Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer.

The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.

Risks of adverse obstetric outcomes among female survivors of adolescent and young adult cancer in England (TYACSS): a population-based, retrospective cohort study.

BACKGROUND: There are limited data on the risks of obstetric complications among survivors of adolescent and young adult cancer with most previous studies only reporting risks for all types of cancers combined. The aim of this study was to quantify deficits in birth rates and risks of obstetric complications for female survivors of 17 specific types of adolescent and young adult cancer. METHODS: The Teenage and Young Adult Cancer Survivor Study (TYACSS)-a retrospective, population-based cohort of 200 945 5-year survivors of cancer diagnosed at age 15-39 years from England and Wales-was linked to the English Hospital Episode Statistics (HES) database from April 1, 1997, to March 31, 2022. The cohort included 17 different types of adolescent and young adult cancers. We ascertained 27 specific obstetric complications through HES among 96 947 women in the TYACSS cohort. Observed and expected numbers for births and obstetric complications were compared between the study cohort and the general population of England to identify survivors of adolescent and young adult cancer at a heighted risk of birth deficits and obstetric complications relative to the general population. FINDINGS: Between April 1, 1997, and March 31, 2022, 21 437 births were observed among 13 886 female survivors of adolescent and young adult cancer from England, which was lower than expected (observed-to-expected ratio: 0·68, 95% CI 0·67-0·69). Other survivors of genitourinary, cervical, and breast cancer had under 50% of expected births. Focusing on more common (observed ≥100) obstetric complications that were at least moderately in excess (observed-to-expected ratio ≥1·25), survivors of cervical cancer were at risk of malpresentation of fetus, obstructed labour, amniotic fluid and membranes disorders, premature rupture of membranes, preterm birth, placental disorders including placenta praevia, and antepartum haemorrhage. Survivors of leukaemia were at risk of preterm delivery, obstructed labour, postpartum haemorrhage, and retained placenta. Survivors of all other specific cancers had no more than two obstetric complications that exceeded an observed-to-expected ratio of 1·25 or greater. INTERPRETATION: Survivors of cervical cancer and leukaemia are at risk of several serious obstetric complications; therefore, any pregnancy should be considered high-risk and would benefit from obstetrician-led antenatal care. Despite observing deficits in birth rates across all 17 different types of adolescent and young adult cancer, we provide reassurance for almost all survivors of adolescent and young adult cancer concerning their risk of almost all obstetric complications. Our results provide evidence for the development of clinical guidelines relating to counselling and surveillance of obstetrical risk for female survivors of adolescent and young adult cancer. FUNDING: Children with Cancer UK, The Brain Tumour Charity, and Academy of Medical Sciences.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Eggsurance? A randomized controlled trial of a decision aid for elective egg freezing.

STUDY QUESTION: Does a purpose-designed Decision Aid for women considering elective egg freezing (EEF) impact decisional conflict and other decision-related outcomes? SUMMARY ANSWER: The Decision Aid reduces decisional conflict, prepares women for decision-making, and does not cause distress. WHAT IS ALREADY KNOWN: Elective egg-freezing decisions are complex, with 78% of women reporting high decisional conflict. Decision Aids are used to support complex health decisions. We developed an online Decision Aid for women considering EEF and demonstrated that it was acceptable and useful in Phase 1 testing. STUDY DESIGN, SIZE, DURATION: A single-blind, two-arm parallel group randomized controlled trial was carried out. Target sample size was 286 participants. Randomization was 1:1 to the control (existing website information) or intervention (Decision Aid plus existing website information) group and stratified by Australian state/territory and prior IVF specialist consultation. Participants were recruited between September 2020 and March 2021 with outcomes recorded over 12 months. Data were collected using online surveys and data collection was completed in March 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females aged ≥18 years, living in Australia, considering EEF, proficient in English, and with internet access were recruited using multiple methods including social media posts, Google advertising, newsletter/noticeboard posts, and fertility clinic promotion. After completing the baseline survey, participants were emailed their allocated website link(s). Follow-up surveys were sent at 6 and 12 months. Primary outcome was decisional conflict (Decisional Conflict Scale). Other outcomes included distress (Depression Anxiety and Stress Scale), knowledge about egg freezing and female age-related infertility (study-specific measure), whether a decision was made, preparedness to decide about egg freezing (Preparation for Decision-Making Scale), informed choice (Multi-Dimensional Measure of Informed Choice), and decision regret (Decision Regret Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 306 participants (mean age 30 years; SD: 5.2) were randomized (intervention n = 150, control n = 156). Decisional Conflict Scale scores were significantly lower at 12 months (mean score difference: -6.99 [95% CI: -12.96, -1.02], P = 0.022) for the intervention versus control group after adjusting for baseline decisional conflict. At 6 months, the intervention group felt significantly more prepared to decide about EEF than the control (mean score difference: 9.22 [95% CI: 2.35, 16.08], P = 0.009). At 12 months, no group differences were observed in distress (mean score difference: 0.61 [95% CI: -3.72, 4.93], P = 0.783), knowledge (mean score difference: 0.23 [95% CI: -0.21, 0.66], P = 0.309), or whether a decision was made (relative risk: 1.21 [95% CI: 0.90, 1.64], P = 0.212). No group differences were found in informed choice (relative risk: 1.00 [95% CI: 0.81, 1.25], P = 0.983) or decision regret (median score difference: -5.00 [95% CI: -15.30, 5.30], P = 0.337) amongst participants who had decided about EEF by 12 months (intervention n = 48, control n = 45). LIMITATIONS, REASONS FOR CAUTION: Unknown participant uptake and potential sampling bias due to the recruitment methods used and restrictions caused by the coronavirus disease 2019 pandemic. Some outcomes had small sample sizes limiting the inferences made. The use of study-specific or adapted validated measures may impact the reliability of some results. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized controlled trial to evaluate a Decision Aid for EEF. The Decision Aid reduced decisional conflict and improved women's preparation for decision making. The tool will be made publicly available and can be tailored for international use. STUDY FUNDING/COMPETING INTEREST(S): The Decision Aid was developed with funding from the Royal Women's Hospital Foundation and McBain Family Trust. The study was funded by a National Health and Medical Research Council (NHMRC) Project Grant APP1163202, awarded to M. Hickey, M. Peate, R.J. Norman, and R. Hart (2019-2021). S.S., M.P., D.K., and S.B. were supported by the NHMRC Project Grant APP1163202 to perform this work. R.H. is Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Fertility. He has received grants from MSD, Merck-Serono, and Ferring Pharmaceuticals unrelated to this study and is a shareholder of CHA-SMG. R.L. is Director of Women's Health Melbourne (Medical Practice), ANZSREI Executive Secretary (Honorary), RANZCOG CREI Subspecialty Committee Member (Honorary), and a Fertility Specialist at Life Fertility Clinic Melbourne and Royal Women's Hospital Public Fertility Service. R.A.A. has received grants from Ferring Pharmaceuticals unrelated to this study. M.H., K.H., and R.J.N. have no conflicts to declare. TRIAL REGISTRATION NUMBER: ACTRN12620001032943. TRIAL REGISTRATION DATE: 11 August 2020. DATE OF FIRST PATIENT'S ENROLMENT: 29 September 2020.

Kisspeptin and neurokinin B neuroendocrine pathways in the control of human ovulation.

The roles of initially kisspeptin and subsequently neurokinin B pathways in the regulation of human reproduction through the control of GnRH secretion were first identified 20 years ago, as essential for the onset of puberty in both boys and girls. Within that short time we already now have the first licence for clinical use for a neurokinin antagonist in a related indication, for menopausal vasomotor symptoms. Between these two markers of the start and end of the reproductive lifespan, it is clear that these pathways underlie many of the aspects of the hypothalamic regulation of reproduction which had hitherto been enigmatic. In this review, we describe the data currently available from studies designed to elucidate the roles of kisspeptin and neurokinin B in human ovarian function, specifically the regulation of follicle development leading up to ovulation, and in the control of the mid-cycle GnRH/LH surge that triggers ovulation. These studies, undertaken with only very limited pharmacological tools, provide evidence that the neurokinin B pathway is important in controlling the hypothalamic contribution to the precise gonadotropic drive to the ovary that is necessary for mono-ovulation, whereas the switch from negative to positive estrogenic feedback results in kisspeptin-mediated increased GnRH secretion. Potential therapeutic opportunities in conditions characterised by disordered hypothalamic/pituitary function, polycystic ovary syndrome, and functional hypothalamic amenorrhoea, and in the induced LH surge that is a necessary part of IVF treatment are discussed.

Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptoms.

INTRODUCTION: Menopausal vasomotor symptoms (VMS) are experienced by most women and are often debilitating and can last for years. While hormone replacement therapy is effective, it carries risks that have impacted its wider use, and it can be contraindicated. There is a large unmet need for a safe, effective non-hormonal therapy. AREAS COVERED: The importance of the neurokinin (NK) system in the hypothalamic regulation of the vasomotor center has become clear. NK antagonists, previously developed for other indications, have therefore been investigated for the treatment of VMS. Elinzanetant is a potent antagonist at both NK1 (endogenous ligand Substance P) and NK3 (neurokinin B) receptors, whereas other related drugs in development are selective NK3 antagonists. Elinzanetant has been investigated in 2 Phase II trials for menopausal VMS, demonstrating rapid onset and dose-dependant efficacy for the relief of VMS and improvement in quality of life for up to 12 weeks. Phase III trials are underway in women both with physiological menopause and after treatment for breast cancer. EXPERT OPINION: Elinzanetant is a very promising non-hormonal approach to a highly prevalent symptom constellation, with rapid onset and high efficacy. Wider indications are being explored in current Phase III trials.

Clinical dilemmas in ovarian tissue cryopreservation.

Ovarian tissue cryopreservation (OTC) is increasingly offered globally as a fertility preservation strategy for both postpubertal women and prepubertal girls, with subsequent reimplantation of cryopreserved ovarian cortex resulting in a rapidly growing number of live births. There remains very limited evidence of efficacy from tissue stored when the patient was prepubertal or from conditions affecting the ovary directly, e.g., Turner syndrome. Although OTC is becoming a more established practice, several clinical dilemmas remain from a practical and ethical standpoint. This review discusses the challenges regarding optimal patient selection for the procedure, the use of OTC in patients with a poor prognosis, the potential of reimplantation of tissue contaminated with malignant cells, and the role of OTC in those with an intrinsic ovarian disorder.

Regulation of the poly(A) Polymerase Star-PAP by a Nuclear Phosphoinositide Signalosome.

Star-PAP is a noncanonical poly(A) polymerase that controls gene expression. Star-PAP was previously reported to bind the phosphatidylinositol 4-phosphate 5-kinase PIPKI⍺ and its product phosphatidylinositol 4,5-bisphosphate, which regulate Star-PAP poly(A) polymerase activity and expression of specific genes. Recent studies have revealed a nuclear PI signaling pathway in which the PI transfer proteins PITP⍺/ß, PI kinases and phosphatases bind p53 to sequentially modify protein-linked phosphatidylinositol phosphates and regulate its function. Here we demonstrate that multiple phosphoinositides, including phosphatidylinositol 4-monophosphate and phosphatidylinositol 3,4,5-trisphosphate are also coupled to Star-PAP in response to stress. This is initiated by PITP⍺/ß binding to Star-PAP, while the Star-PAP-linked phosphoinositides are modified by PI4KII⍺, PIPKI⍺, IPMK, and PTEN recruited to Star- PAP. The phosphoinositide coupling enhances the association of the small heat shock proteins HSP27/⍺B-crystallin with Star-PAP. Knockdown of the PITPs, kinases, or HSP27 reduce the expression of Star-PAP targets. Our results demonstrate that the PITPs generate Star-PAP-PIPn complexes that are then modified by PI kinases/phosphatases and small heat shock proteins that regulate the linked phosphoinositide phosphorylation and Star-PAP activity in response to stress.

Expression of transforming growth factor ß signalling molecules and their correlations with genes in loci linked to polycystic ovary syndrome in human foetal and adult tissues.

Context Altered signalling of androgens, anti-Müllerian hormone or transforming growth factor beta (TGFß) during foetal development have been implicated in the predisposition to polycystic ovary syndrome (PCOS) in later life, aside from its genetic predisposition. In foetal ovarian fibroblasts, TGFß1 has been shown to regulate androgen signalling and seven genes located in loci associated with PCOS. Since PCOS exhibits a myriad of symptoms, it likely involves many different organs. Aims To identify the relationships between TGFß signalling molecules and PCOS candidate genes in different tissues associated with PCOS. Methods Using RNA sequencing data, we examined the expression patterns of TGFß signalling molecules in the human ovary, testis, heart, liver, kidney, brain tissue, and cerebellum from 4 to 20weeks of gestation and postnatally. We also examined the correlations between gene expression of TGFß signalling molecules and PCOS candidate genes. Key results TGFß signalling molecules were dynamically expressed in most tissues prenatally and/or postnatally. FBN3 , a PCOS candidate gene involved in TGFß signalling, was expressed during foetal development in all tissues. The PCOS candidate genes HMGA2, YAP1 , and RAD50 correlated significantly (P TGFBR1 in six out of the seven tissues examined. Conclusions This study suggests that possible crosstalk occurs between genes in loci associated with PCOS and TGFß signalling molecules in multiple tissues, particularly during foetal development. Implications Thus, alteration in TGFß signalling during foetal development could affect many tissues contributing to the multiple phenotypes of PCOS in later life.

Individualized dosing of follitropin delta affects live birth and safety in in vitro fertilization treatment: an individual participant data meta-analysis of randomized controlled trials.

OBJECTIVE: To undertake a one-stage meta-analysis of individual patient data from randomized trials comparing individualized dosing of follitropin delta vs. other forms of follitropin (alpha and beta) for live birth (LB) rates (LBR) and safety parameters in women undergoing ovarian stimulation for in vitro fertilization treatment. DESIGN: Systematic review with individual patient data meta-analysis. SETTING: Not applicable. PATIENTS: Women undergoing ovarian stimulation for in vitro fertilization treatment. INTERVENTIONS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Web of Science to identify eligible phase 3 trials between January 1, 2000, and February 1, 2023. MAIN OUTCOME MEASURES: All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drugs interacting with log (AMH) level, age, and random effects for country and trial to compare the primary efficacy and safety outcomes of LB and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration: CRD42023399711. RESULTS: Three trials met inclusion criteria and included 2,685 women undertaking 2,682 cycles between October 2013 and May 2020, with LB follow-up through to February 1, 2023. For women with an elevated AMH level (≥15 pmol/L), there was high-quality evidence that the use of individualized dosing of follitropin delta was associated with an increased LB rate (adjusted odds ratio [adj OR] 1.64, 95% confidence interval [CI] 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (-48.7 µg, 95% CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar LB rates (adj OR 0.86, 95% CI 0.63, 1.17) and safety outcomes (adj OR 1.92, 95% CI 0.76, 4.87) were observed for women with an AMH level of <15 pmol/L. There were no clinically meaningful differences in neonatal outcomes. CONCLUSION: Using follitropin delta in an AMH level and weight-based algorithm rather than conventional licensed dosing of follitropin alpha or beta for ovarian stimulation in women is associated with improved LB rates and safety outcomes for women with elevated AMH levels.

Age-dependent loss of cohesion protection in human oocytes.

Aneuploid human eggs (oocytes) are a major cause of infertility, miscarriage, and chromosomal disorders. Such aneuploidies increase greatly as women age, with defective linkages between sister chromatids (cohesion) in meiosis as a common cause. We found that loss of a specific pool of the cohesin protector protein, shugoshin 2 (SGO2), may contribute to this phenomenon. Our data indicate that SGO2 preserves sister chromatid cohesion in meiosis by protecting a "cohesin bridge" between sister chromatids. In human oocytes, SGO2 localizes to both sub-centromere cups and the pericentromeric bridge, which spans the sister chromatid junction. SGO2 normally colocalizes with cohesin; however, in meiosis II oocytes from older women, SGO2 is frequently lost from the pericentromeric bridge and sister chromatid cohesion is weakened. MPS1 and BUB1 kinase activities maintain SGO2 at sub-centromeres and the pericentromeric bridge. Removal of SGO2 throughout meiosis I by MPS1 inhibition reduces cohesion protection, increasing the incidence of single chromatids at meiosis II. Therefore, SGO2 deficiency in human oocytes can exacerbate the effects of maternal age by rendering residual cohesin at pericentromeres vulnerable to loss in anaphase I. Our data show that impaired SGO2 localization weakens cohesion integrity and may contribute to the increased incidence of aneuploidy observed in human oocytes with advanced maternal age.

Current global status of male reproductive health.

BACKGROUND: The widespread interest in male reproductive health (MRH), fueled by emerging evidence, such as the global decline in sperm counts, has intensified concerns about the status of MRH. Consequently, there is a pressing requirement for a strategic, systematic approach to identifying critical questions, collecting pertinent information, and utilizing these data to develop evidence-based strategies. The methods for addressing these questions and the pathways toward their answers will inevitably vary based on the variations in cultural, geopolitical, and health-related contexts. To address these issues, a conjoint ESHRE and Male Reproductive Health Initiative (MRHI) Campus workshop was convened. OBJECTIVE AND RATIONALE: The three objectives were: first, to assess the current state of MRH around the world; second, to identify some of the key gaps in knowledge; and, third, to examine how MRH stakeholders can collaboratively generate intelligent and effective paths forward. SEARCH METHODS: Each expert reviewed and summarized the current literature that was subsequently used to provide a comprehensive overview of challenges related to MRH. OUTCOMES: This narrative report is an overview of the data, opinions, and arguments presented during the workshop. A number of outcomes are presented and can be summarized by the following overarching themes: MRH is a serious global issue and there is a plethora of gaps in our understanding; there is a need for widespread international collaborative networks to undertake multidisciplinary research into fundamental issues, such as lifestyle/environmental exposure studies, and high-quality clinical trials; and there is an urgent requirement for effective strategies to educate young people and the general public to safeguard and improve MRH across diverse population demographics and resources. LIMITATIONS REASONS FOR CAUTION: This was a workshop where worldwide leading experts from a wide range of disciplines presented and discussed the evidence regarding challenges related to MRH. While each expert summarized the current literature and placed it in context, the data in a number of areas are limited and/or sparse. Equally, important areas for consideration may have been missed. Moreover, there are clear gaps in our knowledge base, which makes some conclusions necessarily speculative and warranting of further study. WIDER IMPLICATIONS: Poor MRH is a global issue that suffers from low awareness among the public, patients, and heathcare professionals. Addressing this will require a coordinated multidisciplinary approach. Addressing the significant number of knowledge gaps will require policy makers prioritizing MRH and its funding. STUDY FUNDING/COMPETING INTERESTS: The authors would like to extend their gratitude to ESHRE for providing financial support for the Budapest Campus Workshop, as well as to Microptic S.L. (Barcelona) for kindly sponsoring the workshop. P.B. is the Director of the not-for-profit organization Global Action on Men's Health and receives fees and expenses for his work, (which includes the preparation of this manuscript). Conflicts of interest: C.J.D.J., C.L.R.B., R.A.A., P.B., M.P.C., M.L.E., N.G., N.J., C.K., AAP, M.K.O., S.R.-H., M.H.V.-L.: ESHRE Campus Workshop 2022 (Travel support-personal). C.J.D.J.: Cambridge University Press (book royalties-personal). ESHRE Annual Meeting 2022 and Yale University Panel Meeting 2023 (Travel support-personal). C.L.R.B.: Ferring and IBSA (Lecture), RBMO editor (Honorarium to support travel, etc.), ExSeed and ExScentia (University of Dundee), Bill & Melinda Gates Foundation (for research on contraception). M.P.C.: Previously received funding from pharmaceutical companies for health economic research. The funding was not in relation to this work and had no bearing on the contents of this work. No funding from other sources has been provided in relation to this work (funding was provided to his company Global Market Access Solutions). M.L.E.: Advisor to Ro, Doveras, Next, Hannah, Sandstone. C.K.: European Academy of Andrology (Past president UNPAID), S.K.: CEO of His Turn, a male fertility Diagnostic and Therapeutic company (No payments or profits to date). R.I.M.: www.healthymale.org.au (Australian Government funded not for profit in men's health sector (Employed as Medical Director 0.2 FET), Monash IVF Pty Ltd (Equity holder)). N.J.: Merck (consulting fees), Gedeon Richter (honoraria). S.R.-H.: ESHRE (Travel reimbursements). C.N.: LLC (Nursing educator); COMMIT (Core Outcomes Measures for Infertility Trials) Advisor, meeting attendee, and co-author; COMMA (Core Outcomes in Menopause) Meeting attendee, and co-author; International Federation of Gynecology and Obstetrics (FIGO) Delegate Letters and Sciences; ReproNovo, Advisory board; American Board of Urology Examiner; American Urological Association Journal subsection editor, committee member, guidelines co-author Ferring Scientific trial NexHand Chief Technology Officer, stock ownership Posterity Health Board member, stock ownership. A.P.: Economic and Social Research Council (A collaborator on research grant number ES/W001381/1). Member of an advisory committee for Merck Serono (November 2022), Member of an advisory board for Exceed Health, Speaker fees for educational events organized by Mealis Group; Chairman of the Cryos External Scientific Advisory Committee: All fees associated with this are paid to his former employer The University of Sheffield. Trustee of the Progress Educational Trust (Unpaid). M.K.O.: National Health and Medical Research Council and Australian Research Council (Funding for research of the topic of male fertility), Bill and Melinda Gates Foundation (Funding aimed at the development of male gamete-based contraception), Medical Research Future Fund (Funding aimed at defining the long-term consequences of male infertility). M.H.V.-L.: Department of Sexual and Reproductive Health and Research (SRH)/Human Reproduction Programme (HRP) Research Project Panel RP2/WHO Review Member; MRHI (Core Group Member), COMMIT (member), EGOI (Member); Human Reproduction (Associate Editor), Fertility and Sterility (Editor), AndroLATAM (Founder and Coordinator).