Female Meiotic Sex Chromosome Inactivation in Chicken

During meiotic prophase in male mammals, the heterologous X and Y chromosomes remain largely unsynapsed, and meiotic sex chromosome inactivation (MSCI) leads to formation of the transcriptionally silenced XY body. In birds, the heterogametic sex is female, carrying Z and W chromosomes (ZW), whereas males have the homogametic ZZ constitution. During chicken oogenesis, the heterologous ZW pair reaches a state of complete heterologous synapsis, and this might enable maintenance of transcription of Z- and W chromosomal genes during meiotic prophase. Herein, we show that the ZW pair is transiently silenced, from early pachytene to early diplotene using immunocytochemistry and gene expression analyses. We propose that ZW inactivation is most likely achieved via spreading of heterochromatin from the W on the Z chromosome. Also, persistent meiotic DNA double-strand breaks (DSBs) may contribute to silencing of Z. Surprisingly, γH2AX, a marker of DSBs, and also the earliest histone modification that is associated with XY body formation in mammalian and marsupial spermatocytes, does not cover the ZW during the synapsed stage. However, when the ZW pair starts to desynapse, a second wave of γH2AX accumulates on the unsynapsed regions of Z, which also show a reappearance of the DSB repair protein RAD51. This indicates that repair of meiotic DSBs on the heterologous part of Z is postponed until late pachytene/diplotene, possibly to avoid recombination with regions on the heterologously synapsed W chromosome. Two days after entering diplotene, the Z looses γH2AX and shows reactivation. This is the first report of meiotic sex chromosome inactivation in a species with female heterogamety, providing evidence that this mechanism is not specific to spermatogenesis. It also indicates the presence of an evolutionary force that drives meiotic sex chromosome inactivation independent of the final achievement of synapsis

Sexual Function in Women With Polycystic Ovary Syndrome: Design of an Observational Prospective Multicenter Case Control Study

Introduction: The prevalence of polycystic ovary syndrome (PCOS) is 10–15% in women of reproductive age. Its characteristics are (i) clinical or biochemical hyperandrogenism, (ii) oligomenorrhea or amenorrhea, and (iii) polycystic ovaries on ultrasound. PCOS is associated with lower quality of life, depression, anxiety, diabetes, and cardiovascular disease. Treatment commonly entails oral contraceptive use to lower endogenous androgen levels. Androgen levels and comorbidities may affect sexual function. Previous studies have addressed a limited range of possible contributing factors. We will assess sexual function as well as genital and self-reported sexual arousal in a laboratory setting in women with PCOS compared to an age-matched healthy control group. Modulation by biopsychosocial factors mentioned will be studied. Methods: This is a multicenter prospective case control study. The study population includes healthy women with and without PCOS, aged 18–40 years, in a stable heterosexual relationship for at least 6 months. Power is calculated at 67 participants in each group. Anticipating a drop out of 10%, 150 participants will be recruited. Main outcome measures: The main outcomes measured are sexual function using the Female Sexual Function Index, Sexual Desire Inventory, and Female Sexual Distress Scale-Revised; genital sexual arousal measured as vaginal pulse amplitude; and self-reported sexual arousal in response to erotic stimuli in a laboratory setting. The mediators that will be investigated include testosterone, free androgen levels, oral contraceptive use, sensitivity to androgens (using CAG repeat length), body mass index, body image, mental health, and self-esteem. Conclusion: Strengths of this study are the inclusion of a broad range of biopsychosocial outcome measures including DNA analysis, a healthy control group, and standardized assessment of genital and self-reported sexual arousal in a laboratory setting. With the design of this study we aim to provide an insight into which biopsychosocial factors associated with PCOS are related to sexual function, and how sexual function may be affected by treatment. These new insights may help to improve clinical management of PCOS while improving the quality of life. Pastoor H, Both S, Timman R, et al. Sexual Function in Women With Polycystic Ovary Syndrome: Design of an Observational Prospective Multicenter Case Control Study. Sex Med 2020;XX:XXX–XXX

Polycystic ovary syndrome: A brain disorder characterized by eating problems originating during puberty and adolescence

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS

Incomplete meiotic sex chromosome inactivation in the domestic dog

Background: In mammalian meiotic prophase, homologous chromosome recognition is aided by formation and repair of programmed DNA double-strand breaks (DSBs). Subsequently, stable associations form through homologous chromosome synapsis. In male mouse meiosis, the largely heterologous X and Y chromosomes synapse only in their short pseudoautosomal regions (PARs), and DSBs persist along the unsynapsed non-homologous arms of these sex chromosomes. Asynapsis of these arms and the persistent DSBs then trigger transcriptional silencing through meiotic sex chromosome inactivation (MSCI), resulting in formation of the XY body. This inactive state is partially maintained in post-meiotic haploid spermatids (postmeiotic sex chromatin repression, PSCR). For the human, establishment of MSCI and PSCR have also been reported, but X-linked gene silencing appears to be more variable compared to mouse. To gain more insight into the regulation and significance of MSCI and PSCR among different eutherian species, we have performed a global analysis of XY pairing dynamics, DSB repair, MSCI and PSCR in the domestic dog (Canis lupus familiaris), for which the complete genome sequence has recently become available, allowing a thorough comparative analyses. Results: In addition to PAR synapsis between X and Y, we observed extensive self-synapsis of part of the dog X chromosome, and rapid loss of known markers of DSB repair from that part of the X. Sequencing of RNA from purified spermatocytes and spermatids revealed establishment of MSCI. However, the self-synapsing region of the X displayed higher X-linked gene expression compared to the unsynapsed area in spermatocytes, and was post-meiotically reactivated in spermatids. In contrast, genes in the PAR, which are expected to escape MSCI, were expressed at very low levels in both spermatocytes and spermatids. Our comparative analysis was then used to identify two X-linked genes that may escape MSCI in spermatocytes, and 21 that are specifically re-activated in spermatids of human, mouse and dog. Conclusions: Our data indicate that MSCI is incomplete in the dog. This may be partially explained by extensive, but transient, self-synapsis of the X chromosome, in association with rapid completion of meiotic DSB repair. In addition, our comparative analysis identifies novel candidate male fertility genes

First effective mHealth nutrition and lifestyle coaching program for subfertile couples undergoing in vitro fertilization treatment:a single-blinded multicenter randomized controlled trial

Objective: To study compliance and effectiveness of the mHealth nutrition and lifestyle coaching program Smarter Pregnancy in couples undergoing in vitro fertilization (IVF) treatment with or without intracytoplasmic sperm injection (ICSI). Design: Multicenter, single-blinded, randomized controlled trial, conducted from July 2014 to March 2017. Setting: IVF clinics. Patient(s): A total of 626 women undergoing IVF treatment with or without ICSI and 222 male partners. Interventions(s): Couples were randomly assigned to the light (control group) or regular (intervention group) Smarter Pregnancy program. Both groups filled out a baseline screening questionnaire on nutrition and lifestyle behaviors, and the intervention group received coaching tailored to inadequate behaviors during the 24-week period. Main Outcome Measure(s): Difference in improvement of a composite dietary and lifestyle risk score for the intake of vegetables, fruits, folic acid supplements, smoking, and alcohol use after 24 weeks of the program. Result(s): Compared with control subjects, women and men in the intervention group showed a significantly larger improvement of inadequate nutrition behaviors after 24 weeks of coaching. At the same time, the women also showed a significantly larger improvement of inadequate lifestyle behaviors. Conclusion(s): The mHealth coaching program Smarter Pregnancy is effective and improves the most important nutritional and lifestyle behaviors among couples undergoing IVF/ICSI treatment. International multicenter randomized trials are recommended to study the effect of using Smarter Pregnancy on pregnancy, live birth, and neonatal outcome. ((C)2020 by American Society for Reproductive Medicine.)y

Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): A cross-sectional study

Objective To compare vitamin D status in women with PCOS versus fertile women and subsequently evaluate the association between vitamin D status and metabolic disturbances in PCOS women. Methods We conducted a cross-sectional comparison study of 639 women with PCOS and 449 fertile women. Serum 25-hydroxyvitamin D (25(OH)D) was stratified into a severe deficient ( 75 nmol/l) status. The main outcome measures were the difference in vitamin D status between PCOS and fertile women, and the association between serum 25(OH)D and metabolic disturbances in PCOS women only. Results Serum 25(OH)D was significantly lower in PCOS women compared to fertile controls (mean 25(OH)D of 49.0 nmol/l versus 64.5 nmol/l). An adjusted significant difference was seen between serum 25(OH)D and homeostasis model assessment (HOMA-IR) (β = 0.76; 95% CI: 0.63–0.91; p < 0.01), HDL-cholesterol (β = 0.20; 95% CI: 0.05–0.60, p < 0.01) and apolipoprotein A1 (β = 26.2; 95% CI: 7.5–45.0, p < 0.01) between the highest vitamin D group compared to the lowest vitamin D group. Conclusions This study demonstrates that women

Cumulative live birth rates in low-prognosis women

STUDY QUESTION: Do cumulative live birth rates (CLBRs) over multiple IVF/ICSI cycles confirm the low prognosis in women stratified according to the POSEIDON criteria? SUMMARY ANSWER: The CLBR of low-prognosis women is ~56% over 18 months of IVF/ICSI treatment and varies between the POSEIDON groups, which is primarily attributable to the impact of female age. WHAT IS KNOWN ALREADY: The POSEIDON group recently proposed a new stratification for low-prognosis women in IVF/ICSI treatment, with the aim to define more homogenous populations for clinical trials and stimulate a patient-tailored therapeutic approach. These new criteria combine qualitative and quantitative parameters to create four groups of low-prognosis women with supposedly similar biologic characteristics. STUDY DESIGN, SIZE, DURATION: This study analyzed the data of a Dutch multicenter observational cohort study including 551 low-prognosis women, aged <44 years, who initiated IVF/ICSI treatment between 2011 and 2014 and were treated with a fixed FSH dose of 150 IU/day in the first treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Low-prognosis women were categorized into one of the POSEIDON groups based on their age (younger or older than 35 years), anti-Müllerian hormone (AMH) level (above or below 0.96 ng/ml), and the ovarian response (poor or suboptimal) in their first cycle of standard stimulation. The primary outcome was the CLBR over multiple complete IVF/ICSI cycles, including all subsequent fresh and frozen-thawed embryo transfers, within 18 months of treatment. Cumulative incidence curves were obtained using an optimistic and a conservative analytic approach. MAIN RESULTS AND THE ROLE OF CHANCE: The CLBR of the low-prognosis women was on average ~56% over 18 months of IVF/ICSI treatment. Younger unexpected poor (n = 38) and suboptimal (n = 179) responders had a CLBR of ~65% and ~68%, respectively, and younger expected poor responders (n = 65) had a CLBR of ~59%. The CLBR of older unexpected poor (n = 41) and suboptimal responders (n = 102) was ~42% and ~54%, respectively, and of older expected poor responders (n = 126) ~39%. For comparison, the CLBR of younger (n = 164) and older (n = 78) normal responders with an adequate ovarian reserve was ~72% and ~58% over 18 months of treatment, respectively. No large differences were observed in the number of fresh treatment cycles between the POSEIDON groups, with an average of two fresh cycles per woman within 18 months of follow-up. LIMITATIONS, REASONS FOR CAUTION: Small numbers in some (sub)groups reduced the precision of the estimates. However, our findings provide the first relevant indication of the CLBR of low-prognosis women in the POSEIDON groups. Small FSH dose adjustments between cycles were allowed, inducing therapeutic disparity. Yet, this is in accordance with current daily practice and increases the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: The CLBRs vary between the POSEIDON groups. This heterogeneity is primarily determined by a woman's age, reflecting the importance of oocyte quality. In younger women, current IVF/ICSI treatment reaches relatively high CLBR over multiple complete cycles, despite reduced quantitative parameters. In older women, the CLBR remains relatively low over multiple complete cycles, due to the co-occurring decline in quantitative and qualitative parameters. As no effective interventions exist to counteract this decline, clinical management currently relies on proper counselling. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. J.A.L. is supported by a Research Fellowship grant and received an unrestricted personal grant from Merck BV. S.C.O., T.C.v.T., and H.L.T. received an unrestricted personal grant from Merck BV. C.B.L. received research grants from Merck, Ferring, and Guerbet. K.F. received unrestricted research grants from Merck Serono, Ferring, and GoodLife. She also received fees for lectures and consultancy from Ferring and GoodLife. A.H. declares that the Department of Obstetrics and Gynaecology, University Medical Centre Groningen received an unrestricted research grant from Ferring Pharmaceuticals BV, the Netherlands. J.S.E.L. has received unrestricted research grants from Ferring, Zon-MW, and The Dutch Heart Association. He also received travel grants and consultancy fees from Danone, Euroscreen, Ferring, AnshLabs, and Titus Healthcare. B.W.J.M. is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, and Guerbet. He also received a research grant from Merck BV and travel support from Guerbet. F.J.M.B. received monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands) and Ferring Pharmaceuticals BV (the Netherlands) for advisory work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development, and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Not applicable

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment : protocol for a systematic review and individual participant data meta-analysis

Funding Information: This project is partly supported by the Centre for Research Excellence in Women's Health in Reproductive Life (app1171592) through a project support grant. RW is supported by a National Health and Medical Research Council (NHRMC) Investigator grant (2009767). LM is supported by a Heart Foundation Future Leader Fellowship. Funding Information: AH reports consultancy for Ferring with respect to the development of a lifestyle app. BWM is supported by an NHMRC Investigator grant (GNT1176437). BWM reports personal fees from ObsEva and Merck, and travel support from Merck, outside the submitted work. RW reports grants from the NHMRC. TM is supported by a Future Leader in Diabetes Award from the European Foundation for the Study of Diabetes/Novo Nordisk Foundation (NNF19SA058975) and grants from the regional health authority in Central Norway. ATK reports personal fees from Merck for lectures. The other authors do not have competing interest to declare. Funding Information: This project is partly supported by the Centre for Research Excellence in Women’s Health in Reproductive Life (app1171592) through a project support grant. RW is supported by a National Health and Medical Research Council (NHRMC) Investigator grant (2009767). LM is supported by a Heart Foundation Future Leader Fellowship. Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Peer reviewedPublisher PD

Trabecular bone density in middle-aged women with reproductive disorders

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 (P E) 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 w ell as trabecular BD

Meiotic silencing and fragmentation of the male germline restricted chromosome in zebra finch

During male meiotic prophase in mammals, X and Y are in a largely unsynapsed configuration, which is thought to trigger meiotic sex chromosome inactivation (MSCI). In avian species, females are ZW, and males ZZ. Although Z and W in chicken oocytes show complete, largely heterologous synapsis, they too undergo MSCI, albeit only transiently. The W chromosome is already inactive in early meiotic prophase, and inactive chromatin marks may spread on to the Z upon synapsis. Mammalian MSCI is considered as a specialised form of the general meiotic silencing mechanism, named meiotic silencing of unsynapsed chromatin (MSUC). Herein, we studied the avian form of MSUC, by analysing the behaviour of the peculiar germline restricted chromosome (GRC) that is present as a single copy in zebra finch spermatocytes. In the female germline, this chromosome is present in two copies, which normally synapse and recombine. In contrast, during male meiosis, the single GRC is always eliminated. We found that the GRC in the male germline is silenced from early leptotene onwards, similar to the W chromosome in avian oocytes. The GRC remains largely unsynapsed throughout meiotic prophase I, although patches of SYCP1 staining indicate that part of the GRC may self-synapse. In addition, the GRC is largely devoid of meiotic double strand breaks. We observed a lack of the inner centromere protein INCENP on the GRC and elimination of the GRC following metaphase I. Subsequently, the GRC forms a micronucleus in which the DNA is fragmented. We conclude that in contrast to MSUC in mammals, meiotic silencing of this single chromosome in the avian germline occurs prior to, and independent of DNA double strand breaks and chromosome pairing, hence we have named this phenomenon meiotic silencing prior to synapsis (MSPS)