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17-Hydroxyprogesterone Responses to Leuprolide and Serum Androgens in Obese Women with and without Polycystic Ovary Syndrome after Dietary Weight Loss¹

Department of Internal Medicine (D.J.J.), Hospital de Clinicas Caracas, Caracas, Venezuela; and the Departments of Internal Medicine, Obstetrics and Gynecology, and Pharmacology and Toxicology (J.E.N.), Division of Endocrinology and Metabolism, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia 23298

Address all correspondence and requests for reprints to: John E. Nestler, M.D., Medical College of Virginia, P.O. Box 980111, Richmond, Virginia 23298-0111. E-mail: nestler{at}gems.vcu.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Insulin resistance and increased ovarian cytochrome P450c17 activity (i.e. increased 17-hydroxylase and, to a lesser extent, increased 17,20-lyase) are both features of the polycystic ovary syndrome (PCOS). Evidence suggests that hyperinsulinemia may stimulate ovarian P450c17 activity in obese women with PCOS.

We hypothesized that weight loss would decrease serum insulin and P450c17 activity in PCOS. Therefore, we measured serum steroid concentrations and 17-hydroxyprogesterone responses to leuprolide administration and performed oral glucose tolerance tests before and after 8 weeks of a hypocaloric diet in 12 obese women with PCOS (PCOS group) and 11 obese women with normal menses (control group). Serum insulin decreased in both groups. In the PCOS group, basal serum 17-hydroxyprogesterone decreased from 4.2 ± 0.6 to 3.0 ± 0.5 nmol/L (P < 0.05), and leuprolide-stimulated peak serum 17-hydroxyprogesterone decreased from 14.9 ± 2.6 to 8.9 ± 0.8 nmol/L (P < 0.025). Serum testosterone decreased from 2.47 ± 0.52 to 1.56 ± 0.33 nmol/L (P < 0.05), and free testosterone decreased from 9.03 ± 1.39 to 5.95 ± 0.50 pmol/L (P < 0.02). None of these values changed in the control group. Serum sex hormone-binding globulin increased by 4.5- and 3-fold in the PCOS (P < 0.003) and control (P < 0.007) groups, respectively.

We conclude that dietary weight loss decreases ovarian P450c17 activity and reduces serum free testosterone concentrations in obese women with PCOS, but not in obese ovulatory women. The changes in women with PCOS may be related to a reduction in serum insulin.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE POLYCYSTIC ovary syndrome (PCOS) affects approximately 6% of women of reproductive age and is characterized by anovulation and hyperandrogenism (1). A frequent feature of PCOS is insulin resistance and a compensatory hyperinsulinemia, and obese and nonobese women with PCOS are more insulin resistant and hyperinsulinemic than age- and weight-matched normal women (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13).

Hyperinsulinemia plays a pathogenic role in producing the hyperandrogenism of PCOS (14, 15) by both increasing ovarian androgen production (16, 17, 18) and decreasing serum sex hormone-binding globulin (SHBG) (18, 19, 20, 21). Hence, serum free testosterone declines in women with PCOS when circulating insulin is reduced by either pharmacological intervention (17, 18, 22) or diet (23, 24). Hyperinsulinemic insulin resistance is a salient feature of adolescent girls with hyperandrogenism (13), supporting the idea that hyperinsulinemia plays an early and central role in the pathogenesis of PCOS.

17-Hydroxylase and 17,20-lyase are both functions of a single protein, cytochrome P450c17. Many women with PCOS also have increased ovarian 17-hydroxylase activity and, to a lesser extent, increased 17,20-lyase activity (25, 26). A hallmark of increased ovarian P450c17 activity is an exaggerated serum 17-hydroxyprogesterone response to stimulation by GnRH agonists (25, 26, 27, 28, 29).

Hyperinsulinemia may stimulate ovarian cytochrome P450c17 activity in PCOS. We demonstrated that administration of the insulin-sensitizing agent metformin to obese women with PCOS lowers serum insulin, decreases ovarian P450c17 activity toward normal, decreases serum free testosterone, and increases serum SHBG (18).

If hyperinsulinemia stimulates ovarian P450c17 activity in obese women with PCOS, then nonpharmacological methods for lowering serum insulin, such as weight loss, should also be associated with an improvement in ovarian P450c17 activity. Obesity is an insulin-resistant state (30), and weight loss in obese individuals is accompanied by improved insulin sensitivity and a reduction in serum insulin (31, 32, 33). To test this possibility, we assessed ovarian P450c17 activity by a leuprolide stimulation test in obese women with and without PCOS before and after dietary weight loss.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Twelve women with PCOS (PCOS group) and 11 women with normal menses (control group) were studied. All women were obese [body mass index (BMI), 27.5 kg/m²] and 18–35 yr old. None had taken any medications for 2 months or more before the study, and none had diabetes mellitus.

PCOS was defined by oligomenorrhea (<6 menstrual periods in the last year) and hyperandrogenemia (elevated serum free testosterone). All women had normal serum PRL and thyroid function tests. Late-onset adrenal hyperplasia was excluded by a morning serum 17-hydroxyprogesterone level below 6 nmol/L. Women with PCOS had ovarian ultrasonic findings consistent with the diagnosis of PCOS (34). Women in the control group had regular monthly menses and no evidence of androgen excess. The study was approved by the institutional review board of the Hospital de Clinicas Caracas; each woman gave informed consent.

Experimental protocol

Women were studied during the follicular phase of the menstrual cycle, as documented by serum progesterone levels below 6.4 nmol/L. After a 12-h overnight fast, weight, height, and waist to hip ratio (WHR) were measured on day 1. Blood samples were drawn at 0830, 0845, and 0900 h, and equal volumes of serum were pooled for measurement of baseline insulin, glucose, steroid, and SHBG. At 0900 h, 75 g oral dextrose (Glycolab, Relab Laboratory, Caracas, Venezuela) were given, and blood samples were collected for serum glucose and insulin at 60 and 120 min.

On day 2, the women ate breakfast at 0900 h and fasted until 1400 h, when a leuprolide stimulation test was performed (see below). The women were then placed for 2 months on a standardized hypocaloric weight reduction diet consisting of 1000–1200 Cal daily based on the meal-planning exchange list of the American Diabetes Association. Total daily intake consisted of approximately 134 g carbohydrate, 68 g protein, and 47 g fat.

The women returned for the second study after 8 weeks, after the follicular phase of the menstrual period had been confirmed by low serum progesterone levels, and all tests performed at baseline were repeated.

Leuprolide test

After baseline blood samples had been obtained at 1400 h on day 2, leuprolide (10 µg/kg; Lupron, Abbott, Takeda, Japan) was administered sc. Blood samples were collected immediately before and 0.5, 1.0, 16, 20, and 24 h after leuprolide administration for measurement of serum LH and before and 16, 20, and 24 h after leuprolide treatment for measurement of serum 17-hydroxyprogesterone. Women ate supper on day 2, but fasted thereafter until completion of the test. Equal volumes of serum from the 0.5 and 1.0 h blood samples were pooled for measurement of the early serum LH response, and sera from the 16, 20, and 24 h samples were pooled for determination of the late serum LH response.

Assays

Blood samples were centrifuged immediately, and serum was stored at -20 C until assayed. All hormones and SHBG were assayed as previously described (18). To avoid interassay variation, all samples were analyzed in duplicate in a single assay for each hormone. Intraassay coefficients of variation for the insulin and LH assays were 5.5% and 1.6%, respectively, and less than 10% for all steroid assays.

Statistical analysis

Results are reported as the mean ± SE. Within a group, results before and after treatment were compared by testing for normality with the Wilk-Shapiro test and using Student’s two-tailed paired t test or the Wilcoxon signed rank test. Comparisons between groups were made by Student’s two-tailed unpaired t test or the Mann-Whitney rank sum test.

Serum glucose and insulin profiles during the oral glucose tolerance tests and serum LH and 17-hydroxyprogesterone profiles during the leuprolide tests were analyzed by transforming data into the area under the curve (AUC) by the trapezoidal rule using absolute values. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline characteristics

Women in the PCOS and control groups did not differ significantly at baseline with respect to age, BMI, or serum progesterone, testosterone, androstenedione, estradiol, dehydroepiandrosterone sulfate (DHEAS), or SHBG levels (Tables 1 and 2). They also did not differ with respect to fasting serum insulin, insulin, or glucose responses after oral glucose administration or to basal and leuprolide-stimulated LH values (Table 1 and Fig. 1). Basal serum 17-hydroxyprogesterone (P = 0.10), leuprolide-stimulated peak serum 17-hydroxyprogesterone (P = 0.12), and the AUC of 17-hydroxyprogesterone (AUC_{17-HYDROXYPROGESTERONE}; P = 0.07) did not differ significantly between PCOS and control groups, but the power to exclude a true difference was small (0.33) because of the limited sample size.

View larger version (29K): [in this window] [in a new window]   Figure 1. Serum LH concentrations in obese women with PCOS (PCOS group) or obese women with normal menses (control group) at baseline and after dietary weight loss. The women were studied before and after stimulation with leuprolide (10 µg/kg). Values are the mean ± SE.

Anthropometric variables (Table 1)

BMI decreased by 7.5% (P < 0.0001) and 7.1% (P < 0.0001) with diet in the PCOS and control groups, respectively. WHR did not change in either group.

Serum insulin and glucose profiles (Table 1)

Fasting serum insulin and AUC_INSULIN decreased significantly in both the PCOS and control groups. Neither fasting serum glucose nor AUC_GLUCOSE changed in either group.

Serum LH responses to leuprolide (Fig. 1)

In the PCOS group, basal serum LH (P = 0.21) and early (P = 0.34) and late (P = 0.25) serum LH responses to leuprolide after the diet did not differ significantly from those at baseline. In the control group, basal serum LH (P = 0.90) and the early (P = 0.64) and late (P = 0.83) serum LH responses to leuprolide were virtually identical at baseline and after the diet.

Serum 17-hydroxyprogesterone responses (Fig. 2)

Basal serum 17-hydroxyprogesterone decreased by 26% from 4.2 ± 0.6 to 3.0 ± 0.5 nmol/L (P < 0.04) in the PCOS group, but did not change in the placebo group. In the PCOS group leuprolide-stimulated peak serum 17-hydroxyprogesterone decreased from 14.9 ± 2.6 to 8.9 ± 0.8 nmol/L (P < 0.025), and AUC_{17-HYDROXYPROGESTERONE} decreased from 242 ± 42 to 145 ± 13 nmol/L·min (P < 0.02). These values did not change in the control group.

View larger version (17K): [in this window] [in a new window]   Figure 2. Serum 17-hydroxyprogesterone concentrations in obese women with PCOS (PCOS group) or obese women with normal menses (control group) at baseline and after dietary weight loss. The women were studied before and after stimulation with leuprolide (10 µg/kg). Values are the mean ± SE. *, P < 0.05; **, P < 0.025; ***, P < 0.02 (compared with the baseline value in the same group).

Serum sex steroids (Table 2)

Weight loss in the PCOS group was associated with a decrease in serum testosterone from 2.47 ± 0.52 to 1.56 ± 0.33 nmol/L (P < 0.05) and a 34% decrease in serum free testosterone from 9.03 ± 1.39 to 5.95 ± 0.50 pmol/L (P < 0.02); these values did not change in the control group. Serum SHBG increased with weight loss by 4.5- and 3-fold in the PCOS (P < 0.003) and control (P < 0.007) groups, respectively. In the control group, serum DHEAS was increased after the diet compared with the baseline values, but did not change in the PCOS group. Other measured steroids did not change significantly in either group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We conducted this study to determine whether a nonpharmacological method for lowering serum insulin, namely dietary weight loss, would decrease P450c17 activity in obese women with PCOS. In these women, weight loss reduced fasting serum insulin and the insulin response to an oral glucose challenge. Concomitantly, ovarian P450c17 enzyme activity decreased, as demonstrated by substantial reductions in basal serum 17-hydroxyprogesterone and the serum 17-hydroxyprogesterone responses after leuprolide administration. P450c17 activity was reduced to a level nearly equivalent to that in obese control women, suggesting that P450c17 activity in women with PCOS essentially had been rendered normal. The reduction in P450c17 activity was accompanied by decreases in both serum total testosterone and free testosterone concentrations, with mean serum free testosterone decreasing into the normal range. These findings are consistent with the idea that stimulation of ovarian P450c17 activity in obese women with PCOS is not a fixed genetic defect, is induced by insulin, and can be reversed by reducing insulin secretion through weight loss.

Weight loss produces multiple metabolic alterations, and the study’s design does not permit identification of any single cause for the reduction in ovarian P450c17 activity in women with PCOS. Nonetheless, the findings are consistent with evidence that insulin stimulates ovarian androgen production in women with PCOS (14, 15, 16, 17, 18, 22). Other diet-related factors, such as changes in fat or protein intake, might have affected P450c17 activity through some unidentified and insulin-independent mechanism, but little evidence exists to support such a contention.

We previously used metformin to reduce insulin secretion in women with PCOS, and observed that decreased serum insulin concentrations were associated with decreased secretion of LH (18). In the present study, basal and leuprolide-stimulated serum LH did not change with diet in women with PCOS, but the power to exclude an effect was low (0.12).

In contrast to women with PCOS, weight loss in obese women with normal menses did not change P450c17 activity or serum total or free testosterone despite reductions in fasting serum insulin and the insulin response to oral glucose challenge equivalent to those in the PCOS group. This suggests that the ability of insulin to stimulate ovarian cytochrome P450c17 is probably limited to women with PCOS and may represent an inheritable abnormality (15, 35), and is consistent with the observation that many obese ovulatory women have neither hyperandrogenism nor hyperresponsiveness to GnRH stimulation (26).

Weight loss was also associated with marked (3- to 4.5-fold) increases in serum SHBG in both the PCOS and control groups, but serum total and free testosterone decreased only in women with PCOS. Insulin reportedly lowers serum SHBG in both normal women (36) and women with PCOS (18, 20). Notably, although serum SHBG rose in both groups, serum free testosterone decreased only in women with PCOS. This suggests that the increase in this binding protein in normal women was accompanied by increased ovarian testosterone production and/or decreased testosterone clearance, the net result of which was maintenance of a constant serum free testosterone level. In contrast, the increase in serum SHBG in women with PCOS was accompanied presumably by decreased ovarian testosterone production, thus yielding a decrease in serum free testosterone.

Finally, serum DHEAS rose in the control group, but did not change in the PCOS group. Whether insulin or weight loss affects serum DHEAS in normal or PCOS women remains unclear (37). Serum DHEAS did not change with weight loss in three studies performed in premenopausal (38) and postmenopausal (39, 40) women, but rose in two other studies performed in women (41, 42).

In summary, dietary weight loss in obese women with PCOS decreases ovarian cytochrome P450c17 activity and reduces serum total and free testosterone. These findings are consistent with the idea, but do not prove, that two features of PCOS, namely hyperinsulinemic insulin resistance and increased ovarian P450c17 activity, are pathogenetically linked, and that hyperinsulinemia stimulates ovarian cytochrome P450c17. The clinical implication is that therapeutic measures directed at lowering insulin secretion, including dietary weight loss, should ameliorate the hyperandrogenism of obese women with PCOS.

	Acknowledgments

 
We thank Terre Williams, Carmen Medina, and Gladys Coz for their technical assistance.

	Footnotes

 
¹ This work was supported in part by NIH Grants RO1-AG-11227 and RO1-CA-64500 (to J.E.N.).

Received August 2, 1996.

Revised September 30, 1996.

Accepted November 4, 1996.

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