A total fertility rate (the average number of children born per woman during their reproductive lifespan) of 2.1, termed the 'replacement level', is needed to keep a population size stable. This index is already below 2 in the great majority of developed and middle-income countries, and current estimates show that by the year 2100, many countries will experience a population decline of more than 50%. This poses an extraordinary challenge to our societies, as a shrinking workforce will produce fewer products and services and therefore less income from taxes to sustain children and elderly individuals. Economic factors such as household income and the cost of housing and childcare have been shown to be strong drivers of the willingness to establish a family; however, current trends in attitudes to childbearing reveal a high percentage of voluntary childlessness, i.e. individuals not willing to have children. The International Federation of Fertility Societies (IFFS) MoreJoy™ campaign seeks to explore the reasons for these cultural changes, is raising awareness of the fertility decline and is committed to promoting education on fertility and infertility prevention, and access to infertility care to all, irrespective of gender or marital status.

Since its early days, assisted reproductive technology (ART) has undergone tremendous developments and is now largely used to treat a wide range of causes of infertility and to prevent the transmission of genetic disorders. Nevertheless, success rates per cycle remain relatively low (especially in poor-prognosis patients), while the high costs associated with treatment frequently limit the completion of an adequate number of cycles, thus increasing drop-out rates. In this context, the availability of reliable data and provision of comprehensive information by reproductive medicine specialists are essential. However, current metrics and indicators are not up to date with recent innovations in clinical and laboratory practice. This paper supports an approach based on identifying, before starting a treatment, the realistic number of embryo transfers required by a specific couple to achieve the expected chance of a live birth, defined as expected live birth rate, based on a thorough diagnostic assessment. Furthermore, once a treatment strategy is agreed upon by clinicians and patients, postponing embryo transfer until the necessary number of embryos has been cryopreserved may reduce the risk of treatment discontinuation before all the embryos are used. This approach may also improve clinical outcomes and enhance the cost-effectiveness of ART treatments.

The remarkable advances in the efficacy and safety of IVF treatment that have been achieved since the first IVF baby was born in 1978 stand comparison with any other branch of medicine. These advances have continued despite the withdrawal of public investment in clinical reproductive medicine and research, raising a number of questions. How is this global shift from public to largely private sector care provision affecting the quality and direction of research, innovation and clinical training? This Commentary reviews the implications, both positive and less so, for academic reproductive medicine and training, and outline the opportunities that exist to secure the future of the subspeciality and ongoing progress in fertility care in this changing environment.

Since the early 1970s, family planning policies aiming to reduce global population growth have been successful. Currently, more than 50% of all countries are (way) below the replacement level of 2.1 child per woman. Underpopulation causes distinct society challenges in many countries. More focus on family-building strategies (including decreasing barriers for people who would like to establish a family) is urgently needed.

Importance:Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. Objective:To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. Design, Setting, and Participants:This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. Interventions:Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. Main Outcomes and Measures:The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). Results:Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). Conclusions and Relevance:Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. Trial Registration:onderzoekmetmensen.nl Identifier: NL67329.078.18.

No consensus exists on the preferred way to represent the outcomes of assisted reproductive technology (ART). Currently used outcomes are usually procedure driven and generated by healthcare professionals. Value-based healthcare, emphasizing the need to define preferred outcomes with and around patients, has raised much attention in medicine outside fertility care. This commentary outlines how currently used outcome measures could detrimentally affect the way ART is practised, and proposes ways to improve such outcomes.

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 functional ovarian reserve. Hormonal regulation in the aetiology of this condition, through metabolic and reproductive features, was emphasised. The proteomic analysis highlighted perturbations of metabolically-related biology that are typical in women with PCOS. A PCOS polygenic risk score was associated with adverse cardio-metabolic outcomes, with differing contributions of testosterone and BMI in women and men. Finally, while oligo- and anovulatory infertility are characteristic features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

BACKGROUND:Family-planning policies have focused on contraceptive approaches to avoid unintended pregnancies, postpone, or terminate pregnancies and mitigate population growth. These policies have contributed to significantly slowing world population growth. Presently, half the countries worldwide exhibit a fertility rate below replacement level. Not including the effects of migration, many countries are predicted to have a population decline of >50% from 2017 to 2100, causing demographic changes with profound societal implications. Policies that optimize chances to have a child when desired increase fertility rates and are gaining interest as a family-building method. Increasingly, countries have implemented child-friendly policies (mainly financial incentives in addition to public funding of fertility treatment in a limited number of countries) to mitigate decreasing national populations. However, the extent of public spending on child benefits varies greatly from country to country. To our knowledge, this International Federation of Fertility Societies (IFFS) consensus document represents the first attempt to describe major disparities in access to fertility care in the context of the global trend of decreasing growth in the world population, based on a narrative review of the existing literature. OBJECTIVE AND RATIONALE:The concept of family building, the process by which individuals or couples create or expand their families, has been largely ignored in family-planning paradigms. Family building encompasses various methods and options for individuals or couples who wish to have children. It can involve biological means, such as natural conception, as well as ART, surrogacy, adoption, and foster care. Family-building acknowledges the diverse ways in which individuals or couples can create their desired family and reflects the understanding that there is no one-size-fits-all approach to building a family. Developing education programs for young adults to increase family-building awareness and prevent infertility is urgently needed. Recommendations are provided and important knowledge gaps identified to provide professionals, the public, and policymakers with a comprehensive understanding of the role of child-friendly policies. SEARCH METHODS:A narrative review of the existing literature was performed by invited global leaders who themselves significantly contributed to this research field. Each section of the review was prepared by two to three experts, each of whom searched the published literature (PubMed) for peer reviewed full papers and reviews. Sections were discussed monthly by all authors and quarterly by the review board. The final document was prepared following discussions among all team members during a hybrid invitational meeting where full consensus was reached. OUTCOMES:Major advances in fertility care have dramatically improved family-building opportunities since the 1990s. Although up to 10% of all children are born as a result of fertility care in some wealthy countries, there is great variation in access to care. The high cost to patients of infertility treatment renders it unaffordable for most. Preliminary studies point to the increasing contribution of fertility care to the global population and the associated economic benefits for society. WIDER IMPLICATIONS:Fertility care has rarely been discussed in the context of a rapid decrease in world population growth. Soon, most countries will have an average number of children per woman far below the replacement level. While this may have a beneficial impact on the environment, underpopulation is of great concern in many countries. Although governments have implemented child-friendly policies, distinct discrepancies in access to fertility care remain.

There is mounting evidence that the proportion of high-grade or euploid embryo cannot be increased by intensifying ovarian stimulation in IVF. Randomised controlled trials failed to demonstrate improvement in the livebirth rates by administering >150 IU daily dose of gonadotropins. There is no convincing evidence of improved cumulative livebirth with higher stimulation dose. IVF success relates to ovarian response, which correlates with woman's age and ovarian reserve but not with the intensity of stimulation. Mild ovarian stimulation, defined as less than or equal to 150 IU of daily gonadotropin, adjusted with BMI, may result in equivalent level of success whilst reducing the risk of OHSS and other risks associated with over-response. Mild stimulation IVF is the way forward to make IVF safer, woman-friendly and more affordable.

Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (PE) are expected to have normal estrogen exposure. Within the CREw-IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with a reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) −26.8, 95% CI −37.2 to −16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3–25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD. Significance statement Our results suggest that middle-aged women with PCOS have a higher BD and women with POI have a lower BD. We hypothesized that this is due to either a prolonged estrogen exposure, as seen in women with PCOS, or a reduced estrogen exposure, as in women with POI. In the counseling of women with reproductive disorders on long-term health issues, coronary CT provides a unique opportunity to assess both coronary artery calcium score for cardiovascular screening as well as trabecular BD.

Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.

The new classification of disorders of ovulation has stirred up a healthy debate about the need for change and brings to mind the phrase from which the title of this article derives “I know it’s an ugly-looking antenna, but it gets the job done, and if it ain't broke, don't fix it” (1Attributed to Thomas Bertram Lance. 1977https://en.wikipedia.org/wiki/Bert_LanceGoogle Scholar). The human condition, however, is about striving to improve what we have and enhance the utility of any available tools. To quote Henry Ford “We do not make changes for the sake of making them, but we never fail to make a change when once it is demonstrated that the new way is better than the old way.” Indeed it was this philosophy that 20 years ago led our esteemed opponent to co-convene the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine consensus workshop, in which one of us (A.H.B.) was privileged to participate, and gave us a new definition for polycystic ovary syndrome (PCOS) (2Fauser B. Tarlatzis B. Chang J. Azziz R. Legro R. Dewailly D. et al.The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Hum Reprod. 2004; 19 (Joint publication Fertil Steril 2004;81:19–47): 41-47Crossref PubMed Scopus (4694) Google Scholar). Moreover, we have all witnessed the stormy debate that has rumbled, sometimes explosively, since then, with even some consensus group members arguing against its own conclusions. The European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine definition of PCOS replaced an earlier National Institutes of Health consensus from 1990 that arose from a symposium but was never published in a peer-reviewed journal. Similarly, the World Health Organization (WHO) first presented a classification of ovulation disorders as a monograph (3WHO Scientific Group on Agents Stimulating Gonadal Function in the Human & World Health Organization. Agents stimulating gonadal function in the human: report of a WHO Scientific Group; 1972 August 28–September 1; Geneva. Geneva: World Health Organization 1973.https://apps.who.int/iris/handle/10665/38216Google Scholar), which also did not appear in a peer-reviewed journal. The early iterations of the WHO classification contained between 1 and 7 groups, distinguished by estrogen activity, the presence or absence of hyperprolactinemia, and whether there was a pituitary tumor (4Agents stimulating gonadal function in the human. Report of a WHO scientific group.World Health Organ Tech Rep Ser. 1976; 514: 1-30Google Scholar). This has been modified over time in various reviews and book chapters by single investigators, not by consensus or peer review. Indeed its pathway to the current incarnation is somewhat opaque and peppered by mis-citations. For example, the United Kingdom Guidelines on the investigation and management of infertility, first published in 2004 and updated in 2013 (5National Institute for Health and Care Excellence (NICE). Fertility problems: assessment and treatment. Clinical guideline CG156. London: NICE and RCOG; 2013.https://www.nice.org.uk/guidance/cg156Google Scholar), in discussing the diagnosis of anovulation makes reference to the WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple (6World Health Organization Rowe P.J. Comhaire F.H. Hargreave T.B. Mellows H.J. Laboratory manual for the standardized investigation and diagnosis of the infertile couple. Cambridge University Press, Cambridge, MA1993: 83Google Scholar), yet there is no mention of a classification of ovulatory disorders therein. The National Institute for Health and Care Excellence classification (5National Institute for Health and Care Excellence (NICE). Fertility problems: assessment and treatment. Clinical guideline CG156. London: NICE and RCOG; 2013.https://www.nice.org.uk/guidance/cg156Google Scholar) describes the 3 groups that most investigators currently refer to, namely: group I, comprising women with low serum gonadotropin and estradiol concentrations and thereby encompassing hypogonadotropic hypogonadism, pituitary insufficiency, and hyperprolactinemia; group II is perhaps less well defined and often labeled “gonadotropin disorder” or “hypothalamic/pituitary dysfunction,” with normal serum estradiol levels and therefore predominantly includes those with PCOS; and group III comprises those with high serum gonadotropin and low estradiol concentrations, namely, women with premature ovarian insufficiency (POI). Those of us working in clinical practice see daily that hormone levels do not obey clear rules, so a classification based purely on their measurement is flawed. For example, underweight women with hypothalamic amenorrhea may have suppressed serum concentrations of luteinizing hormone (LH), whereas follicle-stimulating hormone (FSH) levels are often in the normal range (7Morrison A.E. Fleming S. Levy M.J. A review of the pathophysiology of functional hypothalamic amenorrhoea in women subject to psychological stress, disordered eating, excessive exercise or a combination of these factors.Clin Endocrinol (Oxf). 2021; 95: 229-238Crossref PubMed Scopus (20) Google Scholar). Additionally, those with PCOS often have serum FSH and LH levels in the normal range (8Balen A. The pathophysiology of polycystic ovary syndrome: trying to understand PCOS and its endocrinology.Best Pract Res Clin Obstet Gynaecol. 2004; 18: 685-706Crossref PubMed Scopus (117) Google Scholar). Furthermore, ovulatory disorders comprise a spectrum of manifestations ranging from intermittent episodes of cyclical ovarian activity to chronic ovulatory failure and amenorrhea—and these states may fluctuate in an individual over time. Over the last 50 years, since the first iterations of the WHO classifications, our understanding of the pathophysiology of ovulatory disorders has developed with advancements in assay technology, imaging techniques, and genomics. Hence, the International Federation of Gynecology and Obstetrics (FIGO) undertook a Delphi process whereby the international community of stakeholders in ovulatory disorders, including consumer organizations, designed a new system that has revised the WHO classification to meet better the needs of investigators, clinicians, and medical educators (9Munro M.G. Balen A.H. Cho S. Critchley H.O.D. Díaz I. Ferriani R. et al.The FIGO ovulatory disorders classification system.Fertil Steril. 2022; 118: 768-776Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). The FIGO consensus now provides a practical classification and a logical framework for making a precise diagnosis for any woman who presents with features of an ovulatory disorder. We now have 3 clear groups based on the anatomical origin: Hypothalamic, Pituitary, and Ovarian, and a fourth group comprises those with PCOS - resulting in a new acronym HyPO-P. Within the first 3 groups, we have subdivided causes into genetic, autoimmune, iatrogenic, neoplastic, functional, inflammatory/infectious, trauma and vascular, physiological, idiopathic, and endocrine, giving us the mnemonic “GAIN FIT PIE.” Although we appreciate that acronyms may seem contrived and even irritating to some, they serve as an aide memoire for students and those less familiar with the broad complexities of reproductive endocrinology. So why separate PCOS into a category of its own? First, the ovarian category comprises those within the spectrum of ovarian insufficiency, with elevated serum gonadotropins and hypo-estrogenism. Second, we feel that this should be self-evident as the pathophysiology of PCOS is multifaceted and encompasses disturbances of the hypothalamic-pituitary-ovarian axis, androgen production, and insulin metabolism, which in turn may each vary significantly depending on ethnicity and genetic as well as environmental influences (10Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Misso M.L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Fertil Steril. 2018; 110: 364-379Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar, 11Wijeyeratne C. Udayangani D. Balen A.H. Ethnic specific PCOS.Expert Rev Endocrinol Metab. 2013; 8: 71-79PubMed Google Scholar). Indeed, PCOS is such a complex and heterogeneous condition that it deserves special recognition, particularly as it accounts for approximately 90% of those with ovulatory disorders. This circumstance demands extensive guidance devoted to the diagnosis and management of PCOS at different life stages, not only of the impact on ovulation but also its numerous other manifestations whether hyperandrogenism, metabolic, or on long-term health (10Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Misso M.L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Fertil Steril. 2018; 110: 364-379Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar). Every other cause of ovulatory disorder is more simply and clearly defined with respect to symptoms and pathophysiology and, therefore, easily sits within the HyPO–GAIN-FIT-PIE algorithm (review Balen et al, Human Reproduction Update, unpublished data). The features of PCOS include menstrual cycle disturbances, signs of androgen excess, and abnormalities of biochemical profiles, including elevated serum concentrations of LH, testosterone (T), androstenedione, and antimüllerian hormone (AMH). Hyperinsulinemia and metabolic disturbances are associated features, particularly in the 40% to 50% of women with PCOS who are overweight. Presentation of the syndrome is so varied that one, all, or any combination of the aforementioned features may be present in association with/or without an ultrasound picture of the polycystic ovaries. There is considerable heterogeneity of symptoms and signs among women with PCOS, and, for an individual, these often change over time. Young women may, for example, be particularly troubled by the over-secretion of ovarian androgens, manifesting in acne and hirsutism, or by the effects of irregular and heavy menstrual periods. Then, when fertility is desired, PCOS is the commonest cause of anovulatory infertility, and there are significant challenges in providing effective and safe ovulation induction therapy (12Balen A.H. Morley L.C. Misso M. Franks S. Legro R.S. Wijeyaratne C.N. et al.WHO recommendations for the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS).Hum Reprod Update. 2016; 22: 687-708Crossref PubMed Scopus (337) Google Scholar). Although, paradoxically, women with PCOS may take longer to conceive, they end up with family sizes similar to those of the general population, their menstrual cycles tend to become more regular toward the end of their reproductive years, and their ovaries fertile for longer. For older women with PCOS, there are significant associations with metabolic problems, diabetes, and cardiovascular disease, although these do not always translate to high mortality. Several interlinking factors affect the expression of PCOS: weight gain is associated with worsening symptoms, whereas weight loss may ameliorate symptomatology and the endocrine and metabolic profile. Overall, PCOS can be considered “a condition of our time,” and as the epidemic of obesity and metabolic disease risk spreads, research that explores how this condition affects the health and well-being of future generations is becoming increasingly relevant. Although the manifestations of PCOS are well characterized, the pathophysiology of ovarian dysfunction originates in several ways. Ovarian dysfunction is evidenced by numerous immature egg-containing follicles (the eponymous “cysts”) that fail to grow and ovulate in a coordinated fashion because of the hypersecretion of LH and insulin promoting the overproduction of androgens together with excess ovarian AMH production that disrupts follicle recruitment. To understand the pathophysiology of PCOS, one has to consider both the nature of the dysfunction within the ovary and the external influences that prevail to modify ovarian behavior. These environmental influences may start as early as embryogenesis and certainly occur during fetal development and throughout life. The scene is set in utero through the combination of maternal endocrine milieu and placental function influencing fetal hypothalamic function, gonadal development, and fat deposition. Some of these elements may be further affected by epigenetic factors and the interaction of maternal and in utero environments. The pathogenesis of polycystic ovaries and the associated syndrome is still being elucidated. Still, the heterogeneity of the presentation of PCOS suggests that there are multiple routes to the development of the condition. Furthermore, there are numerous phenotypes and quite significant ethnic variations. Historically, the genetic propensity to gain weight easily in some populations may have preserved fertility in times of famine (the “thrifty genotype”), as underweight women do not have the nutrition to sustain a healthy pregnancy. So the gene(s) that lead to PCOS may have previously conferred an evolutionary advantage. There have been numerous attempts to elucidate the genes that may be involved, with the latest genome-wide association studies identifying several potential loci of interest, but still no firm conclusions (13Day F. Karaderi T. Jones M.R. Meun C. He C. Drong A. et al.Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.PLoS Genet. 2018; 14e1007813Crossref PubMed Scopus (217) Google Scholar, 14Hiam D. Moreno-Asso A. Teede H.J. Laven J.S.E. Stepto N.K. Moran L.J. et al.The genetics of polycystic ovary syndrome: an overview of candidate gene systematic reviews and genome-wide association studies.J Clin Med. 2019; 8: 1606Crossref PubMed Scopus (47) Google Scholar). Recent data that DNA methylation and other epigenetic changes play a role in the development of PCOS (15Vázquez-Martínez E.R. Gómez-Viais Y.I. García-Gómez E. Reyes-Mayoral C. Reyes-Muñoz E. Camacho-Arroyo I. et al.DNA methylation in the pathogenesis of polycystic ovary syndrome.Reprod (Camb Engl). 2019; 158: R27-R40Crossref PubMed Scopus (51) Google Scholar) and the recent evidence that sperm methylation is affected by male obesity (16Soubry A. Guo L. Huang Z. Hoyo C. Romanus S. Price T. et al.Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study.Clin Epigenetics. 2016; 8: 51Crossref PubMed Scopus (135) Google Scholar) and that this can influence the methylation status of genes for the offspring (17Potabattula R. Dittrich M. Schorsch M. Hahn T. Haaf T. El Hajj N. Male obesity effects on sperm and next-generation cord blood DNA methylation.PLoS One. 2019; 14e0218615Crossref PubMed Scopus (31) Google Scholar), also combine to provide an intriguing hypothesis about the possible paternal influences on the development of PCOS. It is, therefore, clear that PCOS cannot be shoe-horned into the “Hy,” “P,” or “O” categories of the new FIGO classification, and so to quote Hippocrates, we can use the HyPO-P classification to “understand the antecedents, know the present and foretell the future …… in order to mediate these things and have two special objectives in view with regard to disease, namely to do good and to do no harm.” We, therefore, believe that the new HyPO-P classification of disorders of anovulation provides a clear and logical framework with which to better serve our patients for the future. The FIGO relies on opinions and consensus in the midst of a digital transformation, potentially allowing for a more accurate annotation and clearer classification of health conditions in an automated and replicable capacity? We believe that at the present time, a data-first, patient-centric approach to diagnostics, which uses electronic health records, imaging, biobanks, and multiomic datasets, represents the only robust way toward an unbiased assessment of the ovulatory disorders. Indeed, the term ovulatory disorders is not well defined, and it is surprising to realize that the fundamentals of a classification originally put forward some 50 years ago by Insler and Lunenfeld (18Insler V. Melmed H. Mashiah S. Monselise M. Lunenfeld B. Rabau E. Functional classification of patients selected for gonadotropic therapy.Obstet Gynecol. 1968; 32: 620-626PubMed Google Scholar, 19Lunenfeld B. Insler V. Classification of amenorrhoeic states and their treatment by ovulation induction.Clin Endocrinol (Oxf). 1974; 3: 223-237Crossref PubMed Scopus (68) Google Scholar), and subsequently adopted by the WHO (3WHO Scientific Group on Agents Stimulating Gonadal Function in the Human & World Health Organization. Agents stimulating gonadal function in the human: report of a WHO Scientific Group; 1972 August 28–September 1; Geneva. Geneva: World Health Organization 1973.https://apps.who.int/iris/handle/10665/38216Google Scholar), is still used today (20Fauser B.C. Overview of ovulation induction.in: Barbieri R.L. Crowley W.F. Deputy Editor: Martin KA. UpToDate, section. Oct 2022Google Scholar). Although various investigators have proposed some minor modifications over the years, serious attempts aiming to either validate or update the WHO classification based on solid scientific evidence are nonexisting. The WHO classification may not be particularly science-based but instead is focused on the biological insights and newly available treatment options at the time. Clinical practice experience over many decades has proven this classification to represent a useful tool as a starting point for diagnosis and treatment in every day patient care. There should be compelling arguments and robust scientific evidence to replace such a system with a more complex classification, as currently proposed by FIGO. We can easily agree on the many shortcomings of the current classification, as outlined at length in the recently published FIGO proposal (9Munro M.G. Balen A.H. Cho S. Critchley H.O.D. Díaz I. Ferriani R. et al.The FIGO ovulatory disorders classification system.Fertil Steril. 2022; 118: 768-776Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). How to accurately diagnose the absence of ovulation in the first place. Moreover, how to take variations in cyclicity over time in oligo/anovulatory women into consideration, along with difficulty including hyperprolactinemia, prolactin assays only became available in the 1970s (21Melmed S. Casanueva F.F. Hoffman A.R. Kleinberg D.L. Montori V. Schlechte J.A. et al.Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2011; 96: 273-288Crossref PubMed Scopus (1108) Google Scholar), into the system, and so on. The Delphi method, originally developed in the 1950 by the RAND organization, aimed to forecast the effect of technology on warfare (Delphi method | RAND) (22Dalkey N.C. Brown B.B. Cochran S. The Delphi Method: An Experimental Study of Group Opinion.Santa Monica, CA: RAND Corporation. 1969; Google Scholar). More recently, this structured communication technique—using various rounds of consultation based on questionnaires of expert panels—has been applied more widely in business, prediction markets, science and health care. Acknowledging the fact that even today little relevant scientific information considering ovarian dysfunction is available, we remain unconvinced whether the applied Delphi method represents the most suitable tool to come to an updated classification. Moreover, the outcome of such a Delphi exercise very much depends on the questions asked during the first round, the expertise of expert panels involved, and the availability of sufficiently robust scientific evidence to answer such questions. As stated repeatedly in the FIGO document, the focus of these questionnaires has been clinicians, educators, and researchers. How about involving women suffering from cycle abnormalities themselves? Should those individuals not be the starting point for any exercise in the current era dominated by the principle of creating value for patients (23Vijverberg J.R.G. Daniels K. Steinmann G. Garvelink M.M. Rouppe van der Voort M.B.V. Biesma D. et al.Mapping the extent, range and nature of research activity on value-based healthcare in the 15 years following its introduction (2006-2021): a scoping review.BMJ Open. 2022; 12e064983Crossref PubMed Scopus (1) Google Scholar)? Unfortunately, representatives of patients were only involved later in the process. The lack of patient perspectives and data-informed decisions in the proposed FIGO classification somewhat undermines the power of the conclusions made. If we go through the list of 42 questions prioritized for the first FIGO Delphi round, only a single query was dedicated to PCOS, by far the most common condition associated with ovarian dysfunction. Why was PCOS largely ignored in this first round? Moreover, a surprising number of 4 questions were dedicated to rather trivial and poorly defined conditions, such as luteal out of phase cycle and luteinized unruptured follicle. Finally, 4 questions concerning hormone assays (gonadotropins, steroids, and AMH) related to accessibility only. Even more important, the currently available more robust scientific evidence pertinent to the classification of ovulatory disorders seems to be largely ignored, for unknown reasons. There is no mention of vital issues, like:•The impact of the significantly improved quality of hormone assays over time and its potential implications for classification.•The validity of currently used hormone threshold levels for diagnosis, like for instance a FSH concentration of 25 or 40 IU/L, at single or repeated assessments, and at what time interval should they be assessed for POI diagnosis (24Webber L. Davies M. Anderson R. Bartlett J. Braat D. Cartwright D. et al.Management of women with premature ovarian insufficiency European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI.Hum Reprod. 2016; 31: 926-937Crossref PubMed Scopus (727) Google Scholar).•The arbitrary cut-off of 40 years for POI diagnosis.•Whether free or total steroid serum levels should be assessed, and by either immunoassays or liquid chromatography (25Rosner W. Hankinson S.E. Sluss P.M. Vesper H.W. Wierman M.E. Challenges to the measurement of estradiol: an endocrine society position statement.J Clin Endocrinol Metab. 2013; 98: 1376-1387Crossref PubMed Scopus (249) Google Scholar), especially relevant for PCOS diagnosis.•Moreover, above all the distinct role of AMH—a novel marker tightly associated with early follicle development—in the diagnosis of a variety of clinical conditions involving ovarian dysfunction, including PCOS (26Fraissinet A. Robin G. Pigny P. Lefebvre T. Catteau-Jonard S. Dewailly D. Use of the serum anti-Müllerian hormone assay as a surrogate for polycystic ovarian morphology: impact on diagnosis and phenotypic classification of polycystic ovary syndrome.Hum Reprod. 2017; 32: 1716-1722Crossref PubMed Scopus (48) Google Scholar), POI (27Knauff E.A. Eijkemans M.J. Lambalk C.B. ten Kate-Booij M.J. Hoek A. Beerendonk C.C. et al.Anti-Mullerian hormone, inhibin B, and antral follicle count in young women with ovarian failure.J Clin Endocrinol Metab. 2009; 94: 786-792Crossref PubMed Scopus (177) Google Scholar), or the extent of recovery of ovarian function after gonadotoxic treatment (28Anderson R.A. Cameron D. Clatot F. Demeestere I. Lambertini M. Nelson S.M. et al.Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review.Hum Reprod Upd. 2022; 28: 417-434Crossref PubMed Scopus (9) Google Scholar) is not discussed. This true innovation in reproductive endocrinology has certainly shed important new light on the classification of ovulatory disorders. Nobody would object to using etiology or anatomy as the guiding principle of any medical classification, but we question whether sufficiently robust diagnostic tools have been developed to do so. For instance, the primary hypothalamic or ovarian origin of PCOS is still debated, and a distinct overlap between these 2 options may occur. Consequently, what purpose does it serve to propose a new FIGO category - separate from hypothalamic or ovarian forms of ovulatory disorders—for the notoriously heterogeneous condition PCOS? It remains enigmatic on which data the proposed new FIGO classification is based, and how future patient care might benefit from such a complex and overlapping classification system. In addition, the potential importance of co-morbidity, both short- and long-term, for the proposed modified diagnostic classification has not been addressed. For instance, women with PCOS might present at a relatively young age with irregular bleeding, hirsutism, infertility, and signs of (cardio) metabolic dysfunction (29Fauser B.C. Tarlatzis B.C. Rebar R.W. Legro R.S. Balen A.H. Lobo R. et al.Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group.Fertil Steril. 2012; 97: 28-38Abstract Full Text Full Text PDF PubMed Scopus (1100) Google Scholar). This clearly affects the preferred diagnostic tools as well as follow-up strategies and management of potential long-term general health risks. Such an approach would certainly also apply to other conditions of ovulatory disorders, like POI. Current health care developments encompass a shift in attention from group diagnosis to individual prognosis, i.e., away from developing strategies for all patients toward interventions based on the complaint, context, and the desired outcome of a given individual (30Macklon N.S. Fauser B.C.J.M. Context-based infertility care.Reprod Biomed Online. 2020; 40: 2-3Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Available digital tools pave the way for a more personalized medicine-based approach. Such a patient-tailored strategy would take into account individual symptoms, biometrics, endocrinology, patient-led monitoring of cycle variability, and lifestyle factors. The construction of (multivariate) prediction models, informed by prospective, cohort, follow-up studies of well-phenotyped patients, and carefully defined study endpoints, has developed into serious science (31Collins G.S. Reitsma J.B. Altman D.G. Moons K.G. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement.Ann Intern Med. 2015; 162: 55-63Crossref PubMed Scopus (1327) Google Scholar). Such novel approaches have already revolutionized patient-tailored health care, especially in cardiovascular and cancer care. In more recent years, infertility care is slowly catching up: such developments include the assessment of pregnancy chances without medical intervention in a given couple with subfertility (32Bensdorp A.J. van der Steeg J.W. Steures P. Habbema J.D.F. Hompes P.G.A. Bossuyt P.M.M. et al.CECERM study group. A revised prediction model for natural conception.Reprod Biomed Online. 2017; 34: 619-626Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar), identifying patient characteristics involved in ovulation induction success rates in women with PCOS (33Gunning M.N. Christ J.P. van Rijn B.B. Koster M.P.H. Bonsel G.J. Laven J.S.E. et al.Predicting pregnancy chances leading to term live birth in oligo/anovulatory women diagnosed with PCOS.Reprod Biomed Online. 2023; 46: 156-163Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar), and even identifying predictors for pregnancy complications in such patients (34Christ J.P. Gunning M.N. Meun C. Eijkemans M.J.C. van Rijn B.B. Bonsel G.J. et al.Pre-conception characteristics predict obstetrical and neonatal outcomes in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2019; 104: 809-818Crossref PubMed Scopus (24) Google Scholar). Could this shift in our thinking along with newly generated knowledge not be included in a modified classification of ovulatory disorders? High levels of data and technology literacy in the general public allow for patient-led, app-based, symptom and hormone monitoring through self-governed inquiry and diagnostic testing (35Acosta J.N. Falcone G.J. Rajpurkar P. Topol E.J. Multimodel biomedical AI.Nat Med. 2022; 28: 1773-1784Crossref PubMed Scopus (25) Google Scholar). This provides a unique opportunity for in-person clinical trials which moves away from one-time snapshot analysis of health in a single appointment and moves toward the assessment of health as a continuous state. Indeed, there is stark mention of the role of genetics in ovulatory disorders. The last 2 decades have seen incredible progress in genetic sequencing, allowing for high-resolution biological data that can be obtained using routine laboratory practice. Although the cost of such assays was previously prohibitive, the current price enables far greater interrogation into these conditions and the subtle differences between them. The complexity of molecular genetics, however, results in a lack of consideration for large or small-scale genomic studies leading to concrete associations with these conditions. There is room for systematically reviewing and meta analyzing these associations in the light of nuclear and mitochondrial genomic data in women with PCOS (36Moosa A. Ghani M. O'Neill H.C. Genetic associations with polycystic ovary syndrome: the role of the mitochondrial genome; a systematic review and meta-analysis.J Clin Pathol. 2022; 75: 815-824Crossref PubMed Scopus (1) Google Scholar). Individually, each of the omics has shown promise in different research and clinical settings. For instance, the clinical integration of genetic markers of malignant tumors resulting in an increase in approvals of companion diagnostic devices by the US Food and Drug Administration (FDA) (https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools). Comprehensive genomic profiling to identify molecular markers in liquid biopsy samples from blood and urine are becoming a widely used tool for precision diagnostics in oncology (37Heitzer E. Haque I.S. Roberts C.E.S. Speicher M.R. Current and future perspectives of liquid biopsies in genomics-driven oncology.Nat Rev Genet. 2019; 20: 71-88Crossref PubMed Scopus (660) Google Scholar). Combining data across multiple modalities including genomic, metabolomic, ultrasonography imaging, clinical records, wearable sensors, and more, whereas allowing consideration for social and environmental determinants, could pave the future of precision health and accurate diagnostics (35Acosta J.N. Falcone G.J. Rajpurkar P. Topol E.J. Multimodel biomedical AI.Nat Med. 2022; 28: 1773-1784Crossref PubMed Scopus (25) Google Scholar, 38Siontis K.C. Noseworthy P.A. Attia Z.I. Friedman P.A. Artificial intelligence-enhanced electrocardiography in cardiovascular disease management.Nat Rev Cardiol. 2021; 18: 465-478Crossref PubMed Scopus (146) Google Scholar) (Table 1). Irrespective of the use of such multimodal AI models, a data-led approach from any modality would be far more reliable in the formation of concrete consensus for a myriad of conditions relating to ovulatory dysfunctions.Table 1Recommendations for improving the diagnostic criteria for ovulatory dysfunction.✓Take a more practical (public health) approach and focus predominantly on the most common conditions.✓Include a more patient-centered approach and the transition from diagnosis to prognosis toward individualized care.✓Discuss the role of genomics, heritability and the impact of lifestyle on the occurrence and prevalence of ovulatory disorders.✓Assess whether the profile of women suffering from ovarian dysfunction may have changed during the 50 year period (for instance, in relation to over- or underweight, exercise, environmental factors) since the introduction of the classification.✓Include discussion regarding possible implications of improved reproductive hormone assays, and relevant threshold values.✓Include the role of antimüllerian hormone in the classification system, especially focusing on polycystic ovary syndrome or primary ovarian insufficiency diagnosis and handling, and ovarian reserve testing.✓Assess the quality of hormone assays in blood, urine or saliva.✓Discuss the role of androgen assays in the classification, and management of women with ovulatory dysfunction.✓Include proper definitions of normal cyclicity, oligomenorrhea and amenorrhea.✓Use large data sets generated by current e-health tools, biobanks, digital clinical trials, genomics.✓Any recommendation should be backed up by proper scientific evidence and should be referenced.✓Relevant knowledge gaps should be identified. Open table in a new tab The wealth and availability of open genetic databases has enabled the characterization of the genetic architecture of complex conditions and traits (39Watanabe K. Stringer S. Frei O. Umićević Mirkov M. de Leeuw C. Polderman T.J.C. et al.A global overview of pleiotropy and genetic architecture in complex traits.Nat Genet. 2019; 51: 1339-1348Crossref PubMed Scopus (396) Google Scholar), including the precise mechanisms which can predict ovarian aging, menopause timing, and breast cancer susceptibility (40Day F.R. Ruth K.S. Thompson D.J. Lunetta K.L. Pervjakova N. Chasman D.I. et al.Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.Nat Genet. 2015; 47: 1294-1303Crossref PubMed Scopus (237) Google Scholar, 41Ruth K.S. Day F.R. Hussain J. Martínez-Marchal A. Aiken C.E. Azad A. et al.Genetic insights into biological mechanisms governing human ovarian ageing.Nature. 2021; 596: 393-397Crossref PubMed Scopus (81) Google Scholar). Although the successful integration of these very distinct types of data remains challenging, combined global datasets could radically expand our understanding of women’s health conditions including infertility (42Bachelot G. Lévy R. Bachelot A. Faure C. Czernichow S. Dupont C. et al.Proof of concept and development of a couple-based machine learning model to stratify infertile patients with idiopathic infertility.Sci Rep. 2021; 1124003Crossref Scopus (2) Google Scholar) and pave the way for precise and personalized characterization in turn leading to preventive and therapeutic strategies. Based on the many arguments outlined above, we fail to see how patients might benefit from the proposed complex anatomical FIGO classification of ovulatory disorders. Why not start with the relevant complaints of women and propose a path to follow? Such an approach would represent modern thinking in health care research at large, identify jointly with women what is the primary complaint and the desired endpoint, and how to achieve this outcome in an efficient and cost-effective manner. Current thinking may require a shift in our thinking from diagnosis to prognosis, incorporating big data, e-health tools concerning individual symptoms, biometrics, improved hormone assays (including AMH), and patient-led monitoring of cycle variability and lifestyle factors.

Research question: Which patient features predict the time to pregnancy (TTP) leading to term live birth in infertile women diagnosed with polycystic ovary syndrome (PCOS)? Design: Prospective cohort follow-up study was completed, in which initial standardized phenotyping was conducted at two Dutch university medical centres from January 2004 to January 2014. Data were linked to the Netherlands Perinatal Registry to obtain pregnancy outcomes for each participant. All women underwent treatment according to a standardized protocol, starting with ovulation induction as first-line treatment. Predictors of pregnancies (leading to term live births) during the first year after PCOS diagnosis were evaluated. Results: A total of 1779 consecutive women diagnosed with PCOS between January 2004 and January 2014 were included. In the first year following screening, 659 (37%) women with PCOS attained a pregnancy leading to term birth (>= 37 weeks of gestational age). A higher chance of pregnancy was associated with race, smoking, body mass index (BMI), insulin, total testosterone and sex hormone-binding globulin (SHBG) concentrations (c-statistic = 0.59). Conclusions: Predictors of an increased chance of a live birth include White race, no current smoking, lower BMI, insulin and total testosterone concentrations, and higher SHBG concentrations. This study presents a nomogram to predict the chances of achieving a pregnancy (leading to a term live birth) within 1 year of treatment.

BACKGROUND AND AIMS:To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine. METHODS:We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured. RESULTS:While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups. CONCLUSIONS:In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.

Since the early days, IVF has often been combined with ovarian stimulation. Starting the in viteo fertilization procedure with multiple oocytes, may compensate for suboptimal laboratory performance. This trend has developed during 4 decades into the development of extremely complex and expensive ovarian stimulation regimens, along with the widespread belief that the ‘more oocytes the better’ for IVF success rates. Moreover, ovarian response to standard stimulation varies greatly, and over-response is clearly linked to added side effects and health risks for women. Multiple studies emphasize that current standard IVF represents a very wasteful procedure, since only 1 out of 20 to 50 oocytes generated does result in a live birth. The concept of ‘the more oocytes the better’ is largely based on the observation that few oocytes are associated with poor clinical outcomes. However, generating few oocytes following maximal stimulation in conventional IVF is mostly due to diminished ovarian reserve, an intrinsic problem of the ovary unrelated to the extent of stimulation and clearly associated with poor outcomes. Increasing evidence suggests that few oocytes retrieved following mild stimulation do coincide with good IVF success rates. This difference is often ignored. It would be most important to reach a more broad scope consensus on the optimal number of oocytes to be retrieved for IVF, taking cost, patient discomfort, and safety into consideration next to clinical success rates. Subsequently, individualized stimulation regimens should be developed to reach the optimal response in the majority of women undergoing IVF. individual patient characteristics should be identified which are linked to ovarian response, such as female age, body weight, ovarian reserve biomarkers (like Anti-Mullerian hormone, and antral follicle count) soon to be complemented with genomic ovarian markers. In the current transition from mass medicine (the same treatment for all) to patient-tailored approaches, individualized ovarian stimulation based on robust markers would represent a true step forward giving rise to safer, simpler, and more cost-effective IVF with comparable success rates.

Abstract Objective Reproductive disorders, such as premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS), are associated with hormonal and metabolic changes, which might lead to changes in bone mineral density (BMD). On the one hand women with POI enter menopause too early and have less estrogen exposure rendering them more prone to develop low BMD. On the other hand women with PCOS, who often have a delayed menopause and therefore experience longer estrogen exposure, may have an increased BMD. A third reproductive disorder, preeclampsia (PE) does not seem to affect BMD or menopausal age. The effect of these reproductive disorders, with different menopausal ages, on BMD could be most evident in middle-aged women. We hypothesized that the duration of estrogen exposure is a key factor in BMD. Materials and methods In this cross-sectional study we compared the BMD of 258 women with a history of PE as a reference group (age 46.0; 40% postmenopausal) to 90 women with POI (age 48.1; 100% postmenopausal) and 84 women with PCOS (age 48.3; 26% postmenopausal). BMD was measured using non-contrast coronary CT scans in three consecutive thoracic vertebrae (in the T7-T10 range). Secondary outcomes included T-scores, prevalence of osteoporosis and osteopenia and the comparison of measured BMD to predicted BMD, calculated by a formula based on age. We performed linear regression analysis to assess differences in BMD between groups, adjusted for age and BMI. Results Compared to women with a history of PE, women with POI had lower BMD (p<0.001) and women with PCOS had higher BMD (p=0.003). Prevalence of osteoporosis was higher in women with POI (12.2%) compared to PE (0.8%; P=0.002) and none of the women with PCOS fulfilled the criteria for osteoporosis. Prevalence of osteopenia was significantly higher in the POI group and lower in the PCOS group compared to the PE group (57.8%, 17.9% and 26.4% respectively; p<0.01). As expected, measured BMD of women with POI was significantly lower than the predicted BMD. On the contrary, the measured BMD of women with PCOS was significantly higher than the predicted BMD. Interestingly, the measured BMD of women with a history of PE was also higher than the predicted BMD. Conclusion Our results imply that prolonged estrogen exposure as in PCOS is associated with a higher BMD. A lower estrogen exposure associated with an early menopause in POI is associated with a lower BMD and osteoporosis. Patients with a history of PE could be seen as an intermediate group in terms of BMD and estrogen exposure, however, the measured BMD of women with a history of PE was higher than the predicted BMD. This study emphasizes the importance of adequate counseling on long term health issues when diagnosing a reproductive disorder. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.