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      Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice

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          Abstract

          Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high-complexity reproduction treatment ( in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety.

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          A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome.

          C Boomsma, M. Eijkemans, E Hughes … (2015)
          Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70-5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98-6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95-6.17) and preterm birth (OR 1.75; 95% CI: 1.16-2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25-4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03-9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.
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            Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.

            Heping Zhang, Rebecca Usadi, Peter Snyder … (2014)
            Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
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              Gonadotrophin-releasing hormone antagonists for assisted reproductive technology.

              Frank J Broekmans, Abdulhadi H Al-Marri, Janine Smit … (2010)
              Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-estrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotropin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimes have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006. To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycle We performed electronic searches of major databases, for example Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE (from 1987 to April 2010); and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). A date limited search of Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL from April 2010 to April 2011 was run. Eighteen studies have been entered into the Classification pending references section of this update. These studies will be appraised for inclusion or exclusion in the next update of this review, due April 2012. Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different agonist versus antagonist protocols in women undergoing IVF or ICSI. Two review authors independently assessed trial risk of bias and extracted data. If relevant data were missing or unclear, the authors were contacted for clarification. Forty-five RCTs (n = 7511) comparing the antagonist to the long agonist protocols fulfilled the inclusion criteria. There was no evidence of a statistically significant difference in rates of live-births (9 RCTs; odds ratio (OR) 0.86, 95% CI 0.69 to 1.08) or ongoing pregnancy (28 RCTs; OR 0.87, 95% CI 0.77 to 1.00). There was a statistically significant lower incidence of OHSS in the GnRH antagonist group (29 RCTs; OR 0.43, 95% CI 0.33 to 0.57). The use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS and there was no evidence of a difference in live-birth rates.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clinics (Sao Paulo)
                Journal ID (iso-abbrev): Clinics (Sao Paulo)
                Title: Clinics
                Publisher: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
                ISSN (Print): 1807-5932
                ISSN (Electronic): 1980-5322
                Publication date (Electronic): November 2015
                Publication date (Print): November 2015
                Volume: 70
                Issue: 11
                Pages: 765-769
                Affiliations
                Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Ginecologia e Obstetrícia, Ribeirão Preto/SP, Brazil
                Author notes

                Melo AS reviewed the literature and wrote the manuscript. Navarro PA coordinated the study and conducted a systematic review of the manuscript. Ferriani RA conducted a systematic review of the manuscript and reviewed the literature.

                Corresponding author: E-mail: pnavarro@ 123456fmrp.usp.br
                Article
                Publisher ID: cln_70p765
                DOI: 10.6061/clinics/2015(11)09
                PMC ID: 4642490
                PubMed ID: 26602525
                SO-VID: 72995e19-de2f-4f28-98fc-3a4d8439eecc
                Copyright © Copyright © 2015 CLINICS
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 June 2015
                Date revision received : 8 July 2015
                Date accepted : 25 August 2015
                Categories
                Subject: Review

                ScienceOpen disciplines: Medicine
                Keywords: polycystic ovary syndrome,infertility,clomiphene citrate,ovarian drilling,in vitro fertilization
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: polycystic ovary syndrome, infertility, clomiphene citrate, ovarian drilling, in vitro fertilization

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