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Objective, Design, and Methods: Although 17-hydroxyprogesterone (17OHP) has historically been the steroid assayed in the diagnosis of congenital adrenal 21-hydroxylase deficiency (CAH-21D), its C11-hydroxylated metabolite, 21-deoxycortisol (21DF), which is strictly of adrenal origin, is assayed in parallel in this pathology. This steroid (21DF) is oxidized by 11beta-hydroxysteroid dehydrogenase type 2 into 21-deoxycortisone (21DE). In the context of CAH-21D confirmation testing, confounding factors (such as intensive care unit admission, stress, prematurity, early sampling, and variations of sex development) can interfere with the interpretation of the gold-standard biomarkers (17OHP and 21DF). Since its tissue concentrations are especially high in the placenta, we hypothesized that 21DE quantification in the neonatal periods could be an interesting biomarker in addition to 17OHP and 21DF. To verify this hypothesis, we developed a new mass spectrometry-based assay for 21DE in serum and applied it to newborns screened for CAH-21D., Results: In newborns with CAH-21D, the mean serum levels of 21DE reached 17.56 ng/mL (ranging from 8.58 ng/mL to 23.20 ng/mL), and the mean 21DE:21DF ratio was 4.99. In contrast, in newborns without CAH-21D, the 21DE serum levels were low and not statistically different from the analytical 21DE limit of quantification (0.01 ng/mL)., Conclusion: Basal serum 21DE appears to be a novel sensitive and specific biomarker of CAH-21D in newborns., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Question: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons?, Summary Answer: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART., What Is Known Already: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear., Study Design Size Duration: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited., Participants/materials Setting Methods: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling., Main Results and the Role of Chance: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P  =   0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P  =   0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b  = 0.025, P  <   0.05) and a negative indirect effect of breastfeeding ( b  = -0.012, P  <   0.05) on the association between ART and asthma in singleton offspring., Limitations Reasons for Caution: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution., Wider Implications of the Findings: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions., Study Funding/competing Interests: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests., Trial Registration Number: ChiCTR2300069906., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Male infertility is a global health problem that disturbs numerous couples worldwide. Basonuclin 1 (BNC1) is a transcription factor mainly expressed in proliferative keratinocytes and germ cells. A frameshift mutation of BNC1 was identified in a large Chinese primary ovarian insufficiency pedigree. The expression of BNC1 was significantly decreased in the testis biopsies of infertile patients with nonobstructive azoospermia. Previous studies have revealed that mice with BNC1 deficiency are generally subfertile and undergo gradual spermatogenic failure. We observed that apoptosis of spermatogonia is tightly related to spermatogenic failure in mice with a Bnc1 truncation mutation. Such impairment is related to mitochondrial dysfunction causing lower mitochondrial membrane potential and higher reactive oxygen species. We showed that downregulation of CREB/SIRT1/FOXO3 signaling participates in the above impairment. Administration of nicotinamide riboside or metformin reversed mitochondrial dysfunction and inhibited apoptosis in Bnc1-knockdown spermatogonia by stimulating CREB/SIRT1/FOXO3 signaling. Dietary supplementation with nicotinamide riboside or metformin in mutated mice increased SIRT1 signaling, improved the architecture of spermatogenic tubules, inhibited apoptosis of the testis, and improved the fertility of mice with a Bnc1 truncation mutation. Our data establish that oral nicotinamide riboside or metformin can be useful for the treatment of spermatogenic failure induced by Bnc1 mutation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: The authors have no conflict of interest to declare.

Study Question: Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology?, Summary Answer: Endogenous cortisol excess caused by CS leads to varying degrees of hypogonadotropic hypogonadism (HH) with more severe GA/TF impairment and altered spermatogenesis in men with intense hypercortisolism associated with paraneoplastic/ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS)., What Is Known Already: CS is very rarely studied in men due to its lower prevalence in men than in women. In a few old reports focusing exclusively on a limited number of men with Cushing's disease (CD), the occurrence of hypogonadism was reported. However, a detailed assessment of the impact of CS on the GA/TF in a significant series of patients has not been performed. Yet, hypogonadism could worsen CS-associated comorbidities such as osteoporosis and myopathy. To date, the full spectrum of GA/TF impairment in men with CS of different etiologies and intensity remains unknown., Study Design, Size, Duration: In this monocentric study, 89 men with CS diagnosed at a tertiary endocrine university center (Bicêtre, Paris Saclay) between January 1990 and July 2021 were evaluated and compared to 40 normal men of similar age., Participants/materials, Setting, Methods: The CS patient cohort of 89 men included 51 with CD, 29 with EAS and 9 with CS of adrenal origin i.e. (ACTH-independent CS (AI-CS)). They all had frank hypercortisolism, with increased 24 h-urinary-free cortisol (24 h-UFC) in two separate samples. A case-control study was performed focusing on pituitary gonadotrope function and testicular sex steroids and peptides. An additional set of six CS men had an evaluation including semen analysis. In a subgroup of 20 men with available data after CS remission, a longitudinal analysis was conducted to assess the reversibility of GA/TF defects., Main Results and the Role of Chance: Compared to controls, men with CS had significantly lower total testosterone (TT), bioavailable TT, and free TT (P < 0.0001). Hypogonadism, defined as serum TT levels <3.0 ng/ml, was present in 83% of men with EAS, in 61% of men with CD, and in 33% of men with AI-CS. Low-normal LH concentrations in the included men with hypercortisolism indicated HH. Serum sex hormone-binding globulin levels were moderately decreased in men with CD (P = 0.01 vs controls). Among the CS men, those with EAS had significantly lower TT, LH, and FSH levels than those with CD or AI-CS. When compared to controls, patients with EAS were the only group exhibiting a significant decrease in both serum FSH (P = 0.002) and the testicular peptides inhibin B (P < 0.0001) and anti-Müllerian hormone (P = 0.003). Serum INSL3 levels were significantly lower in men with CD than in the controls (P = 0.03). Of note, 24 h-UFC and ACTH were inversely and significantly associated with the majority of reproductive hormones including LH, FSH, TT, and inhibin B. Following successful curative therapy, reproductive assessment at a mean of 6.0 ± 4.3 years showed a significant increase in serum TT (P < 0.0001) and plasma LH (P = 0.02) levels, indicating a reversal of HH in 75% of the affected males. Among the six patients with available semen analysis, the two EAS cases exhibited a decrease in Sertoli cell peptides associated with a severe oligozoospermia, which completely normalized following removal of the source of hypercortisolism., Limitations, Reasons for Caution: The potential bias due to the retrospective design is counteracted by the analysis of the largest male CS cohort to date as well as the use of stringent inclusion and exclusion criteria. Due to the low number of patients with semen analysis in this study, further research is needed to unravel the full spectrum of spermatogenesis defects in men with CS., Wider Implications of the Findings: This work reveals the variable spectrum of reproductive impact in men with CS. We demonstrate that GA/TF impairment depends on the intensity of hypercortisolism which in turn is related to the underlying etiology. The causal link between hypercortisolism and GA/TF impairment was attested by its reversibility in most patients after CS remission. The wider implications of our findings lie in the potential generalization to a much commoner entity, iatrogenic CS due to chronic exposure to exogenous glucocorticoids., Study Funding/competing Interest(s): Several research grants were attributed to J.Y.: (i) a grant from Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO); (ii) a grant from the French Association of Patients with Adrenal Diseases ('Association surrénales'); and (iii) independent Investigator Research Grants from HRA Pharma, Novartis and Recordati Pharma. A SICPA Foundation grant (Lausanne, Switzerland) allowed protected research time for G.E.P. The above sponsors were not involved in any part of the study. The authors have no competing or other conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Does double vitrification and thawing of an embryo compromise the chance of live birth after a single blastocyst transfer?, Summary Answer: The live birth rate (LBR) obtained after double vitrification was comparable to that obtained after single vitrification., What Is Known Already: Double vitrification-warming (DVW) is commonly practiced to accommodate surplus viable embryos suitable for transfer, to allow retesting of inconclusively diagnosed blastocysts in preimplantation genetic testing (PGT), and to circumvent limitations associated with national policies on embryo culture in certain countries. Despite its popularity, the evidence concerning the impact of DVW practice on ART outcomes is limited and lacking credibility. This is the first thorough investigation of clinical pregnancy and LBR following DVW in the case where the first round of vitrification occurred at the zygote stage and the second round occurred at the blastocyst stage in the absence of biopsy., Study Design Size Duration: This is a retrospective observational analysis of n = 407 single blastocyst transfers whereby embryos created by IVF/ICSI were vitrified-warmed once (single vitrification-warming (SVW) n = 310) or twice (DVW, n = 97) between January 2017 and December 2021., Participants/materials Setting Methods: In the SVW group, blastocysts were vitrified on Day 5/6 and warmed on the day of embryo transfer (ET). In the DVW group, two pronuclear (2PN) zygotes were first vitrified-warmed and then re-vitrified on Day 5/6 and warmed on the day of ET. Exclusion criteria were ETs from PGT and vitrified-warmed oocyte cycles. All of the ETs were single blastocyst transfers performed at the University Hospital Zurich in Switzerland following natural or artificial endometrial preparation., Main Results and the Role of Chance: The biochemical pregnancy rate, clinical pregnancy rate (CPR), and LBR were all comparable between the DVW and SVW groups. The CPR for DVW was 44.3% and for SVW it was 42.3% ( P  = 0.719). The LBR for DVW was 30.9% and for SVW it was 28.7% ( P  = 0.675). The miscarriage rate was additionally similar between the groups: 27.9% for DVW and 32.1% for SVW groups ( P  = 0.765)., Limitations Reasons for Caution: The study is limited by its retrospective nature. Caution should be taken concerning interpretation of these findings in cases where DVW occurs at different stages of embryo development., Wider Implications of the Findings: The result of the present study on DVW procedure provides a framework for counselling couples on their chance of clinical pregnancy per warming cycle. It additionally provides confidence and reassurance to laboratory professionals in certain countries where national policies limit embryo culture strategies making DVW inevitable., Study Funding/competing Interests: This work was supported by the University Research Priority Program 'Human Reproduction Reloaded' of the University of Zurich. The authors have no conflict of interest related to this study to declare., Trial Registration Number: N/A., Competing Interests: The authors have no conflict of interest related to this study to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Context: Gestational diabetes mellitus (GDM) is a common obstetric complication. Although early intervention could prevent the development of GDM, there was no consensus on early identification for women at high risk of GDM., Objective: To develop a reliable prediction model of GDM in early pregnancy., Methods: In this prospective cohort study, between May 30, 2021, and August 13, 2022, a total of 721 women were included from Women's Hospital, Zhejiang University School of Medicine. Participants were asked to complete an oral glucose tolerance test (OGTT) during gestational weeks 7 through 14 for early prediction of GDM, and at weeks 24 through 28 for GDM diagnosis. Using OGTT results and baseline characteristics, logistic regression analysis was used to construct the prediction model. Receiver operating characteristic (ROC) curve, Hosmer-Lemeshow test, decision clinical analysis, and a nomogram were used for model performances assessment and visualization. Internal and external validation was performed to testify the stability of this model., Results: According to the International Association of Diabetes and Pregnancy Study Groups criteria in early OGTT, the mean (SD) age was 30.5 ± 3.7 years in low-risk participants and 31.0 ± 3.9 years in high-risk participants. The area under ROC curve (AUC) of the existing criteria at weeks 7 through 14 varied from 0.705 to 0.724. Based on maternal age, prepregnancy body mass index, and results of early OGTT, the AUC of our prediction model was 0.8720, which was validated by both internal (AUC 0.8541) and external (AUC 0.8241) confirmation., Conclusions: The existing diagnostic criteria were unsatisfactory for early prediction of GDM. By combining early OGTT, we provided an effective prediction model of GDM in the first trimester., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: While the sexuality of patients with endometriosis is an established topic in research, the possible effect of endometriosis on partnership sexuality has come to the fore only recently. To improve counseling, more information is needed on how both partners experience sexuality in the context of endometriosis., Aim: Previous research regarding endometriosis and sexuality normally focused on one partner to explore couples' intimate relations, whereas this study provides a comparison on both partners' perspectives on their common sexuality., Methods: An overall 302 couples received a questionnaire based on the Brief Index of Sexual Functioning and Sexual History Form, which was modified by endometriosis specialists to better focus on endometriosis-specific aspects. To detect different perspectives on common sexuality within the couple, the Wilcoxon test and the Pearson chi-square test were performed., Outcomes: Various aspects of couple sexuality were assessed by both partners to investigate divergent perspectives between the man and the woman within a couple., Results: On one hand, male and female partners seem to have divergent perspectives on sexual satisfaction in general, desired frequency of sexual contacts, and the question of the female partner engaging in sexual activity despite discomfort. On the other, they have similar perspectives on who takes initiative in sexual contacts, satisfaction with variety in the sexual relationship, and the impact of sexual limitations on their satisfaction within the partnership., Clinical Implications: Endometriosis research addressing issues related to sexuality should include male partners; the same applies to consulting women with endometriosis in the context of their relationships rather than as individuals., Strengths and Limitations: This is the first analysis conducted on a larger scale of data from both partners in couples dealing with endometriosis. As it provides quantitative information only, some qualitative information remains unexplored., Conclusion: As both partners showed tendencies to overestimate their partners' sexual satisfaction and had different perspectives on sensitive topics in sexuality, such as the female partner engaging in sexual activity despite discomfort, addressing sexual communication could be a starting point in counseling couples dealing with endometriosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients., (© The Author(s) 2023. Published by Oxford University Press.)

Study Question: Can a combination of metabolomic signature and machine learning (ML) models distinguish nonclassic 21-hydroxylase deficiency (NC21OHD) from polycystic ovary syndrome (PCOS) without adrenocorticotrophic hormone (ACTH) testing?, Summary Answer: A single sampling methodology may be an alternative to the dynamic ACTH test in order to exclude the diagnosis of NC21OHD in the presence of a clinical hyperandrogenic presentation at any time of the menstrual cycle., What Is Known Already: The clinical presentation of patients with NC21OHD is similar with that for other disorders of androgen excess. Currently, cosyntropin stimulation remains the gold standard diagnosis of NC21OHD., Study Design, Size, Duration: The study was designed using a bicentric recruitment: an internal training set included 19 women with NC21OHD and 19 controls used for developing the model; a test set included 17 NC21OHD, 72 controls and 266 PCOS patients used to evaluate the performance of the diagnostic strategy thanks to an ML approach., Participants/materials, Setting, Methods: Fifteen steroid species were measured in serum by liquid chromatography-mass spectrometry (LC-MS/MS). This set of 15 steroids (defined as 'steroidome') used to map the steroid biosynthesis pathway was the input for our models., Main Results and the Role of Chance: From a single sample, modeling involving metabolic pathway mapping by profiling 15 circulating steroids allowed us to identify perfectly NC21OHD from a confounding PCOS population. The constructed model using baseline LC-MS/MS-acquired steroid fingerprinting successfully excluded all 17 NC21OHDs (sensitivity and specificity of 100%) from 266 PCOS from an external testing cohort of originally 549 women, without the use of ACTH testing. Blood sampling timing during the menstrual cycle phase did not impact the efficiency of our model., Limitations, Reasons for Caution: The main limitations were the use of a restricted and fully prospective cohort as well as an analytical issue, as not all laboratories are equipped with mass spectrometers able to routinely measure this panel of 15 steroids. Moreover, the robustness of our model needs to be established with a larger prospective study for definitive validation in clinical practice., Wider Implications of the Findings: This tool makes it possible to propose a new semiology for the management of hyperandrogenism. The model presents better diagnostic performances compared to the current reference strategy. The management of patients may be facilitated by limiting the use of ACTH tests. Finally, the modeling process allows a classification of steroid contributions to rationalize the biomarker approach and highlight some underlying pathophysiological mechanisms., Study Funding/competing Interest(s): This study was supported by 'Agence Française de Lutte contre le dopage' and DIM Région Ile de France. This study was supported by the French institutional PHRC 2010-AOR10032 funding source and APHP. All authors declare no competing financial interests., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Individual cells are basic units of life. Despite extensive efforts to characterize the cellular heterogeneity of different organisms, cross-species comparisons of landscape dynamics have not been achieved. Here, we applied single-cell RNA sequencing (scRNA-seq) to map organism-level cell landscapes at multiple life stages for mice, zebrafish and Drosophila. By integrating the comprehensive dataset of > 2.6 million single cells, we constructed a cross-species cell landscape and identified signatures and common pathways that changed throughout the life span. We identified structural inflammation and mitochondrial dysfunction as the most common hallmarks of organism aging, and found that pharmacological activation of mitochondrial metabolism alleviated aging phenotypes in mice. The cross-species cell landscape with other published datasets were stored in an integrated online portal-Cell Landscape. Our work provides a valuable resource for studying lineage development, maturation and aging., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Context: Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates. However, OSCM has high iodine content and long half-life, leading to potential iodine excess., Objective: This work aimed to determine the pattern of iodine excess after OSCM HSG and the effect on thyroid function., Methods: A prospective cohort study was conducted of 196 consecutive consenting eligible women without overt hypothyroidism or hyperthyroidism. All completed the study with compliance greater than 95%. Participants underwent OSCM HSG (Auckland, 2019-2021) with serial monitoring of thyrotropin (TSH), free thyroxine (FT4), and urine iodine concentration (UIC) for 24 weeks. The main outcome measure was the development of subclinical hypothyroidism (SCH), defined as a nonpregnant TSH greater than 4 mIU/L with normal FT4 (11-22 pmol/L) in those with normal baseline thyroid function., Results: Iodine excess (UIC ≥ 300 μg/L) was almost universal (98%) with UIC peaking usually by 4 weeks. There was marked iodine excess, with 90% and 17% of participants having UIC greater than or equal to 1000 μg/L and greater than 10 000 μg/L, respectively. Iodine excess was prolonged with 67% having a UIC greater than or equal to 1000 μg/L for at least 3 months. SCH developed in 38%; the majority (96%) were mild (TSH 4-10 mIU/L) and most developed SCH by week 4 (75%). Three participants met the current treatment guidelines (TSH > 10 mIU/L). Thyroxine treatment of mild SCH tended to improve pregnancy success (P = .063). Hyperthyroidism (TSH < 0.3 mIU/L) occurred in 9 participants (5%)., Conclusion: OSCM HSG resulted in marked and prolonged iodine excess. SCH occurred frequently with late-onset hyperthyroidism occasionally. Regular thyroid function tests are required for 6 months following this procedure., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

To better understand the physiological basis of obesity in women, we investigated whether obesity or menstrual cycle phase affects laboratory test-meal size or meal-stimulated plasma cholecystokinin (CCK) concentration. Women with healthy weight (body mass index [BMI] of 18.5-24.9 kg/m2, N = 16) or obesity (BMI 30-39.9 kg/m2, N = 20) were tested once in the late-follicular or peri-ovulatory phase (LF/PO) and once in the mid-luteal phase (ML). Meals of ham sandwiches were offered and blood was sampled. Menstrual cycle phases were verified with participants' reports of menses and measurements of progesterone and luteinizing hormone (LH) concentrations. Women with obesity ate significantly larger meals than women with healthy weight, (mean, 711 [95% CI, 402-1013] kJ, P = 0.001, during the LF/PO and 426 [105-734] kJ, P = 0.027, larger during the ML). Women with healthy weight ate smaller meals during LF/PO than ML (decrease, 510 [192-821 kJ], P = 0.008), but women with obesity did not (decrease, 226 [-87-542] kJ, P = 0.15). CCK concentrations 18 to 30 minutes after meal onset were lower in women with obesity than in women with healthy weight during LF/PO (3.6 [3.1-4.1] vs 6.1 [4.5-7.7] pmol/L; P = 0.004), but not during ML, with a significant interaction effect (1.8 [1.2-2.4] pmol/L, P = 0.048). Women with obesity consumed larger meals than women with healthy weight but displayed reduced meal-stimulated plasma CCK concentrations. These data are consistent with the hypothesis that a defect in CCK secretion compromises satiation in obese women and contributes to the development or maintenance of obesity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Spontaneous abortion (SA) is a common disorder in early pregnancy. Circular RNAs (circRNAs) have been reported to exert important regulatory effects on trophoblast function and embryo development., Objective: The aim of this study was to explore whether and how circRNAs regulate trophoblast function in SA during early pregnancy., Methods: Cell proliferation, 5-bromo-2-deoxyuridine (BrdU) staining, Transwell, immunofluorescence, Western blot, RNA pull-down, and dual luciferase reporter assays were performed to investigate the effect of circRNA cyclin B1 (circ-CCNB1) on trophoblast function in HTR-8/SVneo and JEG-3 cells., Results: An in vitro study demonstrated that upregulation of circ-CCNB1 significantly inhibited trophoblast proliferation and invasion compared with the controls using HTR-8/SVneo and JEG-3 cells, respectively. Moreover, miR-223 was downregulated in the villous tissues of patients with SA and was further predicted and shown to negatively interact with circ-CCNB1, which is involved in trophoblast proliferation and invasion. Using bioinformatics tools and subsequent RNA pull-down and dual luciferase assays, we found that miR-223 directly targets seven in absentia homolog-1 (SIAH1) and that upregulation of miR-223 decreased circ-CCNB1-induced SIAH1 expression levels in HTR-8/SVneo cells. Interestingly, upregulation of circ-CCNB1 suppressed trophoblast proliferation and invasion through inhibition of CCNB1 nuclear translocation induced by SIAH1. Downregulation of SIAH1 enhanced circ-CCNB1-suppressed CCNB1 nuclear protein expression in trophoblast cells., Conclusion: Circ-CCNB1 served as a modulator of trophoblast proliferation and invasion by sponging miR-223, thus forming a regulatory network of circ-CCNB1/miR-223/SIAH1 in modulating CCNB1 nuclear translocation, which enabled us to elucidate the molecular mechanisms involved in normal embryo implantation or in SA., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally., Objective: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center., Methods: We included 172 controls, 668 male HH patients (CHH: n = 201 [age 16.9 ± 9.0 years], lesional AHH: n = 467 [age 45.6 ± 18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases., Results: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4 ± 2.7 mL) but in only 30% of those with AHH (mean TV: 20.8 ± 5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH., Conclusion: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Is the morphological grading system for blastocysts associated with perinatal outcomes in women undergoing frozen-thawed single blastocyst transfer (SBT)?, Summary Answer: Preferential transfer of a blastocyst based on their inner cell mass (ICM) and trophectoderm (TE) grading appears to be supported by observed differences in perinatal outcomes., What Is Known Already: The transfer of a morphologically good quality blastocyst is associated with a higher chance of implantation and pregnancy as compared to transfer of a poor quality blastocyst. However, to date, the association of the morphological parameters of the blastocyst with perinatal outcomes after blastocyst transfer remains unknown., Study Design Size Duration: This retrospective cohort study started with 27 336 frozen-thawed SBT cycles from January 2013 to December 2019., Participants/materials Setting Methods: There were 7469 women with singleton deliveries in Peking University Third Hospital eligible for analysis. Multivariate logistic regression was used to test the risk of factors with the expression of crude odds ratios (ORs) and adjusted OR with 95% CIs., Main Results and the Role of Chance: Transfer of a blastocyst with a low overall grading was associated with a higher chance of female baby (48% vs 42%, adjusted OR = 1.26 (1.13, 1.39)) and a higher rate of caesarian section (C-section; 71% vs 68%, adjusted OR = 1.15 (1.02, 1.29)). Compared with Grade A ICM blastocyst transfer, Grade B ICM and Grade C ICM blastocyst transfers were associated with a lower chance of a female baby (adjusted OR = 0.83 (0.73, 0.95), 0.63 (0.50, 0.79), respectively) and a higher risk of large for gestational age (LGA; adjusted OR = 1.23 (1.05, 1.45), 1.47 (1.12, 1.92), respectively); Grade C ICM blastocyst transfer was also associated with an increased risk of macrosomia (adjusted OR = 1.66 (1.20, 2.30)). Compared with Grade A TE blastocyst transfer, there was an increased risk of small for gestational age with Grade C TE blastocyst transfer (adjusted OR = 1.74 (1.05, 2.88)). Both Grade B TE and Grade C TE blastocyst transfer had a higher chance of female baby (adjusted OR = 1.30 (1.11, 1.53), 1.88 (1.57, 2.26), respectively) and a lower risk of gestational diabetes mellitus (adjusted OR = 0.74 (0.59, 0.94), 0.67 (0.50, 0.88), respectively) than Grade A TE blastocyst transfer., Limitations Reasons for Caution: The main limitations of this study were its retrospective nature and the relative subjectivity of blastocyst scoring. The follow-up was conducted through a phone call and some patients may not have reported their obstetrical and neonatal outcomes, leading to a relatively lower rate of several obstetrical outcomes. Due to the missing information in our dataset, we were not able to separate out iatrogenic preterm birth nor adjust for obstetric complications in previous pregnancies as a confounder in the mutivariate analysis. Because the days of blastocyst culture in total were unclear in our dataset, analysis of the association between the time to reach blastocyst expansion and perinatal outcomes was not performed., Wider Implications of the Findings: Transfer of a blastocyst with a low overall grading is associated with a higher rate of C-section and a higher chance of a female baby. The association between ICM grading and LGA would suggest that Grade A ICM blastocysts should be transferred preferentially to Grade B/C ICM blastocysts. Our results support the use of current morphological systems for embryo prioritization., Study Funding/competing Interests: This study was supported by the National Key Research and Development Program of China (2018YFC1004100 to R.L.), the National Science Fund for Distinguished Young Scholars (81925013 to R.L.) and a Zhejiang University Scholarship for Outstanding Doctoral Candidates (to K.-L.H.). All authors have read the journal's authorship agreement and policy on disclosure of potential conflicts of interest, and have no conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Context: Obesity management prior to infertility treatment remains a challenge. To date, results from randomized clinical trials involving weight loss by lifestyle interventions have shown no evidence of improved live birth rate., Objective: This work aimed to determine whether pharmacologic weight-loss intervention before in vitro fertilization and embryo transfer (IVF-ET) can improve live birth rate among overweight or obese women., Methods: We conducted a randomized, double-blinded, placebo-controlled trial across 19 reproductive medical centers in China, from July 2017 to January 2019. A total of 877 infertile women scheduled for IVF who had a body mass index of 25 or greater were randomly assigned to receive orlistat (n = 439) or placebo (n = 438) treatment for 4 to 12 weeks. The main outcome measurement was the live birth rate after fresh ET., Results: The live birth rate was not significantly different between the 2 groups (112 of 439 [25.5%] with orlistat and 112 of 438 [25.6%] with placebo; P = .984). No significant differences existed between the groups as to the rates of conception, clinical pregnancy, or pregnancy loss. A statistically significant increase in singleton birth weight was observed after orlistat treatment (3487.50 g vs 3285.17 g in the placebo group; P = .039). The mean change in body weight during the intervention was -2.49 kg in the orlistat group, as compared to -1.22 kg in the placebo group, with a significant difference (P = .005)., Conclusion: Orlistat treatment, prior to IVF-ET, did not improve the live birth rate among overweight or obese women, although it was beneficial for weight reduction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown., Objective: To characterize bone geometry, volumetric density and microarchitecture in CHH/KS., Methods: This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture., Results: CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia., Conclusion: Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Model-based approaches to safety and efficacy assessment of pharmacological drugs, treatment strategies or medical devices (In Silico Clinical Trial, ISCT) aim to decrease time and cost for the needed experimentations, reduce animal and human testing, and enable precision medicine. Unfortunately, in presence of non-identifiable models (e.g. reaction networks), parameter estimation is not enough to generate complete populations of Virtual Patients (VPs), i.e. populations guaranteed to show the entire spectrum of model behaviours (phenotypes), thus ensuring representativeness of the trial., Results: We present methods and software based on global search driven by statistical model checking that, starting from a (non-identifiable) quantitative model of the human physiology (plus drugs PK/PD) and suitable biological and medical knowledge elicited from experts, compute a population of VPs whose behaviours are representative of the whole spectrum of phenotypes entailed by the model (completeness) and pairwise distinguishable according to user-provided criteria. This enables full granularity control on the size of the population to employ in an ISCT, guaranteeing representativeness while avoiding over-representation of behaviours. We proved the effectiveness of our algorithm on a non-identifiable ODE-based model of the female Hypothalamic-Pituitary-Gonadal axis, by generating a population of 4 830 264 VPs stratified into 7 levels (at different granularity of behaviours), and assessed its representativeness against 86 retrospective health records from Pfizer, Hannover Medical School and University Hospital of Lausanne. The datasets are respectively covered by our VPs within Average Normalized Mean Absolute Error of 15%, 20% and 35% (90% of the latter dataset is covered within 20% error). Availability and implementation. Our open-source software is available at https://bitbucket.org/mclab/vipgenerator., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: What is the sperm DNA methylation status of imprinted genes in male partners from couples experiencing recurrent pregnancy loss (RPL)?, Summary Answer: Aberrations in sperm DNA methylation status of several imprinted genes, such as insulin like growth factor-2-H19 differentially methylated region (IGF2-H19 DMR), intergenic differentially methylated region (IG-DMR), mesoderm specific transcript (MEST), zinc finger protein which regulates apoptosis and cell cycle arrest (ZAC), DMR in intron 10 of KCNQ1 gene (KvDMR), paternally expressed gene 3 (PEG3) and paternally expressed gene 10 (PEG10), as well as decreased sperm global 5-methylcytosine (5mC) levels, are associated with RPL., What Is Known Already: RPL is defined as loss of two or more pregnancies, affecting 1-2% of couples of reproductive age. Although there are several maternal and paternal aetiological factors contributing to RPL, nearly 50% of the cases remain idiopathic. Thus, there is a need to identify putative paternal factors that could be contributing towards pregnancy loss in cases of idiopathic RPL., Study Design, Size, Duration: In this case-control study, 112 couples undergoing RPL with no identifiable cause were recruited from September 2015 to May 2018. The control group comprised of 106 healthy proven fertile couples with no history of infertility or miscarriage., Participants/materials, Setting, Methods: In this study, we investigated the paternal genetic and epigenetic factors that could be associated with RPL. We studied DNA methylation, by pyrosequencing, of selected imprinted genes implicated in embryo development, such as IGF2-H19 DMR, IG-DMR, MEST, ZAC, KvDMR, PEG3, PEG10 and small nuclear ribonucleoprotein polypeptide N (SNRPN) in sperm of men whose partners present RPL. Global DNA methylation in sperm was evaluated by studying 5mC content and long interspersed nuclear element 1 (LINE1) promoter methylation. We also studied polymorphisms by pyrosequencing in the IGF2-H19 DMR as well in the IGF2 promoter in both groups., Main Results and the Role of Chance: In the RPL group, we found a significant decrease in the global sperm 5mC levels and significant decrease in DNA methylation at three CpG sites in LINE1 promoter. For IGF2-H19 DMR and IG-DMR, a significant decrease in sperm DNA methylation at specific CpG sites was observed in RPL group. For maternally imprinted genes like MEST, ZAC, KvDMR, PEG3 and PEG10 hypermethylation was noted. Polymorphism studies for IGF2-H19 DMR and IGF2 revealed significant differences in the genotypic frequencies in males., Limitations, Reasons for Caution: In this study, we analysed the methylation levels of selected candidate imprinted genes implicated in embryo development. Detection of methylation changes occurring at the genome-wide level may reveal further candidate genes having a better distinction between the control and study groups., Wider Implications of the Findings: Our study demonstrates that certain polymorphisms and aberrant sperm methylation status in imprinted genes are associated with RPL and could contribute to the aetiology of RPL. This study suggests that investigation of paternal genetic and epigenetic factors could be useful in identification of possible causes of idiopathic RPL., Study Funding/competing Interest(s): This study was funded by Department of Science and Technology-Science and Engineering Research Board (EMR/2014/000145) and National Institute for Research in Reproductive Health intramural funds (RA/872/01-2020). All authors declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed?, Summary Answer: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility., What Is Known Already: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret., Study Design, Size, Duration: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries)., Participants/materials, Setting, Methods: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods., Main Results and the Role of Chance: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable., Limitations, Reasons for Caution: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold., Wider Implications of the Findings: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set., Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form., Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Dyspareunia, one of the main symptoms of the chronic gynecological pelvic pain disorder endometriosis, may interfere with the likelihood of reaching an orgasm, yet for women with dyspareunia, no data on orgasm rates in different sexual activities are available., Aim: The aim of this study was to evaluate the ability to reach an orgasm and its association with sexual satisfaction during different sexual activities in women with a chronic pelvic pain disorder and in healthy control women., Methods: A set of questionnaires including the brief index of sexual functioning and global sexual functioning was used to evaluate sexuality in women affected with endometriosis (n = 434) and a nonaffected control group (n = 434) recruited in German-speaking countries., Outcomes: The primary outcome measure of this study was the orgasm rate during different types of sexual activities., Results: Only the ability to have an orgasm during sexual intercourse (P = .002) but not during masturbation (P = .509) or partnered noncoital sexual activities (P = .229) is affected by endometriosis. Dyspareunia was associated with a reduced ability to experience an orgasm during intercourse for endometriosis patients (P = .020) and control women (P = .006). The ability to orgasm during noncoital sexual activities (P = .006) and sexual intercourse (P = .038) was associated with a higher sexual satisfaction in women with endometriosis. For controls, only the ability to achieve an orgasm with sexual intercourse was associated with sexual satisfaction (P = .038)., Clinical Implications: Sexual counselling as part of medical support could help couples living with chronic pelvic pain of the female partner integrate noncoital sexual activities in their sex lives, leading to fewer sex-related problems and higher sexual desire and satisfaction., Strengths and Limitations: This study is the first to examine different ways of achieving an orgasm and sexual satisfaction in a large group of women with endometriosis and a matched control group. The breadth of the questionnaire allowed a differentiated analysis of factors influencing the likelihood of achieving an orgasm and overall sexual satisfaction. The one limitation is that the length and the intimate nature of the questionnaire possibly resulted in reluctance to answer this part of the questionnaire., Conclusion: Partnered noncoital sexual activities may represent an alternative to reach orgasm for women with endometriosis-related chronic pelvic pain or anorgasmia during sexual intercourse. Hämmerli S, Kohl-Schwartz A, Imesch P, et al. Sexual Satisfaction and Frequency of Orgasm in Women With Chronic Pelvic Pain due to Endometriosis. J Sex Med 2020;17:2417-2426., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life?, Summary Answer: Both parameters lack the specificity to discriminate CDGP from CHH., What Is Known Already: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms., Study Design, Size, Duration: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls., Participants/materials, Setting, Methods: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test., Main Results and the Role of Chance: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold., Limitations, Reasons for Caution: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here., Wider Implications of the Findings: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP., Study Funding/competing Interest(s): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Does follicular flushing increase the number of mature oocytes in monofollicular IVF?, Summary Answer: Follicular flushing increases the number of mature oocytes in monofollicular IVF., What Is Known Already: Flushing increases neither the oocyte yield nor the pregnancy rate in polyfollicular IVF or in poor responder patients. In monofollicular IVF, the effect of flushing has so far been addressed by two studies: (i) a prospective study with minimal stimulation IVF demonstrated an increased oocyte yield, and (ii) a retrospective study with natural cycle (NC)-IVF showed an increased oocyte yield and an increased transfer rate., Study Design, Size, Duration: Randomized controlled trial including 164 women who were randomized for either aspiration with or without flushing from 2016 to 2019., Participants/materials, Setting, Methods: Infertile women 18-42 years of age with an indication for IVF treatment at a university-based infertility unit. Women undergoing monofollicular IVF were randomized to either follicular aspiration only or follicular aspiration directly followed by five follicular flushes at a 1:1 ratio. The intervention was done without anaesthesia, using a gauge 19 single-lumen needle. Flushing volume was calculated (sphere formula) based on the size of the follicle., Main Results and the Role of Chance: A total of 164 women were included; 81 were allocated to 'aspiration only' and 83 to additional 'flushing'. Primary analysis was based on the intention-to-treat: oocyte yield, defined as the collected mature oocyte rate, was higher (n = 64/83, 77.1%) in the flushing group compared to the aspiration only group (n = 48/81, 59.3%, adjusted risk difference (RD): 18.2% (95% CI 3.9-31.7%), P-value = 0.02). In the flushing group, most oocytes were retrieved within the first three flushes (63/83, 75.8%). Fertilization rate was higher in the flushing group (n = 53/83, 63.9% vs n = 38/81, 46.9%; adjusted RD: 16.8% (96% CI 1.5-31.4%), P = 0.045). Transfer rate was also higher in the flushing group (n = 52/83, 62.7% vs n = 38/81, 46.9%; RD: 15.71 (95% CI 0.3-30.3%)), but the difference was not significant (P = 0.06). The clinical pregnancy rate n = 9/83 versus n = 9/81 (RD: -0.3% (95% CI -9.9% to 9.5%)) and live birth rate n = 7/83 versus n = 8/81 (RD: -1.5% (95% CI -10.4% to 7.1%)) were not significantly different between the flushing and the aspiration group. The median duration of the intervention was significantly longer with flushing (2.38 min; quartiles 2.0, 2.7) versus aspiration only (0.43 min; quartiles 0.3, 0.5) (P < 0.01). There was no significant difference in the mean (±SD) visual analogue scales pain score between the follicular flushing (3.4 ± 1.8) and the aspiration group (3.1 ± 1.89)., Limitations, Reasons for Caution: Blinding of the procedure was not possible., Wider Implications of the Findings: Our study proved that flushing of single follicles in NC-IVF increases the oocyte yield. In contrast to polyfollicular IVF flushing seems to be beneficial in a monofollicular setting if the technique used in our study (single-lumen needle, 5 flushings with flushing volume adaptation) is applied., Study Funding/competing Interest(s): The study was funded by the financial sources of the division and in part by a research grant provided by NMS Biomedical SA, Switzerland. The company did not have any roles in design or conduct of the study or in the preparation of the manuscript. The authors have no other conflicts of interest., Trial Registration Number: Clinicaltrials.gov NCT02641808., Trial Registration Date: 29 December 2015., Date of First Patient’s Enrolment: 22 August 2016., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Can cytochrome P450 oxidoreductase deficiency (PORD) be revealed in adult women with menstrual disorders and/or infertility?, Summary Answer: PORD was biologically and genetically confirmed in five adult women with chronically elevated serum progesterone (P) who were referred for oligo-/amenorrhea and/or infertility., What Is Known Already: PORD is an autosomal recessive disease typically diagnosed in neonates and children with ambiguous genitalia and/or skeletal abnormalities. It is responsible for the decreased activity of several P450 enzymes, including CYP21A2, CYP17A1 and CYP19A1, that are involved in adrenal and/or gonadal steroidogenesis. Little is known about the optimal way to investigate and treat patients with adult-onset PORD., Study Design, Size, Duration: In this series, we report five adult females who were evaluated in three tertiary endocrine reproductive departments between March 2015 and September 2018., Participants/materials, Setting, Methods: Five women aged 19-38 years were referred for unexplained oligo-/amenorrhea and/or infertility. Genetic testing excluded 21-hydroxylase deficiency (21OH-D), initially suspected due to the increased 17-hydroxyprogesterone (17-OHP) levels. Extensive phenotyping, steroid profiling by mass spectrometry, pelvic imaging and next-generation sequencing of 84 genes involved in gonadal and adrenal disorders were performed in all patients. IVF followed by frozen embryo transfer (ET) under glucocorticoid suppression therapy was performed for two patients., Main Results and the Role of Chance: All patients had oligomenorrhea or amenorrhea. None had hyperandrogenism. Low-normal serum estradiol (E2) and testosterone levels contrasted with chronically increased serum P and 17-OHP levels, which further increased after adrenocorticotrophic hormone (ACTH) administration. Despite excessive P, 17OH-P and 21-deoxycortisol rise after ACTH stimulation suggesting non-classic 21OH-D, CYP21A2 sequencing did not support this hypothesis. Basal serum cortisol levels were low to normal, with inadequate response to ACTH in some women, suggesting partial adrenal insufficiency. All patients harbored rare biallelic POR mutations classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics standards. Pelvic imaging revealed bilateral ovarian macrocysts in all women. IVF was performed for two women after retrieval of a normal oocyte number despite very low E2 levels during ovarian stimulation. Frozen ET under glucocorticoid suppression therapy led to successful pregnancies., Limitations, Reasons for Caution: The number of patients described here is limited and these data need to be confirmed on a larger number of women with non-classic PORD., Wider Implications of the Findings: The diagnosis of PORD must be considered in infertile women with chronically elevated P and 17OH-P levels and ovarian macrocysts. Differentiation of this entity from non-classic 21OH-D is important, as the multiple enzyme deficiency requires a specific management. Successful fertility induction is possible by IVF, providing that P levels be sufficiently suppressed by glucocorticoid therapy prior to implantation., Study Funding/competing Interest(s): No specific funding was used for this study. There are no potential conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gonadotropin-releasing hormone agonists (GnRHa) are used as an alternative to human chorionic gonadotropin (hCG) to trigger ovulation and decrease the risk of ovarian hyperstimulation syndrome. GnRHa is less potent at inducing ovarian vascular endothelial growth factor (VEGF), but may also affect endometrial angiogenesis and early placental development. In this study, we explore the effect of superovulation on endometrial angiogenesis during critical periods of gestation in a mouse model. We assigned female mice to three groups: natural mating or mating following injection with equine chorionic gonadotropin and trigger with GnRHa or hCG trigger. Females were killed prior to implantation (E3.5), post-implantation (E7.5), and at midgestation (E10.5), and maternal serum, uterus, and ovaries were collected. During peri-implantation, endometrial Vegfr1 and Vegfr2 mRNA were significantly increased in the GnRHa trigger group (P < 0.02) relative to the hCG group. Vegfr1 is highly expressed in the endometrial lining and secretory glands immediately prior to implantation. At E7.5, the ectoplacental cone expression of Vegfa and its receptor, Vegfr2, was significantly higher in the hCG trigger group compared to the GnRHa group (P < 0.05). Soluble VEGFR1 and free VEGFA were much higher in the serum of mice exposed to the hCG trigger compared to GnRHa group. At midgestation, there was significantly more local Vegfa expression in the placenta of mice triggered with hCG. GnRHa and hCG triggers differentially disrupt the endometrial expression of key angiogenic factors during critical periods of mouse gestation. These results may have significant implications for placental development and neonatal outcomes following human in vitro fertilization., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic., Objective: To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI., Methods: The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments., Results: We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling., Conclusion: In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Most premenopausal women in China have normal lipid profiles while the sexual function among them was scarcely demonstrated., Aim: To find out the characteristics of the sexual function in premenopausal Chinese women without hyperlipidemia using the Female Sexual Function Index (FSFI) and the Golombok Rust Inventory of Sexual Satisfaction (GRISS)., Methods: This cross-sectional study was performed to find out the characteristics of sexual function in premenopausal Chinese women without hyperlipidemia. Between January 2019 and March 2019, we recruited 216 women, 25-49 years of age. Data from questionnaires and health checkups were collected and analyzed., Main Outcome Measure: We report the prevalence of and factors related to female sexual dysfunction (FSD) in premenopausal Chinese women without hyperlipidemia in accordance with the FSFI and the GRISS., Results: The prevalence of FSD in our study was 46.2%. The mean age was 38.07 ± 6.94 years. More highly educated women suffered from FSD than those in the control group (61.1% vs 35.2%, P < .05). Binge eating was significantly different between the groups (P = .023). Multiple logistic regression analyses demonstrated that total cholesterol level was positively associated with low desire (OR, 2.13; 95% CI, 1.10-4.13; P = .025) and so was the low-density lipoprotein level (OR, 2.18; 95% CI, 1.03-4.62; P = .0.041). The high-density lipoprotein level was inversely associated with infrequency (OR, 0.18; 95% CI, 0.06-0.59; P = .004). More women with FSD had orgasm disorder than those in the control group, for 83.3% vs 35.2% in the FSFI (P < .001), 88.9% vs 54.3% in the GRISS (P < .001), respectively. Dissatisfaction remained the most common issue for the control group in both the FSFI and the GRISS (90.50% and 58.10%, respectively)., Conclusions: FSD is frequent in premenopausal Chinese women without hyperlipidemia. Dissatisfaction as the common problem influenced over half of them and orgasm disorder is a severe sexual issue for women with FSD. Xiang Y, Tang Y, Li J, et al. How Is the Sexual Function of Premenopausal Chinese Women Without Hyperlipidemia. J Sex Med 2019;8:65-75., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Basonuclin (BNC1) is expressed primarily in proliferative keratinocytes and gametogenic cells. However, its roles in spermatogenesis and testicular aging were not clear. Previously we discovered a heterozygous BNC1 truncation mutation in a premature ovarian insufficiency pedigree. In this study, we found that male mice carrying the truncation mutation exhibited progressively fertility loss and testicular premature aging. Genome-wide expression profiling and direct binding studies (by chromatin immunoprecipitation sequencing) with BNC1 in mouse testis identified several spermatogenesis-specific gene promoters targeted by BNC1 including kelch-like family member 10 (Klhl10), testis expressed 14 (Tex14), and spermatogenesis and centriole associated 1 (Spatc1). Moreover, biochemical analysis showed that BNC1 was associated with TATA-box binding protein-associated factor 7 like (TAF7L), a germ cell-specific paralogue of the transcription factor IID subunit TAF7, both in vitro and in testis, suggesting that BNC1 might directly cooperate with TAF7L to regulate spermatogenesis. The truncation mutation disabled nuclear translocation of the BNC1/TAF7L complex, thus, disturbing expression of related genes and leading to testicular premature aging. Similarly, expressions of BNC1, TAF7L, Y-box-binding protein 2 (YBX2), outer dense fiber of sperm tails 1 (ODF1), and glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) were significantly decreased in the testis of men with non-obstructive azoospermia. The present study adds to the understanding of the physiology of male reproductive aging and the mechanism of spermatogenic failure in infertile men., (© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Study Question: Is there an effect of male factor infertility (MFI) on either early or late morphokinetic parameters obtained during embryonic culture to blastocyst stage in a time-lapse imaging (TLI) incubator?, Summary Answer: Neither mild nor severe MFI had an impact on overall time to blastocyst or duration of individual cleavage stages in the total embryo population., What Is Known Already: Prior studies have suggested that paternal DNA and sperm quality affect embryo morphokinetic parameters, but the impact of MFI is not fully understood., Study Design, Size, Duration: This retrospective cohort study, at a major academic fertility centre, included 536 couples (women, ≤44 years of age) undergoing IVF between September 2013 and September 2016., Participants/materials, Setting, Methods: Data from 4126 embryos cultured to the blastocyst stage in a TLI-monitored incubator were retrospectively reviewed. Embryos derived from the sperm of men with MFI were compared with those derived from patients with other infertility diagnoses. Generalized fixed and random effects models, t-test and χ2 were used as appropriate., Main Results and the Role of Chance: Couples with MFI had a higher rate of ICSI utilization and fewer usable embryos on average, and the men were older compared with couples with other diagnoses. Additionally, the women in MFI couples were younger and had higher antral follicle counts (AFCs) and higher anti-Müllerian hormone (AMH) levels compared with the other women undergoing IVF. When controlling for maternal and paternal ages, AMH and fertilization method (conventional IVF versus ICSI), neither mild nor severe MFI affected duration of individual cleavage stages or overall time to the blastocyst stage, when all or only usable embryos were examined (coefficient 0.44 hours in all embryos, P = 0.57; coefficient 0.39 hours in usable embryos, P = 0.60). Whether the sperm was surgically extracted similarly had no significant effect on embryo morphokinetic parameters. When the fertilization method was assessed independently, ICSI lengthened the overall time to blastocyst stage by 1.66 hours (P = 0.03) on average, primarily due to an increase in duration of the time from 5-cell embryo stage to early blastulation (P5SB)., Limitations, Reasons for Caution: This large cohort study avoided embryo selection bias due to random assignment of embryos to the TLI incubators. However, our findings may not be generalizable to groups under-represented in our clinic population. Future studies should also evaluate the impact of male hormonal status and detailed sperm morphology, such as head versus flagellum defects, on embryo morphokinetic development., Wider Implications of the Findings: Our findings suggest that the fertilization method rather than MFI per se impacts time to early blastulation. The clinical implications of this effect on embryo development warrant further investigation., Study Funding/competing Interest(s): There were no sources of funding for this study. There are no competing interests., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although extremely low frequency magnetic fields (ELF-MFs) have been classified as a possible carcinogen for humans by the International Agency for Research on Cancer (IARC), their biological effects and underlying mechanisms are still unclear. Our previous study indicated that ELF-MF exposure influenced the relative permittivity of the saline solution, suggesting that the MF exposure altered physical properties of the solution. To explore the biophysical mechanism of ELF-MF-induced biological effects, this study examined the effects of 50 Hz sinusoidal MF at 0-4.0 mT on the permittivity of culture medium with phase-interrogation surface plasmon resonance (SPR) sensing. Then, the biological effects of MF pre-exposed culture medium on cell viability, the mitogen-activated protein kinase (MAPK) signaling pathways, oxidative stress, and genetic stabilities were analyzed using Cell Counting Kit-8, western blot, flow cytometry, γH2AX foci formation, and comet assay. The results showed that SPR signals were decreased under MF exposure in a time- and dose-dependent manner, and the decreased SPR signals were reversible when the exposure was drawn off. However, MF pre-exposed culture medium did not significantly change cell viability, intracellular reactive oxygen species level, activation of the MARK signaling pathways, or genetic stabilities in human amniotic epithelial cells (FL cells). In conclusion, our data suggest that the relative permittivity of culture medium was influenced by 50 Hz MF exposure, but this change did not affect the biological processes in FL cells., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development., (Copyright © 2019 Endocrine Society.)

Study Question: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)?, Summary Answer: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS., What Is Known Already: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS., Study Design, Size, Duration: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS., Participants/materials, Setting, Methods: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families., Main Results and the Role of Chance: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart., Limitations, Reasons for Caution: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here., Wider Implications of the Findings: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR., Study Funding/competing Interest(s): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF&#95;004, Italy. The authors declare no conflict of interest.

Epidemiological studies have revealed that offspring conceived by in vitro fertilization (IVF) have an elevated risk of cardiovascular malformations at birth, and are more predisposed to cardiovascular diseases. The renin-angiotensin system (RAS) plays an essential role in both the pathogenesis of congenital heart disease in fetuses and cardiovascular dysfunction in adults. This study aimed to assess the relative expression levels of genes in the RAS pathway in mice conceived using IVF, compared to natural mating with superovulation. Results demonstrated that expression of the angiotensin II receptor type 1 (AGTR1), connective tissue growth factor (CTGF), and collagen 3 (COL3), in the myocardial tissue of IVF-conceived mice, was elevated at 3 weeks, 10 weeks, and 1.5 years of age, when compared to their non-IVF counterparts. These data were supported by microRNA microarray analysis of the myocardial tissue of aged IVF-conceived mice, where miR-100, miR-297, and miR-758, which interact with COL3, AGTR1, and COL1 respectively, were upregulated when compared to naturally mated mice of the same age. Interestingly, bisulfite sequencing data indicated that IVF-conceived mice exhibited decreased methylation of CpG sites in Col1. In support of our in vivo investigations, miR-297 overexpression was shown to upregulate AGTR1 and CTGF, and increased cell proliferation in cultured H9c2 cardiomyocytes. These findings indicate that the altered expression of RAS in myocardial tissue might contribute to cardiovascular malformation and/or dysfunction in IVF-conceived offspring. Furthermore, these cardiovascular abnormalities might be the result of altered DNA methylation and abnormal regulation of microRNAs.

Study Question: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes?, Summary Answer: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study., What Is Known Already: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed., Study Design, Size, Duration: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014., Participants/materials, Setting, Methods: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight., Main Results and the Role of Chance: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth)., Limitations, Reasons for Caution: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress., Wider Implications of the Findings: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia., Study Funding/competing Interest(s): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care., Trial Registration Number: Clinical Trials.gov number: NCT01044862.

Study Question: Is maltreatment during childhood (MC), e.g. sexual abuse, physical abuse, emotional abuse and neglect, associated with diagnosis of endometriosis?, Summary Answer: Childhood sexual abuse, emotional abuse/neglect and inconsistency experiences were associated with the diagnosis of endometriosis while no such association was found for physical abuse/neglect and other forms of maltreatment., What Is Known Already: Symptoms of endometriosis such as chronic pelvic pain, fatigue and depression, are correlated with MC, as are immune reactions linked to endometriosis. These factors support a case for a potential role of MC in the development of endometriosis., Study Design, Size, Duration: The study was designed as a multicentre retrospective case-control study. Women with a diagnosis of endometriosis were matched to control women from the same clinic/doctor's office with regard to age (±3 years) and ethnic background. A total of 421 matched pairs were included in the study., Participants/materials, Setting, Methods: Women with endometriosis and control women were recruited in university hospitals, district hospitals, and doctors' offices in Germany, Switzerland and Austria. A German-language version of the Childhood Trauma Questionnaire (CTQ) was used to evaluate MC. Diagnosis of endometriosis was confirmed histologically and classified according to ASRM criteria., Main Results and the Role of Chance: Women with endometriosis reported significantly more often than control women a history of sexual abuse (20%/14%, P = 0.0197), emotional abuse (44%/28%, P < 0.0001), emotional neglect (50%/42%, P = 0.0123) and inconsistency experiences (53%/41%, P = 0.0007). No statistically significant differences could be demonstrated for physical abuse/neglect (31%/26%, P = 0.1738). Combinations of different abuse/neglect experiences were described significantly more often in women with endometriosis. Frequencies of other MC, i.e. violence against the mother (8%/7%, P = 0.8222), drug abuse in the family (5%/3%, P = 0.0943), mentally handicapped family members (1%/1%, P = 0.7271), suicidal intentions in the family (6%/4%, P = 0.2879) and family members in prison (1%/1%, P = 0.1597) were not statistically different in women with endometriosis and control women., Limitations, Reasons for Caution: Some control women might present asymptomatic endometriosis, which would lead to underestimation of our findings. The exclusion of pregnant women may have biased the results. Statistical power for sub-analyses of physical abuse/neglect and sexual abuse was limited., Wider Implications of the Findings: A link to MC needs to be considered in women with endometriosis. As there are effective strategies to avoid long-term consequences of MC, healthcare professionals should inquire about such experiences in order to be able to provide treatment for the consequences as early as possible., Study Funding/competing Interest(s): None., Trial Registration Number: Endo&#95;QoL NCT02511626., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Context: Although glial cell line-derived neurotrophic factor (GDNF) and microRNAs (miRNAs) have been shown to regulate mammalian oocyte maturation, little is known about their effects on human oocyte maturation and the underlying molecular mechanisms., Objectives: To examine the effects of GDNF on both nuclear and cytoplasmic maturation in cultured immature human oocytes and to investigate the involvement of miRNAs in GDNF-induced oocyte maturation., Design: A total of 200 human immature oocytes were used to evaluate the effects of GDNF on oocyte maturation. The involvement of miRNAs in GDNF-induced oocyte maturation was identified by comparing the miRNA expression profiles of cumulus cells (CCs) either with or without GDNF stimulation., Setting: An in vitro fertilization center at the Women's Hospital, Zhejiang University School of Medicine., Methods: Agilent human miRNA (8*60K) arrays were used to examine the miRNA expression patterns of human CCs either with or without GDNF stimulation. miR-145-5p inhibitor and mimic transfections were performed to study downstream gene expression in human CCs., Results: During the in vitro maturation process, GDNF significantly increased the percentage of metaphase II-stage oocytes and downregulated the expression of miR-145-5p in cultured human CCs. Expression of miR-145-5p in CCs is negatively correlated with oocyte maturation. miR-145-5p mimic significantly decreased the expression of GDNF family receptor-α1, ret proto-oncogene, and epidermal growth factor receptor, whereas miR-145-5p inhibitor reversed these effects. GDNF treatment inhibited cell apoptosis in cultured CCs, and this suppressive effect was reversed by transfection with the miR-145-5p mimic., Conclusion: Downregulation of miR-145-5p may contribute to GDNF-induced enhancement of oocyte maturation and of cell viability against cell apoptosis.

Background: Endometriosis-associated pain and dyspareunia influence female sexuality, but little is known about men's experiences in affected couples., Aim: To investigate how men partners experience sexuality in partnership with women with endometriosis., Methods: A multi-center case-control study was performed between 2010 and 2015 in Switzerland, Germany, and Austria. 236 Partners of endometriosis patients and 236 partners of age-matched control women without endometriosis with a similar ethnic background were asked to answer selected, relevant questions of the Brief Index of Sexual Functioning and the Global Sexual Functioning questionnaire, as well as some investigator-derived questions., Outcomes: We sought to evaluate sexual satisfaction of men partners of endometriosis patients, investigate differences in sexual activities between men partners of women with and without endometriosis, and identify options to improve partnership sexuality in couples affected by endometriosis., Results: Many partners of endometriosis patients reported changes in sexuality (75%). A majority of both groups was (very) satisfied with their sexual relationship (73.8% vs 58.1%, P = .002). Nevertheless, more partners of women diagnosed with endometriosis were not satisfied (P = .002) and their sexual problems more strongly interfered with relationship happiness (P = .001) than in partners of control women. Frequencies of sexual intercourse (P < .001) and all other partnered sexual activities (oral sex, petting) were significantly higher in the control group. The wish for an increased frequency of sexual activity (P = .387) and sexual desire (P = .919) did not differ statistically between both groups., Clinical Translation: There is a need to evaluate qualitative factors that influence sexual satisfaction in endometriosis patients., Conclusions: This is one of the first studies to investigate male sexuality affected by endometriosis. The meticulous verification of diagnosis and disease stage according to operation reports and histology allows for a high reliability of diagnosis. Our men's response rate of almost 50% is higher compared to other studies. Recruiting men through their woman partner may have caused selection bias. The adjustment to the specific situation in endometriosis by selecting questions from the Brief Index of Sexual Functioning and Global Sexual Functioning and adding investigator-derived questions likely influenced the validity of the questionnaires. Despite the fact that both partners of endometriosis patients and of control women largely reported high sexual satisfaction, there are challenges for some couples that arise in the context of a sexual relationship when one partner has endometriosis. Challenges such as sexuality-related pain or a reduced frequency of sexual activities should be addressed by health care professionals to ameliorate any current difficulties and to prevent the development or aggravation of sexual dysfunction. Hämmerli S, Kohl Schwartz AS, Geraedts K, et al. Does Endometriosis Affect Sexual Activity and Satisfaction of the Man Partner? A Comparison of Partners From Women Diagnosed With Endometriosis and Controls. J Sex Med 2018;15:853-865., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and its etiology has not been characterized. Growth differentiation factor 8 (GDF8) is a member of the transforming growth factor-β superfamily that plays a critical role in the regulation of ovarian functions. However, the expression pattern of GDF8 in the human ovary is not yet clear. This study examined the cellular distribution of GDF8 and its putative cellular receptors (ACVR2A, ACVR2B, and ALK5) in a series of normal (n = 34) and PCOS ovaries (n = 14). The immunostaining of GDF8, ACVR2A, ACVR2B, and ALK5 was detected in the oocytes regardless of the developmental stage. All these proteins were localized in antral follicles in normal and PCOS ovaries, and the expression of these proteins increased with increasing follicle diameter. A significantly higher expression of GDF8 was detected in the granulosa cells than in the matched theca cells (TCs). These proteins were also localized in the luteal cells of the corpus luteum. Granulosa cells and TCs of large antral follicles in PCOS ovaries display a higher expression of these proteins. The higher expression levels of GDF8 and its functional receptors (ACVR2A, ACVR2B, and ALK5) in antral follicles of PCOS ovaries than those in normal ovaries suggest the possible involvement of dysregulated GDF8 in the pathogenesis of PCOS.

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients' offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling., (© 2018 European Society of Endocrinology.)

Context: Preeclampsia is a leading cause of fetal and maternal morbidity and mortality during pregnancy. Although the etiology of preeclampsia is unknown, preeclampsia offspring have increased risks of developing cardiovascular disorders in adulthood, implicating that preeclampsia programs fetal vasculature in utero., Objective: We hypothesize that preeclampsia alters expression profiles of endothelial microRNAs (miRNAs) in fetal endothelial cells and disturbs the vascular endothelial growth factor A (VEGFA)- and fibroblast growth factor 2 (FGF2)-induced endothelial function., Design and Setting: Unpassaged (P0) human umbilical vein endothelial cells (HUVECs) were isolated immediately after cesarean-section delivery from normotensive (NT) and preeclamptic (PE) pregnancies. Differentially expressed miRNAs between P0-HUVECs from NT and PE pregnancies were identified using a miRNA polymerase chain reaction (PCR) array and confirmed using reverse transcription quantitative PCR. To determine the function of these differentially expressed miRNAs, miRNAs of interest were knocked down in NT-HUVECs following by cell functional assays., Results: Sixteen miRNAs, including miR-29a/c-3p, were downregulated in P0-HUVECs from the PE group compared with the NT group. Bioinformatics analysis predicted the PI3K-v-akt murine thymoma viral oncogene homolog 1 (AKT) signaling pathway was dysregulated in P0-HUVECs from the PE group, which was associated with the miR-29a/c-3p downregulation. We further demonstrated that miR-29a/c-3p knockdown inhibited the VEGFA- and FGF2-induced endothelial migration as well as FGF2-induced AKT1 phosphorylation in HUVECs. However, miR-29a/c-3p knockdown did not alter the extracellular signal-regulated kinase 1/2 phosphorylation, cell proliferation, and endothelial monolayer integrity in response to VEGFA and FGF2 in HUVECs., Conclusions: Preeclampsia-downregulated miR-29a/c-3p may impair fetal endothelial function by disturbing the FGF2-activated PI3K-AKT signaling pathway, hence inhibiting endothelial cell migration., (Copyright © 2017 Endocrine Society)