Menopause hormone therapy prescribing in ambulatory care visits among midlife and older U.S. women from 2018 to 2019.

The rates of prescription for menopause hormone therapy have been low in the U.S. since the 2002 Women's Health Initiative study, but no recent studies have assessed the prescribing of hormone therapy in the U.S. Using the National Ambulatory Medical Care Survey data from 2018 to 2019, we found that hormone therapy was prescribed in 3.8 % of U.S. visits by midlife and older women, with 60 % of these visits including estradiol-only prescriptions. Older age and Hispanic/Latina ethnicity were associated with decreased odds of prescribing, while White race and depression were associated with increased odds, indicating possible disparities in menopause care.

Relugolix/Estradiol/Norethisterone Acetate: A Review in Endometriosis-Associated Pain.

An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain.

Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree^® (USA); Ryeqo^® (EU)] (hereafter referred to as relugolix combination therapy) has been approved to treat endometriosis-associated pain. The treatment works by decreasing levels of ovarian hormones (estrogen and progesterone). In clinical trials, relugolix combination therapy improved period pain and pain between periods in women with moderate to severe pain associated with endometriosis. The treatment also improved other symptoms (overall pelvic pain and pain during sex), reduced the need for pain medications and improved health-related quality of life. Relugolix combination therapy was generally well tolerated and caused minimal bone loss, which is known to occur with some hormone therapies. With the convenience of a once daily oral pill, relugolix combination therapy is a valuable addition to the options currently available for women with endometriosis-associated pain.

Prolame produces anxiolytic- and antidepressant-like effects in middle-aged female rats with less uterotrophic effects than 17ß-estradiol.

Estrogen hormone replacement therapy (EHRT), improving women's life quality at menopause, reduces anxiety and depression symptoms associated with ovarian hormonal decline. However, its potential adverse effects, like thromboembolism and cancer risk, limit its use. Prolame is a synthetic 17ß-amino estrogen with antithrombotic actions that exerts anxiolytic- and antidepressant-like effects on young adult ovariectomized female rats. It is unknown if prolame's effects may be observed in age and endocrine conditions emulating menopause. This study aimed to identify the antidepressant- and anxiolytic-like effects of prolame and E2 (used as a reference estrogen treatment) in middle-aged female rats coursing with irregular cycles, in two different conditions: ovariectomized or gonadally intact. Results were compared with those from young adult ovariectomized rats. Prolame (60 or 120 µg/kg), 17ß-estradiol (E2, 40 or 80 µg/kg), or vehicle were chronically administered, and their effects were evaluated in the elevated plus-maze, defensive burying behavior test, open field test, and forced swimming test. Uterotrophic actions were estimated by uterine weight related to body weight. Prolame and E2 produced robust anxiolytic- and antidepressant-like effects in young adult ovariectomized rats, but these effects were absent in gonadally intact middle-aged rats. Interestingly, only prolame induced anxiolytic- and antidepressant-like effects in middle-aged ovariectomized rats. Uterotrophic effects of prolame were weaker than E2 effects, notably in middle-aged females. Altogether, present data support the notion that prolame has the potential to be considered an EHRT with relevant psychoactive actions and with apparently lower adverse-side effects, especially in middle-aged populations.

A comparison of hyaluronic acid and estradiol treatment in vulvovaginal atrophy.

OBJECTIVE: This study aims to compare the effects of vaginal estrogen and hyaluronic acid on vulvovaginal atrophy. PATIENTS AND METHODS: This randomized controlled study included a total of 300 patients, with 150 patients in each group (Group E and Group H). The VHI score was determined based on a pre-treatment evaluation conducted by a gynecologist. After one month of receiving vaginal estrogen in Group E and vaginal hyaluronic acid in Group H, the patients were re-evaluated by their physicians. RESULTS: A statistically significant difference was found between the pre- and post-treatment VHI scores in Group E and Group H (p = 0.000; p = 0.000). No statistical difference was found between Group E and Group H in terms of treatment efficacy (p = 0.712). The pre- and post-treatment complaints of dryness, itching, dyspareunia, burning, and dysuria were found to be statistically significant in Group E and Group H (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group E, respectively) (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group H, respectively). No statistical difference was observed regarding dyspareunia, dysuria, and burning complaints (p = 0.632; p = 0.106; p = 0.128, respectively). However, hyaluronic acid was found to be significantly more effective for itching complaints (p = 0.002), while estrogen was found to be significantly more effective for dryness complaints (p = 0.012). CONCLUSIONS: Hyaluronic acid and estrogen were equally effective in vaginal treatment. Hyaluronic acid may be preferred for patients in whom hormonal therapy is contraindicated or for those who prefer non-hormonal therapy.

Risk assessment of transgender people: implementation of a demasculinizing-feminizing rodent model including the evaluation of thyroid homeostasis.

BACKGROUND: Individuals whose gender identity differs from the biological sex and the social norms are defined as transgender. Sometimes transgender undergo gender affirming hormone therapy, which lasts for the entire life making essential to evaluate its potential long-term effects. Moreover, transgender can represent a susceptible sub-group of population and specific attention is needed in risk assessment, including the development of targeted animal models. Aim of the study is the implementation of a rodent demasculinizing-feminizing model through the setting of appropriate dose of hormone therapy and the selection of specific biomarkers to evaluate the sex transition. Specific attention is paid to thyroid homeostasis due to the close link with reproductive functions. Four male adult rats/group were subcutaneously exposed to three doses plus control of ß-estradiol valerate plus cyproterone acetate at: 0.045 + 0.2 (low), 0.09 + 0.2 (medium) and 0.18 + 0.2 (high) mg/dose, five times/week. The doses were selected considering the most recent recommendations for transgender woman. Sperm count, histopathological analysis (testis, liver, thyroid), testosterone, estradiol, triiodothyronine and thyroid-stimulating hormone serum levels and gene expression of sex dimorphic CYP450 were evaluated. RESULTS: The doses induced feminizing-demasculinizing effects: decreased testosterone serum levels at the corresponding cisgender, increased estradiol, impairment of male reproductive function and reversal of sex-specific CYP liver expression. However, the medium and high doses induced marked liver toxicity and the low dose is considered the best choice, also for long-term studies in risk assessment. The alterations of thyroid indicated follicular cell hypertrophy supported by increased thyroid-stimulating hormone serum levels at the higher doses. CONCLUSIONS: The implementation of animal models that mimic the effects of gender affirming hormone therapy is essential for supporting clinical studies in transgender people and filling data gap in order to ensure an appropriate risk assessment and a more accurate, personalized care for transgender people.

Hormone Replacement Therapy after Pubertal Induction in Adolescents and Young Adults with Turner Syndrome: A Survey Study.

INTRODUCTION: Turner syndrome (TS) is associated with primary ovarian insufficiency (POI) and most adolescents and young adults (AYA) with TS require treatment with hormone replacement therapy (HRT). International consensus guidelines are unclear on the optimal formulation and dosing for HRT after pubertal induction. This study assessed current HRT practice patterns of endocrinologists and gynecologists in North America. METHODS: Email listserv members of the North American Society for Pediatric and Adolescent Gynecology (NASPAG) and the Pediatric Endocrine Society (PES) were invited to complete a 19-question survey to assess HRT treatment preferences for the management of POI after completion of pubertal induction in AYA with TS. Descriptive analysis and multinomial logistic regression to predict factors associated with preferred HRT are presented. RESULTS: 155 providers (79% pediatric endocrinology, 17% pediatric gynecology) completed the survey. Although 87% (135) reported confidence in prescribing HRT, only half (51%, 79) were aware of published guidelines. Factors significantly associated with preferred HRT included specialty (p = 0.032) and number of patients with TS seen every 3 months (p = 0.024). Gynecologists were 4 times less likely than endocrinologists to prefer hormonal contraceptives and 4 times more likely to favor transdermal estradiol dose of 100 µg/day as compared to lower doses. CONCLUSION: Although most endocrinologists and gynecologists report confidence in prescribing HRT to AYA with TS after pubertal induction, there are clear differences in provider preferences based on specialty and higher volume of patients with TS in their practice. Additional studies on comparative effectiveness of the HRT regimens and evidence-based guidelines are necessary for AYA with TS.

Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial.

BACKGROUND: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. METHODS: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. FINDINGS: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). INTERPRETATION: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. FUNDING: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Use of MHT in women with cardiovascular disease: a systematic review and meta-analysis.

This systematic review assesses the effect of menopausal hormone therapy (MHT) on cardiovascular outcomes and risk factors in postmenopausal women with cardiovascular disease (CVD). The Medline, Embase and Cochrane databases were searched from inception to December 2022 for randomized controlled trials (RCTs) and observational studies using methodology from a previous Cochrane review. Quality assessment used the Cochrane risk of bias tool and Newcastle-Ottawa scale, respectively. From 5647 studies identified, 29 (23 RCTs and six observational studies) were included. Most studies were conducted in North America or Europe and investigated oral estrogens. Participants were older with varying frequency of cardiac risk factors and underlying CVD. No significant difference was observed between MHT users and controls regarding primary outcomes of non-fatal myocardial infarction, cardiovascular death or stroke. No difference in frequency of angina, heart failure and transient ischemic attacks was observed. Inconsistent effects of MHT on angiographic progression were seen and varied with glycemic status. Estradiol had a positive effect on flow-mediated dilatation. Limited studies identified differing effects of MHT on cardiac risk factors, varying with estrogen preparation. This study confirms no benefit of MHT for secondary CVD prevention, highlighting evidence limitations and the importance of shared decision-making when managing menopausal symptoms in women with CVD.

Evaluating the cost utility of estradiol plus dydrogesterone for the treatment of menopausal women in China.

AIM: Evaluate the cost utility of menopausal hormone therapy for women in China. MATERIALS AND METHODS: A bespoke Markov cost utility model was developed to evaluate a cohort of symptomatic perimenopausal women (>45 years) with intact uterus in China in accordance with China's Pharmacoeconomic guideline. Short (5-year) and long (10-year) treatment durations were evaluated over a lifetime model time horizon with 12-month cycle duration. Societal and healthcare payer perspectives were evaluated in the context of a primary care provider/prescriber, outpatient setting with inpatient care for patients with chronic conditions. Disease risk and mortality parameters were derived from focused literature searches, and China Diagnosis-related Group cost data was included. Comprehensive scenario, univariate and probabilistic sensitivity analysis were undertaken along with independent validation. This is the first model to include MHT-related disease risks. RESULTS: According to base case results, the total cost for MHT was 22,516$ (150,106¥) and total quality adjusted life years 12.32 versus total cost of no MHT 30,824$ (205,495¥) and total quality adjusted life years 11.16 resulting in a dominant incremental cost effectiveness ratio of -7,184$ (-47,898¥) per QALY. Results hold true over a range of univariate deterministic sensitivity and scenario analyses. Probabilistic analysis showed a 91% probability of being cost effective at a willingness to pay threshold of three times Gross Domestic Product per capita in China. CONCLUSION: Contingent on the structure and assumptions of the model, combination of estradiol plus dydrogesterone MHT is potentially cost saving in symptomatic women over the age of 45 years in China.

Menopausal hormone therapy is publicly funded in many countries to alleviate symptoms of menopause; however, uptake has been comparatively slow in China. This has implications for the estimated 168 million menopausal-aged women. This analysis is the first to evaluate the cost effectiveness of menopausal hormone therapy in China using best practice principles and incorporating longer term disease risks. Menopausal hormone therapy is potentially cost saving in the context of China.

Cistanche deserticola improves ovariectomized-induced osteoporosis mainly by regulating lipid metabolism: Insights from serum metabolomics using UPLC/Q-TOF-MS.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche deserticola (C. deserticola) is an edible and traditional medicine widely used in China, which has been confirmed to be effective in the treatment of postmenopausal osteoporosis (PMOP). Despite its proven efficacy, the exact role of C. deserticola in bone metabolism and its underlying mechanism has remained unclear. AIM OF THE STUDY: In this research, we employed an in vivo model utilizing ovariectomized (OVX) rats to characterize the anti-osteoporotic activity and metabolic mechanism of the ethanol extract of C. deserticola (CHE). MATERIALS AND METHODS: Fifty female Sprague-Dawley (SD) rats were randomly divided into five groups including sham operation group, model group, 0.1 g/kg estradiol valerate (EV) group as the positive control, low (0.6 g/kg) and high (1.2 g/kg) dosage CHE groups. Biochemical parameter analyses and histopathological experiments were conducted to assess the pharmacodynamic effects. Metabolomic analysis was conducted on serum samples to examine the metabolic profiles, identify potential biomarkers, and elucidate the metabolic pathways associated with CHE in OVX rats. RESULTS: CHE treatment demonstrated significant anti-osteoporosis activity by regulating serum biochemical markers of bone turnover, improving cancellous bone structure, and reversing the decrease in bone mineral density. Furthermore, the clinical equivalent dose group (CHL) achieved superior overall outcomes. The main interventions of CHE on OVX rats involved the modulation of several key pathways, including steroid hormone biosynthesis, arachidonic acid metabolism, tyrosine and tryptophan metabolism, biotin metabolism, regulation of TRP channels by inflammatory mediators, primary bile acid biosynthesis, regulation of lipolysis in adipocytes, and bile secretion. 23 potential efficacy-related biomarkers within the metabolic network were identified. Among them, long-chain unsaturated fatty acids (eg. DHA and docosapentaenoic acid), steroid hormones, amino acids and carbohydrates were strongly correlated with bone resorption and formation markers. Additionally, it was observed four pathways (nucleotide, carbon, amino acid, and lipid metabolism) were implicated in the effects of CHE. CONCLUSION: This study demonstrates that CHE improves bone loss in PMOP mainly through regulating lipid metabolism pathways, which provides an evidence base for CHE treatment of PMOP.

Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial.

BACKGROUND: Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure. METHODS: This is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure. DISCUSSION: This study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT. TRIAL REGISTRATION: WHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL .

Treatments of Epistaxis in Hereditary Hemorrhagic Telangiectasia: Systematic Review and Network Meta-Analysis.

PURPOSE OF REVIEW: To analyze and compare the effects of epistaxis treatments for Hereditary Hemorrhagic Telangiectasia (HHT) patients. RECENT FINDINGS: Of total of 21 randomized controlled trials (RCT), the data from 15 RCTs (697 patients, 7 treatments: timolol, propranolol, bevacizumab, doxycycline, tacrolimus, estriol/estradiol, and tranexamic acid) were pooled for the meta-analyses while the other 6 studies (treatments: electrosurgical plasma coagulation, KTP laser, postoperative packing, tamoxifen, sclerosing agent, and estriol) were reviewed qualitatively. When compared to placebo, propranolol offered the most improved epistaxis severity score, mean difference (MD), -1.68, 95% confidence interval (95%CI) [-2.80, -0.56] followed by timolol, MD -0.40, 95%CI [-0.79, -0.02]. Tranexamic acid significantly reduced the epistaxis frequency, MD -1.93, 95%CI [-3.58, -0.28]. Other treatments had indifferent effects to placebo. Qualitative analysis highlighted the benefits of tamoxifen and estriol. The adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol were significantly reported. Propranolol, timolol, tranexamic acid, tamoxifen, and estriol were effective treatments which offered benefits to HHT patients in epistaxis management. Adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol should be concerned.

Oestradiol implants for gender-affirming hormone therapy: an observational study of serum oestradiol levels and consumer survey.

BACKGROUND: Custom-compounded subcutaneous implants are being used widely in Australia for gender-affirming hormone therapy. However, there is no published literature regarding their use for this purpose. METHODS: Electronic medical records were audited for consecutive clients who received oestradiol implants April 2019-November 2022 in gender clinics held within Hunter New England Health District in New South Wales, Australia. Serum oestradiol levels were analysed for implant doses 50-200mg, and predicted oestradiol level was modelled following 100mg implant insertion. An electronic consumer survey was sent to a convenience sample of implant recipients. RESULTS: A total of 38 clients received 88 implants, with 100mg oestradiol implants being the most frequently used (68%). The median interval between insertion procedures was 270 (IQR 186-399) days. The median serum oestradiol levels following implant insertion, for all implants combined, were within the target range of 250-600pmol/L at 1-, 3-, 6-, 9- and 12-month time points. Following insertion of a 100mg implant, the estimated time to reach a predicted serum oestradiol of ≤250pmol/L was 4months after an initial implant, and 13months after subsequent implants. Seventeen consumer surveys were received from 28 invitations. All respondents had previous experience of oral and/or transdermal oestradiol use. Oestradiol implants were preferred due to ease of use, perceived effectiveness, and the belief that other methods were less safe or associated with intolerance and side effects. CONCLUSIONS: Oestradiol implants are effective in achieving target serum oestradiol levels over a sustained period. Further research with larger cohorts could identify the optimal dosage regimen.

Safety, Pharmacokinetics, and Pharmacodynamics of SHR7280, a Non-peptide GnRH Antagonist in Premenopausal Women with Endometriosis: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

BACKGROUND: Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral non-peptide GnRH antagonist in premenopausal women with endometriosis. METHODS: In the Phase 1 part of the randomized, double-blinded, placebo-controlled, dose-ascending, Phase 1/2 trial, premenopausal women with endometriosis were randomized (4:1) to receive SHR7280 or placebo treatment for 21 consecutive days. The treatment dose started from 200 mg QD, and then increased to 300 mg QD and 200 mg BID. Safety, PK, and PD parameters were assessed. RESULTS: In total, 30 patients received assigned treatment, 24 with SHR7280 and 6 with placebo. SHR7280 was well tolerated. Adverse events (AEs) were reported in 19 (79.2%, 19/24) patients in the SHR7280 group and 5 (83.3%, 5/6) patients in the placebo group. Most AEs were mild and no severe AEs occurred. SHR7280 showed a rapid absorption, with a time to maximum plasma concentration (Tmax) of 1.0 h, 1.0 h, and 0.8 h for the 200 mg QD, 300 mg QD, and 200 mg BID regimens, respectively. Plasma concentration of SHR7280 was dose dependent. The mean half-life (t1/2) at steady state was 6.9 h, 7.4 h, and 2.8 h, respectively, and little or no accumulation was observed. Pharmacodynamic analysis showed that SHR7280 could effectively suppress estradiol and luteinizing hormone concentrations and prevent progesterone increase in a dose-dependent manner. SHR7280 at doses of 300 mg QD and 200 mg BID could suppress estradiol levels within the desired therapeutic window of 20-50 pg/mL throughout the treatment period. CONCLUSIONS: SHR7280 showed favorable safety, PK, and PD profiles in the doses of 200 mg QD, 300 mg QD, and 200 mg BID. The results of this study provide evidence to support the further development of SHR7280 as a GnRH antagonist for the treatment of endometriosis-related pain in the subsequent Phase 2 trial. TRIAL REGISTRY: Trial registration number: Clinicaltrials.gov, identifier: NCT04417972. Trial registration date: 5 June 2020.

Autologous Platelet-Rich Plasma (PRP) Efficacy on Endometrial Thickness and Infertility: A Single-Centre Experience from Romania.

(1) Background: During IVF (in vitro fertilization), a proper endometrium thickness is one of the most difficult parameters to achieve and one of the most important prognostic factors of the success rate. One major problem is the high cancelation percentage in frozen embryo transfer cycles. The focus on the adjuvant methods for improving endometrium thickness is an on-going subject of interest. (2) Methods: This prospective single-arm self-control study was conducted in an IVF centre in Oradea, Romania. The patients were divided into two groups. The control group included 51 patients with at least one attempt to transfer a good-quality blastocyst, but the endometrial thickness did not surpass 7 mm under standard endometrial preparation protocol with oestradiol and with adjuvant therapy (other than PRP, such as aspirin, vitamin C, and vitamin E), and the study group included the same 51 patients that had the embryo transfer performed under the same standard endometrial preparation protocol with oestradiol preparation protocol and intrauterine PRP infusion. (3) Results: In our study, the PRP treatment had a positive impact on the parameters that were followed for the evaluation of the success rate of the embryo transfer procedure. The endometrial thickness (an increase in endometrial thickness by 0.6 mm after PRP treatment with p = 0.0001) and the clinical pregnancy rate (having a MD ± SD of 0 ± 0.38 before PRP treatment and with an increase to 0.5 ± 0.1 after the PRP treatment, p = 0.0004) were statistically significant (4) Conclusions: PRP has a positive effect in promoting endometrial proliferation, improving embryo implantation rate and clinical pregnancy rate for women with thin endometrium.

Estrogen Effects Differ Between Medium Maintenance and Replacement from Transcriptional and Clinical Perspectives in T47D Breast Cancer Cells.

BACKGROUND/AIM: Our most recent study revealed that the responsiveness of hormone receptor-positive breast cancer (HR+ BC) cells to estrogen or endocrine therapy can be altered by certain cell culture or ambient environmental conditions. Nevertheless, we were unable to investigate the relevant molecular mechanism and clinical relevance. Therefore, this study was planned as a follow-up. MATERIALS AND METHODS: RNA sequencing was mainly used with T47D cells treated with or without 17ß-estradiol (E2) under medium maintenance (MTN; conventional culture method) and medium exchange (EXC; daily replacing the existing medium with fresh medium). RESULTS: The role of E2 in transcription differed between MTN and EXC, and E2 played more important roles in transcription in terms of cancer development under EXC than under MTN, consistent with the previous functional effects of EXC. The novel concept of the "estrogen-responsive and proliferation-related gene (ERPG)" was introduced. The expression of ERPGs, which were distinguished from typical estrogen-responsive genes, was correlated with that of prognostic and predictive factors for HR+ BC. The transcriptional induction of ERPGs and typical estrogen-responsive genes regardless of E2 treatment under MTN was reminiscent of constitutive estrogen receptor (ER) activation. Additionally, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors were more effective under EXC than under MTN. CONCLUSION: This study, demonstrating the more important roles of estrogen in terms of cancer development under EXC than under MTN, supports the use of our research model in future studies to overcome endocrine resistance in HR+ BC.

Normalization of puberty and adult height in girls with Turner syndrome: results of the Swedish Growth Hormone trials initiating transition into adulthood.

Objective: To study the impact of GH dose and age at GH start in girls with Turner syndrome (TS), aiming for normal height and age at pubertal onset (PO) and at adult height (AH). However, age at diagnosis will limit treatment possibilities. Methods: National multicenter investigator-initiated studies (TNR 87-052-01 and TNR 88-072) in girls with TS, age 3-16 years at GH start during year 1987-1998, with AH in 2003-2011. Of the 144 prepubertal girls with TS, 132 girls were followed to AH (intention to treat), while 43 girls reduced dose or stopped treatment prematurely, making n=89 for Per Protocol population. Age at GH start was 3-9 years (young; n=79) or 9-16 years (old; n=53). Treatment given were recombinant human (rh)GH (Genotropin® Kabi Peptide Hormones, Sweden) 33 or 67 µg/kg/day, oral ethinyl-estradiol (2/3) or transdermal 17ß-estradiol (1/3), and, after age 11 years, mostly oxandrolone. Gain in heightSDS, AHSDS, and age at PO and at AH were evaluated. Results: At GH start, heightSDS was -2.8 (versus non-TS girls) for all subgroups and mean age for young was 5.7 years and that of old was 11.6 years. There was a clear dose-response in both young and old TS girls; the mean difference was (95%CI) 0.66 (-0.91 to -0.26) and 0.57 (-1.0 to -0.13), respectively. The prepubertal gainSDS (1.3-2.1) was partly lost during puberty (-0.4 to -2.1). Age/heightSDS at PO ranged from 13 years/-0.42 for GH67young to 15.2 years/-1.47 for GH33old. At AH, GH67old group became tallest (17.2 years; 159.9 cm; -1.27 SDS; total gainSDS, 1.55) compared to GH67young group being least delayed (16.1 years; 157.1 cm; -1.73 SDS; total, 1.08). The shortest was the GH33young group (17.3 years; 153.7 cm: -2.28 SDS; total gainSDS, 0.53), and the most delayed was the GH33old group, (18.5 years; 156.5 cm; -1.82 SDS; total gainSDS, 0.98). Conclusion: For both young and old TS girls, there was a GH-dose growth response, and for the young, there was less delayed age at PO and at AH. All four groups reached an AH within normal range, despite partly losing the prepubertal gain during puberty. Depending on age at diagnosis, low age at start with higher GH dose resulted in greater prepubertal height gain, permitting estrogen to start earlier at normal age and attaining normal AH at normal age, favoring physiological treatment and possibly also bone health, hearing, uterine growth and fertility, psychosocial wellbeing during adolescence, and the transition to adulthood.

A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE. SCOPING REVIEW STRUCTURED SUMMARY: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms. OBJECTIVE: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable. CHARTING METHODS: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial. RESULTS: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders. CONCLUSIONS: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Evaluation of the therapeutic effects of oestradiol on the systemic inflammatory response and on lung injury caused by the occlusion of the proximal descending aorta in male rats.

OBJECTIVES: Ischaemia and reperfusion-induced microvascular dysfunction is a serious problem encountered during a variety surgical procedures, leading to systemic inflammation and affecting remote organs, specially the lungs. 17ß-Oestradiol reduces pulmonary repercussions from various acute lung injury forms. Here, we focused on the 17ß-oestradiol therapeutic effects after aortic ischaemia and reperfusion (I/R) by evaluating lung inflammation. METHODS: Twenty-four Wistar rats were submitted to I/R by insufflation of a 2-F catheter in thoracic aorta for 20 min. Reperfusion took 4 h and 17ß-oestradiol (280 µg/kg, i.v.) was administered after 1 h of reperfusion. Sham-operated rats were controls. Bronchoalveolar lavage was performed and lung samples were prepared for histopathological analysis and tissue culture (explant). Interleukin (IL)-1ß, IL-10 and tumour necrosis factor-α were quantified. RESULTS: After I/R, higher number of leukocytes in bronchoalveolar lavage were reduced by 17ß-oestradiol. The treatment also decreased leukocytes in lung tissue. I/R increased lung myeloperoxidase expression, with reduction by 17ß-oestradiol. Serum cytokine-induced neutrophil chemoattractant 1 and IL-1ß increased after I/R and 17ß-oestradiol decreased cytokine-induced neutrophil chemoattractant 1. I/R increased IL-1ß and IL-10 in lung explants, reduced by 17ß-oestradiol. CONCLUSIONS: Our results showed that 17ß-oestradiol treatment performed in the period of reperfusion, modulated the systemic response and the lung repercussions of I/R by thoracic aortic occlusion. Thus, we can suggest that 17ß-oestradiol might be a supplementary approach leading the lung deterioration after aortic clamping in surgical procedures.