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Objective: To describe the clinical management of menorrhagia in a woman with hyperparathyroidism-jaw tumor syndrome (HPT-JT).Design: Case report.Setting: Large translation research hospital.Patient(s): A 26-year-old nulligravid woman with familial HPT-JT presented with life-long menorrhagia resistant to progesterone intrauterine device (IUD) therapy and a desire for fertility.Intervention(s): Aromatase inhibitor therapy.Main Outcome Measure(s): Clinical response to therapy and pregnancy.Result(s): Imaging demonstrated an enlarged endometrial lining and thickening of the junctional zone. At operative hysteroscopy, multiple atypical endometrial polyp-like lesions filled the entire uterine cavity and were removed. Histologic evaluation demonstrated the lesions to be adenomyomas with an abundance of aromatase expression. Postoperative treatment included an aromatase inhibitor. The patient's menorrhagia, which had previously been resistant to progesterone IUD therapy, resolved with the aromatase inhibitor. After 10 months of this treatment, the aromatase inhibitor was discontinued and a repeated hysteroscopy revealed a markedly improved uterine cavity. The patient subsequently became pregnant on her first natural cycle and delivered a healthy term infant.Conclusion(s): Aromatase inhibitors may represent a novel treatment for benign uterine pathology in HPT-JT. [ABSTRACT FROM AUTHOR]

Fibroids significantly impact the quality of life (QOL) and mental health of affected women. However, there are limited comparative data on QOL measures after medical, surgical, and radiologic interventions in women with fibroids. This study aimed to assess the current literature evaluating the impact of fibroids on QOL measures using several validated questionnaires for radiologic, medical, or surgical interventions or a combination of interventions before and after treatment. PubMed, PsycINFO, ClinicalTrials.gov, Embase, and Cochrane Library were searched from January 1990 to October 2023 to evaluate the available evidence, and the risk of bias was assessed using Cochrane RoB 2.0 or the Newcastle-Ottawa Scale. The review criteria included randomized controlled trials (RCTs) and observational cohort studies that included premenopausal women with symptomatic uterine fibroids, confirmed by imaging, who underwent an intervention to target fibroid disease. Only reports using validated questionnaires with a numerical baseline (pretreatment) and posttreatment scores were included. The exclusion criteria included perimenopausal or postmenopausal patients, conditions in addition to uterine fibroids that share similar symptoms, or studies that did not focus on QOL assessment. Abstracts were screened, and full texts were reviewed to determine whether studies met the inclusion criteria. A total of 67 studies were included after final review: 18 RCTs and 49 observational studies. All interventions were associated with a significant improvement in uterine fibroid-specific QOL measures, mental health metrics, and a reduction in symptom severity scores after treatment. These data reveal a substantial impact of uterine fibroids on the QOL and mental health of women with fibroids and indicate the metrics that can be used to compare the effectiveness of fibroid treatment options., Competing Interests: Declaration of interests B.N. has nothing to disclose. B.S. has nothing to disclose. J. Brennan has nothing to disclose. J. Blanck has nothing to disclose. J.H.S. reports funding from Howard and Georgeanna Jones Endowment outside the submitted work., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility., Methods and Analysis: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores., Ethics and Dissemination: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial., Trial Registration Number: NCT05364008., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Autoimmune primary ovarian insufficiency (POI) is a devastating disease with limited clinical guidance. The objective of this systematic review was to identify treatments for autoimmune POI and analyze their efficacy. A comprehensive search of CINAHL, Cochrane, Embase, PubMed, Scopus, and Web of Science was performed from inception to April 2022. English language publications that evaluated women with autoimmune POI after a documented intervention were included. Animal models of autoimmune POI were also included. Risk of bias was assessed with the SYRCLE's risk of bias tool for animal studies or the NIH Quality Assessment Tool for Case Series as appropriate. Twenty-eight studies were included in this review, with 11 RCTs, 15 case reports, and 2 case series. Seventeen studies were in humans, and 11 were in animal models. No completed RCTs, cohort studies, or case-control studies were identified in humans. In observational human studies, corticosteroids were effective in select patients. In many case reports, adequate treatment of comorbid autoimmune conditions resulted in return of menses, hormonal normalization, or spontaneous pregnancy. In terms of assisted reproductive technologies, there was case report evidence for both in vitro fertilization (IVF) and in vitro maturation (IVM) in women wishing to conceive with their own oocytes. Ovulation induction, IVF, and IVM resulted in a total of 15 pregnancies and 14 live births. In animal models, there was additional evidence for stem cell therapies and treatments used in traditional Chinese medicine, although this research may not be generalizable to humans. Furthermore, litter size was not evaluated in any of the animal studies. Additional research is needed to establish the efficacy of current treatments for autoimmune POI with a controlled experimental design and larger sample size. Additionally, there is a critical need to develop novel therapies for this condition, as understanding of its pathophysiology and  available tools to modulate the immune response have progressed., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Objective: Is prior beta blocker (BB) use associated with reduced odds of the clinical incidence of leiomyomas?, What Is Known Already: In-vitro and in-vivo evidence has supported the role of beta receptor blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association., Study Design, Size, Duration: A nested case-control study was conducted in a population of women aged 18-65 with arterial hypertension (n = 699,966). Cases (n = 18,918) with a leiomyoma diagnosis were matched to controls (n = 681,048) with no such diagnosis at a 1:36 ratio by age and region of origin within the United States., Participants/materials, Setting, Methods: This population was assembled from the Truven Health MarketScan® Research Database, which includes health insurance claims from January 1st, 2012 to December 31st, 2017. Prior use of BB wasdetermined fromoutpatient drug claims and leiomyoma development was indicated by a first-time diagnosis code. We conducted a conditional logistic regression to determine the odds of uterine fibroid development in women with prior use of BB compared to women with no such history. We then conducted subset analyses, stratifying the women by age group and by type of BB., Results: Women on a BB experienced 15% reduced odds of developing clinically recognized leiomyoma compared to non-users (OR 0.85, 95% CI 0.76-0.94). This association was significant for the 30-39 age group (OR 0.61, 95% CI 0.40-0.93) but no other age group. Of the BBs, propranolol (OR 0.58, 95% CI 0.36-95) demonstrated a significant association with reduced leiomyoma incidence and metoprolol (OR 0.82, 95% CI 0.70-0.97) was associated with lower uterine fibroid incidence after adjustment for comorbidities., Conclusions: Hypertensive women with prior BB use experienced reduced odds of developing clinically recognized leiomyoma compared to non-users. A key predisposing risk factor for uterine leiomyoma is elevated blood pressure. Thus, the results of this analysis may have clinical relevance to women with hypertension, as the use of this drug may introduce a dual benefit of managing hypertension as well as curbing an increased risk of leiomyomas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fibrosis is characterized by excessive accumulation of extracellular matrix, which is a key feature of uterine fibroids. Our prior research supports the tenet that inhibition of fibrotic processes may restrict fibroid growth. Epigallocatechin gallate (EGCG), a green tea compound with powerful antioxidant properties, is an investigational drug for uterine fibroids. An early phase clinical trial showed that EGCG was effective in reducing fibroid size and its associated symptoms; however, its mechanism of action(s) has not been completely elucidated. Here, we probed effects of EGCG on key signaling pathways involved in fibroid cell fibrosis. Viability of myometrial and fibroid cells was not greatly affected by EGCG treatment (1-200 µM). Cyclin D1, a protein involved in cell cycle progression, was increased in fibroid cells and was significantly reduced by EGCG. EGCG treatment significantly reduced mRNA or protein levels of key fibrotic proteins, including fibronectin (FN1), collagen (COL1A1), plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and actin alpha 2, smooth muscle (ACTA2) in fibroid cells, suggesting antifibrotic effects. EGCG treatment altered the activation of YAP, β-catenin, JNK and AKT, but not Smad 2/3 signaling pathways involved in mediating fibrotic process. Finally, we conducted a comparative study to evaluate the ability of EGCG to regulate fibrosis with synthetic inhibitors. We observed that EGCG displayed greater efficacy than ICG-001 (β-catenin), SP600125 (JNK) and MK-2206 (AKT) inhibitors, and its effects were equivalent to verteporfin (YAP) or SB525334 (Smad) for regulating expression of key fibrotic mediators. These data indicate that EGCG exhibits anti-fibrotic effects in fibroid cells. These results provide insight into mechanisms behind the observed clinical efficacy of EGCG against uterine fibroids., (© 2023. The Author(s).)

Granulosa cells (GCs) must respond appropriately to follicle-stimulating hormone (FSH) for proper follicle maturation. FSH activates protein kinase A (PKA) leading to phosphorylation of the cyclic AMP response element binding protein-1 (CREB1). We identified a unique A-kinase anchoring protein (AKAP13) containing a Rho guanine nucleotide exchange factor (RhoGEF) region that was induced in GCs during folliculogenesis. AKAPs are known to coordinate signaling cascades, and we sought to evaluate the role of AKAP13 in GCs in response to FSH. Aromatase reporter activity was increased in COV434 human GCs overexpressing AKAP13. Addition of FSH, or the PKA activator forskolin, significantly enhanced this activity by 1.5- to 2.5-fold, respectively (p < 0.001). Treatment with the PKA inhibitor H89 significantly reduced AKAP13-dependent activation of an aromatase reporter (p = 0.0067). AKAP13 physically interacted with CREB1 in co-immunoprecipitation experiments and increased the phosphorylation of CREB1. CREB1 phosphorylation increased after FSH treatment in a time-specific manner, and this effect was reduced by siRNA directed against AKAP13 (p = 0.05). CREB1 activation increased by 18.5-fold with co-expression of AKAP13 in the presence of FSH (p < 0.001). Aromatase reporter activity was reduced by inhibitors of the RhoGEF region, C3 transferase and A13, and greatly enhanced by the RhoGEF activator, A02. In primary murine and COV43 GCs, siRNA knockdown of Akap13/AKAP13 decreased aromatase and luteinizing hormone receptor transcripts in cells treated with FSH, compared with controls. Collectively, these findings suggest that AKAP13 may function as a scaffolding protein in FSH signal transduction via an interaction with CREB, resulting in phosphorylation of CREB., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

The objective of this study was to evaluate the utility and impact of the Painful Periods Screening Tool (PPST) to improve healthcare delivery for people with symptoms of pelvic pain. The design of this study was a survey study. After IRB approval, patients aged 18-55 years with self-reported pelvic, abdominal, or lower back pain before, during, or after menstrual periods were invited to participate in the study from September 2020 to June 2021. Participants filled out the PPST questionnaire on the day of their Johns Hopkins clinic visit and the follow-up questionnaire 1-14 days after the clinic visit. Demographics and duration of pain were assessed, and participants who completed the PPST questionnaire were sent a follow-up questionnaire to assess utility and impact of PPST. Of the 1352 patients who met study eligibility, 1000 participants responded to both questionnaires. Most subjects (82.9%; 95% CI: 80.4-85.2%) reported having severe pelvic/abdominal or lower back pain during menses. Nine hundred fifteen participants (91.5%; 95% CI: 89.6-93.2%) reported that if given regularly, the PPST would help women discuss their pain symptoms with their healthcare provider. Six hundred seventy-eight participants (67.8%; 95% CI: 64.8-70.7%) reported that the PPST helped them initiate a conversation about their symptoms. Seven hundred seven participants (70.7%; 95% CI: 67.8-73.5%) were more comfortable discussing symptoms of pelvic pain with their provider after filling out the PPST. These findings support the utility of PPST as an endometriosis screening tool and suggest that this tool facilitated communication between patients and providers about pain symptoms., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

The ovaries are the female gonads that are crucial for reproduction, steroid production, and overall health. Historically, the ovary was broadly divided into regions defined as the cortex, medulla, and hilum. This current nomenclature lacks specificity and fails to consider the significant anatomic variations in the ovary. Recent technological advances in imaging modalities and high-resolution omic analyses have brought about the need for revision of the existing definitions, which will facilitate the integration of generated data and enable the characterization of organ subanatomy and function at the cellular level. The creation of these high-resolution multimodal maps of the ovary will enhance collaboration and communication among disciplines and between clinicians and researchers. Beginning in March 2021, the Pediatric and Adolescent Gynecology Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited subject-matter experts to participate in a series of workshops and meetings to standardize ovarian nomenclature and define the organ's features. The goal was to develop a spatially defined and semantically consistent terminology of the ovary to support collaborative, team science-based endeavors aimed at generating reference atlases of the human ovary. The group recommended a standardized, 3-dimensional description of the ovary and an ontological approach to the subanatomy of the ovary and definition of follicles. This new greater precision in nomenclature and mapping will better reflect the ovary's heterogeneous composition and function, support the standardization of tissue collection, facilitate functional analyses, and enable clinical and research collaborations. The conceptualization process and outcomes of the effort, which spanned the better part of 2021 and early 2022, are introduced in this article. The institute and the workshop participants encourage researchers and clinicians to adopt the new systems in their everyday work to advance the overarching goal of improving human reproductive health., (Published by Elsevier Inc.)

Introduction: Infertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing fertility treatment for endometriosis-associated infertility compared with other etiologies of infertility. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility., Methods and Analysis: This study is a multicentre, prospective, randomised, double-blind, placebo-controlled trial to study the efficacy of GnRH antagonist pretreatment for women with endometriosis who are undergoing IVF. A total of 814 patients with endometriosis undergoing fertility treatment will be enrolled and randomised 1:1 into two groups: elagolix 200 mg two times per day or placebo for 8 weeks, prior to undergoing IVF. All participants will then undergo IVF treatment per local protocols. The primary outcome is live birth. Secondary outcomes include oocyte number, fertilisation rate, embryo morphology and implantation rates, as well as rates of known endometriosis-related obstetrical outcomes (pregnancy-induced hypertension, antepartum haemorrhage, caesarean delivery and preterm birth)., Ethics and Dissemination: The PREGnant trial was approved by the Institutional Review Board at Johns Hopkins University. Results will be published in a peer-reviewed journal., Trial Registration Number: NCT04173169., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Common benign gynecologic conditions such as uterine fibroids and endometriosis are linked to chronic pelvic pain, abnormal and heavy uterine bleeding, and infertility. Effective medical management of these diseases is an unmet need. The steroid hormones progesterone (P4), estrogen (E2), and testosterone play a major role in reproductive physiology and uterine pathologies. Notably, selective progesterone receptor modulators have shown considerable promise as treatment options for some hormone-dependent conditions. More limited data are available regarding the safety and efficacy of selective androgen receptor modulators. In this report we review current evidence for selective progesterone receptor modulators and selective androgen receptor modulators as treatment options for benign gynecologic conditions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Uterine allotransplantation (UTx) is a novel therapy to allow women with uterine factor infertility (UFI) to bear their own children. To date, over 60 UTx have been performed, resulting in 15 live births. Our study investigates the attitudes, perspectives, and interests of women with UFI towards UTx., Methods: Anonymous questionnaires were distributed electronically to women diagnosed with UFI at Johns Hopkins Hospital between the years 2003 and 2018., Results: Thirty-one women with UFI were identified, resulting in 10 completed surveys. The average age was 31.7 ± 6.31 years, and the average age of diagnosis was 20 years (range 14-31); all 10 surveyed women had congenital UFI. Of note, 80% of women agreed that UTx should be an option for women with UFI, and 90% would consider receiving a UTx. The majority of the nine (90%) women who had previously heard of UTx learned about it from the news (5, 50%). When asked to rank the risks related to UTx in order of personal importance, only two women ranked themselves most important; the other woman ranked fetus and donor as more important. All women had health insurance (70% had private insurance), and 90% believed that UTx should be covered by health insurance., Conclusions: We surveyed women with UFI and found that the majority are willing to have UTx, despite the associated risks of the procedure. Taking into consideration the responses for ranking the importance of risks of the procedure, women with UFI should be considered a vulnerable population, requiring special considerations for UTx informed consents., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2021, Xun et al.)

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E 2 ), a steroid-derived hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of leiomyomas. We previously demonstrated that simvastatin, a drug used for hyperlipidemia, also possesses anti-leiomyoma properties. The aim of this work is to investigate the impact of simvastatin on ER-α signaling in leiomyoma cells, including its expression, downstream signaling, transcriptional activity, post-translational modification, trafficking and degradation. Primary and immortalized human uterine leiomyoma (HuLM) cells were used for in vitro experiments. Immunodeficient mice xenografted with human leiomyoma tissue explants were used for in vivo studies. Leiomyoma samples were obtained from patients enrolled in an ongoing double-blinded, phase II, randomized controlled trial. Here, we found that simvastatin significantly reduced E 2 -induced proliferation and PCNA expression. In addition, simvastatin reduced total ER-α expression in leiomyoma cells and altered its subcellular localization by inhibiting its trafficking to the plasma membrane and nucleus. Simvastatin also inhibited E 2 downstream signaling, including ERK and AKT pathways, E 2 /ER transcriptional activity and E 2 -responsive genes. To explain simvastatin effects on ER-α level and trafficking, we examined its effects on ER-α post-translational processing. We noticed that simvastatin reduced ER-α palmitoylation; a required modification for its stability, trafficking to plasma membrane, and signaling. We also observed an increase in ubiquitin-mediated ER-α degradation. Importantly, we found that the effects of simvastatin on ER-α expression were recapitulated in the xenograft leiomyoma mouse model and human tissues. Thus, our data suggest that simvastatin modulates several E 2 /ER signaling targets with potential implications in leiomyoma therapy and beyond., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Uterine fibroids feature excessive deposition of types I and III collagen. Previous ex vivo studies showed an FDA-approved collagenase (EN3835)-digested types I and III collagen fibers in fibroid tissues; however, collagenase had not been evaluated in vivo for effects on uterine fibroids. The objective was to assess the safety and tolerability of collagenase injection directly into uterine fibroids. This was a prospective, open label, dose escalation study. The study participants were fifteen women aged 35-50 years with symptomatic uterine fibroids planning to undergo hysterectomy. Three subjects received saline and methylene blue, three subjects received a fixed dose of EN3835, and 9 subjects received stepped, increasing dosages of EN3835, all by transvaginal, ultrasound-guided injections. Primary outcome measures were safety and tolerability of the injection and change in collagen content between treated and control tissues. There were no significant adverse events following injection of EN3835 into uterine fibroids. Masson's trichrome stains revealed a 39% reduction in collagen content in treated samples compared to controls (p <0.05). Second harmonic generation (SHG) analysis showed treated samples to have a 21% reduction in density of collagen compared to controls. Picrosirius-stained collagenase-treated fibroids showed collagen fibers to be shorter and less dense compared to controls. Subjects reported a decrease in fibroid-related pain on the McGill Pain Questionnaire after study drug injection in Group 2 at both 4-8 days and 60-90 days post-injection. The findings indicated that injection of collagenase was safe and well tolerated. These results support further clinical investigation of collagenase as a minimally invasive treatment of uterine fibroids. NCT0289848., (© 2021. The Author(s).)

Objective: To determine if A-kinase anchoring protein 13 (AKAP13) interacts with the vitamin D receptor (VDR) to alter vitamin D-dependent signaling in fibroid cells. Uterine leiomyomas (fibroids) are characterized by a fibrotic extracellular matrix and are associated with vitamin D deficiency. Treatment with vitamin D (1,25-dihydroxyvitamin D 3 ) reduces fibroid growth and extracellular matrix gene expression. A-kinase anchoring protein 13 is overexpressed in fibroids and interacts with nuclear hormone receptors, but it is not known whether AKAP13 may interact with the VDR to affect vitamin D signaling in fibroids., Design: Laboratory studies., Setting: Translational science laboratory., Intervention(s): Human immortalized fibroid or myometrial cells were treated with 1,25-hydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and transfected using expression constructs for AKAP13 or AKAP13 mutants, RhoQL, C3 transferase, or small interfering ribonucleic acids (RNAs)., Main Outcome Measure(s): Messenger ribonucleic acid (mRNA) levels of AKAP13, fibromodulin, and versican as measured by quantitative real-time polymerase chain reaction. Glutathione S-transferase-binding assays. Vitamin D-dependent gene activation as measured by luciferase assays., Result(s): 1,25(OH) 2 D 3 resulted in a significant reduction in mRNA levels encoding AKAP13, versican, and fibromodulin. Small interfering RNA silencing of AKAP13 decreased both fibromodulin and versican mRNA levels. Glutathione S-transferase-binding assays revealed that AKAP13 bound to the VDR through its nuclear receptor interacting region. Cotransfection of AKAP13 and VDR significantly reduced vitamin D-dependent gene activation. RhoA pathway inhibition partially relieved repression of vitamin D-dependent gene activation by AKAP13., Conclusion(s): These data suggest that AKAP13 inhibited the vitamin D receptor activation by a mechanism that required, at least in part, RhoA activation., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To test whether mechanical substrate stiffness would influence progesterone receptor B (PRB) signaling in fibroid cells. Uterine fibroids feature an excessive extracellular matrix, increased stiffness, and altered mechanical signaling. Fibroid growth is stimulated by progestins and opposed by anti-progestins, but a functional interaction between progesterone action and mechanical signaling has not been evaluated., Design: Laboratory studies., Setting: Translational science laboratory., Patient(s)/animal(s): Human fibroid cell lines and patient-matched fibroid and myometrial cell lines., Intervention(s): Progesterone receptor B-dependent reporter assays and messenger RNA quantitation in cells cultured on stiff polystyrene plates (3GPa) or soft silicone plates (930KPa). Pharmacologic inhibitors of extracellular signal-related protein kinase (ERK) kinase 1/2 (MEK 1/2; PD98059), p38 mitogen-activated protein kinase (SB202190), receptor tyrosine kinases (RTKs; nintedanib), RhoA (A13), and Rho-associated coiled-coil kinase (ROCK; Y27632)., Main Outcome Measure(s): Progesterone-responsive reporter activation., Result(s): Fibroid cells exhibited higher PRB-dependent reporter activity with progesterone (P4) in cells cultured on stiff vs. soft plates. Mechanically induced PRB activation with P4 was decreased 62% by PD98059, 78% by nintedanib, 38% by A13, and 50% by Y27632. Overexpression of the Rho-guanine nucleotide exchange factor (Rho-GEF), AKAP13, significantly increased PRB-dependent reporter activity. Collagen 1 messenger RNA levels were higher in fibroid cells grown on stiff vs. soft plates with P4., Conclusion(s): Cells cultured on mechanically stiff substrates had enhanced PRB activation via a mechanism that required MEK 1/2 and AKAP13/RhoA/ROCK signaling pathways. These studies provide a framework to explore the mechanisms by which mechanical stiffness affects progesterone receptor activation., (Copyright © 2020. Published by Elsevier Inc.)

Background: Uterine fibroids are highly prevalent, collagen-rich, mechanically stiff, fibrotic tumors for which new therapeutic options are needed. Increased extracellular matrix (ECM) stiffness activates mechanical signaling and Hippo/YAP promoting fibroid growth, but no prior studies have tested either as a therapeutic target. We tested the hypothesis that injection of a purified form of collagenase Clostridium histolyticum (CCH) that selectively digests type I and type III collagens would alter ECM stiffness, Hippo signaling, and selectively reduce fibroid cell growth. We also used two FDA-approved drugs, verteporfin and nintedanib, to elucidate the role of Hippo/YAP signaling in uterine fibroid and myometrial cells., Methods: The clinical trial was registered (NCT02889848). Stiffness of samples was measured by rheometry. Protein expression in surgical samples was analyzed via immunofluorescence. Protein and gene expression in uterine fibroid or myometrial cell lines were measured by real time PCR and western blot, and immunofluorescence., Results: Injection of CCH at high doses (0.1-0.2 mg/cm 3 ) into fibroids resulted in a 46% reduction in stiffness in injected fibroids compared to controls after 60 days. Levels of the cell proliferation marker proliferative cell nuclear antigen (PCNA) were decreased in fibroids 60 days after injection at high doses of CCH. Key Hippo signaling factors, specifically the transcriptionally inactive phosphorylated YAP (p-YAP), was increased at high CCH doses, supporting the role of YAP in fibroid growth. Furthermore, inhibition of YAP via verteporfin (YAP inhibitor) decreased cell proliferation, gene and protein expression of key factors promoting fibrosis and mechanotransduction in fibroid cells. Additionally, the anti-fibrotic drug, nintedanib, inhibited YAP and showed anti-fibrotic effects., Conclusions: This is the first report that in vivo injection of collagenase into uterine fibroids led to a reduction in Hippo/YAP signaling and crucial genes and pathways involved in fibroid growth. These results indicate that targeting ECM stiffness and Hippo signaling might be an effective strategy for uterine fibroids., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The coronavirus disease 2019 (COVID-19) caused by infection of the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) significantly impacted human society. Recently, the synthetic pure glucocorticoid dexamethasone was identified as an effective compound for treatment of severe COVID-19. However, glucocorticoids are generally harmful for infectious diseases, such as bacterial sepsis and severe influenza pneumonia, which can develop respiratory failure and systemic inflammation similar to COVID-19. This apparent inconsistency suggests the presence of pathologic mechanism(s) unique to COVID-19 that renders this steroid effective. We review plausible mechanisms and advance the hypothesis that SARS-CoV-2 infection is accompanied by infected cell-specific glucocorticoid insensitivity as reported for some other viruses. This alteration in local glucocorticoid actions interferes with undesired glucocorticoid to facilitate viral replication but does not affect desired anti-inflammatory properties in non-infected organs/tissues. We postulate that the virus coincidentally causes glucocorticoid insensitivity in the process of modulating host cell activities for promoting its replication in infected cells. We explore this tenet focusing on SARS-CoV-2-encoding proteins and potential molecular mechanisms supporting this hypothetical glucocorticoid insensitivity unique to COVID-19 but not characteristic of other life-threatening viral diseases, probably due to a difference in specific virally-encoded molecules and host cell activities modulated by them.

Objectives: To investigate the personal, ethical, and financial perspectives of individuals with Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), a congenital uterine factor infertility condition, regarding uterine transplantation (UTx)., Design: Cross-sectional, quantitative survey., Setting: A 60-item anonymous electronic questionnaire was disseminated via social media sites., Patients: International members of the Beautiful You MRKH Foundation., Interventions: None., Main Outcome Measures: The survey contained UTx educational materials followed by questions assessing participants' baseline knowledge, global perceptions, financial concerns, and ethical considerations regarding UTx., Results: We received 281 responses, with a mean participant age of 28.2 ± 9.8 years. After reviewing the education material, most participants considered receiving a UTx (73%), believed that it should be an option for all women with uterine factor infertility (86%), and believed that it should be covered by health insurance (78%). Respondents perceived the benefits of the procedure to outweigh the risks (67%) and considered it to be an ethical procedure (82%). Almost one-half (49%) were willing to spend more than $10,000 out of pocket to receive the procedure. When asked to rank the risk of UTx to self, donor, and fetus in order of personal importance, 21% ranked their own safety last., Conclusion: There is a profound desire in the MRKH community for UTx to become more widely available and affordable. MRKH patients may represent a vulnerable population requiring special considerations for informed consent and rigorous evaluation for UTx. Providers caring for MRKH patients should be prepared to provide education about UTx and to thoughtfully engage with news and media outlets to communicate evidence-supported information., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Context: In vitro and in vivo evidence has supported the role of angiotensin II blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association., Objective: This work aims to determine whether prior angiotensin-converting enzyme inhibitor (ACEi) use is associated with a reduced odds of leiomyoma development., Design: A nested case-control study was conducted., Setting: The population was assembled from the Truven Health MarketScan Research Database, which includes private health insurance claims from January 1, 2012 to December 31, 2017., Patients or Other Participants: We included (n = 353 917) women age 18 to 65 with hypertension. Cases (n = 13 108) with a leiomyoma diagnosis were matched to controls (n = 340 808) with no such diagnosis at a 1:26 ratio by age and region of origin within the United States., Intervention: Prior ACEi use was determined from outpatient drug claims., Main Outcome Measure: Leiomyoma development was indicated by a first-time diagnosis code., Results: Women on an ACEi experienced a 31.8% reduced odds of developing clinically recognized leiomyoma compared to nonusers (odds ratio [OR] 0.68; 95% CI, 0.65-0.72). This association was significant for each age group: 30 to 39 years (OR 0.86; 95% CI, 0.74-0.99), 40 to 49 years (OR 0.71; 95% CI, 0.66-0.76), 50 to 59 years (OR 0.63; 95% CI, 0.58-0.69), and 60 to 65 years (OR 0.58; 95% CI, 0.50-0.69). Of the ACEis, lisinopril (OR 0.67; 95% CI, 0.64-0.71), quinapril (OR 0.62; 95% CI, 0.41-0.92), and ramipril (OR 0.35; 95% CI, 0.23-0.50) demonstrated a significant association with reduced leiomyoma incidence., Conclusions: ACEi use was associated with a reduced odds of developing clinically recognized leiomyoma in adult hypertensive women., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Menopause is associated with bothersome symptoms for many women, including mood changes, hot flushes, sleep problems, and fatigue. Progesterone is commonly prescribed in combination with estrogen therapy. Although monotherapy with progestins has been used as treatment of menopausal symptoms in women with contraindications to estrogens, the optimal route, and dosage of progestin monotherapy has not been established., Objective: To assess whether progestin as a standalone treatment is effective for treating vasomotor and mood symptoms associated with menopause., Evidence Review: We conducted a systematic review using PubMed and Embase databases from January 1980 to January 2020. We included randomized controlled trials (RCTs) that investigated different forms of progestin for the treatment of vasomotor or mood symptoms associated with menopause., Findings: A systematic search of 892 studies identified seven RCTs involving a total of 601 patients. The available literature was heterogeneous in terms of formulation and dose of progesterone; administration ranged from 5 to 60 mg of transdermal progesterone, 10 to 20 mg oral medroxyprogesterone acetate, and 300 mg of oral micronized progesterone. Duration of treatment also differed between studies, ranging from 21 days to 12 months (median: 12 wks). Three of seven RCTs reported that progestin therapy led to an improvement of vasomotor symptoms (VMS) in postmenopausal women. The largest study administering oral progestin using 300 mg micronized progesterone reported a 58.9% improvement in VMS (vs 23.5% in placebo group, n = 133), whereas the largest study using transdermal progesterone reported no improvement (n = 230). No study reported an improvement of mood symptoms. Side effects, such as headaches and vaginal bleeding, were significant in five of seven RCTs and led to discontinuation of treatment in 6% to 21% of patients., Conclusions and Relevance: A beneficial effect was reported in some trials with the transdermal route at longer duration and with oral treatment at higher doses for VMS for progesterone-only therapy. This report may help to inform future studies of progestin-only therapy for the treatment of menopausal symptoms., Competing Interests: Financial disclosure/conflicts of interest: J.H.S. is active on the following boards: the American Society of Reproductive Medicine, The American Board of Obstetrics and Gynecology, the Society for Reproductive Investigation and the American Gynecological and Obstetrical Society. Dr. Segars has received sponsored research funding for clinical trials involving from Biospecifics, Bayer, Allergan, and Abbvie and served as a consultant for Myovant. All other authors have nothing to disclose., (Copyright © 2020 by The North American Menopause Society.)

Objective: Despite the high prevalence of uterine fibroids, the psychosocial impact of fibroids has not been evaluated across different quality of life indicators and compared with other chronic conditions. Here, we rigorously analyzed available evidence pertaining to the psychosocial burden of uterine fibroids in premenopausal women and compared validated quality of life and symptom scores before and after treatment., Data Sources: We searched PubMed, PsycINFO, ClinicalTrials.gov, Embase, and Cochrane Library for publications from January 1990 to January 2020., Study Eligibility Criteria: We considered English-language publications that evaluated the association between uterine fibroids diagnosed by imaging studies in premenopausal women and quality of life by standardized and validated questionnaires at baseline and after treatment. We used a detailed list of terms related to quality of life, questionnaires, and uterine fibroids to conduct the search., Methods: Three reviewers screened titles and abstracts and then obtained full-text articles for further analysis. The reviewers assessed risk of bias using established Cochrane and Newcastle-Ottawa Scale guidelines. The quality of life scores of premenopausal women with fibroids were reviewed at baseline and compared with those of published quality of life scores in other disease populations in addition to after fibroid treatment., Results: A total of 57 studies were included in the review: 18 randomized controlled trials and 39 observational studies. Of note, the 36-Item Short Form Survey and European Quality of Life Five-Dimension Scale questionnaires both indicated a diagnosis of uterine fibroids to have a disability score that was similar to or exceeded (was a greater psychosocial stressor) a diagnosis of heart disease, diabetes mellitus, or breast cancer. Quality of life scores were lower at baseline than after treatment in all instruments measuring these variables in women with uterine fibroids, indicating significantly impaired psychosocial functioning. Uterine fibroids were associated with significant patient-reported health disabilities related to bodily pain, mental health, social functioning, and satisfaction with sex life., Conclusion: A diagnosis of uterine fibroids was a significant psychosocial stressor among women at baseline and relative to other diseases. Validated quality of life instruments indicated therapeutic success and the improvement of both physical and emotional symptoms after treatment., (Copyright © 2020. Published by Elsevier Inc.)

Background: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress β1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies., Objective: This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells., Study Design: This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 μM, or control) for 48 hours. Protein and mRNA levels of β1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction., Results: We found that simvastatin significantly reduced the protein expression of β1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in β1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1., Conclusion: The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This article aims to evaluate the impact of a mentorship program to enhance the training of clinical and research scientists in obstetrics and gynecology (OBGYN). A departmental course was developed for junior faculty and fellows based on their areas of interest. The research was IRB-approved. The curriculum consisted of monthly interactive workshops for an interdisciplinary group of trainees in OBGYN. Themes included research, education, and leadership in academic OBGYN. There was a strong emphasis on participatory exercises. Examples of curriculum topics included manuscript publication and review, grant writing, working with an IRB, promotion, and time management. Pre- and post-course questionnaires assessed participants' confidence in skills related to the course topics. Generalized linear models were used to assess changes in post-course response, using each question as the dependent variable and an indicator for post-course as the predictor variable. The control group was composed of junior faculty and fellows before the course was initiated. Outcome measures included the number and impact factor of published manuscripts. A Wilcoxon rank-sum test was used to assess outcome measures. Of the 118 attendees, 26 (22.0%) were junior faculty, 35 (29.66%) were clinical fellows, and 28 (23.7%) were research fellows, other research staff, or students. For each 3-year course series, an average of 20 participants completed the post-course surveys, of which 72% were clinical fellows, 22% were assistant professors, and 5% were instructors. The data revealed a statistically significant change in the participant's overall confidence in skills related to research, education, and leadership when comparing the cumulative results from the pre-to-post course surveys ( p  < 0.001). Specifically, participants noted improved confidence in their skills related to clinical and translation research ( p  < 0.001) and leadership and academic career advancement ( p  = 0.001). Additionally, junior faculty and clinical fellows who attended the course had a higher number of publications during the course period compared with controls ( p  = 0.003 and p  = 0.008, respectively). This subspecialty-tailored, departmental training program was effective in increasing junior faculty and clinical fellows' confidence in skills related to career advancement and research and in the number of peer-reviewed publications., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood., Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids., Methods and Results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus., Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: Mammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis., Methods: We performed a systematic review to assess and summarize the effects of mechanical signaling and mechanotransduction in oocyte maturation and folliculogenesis and to explore possible clinical applications. The review identified 2568 publications of which 122 met the inclusion criteria., Results: The integration of mechanical and cell signaling pathways in gametogenesis is complex. Follicular activation or quiescence are influenced by mechanical signaling through the Hippo and Akt pathways involving the yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene, the mammalian target of rapamycin (mTOR), and forkhead box O3 (FOXO3) gene., Conclusions: There is overwhelming evidence that mechanical signaling plays a crucial role in development of the ovary, follicle, and oocyte throughout gametogenesis. Emerging data suggest the complexities of mechanotransduction and the biomechanics of oocytes and follicles are integral to understanding of primary ovarian insufficiency, ovarian aging, polycystic ovary syndrome, and applications of fertility preservation.

Objective: Hormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model., Materials and Methods: Targeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/-) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open- field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotype*sex, and genotype*sex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions., Results: The marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p = .0025) and a trend towards increased grooming behavior (p = .06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p > 0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p > 0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p > 0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to <7 months age range (p = .0051). Male Akap13 haploinsufficient mice showed no differences in weight compared to male WT mice (p = >0.05) at any age range examined., Conclusion: Akap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may examine the involvement of AKAP13 in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The majority of serious thromboembolic events occurring in assisted reproductive technologies (ART) are in women with ovarian hyperstimulation syndrome (OHSS)., Objectives: The purpose of this study was to present a thorough review and cost analysis regarding the use of venous thromboembolism (VTE) prophylaxis in OHSS to inform clinical management., Data Sources: Databases used were Pubmed and Embase, in addition to checking reference lists of retrieved articles (inception to November 2017)., Methods: The systematic search strategy identified 365 titles and abstracts. Articles included in the qualitative synthesis had identified venous thrombosis incidence rates or ratios. A separate search for the cost model was conducted recognizing all associated complications of VTE. The decision tree was modeled to best fit the patient population and a sensitivity analysis was performed over a range of variables., Results: The cost of VTE event per OHSS patient not on prophylaxis was €5940 (range €3405 to €38,727), versus €4134 (€2705 to €23,192) per event per patient on prophylaxis, amounting to a saving of (€19 to €23,192) per VTE per patient. Sensitivity analysis found VTE prophyaxis to be cost effective if the incidence of VTE in the OHSS population was greater than 2.79%. Prophylactic therapy was cost effective through 16 weeks of treatment., Limitations: OHSS is infrequent and hence, the incidence of VTE in patients with OHSS is low; therefore, the data used to inform the incidence of VTE in OHSS in the model carry some uncertainty. Further, low molecular weight heparin (LMWH) has side effects therefore individualization of care must be considered., Conclusions: With the increasing incidence of infertility and requirement for ART, thromboembolism in OHSS poses a major health threat for patients. VTE prophylaxis using enoxaparin was cost effective in patients with severe OHSS over a wide range of costs and incidences. Prophylaxis was also cost effective through the completion of the first trimester of pregnancy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas., Methods: This phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18-50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo., Results: From March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6-63.2]) and 28 of 48 (58.3% [97.5% CI 41.2-74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0-10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign., Conclusion: Ulipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas., Clinical Trial Registration: Clinicaltrials.gov number, NCT02147197.

There are large variations in the number of oocytes within each woman, and biologically, the total quantity is at its maximum before the woman is born. Scientific knowledge is limited about factors controlling the oocyte pool and how to measure it. Within fertility clinics, there is no uniform agreement on the diagnostic criteria for each common measure of ovarian reserve in women, and thus, studies often conflict. While declining oocyte quantity/quality is a normal physiologic occurrence as women age, some women experience diminished ovarian reserve (DOR) much earlier than usual and become prematurely infertile. Key clinical features of DOR are the presence of regular menstrual periods and abnormal-but-not-postmenopausal ovarian reserve test results. A common clinical challenge is counseling patients with conflicting ovarian reserve test results. The clinical diagnosis of DOR and the interpretation of ovarian reserve testing are complicated by changing lab testing options and processing for anti-mullerian hormone since 2010. Further, complicating the diagnostic and research scenario is the existence of other distinct yet related clinical terms, specifically premature ovarian failure, primary ovarian insufficiency, poor ovarian response, and functional ovarian reserve. The similarities and differences between the definitions of DOR with each of these four terms are reviewed. We recommend greater medical community involvement in terminology decisions, and the addition of DOR-specific medical subject-heading search terms.

Uterine fibroids (myomas or leiomyomas) are common benign tumors of reproductive aged women. Fibroids are clinically apparent in 20-50% of women, and cause abnormal uterine bleeding, abdominal pain and discomfort, pregnancy complications and infertility. Unfortunately, limited numbers of medical treatment are available but no effective preventive strategies exist. Moreover, the benefits of medical treatments are tempered by lack of efficacy or serious adverse side effects. Fibrosis has recently been recognized as a key pathological event in leiomyoma development and growth. It is defined by the excessive deposition of extracellular matrix (ECM). ECM plays important role in making bulk structure of leiomyoma, and ECM-rich rigid structure is believed to be a cause of abnormal bleeding and pelvic pain/pressure. Dietary phytochemicals are known to regulate fibrotic process in different biological systems, and being considered as potential tool to manage human health. At present, very few dietary phytochemicals have been studied in uterine leiomyoma, and they are mostly known for their antiproliferative effects. Therefore, in this review, our aim was to introduce some dietary phytochemicals that could target fibrotic processes in leiomyoma. Thus, this review could serve as useful resource to develop antifibrotic drugs for possible prevention and treatment of uterine fibroids.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Maternal immune tolerance of fetal engraftment is critical for the establishment and maintenance of pregnancy, but the exact mechanisms permitting this semi-allograft in the maternal host are not completely understood. Further, failure of the embryo to implant in the uterus accounts for at least 30% of the best prognosis in vitro fertilization cycles when a perfect embryo is transferred to a normal uterus. We hypothesized that T regulatory cells (T regs ), defined by CD4 + CD25hi surface expression and the FoxP3+ transcription factor, play an important role in the initiation of the earliest stages of pregnancy, specifically implantation of the embryo. In this study, we evaluated the role of T regs in the establishment of pregnancy using a conditional depletion of T reg transgenic mouse model. We found that embryo implantation in the syngeneic mating was defective as evidenced by smaller litter sizes after T reg depletion and that embryo implantation could be restored by adoptively transferring T regs into the mating mice. In allogeneic mating, litter sizes were not different but breeding efficiency was significantly decreased. These data reveal that T regs are important for the establishment of the earliest stages of pregnancy and may be a potential cause of infertility due to recurrent implantation failure, which may be amenable to cellular or pharmacologic therapy to improve maternal immune tolerance of embryo implantation.

The cost of fertility treatment is expensive and interventions that reduce cost can lead to greater efficiency and fewer embryos transferred. Endometrial polyps contribute to infertility and are frequently removed prior to infertility treatment. It is unclear whether polypectomy reduces fertility treatment cost and if so, the magnitude of cost reduction afforded by the procedure. The aim of this study was to determine whether performing office or operative hysteroscopic polypectomy prior to infertility treatment would be cost-effective. PubMed, Embase, and Cochrane libraries were used to identify publications reporting pregnancy rates after hysteroscopic polypectomy. Studies were required to have a polypectomy treatment group and control group of patients with polyps that were not resected. The charges of infertility treatments and polypectomy were obtained through infertility organizations and a private healthcare cost reporting website. These charges were applied to a decision tree model over the range of pregnancy rates observed in the representative studies to calculate an average cost per clinical or ongoing pregnancy. A sensitivity analysis was conducted to assess cost savings of polypectomy over a range of pregnancy rates and polypectomy costs. Pre-treatment office or operative hysteroscopic polypectomy ultimately saved €6658 ($7480) and €728 ($818), respectively, of the average cost per clinical pregnancy in women treated with four cycles of intrauterine insemination. Polypectomy prior to intrauterine insemination was cost-effective for clinical pregnancy rates greater than 30.2% for office polypectomy and 52.6% for operative polypectomy and for polypectomy price <€4414 ($4959). Office polypectomy or operative polypectomy saved €15,854 ($17,813) and €6644 ($7465), respectively, from the average cost per ongoing pregnancy for in vitro fertilization/intracytoplasmic sperm injection treated women and was cost-effective for ongoing pregnancy rates greater than 26.4% (office polypectomy) and 31.7% (operative polypectomy) and polypectomy price <€6376 ($7164). These findings suggested that office or operative hysteroscopic polypectomy was cost-effective when performed prior to both intrauterine insemination and in vitro fertilization over a range of plausible pregnancy rates and procedural costs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to summarize the latest advances and successes in the field of ovarian tissue cryopreservation while identifying gaps in current knowledge that suggest opportunities for future research., Methods: A systematic review was performed according to PRISMA guidelines for all relevant full-text articles in PubMed published in English that reviewed or studied historical or current advancements in ovarian tissue cryopreservation and auto-transplantation techniques., Results: Ovarian tissue auto-transplantation in post-pubertal women is capable of restoring fertility with over 80 live births currently reported with a corresponding pregnancy rate of 23 to 37%. The recently reported successes of live births from transplants, both in orthotopic and heterotopic locations, as well as the emerging methods of in vitro maturation (IVM), in vitro culture of primordial follicles, and possibility of in vitro activation (IVA) suggest new fertility options for many women and girls. Vitrification, as an ovarian tissue cryopreservation technique, has also demonstrated successful live births and may be a more cost-effective method to freezing with less tissue injury. Further, transplantation via the artificial ovary with an extracellular tissue matrix (ECTM) scaffolding as well as the effects of sphingosine-1-phosphate (SIP) and fibrin modified with heparin-binding peptide (HBP), heparin, and a vascular endothelial growth factor (VEGF) have demonstrated important advancements in fertility preservation. As a fertility preservation method, ovarian tissue cryopreservation and auto-transplantation are currently considered experimental, but future research may pave the way for these modalities to become a standard of care for women facing the prospect of sterility from ovarian damage.