Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome

Objective

To evaluate the effect of a short-course pretreatment with metformin on hyperandrogenism, insulin resistance, cervical scores, and pregnancy rates in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS).

Methods

Thirty-seven women with CC-resistant PCOS were randomly assigned to be pretreated with 500 mg of metformin or placebo 3 times per day for 2 cycles, and 100 mg of CC was given on days 5 through 9 of the second cycle in both groups. Luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrostendione sulfate (DHEAS), total testosterone (T), glucose, and insulin levels were measured at baseline and after the first cycle, as well as body mass index (BMI), cervical score, and pregnancy rate.

Results

After 1 cycle, BMI, total T level, and percentage of participants with insulin resistance were significantly decreased in the metformin group, without any significant decrease in LH, FSH, and DHEAS levels; and in the second cycle, CC treatment resulted in a higher ovulation rate and a thicker endometrium in the metformin group. The pregnancy rate and cervical scores were also higher in that group.

Conclusion

The short-course pretreatment with metformin decreased hyperandrogenism and insulin resistance and improved cervical sores, ovulation rate, and pregnancy rate among women with CC-resistant PCOS.     

Outlook: metformin use in infertile patients with polycystic ovary syndrome: an evidence-based overview

Metformin is an insulin sensitizer currently used for treating type-2 diabetes mellitus and recently administered for inducing ovulatory menstrual cycles in oligo-amenorrhoeic patients with polycystic ovary syndrome (PCOS). The aim of the present review is to describe the efficacy of metformin as an ovulation inducer on the basis of the most important evidence-based medicine supported data, including meta-analyses and randomized controlled trials. Specifically, we reviewed the uses of metformin as first- and second-step treatment for PCOS related anovulatory infertility and as co-treatment in infertile PCOS patients who receive gonadotrophins. To date, there is evidence that metformin is effective for restoring normal menstrual cycles in anovulatory PCOS patients, and that it is more effective and cheaper than laparoscopic ovarian drilling as the second therapeutic step in PCOS patients previously defined as resistant to clomiphene citrate. Co-administration of metformin in PCOS patients treated with gonadotrophin improves the mono-ovulation rate and can prevent ovarian hyperstimulation syndrome in patients treated with gonadotrophins for IVF cycles.     

Pregnancy considerations in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are subfecund, and while anovulatory infertility is most likely the primary cause, other factors may contribute. Recent data suggest that women with PCOS are at increased risk for preterm labor, preeclampsia, and gestational diabetes, though the evidence for increased miscarriage rates is less certain. There is no evidence-based schema for achieving pregnancy in women with PCOS, though lifestyle modification, clomiphene citrate, and metformin are the current front line therapies. There are few data to support treatment during pregnancy with metformin in women with PCOS to prevent pregnancy loss or pregnancy complications.     

Pregnancy complications in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. There is an increasing body of evidence indicating that PCOS may have significant implications for pregnancy outcomes and long-term health of a woman and her offspring. Whether or not PCOS itself or the symptoms that coincide with PCOS, like obesity and fertility treatment, are responsible for these increased risks is a continuing matter of debate. Miscarriage rates among women with PCOS are believed to be increased compared with normal fertile women, although supporting evidence is limited. Pregnant women with PCOS experience a higher incidence of perinatal morbidity from gestational diabetes, pregnancy-induced hypertension, and preeclampsia. Their babies are at an increased risk of neonatal complications, such as preterm birth and admission at a neonatal intensive care unit. Pre-pregnancy, antenatal, and intrapartum care should be aimed at reducing these risks. The use of insulin sensitizing drugs to decrease hyperinsulinemic insulin resistance has been proposed during pregnancy to reduce the risk of developing preeclampsia or gestational diabetes. Although metformin appears to be safe, there are too few data from prospective, randomized controlled trials to support treatment during pregnancy.     

The use of metformin in women with polycystic ovary syndrome: an updated review

Journal of Assisted Reproduction and Genetics - Polycystic ovary syndrome (PCOS) is a major cause of female infertility, being present in up to 20% of women of childbearing age. Insulin resistance...     

Placental passage of metformin in women with polycystic ovary syndrome

Metformin passes the placenta. Fetal serum levels are comparable with maternal values.     

Prediction of the effect of metformin treatment in patients with polycystic ovary syndrome

The objective of the study was to find predictors of a successful therapy with metformin in polycystic ovary syndrome. 24 women with polycystic ovary syndrome were examined (oral glucose tolerance test and gonadotropin-releasing hormone analogue test) before and after a 6-month course of metformin (1 g/day). In 58% of the women, a significant improvement in the menstrual cycle pattern was observed. After a treatment course, a significant reduction in gonadotropin-releasing hormone analogue stimulated levels of testosterone (p < 0.05), free testosterone index (p < 0.01), luteinizing hormone (p < 0.05), and estradiol (p < 0.01) was found. The best prediction of the improvement in menstrual cyclicity after metformin was achieved with a combination of basal values of 17-hydroxyprogesterone, testosterone, sex hormone binding globulin, and androstenedione. These variables correctly classified 86.7% of the responders. The best predictor of changes in the index of free testosterone after metformin treatment was the combination of estradiol and androstenedione in the gonadotropin-releasing hormone analogue test, with basal testosterone correctly classifying 91.7% of the subjects.     

The effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome

Objective  To evaluate the effects of metformin on the ovarian stromal blood perfusion in the patients with polycystic ovary syndrome (PCOS). Methods  Twenty-five women with PCOS who underwent a Doppler examination of the ovarian stroma was evaluated; hormonal, anthropometric, and biochemical parameters of patients were determined. After the patients were treated with 850 mg metformin twice a day for 6 months, the same parameters were evaluated in the same patients. Results  After metformin treatment, although pulsatility index (PI) was increased from 1.80 ± 1.23, 1.84 ± 1.28 to 2.20 ± 1.10, 2.19 ± 0.83 in the right and left ovary, respectively, and resistance index was increased from 0.84 ± 0.25, 0.83 ± 0.23 to 1.16 ± 0.37, 1.10 ± 0.26 in the right and left ovary respectively (P < 0.05), peak systolic velocity (PSV) was decreased from 12.30 ± 1.72, 12.34 ± 1.55 to 10.25 ± 0.97, 10.53 ± 1.33 in the right and left ovary respectively (P < 0.05). PI and RI did not show any difference between the homeostatic model assessment insulin resistance index (HOMA-IR) ≥ 2.38 and HOMA-IR < 2.38 groups before and after metformin treatment (P > 0.05). However, PSV was decreased significantly from 13.05 ± 1.35, 12.82 ± 2.02 to 11.03 ± 0.71, 10.25 ± 0.42 in HOMA-IR ≥ 2.38 group in the right and left ovary, respectively, and PSV was decreased from 11.50 ± 2.67, 11.28 ± 0.26 to 9.10 ± 0.58, 9.28 ± 0.25 in HOMA-IR < 2.38 group in the right and left ovary, respectively, before and after metformin treatment (P < 0.05). PSV for both ovaries were positively correlated with HOMA scores before and after metformin treatment [(r = 0.713, P = 0.000; r = 0.617, P = 0.04 and r = 0.635, P= 0.03; r = 0.483, P = 0.031 respectively]. Conclusion  Metformin treatment affected ovarian stromal blood flow in PCOS patients.     

Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin

OBJECTIVE: To determine the clinical, hormonal, and biochemical effects of metformin therapy in obese and nonobese patients with polycystic ovary syndrome (PCOS). DESIGN: Controlled clinical study. SETTING: Department of Gynecology of Federal University of S?o Paulo, S?o Paulo, Brazil. PATIENT(S): Twenty-nine patients with PCOS. INTERVENTION(S): Patients were treated with 500 mg of p.o. metformin t.i.d. for 6 months. MAIN OUTCOME MEASURE(S): Clinical data as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, leptin, GH, lipids, insulin, and glucose levels were assessed before and after treatment. RESULT(S): In the metformin group of nonobese patients, the mean fasting serum insulin concentration decreased from a pretreatment value of 12.1 +/- 2.4 to 6.3 +/- 0.6 microU/mL after treatment, and the area under the curve of insulin decreased from 5,189.1 +/- 517.4 to 3,035.6 +/- 208.9 microU/mL per minute. Also in the metformin group of nonobese patients, the mean basal serum total testosterone, free testosterone, and androstenedione concentrations decreased by 38%, 58%, and 30%, respectively. In the obese patients treated with metformin, only free testosterone showed a statistically significant decrease (1.7 +/- 0.2). CONCLUSION(S): Our data suggest that nonobese patients respond better than obese patients to a 1.5 g/day metformin regimen.     

Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance

Polycystic ovary syndrome (PCOS) affects 5–10% of women at reproductive age, and is the most common reason for hyperandrogenism and chronic anovulation. Some patients with PCOS are insulin-resistant. Also, lowered sex hormone-binding globulin (SHBG) concentration is usually observed. As a consequence, the amount of free and biologically active androgens increases. This implies that, by improving insulin and carbohydrate metabolism, metformin administration in PCOS patients could indirectly contribute to increase SHBG concentration. The aim of the present study was to assess the effects of metformin treatment in PCOS patients both with and without insulin resistance. Thirty-six patients completed treatment. Body mass index (BMI) was considerably reduced after therapy. Statistically significant decreases were noted in luteinizing hormone (LH) and fasting insulin concentrations and the free androgen index (FAI), and significant increases in follicle-stimulating hormone (FSH)/LH ratio and SHBG concentration. In the insulin-resistant group, BMI and fasting insulin concentrations were reduced considerably after treatment, and SHBG increased slightly. In the group of patients without insulin resistance, BMI, LH and FAI showed significant reductions, and FSH/LH and SHBG considerable increases. Considering the favorable effects of metformin treatment in PCOS patients both with insulin resistance and without it, it is purposeful to use this drug in both groups of women.     

Plasma cytokines in obese women with polycystic ovary syndrome,before and after metformin treatment

Objectives. Most research confirms that metformin therapy has a positive influence on cardiovascular risk factors (CVRF) such as dyslipidemia, insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS). The aims of the present study were to establish other CVRF, such as plasma adiponectin, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and C-reactive protein (CRP) levels, in obese premenopausal women with PCOS and to investigate the effect of metformin treatment on these factors.

Materials and methods. The study group consisted of 29 PCOS woman with body mass index (BMI) >25 kg/m². They were treated over 6 months with 500 mg metformin twice daily. Twenty-nine healthy individuals matched for age and BMI were controls. Adiponectin, TNFα, IL-6 and CRP levels were examined in all PCOS (before and after treatment) and control women.

Results. In the PCOS group significantly lower plasma adiponectin and TNFα levels were observed, whereas there were no differences in plasma IL-6 and CRP levels between PCOS and control groups. Plasma adiponectin increased significantly after metformin treatment, but levels of inflammatory factors did not change.     

Assessment of ovarian stromal blood flow after metformin treatment in women with polycystic ovary syndrome

Purpose

To authenticate the effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS) using 3-dimensional (3D) power Doppler.

Methods

The current case–control study was conducted at Ain Shams University Maternity Hospital. A total of 60 women diagnosed to have PCOS were included as group 1. Another 40 fertile women who were recruited from outpatient clinic for contraception without PCOS with regular menstrual cycles were included as control group (group 2). All women underwent 3D power Doppler evaluations of ovarian stroma. Anthropometric, hormonal and biochemical criteria were also measured. All women in group 1 received metformin hydrochloride 500 mg tablets, which were started in a step-up maneuver every 5 days, from one to three tablets per day. The same parameters were also measured after the 3 months duration of treatment.

Results

A total of 100 women were finally analyzed. At the start of the study, there were no statistically significant differences between group 1 and group 2 and regarding age and body mass index, but the waist/hip ratio and Ferriman–Gallwey scoring were statistically different between the 2 groups. The mean ovarian volume and stromal volume were significantly larger in group 1. 3D power Doppler indices [the vascularization index (VI), the flow index (FI) and the (VFI) vascularization-flow index] were much higher in group 1 than in group 2 (1.38 ± 0.76 vs. 4.69 ± 1.37, P < 0.05, 26.59 ± 2.26 vs. 32.66 ± 4.37, P < 0.05, and 0.76 ± 0.39 vs. 1.54 ± 0.69, P < 0.05, respectively). After 3 months of using metformin in normal weight PCO women, there was a statistically significant improvement in group 1 regarding, hirsutism, most of hormonal measurements. Also 3 months metformin treatment significantly reduce VI, FI and VFI (4.69 ± 1.37 vs. 2.95 ± 1.52, P < 0.05, 32.66 ± 4.37 vs. 29.48 ± 4.98, P < 0.05 and 1.54 ± 0.69 vs. 1.21 ± 0.7 P < 0.05, respectively). Using Receiver operator characteristic, there was no cut-off value of VI, FI or VFI to detect ovulation in women of PCOS.

Conclusions

Metformin seems to have a beneficial effect in normal weight PCO women via correcting ovarian stromal blood flow and hormonal profiles.     

Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance.

Polycystic ovary syndrome (PCOS) affects 5-10% of women at reproductive age, and is the most common reason for hyperandrogenism and chronic anovulation. Some patients with PCOS are insulin-resistant. Also, lowered sex hormone-binding globulin (SHBG) concentration is usually observed. As a consequence, the amount of free and biologically active androgens increases. This implies that, by improving insulin and carbohydrate metabolism, metformin administration in PCOS patients could indirectly contribute to increase SHBG concentration. The aim of the present study was to assess the effects of metformin treatment in PCOS patients both with and without insulin resistance. Thirty-six patients completed treatment. Body mass index (BMI) was considerably reduced after therapy. Statistically significant decreases were noted in luteinizing hormone (LH) and fasting insulin concentrations and the free androgen index (FAI), and significant increases in follicle-stimulating hormone (FSH)/LH ratio and SHBG concentration. In the insulin-resistant group, BMI and fasting insulin concentrations were reduced considerably after treatment, and SHBG increased slightly. In the group of patients without insulin resistance, BMI, LH and FAI showed significant reductions, and FSH/LH and SHBG considerable increases. Considering the favorable effects of metformin treatment in PCOS patients both with insulin resistance and without it, it is purposeful to use this drug in both groups of women.     

Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome

Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS).

Design: Prospective trial.

Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy.

Patient(s): Fourteen women with PCOS.

Intervention(s): Blood samples were obtained before (−15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 μg). Metformin then was given at a dosage of 500 mg three times a day for 30–32 days, at which time the pretreatment study was repeated.

Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin.

Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17-hydroxyprogesterone to progesterone, which indicates 17-hydroxylase activity, and the ratio of androstenedione to 17-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes.

Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.     

Effects of low-dose metformin in Japanese women with clomiphene-resistant polycystic ovary syndrome

Background and Aims  The aim of the present prospective observational study was to evaluate the effects of low-dose, short-term metformin, in combination with domiphene (CC), in CC-resistant infertile Japanese women with polycystic ovary syndrome (PCOS). Methods  Metformin therapy was administered orally (one 250 mg tablet, twice daily) to 15 CC-resistant infertile patients with PCOS, beginning on the third day of progestin-induced withdrawal bleeding, and was continued for 14 days in the first cycle. In the event of anovulation, 100 mg/day of CC was given during subsequent cycles on days 5–9, in addition to the aforementioned dose of metformin. Hormonal and metabolic parameters were measured on the second or third days of the first cycle and also the fourth cycle, following an overnight fast. Results  None of the 15 women successfully ovulated during the first cycle with metformin treatment alone. After two subsequent cycles with the combination of CC and metformin, ovulation was confirmed in 17 of 29 cycles (61%) and in 13 of 15 patients (87%). Two women became pregnant within 2 months of therapy (13%). There were no cases of ovarian hyperstimulation syndrome. Following three cycles of metformin therapy, a slight reduction in serum levels of luteinizing hormone (LH), free testosterone, androstenedione, dehydroepiandrosterone sulfate, hemoglobin Alc and total cholesterol was seen, while serum LH/follide-stimulating hormone ratio and serum level of low-density lipoprotein cholesterol were significantly decreased. Although there were no significant differences between the responder (n = 11) and non-responder (n = 2) groups at baseline, the levels of plasma fasting insulin was significantly higher and fasting glucose/insulin ratio was significantly lower in the non-responder group compared with the responder group after three cycles. Conclusion  Low-dose, short-term metformin, combined with CC, can improve ovulation rates in CC-resistant infertile Japanese women with PCOS.     

Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome

The purpose of this retrospective study was to compare the frequency of menstrual cyclicity between two groups of patients with polycystic ovary syndrome: women who were followed while on metformin for 3-6 months and those who were followed for >6 months. The results showed that metformin is highly effective in normalizing menstrual cyclicity in women with polycystic ovary syndrome (the overall response rate was 69%, with 88% of responders achieving normal cyclicity), especially with a treatment duration of 6 months or longer (the response rate was 40% higher for women who were treated with metformin for >6 months vs. 3-6 months, 77% vs. 55%).