The impact of fibroid treatments on quality of life and mental health: a systematic review.

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.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

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.

A Systematic Review of Autoimmune Oophoritis Therapies.

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.

Beta blockers reduce uterine fibroid incidence in hypertensive women.

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.

Targeting fibrotic signaling pathways by EGCG as a therapeutic strategy for uterine fibroids.

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, ß-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 (ß-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.

AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells.

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.

The Utility and Impact of the Painful Periods Screening Tool (PPST) to Improve Healthcare Delivery for People with Symptoms of Pelvic Pain.

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.

Anatomic nomenclature and 3-dimensional regional model of the human ovary: call for a new paradigm.

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.

Pre-IVF treatment with a GnRH antagonist in women with endometriosis (PREGNANT): study protocol for a prospective, double-blind, placebo-controlled trial.

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.

Recognizing the Vulnerable: Perspectives, Attitudes, and Interests of Women With Uterine Factor Infertility Towards Uterus Allotransplantation.

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.

Selective Progesterone Receptor Modulators (SPRMs) and Androgen Receptor Modulators (SARMs) as Treatment for Benign Gynecologic Diseases.

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.

Simvastatin modulates estrogen signaling in uterine leiomyoma via regulating receptor palmitoylation, trafficking and degradation.

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E2), 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 E2-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 E2 downstream signaling, including ERK and AKT pathways, E2/ER transcriptional activity and E2-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 E2/ER signaling targets with potential implications in leiomyoma therapy and beyond.

Dexamethasone for Severe COVID-19: How Does It Work at Cellular and Molecular Levels?

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.

Extracellular matrix and Hippo signaling as therapeutic targets of antifibrotic compounds for uterine fibroids.

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/cm3 ) 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.

A Phase I Clinical Trial to Assess Safety and Tolerability of Injectable Collagenase in Women with Symptomatic Uterine Fibroids.

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.

Mechanical stiffness augments ligand-dependent progesterone receptor B activation via MEK 1/2 and Rho/ROCK-dependent signaling pathways in uterine fibroid cells.

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.

Perspectives of 281 patients with Mayer-Rokitansky-Küster-Hauser Syndrome on uterine transplantation.

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.