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The Effects of Short-Term Medroxyprogesterone Acetate and Micronized Progesterone on Glucose Metabolism and Lipid Profiles in Patients with Polycystic Ovary Syndrome: A Prospective Randomized Study

Baskent University Faculty of Medicine, Department of Obstetrics and Gynecology (T.B., H.B.Z., E.T., E.B.K., B.H.), and Endocrinology and Metabolism Division (A.G.), 01170 Adana, Turkey

Address all correspondence and requests for reprints to: Tayfun Bagis, M.D., Assistant Professor, Obstetrics and Gynecology Department, Guzelyali Mahalle, Adnan Kahveci Bulvari, Bilgin Apartman, Kat:6 No. 11, Seyhan-Adana, Turkey. E-mail: bagistayfun{at}hotmail.com.

Abstract

In this prospective, randomized study we determined 10-d effects of medroxyprogesterone acetate (MPA) and micronized progesterone (MP) either orally or per vaginally on hormonal parameters, glucose metabolism and lipid profiles in patients with polycystic ovary syndrome (PCOS). Twenty-eight consecutive women with PCOS were randomized to receive 10-d MPA, oral MP, or vaginal MP. Hormonal parameters, insulin levels, oral glucose tolerance test, lipid profiles, and homeostasis model assessment and quantitative insulin sensitivity check indexes were assessed in all groups before and after treatment. Oral MPA and oral MP decreased LH (15.64 ± 13.17 to 7.27 ± 4.35 IU/liter, P = 0.028, and 18.85 ± 11.86 to 10.49 ± 6.48 IU/liter, P = 0.009, respectively) and total testosterone (5.85 ± 2.80 to 3.40 ± 1.72 nmol/liter, P = 0.013, and 5.29 ± 2.98 to 3.43 ± 2.10 nmol/liter, P = 0.037, respectively) levels. Hormonal parameters did not change with vaginal MP. Basal insulin (123.42 ± 97.50 to 87.38 ± 48.68 pmol/liter; P = 0.021) and homeostasis model assessment levels decreased, and quantitative insulin sensitivity check index increased significantly in the oral MPA group. Low density lipoprotein cholesterol and lipoprotein (a) levels decreased only in the MPA group. In conclusion, short-term oral MP and especially oral MPA might ameliorate insulin sensitivity in patients with PCOS. Vaginal MP has no effect on glucose metabolism and lipid profiles. LH, total testosterone, and insulin levels may be affected from the short-term progesterone treatment.

POLYCYSTIC OVARY SYNDROME (PCOS) is characterized by hyperandrogenism, oligo-amenorrhea, obesity, infertility, and typical ultrasonographic findings. It is the most common endocrinopathy among reproductive-aged women. After the first report of Burghen et al. (1) in 1980, the association between hyperandrogenemia and insulin resistance in PCOS had been studied by many investigators in the last decade (2, 3, 4, 5, 6, 7). PCOS patients develop gestational diabetes mellitus (DM) during their pregnancies more frequently, and it is reported that type 2 diabetic patients had an increased rate of PCOS diagnosis in their history compared with controls (8, 9).

Because PCOS is considered to be a systemic metabolic endocrinopathy closely associated with insulin resistance, more attention is required for the evaluation and treatment of this situation. Oral contraceptive pills or medroxyprogesterone acetate (MPA) are commonly used drugs for the management of conditions associated with PCOS, such as hirsutism and oligomenorrhea. Androgenic properties of MPA and other progestins in the oral contraceptive cells may decrease insulin sensitivity (10, 11, 12). Therefore, long-term use of these drugs may play a contributory role in the development of DM in PCOS patients.

The hyperinsulinemic euglycemic glucose clamp and the iv glucose tolerance test are standard methods for quantifying insulin sensitivity in research, but they are impractical in clinical practice and are difficult to perform (13, 14). Homeostasis model assessment (HOMA) formula was developed in 1985 and widely used to predict insulin sensitivity (15). Katz et al. (16) reported a new quantitative insulin sensitivity check index (QUICKI) for assessment of insulin sensitivity, which correlated better than HOMA with minimal model and clamp methods.

As it has been demonstrated that MPA may attenuate beneficial effects of estrogens on insulin sensitivity by way of delayed insulin clearance (17) and may have deleterious effects on lipid profiles in healthy postmenopausal women (18), we aimed to evaluate the effects of 10-d MPA orally (10 mg twice a day), which is our common practice, on insulin sensitivity, lipid profile, and hormonal parameters and compare the results with micronized progesterone (MP) either taken orally or placed vaginally in patients with PCOS.

Materials and Methods

This randomized, prospective study included 28 reproductive age patients with PCOS who presented to Baskent University Obstetrics and Gynecology Department and Endocrinology and Metabolism Clinics. The study was approved by the Ethical Committee of Baskent University. Each patient gave her written informed consent to participate. All patients with oligomenorrhea or amenorrhea who also had at least one of the following evidence of hyperandrogenism—a hirsutism score of more than 7, according to Ferriman and Gallway (3 of 10 patients in oral MPA group, 4 of 10 patients in oral MP group, and 2 of 8 patients in vaginal MP group); and/or an elevated (>3.15 nmol/liter) serum testosterone level (9 of 10 patients in oral MPA group, 7 of 10 patients in oral MP and 6 of 8 patients in vaginal MP group)—were diagnosed as PCOS, after all the other causes of hyperandrogenism were excluded. Subjects treated with hormonal medications within 3 months were excluded from the study. The patients were randomized into three groups. The first group (n = 10) received MPA (10 mg/d) (Farlutal, Deva, Turkey) orally for 10 d, the second group (n = 10) received MP (300 mg/d) (Progestan, Kocak, Turkey) orally for 10 d, and the third group (n = 8) received MP (600 mg/d) (Progestan) per vaginal for 10 d. Spontaneous luteal phase was excluded by serum progesterone measurements before blood samples were obtained (serum progesterone level < 6 nmol/liter). Hormonal parameters [FSH, LH, estradiol (E₂), total testosterone, dehydroepyandrosterone sulfate (DHEAS) and prolactin (PRL)], lipid profile [total cholesterol, high density lipoprotein cholesterol (HDL cholesterol), low density lipoprotein cholesterol (LDL cholesterol), very low density lipoprotein cholesterol (VLDL cholesterol), triglyceride, lipoprotein (Lp) (a), Apolipoprotein (Apo) A1, and Apo B], and basal insulin levels were assessed, and 75 g oral glucose tolerance test was performed, before and after progesterone treatment in all patients. First blood samples were obtained before progesterone administration, and second samples were obtained on the first day of the progesterone-induced menstruation. The time interval between two samples was 12–14 d.

Blood samples were drawn in the morning, after each patient had been fasting for at least 8 h. Levels of plasma glucose, total cholesterol, HDL cholesterol, and triglycerides were determined by the calorimetric method using a Cobas Mira Plus autoanalyzer (Roche Diagnostics, Mannheim, Germany). LDL cholesterol and VLDL cholesterol levels were calculated by the Friedwald formula. Apo A1, Apo B, and Lp (a) were quantitated by the immunoturbidimetric method in a Roche/Hitachi 912 autoanalyzer. Insulin, LH, FSH, E₂, and PRL were measured in an AXSYM autoanalyzer (Abbott Laboratories, Abbott Park, IL) using the microparticle enzyme immunoassay method. Total testosterone and DHEAS were measured in an Immulite One autoanalyzer (Bio-Diagnostic Products Corp., Los Angeles, CA) using the chemiluminescent method. Insulin sensitivity was calculated using the HOMA [formula: fasting glucose (mmol/liter) x fasting insulin (µU/ml)/22.5] and QUICKI [formula: 1/(log fasting insulin (µu/ml) + log fasting glucose (mg/dl)] indexes.

Data are expressed as means ± SD. ANOVA test was used to analyze baseline differences in the treatment groups. The difference between the two groups was analyzed by independent Student’s t test. Homogeneity of variances were calculated by Levene’s test and Lilliefors significance correction test. Post hoc analysis was performed by Bonferroni test. Difference between the parameters, before and after the treatment, of the groups were tested by Wilcoxon Rank Test, because the number of subjects in the treatment groups were less than 30 and Lilliefors significance correction test was significant. Correlations between groups were assessed by Pearson’s correlation coefficient and regression analyses. A value of P less than 0.05 was considered statistically significant. Data were analyzed using the SPSS, Inc. for Windows (version 9.05; SPSS, Inc., Chicago, IL).

Results

Baseline characteristics of the patients are given in Table 1. There was a small but statistically significant difference between ages of the second and third groups as determined by independent sample test (P = 0.039). There were no statistically significant differences according to body mass index (BMI), waist/hip ratio, baseline hormonal parameters (FSH, LH, E₂, total testosterone, PRL, basal insulin, and DHEAS), and lipid profiles (total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglyceride, Lp(a), Apo A1, and Apo B) between the groups (Table 2).

Only MPA reduced mean basal insulin level (8 of 10 patients) from 123.42 ± 97.50 to 87.38 ± 48.68 pmol/liter (P = 0.021), HOMA index (8 of 10 patients) from 4.87 ± 5.17 to 2.85 ± 2.0 (P = 0.021), LDL cholesterol (8 of 10 patients) from 2.80 ± 0.59 to 2.47 ± 0.42 mmol/liter (P = 0.038) and Lp (a) (5 of 10 patients) from 206.60 ± 180.60 to 165 ± 150.80 mg/liter (P = 0.043) levels, and increased the QUICKI index (8 of 10 patients) from 0.32 ± 0.03 to 0.34 ± 0.03 (P = 0.021) significantly. Oral MP treatment also reduced basal insulin level, HOMA index, total cholesterol, HDL cholesterol, LDL cholesterol and VLDL cholesterol levels and increased QUICKI index, but only drop in total cholesterol level in 8 of 10 patients (4.05 ± 0.59 to 3.73 ± 0.64 mmol/liter; (P = 0.021) was statistically significant (Table 3).

The role of progesterone on the pathogenesis of PCOS is not known. Fiad et al. (19) had shown that 5-d MPA treatment reduced integrated LH levels, LH response to GnRH, LH/FSH ratio and androstenedione levels in PCOS patients. They postulated that progesterone deficiency might play a faciliatory role in the development of hypothalamic-pituitary abnormalities in PCOS patients. It was also confirmed by Anttila et al. (20) that serum levels of testosterone, androstenodione, and LH levels decrease with 1 wk MPA treatment.

In recent years, the association between hyperinsulinemia, insulin resistance, and PCOS had been demonstrated clearly (2, 3, 4, 5, 6, 7) and selection of progesterone type had become an important issue in the management of PCOS patients. The effect of MPA on insulin resistance had been evaluated in surgically postmenopausal cynomolgus monkeys (Macaca fuscicularis) (10). In these postmenopausal monkeys, MPA alone or in combination with estrogen decreased insulin sensitivity significantly when compared with control group and estrogen alone group. Furthermore, it was also demonstrated by the same authors (21) that a potent progestin, Nomegestrol, which lacks androgenic activity, and estrogen combination decreased insulin sensitivity less than the estrogen-MPA combination. In contrast to these findings, in the Postmenopausal Estrogen/Progestin Interventions trial it was found that the impact on insulin and glucose levels of adding three progestin regimens (MPA at 2.5 mg daily, MPA at 10 mg on d 1–12, and MP at 200 mg on d 1–12) to estrogen therapy was small (18).

It is clearly possible to expect that MPA treatment could deteriorate insulin sensitivity in PCOS patients, and insulin resistance is a risk factor for the development of type 2 DM and cardiovascular disease, and is associated with dyslipidemia, especially hypertriglyceridemia (22, 23, 24). But surprisingly, we found that short-term MPA treatment improved insulin sensitivity as determined by decreased HOMA and increased QUICKI indexes. In the recent report of Escobar-Morrele et al. (25), it was revealed that treatment of hirsutism with ethynyl E₂-desogestrel contraceptive pill has a beneficial effect on lipid profile and also improves insulin sensitivity.

In our study, statistical analyses revealed that there was a correlation between insulin resistance and total testosterone variances in the MPA group. LH, testosterone, insulin, and HOMA levels also decreased in oral MP group, but decreases in insulin and HOMA levels, and increase in QUICKI index did not reach to statistical significance. Reason of this finding may be due to the small number of our study group. Vaginal application of MP seems to have null effect on insulin sensitivity. This might be explained by way of the uterine first-pass effect and the low progesterone level in circulation (26). LDL cholesterol and Lp (a) levels decreased after MPA treatment (P = 0.03 and P = 0.04, respectively). It is also well known that reduction of atherogenic lipoprotein, LDL cholesterol, and independent risk factor, Lp (a), lowers the risk of cardiovascular disease.

In conclusion, we suggest that 10-d oral MPA and oral and vaginal MP treatments do not have any adverse effect on glucose and lipid metabolism in PCOS patients. In addition, oral MP and especially oral MPA treatments might ameliorate insulin sensitivity and oral MPA may decrease LDL and Lp(a) levels. So, according to the results of our study, short-term oral MP and oral MPA may be used for the management of PCOS. It is also important to note that, because short-term oral progesterone treatment may affect LH, total testosterone and insulin levels, measurement of these parameters for the evaluation of hormonal status should not be done shortly after oral progesterone treatment. The effects of long-term cyclic progesterone treatment should be clarified with further studies in PCOS patients.

Acknowledgments

Footnotes

Abbreviations: Apo, Apolipoprotein; BMI, body mass index; DHEAS, dehydroepyandrosterone sulfate; DM, diabetes mellitus; E₂, estradiol; HDL, high density lipoprotein; HOMA, homeostasis model assessment; LDL, low density lipoprotein; Lp, lipoprotein; MP, micronized progesterone; MPA, medroxyprogesterone acetate; PCOS, polycystic ovary syndrome; PRL, prolactin; QUICKI, quantitative insulin sensitivity check; VLDL, very low density lipoprotein.

Received February 25, 2002.

Accepted July 18, 2002.

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