Early pregnancy loss affects ∼15% of all implantation-confirmed human conceptions. However, evolutionarily conserved molecular mechanisms that regulate self-renewal of trophoblast progenitors and their association with early pregnancy loss are poorly understood. Here, we provide evidence that transcription factor TEAD4 ensures survival of postimplantation mouse and human embryos by controlling self-renewal and stemness of trophoblast progenitors within the placenta primordium. In an early postimplantation mouse embryo, TEAD4 is selectively expressed in trophoblast stem cell–like progenitor cells (TSPCs), and loss of Tead4 in postimplantation mouse TSPCs impairs their self-renewal, leading to embryonic lethality before embryonic day 9.0, a developmental stage equivalent to the first trimester of human gestation. Both TEAD4 and its cofactor, yes-associated protein 1 (YAP1), are specifically expressed in cytotrophoblast (CTB) progenitors of a first-trimester human placenta. We also show that a subset of unexplained recurrent pregnancy losses (idiopathic RPLs) is associated with impaired TEAD4 expression in CTB progenitors. Furthermore, by establishing idiopathic RPL patient-specific human trophoblast stem cells (RPL-TSCs), we show that loss of TEAD4 is associated with defective self-renewal in RPL-TSCs and rescue of TEAD4 expression restores their self-renewal ability. Unbiased genomics studies revealed that TEAD4 directly regulates expression of key cell cycle genes in both mouse and human TSCs and establishes a conserved transcriptional program. Our findings show that TEAD4, an effector of the Hippo signaling pathway, is essential for the establishment of pregnancy in a postimplantation mammalian embryo and indicate that impairment of the Hippo signaling pathway could be a molecular cause for early human pregnancy loss.

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A variety of data suggest that estrogen action on kisspeptin (Kiss1)-containing arcuate nucleus neurons (which coexpress Kiss1, neurokinin B (the product of Tac2) and dynorphin (KNDy) neurons restrains reproductive onset and function, but roles for estrogen action in these Kiss1 neurons relative to a distinct population of rostral hypothalamic Kiss1 neurons (which does not express Tac2 or dynorphin) have not been directly tested. To test the role for estrogen receptor (ER)α in KNDy cells, we thus generated Tac2(Cre) and Kiss1(Cre) knock-in mice and bred them onto the Esr1(flox) background to ablate ERα specifically in Tac2-expressing cells (ERα(Tac2)KO mice) or all Kiss1 cells (ERα(Kiss1)KO mice), respectively. Most ERα-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ERα(Tac2)KO and ERα(Kiss1)KO females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ERα(Tac2)KO but decreased in ERα(Kiss1)KO females; this suggests that ERα in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ERα(Kiss1)KO and ERα(Tac2)KO females displayed early vaginal opening, early and persistent vaginal cornification, increased gonadotropins, uterine hypertrophy, and other evidence of estrogen excess. Thus, deletion of ERα in Tac2 neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ERα in Tac2 neurons typically restrains pubertal onset and hypothalamic reproductive drive.

A modification of the Morey tail suspension model was used to determine atrophic responses of rat bone and muscle with 14-90 days unloading of the hindlimbs. Bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in bone formation rate in immobilized dogs and rats. Increased uptake at 60 days (P = 0.01, femur) indicated an increased bone metabolism. Regional densitometry demonstrated a preferential loss of bone mineral in the trabecular mass (P = 0.02) at 30 days and in the cortical shaft by 90 days (P = 0.03). Maximal muscle atrophy occurred within 14-30 days. The gastrocnemius was less severely affected by suspension than by immobilization techniques, whereas the soleus atrophied (by weight) similarly, suggesting that muscle atrophy in the suspension model is distinctly different from immobilization atrophy. One significant response of skeletal muscle to suspension was an altered blood distribution. Muscle blood distribution changes reflect the hypodynamic state of muscle that continues to contract but probably at an altered rate in response to altered functional demands.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines – oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health – in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

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Objective To evaluate emotional processing in women with insulin-resistant polycystic ovary syndrome (IR-PCOS) and its relationship to glucose regulation and the mu-opioid system. Design Case-control pilot. Setting Tertiary referring medical center. Patient(s) Seven women with IR-PCOS and five non-insulin-resistant controls, aged 21–40 years, recruited from the general population. Intervention(s) Sixteen weeks of metformin (1,500 mg/day) in women with IR-PCOS. Main Outcome Measure(s) Assessment of mood, metabolic function, and neuronal activation during an emotional task using functional magnetic resonance imaging (fMRI), and mu-opioid receptor availability using positive emission tomography (PET). Result(s) We found that insulin-resistant PCOS patients [1] had greater limbic activation during an emotion task than controls (n = 5); [2] trended toward decreased positive affect and increased trait anxiety; [3] after metformin treatment, had limbic activation that no longer differed from controls; and [4] had positive correlations between fMRI limbic activation during emotional processing and mu-opioid binding potential. Conclusion(s) Patients with IR-PCOS had greater regional activation during an emotion task than the controls, although this resolved with metformin therapy. Alterations in mu-opioid neurotransmission may underlie limbic system activity and mood disorders in IR-PCOS. Clinical Trial Registration Number NCT00670800.