R J Norman, S Mahabeer, S Masters
Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome.
Fertil Steril. 1995 Jan;63(1):58-62.
Abstract/Text
OBJECTIVE: To examine different patterns of glucose and insulin secretion in women (of both Indian and white ethnic backgrounds) with polycystic ovary syndrome (PCOS).
DESIGN: A 75-g oral glucose tolerance test was performed in 11 subjects from each group.
SETTING: Reproductive Medicine and Gynecological Clinics from The Queen Elizabeth Hospital, Woodville, South Australia, and King Edward the VIIIth Hospital, Durban, South Africa.
PATIENTS: Couples were grouped as follows: Indian nonobese and obese PCOS, Indian nonobese and obese reference subjects, white nonobese and obese PCOS, white nonobese and obese reference subjects.
MAIN OUTCOME MEASURE: Insulin and glucose in plasma after oral glucose testing.
RESULTS: Indian PCOS and nonobese reference subjects had higher insulin responses than whites. The ethnic difference was less pronounced in obese women. There were no ethnic differences in glucose response.
CONCLUSION: This study demonstrates that the ethnic background of subjects with PCOS needs to be considered in studies on the metabolic parameters in this condition.
Brooke Tata, Nour El Houda Mimouni, Anne-Laure Barbotin, Samuel A Malone, Anne Loyens, Pascal Pigny, Didier Dewailly, Sophie Catteau-Jonard, Inger Sundström-Poromaa, Terhi T Piltonen, Federica Dal Bello, Claudio Medana, Vincent Prevot, Jerome Clasadonte, Paolo Giacobini
Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood.
Nat Med. 2018 Jun;24(6):834-846. doi: 10.1038/s41591-018-0035-5. Epub 2018 May 14.
Abstract/Text
Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.
Sanjiv Risal, Yu Pei, Haojiang Lu, Maria Manti, Romina Fornes, Han-Pin Pui, Zhiyi Zhao, Julie Massart, Claes Ohlsson, Eva Lindgren, Nicolas Crisosto, Manuel Maliqueo, Barbara Echiburú, Amanda Ladrón de Guevara, Teresa Sir-Petermann, Henrik Larsson, Mina A Rosenqvist, Carolyn E Cesta, Anna Benrick, Qiaolin Deng, Elisabet Stener-Victorin
Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.
Nat Med. 2019 Dec;25(12):1894-1904. doi: 10.1038/s41591-019-0666-1. Epub 2019 Dec 2.
Abstract/Text
How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.
E S Knochenhauer, T J Key, M Kahsar-Miller, W Waggoner, L R Boots, R Azziz
Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study.
J Clin Endocrinol Metab. 1998 Sep;83(9):3078-82. doi: 10.1210/jcem.83.9.5090.
Abstract/Text
Estimates of the prevalence of the polycystic ovary syndrome (PCOS) in the general population have ranged from 2-20%. The vast majority of these reports have studied White populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the United States and address these limitations, we prospectively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women (174 White and 195 Black; aged 18-45 yr), examined at the time of their preemployment physical. Body measures were obtained, and body hair was quantified by a modified Ferriman-Gallwey (F-G) method. All exams were initially performed by 2 trained nurses, and any subject with an F-G score above 3 was reexamined by a physician, the same for all patients. Of the 369 women, 277 (75.1%) also agreed to complete a questionnaire and have additional blood drawn. Subjects were studied regardless of current estrogen/progestin hormonal use (28.5%). PCOS was defined as 1) oligoovulation, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) exclusion of other related disorders, such as hyperprolactinemia, thyroid abnormalities, and non-classic adrenal hyperplasia. Hirsutism was defined by a F-G score of 6 or more, and hyperandrogenemia was defined as a total or free testosterone, androstenedione, and/or dehydroepiandrosterone sulfate level above the 95th percentile of control values [i.e. all eumenorrheic women in the study, who had no hirsutism (F-G < or = 5) or acne and were receiving no hormonal therapy; n = 98]. Considering all 369 women studied, White and Black women had similar mean ages (29.4 +/- 7.1 and 31.1 +/- 7.8 yr, respectively), although White women had a lesser body mass than Black women (24.9 +/- 6.1 vs. 29.2 +/- 8.1 kg/m2, respectively; P < 0.001). Of these 7.6%, 4.6%, and 1.9% demonstrated a F-G score of 6 or more, 8 or 10, respectively, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in Whites, and 7.1%, 6.1%, and 2.1% in Blacks, respectively. Of the 277 women consenting to a history and hormonal evaluation, 4.0% had PCOS as defined, 4.7% (6 of 129) of Whites and 3.4% (5 of 148) of Blacks. In conclusion, in our consecutive population of unselected women the prevalence of hirsutism varied from 2-8% depending on the chosen cut-off F-G score, with no significant difference between White and Black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of Blacks and 4.7% of Whites had PCOS as defined. These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women.
Robert J Norman, Didier Dewailly, Richard S Legro, Theresa E Hickey
Polycystic ovary syndrome.
Lancet. 2007 Aug 25;370(9588):685-97. doi: 10.1016/S0140-6736(07)61345-2.
Abstract/Text
Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects about one in 15 women worldwide. The major endocrine disruption is excessive androgen secretion or activity, and a large proportion of women also have abnormal insulin activity. Many body systems are affected in polycystic ovary syndrome, resulting in several health complications, including menstrual dysfunction, infertility, hirsutism, acne, obesity, and metabolic syndrome. Women with this disorder have an established increased risk of developing type 2 diabetes and a still debated increased risk of cardiovascular disease. The diagnostic traits of polycystic ovary syndrome are hyperandrogenism, chronic anovulation, and polycystic ovaries, after exclusion of other conditions that cause these same features. A conclusive definition of the disorder and the importance of the three diagnostic criteria relative to each other remain controversial. The cause of polycystic ovary syndrome is unknown, but studies suggest a strong genetic component that is affected by gestational environment, lifestyle factors, or both.
生殖・内分泌委員会: 本邦における多囊胞性卵巣症候群の新しい診断基準の設定に関する小委員会(平成17年度～平成18年度)検討結果報告. 日産婦誌. 2007;59:868-886.
C K Avvad, R Holeuwerger, V C Silva, M A Bordallo, M M Breitenbach
Menstrual irregularity in the first postmenarchal years: an early clinical sign of polycystic ovary syndrome in adolescence.
Gynecol Endocrinol. 2001 Jun;15(3):170-7.
Abstract/Text
We determined the hormonal, metabolic and ultrasonographic pattern of adolescents with menstrual irregularity since menarche but without clinical signs of hyperandrogenism with the aim of evaluating whether this condition represents an early stage of polycystic ovary syndrome (PCOS). These adolescents were divided in two groups: 13 adolescents with irregular cycles (IC) within the first 3 postmenarchal years (IC < or = 3) and 15 adolescents having persistent irregular cycles for more than three postmenarchal years (IC > 3). These adolescents were compared with 15 adolescents with PCOS and 18 normal adolescents. The values of free testosterone, free androgen index, luteinizing hormone (LH) and LH/follicle-stimulating hormone (FSH) ratio were similar in IC < or = 3, IC > 3 and PCOS, and higher than in the normal group (p < 0.005). The total testosterone and androstenedione levels were higher and sex hormone-binding globulin (SHBG) lower in PCOS only when compared with the normal group (p < 0.05). The ovarian volume was similar in IC < or = 3, IC > 3 and PCOS, and higher than in the normal group (p < 0.005). A higher incidence of polycystic structure was found in IC < or = 3, IC > 3 and PCOS, whereas normal structure was more common in normal adolescents (p < 0.0005). There were no significant differences in glucose and insulin parameters between groups. These results indicate that menstrual irregularity within the first postmenarchal years can be an early clinical sign of PCOS.
Roberto Franceschi, Rossella Gaudino, Alma Marcolongo, Maria Chiara Gallo, Luigi Rossi, Franco Antoniazzi, Luciano Tatò
Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty.
Fertil Steril. 2010 Mar 1;93(4):1185-91. doi: 10.1016/j.fertnstert.2008.11.016. Epub 2009 Jan 9.
Abstract/Text
OBJECTIVE: To assess the prevalence of polycystic ovary syndrome (PCOS) in a cohort of young women with previous idiopathic central precocious puberty (ICPP) at least 3 years after menarche, and to look for any predictive factors of PCOS at the time ICPP was diagnosed.
DESIGN: Longitudinal study.
SETTING: Pediatrics unit, Verona, Italy.
PATIENT(S): Forty-six young women (18.1 +/- 3.0 years) who had been treated with GnRH analogues during childhood, observed at gynecologic age of 6.23 +/- 3.3 years.
INTERVENTION(S): Semistructured interview concerning cycles, physical exam, blood sampling, and transabdominal pelvic ultrasound.
MAIN OUTCOME MEASURE(S): Oligomenorrhea, LH, FSH, E(2), T, DHEAS, free T, delta4-androstenedione, 17-OHP, P, polycystic ovary morphology (PCOM).
RESULT(S): Fifteen percent of the young women had oligomenorrhea, 28% clinical hyperandrogenism, 48% biochemical hyperandrogenism, and 37% PCOM. A total of 32% of the patients had PCOS according to the Rotterdam definition and 30% had PCOS according to the Androgen Exess Society. The prevalent phenotype of PCOS was characterized by clinical and/or biochemical hyperandrogenism and PCOM. We did not find any predictive factors for PCOS at the time ICPP was diagnosed.
CONCLUSION(S): Patients with ICCP are prone to developing PCOS. The prominent phenotype in this cohort was PCOM associated with clinical and/or biochemical hyperandrogenism. Further follow-ups of these young adult patients will clarify whether this phenotype persists and if it will have important long-term implications regarding increased risk of infertility or metabolic complications.
Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
Hum Reprod. 2004 Jan;19(1):41-7.
Abstract/Text
Since the 1990 NIH-sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome and, as such, no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include: menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.
B G Chittenden, G Fullerton, A Maheshwari, S Bhattacharya
Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review.
Reprod Biomed Online. 2009 Sep;19(3):398-405.
Abstract/Text
The objective of this study was to perform a systematic review of the literature to determine whether there is an association between polycystic ovary syndrome (PCOS) and gynaecological malignancy. Medline and Embase databases (1968-2008) were searched to identify publications on the association between PCOS and gynaecological cancers including breast cancer. Studies were selected that examined the association between PCOS and all types of gynaecological malignancies. A total of 19 studies exploring the association between PCOS and breast, endometrial and ovarian cancer were identified. Of these, only eight could be included after review. The data showed variability in the definition of PCOS. A meta-analysis of the data suggests that women with PCOS are more likely to develop cancer of the endometrium (OR 2.70, 95% CI 1.00-7.29) and ovarian cancer (OR 2.52, 95% CI 1.08-5.89) but not breast cancer (OR 0.88, 95% CI 0.44-1.77). Women with PCOS appear to be three times more likely to develop endometrial cancer but are not at increased risk of breast cancer. There is insufficient evidence to implicate PCOS in the development of vaginal, vulval, cervical or ovarian cancers. The paucity of studies investigating the association between PCOS and gynaecological cancers is likely to affect the reliability of the conclusions.
Sudhindra Mohan Bhattacharya, Ayan Jha
Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome.
Fertil Steril. 2012 Oct;98(4):1053-9. doi: 10.1016/j.fertnstert.2012.06.035. Epub 2012 Jul 13.
Abstract/Text
OBJECTIVE: To compare the effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone, in polycystic ovary syndrome (PCOS), after 6 and 12 months of therapy.
DESIGN: Double-blind randomized controlled trial.
SETTING: Gynecologic clinic of the first author.
PATIENT(S): Women (n = 171) with PCOS (Androgen Excess Society criteria, 2006).
INTERVENTION(S): The three-arm trial involved 58, 56, and 57 cases in desogestrel, cyproterone acetate, and drospirenone groups, respectively. Body mass index, abdominal circumference, hirsutism score (modified Ferriman Galwey), acne and acanthosis nigricans scores, and blood pressure were noted. Blood levels of total T, sex hormone-binding globulin, fasting glucose, and fasting insulin were measured. Free androgen index, glucose-insulin ratio, and homeostasis model assessment-insulin resistance were calculated. Follow-up was after 6 and 12 months of treatment.
MAIN OUTCOME MEASURE(S): Primarily, absolute change in the Free Androgen Index score between the three groups and, secondarily, changes in the clinical and other hormonal and biochemical parameters were studied.
RESULT(S): Six months of treatment showed similar effects. After 12 months, cyproterone acetate significantly decreased the modified Ferriman Galwey score (change = -5.29) compared with both desogestrel (change = -1.69) and drospirenone (change = -2.12); cyproterone acetate significantly increased sex hormone-binding globulin (change = 142.91) compared with desogestrel (change = 99.53); drospirenone significantly increased sex hormone-binding globulin (change = 131.52) compared with desogestrel; and cyproterone acetate significantly decreased the Free Androgen Index (change = -10.57) compared with desogestrel (change = -5.58).
CONCLUSION(S): No difference in effects after 6 months. At 12 months, cyproterone acetate showed the strongest antiandrogen activities. Effects on metabolic parameters were identical.
CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2010/091/000332.
Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Richard S Legro, Huiman X Barnhart, William D Schlaff, Bruce R Carr, Michael P Diamond, Sandra A Carson, Michael P Steinkampf, Christos Coutifaris, Peter G McGovern, Nicholas A Cataldo, Gabriella G Gosman, John E Nestler, Linda C Giudice, Phyllis C Leppert, Evan R Myers, Cooperative Multicenter Reproductive Medicine Network
Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.
N Engl J Med. 2007 Feb 8;356(6):551-66. doi: 10.1056/NEJMoa063971.
Abstract/Text
BACKGROUND: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior.
METHODS: We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery.
RESULTS: The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group.
CONCLUSIONS: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.
Nathalie Neveu, Louis Granger, Pierre St-Michel, Hélène B Lavoie
Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome.
Fertil Steril. 2007 Jan;87(1):113-20. doi: 10.1016/j.fertnstert.2006.05.069. Epub 2006 Nov 1.
Abstract/Text
OBJECTIVE: To determine which first-line medication is more effective in polycystic ovary syndrome (PCOS) patients for ovulation induction and pregnancy achievement and to verify whether any patient characteristic is associated with a better response to therapy.
DESIGN: Observational comparative study.
SETTING: Fertility clinic.
PATIENT(S): One hundred fifty-four infertile women with oligomenorrhea and hyperandrogenism.
INTERVENTION(S): Group 1 (56 patients) received clomiphene citrate (CC) 50 mg from days 5-9 of the cycle. Group 2 (57 patients) received 500 mg of metformin 3 times a day. Group 3 (41 patients) received both medications.
MAIN OUTCOME MEASURE(S): Ovulation and pregnancy.
RESULT(S): Patients receiving metformin alone had an increased ovulation rate compared with those receiving CC alone (75.4% vs. 50%). Patients on metformin had similar ovulation rates compared with those in the combination group (75.4% vs. 63.4%). Pregnancy rates were equivalent in the 3 groups. Response to metformin was independent of body weight and dose. Finally, nonsmoking predicted better ovulatory response overall as well as lower fasting glucose for CC and lower androgens for metformin.
CONCLUSION(S): Metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. We suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile.
Murizah Mohd Zain, Ridzuan Jamaluddin, Adibah Ibrahim, Robert J Norman
Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial.
Fertil Steril. 2009 Feb;91(2):514-21. doi: 10.1016/j.fertnstert.2007.12.002. Epub 2008 Mar 5.
Abstract/Text
OBJECTIVE: To determine the first-line medication to be used in anovulatory patients with polycystic ovary syndrome (PCOS) for ovulation induction and pregnancy achievement.
DESIGN: Randomized controlled trial.
SETTING: Infertility unit of a public hospital.
PATIENT(S): One hundred fifteen newly diagnosed patients with PCOS based on ESHRE/ASRM criteria.
INTERVENTION(S): These patients were assigned to three groups: group 1 (38 patients) received 500 mg of metformin three times a day; group 2 (39 patients) received clomiphene citrate (CC) at an incremental dose; group 3 (38 patients) received both medications.
MAIN OUTCOME MEASURE(S): Rates of ovulation, pregnancy (PR), and live birth.
RESULT(S): The ovulation rate was 23.7% in the metformin group, 59% in the CC group, and 68.4% in the combination treatment group. This was translated into a similar PR and live birth rate, which were higher in the CC and combination groups compared to the metformin group (PR: 7.9%, 15.4%, and 21.1%; live birth rate: 7.9%, 15.4%, and 18.4% in metformin, CC, and combination treatment groups, respectively), although statistically the differences were not significant. There were no multiple pregnancies and the rate of spontaneous first trimester loss was similar to the general population.
CONCLUSION(S): Clomiphene citrate should be the first-line treatment for ovulation induction in anovulatory patients with PCOS.
Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Practice Committee of the American Society for Reproductive Medicine
Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline.
Fertil Steril. 2017 Sep;108(3):426-441. doi: 10.1016/j.fertnstert.2017.06.026.
Abstract/Text
Metformin alone compared with placebo increases the ovulation rate in women with polycystic ovary syndrome (PCOS) but should not be used as first-line therapy for anovulation because oral ovulation induction agents such as clomiphene citrate or letrozole alone are much more effective in increasing ovulation, pregnancy, and live-birth rates in women with PCOS. There is fair evidence that metformin alone does not increase rates of miscarriage when stopped at the initiation of pregnancy and insufficient evidence that metformin in combination with other agents used to induce ovulation increases live-birth rates.
Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
生殖・内分泌委員会： 本邦における多嚢胞性卵巣症候群の治療に関する治療指針作成のための小委員会(平成19年度～平成20年度)報告. 日産婦誌. 2009;61(3):902-912.
Maria-Elena Lautatzis, Dimitrios G Goulis, Maria Vrontakis
Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.
Metabolism. 2013 Nov;62(11):1522-34. doi: 10.1016/j.metabol.2013.06.006. Epub 2013 Jul 23.
Abstract/Text
BACKGROUND: Metformin is an effective oral anti-hyperglycemic agent that is widely used to manage diabetes mellitus type 2 in the general population and more recently, in pregnancy. However, as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus.
OBJECTIVE: (i) To provide background for the use of metformin during pregnancy through a narrative review and (ii) to critically appraise the published evidence on the efficacy and safety of using metformin during pregnancy through a systematic review.
RESULTS: Metformin appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight or obese women. However, patients with multiple risk factors for insulin resistance may not meet their treatment goals with metformin alone and may require supplementary insulin. Evidence suggests that there are potential advantages for the use of metformin over insulin in GDM with respect to maternal weight gain and neonatal outcomes. Furthermore, patients are more accepting of metformin than insulin. The use of metformin throughout pregnancy in women with polycystic ovary syndrome reduces the rates of early pregnancy loss and preterm labor and protects against fetal growth restriction. There have been no demonstrable teratogenic effects, intra-uterine deaths or developmental delays with the use of metformin.
CONCLUSIONS: The publications reviewed in this paper support the efficacy and safety of metformin during pregnancy with respect to immediate pregnancy outcomes. Because there are no guidelines for the continuous use of metformin in pregnancy, the duration of treatment is based on clinical judgment and experience on a case-by-case basis.
© 2013.
Richard S Legro, Robert G Brzyski, Michael P Diamond, Christos Coutifaris, William D Schlaff, Peter Casson, Gregory M Christman, Hao Huang, Qingshang Yan, Ruben Alvero, Daniel J Haisenleder, Kurt T Barnhart, G Wright Bates, Rebecca Usadi, Scott Lucidi, Valerie Baker, J C Trussell, Stephen A Krawetz, Peter Snyder, Dana Ohl, Nanette Santoro, Esther Eisenberg, Heping Zhang, NICHD Reproductive Medicine Network
Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.
N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517.
Abstract/Text
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.).
Sebastian Franik, Stephanie M Eltrop, Jan Am Kremer, Ludwig Kiesel, Cindy Farquhar
Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome.
Cochrane Database Syst Rev. 2018 May 24;5:CD010287. doi: 10.1002/14651858.CD010287.pub3. Epub 2018 May 24.
Abstract/Text
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC).
OBJECTIVES: To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI).
SEARCH METHODS: We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status.
SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods.
MAIN RESULTS: This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary.
AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.
Rui Wang, Bobae V Kim, Madelon van Wely, Neil P Johnson, Michael F Costello, Hanwang Zhang, Ernest Hung Yu Ng, Richard S Legro, Siladitya Bhattacharya, Robert J Norman, Ben Willem J Mol
Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis.
BMJ. 2017 Jan 31;356:j138. doi: 10.1136/bmj.j138. Epub 2017 Jan 31.
Abstract/Text
OBJECTIVE: To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive.
DESIGN: Systematic review and network meta-analysis.
DATA SOURCES: Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016.
STUDY SELECTION: Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes.
RESULTS: Of 2631 titles and abstracts initially identified, 57 trials reporting on 8082 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively).
CONCLUSIONS: In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of ovulation and pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027579.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Neriman Bayram, Madelon van Wely, Eugenie M Kaaijk, Patrick M M Bossuyt, Fulco van der Veen
Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial.
BMJ. 2004 Jan 24;328(7433):192. doi: 10.1136/bmj.328.7433.192.
Abstract/Text
OBJECTIVE: To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with polycystic ovary syndrome.
DESIGN: Randomised controlled trial.
SETTING: Secondary and tertiary hospitals in the Netherlands.
PARTICIPANTS: 168 patients with clomiphene citrate resistant polycystic ovary syndrome: 83 were allocated electrocautery and 85 were allocated recombinant follicle stimulating hormone.
INTERVENTION: Laparoscopic electrocautery of the ovaries followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or induction of ovulation with recombinant follicle stimulating hormone.
MAIN OUTCOME MEASURE: Ongoing pregnancy within 12 months.
RESULTS: . The cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormone was 67%. With only electrocautery it was 34%, which increased to 49% after clomiphene citrate was given. Subsequent recombinant follicle stimulating hormone increased the rate to 67% at 12 months (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). No complications occurred from electrocautery with or without clomiphene citrate. Patients allocated to electrocautery had a significantly lower risk of multiple pregnancy (0.11, 0.01 to 0.86).
CONCLUSION: The ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or recombinant follicle stimulating hormone, seems equivalent to ovulation induction with recombinant follicle stimulating hormone, but the former procedure carries a lower risk of multiple pregnancy.
C Farquhar, R J Lilford, J Marjoribanks, P Vandekerckhove
Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome.
Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001122. doi: 10.1002/14651858.CD001122.pub3. Epub 2007 Jul 18.
Abstract/Text
BACKGROUND: Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned due to the risk of postsurgical adhesions and the introduction of medical ovulation induction with clomiphene and gonadotrophins. However, women with PCOS who are treated with gonadotrophins often have an over-production of follicles which may result in ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Moreover, gonadotrophins, though effective, are costly and time-consuming requiring intensive monitoring. Surgical therapy with laparoscopic ovarian 'drilling' (LOD) may avoid or reduce the need for gonadotrophins or may facilitate their usefulness. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with traditional surgical approaches. Many uncontrolled observational studies have claimed that ovarian drilling is followed, at least temporarily, by a high rate of spontaneous ovulation and conception or that subsequent medical ovulation induction becomes easier.
OBJECTIVES: To determine the effectiveness and safety of laparoscopic ovarian drilling compared with ovulation induction for subfertile women with clomiphene-resistant PCOS.
SEARCH STRATEGY: We used the search strategy of the Menstrual Disorders and Subfertility Group.
SELECTION CRITERIA: We included randomised controlled trials of subfertile women with clomiphene-resistant PCOS who undertook laparoscopic ovarian drilling in order to induce ovulation.
DATA COLLECTION AND ANALYSIS: Sixteen trials were identified and nine were included in the review. All trials were assessed for quality criteria. The primary outcomes were live birth, ovulation and pregnancy rates and the secondary outcomes were rates of miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome and cost.
MAIN RESULTS: There was no evidence of a difference in live birth or clinical pregnancy rate between LOD and gonadotrophins and the pooled odds ratios (OR) (all studies) were 1.04 (95% CI 0.59 to 1.85) and 1.08 (95% CI 0.69 to 1.71) respectively. Multiple pregnancy rates were lower with ovarian drilling than with gonadotrophins (1% versus 16%; OR 0.13, 95% CI 0.03 to 0.52). There was no evidence of a difference in miscarriage rates between the two groups (OR 0.81, 95% 0.36 to 1.86).
AUTHORS' CONCLUSIONS: There was no evidence of a difference in the live birth rate and miscarriage rate in women with clomiphene-resistant PCOS undergoing LOD compared to gonadotrophin treatment. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive. However, there are ongoing concerns about long-term effects of LOD on ovarian function.
Cynthia M Farquhar, Karen Williamson, Guy Gudex, Neil P Johnson, Jules Garland, Lynn Sadler
A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome.
Fertil Steril. 2002 Aug;78(2):404-11.
Abstract/Text
OBJECTIVE: To compare the effectiveness of laparoscopic ovarian diathermy with gonadotropin ovulation induction for women with clomiphene citrate-resistant polycystic ovary syndrome.
DESIGN: Randomized controlled trial.
SETTING: A tertiary referral fertility clinic.
PATIENT(S): Women with anovulatory infertility secondary to clomiphene-resistant polycystic ovary syndrome. Inclusion criteria were age of <39 years, body mass index of <35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, >12 months of infertility, and no other causes of infertility.
INTERVENTION(S): Laparoscopic ovarian diathermy versus three cycles of urinary or recombinant gonadotropins.
MAIN OUTCOME MEASURE(S): Cumulative pregnancy and miscarriage rates.
RESULT(S): Cumulative pregnancy rates were 28% at 6 months for laparoscopic ovarian diathermy and 33% for three cycles of ovulation induction with gonadotropins. There were three miscarriages in each group. Women in the laparoscopic ovarian diathermy arm of the study had four additional spontaneous pregnancies 6 to 12 months after surgery.
CONCLUSION(S): There was no statistically significant difference in pregnancy or miscarriage rates during the 6-month follow-up period or the three cycles. Laparoscopic ovarian diathermy is a safe and effective alternative to ovulation induction with gonadotropins.
D Nugent, P Vandekerckhove, E Hughes, M Arnot, R Lilford
Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome.
Cochrane Database Syst Rev. 2000;(4):CD000410. doi: 10.1002/14651858.CD000410.
Abstract/Text
BACKGROUND: Approximately 15% of patients with PCOS remain anovulatory despite treatment with oral anti-oestrogen medications such as clomiphene citrate. In addition, about half of women with PCOS ovulating on anti-oestrogen treatment fail to conceive. Gonadotrophin stimulation is the next step in treatment for women who are "clomiphene resistant", however, results of gonadotrophin stimulation in women with PCOS are less successful. In PCOS associated with hypersecretion of LH, purified urinary follicle-stimulating hormone (u-FSH) preparations have theoretical advantages over the use of human menopausal gonadotrophin (hMG) preparations (containing both FSH and LH), but whether this claimed advantage extends into clinical practice remains uncertain. In addition, the use of gonadotrophin-releasing hormone analogues (GnRH-a) to produce pituitary desensitisation prior to ovulation induction in PCOS has been claimed to increase the success rates of treatment as well as reduce complications such as OHSS and multiple pregnancy. Gonadotrophin preparations have also been administered via different routes (intramuscular or subcutaneous), or using different stimulation regimens and protocols (step-up or standard) in an attempt to improve efficacy.
OBJECTIVES: To determine the effectiveness of urinary-derived gonadotrophins as ovulation induction agents in patients with PCOS trying to conceive. In particular, to assess the effectiveness of (1) different gonadotrophin preparations, (2) the addition of a gonadotrophin-releasing hormone agonist (GnRH-a) to gonadotrophin stimulation and (3) different modalities of gonadotrophin administration.
SEARCH STRATEGY: The search strategy to identify RCTs consisted of (1) the Group's Specialised Register of Controlled Trials using the search strategy developed for the Menstrual Disorders and Subfertility Group as a whole (see the Review Group details for more information), (2) additional specific electronic Medline searches and (3) bibliographies of identified studies and narrative reviews.
SELECTION CRITERIA: RCTs in which urinary-derived gonadotrophins were used for ovulation induction in patients with primary or secondary subfertility attributable to PCOS.
DATA COLLECTION AND ANALYSIS: Twenty three RCTs were identified, 9 of which were excluded from analysis. The data were extracted independently by 2 authors. The following criteria were assessed: (1) the methodological characteristics of the trials, (2) the baseline characteristics of the studied groups and (3) the outcomes of interest: pregnancy rate (per cycle), ovulation rate (per cycle), miscarriage rate (per pregnancy), multiple pregnancy rate (per pregnancy), overstimulation rate (per cycle) and ovarian hyperstimulation syndrome (OHSS) rate (per cycle). Where suitable, meta-analysis was performed using Peto's OR with 95% CI with the fixed effect Mantel-Haentszel equation.
MAIN RESULTS: (1) A reduction in the incidence of OHSS with FSH compared to hMG in stimulation cycles without the concomitant use of a GnRH-a (OR 0.20; 95% CI 0.08-0.46) and (2) a higher overstimulation rate when a GnRH-a is added to gonadotrophins (OR 3.15; 95% CI 1.48-6.70).
REVIEWER'S CONCLUSIONS: Although 14 RCTs were included in this review, few dealt with the same comparisons, all were small to moderate size and their methodological quality was generally poor. Any conclusions, therefore, remain tentative as they are based on a limited amount of data and will require further RCTs to substantiate them. In none of the comparisons was there a significant improvement in pregnancy rate but this may be due to the lack of power (i.e. insufficient patients randomised to demonstrate a significant difference between treatments). There was a trend towards better pregnancy rates with the addition of a GnRH-a to gonadotrophin stimulation and these interventions warrant further study. Despite theoretical advantages, urinary-derived FSH preparations did not improve pregnancy rates when compared to traditional and cheaper hMG preparations; their only demonstrable benefit was a reduced risk of OHSS in cycles when administered without the concomitant use of a GnRH-a. No conclusions can be drawn on miscarriage and multiple pregnancy rates due to insufficient reporting of these outcomes in the trials.
Stefano Palomba, Angela Falbo, Giovanni B La Sala
Metformin and gonadotropins for ovulation induction in patients with polycystic ovary syndrome: a systematic review with meta-analysis of randomized controlled trials.
Reprod Biol Endocrinol. 2014 Jan 3;12:3. doi: 10.1186/1477-7827-12-3. Epub 2014 Jan 3.
Abstract/Text
The current systematic review with meta-analysis of randomized controlled trials (RCTs) was aimed to evaluate the effects of metformin on reproductive outcomes in patients with polycystic ovary syndrome (PCOS) who receive gonadotropins for ovulation induction. After systematic review of electronic databases and websites for registration of RCTs, a total of 7 RCTs reporting data on 1023 cycles were included in the final analysis. Descriptive data showed an overall low studies' quality due to unclear sequence generation and allocation concealment, lack of blinding procedure, incomplete outcome data and several biases and/or confounders. Data synthesis showed that metformin improved live-birth (odds ratio [OR] = 1.94, 95% confidence interval [CI] 1.10 to 3.44; P = 0.020) and pregnancy (OR = 2.25, 95% CI 1.50 to 3.38; P < 0.0001) rates, without significant heterogeneity across the studies (P = 0.230, estimation of inconsistency = 30%; and P = 0.710, estimation of inconsistency = 0%, respectively, for live-birth and pregnancy rates). A significant reduction of cancellation rate was observed after metformin administration (OR = 0.41, 95% CI 0.24 to 0.72, P = 0.002) without significant heterogeneity across the studies (P = 0.500, estimation of inconsistency = 0%). Metformin administration influenced or did not influence other secondary endpoints assessed with a significant heterogeneity. In conclusion, metformin administration increases the live-birth and pregnancy rate in PCOS patients who receive gonadotropins for ovulation induction. Further well designed, blinded, placebo-controlled, and adequately powered RCTs are need to confirm that metanalytic results.
