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Müllerian-inhibiting substance (MIS), also known as anti-Müllerian hormone, is thought to be a negative regulator of primordial follicle activation. We have previously reported that treatment with exogenous MIS can induce complete ovarian suppression within 5 weeks of treatment in mice. To investigate the kinetics of the return of folliculogenesis following the reversal of suppression, we treated animals with recombinant human MIS (rhMIS) protein for 40 days in adult female Nu/Nu mice and monitored the recovery of each follicle type over time. Following cessation of MIS therapy, secondary, and antral follicles returned within 30 days, along with the normalization of reproductive hormones, including LH, FSH, MIS, and Inhibin B. Furthermore, 30 days following MIS pretreatment, the number of antral follicles were significantly higher than controls, and superovulation with timed pregnant mare serum gonadotropin and human chorionic gonadotropin stimulation at this time point resulted in an approximately threefold increased yield of eggs. Use of the combined rhMIS-gonadotropin superovulation regimen in a diminished ovarian reserve (DOR) mouse model, created by 4-vinylcyclohexene dioxide treatment, also resulted in a twofold improvement in the yield of eggs. In conclusion, treatment with rhMIS can induce a reversible ovarian suppression, following which a rapid and synchronized large initial wave of growing follicles can be harnessed to enhance the response to superovulation. Therapies modulating MIS signaling may therefore augment the response to current ovarian stimulation protocols and could be particularly useful to women with DOR or poor responders to controlled ovarian hyperstimulation during in vitro fertilization.

PURPOSE OF REVIEW The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Mullerian inhibiting substance (MIS) as an ovarian fertoprotectant. RECENT FINDINGS MIS is unique in its mechanisms of ovarian protection by virtue of acting directly on granulosa cells of primordial follicles and for being a benign reproductive hormone, with few side effects. We will explore in this review how it may be utilized to protect the ovary from chemotherapy, or to enhance ovarian tissue cryopreservation therapy. We will also examine potential mechanisms of action of MIS across multiple cell types, as well as current limitations in our understanding of the pharmacology of recombinant MIS. SUMMARY The usefulness of MIS as a fertoprotectant may be dependent on the mechanisms of gonadotoxicity of each chemotherapeutic. Further investigation is needed to determine how to best deliver and combine MIS treatment to existing fertility management strategies.

A Woman with Infertility A 31-year-old woman with a history of primary amenorrhea and infertility was seen in the fertility center to discuss family-planning options. She had minimal body hair and ...

Context There is increasing evidence for Mullerian-inhibiting substance (MIS)/anti-Mullerian hormone (AMH) physiologic activity in the human uterus, so it is relevant to study how MIS/AMH levels impact pregnancy. Objective To investigate the association of MIS/AMH levels with the risk of adverse obstetric outcomes. Design Retrospective cohort study. Setting Academic fertility center. Patients Women who became pregnant through in vitro fertilization between January 2012 and October 2016. Exclusion criteria were: oocyte donation, gestational carrier, multiple gestations, miscarriage before 20 weeks, or medically indicated preterm deliveries. Interventions None. Main Outcome Measures There were two primary outcomes, preterm birth and cesarean delivery for arrest of labor. Because MIS/AMH level is highly skewed by certain infertility diagnoses, the preterm birth analysis was stratified by polycystic ovary syndrome (PCOS) diagnosis, and the cesarean delivery for arrest of labor analysis was stratified by diminished ovarian reserve diagnosis. χ2, Mann-Whitney, and t tests were used as appropriate. A P value of

In the fertility clinic setting, a negative DNA paternity test result usually suggests a sample mix-up likely occurred at the testing company or in the clinic. However, we report a case where, despite repeat negative paternity test results, the alleged father (referred to as “the proband”) was confirmed to be the baby’s father. The proband, a 34 year-old male, contacted our research group when routine blood testing revealed discrepant blood types between the parents and the baby, repeat paternity tests were negative (excluding the proband as the baby’s father), and the fertility clinic found no evidence of any wrongdoing. Microarray technology was utilized to confirm biological relatedness, which revealed an avuncular (uncle/nephew) relationship. Additional tissue samples were analyzed and family studies were conducted at paternity and forensic laboratories using STR-based DNA tests to elucidate the proband’s condition of congenital tetragametic chimerism. His paternity was subsequently affirmed and the fertility clinic exonerated of claims of a semen sample mix-up. This case underscores the possibility that some allegations of fertility clinic missteps may be explained by undiagnosed chimerism, a condition where an individual harbors two distinct genomes. We offer specific suggestions for improving laboratory reporting and creating clinical guidelines to aid in identifying and rectifying future cases of false exclusions of paternity due to chimerism. Electronic supplementary material The online version of this article (10.1007/s10815-017-1064-6) contains supplementary material, which is available to authorized users.

Objective To evaluate the association of oocyte donor–recipient characteristics, oocyte donor response, and live birth pregnancy rate following fresh donor oocyte IVF-ET. Design Retrospective cohort study. Setting Academic reproductive medicine practice. Patient(s) Two hundred thirty-seven consecutive fresh donor oocyte IVF-ET cycles from January 1, 2007 to December 31, 2013 at the Massachusetts General Hospital Fertility Center. Intervention(s) None. Main Outcome Measure(s) Live birth rate per cycle initiated. Result(s) The mean (±SD) age of oocyte donors and recipients was 27.0 ± 3.7 and 41.4 ± 4.6 years, respectively. Oocyte donor demographic/reproductive characteristics, ovarian reserve testing, and peak serum E 2 during ovarian stimulation were similar among cycles which did and did not result in live birth, respectively. Overall implantation, clinical pregnancy, and live birth pregnancy rates per cycle initiated were 40.5%, 60.8%, and 54.9%, respectively. The greatest probability of live birth was observed in cycles with >10 oocytes retrieved, mature oocytes, oocytes with normal fertilization (zygote–two pronuclear stage), and cleaved embryos. Conclusion(s) The number of oocytes (total and mature), zygotes, and cleaved embryos are associated with live birth following donor oocyte IVF cycles. These findings suggest that specific peri-fertilization factors may be predictive of pregnancy outcomes following donor oocyte IVF cycles.

The Mullerian ducts are the anlagen of the female reproductive tract, which regress in the male fetus in response to MIS. This process is driven by subluminal mesenchymal cells expressing Misr2, which trigger the regression of the adjacent Mullerian ductal epithelium. In females, these Misr2+ cells are retained, yet their contribution to the development of the uterus remains unknown. Here, we report that subluminal Misr2+ cells persist postnatally in the uterus of rodents, but recede by week 37 of gestation in humans. Using single-cell RNA sequencing, we demonstrate that ectopic postnatal MIS administration inhibits these cells and prevents the formation of endometrial stroma in rodents, suggesting a progenitor function. Exposure to MIS during the first six days of life, by inhibiting specification of the stroma, dysregulates paracrine signals necessary for uterine development, eventually resulting in apoptosis of the Misr2+ cells, uterine hypoplasia, and complete infertility in the adult female., eLife digest In the womb, mammals possess all of the preliminary sexual structures necessary to become either male or female. This includes the Mullerian duct, which develops into the Fallopian tubes, uterus, cervix, and vagina in female fetuses. In male fetuses, the testis secretes a hormone called Mullerian inhibiting substance (MIS). This triggers the activity of a small group of cells, known as Misr2+ cells, that cause the Mullerian duct to degenerate, preventing males from developing female sexual organs. It was not clear what happens to Misr2+ cells in female fetuses or if they affect how the uterus develops. Saatcioglu et al. now show that in newborn female mice and rats, a type of Misr2+ cell that sits within a thin inner layer of the developing uterus still responds to MIS. At this time, the uterus is in a critical early period of development. Treating the mice and rats with MIS protein during their first six days of life eventually caused the Misr2+ cells to die. The treatment also prevented a layer of connective tissue, known as the endometrial stroma, from forming in the uterus. As a result, the mice and rats were infertile and had severely underdeveloped uteri. While the Misr2+ cells are present in newborn rats and mice, Saatcioglu et al. found that they disappeared before birth in humans. However, the overall results suggest that Misr2+ cells act as progenitor cells that develop into the cells of the endometrial stroma. Future work could investigate the roles these cells play in causing uterine developmental disorders and infertility disorders. Furthermore, the finding that MIS inhibits the Misr2+ cells could help researchers to develop treatments for uterine cancer and other conditions where the cells of the uterus grow and divide too much.

Objective To explore the relationship between urinary paraben concentrations and IVF outcomes among women attending an academic fertility center. Design Prospective cohort study. Setting Fertility clinic in a hospital setting. Patient(s) A total of 245 women contributing 356 IVF cycles. Intervention(s) None. Quantification of urinary concentrations of parabens by isotope-dilution tandem mass spectrometry, and assessment of clinical endpoints of IVF treatments abstracted from electronic medical records at the academic fertility center. Main Outcome Measure(s) Total and mature oocyte counts, proportion of high-quality embryos, fertilization rates, and rates of implantation, clinical pregnancy, and live births. Result(s) The geometric means of the urinary concentrations of methylparaben, propylparaben, and butylparaben in our study population were 133, 24, and 1.5 μg/L, respectively. In models adjusted for age, body mass index, race/ethnicity, smoking status, and primary infertility diagnosis, urinary methylparaben, propylparaben, and butylparaben concentrations were not associated with IVF outcomes, specifically total and mature oocyte counts, proportion of high embryo quality, and fertilization rates. Moreover, no significant associations were found between urinary paraben concentrations and rates of implantation, clinical pregnancy, and live births. Conclusion(s) Urinary paraben concentrations were not associated with IVF outcomes among women undergoing infertility treatments.

Research question What are the perspectives of women’s health providers on the use of preimplantation genetic testing (PGT) for common medical disorders? Design A cross-sectional 15-question online anonymous survey was conducted of women’s health providers specializing in general obstetrics/gynaecology, gynaecologic oncology and infertility at a tertiary care academic institution in Massachusetts, USA. Respondents could answer ‘yes’, ‘no’ or ‘unsure’ to each thematic question. Results The survey was sent to 1060 providers and 240 providers responded (response rate 22.6%). Overall, 93% of respondents supported the use of PGT for the identification of genetic mutations which lead to childhood-onset disease, 83% supported the use of PGT for chromosomal aneuploidy screening, and 76% supported the use of PGT for cancer-related genetic disorders. Only 1.7% of respondents supported the use of PGT for non-disease-related indications, including sex selection and physical traits. Compared with general obstetrics/gynaecology providers, infertility specialists were more supportive of PGT. In total, 22.5% of respondents reported no prior knowledge of PGT. Conclusions In a sample of women’s health providers across multiple different obstetrics/gynaecology specialties, there was overall support for the use of PGT for a variety of common indications. Infertility specialists were the most supportive, which may reflect the familiarity that these providers have with this procedure. There was an overwhelmingly non-supportive response for the use of PGT for non-disease-related indications. The percentage of medical professionals working in women’s health without prior knowledge of PGT (22.5%) was higher than expected, identifying the need for more education regarding the availability and potential indications for this procedure.

Research question What are the perspectives of women’s health providers on the use of preimplantation genetic testing (PGT) for common medical disorders? Design A cross-sectional 15-question online anonymous survey was conducted of women’s health providers specializing in general obstetrics/gynaecology, gynaecologic oncology and infertility at a tertiary care academic institution in Massachusetts, USA. Respondents could answer ‘yes’, ‘no’ or ‘unsure’ to each thematic question. Results The survey was sent to 1060 providers and 240 providers responded (response rate 22.6%). Overall, 93% of respondents supported the use of PGT for the identification of genetic mutations which lead to childhood-onset disease, 83% supported the use of PGT for chromosomal aneuploidy screening, and 76% supported the use of PGT for cancer-related genetic disorders. Only 1.7% of respondents supported the use of PGT for non-disease-related indications, including sex selection and physical traits. Compared with general obstetrics/gynaecology providers, infertility specialists were more supportive of PGT. In total, 22.5% of respondents reported no prior knowledge of PGT. Conclusions In a sample of women’s health providers across multiple different obstetrics/gynaecology specialties, there was overall support for the use of PGT for a variety of common indications. Infertility specialists were the most supportive, which may reflect the familiarity that these providers have with this procedure. There was an overwhelmingly non-supportive response for the use of PGT for non-disease-related indications. The percentage of medical professionals working in women’s health without prior knowledge of PGT (22.5%) was higher than expected, identifying the need for more education regarding the availability and potential indications for this procedure.

SummaryColonization by Lactobacillus in the female genital tract is thought to be critical for maintaining genital health. However, little is known about how genital microbiota influence host immune function and modulate disease susceptibility. We studied a cohort of asymptomatic young South African women and found that the majority of participants had genital communities with low Lactobacillus abundance and high ecological diversity. High-diversity communities strongly correlated with genital pro-inflammatory cytokine concentrations in both cross-sectional and longitudinal analyses. Transcriptional profiling suggested that genital antigen-presenting cells sense gram-negative bacterial products in situ via Toll-like receptor 4 signaling, contributing to genital inflammation through activation of the NF-κB signaling pathway and recruitment of lymphocytes by chemokine production. Our study proposes a mechanism by which cervicovaginal microbiota impact genital inflammation and thereby might affect a woman’s reproductive health, including her risk of acquiring HIV.

The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman’s reproductive lifespan, resulting in menopause. Mullerian inhibiting substance (MIS) (or anti-Mullerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS–treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.

MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.

To compare the in-vitro fertilization (IVF) outcomes of cancer patients who underwent oocyte retrieval and embryo/oocyte cryopreservation prior to gonadotoxic therapy to those of age and time-matched controls with tubal factor infertility.All cancer patients who underwent embryo/oocyte cryopreservation at our institution from 1997 to 2014 were reviewed. Primary outcomes were total dose of gonadotropins used, number of oocytes retrieved, and number of 2pn embryos obtained. Outcomes were compared to age-matched controls with tubal-factor infertility who underwent a fresh embryo transfer within the same relative time period as the IVF cycle of the cancer patient.Sixty-three cancer patients underwent 65 IVF cycles, and 21 returned for frozen embryo transfer. One hundred twenty-two age-matched controls underwent IVF cycles with fresh transfer, and 23 returned for frozen embryo transfer. No difference was seen between cancer patients and controls with respect to total ampules of gonadotropin used (38.0 vs. 35.6 respectively; p = 0.28), number of oocytes retrieved (12.4 vs. 10.9 respectively; p = 0.36) and number of 2pn embryos obtained (6.6 vs. 7.1 respectively; p = 0.11). Cumulative pregnancy rate per transfer for cancer patients compared to controls was 37 vs. 43 % respectively (p = 0.49) and cumulative live birth rate per transfer was 30 vs. 32 % respectively (p = 0.85). Cancer patients had a higher likelihood of live birth resulting in twins (44 vs. 14 %; p = 0.035).Most IVF outcomes appear comparable for cancer patients and age-matched controls. Higher twin pregnancy rates in cancer patients may reflect lack of underlying infertility or need for cancer-specific transfer guidelines.

Objective To describe two cases of successful pregnancy after a rescue course of hCG in the setting of false empty follicle syndrome. Design Case report. Setting Academic medical center. Patient(s) Two patients undergoing ultrasound-guided oocyte retrieval with failure to obtain oocytes during oocyte retrieval. Intervention(s) Rescue course of hCG with second oocyte retrieval 35 hours later. Main Outcome Measure(s) Live birth. Result(s) Two live-birth pregnancies. Conclusion(s) Live-birth pregnancies are a realistic possibility after administration of a rescue course of hCG and repeat oocyte retrieval in the setting of false empty follicle syndrome.

Background Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS)-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function. Methods We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization ( progesterone production) in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype. Conclusions Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their response to metformin is related to elevated leptin levels and/or if a subset of PCOS women with hyperleptinemia may be responsive to metformin therapy. Further study is needed to better define a subset of women with PCOS that may be responsive to metformin.

To evaluate pregnancy rate (PR) and live birth rate (LBR) after freezing pronuclear (PN) embryos for two purposes: to reduce the risk of ovarian hyperstimulation syndrome (OHSS) and to bank embryos for cancer patients anticipating gametotoxic chemotherapy/radiotherapy.Data from 3,621 consecutive IVF cycles were retrospectively analyzed. PN freezing was offered to patients at risk for OHSS and for those wishing to preserve fertility prior to cancer therapy. Primary outcomes evaluated were PR and LBR. Outcomes were compared to patients who underwent fresh embryo transfer (ET) in 2006.Sixty-six patients froze PN embryos. Thirty-eight were at risk for OHSS. The LBR was 34.3% after one transfer, and 51.4% after a mean of 1.4 transfers. Twenty-eight cancer patients froze embryos. The LBR was 16.7% after one transfer and 25.0% after a mean of 1.5 transfers. The LBR was 35.5% for patients who underwent fresh ET.PN freezing with delayed ET is an effective tool for achieving pregnancy for patients at risk of OHSS and for cancer patients wishing to preserve fertility.

Brain-derived neurotrophic factor (BDNF) has been reported to be critical for the development of cortical inhibitory neurons. However, the effect of BDNF on the expression of transcripts whose protein products are involved in gamma amino butric acid (GABA) neurotransmission has not been assessed. In this study, gene expression profiling using oligonucleotide microarrays was performed in prefrontal cortical tissue from mice with inducible deletions of BDNF. Both embryonic and adulthood ablation of BDNF gave rise to many shared transcriptome changes. BDNF appeared to be required to maintain gene expression in the SST-NPY-TAC1 subclass of GABA neurons, although the absence of BDNF did not alter their general phenotype as inhibitory neurons. Furthermore, we observed expression alterations in genes encoding early-immediate genes (ARC, EGR1, EGR2, FOS, DUSP1, DUSP6) and critical cellular signaling systems (CDKN1c, CCND2, CAMK1g, RGS4). These BDNF-dependent gene expression changes may illuminate the biological basis for transcriptome changes observed in certain human brain disorders.

The debate regarding the Defense of Marriage Act (DOMA) is centered on issues of sexuality. Yet, surprisingly within the statute there are no definitions for “man” and “woman.” These terms may seem self-evident; however, we would argue that it is not always clear.

Nature 439, 283–289 (2006) The protocol for penetratin-coupling of siRNA-like molecules used in this Article incorporated suggestions by Carol M. Troy that were based on the method described in ref. 1.