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Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Medical School (S.N.), Houston, Texas 77030; and the Department of Medicine, University of Southern California Medical School (M.G.R.-G., M.F.S.), Los Angeles, California 90033
Address all correspondence and requests for reprints to: Shahla Nader, M.D., Division of Reproductive Endocrinology, University of Texas Medical School, 6431 Fannin, Suite 3.036, Houston, Texas 77030.
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Abstract |
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Introduction |
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Oral contraceptive pills (OC) are often used in the treatment of ovarian hyperandrogenism because they can suppress gonadotropins and, subsequently, ovarian androgen secretion. They may, however, worsen insulin resistance and lead to deterioration of glucose tolerance (18). The increase in insulin resistance has been linked to the progestogen component, which in many available OC is androgenic in nature (19, 20), and androgens themselves can induce insulin resistance (20). This work was undertaken to examine 1) the effect of an OC-containing desogestrel (a progestogen of low androgenicity) (21) on glucose tolerance and insulinemia in hyperandrogenic women, and 2) the impact of changes in androgenic/estrogenic status on plasma leptin levels.
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Subjects and Methods |
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This study included 16 nondiabetic women, aged 29 ± 1 yr (mean ± SE) with a body mass index (BMI) of 36.8 ± 1.8 kg/m2 (range, 25.9–55.2). All women had acanthosis nigricans, suggestive of insulin resistance (22), and hyperandrogenism manifested by acne or hirsutism and/or irregular menses. All but one were oligomenorrheic (menses 6 or more weeks apart). All women had a plasma total testosterone level above 40 ng/dL (higher than the mean plus 2 SD of the follicular phase total testosterone level in nonobese, normally cycling women in our laboratory). They were otherwise healthy and not taking medications known to affect ovarian function or glucose tolerance. The study was approved by the committee for protection of human subjects of the University of Texas Medical School (Houston, TX), and all subjects gave informed consent.
An oral glucose tolerance test was performed after a 10- to 12-h overnight fast. Blood was collected at 0, 30, 60, 90, 120, 150, and 180 min for determination of plasma glucose and at 0, 60, 120, and 180 min for measurement of serum insulin. According to WHO criteria (23), nine women had normal glucose tolerance (NGT), and seven had impaired glucose tolerance (IGT). Serum leptin, total and free testosterone, and sex hormone-binding globulin (SHBG) concentrations were measured at time zero. The test was performed either in the early midfollicular phase or at any time in anovulatory women with menses more than 6 weeks apart. The OC Desogen (30 µg ethinyl estradiol and 150 µg desogestrel; Organon, West Orange, NJ) was given for 21 days for six cycles. The oral glucose tolerance test was repeated in the third week of the last cycle. Weight, height, and waist and hip circumferences were determined before and after treatment.
Biochemical analysis
Plasma glucose was determined with the glucose oxidase method. Insulin was measured by a specific RIA, using reagents from Linco Research (St. Louis, MO), with a detection limit of 12 pmol/L and an interassay coefficient of variation of 6–8%. Leptin was determined by a RIA (Linco Research) that uses a polyclonal antibody raised in rabbits against recombinant human leptin (24). The assay had a sensitivity of 0.5 ng/mL and an interassay coefficient of variation of 5–7%. Estradiol and estrone were measured by RIA with kits from Diagnostic Products Corp. (Los Angeles, CA) and Diagnostic Systems Laboratories (Webster, TX), respectively. Total and free testosterone and SHBG levels were determined by Endocrine Sciences (Calabas Hill, CA).
Statistical analysis
Data are expressed as the mean ± SEM or as the mean with the 95% confidence interval. Insulin and leptin concentrations were log transformed to normalize the distribution. Statistical analyses were performed with programs from SPSS (Chicago, IL) (25). Within-group comparisons were performed with repeated measures ANOVA or paired t test. Linear regression and/or Pearson product moment correlations were used to evaluate the relation among different variables.
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Results |
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). The plasma estradiol concentration
was 57 ± 4 pg/mL before treatment with OC, which resulted in a
marked suppression of its levels in all patients (below the detection
limit of the assay in 13). The plasma estrone concentration decreased
from 47 ± 3 to 28 ± 4 pg/mL (P = 0.002)
after OC therapy.
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). Of the nine
patients with NGT, four continued to have NGT, and five developed IGT.
Of the seven patients with IGT, one reverted to NGT, four continued to
have IGT, and two developed diabetes. Thus, after 6 months of treatment
with this OC, five women had NGT, nine had IGT, and two had
noninsulin-dependent diabetes mellitus (NIDDM). However, serum insulin
concentrations did not show a significant change. Neither body weight
(94 ± 6 vs. 93 ± 5 kg; P = 0.18)
nor BMI (36.8 ± 1.8 vs. 36.2 ± 1.7
kg/m2; P = 0.19) changed significantly
during follow-up.
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). Leptin correlated with BMI before
(r = 0.56; P = 0.02) and after (r = 0.51;
P = 0.04) treatment (Fig. 2), but not with the waist/hip ratio.
Leptin levels did not correlate significantly with glucose, insulin,
total and free testosterone, or SHBG levels before or after treatment.
The change in the leptin concentration during the period of follow-up
correlated with the change in BMI (r = 0.49; P =
0.06), but not with the change in total or free testosterone or
SHBG.
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Discussion |
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The mechanism of deterioration of glucose tolerance while using this OC is not clear. Although insulin resistance was not measured, no change in serum insulin, a commonly used surrogate, was observed. Insulinemia may not correlate well with insulin resistance, however, in subjects with IGT and NIDDM due to deterioration of ß-cell function (27). Conversely, Kuhl et al. (26) reported that a similar OC resulted in a 20–25% increase in insulin levels in women with normal glucose tolerance. It cannot be ruled out, therefore, that this low androgenic OC resulted in worsening of insulin sensitivity. Godsland and colleagues (28) showed that women taking a preparation similar to that used in the current study were more insulin resistant than controls. Watanabe et al. (29) suggested that some OC could impair glucose effectiveness.
In keeping with other studies (7, 8, 9, 10, 11), the plasma leptin concentration correlated positively with BMI. Human (30, 31) and animal (32, 33) data suggest that the increased leptin levels with adiposity are due to augmented ob gene expression and increased leptin production. The mechanism of this increase is not known, but possibly involves enlargement of adipocytes (30, 34). As the leptin level varies in proportion to fat mass, it could conceivably serve as an afferent signal that provides sensory input about the degree of adiposity to the central nervous system. In response, adjustments in food intake and/or energy expenditure would be made to ensure long term body weight stability.
Our data suggest that the sexual dimorphism in leptin is not caused by differences in sex hormones. Leptin levels were similar before and after treatment with OC and were not affected by changes in the androgenic/estrogenic status, as reflected by the decrease in free and total testosterone and the increase in SHBG. Further, leptin levels were not related to total and free testosterone or to SHBG levels before or after treatment with OC. Changes in the androgenic/estrogenic status did not have any affect on the relation between leptin levels and adiposity. This is in agreement with previous data showing similar leptin levels in pre- and postmenopausal women after controlling for adiposity (11). Havel et al. (17) also found that hormone replacement therapy had no effect on leptin levels in postmenopausal women. Furthermore, Haffner et al. (35) showed that leptin levels were not related to total and free testosterone or SHBG in men. Thus, the mechanism of the sexual dimorphism in leptin remains unclear, but could be caused by a sex difference in the hypothalamic regulation of leptin production (36, 37).
In conclusion, therapy with a desogestrel-containing OC caused a mild deterioration of glucose tolerance without a significant change in insulinemia in a group of hyperandrogenic women. Therefore, glucose tolerance should be monitored even when an OC of low androgenicity is used in such women. Changes in the androgenic/estrogenic status did not affect serum leptin concentrations, suggesting that the sexual dimorphism of leptin is not related to sex steroids.
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Footnotes |
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Received February 4, 1997.
Revised March 21, 1997.
Revised May 16, 1997.
Accepted May 20, 1997.
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