Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome
Alessandro D Genazzani, Cesare Battaglia , Ombretta Gamba
Barbara Malavasi , Claudia Strucchi , Francesca Tortolani
To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary (PCOS) patients.
Design
Controlled clinical study.
Setting
PCOS patients in a clinical research environment.
PATIENT(S): Twenty nonobese PCOS patients were enrolled after informed consent.
INTERVENTION(S): All patients underwent hormonal evaluations and a pulsatility study (sampling every 10 minutes for 4 hours) before and at the sixth month of therapy (metformin, 500 mg, p.o. b.i.d.). Ultrasound examinations and Ferriman-Gallwey scoring were also performed.
MAIN OUTCOME MEASURE(S): Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17-hydroxy-progesterone (17-OHP), and testosterone (T), glucose, insulin, and C-peptide concentrations.
RESULT(S): After 6 months of metformin administration, the plasma LH, 17-OHP, A, and T levels and LH/FSH ratio were significantly reduced. Insulin sensitivity, expressed as the glucose-to-insulin ratio, was significantly improved under glucose load after 6 months of treatment. Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women. The ovarian volume and Ferriman-Gallwey scores also were significantly reduced.
CONCLUSION(S): Metformin administration improves reproductive axis functioning in hyperandrogenic nonobese PCOS patients. By acting on the ovary and restoring normal ovarian activity, metformin positively modulates the reproductive axis (namely GnRH-LH episodic release).
PMID 14711553 14711553 DOI 10.1016/j.fertnstert.2003.05.020 10.1016/j.fertnstert.2003.05.020
Cite this article
Genazzani, A. D., Battaglia, C., Malavasi, B., Strucchi, C., Tortolani, F., & Gamba, O. (2004). Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertility and sterility, 81(1), 114-119. https://doi.org/10.1016/j.fertnstert.2003.05.020
Genazzani AD, Battaglia C, Malavasi B, Strucchi C, Tortolani F, Gamba O. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril. 2004;81(1):114-119. doi:10.1016/j.fertnstert.2003.05.020
Genazzani, Alessandro D., et al. "Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome." Fertility and sterility, vol. 81, no. 1, 2004, pp. 114-119.
Polycystic ovary syndrome (PCOS) is a common disorder affecting women of reproductive age. Its cardinal features are hyperandrogenism, chronic anovulation, and infertility. Some of the most important pathogenic associations of PCOS are insulin resistance and compensatory hyperinsulinemia (1, 2, 3). The hyperinsulinemia in turn stimulates ovarian androgen production. Several clinical studies have demonstrated that a reduction in the insulin level results in decreased ovarian androgen production (4, 5, 6).
Metformin is a biguanide used extensively in type 2 diabetes. It inhibits hepatic gluconeogenesis and increases peripheral insulin sensitivity and glucose uptake but does not cause hypoglycemia (6, 7, 8). The correction of the hyperinsulinemia by metformin in PCOS patients is accompanied by normalization of the elevated serum LH and ovarian androgen levels, leading to resumption of spontaneous ovulatory cycles, or responsiveness to ovulation induction by clomiphene citrate (CC) (1, 4, 5, 6, 8, 9). Clinical use of this agent for ovulation induction in CC-resistant PCOS patients has increased with little knowledge of the possible effect on early embryo development. We sought to assess whether metformin was embryotoxic using a mouse embryo model.
During controlled clinical trials, plasma metformin levels do not exceed 5 μg/mL, even at maximum doses (10). Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride; Sigma, St. Louis, MO) was dissolved in human tubal fluid (HTF) media (Irvine Scientific, Santa Ana, CA) to give working concentrations of 5, 25, and 100 μg. The culture dishes containing 1 mL of media at each concentration were incubated for overnight equilibration at 37°C and 5% CO2.
Thawed two-cell mouse embryos (Embryotech, Wilmington, MA) were pooled and randomly distributed into the culture dishes containing the various concentrations of metformin. The control consisted of HTF media alone (group 1). Groups 2, 3, and 4 were supplemented with metformin (5, 25, and 100 μg/mL). There were 40 embryos in each group. The embryos were incubated in an atmosphere of 5% CO2 at 37°C for 72 hours. The blastocyst development rate (BDR) was then calculated by dividing the number of embryos reaching the blastocyst stage by the total number of embryos cultured.
The relationship between BDR and concentration was assessed with repeated measures logistic regression using generalized estimated equation (GEE) methodology with a compound symmetry correlation structure. The sample size was sufficient to detect whether a specific concentration reduced the odds of development by a factor of 2.5. Statistical significance was assessed using two-tailed P<.05. Statistical computations were performed with SAS version 8.1 (SAS Institute Inc, Cary, NC). . .
PCOSMetforminClomiphene CitrateCombined Medical Therapy
To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. Randomized, double-blind, placebo-controlled trial. Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.
PCOSMetforminMiscarriage PreventionRecurrent Pregnancy Loss
To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS). Prospective pilot study. Outpatient. PATIENT(S): Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin. INTERVENTION(S): Metformin, 1.5-2.55 g/day, throughout pregnancy. MAIN OUTCOME MEASURE(S): Rates of first-trimester spontaneous abortion and teratogenicity. RESULT(S): Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04). CONCLUSION(S): Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.
Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin - owing to its metabolic, endocrine, vascular and anti-inflammatory effects - may reduce the incidence of first-trimester abortion in PCOS women. A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000-2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group. Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42). Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.