Effect of Menstrual Cycle and Hormonal Contraception on Musculoskeletal Health and Performance: Protocol for a Prospective Cohort Design and Cross-Sectional Comparison.

BACKGROUND: Women of reproductive age experience cyclical variation in the female sex steroid hormones 17ß-estradiol and progesterone during the menstrual cycle that is attenuated by some hormonal contraceptives. Estrogens perform a primary function in sexual development and reproduction but have nonreproductive effects on bone, muscle, and sinew tissues (ie, ligaments and tendons), which may influence injury risk and physical performance. OBJECTIVE: The purpose of the study is to understand the effect of the menstrual cycle and hormonal contraceptive use on bone and calcium metabolism, and musculoskeletal health and performance. METHODS: A total of 5 cohorts of physically active women (aged 18-40 years) will be recruited to participate: eumenorrheic, nonhormonal contraceptive users (n=20); combined oral contraceptive pill (COCP) users (n=20); hormonal implant users (n=20); hormonal intrauterine system users (n=20); and hormonal injection users (n=20). Participants must have been using the COCP and implant for at least 1 year and the intrauterine system and injection for at least 2 years. First-void urine samples and fasted blood samples will be collected for biochemical analysis of calcium and bone metabolism, hormones, and metabolic markers. Knee extensor and flexor strength will be measured using an isometric dynamometer, and lower limb tendon and stiffness, tone, and elasticity will be measured using a Myoton device. Functional movement will be assessed using a single-leg drop to assess the frontal plane projection angle and the qualitative assessment of single leg loading. Bone density and macro- and microstructure will be measured using ultrasound, dual-energy x-ray absorptiometry, and high-resolution peripheral quantitative computed tomography. Skeletal material properties will be estimated from reference point indentation, performed on the flat surface of the medial tibia diaphysis. Body composition will be assessed by dual-energy x-ray absorptiometry. The differences in outcome measures between the hormonal contraceptive groups will be analyzed in a one-way between-group analysis of covariance. Within the eumenorrheic group, the influence of the menstrual cycle on outcome measures will be assessed using a linear mixed effects model. Within the COCP group, differences across 2 time points will be analyzed using the paired-samples 2-tailed t test. RESULTS: The research was funded in January 2020, and data collection started in January 2022, with a projected data collection completion date of August 2024. The number of participants who have consented at the point of manuscript submission is 66. It is expected that all data analysis will be completed and results published by the end of 2024. CONCLUSIONS: Understanding the effects of the menstrual cycle and hormonal contraception on musculoskeletal health and performance will inform contraceptive choices for physically active women to manage injury risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT05587920; https://classic.clinicaltrials.gov/ct2/show/NCT05587920. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50542.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

Assessment of stress levels and reproductive condition in giant pandas: insights from hair, faecal and saliva samples.

Concerted conservation efforts have brought the giant panda (Ailuropoda melanoleuca) back from the brink of extinction, but pandas continue to face anthropogenic threats in the wild and breeding success in captivity remains low. Because stress can have detrimental impacts on reproduction, monitoring stress- and sex-steroid levels would help assess the effectiveness of conservation mitigation measures in panda populations as well as monitor the welfare and reproductive health of captive animals. In this proof-of-concept study, we used faecal sex steroid and cortisol concentrations (n = 867 samples collected from five males and five females at Beijing Zoo every 4 days over the course of 12 months) as a reference to investigate if testosterone, estradiol, progesterone and cortisol can be meaningfully measured in panda hair (n = 10) using radio-immuno-assays. Additionally, we calculated the ratio of testosterone to cortisol (T:C ratio) for each male, which can provide a biomarker of stress and physical performance. Our findings revealed distinct monthly variations in faecal sex-steroid and cortisol concentrations, reflecting reproductive seasonality and visitor-related stress among individual pandas. Notably, the oldest male had a significantly lower T:C ratio than other males. Our results confirm that the level of sex steroids and cortisol can be assayed by panda hair, and the hair cortisol concentrations correlate significantly with that in faeces with one month lag behind (r = 0.68, P = 0.03). However, the concentrations of hormones detected in saliva are lower than those in faeces by two orders of magnitude, making it difficult to ensure accuracy. By assessing the applicability of hair, faecal and salivary sampling, we can infer their utility in monitoring the reproductive status and acute and chronic stress levels of giant pandas, thereby providing a means to gauge the success of ongoing habitat restoration efforts and to discuss the feasibility of sample collection from wild populations.

Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

Optimizing intrauterine insemination: A systematic review and meta-analysis of the effectiveness and safety of clinical treatment add-ons.

INTRODUCTION: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment. MATERIAL AND METHODS: Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857. RESULTS: Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions. CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Short-Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT Phosphorylation.

Statins, the first-line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short-term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin-induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U-box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin-induced diabetes, while liver specific over-expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α-PAQR9-STUB1-PPM1α axis in controlling the statin-induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy.

Low androgen/progesterone or high oestrogen/androgen receptors ratio in serous ovarian cancer predicts longer survival.

The treatment of ovarian cancer (OC) remains one of the greatest challenges in gynaecological oncology. The presence of classic steroid receptors in OC makes hormone therapy an attractive option; however, the response of OC to hormone therapy is modest. Here, we compared the expression patterns of progesterone (PGR), androgen (AR) and oestrogen alpha (ERα) receptors between serous OC cell lines and non-cancer ovarian cells. These data were analysed in relation to steroid receptor expression profiles from patient tumour samples and survival outcomes using a bioinformatics approach. The results showed that ERα, PGR and AR were co-expressed in OC cell lines, and patient samples from high-grade and low-grade OC co-expressed at least two steroid receptors. High AR expression was negatively correlated, whereas ERα and PGR expression was positively correlated with patient survival. AR showed the opposite expression pattern to that of ERα and PGR in type 1 (SKOV-3) and 2 (OVCAR-3) OC cell lines compared with non-cancer (HOSEpiC) ovarian cells, with AR downregulated in type 1 and upregulated in type 2 OC. A low AR/PGR ratio and a high ESR1/AR ratio were associated with favourable survival outcomes in OC compared with other receptor ratios. Although the results must be interpreted with caution because of the small number of primary tumour samples analysed, they nevertheless suggest that the evaluation of ERα, AR and PGR by immunohistochemistry should be performed in patient biological material to plan future clinical trials.

Effect of body mass index on progesterone level on trigger day in gonadotropin-releasing hormone antagonist cycles.

OBJECTIVE: To investigate the effect of body mass index (BMI) on progesterone (P) level on trigger day in gonadotropin-releasing hormone antagonist (GnRH-ant) cycles. METHODS: This study was a retrospective cohort study. From October 2017 to April 2022, 412 in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients who were treated with GnRH-ant protocol for controlled ovarian hyperstimulation (COH) in the reproductive center of our hospital were selected as the research objects. Patients were divided into three groups according to BMI level: normal weight group (n = 230):18.5 kg/m2≤BMI < 24 kg/m2; overweight group (n = 122): 24 kg/m2≤BMI < 28 kg/m2; Obesity group (n = 60): BMI ≥ 28 kg/m2. Variables with p < .10 in univariate analysis (BMI, basal FSH, basal P, FSH days, Gn starting dose and E2 level on trigger day) and variables that may affect P level on trigger day (infertility factors, basal LH, total FSH, HMG days and total HMG) were included in the multivariate logistic regression model to analyze the effect of BMI on P level on trigger day of GnRH-ant protocol. RESULTS: After adjustment for confounding factors, compared with that in normal weight patients, the risk of serum P elevation on trigger day was significantly lower in overweight and obese patients (OR = 0.434 and 0.199, respectively, p < .05). CONCLUSION: The risk of P elevation on trigger day in GnRH-ant cycles decreased with the increase of BMI, and BMI could be used as one of the predictors of P level on trigger day in GnRH-ant cycles.

Per2 mediated steroid hormone synthesis by regulating transcription of StAR in porcine granulosa cells.

Steroidogenesis is associated with circadian clock genes. However, the regulation of steroid hormone production in sow granulosal cells by Per2, a crucial circadian regulator, remains unexplored. In this study, we have identified the presence of Per2 in ovarian granulosa cells and have observed its circadian expression pattern. Employing siRNA to interfere with Per2 expression, our investigation revealed that Per2 knockdown notably elevated progesterone (P4) levels along with increasing the expression of StAR but interference of Per2 did not alter the rhythm of clock-related gene (Bmal1, Clock, Per1 and Cry1) in granulosa cells. Subsequent mechanistic analysis showed that Per2 formed complexes with PPARγ and interference with Per2 promoted the formation of the PPARγ:RXRα heterodimer. Importantly, we uncovered that PPARγ:RXRα heterodimer could control the expression of StAR via direct peroxisome proliferator response element (PPRE) binding to its promoter to regulate its activity, and knockdown of Per2 promoted the transcription of StAR via increasing the binding of PPARγ:RXRα ligands. Altogether, these findings indicated a noncanonical role of Per2 in controlling PPARγ:RXRα binding to regulate transcription of StAR and progesterone synthesis, thus revealing potential avenues of pharmacological and therapeutic intervention.

Low Dose hCG Support in Modified Natural Frozen Embryo Transfer Cycles.

What is the effect of a single low-dose recombinant hCG injection after embryo transfer (ET) in letrozole-induced modified natural frozen embryo transfer cycles (mNC-FET)?. An observational study was conducted in the university-affiliated referral clinic between 2022 and 2024. Women aged 18-42 with at least one vitrified blastocyst obtained from the previous cycle(s) were included. Ovulation induction for endometrial preparation was initiated with oral letrozol (5 mg/day) for five days. Ovulation was triggered using 6500 IU rec hCG sc when the leading follicle > 17 mm, endometrial thickness > 7.5 mm, and serum progesterone (P) < 1.5 ng/ml. All women received 30 mg dydrogesterone/day po for additional five-day luteal support. On the 6th day, ET was performed. Based on a quasi-randomized design, a group of women additionally received a half single bolus of (3250 IU) rec hCG (sc) on the morning of 3rd day of ET (hCG group). Women who did not receive additional hCG were assigned as controls. One hundred fifty-four women were detected to be eligible for the study among 2150 initiated FET cycles during the period. Demographic data of the groups, including mean women's age, BMI, serum AMH, and infertility etiologies, were comparable in terms of variables. Mean serum progesterone values and the number of transferred embryos were also similar. A significantly higher ongoing pregnancy/started cycle was documented in the hCG group than in controls (46.7% vs 33.6% respectively, p = 0.03*). A single low-dose hCG injection after ET may improve the OPRs of women in letrozole mNC-FET cycles.

Vilaprisan for the treatment of symptomatic endometriosis: results from a terminated phase 2b randomized controlled trial.

Objective: To evaluate the efficacy and safety of 2 doses of vilaprisan vs. placebo in participants with symptomatic endometriosis. Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b trial (NCT03573336). The initially planned sample size was 315 patients. Recruitment was paused to assess long-term toxicity findings in rodents; although the findings were assessed as likely to be of limited clinical relevance in humans, the study was closed by the sponsor. During the pause, enrolled patients completed 3 or 6 months of treatment per their assigned regimen. Setting: University hospitals, a regional hospital, and a private clinic. Patients: Premenopausal adults with confirmed endometriosis and moderate-to-severe pelvic pain (≥4/10 on a numerical rating scale) were enrolled. Inclusion required protocol adherence, including ≥24 diary entries, and an average pain score of ≥3.5. Intervention: Participants were randomly assigned 1:1:1 to receive vilaprisan (2 mg), vilaprisan (4 mg), or placebo. Main Outcome Measures: The primary outcome was a change in the 7-day mean "worst pain" (per the endometriosis symptom diary item 1) from baseline to month 3. All analyses were descriptive only. Results: Eight participants were randomly assigned to treatment before the study pause: 6 received vilaprisan (4 mg, n = 4 and 2 mg, n = 2), and 2 received placebo. The 6 vilaprisan recipients experienced an improvement in endometriosis-associated pelvic pain, whereas the 2 placebo recipients experienced no change or increased pain; all 8 participants had decreased use of pain medication. Bleeding intensity decreased from baseline in the vilaprisan group. Conclusion: The study findings suggest that vilaprisan may improve outcomes in patients with endometriosis. Further studies in larger populations would be needed to accurately assess treatment effects. Clinical Trial Registration Number: NCT03573336.

In mares resistant to endometrial infection, periovulatory treatment with ecbolic drugs does not influence uterine clearance or luteal development.

We aimed to determine associations between experimentally impaired uterine clearance or treatment with ecbolic drugs on luteal development in estrous mares after insemination. In a crossover design, eight mares were treated with saline (CON), clenbuterol (CLEN), oxytocin (OXY) and carbetocin (CARB) from the day of first insemination until 2 days after ovulation. Between treatments, the mares rested for one cycle. Estrous mares were examined for the presence of free intrauterine fluid by transrectal ultrasound. Endometrial swabs for cytology and bacteriology were collected on days 1 and 14. Blood samples were collected daily before AI until day 14 after ovulation for determination of progesterone and PGF2α metabolites (PGFM). Differences between treatments were compared by a general linear model for repeated measures (SPSS 29). One mare was excluded because of a uterine infection in the control cycle. In all other mares, only minor amounts of free intrauterine fluid were present after insemination and decreased over time (P<0.05) with no treatment x time interaction. There was no effect of treatment on polymorphonucleated cells (PMN) in endometrial cytology after ovulation or PGFM secretion. Progesterone release from day 1-14 as well as pregnancy rate and conceptus size on day 14 was not influenced by treatment. In conclusion, treatment with clenbuterol does not impair uterine clearance in estrous mares resistant to endometritis. Repeated injection of the oxytocin analogue carbetocin during the early postovulatory period is not detrimental to corpus luteum function and can be recommended to enhance uterine clearance.

Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? SUMMARY ANSWER: EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). WHAT IS KNOWN ALREADY: EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. STUDY DESIGN SIZE DURATION: A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. PARTICIPANTS/MATERIALS SETTING METHODS: The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). LIMITATIONS REASONS FOR CAUTION: Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. WIDER IMPLICATIONS OF THE FINDINGS: In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. STUDY FUNDING/COMPETING INTERESTS: H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. REGISTRATION NUMBER: PROSPERO CRD42022378464.

Krüppel-like factor 12 decreases progestin sensitivity in endometrial cancer by inhibiting the progesterone receptor signaling pathway.

OBJECTIVE: This study aimed to clarify the mechanism by which Krüppel-like factor 12 (KLF12) affects progesterone sensitivity in endometrial cancer (EC) through the progesterone receptor PGR signaling pathway. METHODS: The relationship of KLF12 with PGR in EC patients was examined by immunohistochemistry, and the expression of KLF12 and PGR in EC cell lines was detected by real-time PCR and western blotting. Cell proliferation assay, plate clone formation, cell apoptosis assay, and cell cycle analysis were conducted to determine the impact of KLF12 intervention on progesterone therapy. CUT&Tag analysis and the dual-luciferase reporter experiment were used to determine the underlying regulatory effect of KLF12 on the PGR DNA sequence. A subcutaneous xenograft nude mouse model was established to validate the in vivo effect of KLF12 on progesterone sensitivity via PGR expression modulation. RESULTS: KLF12 demonstrated decreased progesterone sensitivity and a negative correlation with PGR expression in EC tissues. Progesterone sensitivity was increased by KLF12 deficiency through PGR overexpression, a result that could be significantly reversed by PGR downregulation. PGR was identified as a target gene of KLF12, which could directly bind to the PGR promotor region and inhibit its expression. CONCLUSION: This study is the first to investigate the effect of KLF12 expression on EC cell resistance to progesterone. Our results offer important mechanistic insight into the direct regulation of the PGR promoter region, demonstrating that KLF12 expression strongly suppressed the PGR signaling pathway and, as a result, reduced progesterone sensitivity in EC patients.

Progesterone and 17-hydroxy-progesterone concentrations in follicular fluid and serum reflect their production in granulosa and theca cells.

RESEARCH QUESTION: How is the production of progesterone (P4) and 17-hydroxy-P4 (17-OH-P4) regulated between theca cells and granulosa cells during the follicular phase, during ovulation and after transformation into a corpus luteum? DESIGN: Three cohorts were examined: (i) 31 women undergoing natural and stimulated cycles, with serum hormone measurements taken every 3 days; (ii) 50 women undergoing ovarian stimulation, with hormone concentrations in serum and follicular fluid assessed at five time points during final follicle maturation; and (iii) 12 women undergoing fertility preservation, with hormone concentrations evaluated via the follicular fluid of small antral follicles. RESULTS: In the early follicular phase, theca cells primarily synthesized 17-OH-P4 while granulosa cells produced limited P4, maintaining the P4:17-OH-P4 ratio <1. As follicles reached follicle selection at a diameter of approximately 10 mm, P4 synthesis in granulosa cells was up-regulated, but P4 was mainly accumulated in follicular fluid. During final maturation, enhanced activity of the enzyme HSD3B2 in granulosa cells enhanced P4 production, with the P4:17-OH-P4 ratio increasing to >1. The concentration of 17-OH-P4 in the luteal phase was similar to that in the follicular phase, but P4 production increased in the luteal phase, yielding a P4:17-OH-P4 ratio significantly >1. CONCLUSIONS: The P4:17-OH-P4 ratio reflects the activity of granulosa cells and theca cells during the follicular phase and following luteinization in the corpus luteum. Managing the function of granulosa cells is key for reducing the concentration of P4 during ovarian stimulation, but the concerted action of FSH and LH on granulosa cells during the second half of the follicular phase makes this complex.

Half of most frequently mutated genes in breast cancer are expressed differentially between premenopausal and postmenopausal breast cancer patients.

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.

The value of whole tumor apparent diffusion coefficient histogram parameters in predicting meningiomas progesterone receptor expression.

This letter provides a critical assessment of a previous study on the utility of whole tumor apparent diffusion coefficient (ADC) histogram characteristics in predicting meningioma progesterone receptor expression. While acknowledging the benefits of employing classical diffusion-weighted imaging (DWI) for non-invasive tumor evaluation, it also emphasizes significant drawbacks. Advanced imaging techniques such as diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) were not used in the study, which could have provided a more comprehensive understanding of tumor microstructure and heterogeneity. Furthermore, the inclusion of necrotic and cystic areas in ADC analysis may distort results due to their different diffusion properties. While focusing on first-order ADC histogram characteristics is useful, it ignores the potential insights gained from higher-order features and texture analysis. These limitations indicate that future research should combine improved imaging modalities with thorough analytical methodologies to increase the predictive value of imaging biomarkers for meningioma features and progesterone receptor expression.

Vaginal micronized progesterone on preventing luteinizing hormone untimely surge in ART cycles: A prospective proof-of-concept study.

OBJECTIVE: A new approach to evaluate whether Progestin-Primed Ovarian Stimulation with micronized vaginal progesterone was as effective as using dydrogesterone in suppress LH pulse surge in young women under stimulation in an oocyte donor programme. METHODS: This prospective study included 21 patients aged 19 to 32 years-old stimulated with Elonva® 150, associated or not with Menopur® or Merional® (75 or 150IU) since the beginning of the cycle, plus HMG 150-225IU after the 8th day or just HMG 150-300IU per day. Patients were placed in a PPOS protocol with micronized vaginal progesterone (MVP) 200 mg (Gynpro® Exeltis or Junno Farmoquimica) every 12 hours or dydrogesterone (Duphaston® Abbott) 10 mg every 8 hours from the start of stimulation until the day after the GnRH trigger with Triptorelin 0.2 mg (Gonapeptyl daily®). The primary endpoint was the prevention of untimely LH surge, and secondarily the number of 16 mm follicles, retrieved oocytes and metafase II. RESULTS: Fourteen oocyte donor patients were prescribed MVP while seven others received dydrogesterone (DYG).The gonadotropin protocols included 04 with Corifollitropin alfa 150 plus HMG since the beginning and complemented after the 7th day, and 17 times of just HMG. There was no diferences in the number of follicles >10≤15mm, ≥16mm or number of metafase II oocytes. There was no untimely LH surge on both groups and no OHSS was developed after the agonist trigger. CONCLUSIONS: Progestin-Primed Ovarian Stimulation with micronized vaginal progesterone seems to be a compelling choice for preventing premature ovulation without compromising oocyte quality in women undergoing ovarian stimulation.

Minimal influence of the menstrual cycle or hormonal contraceptives on performance in female rugby league athletes.

We examined performance across one menstrual cycle (MC) and 3 weeks of hormonal contraceptives (HC) use to identify whether known fluctuations in estrogen and progesterone/progestin are associated with functional performance changes. National Rugby League Indigenous Women's Academy athletes [n = 11 naturally menstruating (NM), n = 13 using HC] completed performance tests [countermovement jump (CMJ), squat jump (SJ), isometric mid-thigh pull, 20 m sprint, power pass and Stroop test] during three phases of a MC or three weeks of HC usage, confirmed through ovulation tests alongside serum estrogen and progesterone concentrations. MC phase or HC use did not influence jump height, peak force, sprint time, distance thrown or Stroop effect. However, there were small variations in kinetic and kinematic CMJ/SJ outputs. NM athletes produced greater mean concentric power in MC phase four than one [+0.41 W·kg-1 (+16.8%), p = 0.021] during the CMJ, alongside greater impulse at 50 ms at phase one than four [+1.7 N·s (+4.7%), p = 0.031] during the SJ, without differences between tests for HC users. Among NM athletes, estradiol negatively correlated with mean velocity and power (r = -0.44 to -0.50, p < 0.047), progesterone positively correlated with contraction time (r = 0.45, p = 0.045), and both negatively correlated with the rate of force development and impulse (r = -0.45 to -0.64, p < 0.043) during the SJ. During the CMJ, estradiol positively correlated to 200 ms impulse (r = 0.45, p = 0.049) and progesterone to mean power (r = 0.51, p = 0.021). Evidence of changes in testing performance across a MC, or during active HC use, is insufficient to justify "phase-based testing"; however, kinetic or kinematic outputs may be altered in NM athletes.

Effects of dietary supplementation with benthic diatom Amphora coffeaeformis on blood biochemistry, steroid hormone levels and seed production efficiency of Nile tilapia Oreochromis niloticus broodstock.

Aquafeed additive quality and quantity remain pivotal factors that constrain the sustainability and progress of aquaculture feed development. This study investigates the impact of incorporating the benthic diatom Amphora coffeaeformis into the diet of Nile tilapia (Oreochromis niloticus) broodstock, on the blood biochemistry, steroid hormone (SH) levels and seed production efficiency. Broodstock females displaying mature ovary indications were initially combined with males at a ratio of three females to one male. A total of 384 adult Nile tilapia (288 females and 96 males) were used, with 32 fish (24 females and eight males) assigned to each of 12 concrete tanks (8 m³; 2 m × 4 m × 1 m), with three replicate tanks for each dietary treatment, throughout a 14-day spawning cycle until egg harvest. Fish were fed one of four different dietary treatments: AM0% (control diet), and AM2%, AM4% and AM6% enriched with the diatom A. coffeaeformis at levels of 20, 40 and 60 g/kg of diet respectively. At the trial's conclusion, total protein, albumin, triglyceride and creatinine), SHs (follicle-stimulating hormone, luteinizing hormone, free testosterone, total testosterone, progesterone and prolactin) and seeds production efficiency of Nile tilapia improved significantly (p < 0.05) in alignment with the increment of A. coffeaeformis supplementation. The findings propose that including A. coffeaeformis at levels ranging from 4% to 6% could be effectively employed as a feed additive during the Nile tilapia broodstock's spawning season.