Insulin sensitizing agent improves clinical pregnancy rate and insulin resistant parameters in polycystic ovarian syndrome patients with acanthosis nigricans: a randomized controlled study

Objective: To investigate the effect of adding metformin to clomiphene citrate (CC) in polycystic ovarian syndrome (PCOS) patients with acanthosis nigricans (AN) who were previously not responding to CC. Material and Methods: A double blinded randomized controlled trial (NCT02562664) included 66 PCOS women with acanthosis nigricans who were CC resistant (at least 3 months). Day 3 follicle stimulating hormone (FSH) level, fasting insulin, fasting glucose and homeostatic model assessment were used to quantify insulin resistance. Participants were randomly assigned to either group I (CC with placebo tablets) or group II (CC with metformin) for three cycles. Insulin resistance parameters as well as clinical pregnancy rate had been evaluated in both groups. The statistical analysis was done using Chisquare and Fischer exact tests. Results: The demographic data was comparable in both groups, however; there was higher cumulative pregnancy rate after three cycles of stimulation in group II (18/33) (54.5%) in comparison with group I (7/33) (21.1%) (P=0.03). There was a significant improvement in the insulin resistance parameters after three months of combining clomiphene citrate with metformin as compared with CC alone. Conclusion: Adding metformin to CC in clomiphene citrate resistant PCOS patients who have acanthosis nigricans improves the pregnancy rate and insulin resistant parameters. Obstetrics and Gynecology Department, Assiut University, Assiut, Egypt Department of Dermatology, Venereology and Anderology, Assiut University, Assiut, Egypt Clinical Pathology Department, Assiut University, Assiut, Egypt Proceedings in Obstetrics and Gynecology, 2016;6(1): 2 Metformin & clomiphene citrate in PCOS with acanthosis nigricans 2 Introduction Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder, with a prevalence ranging between 6% to 10% based on the National Institutes of Health (NIH) criteria. When the broader Rotterdam criteria are applied; the prevalence reaches as high as 15%. The typical presentation of POCS includes ovarian dysfunction (anovulation), hyperandrogenism (either clinical or biochemical), and the ultrasonographic picture of polycystic ovaries. The etiology of the syndrome is still unclear and the variability in clinical presentation continues to make the clinical and research implications challenging. Insulin resistance is a common finding in obese women with PCOS. The cellular and molecular mechanisms of insulin resistance in PCOS differ from other common insulin-resistant states such as obesity and type 2 diabetes mellitus (DM). PCOS and obesity both have a negative effect on insulin action. Pancreatic b-cell dysfunction is also present in PCOS but may be more related to type 2 DM risk factors such as women having first-degree relative with the DM. Acanthosis nigricans (AN) is a skin disease characterized by velvety, papillomatous, brownish-black and hyperkeratotic plaques. Typically it presents at intertriginous surfaces and the neck. AN is usually associated with obesity, insulin resistance and PSOS. Hyperkeratosis is increased in melanin pigmentation resulting in the dark color of AN. There is a subtle infiltrate composed of lymphocytes, plasma cells, and neutrophils as well as horn pseudocyst formation. Colloidal iron tissue staining often exhibits infiltration of the papillary dermis with glycosaminoglycans such as hyaluronic acid, especially in patients with PCOS. Elevated insulin concentrations result in direct and indirect activation of insulinlike growth factor 1 (IGF-1) receptors on keratinocytes and fibroblasts, leading to its proliferation. Other mediator’s receptors may also contribute, including Epidermal Growth Factor Receptor (EGFR) and Fibroblast Growth Factor Receptor (FGFR). Hyperinsulinemia may also facilitate the development of AN indirectly by increasing the levels of free IGF-1 in the circulation. Insulinlike growth factor 1 binding protein and insulin-like growth factor 2 binding protein are decreased in obese women with hyperinsulinemia leading to an increase in plasma concentrations of free IGF-1. Metformin has a great effect on PCOS patients. This may be due to a reduction of pituitary secretion of LH, a reduction of ovarian secretion of androgens, a reduction of adrenal secretion and finally an increased level of sex hormone binding globulin. Obesity is usually associated with hyperinsulinemia which is responsible for the low responsiveness of PCOS patients to clomiphene citrate. A significant improvement in ovulation and pregnancy rates was reported when adding metformin to clomiphene citrate in clomiphene-resistant PCOS patients. The current study reviews the effect of adding metformin to clomiphene citrate in PCOS patients with acanthosis nigricans (AN) who were previously did Proceedings in Obstetrics and Gynecology, 2016;6(1): 2 Metformin & clomiphene citrate in PCOS with acanthosis nigricans 3 not respond to CC alone. We hypothesized that adding metformin to this special group of women, AN patients with insulin resistance, may be beneficial for them including an improvement in pregnancy rate and hyperinsulinemia parameters. Materials and Methods The current study is a clinically registered double blinded, parallel, RCT (NCT02562664) compassing the effect of adding metformin to CC in PCOS patients who had acanthosis nigricans. The ethical review board of the Faculty of Medicine of the Assiut University approved the study. The participants were recruited from the Outpatient Infertility Clinic of the Woman’s Health Hospital. It was carried out in the period between the first of August 2013 and the first of November 2014. This trial was designed and reported according to the revised recommendation of ClinicalTrials.gov for improving the quality of reporting RCTs. Eligible participants All participants who presented to the above clinic with acanthosis nigricans associated PCOS and previously not responding to CC were recruited in the study. The patient was considered eligible if she was under age 40 year, fulfilled at least 2 out of the three criteria of Rotterdam consensus 2003 and had AN. All participants had unsatisfactory ovulation after at least 3 months of CC induction. We excluded women with any contraindications to metformin such as liver disease, heart or respiratory failure, alcohol abuse, and kidney disease. All couples signed an informed consent to participate in the study. Randomization Randomization was done using a computer-generated random table. The participants who consented were randomly assigned to receive either CC with placebo or CC with metformin. Allocation concealment was done using serially numbered closed opaque envelopes. Each envelope was labeled with a serial number and had a card showing the intervention type inside. Allocation was never changed after opening the envelopes (study flow chart, Fig. 1).