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Infertility: HELP
Articles by Richard S. Legro
Based on 80 articles published since 2010
(Why 80 articles?)
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Between 2010 and 2020, R. S. Legro wrote the following 80 articles about Infertility.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2. 2015

Goodman, Neil F / Cobin, Rhoda H / Futterweit, Walter / Glueck, Jennifer S / Legro, Richard S / Carmina, Enrico / Anonymous2160851 / Anonymous2170851 / Anonymous2180851. · ·Endocr Pract · Pubmed #26642102.

ABSTRACT: Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2014. Insulin resistance is believed to play an intrinsic role in the pathogenesis of PCOS. The mechanism by which insulin resistance or insulin give rise to oligomenorrhea and hyperandrogenemia, however, is unclear. Hyperinsulinemic-euglycemic clamp studies have shown that both obese and lean women with PCOS have some degree of insulin resistance. Insulin resistance is implicated in the ovulatory dysfunction of PCOS by disrupting the hypothalamic-pituitary-ovarian axis. Given the association with insulin resistance, all women with PCOS require evaluation for the risk of metabolic syndrome (MetS) and its components, including type 2 diabetes, hypertension, hyperlipidemia, and the possible risk of clinical events, including acute myocardial infarction and stroke. Obese women with PCOS are at increased risk for MetS with impaired glucose tolerance (IGT; 31 to 35%) and type 2 diabetes mellitus (T2DM; 7.5 to 10%). Rates of progression from normal glucose tolerance to IGT, and in turn to T2DM, may be as high as 5 to 15% within 3 years. Data suggest the need for baseline oral glucose tolerance test every 1 to 2 years based on family history of T2DM as well as body mass index (BMI) and yearly in women with IGT. Compared with BMI- and age-matched controls, young, lean PCOS women have lower high-density lipoprotein (HDL) size, higher very-low-density lipoprotein particle number, higher low-density lipoprotein (LDL) particle number, and borderline lower LDL size. Statins have been shown to lower testosterone levels either alone or in combination with oral contraceptives (OCPs) but have not shown improvement in menses, spontaneous ovulation, hirsutism, or acne. Statins reduce total and LDL cholesterol but have no effect on HDL, C-reactive protein, fasting insulin, or homeostasis model assessment of insulin resistance in PCOS women, in contrast to the general population. There have been no long-term studies of statins on clinical cardiac outcomes in women with PCOS. Coronary calcification is more prevalent and more severe in PCOS than in controls. In women under 60 years of age undergoing coronary angiography, the presence of polycystic ovaries on sonography has been associated with more arterial segments with >50% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor.

2 Editorial Quo vadis randomized controlled trials in infertility? 2012

Legro, Richard S. · ·Fertil Steril · Pubmed #23084270.

ABSTRACT: -- No abstract --

3 Editorial Metformin as adjuvant therapy to IVF in women with PCOS: when is intention-to-treat unintentional? 2011

Legro, Richard S. · ·Hum Reprod · Pubmed #21606132.

ABSTRACT: -- No abstract --

4 Review Pharmacology of medications used for ovarian stimulation. 2019

Quaas, Alexander M / Legro, Richard S. ·University Hospital, University of Basel, Clinic for Reproductive Medicine and Gynecologic Endocrinology, Basel, Switzerland; Reproductive Partners San Diego, San Diego, CA, USA; Division of Reproductive Endocrinology and Infertility, University of California, San Diego, CA, USA. Electronic address: Alexander.Quaas@usb.ch. · Department of Obstetrics and Gynecology, Penn State University College of Medicine, Hershey, PA, USA. ·Best Pract Res Clin Endocrinol Metab · Pubmed #30470497.

ABSTRACT: Medications to stimulate the ovaries may be used to induce ovulation in patients with anovulatory infertility or to hyperstimulate the ovaries in a controlled fashion in ovulatory patients as part of assisted reproductive treatments (ART). The pharmacology of all current major medications used to stimulate ovarian function is reviewed in this article, including letrozole, clomiphene citrate, gonadotropins, and pulsatile gonadotropin releasing hormone (GnRH). Novel potential compounds and adjuvant treatment approaches are also discussed, such as kisspeptin agonists and androgens.

5 Review A protocol developing, disseminating and implementing a core outcome set for infertility. 2018

Duffy, J M N / Bhattacharya, S / Curtis, C / Evers, J L H / Farquharson, R G / Franik, S / Khalaf, Y / Legro, R S / Lensen, S / Mol, B W / Niederberger, C / Ng, E H Y / Repping, S / Strandell, A / Torrance, H L / Vail, A / van Wely, M / Vuong, N L / Wang, A Y / Wang, R / Wilkinson, J / Youssef, M A / Farquhar, C M / Anonymous350984. ·Balliol College, University of Oxford, Oxford, UK. · Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. · Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. · Fertility New Zealand, Auckland, New Zealand. · School of Psychology, University of Waikato, Hamilton, New Zealand. · Centre for Reproductive Medicine and Biology, University Medical Centre Maastricht, Maastricht, The Netherlands. · Department of Obstetrics and Gynaecology, Liverpool Women's NHS Foundation Trust, Liverpool, UK. · Department of Obstetrics and Gynaecology, Münster University Hospital, Münster, Germany. · Assisted Conception Unit, Guy's Hospital, London, UK. · Department of Obstetrics and Gynaecology, Penn State College of Medicine, PA, USA. · Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. · Department of Obstetrics and Gynaecology, School of Medicine, Monash University, Melbourne, Australia. · Department of Urology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA. · Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong. · Center for Reproductive Medicine, Amsterdam Reproduction and Development Institute, Academic Medical Centre, Amsterdam, The Netherlands. · Sahlgrenska University Hospital, Göteborg, Sweden. · Department of Reproductive Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands. · Centre for Biostatistics, University of Manchester, Manchester, UK. · Department of Obstetrics and Gynaecology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam. · Faculty of Health, University of Technology Sydney, Broadway, Australia. · Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, Australia. · Department of Obstetrics & Gynaecology, Faculty of Medicine, Cairo University, Cairo, Egypt. ·Hum Reprod Open · Pubmed #30895248.

ABSTRACT: STUDY QUESTIONS: We aim to produce, disseminate and implement a core outcome set for future infertility research. WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) evaluating infertility treatments have reported many different outcomes, which are often defined and measured in different ways. Such variation contributes to an inability to compare, contrast and combine results of individual RCTs. The development of a core outcome set will ensure outcomes important to key stakeholders are consistently collected and reported across future infertility research. STUDY DESIGN SIZE DURATION: This is a consensus study using the modified Delphi method. All stakeholders, including healthcare professionals, allied healthcare professionals, researchers and people with lived experience of infertility will be invited to participate. PARTICIPANTS/MATERIALS SETTING METHODS: An international steering group, including people with lived experience of infertility, healthcare professionals, allied healthcare professionals and researchers, has been formed to guide the development of this core outcome set. Potential core outcomes have been identified through a comprehensive literature review of RCTs evaluating treatments for infertility and will be entered into a modified Delphi method. Participants will be asked to score potential core outcomes on a nine-point Likert scale anchored between one (not important) and nine (critical). Repeated reflection and rescoring should promote convergence towards consensus 'core' outcomes. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTERESTS: This project is funded by the Royal Society of New Zealand Catalyst Fund (3712235). BWM reports consultancy fees from Guerbet, Merck, and ObsEva. R.S.L. reports consultancy fees from Abbvie, Bayer, Fractyl and Ogeda and research sponsorship from Ferring. S.B. is the Editor-in-Chief of Human Reproduction Open. The remaining authors declare no competing interests.

6 Review Effects of obesity treatment on female reproduction: results do not match expectations. 2017

Legro, Richard S. ·Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Electronic address: RSL1@psu.edu. ·Fertil Steril · Pubmed #28366412.

ABSTRACT: The adverse effects of obesity of female reproduction have been extensively documented. However, there are few prospective studies that have examined preconception weight loss interventions. There is a need to develop successful interventions with significant weight loss and compliance and most importantly document the effects of preconception interventions on important perinatal outcomes such as live birth and the health of the infant and mother. The existing data from randomized trials that come closest to meeting these criteria have failed to document improved live-birth rates after the intervention compared with control groups. There is a tendency to equate favorable weight change both before and during pregnancy with a direct qualitative improvement in all perinatal outcomes, yet the results from the most successful treatment of morbid obesity, that is, bariatric surgery, with on average 40% weight loss, suggest a mixed risk-benefit ratio on perinatal outcomes. Although interventions to control gestational weight gain have been more completely studied than preconception ones, and have documented successful interventions to achieve appropriate weight gain, there is no clear evidence that controlling gestational weight gain actually improves any important perinatal outcome. Future studies must develop more successful and effective interventions, capture perinatal outcomes instead of weight change as the primary outcomes, use, at least preconception, new antiobesity drugs (in combination with other therapies), and study bariatric surgery in prospective trials to improve our understanding of the effectiveness of obesity treatment before pregnancy.

7 Review Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis. 2017

Wang, Rui / Kim, Bobae V / van Wely, Madelon / Johnson, Neil P / Costello, Michael F / Zhang, Hanwang / Ng, Ernest Hung Yu / Legro, Richard S / Bhattacharya, Siladitya / Norman, Robert J / Mol, Ben Willem J. ·Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine, University of Adelaide, North Adelaide, Australia r.wang@adelaide.edu.au. · Reproductive Medicine Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. · Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine, University of Adelaide, North Adelaide, Australia. · Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. · Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. · School of Women's and Children's Health, University of New South Wales, Sydney, Australia. · Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong, China. · Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, USA. · Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK. · FertilitySA, Adelaide, Australia. · NHMRC (National Health and Medical Research Council) Centre for Research Excellence in Polycystic Ovary Syndrome, Adelaide, Australia. · South Australian Health and Medical Research Institute, Adelaide, Australia. ·BMJ · Pubmed #28143834.

ABSTRACT: 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.

8 Review Ovulation induction in polycystic ovary syndrome: Current options. 2016

Legro, Richard S. ·Department of Obstetrics and Gynecology and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA. Electronic address: RSL1@PSU.EDU. ·Best Pract Res Clin Obstet Gynaecol · Pubmed #27866938.

ABSTRACT: There are a variety of effective treatment options to induce ovulation in women with polycystic ovary syndrome (PCOS). The most effective treatments are primarily reproductive and target the hypothalamic-pituitary-ovarian (HPO) axis. Letrozole, an aromatase inhibitor, is headed toward replacing clomiphene, a selective estrogen receptor modulator, as the first-choice option. Metabolic treatments likely work indirectly through the HPO axis. Many metabolic treatments have shown initial promise and later failed (troglitozone or d-chiro-inositol) or disappointed (metformin); further studies are needed of newer agents to treat type 2 diabetes. Weight loss interventions, lifestyle related, through obesity drugs or through bariatric surgery have shown mixed results on pregnancy outcomes. With both reproductive and metabolic treatments, combination therapies (such as metformin and clomiphene together) may offer greater benefit to distinct subgroups of patients.

9 Review The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. 2016

Balen, Adam H / Morley, Lara C / Misso, Marie / Franks, Stephen / Legro, Richard S / Wijeyaratne, Chandrika N / Stener-Victorin, Elisabet / Fauser, Bart C J M / Norman, Robert J / Teede, Helena. ·Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds LS14 6UH, UK a.balen@nhs.net. · Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds LS14 6UH, UK. · Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Monash Medical Centre, 43-51 Kanooka Grove, Clayton, VIC 3168, Australia. · Institute of Reproductive & Developmental Biology, Hammersmith Hospital, London, UK. · Penn State College of Medicine, 500 University Drive, H103, Hershey, PA 17033, USA. · Faculty of Medicine, University of Colombo, PO Box 271, Kynsey Road, Colombo 008, Sri Lanka. · Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. · Department of Reproductive Medicine & Gynaecology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. · The Robinson Institute, University of Adelaide, Norwich House, 55 King William Street, North Adelaide, SA 5005, Australia. ·Hum Reprod Update · Pubmed #27511809.

ABSTRACT: BACKGROUND: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHODS: The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOMES: Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m WIDER IMPLICATIONS: This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS.

10 Review Treatment strategies for infertile women with polycystic ovary syndrome. 2016

Vitek, Wendy / Hoeger, Kathleen / Legro, Richard S. ·Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA - wendy_vitek@urmc.rochester.edu. ·Minerva Ginecol · Pubmed #26765152.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a common reproductive disorder that can be diagnosed when two of the following three criteria are present: menstrual irregularity, hyperandrogenism and polycystic ovaries. Factors such as the individual's body weight influence the severity of the phenotype and risk of metabolic comorbidities. While anovulatory infertility is a common issue among lean and obese reproductive-aged women with PCOS, obesity is associated with resistance to oral ovulation induction agents, lower pregnancy rates and a higher risk of pregnancy complications. Lifestyle modification is recommended as first line therapy among obese women with PCOS in order to optimize their outcomes. Among lean and obese women with PCOS, ovulation induction can be achieved with aromatase inhibitors, selective estrogen receptor modulators, insulin sensitizing agents, gonadotropins and ovarian drilling with varying rates of ovulation, live birth and multiple gestations. Assisted reproductive technologies are reserved for women who do not conceive despite restoration of ovulation or couples with additional factors contributing to their infertility. This review will outline treatment strategies for achieving a healthy pregnancy among lean and obese women with PCOS and infertility.

11 Review The role of TGF-β in polycystic ovary syndrome. 2014

Raja-Khan, Nazia / Urbanek, Margrit / Rodgers, Raymond J / Legro, Richard S. ·1Division of Endocrinology, Diabetes, and Metabolism, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, Hershey, PA, USA. ·Reprod Sci · Pubmed #23585338.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic oligoanovulation and hyperandrogenism and associated with insulin resistance, type 2 diabetes, and cardiovascular risk. In recent years, genetic studies have linked PCOS to a dinucleotide marker D19S884 in the fibrillin 3 gene. Fibrillins make up the major component of microfibrils in the extracellular matrix (ECM) and interact with molecules in the ECM to regulate transforming growth factor β (TGF-β) signaling. Therefore, variations in fibrillin 3 and subsequent dysregulation of TGF-β may contribute to the pathogenesis of PCOS. Here, we review the evidence from genetic studies supporting the role of TGF-β in PCOS and describe how TGF-β dysregulation may contribute to (1) the fetal origins of PCOS, (2) reproductive abnormalities in PCOS, and (3) cardiovascular and metabolic abnormalities in PCOS.

12 Review Reproductive impact of polycystic ovary syndrome. 2012

Usadi, Rebecca S / Legro, Richard S. ·Center for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, North Carolina, USA. Rebecca.Usadi@carolinashealthcare.org ·Curr Opin Endocrinol Diabetes Obes · Pubmed #23108198.

ABSTRACT: PURPOSE OF REVIEW: The purpose of this review is to highlight the impact of polycystic ovary syndrome (PCOS) on menstrual function, fertility and reproductive outcomes. Women with PCOS often present with anovulation, menstrual disturbances and hyperandrogenism. Management options for the reproductive disorders of PCOS will be discussed. RECENT FINDINGS: The role of metformin in treating PCOS is narrowing. New data show improved live birth rates by skipping a progestin withdrawal bleed and proceeding directly with a dose escalation of clomiphene for ovulation induction. The Pregnancy in PCOS trial II will determine the safety and efficacy of clomiphene citrate compared to letrozole, in achieving live birth in infertile women with PCOS. SUMMARY: Initial treatment for reproductive disorders in overweight and obese women with PCOS is weight loss. This helps menstrual disturbances, shortens the time to conception and reduces adverse obstetric risks. Clomiphene citrate is considered the first-line therapy for ovulatory infertility. Clomiphene citrate-resistant women may be offered aromatase inhibitors or laparoscopic ovarian surgery. Metformin does not improve live birth rate or reduce miscarriage rate and is no longer considered an option for ovulation induction. Women with PCOS need to be counseled about risks of multiple gestations with gonadotropin therapy.

13 Review Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome. 2012

Witchel, Selma F / Recabarren, Sergio E / González, Frank / Diamanti-Kandarakis, Evanthia / Cheang, Kai I / Duleba, Antoni J / Legro, Richard S / Homburg, Roy / Pasquali, Renato / Lobo, Rogerio A / Zouboulis, Christos C / Kelestimur, Fahrettin / Fruzzetti, Franca / Futterweit, Walter / Norman, Robert J / Abbott, David H. ·Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA. witchelsf@upmc.edu ·Endocrine · Pubmed #22661293.

ABSTRACT: The interactive nature of the 8th Annual Meeting of the Androgen Excess and PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.

14 Review Polycystic ovary syndrome: current infertility management. 2011

Aubuchon, Mira / Legro, Richard S. ·Department of Obstetrics, Gynecology, and Women's Health, University of Missouri School of Medicine, Missouri Center for Reproductive Medicine and Fertility, Columbia, Missouri, USA. ·Clin Obstet Gynecol · Pubmed #22031257.

ABSTRACT: This review summarizes the diagnosis of polycystic ovary syndrome and management of associated infertility. The goal is to guide clinicians through basic evaluation, initial treatment, and briefly describe more complex therapies.

15 Review Incomplete and inconsistent reporting of maternal and fetal outcomes in infertility treatment trials. 2011

Dapuzzo, Lisa / Seitz, Faith E / Dodson, William C / Stetter, Christina / Kunselman, Allen R / Legro, Richard S. ·Department of Obstetrics and Gynecology, Lehigh Valley Hospital, Allentown, Pennsylvania, USA. ·Fertil Steril · Pubmed #21435640.

ABSTRACT: Pregnancy outcomes and adverse outcomes in infertility trials are reported to varying extents; for example, 35% of clinical trials reported no information on pregnancy loss, only 43% reported adverse events during the preconception treatment period, and only 7% reported any serious adverse events. Incomplete reporting limits the value of these studies in counseling patients on the risk-benefit ratio of treatment to themselves and their infants.

16 Clinical Trial Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes in Women With Polycystic Ovary Syndrome. 2017

Wei, Daimin / Zhang, Bo / Shi, Yuhua / Zhang, Lin / Zhao, Shigang / Du, Yanzhi / Xu, Lizhen / Legro, Richard S / Zhang, Heping / Chen, Zi-Jiang. ·Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250001, China. · Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China. · National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001, China. · Center for Reproductive Medicine, Maternal and Child Health Hospital in Guangxi, Nanning 530003, China. · Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China. · Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania 17033. · Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut 06520. ·J Clin Endocrinol Metab · Pubmed #28938429.

ABSTRACT: Context: Women with polycystic ovary syndrome (PCOS) commonly have intrinsic insulin resistance and are recommended to undergo an oral glucose tolerance test (OGTT) for diabetes screening. However, the effect of preconception impaired glucose tolerance (IGT) on pregnancy is still unclear. Objective: To prospectively assess the effect of preconception IGT on pregnancy outcomes. Design, Setting, Patients, Interventions, and Main Outcome Measures: This was a secondary analysis of a multicenter randomized trial in 1508 women with PCOS comparing live birth and obstetric complications between fresh and frozen embryo transfer. At baseline, fasting and 2-hour glucose and insulin levels after 75-g OGTT were measured. Results: Women with preconception IGT had higher risks of gestational diabetes in both singleton pregnancy [9.5% vs 3.2%; odds ratio (OR) 3.13; 95% confidence interval (CI) 1.23to 7.69] and twin pregnancy (20.0% vs 3.2%; OR 7.69; 95% CI 2.78 to 20.00) than women with normoglycemia. Preconception IGT was associated with a higher risk of large for gestational age in singleton newborns compared with normoglycemia (34.7% vs 19.8%; OR 2.13; 95% CI 1.19 to 3.85) or isolated impaired fasting glucose (i-IFG) (34.7% vs 15.4%; OR 2.94; 95% CI 1.33 to 6.25). Women with preconception IGT had a higher singleton pregnancy loss rate than women with i-IFG (31.4% vs 17.5%; OR 2.17; 95% CI 1.11 to 4.17). After adjusting for age, body mass index, duration of infertility, total testosterone level, and treatment groups (frozen vs fresh embryo transfer), these associations remained. Conclusions: Preconception IGT, independent from BMI, was associated with adverse pregnancy outcome compared with i-IFG and normoglycemia.

17 Clinical Trial Effects of gastric bypass surgery on female reproductive function. 2012

Legro, Richard S / Dodson, William C / Gnatuk, Carol L / Estes, Stephanie J / Kunselman, Allen R / Meadows, Juliana W / Kesner, James S / Krieg, Edward F / Rogers, Ann M / Haluck, Randy S / Cooney, Robert N. ·Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, 500 University Drive, H103, Hershey, Pennsylvania 17033, USA. rsl1@psu.edu ·J Clin Endocrinol Metab · Pubmed #23066115.

ABSTRACT: CONTEXT: Reproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear. OBJECTIVE: The objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery. DESIGN: This was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery. SETTING: The study was conducted at an academic health center. PATIENTS: Twenty-nine obese, reproductive-aged women not using confounding medications participated in the study. MAIN OUTCOME MEASURES: The primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index. RESULTS: Ninety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months. CONCLUSIONS: Ovulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

18 Clinical Trial Increasing burden of institutional review in multicenter clinical trials of infertility: the Reproductive Medicine Network experience with the Pregnancy in Polycystic Ovary Syndrome (PPCOS) I and II studies. 2011

Schlaff, William D / Zhang, Heping / Diamond, Michael P / Coutifaris, Christos / Casson, Peter R / Brzyski, Robert G / Christman, Gregory M / Barnhart, Kurt T / Trussell, J C / Krawetz, Stephen A / Snyder, Peter J / Ohl, Dana / Santoro, Nanette / Eisenberg, Esther / Huang, Hao / Legro, Richard S / Anonymous5350696. ·Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Academic Office Building 1, 12631 E. 17th Avenue, Aurora, CO 80045, USA. william.schlaff@ucdenver.edu ·Fertil Steril · Pubmed #21645894.

ABSTRACT: CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00068861 and NCT00719186.

19 Article Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins. 2020

Legro, Richard S / Diamond, Michael P / Coutifaris, Christos / Schlaff, William D / Alvero, Ruben / Casson, Peter / Christman, Gregory M / Rosen, R Mitchell / Cedars, Marcelle I / Hansen, Karl R / Robinson, Randal / Baker, Valerie / Usadi, Rebecca / Dodson, William C / Estes, Stephanie J / Kunselman, Allen / Stetter, Christina / Barnhart, Kurt T / Coward, R Matthew / Trussell, J C / Krawetz, Stephen A / Santoro, Nanette / Huang, Hao / Zhang, Heping / Eisenberg, Esther / Anonymous961196. ·Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania. Electronic address: RSL1@PSU.EDU. · Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia. · Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Obstetrics and Gynecology, University of Colorado, Denver, Colorado. · Department of Obstetrics and Gynecology, University of Vermont, Burlington, Vermont. · Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan. · Department of Obstetrics and Gynecology, University of California at San Francisco, San Francisco, California. · Department of Obstetrics and Gynecology University of Oklahoma, Oklahoma City, Oklahoma. · Department of Obstetrics and Gynecology, University of Texas at San Antonio, San Antonio, Texas. · Department of Obstetrics and Gynecology, Stanford University, Palo Alto, California. · Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, North Carolina. · Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania. · Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania. · Department of Urology, University of North Carolina, Raleigh, North Carolina; UNC Fertility LLC, Raleigh, North Carolina. · Department of Urology, SUNY Upstate University Hospital, Syracuse, New York. · Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan. · Department of Biostatistics, Yale University, New Haven, Connecticut. · Fertility and Infertility Branch, National Institute of Child Health and Human Development, Rockville, Maryland. ·Fertil Steril · Pubmed #32386612.

ABSTRACT: OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.

20 Article Androgenicity and fertility treatment in women with unexplained infertility. 2020

Wang, Erica T / Diamond, Michael P / Alvero, Ruben / Casson, Peter / Christman, Gregory M / Coutifaris, Christos / Hansen, Karl R / Sun, Fangbai / Legro, Richard S / Robinson, Randal D / Usadi, Rebecca S / Pisarska, Margareta D / Santoro, Nanette F / Zhang, Heping / Anonymous26801193. ·Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: erica.wang@cshs.org. · Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia. · Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado. · Department of Obstetrics and Gynecology, University of Vermont, Burlington, Vermont. · Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida. · Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. · Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma. · Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut. · Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania. · Department of Obstetrics and Gynecology, University of Texas Health San Antonio Long School of Medicine, San Antonio, Texas. · Department of Obstetrics and Gynecology, Atrium Health, Charlotte, North Carolina. · Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California. ·Fertil Steril · Pubmed #32192596.

ABSTRACT: OBJECTIVE: To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. DESIGN: Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. SETTING: Multicenter university-based clinical practices. PATIENT(S): Nine hundred couples with unexplained infertility were included. Women were 18-40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. RESULT(S): When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. CONCLUSION(S): In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01044862.

21 Article The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. 2020

Steiner, Anne Z / Hansen, Karl R / Barnhart, Kurt T / Cedars, Marcelle I / Legro, Richard S / Diamond, Michael P / Krawetz, Stephen A / Usadi, Rebecca / Baker, Valerie L / Coward, R Matthew / Huang, Hao / Wild, Robert / Masson, Puneet / Smith, James F / Santoro, Nanette / Eisenberg, Esther / Zhang, Heping / Anonymous2661200. ·Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina. Electronic address: anne.steiner@duke.edu. · Department of Obstetrics and Gynecology, Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma. · Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Obstetrics and Gynecology, University of California-San Francisco, San Francisco, California. · Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, Pennsylvania. · Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia. · Department of Obstetrics and Gynecology & Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan. · Department of Reproductive Endocrinology and Infertility, Atrium Health, Charlotte, North Carolina. · Department of Obstetrics and Gynecology, Stanford University, Palo Alto, California. · Department of Urology, University of North Carolina, Chapel Hill, North Carolina. · Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut. · Department of Urology, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Urology, University of California- San Francisco, San Francisco, California. · Department of Obstetrics and Gynecology, University of Colorado, Denver, Colorado. · Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. ·Fertil Steril · Pubmed #32111479.

ABSTRACT: OBJECTIVE: To determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial with an internal pilot study. SETTING: Nine fertility centers in the United States from December 2015 to December 2018. PATIENT(S): Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency. INTERVENTION(S): Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l-carnitine, 20 mg of zinc, 1,000 μg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6. MAIN OUTCOME MEASURE(S): Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment. RESULT(S): In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median -4.0 [interquartile range-12.0, 5.7] million/mL) and placebo group (+2.4 [-9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%. CONCLUSION(S): Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT02421887.

22 Article First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. 2019

Wang, Rui / Li, Wentao / Bordewijk, Esmée M / Legro, Richard S / Zhang, Heping / Wu, Xiaoke / Gao, Jingshu / Morin-Papunen, Laure / Homburg, Roy / König, Tamar E / Moll, Etelka / Kar, Sujata / Huang, Wei / Johnson, Neil P / Amer, Saad A / Vegetti, Walter / Palomba, Stefano / Falbo, Angela / Özmen, Ülkü / Nazik, Hakan / Williams, Christopher D / Federica, Grasso / Lord, Jonathan / Sahin, Yilmaz / Bhattacharya, Siladitya / Norman, Robert J / van Wely, Madelon / Mol, Ben Willem / Anonymous4631008 / Anonymous4641008. ·Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia. · Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia. · Centre for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. · Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA, USA. · Department of Biostatistics, Yale University School of Public Health, New Haven, CO, USA. · Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China. · Department of Obstetrics and Gynecology, Medical Research Center, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland. · Homerton Fertility Centre, Homerton University Hospital, London, UK. · Department of Obstetrics and Gynecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. · Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis (OLVG) West, Amsterdam, the Netherlands. · Department of Obstetrics and Gynaecology, Kar Clinic and Hospital, Bhubaneswar, India. · Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China. · Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. · Department of Obstetrics and Gynaecology, University of Nottingham, Royal Derby Hospital, Derby, UK. · Infertility Unit, Fondazione I.R.C.C.S. Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. · Department of Obstetrics and Gynecology, Grande Ospedale Metropolitano of Reggio Calabria, Reggio Calabria, Italy. · Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, Italy. · Department of Obstetrics and Gynecology, School of Medicine, Zonguldak Bulent Ecevit University, Kozlu, Zonguldak, Turkey. · Department of Obstetrics and Gynaecology, Adana City Training and Research Hospital, Adana, Turkey. · Reproductive Medicine and Surgery Center of Virginia, Charlottesville, VA, USA. · Department of Surgery Obstetrics and Gynecology, University of Catania, Catania, Italy. · Department of Obstetrics and Gynaecology, Royal Cornwall Hospital, University of Exeter Medical School, Truro, UK. · Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. · Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, UK. · Fertility SA, Adelaide, SA, Australia. ·Hum Reprod Update · Pubmed #31647106.

ABSTRACT: BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

23 Article A brief update on the evidence supporting the treatment of infertility in polycystic ovary syndrome. 2019

Costello, Michael F / Misso, Marie L / Balen, Adam / Boyle, Jacqueline / Devoto, Luigi / Garad, Rhonda M / Hart, Roger / Johnson, Louise / Jordan, Cailin / Legro, Richard S / Norman, Rob J / Moran, Lisa / Mocanu, Edgar / Qiao, Jie / Rodgers, Ray J / Rombauts, Luk / Tassone, Eliza C / Thangaratinam, Shakila / Vanky, Eszter / Teede, Helena J. ·University of New South Wales, Sydney, New South Wales, Australia. · National Health and Medical Research Council Centre for Research Excellence in PCOS, Monash University, Melbourne, Victoria, Australia. · Adelaide University, Adelaide, South Australia, Australia. · Monash Centre for Health Research and Implementation, Monash Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Monash Health, Melbourne, Victoria, Australia. · Leeds Fertility, Leeds Teaching Hospitals, London, UK. · Faculty of Medicine, University of Chile, Santiago de Chile, Chile. · Division of Obstetrics and Gynaecology, University of Western Australia, Perth, Western Australia, Australia. · Victorian Assisted Reproductive Treatment Authority, Melbourne, Victoria, Australia. · Genea Hollywood Fertility, Perth, Western Australia, Australia. · Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA, USA. · Robinson Research Institute, University of Adelaide and Fertility SA, Adelaide, South Australia, Australia. · Royal College of Surgeons, Rotunda Hospital, Dublin, Ireland. · Department of Obstetrics and Gynaecology, Medical Center for Human Reproduction, Peking University Third Hospital, Beijing, China. · Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia. · Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia. · Barts Research Centre for Women's Health (BARC), Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. ·Aust N Z J Obstet Gynaecol · Pubmed #31514246.

ABSTRACT: BACKGROUND: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. AIMS: This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. MATERIALS AND METHODS: International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. RESULTS: Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. CONCLUSION: This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.

24 Article Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility. 2019

Costello, M F / Misso, M L / Balen, A / Boyle, J / Devoto, L / Garad, R M / Hart, R / Johnson, L / Jordan, C / Legro, R S / Norman, R J / Mocanu, E / Qiao, J / Rodgers, R J / Rombauts, L / Tassone, E C / Thangaratinam, S / Vanky, E / Teede, H J / Anonymous3941003. ·School of Women's and Children's Health, University of New South Wales, High St, Kensington, Sydney, New South Wales, Australia. · Monash Centre for Health Research and Implementation, Monash Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia. · Monash Health, Clayton, Melbourne, Australia. · Reproductive Medicine and Surgery, Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds, UK. · Department of Obstetrics and Gynecology, Faculty of Medicine, University of Chile, Santiago, Chile. · National Health and Medical Research Council Centre for Research Excellence in PCOS, Monash Centre for Health Research and Implementation, Monash Public Health and Preventive Medicine, Monash University, Victoria, Australia. · Division of Obstetrics and Gynaecology, University of Western Australia, Crawley, WA, Australia. · Victorian Assisted Reproductive Treatment Authority, Victoria, Australia. · Genea Hollywood Fertility, 190 Cambridge St, Wembley WA, Australia. · Department of Obstetrics and Gynecology, Penn State University College of Medicine, USA. · National Health and Medical Research Council Centre for Research Excellence in PCOS, Monash University, Melbourne, Victoria, Australia. · Adelaide University, Adelaide, South Australia, Australia. · Royal College of Surgeons, Rotunda Hospital, 123 St Stephen's Green, Dublin, Ireland. · Peking University Third Hospital, Haidian Qu, Beijing Shi, China. · Robinson Research Institute, University of Adelaide and Fertility SA, Adelaide, South Australia, Australia. · Department of Obstetrics and Gynaecology, Monash University, Clayton, Melbourne, Victoria 3168, Australia. · Barts Research Centre for Women's Health (BARC), Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. ·Hum Reprod Open · Pubmed #31486807.

ABSTRACT: STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. STUDY DESIGN SIZE DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. A (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. The guideline was peer-reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE II criteria and underwent methodological review. This guideline was approved by all members of the GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low ( LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTERESTS: The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine (ASRM). GDG members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

25 Article Association between testosterone, semen parameters, and live birth in men with unexplained infertility in an intrauterine insemination population. 2019

Trussell, J C / Coward, R Matthew / Santoro, Nanette / Stetter, Christy / Kunselman, Allen / Diamond, Michael P / Hansen, Karl R / Krawetz, Stephen A / Legro, Richard S / Heisenleder, Dan / Smith, James / Steiner, Anne / Wild, Robert / Casson, Peter / Coutifaris, Cristos / Alvero, Reuben R / Robinson, R B / Christman, Greg / Patrizio, Pasquale / Zhang, Heping / Lindgren, Mark C / Anonymous6401143. ·Department of Urology, Upstate University Hospital, Syracuse, New York. Electronic address: jctrussell1@verizon.net. · Department of Urology, UNC School of Medicine, Chapel Hill, North Carolina; UNC Fertility, Raleigh, North Carolina. · Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado. · Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. · Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, Georgia. · Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. · Department of Obstetrics and Gynecology and Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan. · Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. · Ligand Assay and Analysis Core, University of Virginia, Charlottesville, Virginia. · Department of Urology, University of California, San Francisco, San Francisco, California. · Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina. · Partner of Northeastern Reproductive Medicine, Colchester, Vermont. · Department of Obstetrics and Gynecology, University of Pennsylvania, Phildelphia, Pennsylvania. · Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, Rhode Island. · University of Texas Health Science Center, San Antonio, San Antonio, Texas. · Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida. · Yale Fertility Center, New Haven, Connecticut. · Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut. · Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. ·Fertil Steril · Pubmed #30982604.

ABSTRACT: OBJECTIVE: To determine whether men with unexplained infertility and low total T (TT) have abnormal spermatogenesis and lower fecundity. DESIGN: Secondary analysis of the prospective, randomized, multicenter clinical trial, Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SETTING: Infertility clinics. PATIENT(S): Nine hundred couples with unexplained infertility enrolled in AMIGOS. Semen analysis with an ejaculate of at least 5 million total motile sperm was required for enrollment. For inclusion in this secondary analysis, a fasting TT was required. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Logistic regression, adjusted for age and body mass index, assessed the association between low TT (defined as <264 ng/dL), semen parameters, and pregnancy outcome. RESULT(S): Seven hundred eighty-one men (mean age, 34.2 ± 5.7 years) with a median (interquartile range) TT of 411 (318-520) ng/dL were included. Men with TT <264 ng/dL were less likely to have normal (≥4% strict Kruger) morphology (unadjusted odds ratio [OR], 0.56; 95% confidence interval [CI], 0.34, 0.92; adjusted OR, 0.59; 95% CI, 0.35, 0.99). There was no association between low TT and semen volume < 1.5 mL, sperm concentration < 15 × 10 CONCLUSION(S): In couples with unexplained infertility, low TT in the male partner was associated with abnormal sperm morphology and lower live birth rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.

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