Richard Legro

• M.D.
• Head of Department at Penn State Hershey Medical Center and Penn State College of Medicine

Objective To test the hypothesis that a freeze-all strategy would increase the chance of live birth compared with fresh embryo transfer in women with low prognosis for in vitro fertilisation (IVF) treatment. Design Pragmatic, multicentre, randomised controlled trial. Setting Nine academic fertility centres in China. Participants 838 women with a...

Background Polycystic ovary syndrome (PCOS) is a common endocrinopathy with significant reproductive, metabolic, and psychological complications. Consensus on PCOS clinical research priorities across end-users is fundamental and necessitates a robust co-development of a clinical research roadmap to guide international research efforts. Methods A m...

Context Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. Objective We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and s...

OBJECTIVE To compare pregnancy and neonatal outcomes in women with hyperandrogenic polycystic ovarian syndrome (PCOS) phenotypes compared with nonhyperandrogenic PCOS phenotypes. METHODS We conducted a retrospective cohort study of participants in the PPCOS (Pregnancy in Polycystic Ovary Syndrome) I and II randomized controlled trials; all of the...

Context Previous studies have shown that the prevalence of polycystic ovary syndrome (PCOS) may vary according to race/ethnicity, although few studies have assessed women of different ethnicities who live in similar geographic and socio-economic conditions. Objective To determine the prevalence of PCOS in an unselected multiethnic population of pr...

Background Abdominal obesity is associated with endothelial dysfunction and poorer vascular health. Avocado consumption improves postprandial endothelial function; however, the longer‐term effects remain unclear. It was hypothesized that the daily addition of 1 avocado to a habitual diet for 6 months would improve flow‐mediated dilation (FMD) and c...

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic and proteomic study, we expand the number of genetic loci from 19 to 29, and identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to a larger...

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women, and its diagnosis rests on three principal features: ovulatory/menstrual dysfunction, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology (PCOM). Currently, data on age- and ethnicity-dependent features of PCOM remain insufficient. We aimed to esti...

Background Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analy...

Keywords: pelvic ultrasound, follicle number per ovary, FNPO, ovarian volume, PCOM, upper normal limits, referral population

Disclosure: C. Parker: None. R. Bauer: None. C.K. Welt: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is a multisystem endocrine disorder and is the most common form of anovulatory infertility of reproductive aged women (6-15%). PCOS is characterized by the presence of hyperandrogenemia, ir...

Disclosure: R. Bauer: None. L. Gorsic: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility among reproductive age women. In addition to experiencing reproductive symptoms, women with PCOS are at elevated risk of developing obesity, insulin resist...

Disclosure: J. Cai: None. K. Brewer: None. R. Sisk: None. R.S. Legro: None. A.E. Dunaif: None. Prenatal exposure to androgens produces phenocopies of PCOS in animal models. In mice, there is evidence for transgenerational prenatal androgen effects. Human studies considered to support the hypothesis that intrauterine actions of androgens play a majo...

Study question: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary answer: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points...

Study question Do dietary and/or physical activity interventions prior to fertility treatment improve live birth rates in women with overweight or obesity? Summary answer Dietary and/or physical activity interventions prior to fertility treatment do not significantly increase live birth rates in women with overweight or obesity. What is known alr...

Objective To determine if moderate physical activity is associated with live birth rates in women with unexplained infertility and obesity. Design Secondary analysis of the Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial. Setting US fertility centers, 2015–2019. Pa...

Androgen assessment is a key element for diagnosing polycystic ovary syndrome (PCOS), and defining a “normal” level of circulating androgens is critical for epidemiological studies. We determined the upper normal limits (UNLs) for androgens in a population-based group of premenopausal “healthy control” women, overall and by ethnicity (Caucasian and...

Introduction: 11-oxygenated C19 steroids (11-oxyandrogens) have been shown to rise during adrenarche and remain higher throughout adulthood than in early childhood. The patterns of circulating 11-oxyandrogens throughout normal puberty has not yet been described. Methods: We conducted a secondary analysis of healthy youth participants, both males...

Introduction: Dietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the eff...

Objective To determine the feasibility, safety and outcomes of an oil-based, iodinated contrast using office-based, ultrasound-imaged hysterosalpingography (Sono-HSG) in women with infertility. Design Randomized Controlled Double Blind Clinical Trial. Setting Academic health center. Intervention(s) Tubal flushing with oil-based contrast medium (...

Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and co...

Polycystic ovary syndrome (PCOS) affects 5–18% of women, and is a reproductive, metabolic, and psychological condition with impacts across the lifespan. The cause is complex, and includes genetic and epigenetic susceptibility, hypothalamic and ovarian dysfunction, excess androgen exposure, insulin resistance, and adiposity-related mechanisms. Diagn...

Background Excess visceral adiposity is associated with increased risk of cardiometabolic disorders. Short‐term well‐controlled clinical trials suggest that regular avocado consumption favorably affects body weight, visceral adiposity, and satiety. Methods and Results The HAT Trial (Habitual Diet and Avocado Trial) was a multicenter, randomized, c...

Introduction Existing randomised controlled trials (RCTs) comparing a freeze-all embryo transfer strategy and a fresh embryo transfer strategy have shown conflicting results. A freeze-all or a fresh transfer policy may be preferable for some couples undergoing in-vitro fertilisation (IVF), but it is unclear which couples would benefit most from eac...

Objective We analyzed the exclusion of pregnant and breastfeeding individuals and those capable of pregnancy in COVID-19 vaccine and clinical treatment trials. Methods Inclusion and exclusion criteria were extracted from all listed COVID-19 vaccine and treatment clinical trials from May 1, 2020 to October 31, 2020 using the U.S. National Library o...

(Abstracted from N Engl J Med 2021;385:2047–2058) To optimize live birth rate per transfer in in vitro fertilization (IVF), morphologic score based on visualization and genetic status based on preimplantation genetic testing for aneuploidy (PGT-A) are used to select the highest quality embryos. Although some studies suggest an increased live birth...

Objective To determine the reproducibility of World Health Organization 5th edition (WHO5) strict grading methodology by comparing the percentage of morphologically normal sperm (PNS) recorded by the core laboratory with results obtained at the fertility centers participating in a multi-site clinical trial. Design Secondary cohort analysis of data...

Background Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight...

BACKGROUND Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF). METHODS In this multicenter, randomized, controlled tria...

PurposeThe understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple...

Importance Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective To determine if active management is more effective in achieving pr...

The goal of this Views and Reviews is to let colleagues and leaders well versed in the African American experience in reproductive medicine address the problems of racism affecting our trainees and patients and, more significantly, propose solutions. The areas in reproductive medicine that will be explored from the African American perspective incl...

Context Sleep plays important roles in metabolic and reproductive function, and polycystic ovary syndrome (PCOS) is associated with sleep disturbances including increased prevalence of obstructive sleep apnea. Objective We sought to evaluate sleep parameters in infertile women with PCOS compared to women with unexplained infertility (UI) and ident...

Objective To examine factors associated with increased DNA fragmentation index (DFI), evaluate pregnancy outcomes with increased DFI, and compare three independent DFI assays. Design Secondary analysis; Setting Nine US-based fertility centers. Patients Infertile males (N=147) with sperm concentration ≤15M/ml, motility ≤ 40%, or normal morphology...

This introduction tees off an outstanding collection of Views and Reviews articles on the effects of the SARS-CoV-2 virus and COVID-19 infection on human reproductive health. These articles written by experts in the field review the current literature on COVID-19 and male reproductive health, female reproductive health and the ART laboratory. Despi...

Background: The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the foetus i...

Study Question Can the priorities for future research in infertility be identified? Summary Answer The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. What is Known...

Study Question Can a core outcome set to standardize outcome selection, collection, and reporting across future infertility research be developed? Summary Answer A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCT) and systematic reviews evaluating potential treatments for infertility. What is K...

Study Question Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? Summary Answer Consensus definitions for individual core outcomes, contextual statements, and a standardized reporting table have been developed. What is Known Already Different definitions exis...

STUDY QUESTION What demographic and baseline characteristics are predictive of adherence to reproductive medicine clinical trial protocols, live birth or participation in genetic studies? SUMMARY ANSWER Race, BMI and lower income are associated with likelihood of non-adherent to reproductive medicine clinical trial protocols, while race influences...

Objective To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. Design Secondary analysis of randomized trials. Setting Multicenter fertility trial sites. Patient(s) A total of 900 women with UI and 750 women with P...

Objective To describe the prevalence of female sexual dysfunction in a well-defined polycystic ovary syndrome (PCOS) population, and to assess the impact of common PCOS treatments on sexual function. Design Secondary analysis of a randomized controlled trial, oral contraceptive pills and weight loss in PCOS. Setting Two academic medical centers....

Objective: To examine effects of common treatments for PCOS on a panel of hormones(reproductive/metabolic). Design: Secondary analysis of blood from a RCT of three 16-week preconception interventions designed to improve PCOS-related abnormalities: continuous oral contraceptives(OCP, N=34 subjects), intensive lifestyle modification(Lifestyle, N =...

Objective: To study the association of endometrial thickness (EMT) with live birth rates (LBR) in ovarian stimulation with intrauterine insemination (OS-IUI) treatments for unexplained infertility. Design: Prospective cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (A...

Objective To determine the relationship between high antimüllerian hormone (AMH) levels and increased preterm delivery risk in populations of women with polycystic ovary syndrome (PCOS) or unexplained infertility undergoing ovulation induction. Design Secondary analysis of data from two multicenter randomized clinical trials: Pregnancy in Polycyst...

Context Hyperandrogenemia (HA) is a consistent reproductive phenotype in women with PCOS and their relatives. Increased testosterone levels are present in premenarchal daughters of affected women (PCOS-d). Obese girls (OB-g) without a family history of PCOS also have peripubertal HA. The sources and significance of HA in these groups remains unknow...

Context Controversy exists regarding if and how body mass index (BMI) impacts antimullerian hormone (AMH) in women with and without polycystic ovary syndrome (PCOS). Understanding the BMI-AMH relationship has critical implications for clinical interpretation of laboratory values and could illuminate underlying ovarian physiology. Objective Test th...

Background Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive...

As the first paper in this series of Views and Reviews on randomized controlled trials (RCTs), we aim to provide the basics of RCTs in infertility research. In this paper, we discuss the need and ethical considerations of large trials in infertility research and important aspects to guarantee the quality of a trial, including protocols, registratio...

Study question: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? Summary answer: Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection t...

We hypothesized that weight loss with an intensive preconception lifestyle (IL) intervention of caloric restriction with meal replacements, daily orlistat and increased physical activity in women with obesity and unexplained infertility (UI) was more likely to result in Good Birth Outcome than a standard lifestyle modification (SL) with increased p...

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 I...

Research question Is there a difference in live birth rate between a freeze-only strategy and fresh embryo transfer, and what is the effect of varying progesterone levels on the day of hCG administration? Design This was a secondary analysis of data from 3 randomized trials comparing the live birth rate after elective frozen vs. fresh embryo trans...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Importance More than 20% of births globally are by cesarean delivery, including more than 30% in the US. Prior studies have reported lower rates of childbearing after cesarean delivery, but it is not clear if this is due to maternal choice or lower conception rates. Objective To investigate the association between mode of first delivery and subseq...

Study question: What are the psychosocial and financial issues experienced among families with children 2-12 years of age conceived by ART? Summary answer: Our results suggest that families with children, 2-12 years of age, conceived via ART are doing well, although impacts were identified on parents of twins and higher-order multiples. What is...

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 cli...

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 stud...

Context: Although reproductive life planning (RLP) is recommended in federal and clinical guidelines and may help insured women make personalized contraceptive choices, it has not been systematically evaluated for effectiveness. Methods: In 2014, some 984 privately insured women aged 18-40 who were not intending to become pregnant in the next ye...

In the Data Availability Statement, the URL does not fully match the data described. The URL should be: https://doi.org/10.17863/CAM.36024. The correct Data Availability Statement is: Summary statistic GWAS meta-analysis results for the combined dataset excluding 23andMe are available at https://doi.org/10.17863/CAM.36024. The most significant 10,0...

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 accur...

Background Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive...

Context The relationship between reproductive and cardio-metabolic aging is unclear. It is unknown if the relationship differs across different clinical populations. Objective To determine whether markers of ovarian reserve are associated with cardio-metabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary synd...

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...

In the United States almost 33% of adults are considered obese (BMI > 30 kg/m2). Both animal models and to a lesser extent human studies, have associated BMI, a measure of obesity, with alterations in sperm DNA methylation and RNAs. Sperm RNAs from the Assessment of Multiple Gestations from Ovarian Stimulation trial, were isolated and sequenced. A...

Context Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this...

BACKGROUND: Serum peptide biomarkers are frequently abnormal in women with PCOS reflecting underlying reproductive and metabolic dysfunction. The effects of treatment on these biomarkers is poorly described. METHODS: We performed a secondary analysis on obese women with PCOS who had participated in a RCT(JCEM, PMID: 26401593) where they were random...

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(...

Context Increased testosterone (T) levels are a cardinal feature of PCOS. Female relatives of affected women, including postmenopausal mothers and premenarchal daughters (PCOS-d), have elevated T levels consistent with a genetic susceptibility to this phenotype. Obese girls (OB-g) also have increased T levels throughout puberty, which may indicate...