR, HOMA-%B, and total and bioavailable testosterone values) were log transformed for all analyses to reduce skewness. Henceforth reference to these variables will always mean their log-transformed values. Student’s t test was used to compare means between PCOS and NHANES. A P value < 0.05 was considered statistically significant. Simple correlation analyses were carried out comparing all possible pairwise combinations of the variables HOMA-%B, HOMA-IR, age, BMI, bioavailable testosterone, and total testosterone for both the PCOS and NHANES populations (testosterone was not measured in NHANES). A large sample test (28) was used to compare corresponding correlation coefficients between the two populations. In the PCOS group, multiple regression analysis was conducted 1) with HOMA-IR, age, BMI, and bioavailable testosterone as independent variables and HOMA-%B as the dependent variable; 2) with HOMA-%B, age, BMI, and bioavailable testosterone as independent variables and HOMA-IR as the dependent variable; and 3) with HOMA-IR, HOMA-%B, age, and BMI as independent variables and bioavailable testosterone as the dependent variable. Analyses were conducted using Statview 5.01 and SAS software (SAS Institute, Cary, NC).

	Results

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Phenotypic correlations in PCOS

The phenotypic correlations among insulin resistance, ß-cell function, testosterone levels, age, and BMI, assessed by pairwise correlations, are displayed in Table 1. HOMA-IR values indicated a wide range of insulin resistance from 0.35–6.9. HOMA-%B values ranged from 58–382%, indicating a broad range of insulin secretion. The highly significant correlation (r = 0.91; P < 0.0001) between HOMA-IR and HOMA-%B indicated increasing (compensatory) insulin secretion with increasing insulin resistance.

Total and bioavailable testosterone values were available for the PCOS group only. Total testosterone was not significantly correlated with insulin resistance, insulin secretion, age, or BMI. However, bioavailable testosterone was correlated with fasting insulin (r = 0.44; P = 0.0005), with HOMA-IR (r = 0.42; P = 0.0016), and with HOMA-%B (r = 0.49; P = 0.0002). Bioavailable testosterone was also correlated with BMI (r = 0.33; P = 0.016).

Given the complex of interrelationships among insulin-related traits, hyperandrogenemia, and body mass, we next used multiple regression analyses to elucidate the most important independent predictors of insulin resistance, ß-cell function, and bioavailable testosterone.

Independent factors influencing ß-cell function, insulin resistance, and bioavailable testosterone in PCOS

Table 2 displays the results of analyses that employed HOMA-%B, HOMA-IR, and bioavailable testosterone as dependent variables in separate multiple regressions. In women with PCOS, regression of age, BMI, HOMA-IR, and bioavailable testosterone on HOMA-%B showed that age and BMI were not significant predictors of HOMA-%B (P = 0.33 and 0.71). The strongest predictor of HOMA-%B as judged by standardized regression coefficients (SRC) was HOMA-IR (SRC = 0.86; P < 0.0001), followed by bioavailable testosterone (SRC = 0.15; P = 0.023).

HOMA-IR and HOMA-%B, as well as age and BMI, were examined as independent predictors of bioavailable testosterone. In this analysis, the only independent predictor of bioavailable testosterone was HOMA-%B (SRC = 0.74; P = 0.023).

Insulin resistance and ß-cell function: PCOS vs. normal women

Anthropometric and metabolic characteristics of the PCOS patients and the age-, BMI-, and ethnicity-matched normal women from NHANES are presented in Table 3. Average levels of fasting glucose and insulin-related traits did not differ significantly between the two groups.

View larger version (23K): [in this window] [in a new window]   FIG. 1. Regression plot of HOMA-IR on HOMA-%B. The plot is an overlay of the simple regression plots for PCOS and for NHANES.

	Discussion

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The use of women from NHANES provided a very large normal control group; even if 5% of this population had PCOS it would not have altered the results. In fact, the presence of PCOS in the NHANES population would tend to hinder detection of differences in a comparison of our PCOS patients with NHANES. Direct comparison of mean trait values, as in Table 3, must be interpreted with some caution because the glucose and insulin determinations were made in different laboratories.

The unsuspected importance of ß-cell function

In PCOS and normal women, the most significant predictor of ß-cell function was insulin resistance. This is consistent with the concept of compensatory insulin hypersecretion in response to insulin resistance. Compensatory hyperinsulinemia serves to maintain normal plasma glucose levels in the face of insulin resistance. Because the patients were selected to have normal fasting glucose levels (range, 69–105 mg/dl or 3.8–5.8 mmol/liter), they had adequate ß-cell function. The most insulin-resistant patients with PCOS in this study had ß-cells secreting insulin at very high levels. These patients may be at increased risk of ß-cell exhaustion and development of type 2 diabetes mellitus (29).

In contrast to insulin resistance in PCOS, there have been comparatively few studies examining ß-cell function/insulin secretion in PCOS. Several studies demonstrated increased insulin secretion in PCOS compared with normal (9, 10, 11, 12, 13, 14, 15, 16), although other studies demonstrated decreased insulin secretion in PCOS (17, 18, 19). Different results have been observed depending on whether insulin secretion was assessed in the basal vs. postabsorptive state (30). Another possible confounding factor is that many studies quantified insulin secretion without accounting for the prevailing level of insulin resistance; this is essential to accurate interpretation of indices of ß-cell function because insulin secretion and insulin sensitivity have been shown to have a hyperbolic relationship (31). Insulin secretion may be adjusted for insulin resistance using statistical means or by employing the disposition index, the product of an index of insulin secretion with an index of insulin sensitivity. Nevertheless, even among careful studies making this adjustment, conflicting results regarding insulin secretion in PCOS are found in the literature (14, 18, 32). We avoided this problem by examining the relationship between insulin secretion and insulin resistance, rather than comparing mean values. Although we did not find BMI to be an independent predictor of ß-cell function, others have observed differences in ß-cell function between lean and obese women with PCOS, with increased insulin secretion in lean PCOS and decreased insulin secretion in obese PCOS (32). Insulin secretion tends to be decreased in women with PCOS and impaired glucose tolerance; a study of obese, insulin-resistant adolescents with PCOS found that those with impaired glucose tolerance or diabetes had impaired ß-cell response to the same degree of insulin resistance as the normoglycemic patients (17). In a separate study, normal glucose-tolerant women with PCOS had increased insulin secretion, whereas those with impaired glucose tolerance had decreased insulin secretion (14). Similarly, women with polycystic ovaries and a history of gestational diabetes have impaired ß-cell function (33, 34). Thus, the heterogeneity observed in ß-cell function in PCOS may reflect its assessment at different stages of the disorder, with increased ß-cell function in lean subjects with normal glucose tolerance and decreased ß-cell function in obese subjects who have mild (manifesting during pregnancy as gestational diabetes) or overt impairment in glucose tolerance.

A key finding in this study was the altered relationship of ß-cell function and insulin resistance in PCOS in comparison with normal women. The correlation coefficients relating HOMA-%B to HOMA-IR were higher in PCOS, indicating a greater degree of compensatory insulin secretion for a given increment in insulin resistance. The basis of this difference is unknown. Perhaps in PCOS there is a genetic variant in the pancreatic ß-cell that leads to insulin hypersecretion. In fact, in studies of families of women with PCOS, insulin secretion levels, quantified directly by the frequently sampled iv glucose tolerance test, showed significant heritability, suggesting a genetic component to ß-cell function in PCOS (35). Higher proinsulin levels in women with PCOS compared with normal have been observed, supporting the hypothesis of altered ß-cell function in PCOS (36). Another study observed that weight loss in a group of women with PCOS led to normalization of insulin resistance but did not alter insulin hypersecretion, suggesting that the latter is a primary, intrinsic factor in PCOS (16). Given that HOMA-%B was a significant predictor of bioavailable testosterone in PCOS, it is possible that the tendency to insulin hypersecretion leads to elevated levels of insulin that then contribute to hyperandrogenemia. Indeed, much experimental evidence exists to suggest that insulin has the ability to stimulate ovarian testosterone production (37, 38, 39). Whether increased insulin secretion stimulates adrenal androgen hypersecretion is more controversial; however, one study of PCOS women found that during an insulin infusion, adrenal -5 androgen output was exaggerated compared with saline infusion, suggesting that hyperinsulinemia potentiated the adrenocortical response to ACTH (40).

The place of insulin resistance

We used HOMA-IR to quantify insulin resistance because this tool has been shown to be a reliable reflection of insulin resistance with a good correlation (r = 0.6–0.88) with the euglycemic hyperinsulinemic glucose clamp study (24, 26, 41). A recent report showed HOMA-IR to have a better correlation with clamp results than even indices derived from oral glucose tolerance tests (42). In women with PCOS and in normal women, HOMA-%B and BMI were significant correlates of HOMA-IR. Whether the insulin resistance often observed in PCOS is because of obesity or an effect of PCOS itself is controversial. Some studies showed similar insulin resistance in weight-matched PCOS and control subjects (19, 43), whereas others demonstrated increased insulin resistance in PCOS compared with weight-matched controls (3, 30, 44). What is widely accepted is that women with both PCOS and obesity have the highest risk for insulin resistance.

In multiple regression analysis in PCOS, BMI was significantly related to HOMA-IR but not to HOMA-%B. This is in agreement with a study wherein weight loss normalized insulin resistance in women with PCOS but did not reduce their increased insulin secretion (16). In another study of lean and obese women with PCOS, insulin resistance was most prominent in the obese subjects, whereas insulin hypersecretion was found in all hyperinsulinemic PCOS patients, regardless of obesity (10). This again highlights the potential importance of pancreatic ß-cell function in the pathophysiology of PCOS. If a tendency to insulin hypersecretion is a primary characteristic of PCOS, insulin resistance may yet have importance as a physiological stressor that, by increasing the body’s need for insulin, causes the insulin secretory abnormality to become manifest. This is suggested by the greater slope of the HOMA-%B vs. HOMA-IR line in PCOS vs. normal (Fig. 1).

The role of androgens: bioavailable testosterone

Some studies suggest that insulin resistance/hyperinsulinemia may cause hyperandrogenemia (37, 38, 39, 40, 45), whereas others suggest the reverse (46, 47). The current study found a significant correlation between insulin resistance and hyperandrogenemia; however, in multiple regression analysis, the relationship between these traits was insignificant. On the other hand, a robust relationship was found between ß-cell function and bioavailable testosterone. As discussed above, this raises the possibility that insulin hypersecretion causes hypersecretion of androgens. Conversely, elevated androgen levels may influence ß-cell function, leading to insulin hypersecretion. Consistent with this possibility, a study demonstrating increased insulin secretion in PCOS compared with normal found no difference after adjusting for free androgen index (14). Another alternative is that a common cellular defect leads to both insulin hypersecretion and androgen hypersecretion. Our results demonstrate a significant correlation between HOMA-%B and bioavailable testosterone but do not allow conclusions on causation. What can be inferred is that the correlation of insulin resistance and hyperandrogenemia often observed in PCOS is likely mediated via compensatory insulin hypersecretion.

Bioavailable (non-SHBG-bound) testosterone exhibited significant pairwise correlations with BMI and with HOMA-%B. Although both obesity and hyperinsulinemia may contribute to decreased levels of SHBG, resulting in higher bioavailable testosterone, multiple regression analysis showed that ß-cell function had the most direct effect on hyperandrogenemia. It has been suggested that hyperinsulinemia may mediate the decrease in SHBG seen with increasing adiposity (48). Thus, insulin suppression of hepatic synthesis of SHBG (49) may contribute to the correlation of ß-cell function and bioavailable testosterone, in addition to a possible effect of insulin on ovarian steroidogenesis (37, 38, 39). The fact that total testosterone exhibited no significant inter-trait correlations demonstrates the importance of low SHBG in the hyperandrogenemia of PCOS.

Implications

Insulin resistance is clearly found in many subjects with PCOS and may contribute to increased risk of the metabolic syndrome, development of type 2 diabetes, and cardiovascular disease (6). However, this study demonstrates the under-recognized importance of ß-cell function in PCOS. ß-Cell function, not insulin resistance, was an important correlate of bioavailable testosterone levels. Women with PCOS demonstrated an altered relationship between insulin resistance and insulin secretion, consistent with an intrinsic ß-cell defect wherein insulin resistance leads to an excessive amount of compensatory insulin secretion, with attendant consequences on androgen production and SHBG levels. Insulin hypersecretion may also help to explain the intense hunger experienced by PCOS patients and their ability to gain large amounts of weight in a short period of time. Possibly this insulin hypersecretion was evolutionarily advantageous in times of nutritional deprivation. More research, both at the clinical and cellular levels, is needed to better understand the importance of insulin secretion in PCOS. If ß-cell function is indeed a central pathogenic defect in PCOS, therapies that directly modulate insulin secretion may achieve greater success than insulin-sensitizing therapies commonly used today.

	Footnotes

 
First Published Online October 26, 2004

Abbreviations: BMI, Body mass index; HOMA, homeostasis model assessment; HOMA-IR, index of insulin resistance; HOMA-%B, index of ß-cell function; NHANES, National Health and Nutrition Examination Study; PCOS, polycystic ovary syndrome; SHBG, sex-hormone-binding globulin; SRC, standardized regression coefficient.

Received May 26, 2004.

Accepted October 18, 2004.

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