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The cyclical changes in sex hormones across the menstrual cycle (MC) are associated with various biological changes that may alter resting metabolic rate (RMR) and body composition estimates. Hormonal contraceptive (HC) use must also be considered given their impact on endogenous sex hormone concentrations and synchronous exogenous profiles. The purpose of this study was to determine if RMR and dual-energy X-ray absorptiometry body composition estimates change across the MC and differ compared with HC users. This was accomplished during a 5-week training camp involving naturally cycling athletes (n = 11) and HC users (n = 7 subdermal progestin implant, n = 4 combined monophasic oral contraceptive pill, n = 1 injection) from the National Rugby League Indigenous Women's Academy. MC phase was retrospectively confirmed via serum estradiol and progesterone concentrations and a positive ovulation test. HC users had serum estradiol and progesterone concentrations assessed at the time point of testing. Results were analyzed using general linear mixed model. There was no effect of MC phase on absolute RMR (p =.877), relative RMR (p =.957), or dual-energy X-ray absorptiometry body composition estimates (p >.05). There was no effect of HC use on absolute RMR (p =.069), relative RMR (p =.679), or fat mass estimates (p =.766), but HC users had a greater fat-free mass and lean body mass than naturally cycling athletes (p =.028). Our findings suggest that RMR and dual-energy X-ray absorptiometry body composition estimates do not significantly differ due to changes in sex hormones in a group of athletes, and measurements can be compared between MC phases or with HC usage without variations in sex hormones causing additional noise. [ABSTRACT FROM AUTHOR]

Introduction: Steroid hormones are widely present in the environment and pose potential risks to organisms. Previous studies of steroid hormones have predominantly focused on terrestrial environments, with few studies conducted in marine environments. Methods: In this study, we analyzed the occurrence of 44 steroid hormones in seawater, sediment, and marine organisms collected from the coast of Guangdong, China. Results: Total concentration of steroid hormones ranged from 0.11 to 30.15 ng/L in seawater, ND to 8.58 ng/g (dw) in sediments, and ND to 80.52 ng/g (ww) in organisms. The highest average concentrations of steroid hormones detected in seawater, sediments, and marine organisms were progestins, estrogens, and glucocorticoids, respectively. Steroid hormone concentrations in seawater were significantly higher during the dry season than the rainy season. The concentrations of steroid hormones in Guanghai Bay, the Pearl River Estuary, Daya Bay, and Zhelin Bay were significantly higher than those in other bays. Discussion: Negative correlations were observed between steroid hormones and salinity, indicating a potential continental input. Risk assessment results indicated that 17α-ethinylestradiol in Zhelin Bay posed high risks. Nevertheless, the consumption of seafood does not pose a significant health risk to humans. To the best of our knowledge, this is the first study to concurrently analyze androgens, glucocorticoids, progestins, and estrogens in water, sediment, and organisms from diverse marine environments. [ABSTRACT FROM AUTHOR]

Progestogens' anti-anxiety and anti-depressive effects and mechanisms are not well-understood. Progestogens are hypothesized to have anti-anxiety and anti-depressive effects on behavior, independent of actions at nuclear progestin receptors (NPRs) and dependent on allopregnanolone (5α-pregnan-3α-ol-20-one; 3α,5α-THP), a 5α-reduced, neuroactive metabolite of progesterone (P4). Adult c57 mice in behavioral estrus (proestrus; pro) showed more anti-anxiety-like and anti-depressant-like behavior and higher levels of estradiol (E2), P4, and allopregnanolone in the hippocampus/amygdala complex. Proestrus c57 > 5α-reductase knockout (5αRKO) mice made more central entries in an open field than diestrus c57 and 5αRKO mice that were not different. Ovariectomized (OVX) c57 mice administered 1, 2, or 4 mg/kg P4 SC showed dosage-dependent increases in central entries in an open field (more anti-anxiety-like behavior); 5αRKO mice had maximal increases at 1–2 mg/kg P4. OVX c57 and 5αRKO mice showed maximum increases in central entries with SC 3α,5α-THP (4 mg/kg), and c57s showed a similar maximal response to P4 (4 mg/kg), but 5αRKOs response was half at that dosage. P4 (4 mg/kg SC to OVX c57 or progestin receptor knockout (PRKO) mice decreased immobility (depression-like behavior) in the forced swim task. Effects of E2 and veh were similar in both groups. Levels of 3α,5α-THP in the hippocampus/amygdala were consistent with effects on central entries in the open field. Levels of brain-derived neurotrophic factor (BDNF) in the hippocampus/amygdala were greater among E2-primed (0.09 mg/kg, SC) vs vehicle-administered mice. In sum, adult female mice can be responsive to P4 for anti-anxiety/anti-depressant-like behavior; such effects may be independent of NPRs but require 5α-reduction and E2's priming actions at BDNF in the hippocampus/amygdala complex. [ABSTRACT FROM AUTHOR]

On 19 July, 2024, at the age of almost 105 years, Joseph W. Goldzieher, the last survivor of the group of pioneers who created oral contraception, peacefully passed away. Here we briefly reconstruct the salient points in his long, productive life, and highlight his achievements in the development of hormonal contraception. His work is indissolubly enshrined in the complex history of hormonal contraception, from the first, fundamental observations, to the first clinical trials, both in the form of combined oestrogen-progestin oral pills and long-acting injectable contraceptives. After Pincus and his Group created an oral contraceptive containing an oestrogen and a progestin, Goldzieher was the second international scientist to conduct clinical trials of the new modality. He teamed-up with investigators in Mexico creating a fruitful, long-lasting collaboration. They produced evidence that ovulation inhibition could be achieved with all the progestins used at the time. Of importance, he was among the first to explore the possibility of using oestrogens to block ovulation, and developed the concept of sequential contraception. For all this lifetime of work, we believe he deserves to be named a 'giant in reproductive endocrinology'. [ABSTRACT FROM AUTHOR]

Purpose: In trans people undergoing feminizing hormone therapy, optimal estradiol concentrations are unclear, and anecdotally, some individuals desire supraphysiologic estradiol concentrations. We aimed to assess associations between estradiol concentration and psychological distress, well-being, and dysphoria. Second, we aimed to explore relationships between estradiol concentration and the risk of medical conditions potentially associated with estradiol therapy. Methods: This exploratory online cross-sectional study was conducted between June 2020 and March 2021, using a nonprobability snowball sampling method. Inclusion criteria included the following: (1) Currently living in Australia, (2) identification as transgender and using estradiol for gender affirmation purposes, and (3) 16 years of age or older. Estradiol concentrations were correlated with the Kessler Psychological Distress Scale (K10), the Personal Wellbeing Index (PWI-A), and gender dysphoria as measured by the Gender Congruence and Life Satisfaction Scale. Results: There were 172 participants, and the median estradiol concentration was 420 pmol/L (interquartile range 269–614). No clinically significant association was found between estradiol concentration with psychological distress, wellbeing, or gender dysphoria. While there was a statistically significant lower K10 score and higher PWI-A General Life Satisfaction score with higher estradiol concentrations, the order of magnitude was small and not clinically significant. There was no association between estradiol concentration and thrombosis, malignancy, stroke, myocardial infarction, migraine, or hypertension. Conclusions: Given no clear association between higher estradiol concentrations, psychological distress, wellbeing, or dysphoria, approaches to estradiol hormone therapy should be individualized. Further prospective research, with larger sample sizes, is required to more thoroughly investigate optimal feminizing hormone therapy regimens. [ABSTRACT FROM AUTHOR]

Background and Purpose Method Results Conclusions Chlormadinone acetate (CMA) is a synthetic progestin for which cases of intracranial meningioma have been reported following prolonged exposure.An observational cohort study was conducted based on the French national health data system. Women aged 10‐70 years and who started CMA between 2007 and 2017 were included. Participants were considered to be exposed if they had received a cumulative dose >360 mg of CMA during the first 6 months and very slightly exposed (control group) when they had received a cumulative dose ≤360 mg. The outcome was surgery or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma.In total, 828,499 women were included: 469,976 in the exposed group (mean age 39.1 years, SD 10.1) and 358,523 in the control group (38.3 years, SD 11.0). Surgery or radiotherapy for intracranial meningioma between 2007 and 2017 was recorded for 164 and 104 women in the exposed and control groups, respectively. The incidence of meningioma was 18.5 and 6.8 per 100,000 person‐years for the exposed and control groups respectively (crude RR = 2.7, 95% confidence interval [CI] 2.1–3.5; age‐adjusted RR = 3.1, 95% CI 2.4–4.0). Meningioma incidence reached almost 47 cases/100,000 person‐years in the most exposed group (>8.64 g), giving an age‐adjusted RR of 6.9, 95% CI 5.1–9.2, relative to the control group.A strong dose–effect relationship was observed between prolonged use of CMA and risk of meningiomas. As with other progestogens, meningiomas associated with CMA are more likely to be found at the base of the skull. [ABSTRACT FROM AUTHOR]

Breakthrough bleeding (BTB) is a common side effect of hormonal contraception and is thought to impact adherence to combined oral contraceptives (COCs) but respective dose–response relationships are not yet fully understood. Therefore, the objective of this model‐based meta‐analysis (MBMA) was to establish dose–response for COCs containing different progestin/EE combinations using BTB as the pharmacodynamic endpoint. Data from 25 studies containing BTB information of 4 progestins (desogestrel, drospirenone, gestodene, and levonorgestrel) in combination with ethinyl estradiol (EE) at various dose levels was used for this analysis. The results of our MBMA show that BTB is significantly increased upon initiation of COC use but subsides over time. The time needed for BTB to return to baseline depends on the EE dose and differs marginally between progestins during the initial months of use at the same EE dose. BTB typically returns to baseline within 3 months at the highest (30 μg) dose, whereas it can take significantly longer to reestablish a regular bleeding pattern at lower EE doses (15 and 20 μg), irrespective of the progestin used. The dose–response relationships established for BTB across different progestin/EE combinations can now be used to support the selection of optimal COC dosing/treatment regimens and serve as the scientific basis for evaluating the impact of clinically relevant factors, including drug–drug interactions and demographics, on BTB. [ABSTRACT FROM AUTHOR]

Dysmenorrhea is one of the most common gynecological disorders, which significantly worsens the quality of life of women of reproductive age. A characteristic manifestation of primary dysmenorrhea is painful spasms in the lower abdomen, which appear shortly before or at the beginning of menstruation and accompany its course in the absence of organic pathology of the pelvic organs. Among women of early reproductive age, the prevalence of dysmenorrhea is about 65%, and about 20% of women complain on the onset of its manifestations in adolescence, which has an extremely negative impact on the quality of life. The objective: to determine the effectiveness of magnesium preparations in the complex treatment of patients of early reproductive age with primary dysmenorrhea. Materials and methods. 51 women aged 18-24 years with clinical manifestations of primary dysmenorrhea were examined. They were divided into the main group and the comparison group at the stage of therapy. Women in the main group received a combined estrogen-gestagen drug containing 20 mcg of ethinyl estradiol and 3 mg of drospirenone, in a cyclic regimen (24+4) in combination with a drug containing the chelated form of marine magnesium "Simag 55" 272 mg (purified natural marine mineral extract of magnesium) with two carriers (vitamin B6 - 2.7 mg and orotic acid - 25 mg) to ensure the highest bioavailability. The second drug was prescribed twice a day in the form of oral capsules for three months with a break of 3 months for 1 year. In order to assess the effectiveness of the proposed therapy all women filled out a visual analog scale (VAS) and underwent testing on the "WAM" scale on the first-second day of menstruation in the 1st, 6th and 12th months from the start of treatment. Results. The study of the intensity of menstrual pain according to VAS after 12 months from the start of treatment established an extremely weak intensity of pain (0-1 point) in the majority of patients in the main group - 16 (59.3%) (comparison group - 8 (33.3%); p < 0.05). In other women in the main group - 11 (40.7%) and the comparison group - 13 (54.2%), a weak intensity of menstrual pain was observed, the number of its cases did not have a significant difference (p > 0.05). After 12 months from the start of treatment on the background of a significant decrease in pain intensity, women in the main group indicated an average number of points that significantly exceeded the average number of points after 6 months from the beginning of treatment and the average number of points in women of the comparison group, for the block "Well-being" (the main group after 12 months from the beginning of treatment - 6.1±0.3 points and after 6 months from the beginning of treatment - 5.3±0.3 points, the comparison group - 5.2 ± 0.2 points; p < 0.05), the block "Activity" (the main group after 12 months from the beginning of treatment - 6.6 ± 0.2 points and after 6 months from the beginning of treatment - 5.7±0.2 points, the comparison group - 5.5±0.3 points; p<0.05). This led to an increased average number of points for the "Mood" block (the main group after 12 months from the start of treatment - 7.1 ± 0.2 points and after 6 months from the start of treatment - 6.3 ± 0.3 points, the comparison group - 6.5 ± 0.2 points; p > 0.05). Conclusions. The use of the drug with the chelated form of marine magnesium "Simag 55" as part of the combined treatment for a year in patients of early reproductive age with primary dysmenorrhea leads to a significantly faster decrease in the intensity of menstrual pain was established from severe (6-8 points on VAS) - 17 cases (63.0%) and unbearable (8-10 points on VAS) - 10 (37.0%) to extremely weak (0-1 point on VAS) - 16 (59.3%) and weak (2-4 points on VAS) - 11 (40.7%) against the background of significantly better results according to the "WAM" questionnaire (block "Well-being": the 1st month from the start of treatment - 2.1 ± 0.2 points, the 12th month from the start of treatment - 6.1 ± 0.3 points; block "Activity": the 1st month from the start of treatment - 1.8 ± 0.3 points, the 12th month from the start of treatment - 6.6 ± 0.3 points; block "Mood": the 1st month from the start of treatment - 2.0 ± 0.2 points, the 12th month from the start of treatment - 7.1 ± 0.2 points). The combined use of the drug, which includes magnesium "Simag 55" with combined estrogen-gestagen drugs is effective in the treatment of primary dysmenorrhea in patients of early reproductive age who do not have reproductive plans. [ABSTRACT FROM AUTHOR]

Oestrogen is considered by many to be a major cause of breast cancer, and yet hormonal contraception and menopausal hormonal therapy have a paradoxically small effect on breast cancer risk. Also, in the oestrogen‐only arm of the Women's Health Initiative, subjects given oestrogen had a reduced risk of breast cancer compared to controls. Initiation of breast cancer likely begins early in life, in the long‐lived ER−PR− breast stem cell. The main mitogen of ER+PR+ breast cancers is oestrogen derived from local breast fat and the tumour itself, rather than circulating oestrogens. Progesterone is relatively breast neutral, but progestins in the laboratory have been shown to expand malignant breast stem cell number. [ABSTRACT FROM AUTHOR]

Progestin-only pills (POPs) have emerged as a crucial contraceptive option for women, particularly those contraindicated to oestrogens. This opinion paper introduces two new indices, the Inhibition Ratio (I.R.) (cyclical and daily) and the Transformation Index (T.I.), to evaluate and compare the efficacy and clinical behaviour of modern POPs. The I.R. quantifies the ratio between the progestin dosage in a POP and the minimum dose required to inhibit ovarian function, providing insights into contraceptive efficacy. The T.I., on the other hand, assesses its clinical impact by considering the ratio between the total progestin dose and the dose required to induce endometrial luteinising changes. Both indices thus offer valuable tools for comparing progestins even at significantly different dosages and regimens, providing information on clinical characteristics and drug effects. The newest formulations of POPs (Desogestrel 28 and Drospirenone 24 + 4) have demonstrated higher I.R. and T.I. in comparison to older versions, indicating significant improvements in contraceptive efficacy and clinical impact with better menstrual cycle control. We believe that using these indices will ensure a more informed and personalised choice of progestin not only for contraceptive purposes but also for therapeutic use in gynaecology. The future goal is to develop other progestins with even more advantageous I.R. and T.I., ensuring the best contraceptive efficacy with fewer side effects, even in women at risk (obese, etc.). SHORT CONDENSATION: The Inhibition Ratio (I.R.) (cyclical and daily) and the Transformation Index (T.I.) are two new proposed indexes to evaluate and compare the efficacy and clinical behaviour of modern and future POPs. [ABSTRACT FROM AUTHOR]

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice. [ABSTRACT FROM AUTHOR]

Adenomyosis is a common gynaecological condition that can cause pelvic pain, heavy menstrual bleeding and adverse reproductive outcomes in reproductive-aged women. Hysterectomy remains the definitive treatment for adenomyosis. However, given the young age of patients at presentation, there is growing interest in fertility-preserving medical treatments. Medical management mainly involves the levonorgestrel-releasing intrauterine system (LNG-IUS), dienogest, oral contraceptives and gonadotropin-releasing hormone (GnRH) agonists. Progestins (LNG-IUS and dienogest) and GnRH agonists can be considered as first- and second- line therapies, respectively, to manage symptoms. Treatments with novel targets are being explored for adenomyosis, but these need further investigation. [ABSTRACT FROM AUTHOR]

Dysmenorrhea treatment with 0.5 mg dienogest tablets twice daily (1 mg/day) has proven useful, but its effect on premenstrual disorders has not yet been evaluated. This study aimed to evaluate the efficacy of 0.5 mg dienogest tablets in relieving premenstrual syndrome (PMS)-like symptoms during the treatment of dysmenorrhea in comparison with that of continuous low-dose estrogen–progestin (LEP/COC) drospirenone/ethinylestradiol combination, which is considered effective in treating premenstrual dysphoric disorder. During the standard course of dysmenorrhea treatment with dienogest or LEP/COC, PMS-like symptoms were scored based on patients' reports, and the treatment effects were compared. As a result, the dienogest group experienced a significant improvement in PMS-like symptoms compared with the LEP/COC group over the 6-month study period (p < 0.01). Furthermore, dienogest was more effective in providing relief from PMS-like symptoms, with 89.7% of patients reporting a complete resolution of PMS-like symptoms at 6 months, compared with 47.1% in the LEP/COC group (p < 0.01). These results indicate that dienogest is effective in relieving PMS-like symptoms, similar to LEP/COC. Further studies are needed to determine whether 0.5 mg dienogest tablets, which are only available in Japan, are effective in treating premenstrual disorders diagnosed via standard methods. [ABSTRACT FROM AUTHOR]

Introduction: Clinical practice guidelines provide inconsistent recommendations regarding progestogen supplementation for threatened and recurrent miscarriage. We conducted a systematic review and meta‐analysis to assess the effectiveness and safety of progestogens for these patients. Material and methods: We searched Medline, Embase, and Cochrane Central Registry of Controlled Trials up to October 6, 2023 for randomized control trials (RCTs) comparing progestogen supplementation to placebo or no treatment for pregnant women with threatened or recurrent miscarriage. We assessed the risk of bias using a modified version of the Cochrane risk‐of‐bias tool and the certainty of evidence using the GRADE approach. Results: Of 15 RCTs (6616 pregnancies) reporting on threatened or recurrent miscarriage, 12 (5610 pregnancies) reported on threatened miscarriage with or without a prior history of miscarriage. Results indicated that progesterone probably increases live births (relative risk (RR) 1.04, 95% confidence interval (CI) 0.99–1.10, absolute increase 3.1%, moderate certainty). Of these RCTs, three (1973 pregnancies) reporting on threatened miscarriage with a prior history of miscarriage indicated that progesterone possibly increases live births (RR 1.06, 95% CI: 0.97–1.16, absolute increase 4.4%; low certainty), while four (2540 pregnancies) reporting on threatened miscarriage and no prior miscarriage left the effect very uncertain (RR 1.02, 95% CI: 0.96–1.10, absolute increase 1.7%; very low certainty). Three trials reporting on 1006 patients with a history of two or more prior miscarriages indicated progesterone probably increases live births (RR 1.08, 95% CI: 0.98–1.19, absolute increase 5.7%, moderate certainty). Six RCTs that reported on 2979 patients with at least one prior miscarriage indicated that progesterone probably increases live births (RR 1.07, 95% CI: 1.01–1.13, absolute increase 5.0%; moderate certainty). Progesterone probably has little or no effect on congenital anomalies (RR 1.06, 95% CI: 0.76–1.48, absolute increase 0.1%; moderate certainty), and other serious adverse pregnancy events (RR 1.07, 95% CI: 0.83–1.40, absolute increase 0.2%, moderate certainty). Conclusions: In women at increased risk of pregnancy loss, progestogens probably increase live births without increasing adverse maternal and neonatal events. It remains possible that the benefit is restricted to those with prior miscarriages. [ABSTRACT FROM AUTHOR]

A five-year-old female cat (Felis catus), of no specific breed, nulliparous, was referred to the JuliPet veterinary clinic in the municipality of Fortaleza-CE. The cat presented with an enlargement of the mammary chain, exhibiting ulcerated lesions with purulent exudation distributed bilaterally, with a history of contraceptive use. Histopathological analysis diagnosed the patient with feline mammary hyperplasia (FMH), a condition characterized by a rapid enlargement of one or more mammary glands and commonly associated with the use of exogenous progestogens. Consequently, performing ovariohysterectomy in young females prevents the occurrence of reproductive and mammary pathologies. The present study aims to describe the anesthetic protocol used for the surgical removal of the right and left mammary chains, along with the ulcerated tumor. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of dienogest treatment on endometrioma (OMA) size, serum anti-Mullerian hormone (AMH) levels and associated pain over a 12-month follow-up period. Material and Methods: A longitudinal cohort study of 104 patients with OMA who were treated with dienogest, between January 2017 and January 2020. Of the included patients, each had a 12-month follow-up period with transvaginal or pelvic ultrasound and measurement of serum AMH concentration at the sixth and twelfth months of follow-up. The alteration in OMA size in the sixth and twelfth months of treatment was the primary outcome measure and the alteration in AMH concentration over the same period was the secondary outcome measure. The only exclusion criterion was having surgical intervention for OMA during the follow-up period (n=44). In patients with bilateral OMA (n=21), the change in size of the largest OMA was considered in the analysis. Results: A total of 60 patients with a mean ± standard deviation (SD) age of 31.5±8.0 years were included. The mean ± SD OMA size on the day the dienogest was started was 46.3±17.4 mm and the mean AMH level was 3.6±2.4 ng/mL. After six months, the mean OMA size had decreased to 38.6±14.0 mm, with a median difference of 7.8 mm [95% confidence interval (CI): 3.0 to 12.6; p=0.003]. The mean AMH level was 3.3±2.7 ng/mL at 6 months follow-up (95% CI: -0.2 to 0.8; p=0.23) and the average difference was 0.3 ng/mL. At the 12th-month visit, when compared with the beginning of the treatment, OMA size had again significantly decreased by a median of -8.9 mm (95% CI: -2.9 to -14.9; p=0.005), and the decline in median AMH was also significant (-0.9 ng/mL, 95% CI: -0.1 to -1.7; p=0.045). The initial mean ± SD visual analog scale pain score at the commencement of dienogest treatment was 6.3±3.4. The mean values at the sixth and twelfth months of dienogest therapy were 1.08±1.8 and 0.75±1.5, respectively (both p<0.001 compared to baseline). Conclusion: At the sixth and twelfth months of dienogest treatment a significant decrease in OMA size and reported pain scores were observed, whereas the AMH concentrations did not change significantly. [ABSTRACT FROM AUTHOR]

Purpose: To assess metformin's effectiveness in adding it to progestin-based hormone therapy for treating atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC). Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines (registration number CRD42023399094). We searched databases for studies up to March 2023, including randomized and non-randomized clinical trials in English. Results: Out of 280 studies, 9 studies (1104 patients) were eligible. A total of 408 patients were allocated to receive metformin, and 696 patients entered the control group. Primary analysis focused on evaluating the CR showed a significant difference in patients with AEH treated with metformin (RR = 1.10, 95% CI 1.02−1.20, p = 0.02). Relapse rate (RR = 0.62, 95% CI 0.33−1.17, p = 0.14) was also evaluated. Secondary analysis indicated higher pregnancy rates (RR = 1.28, 95% CI 1.04−1.57, p = 0.02) with no significant difference in live birth rates (RR = 0.56, 95% CI 0.29−1.10, p = 0.09). Conclusion: Combined therapy is effective. Metformin shows superiority to the standard regimen in achieving better CR rate in patients with AEH and benefits pregnancy rates but not recurrence or live birth rates. Therefore, the ideal fertility-sparing treatment for EC has not yet been determined and further clinical trials are needed. [ABSTRACT FROM AUTHOR]

The article offers information on the potential link between progestins and the development of central nervous system meningiomas. Topics include the controversial role of various progestins in meningioma growth, the specific high-dose progestins implicated in this relationship, and the findings of a case-control study conducted using data from the French national health system.

Concerns are growing about adverse effects of progestins on biota, even at ultra-trace concentrations. The enrichment factor (EF) from extraction of analytes in environmental samples that is needed for sample pre-concentration can affect not only performance of the analytical method but also the matrix effect. Therefore, the present study aimed to assess the influence of high sample EF on performance of the high-performance liquid chromatography with atmospheric pressure chemical ionization and photoionization coupled with high-resolution mass spectrometry (HPLC-APCI/APPI-HRMS) method for analysis of progestins in waste water treatment plant (WWTP) effluents and surface waters and analysis of (anti-)progestogenic activities measured by (anti-)PR-CALUX bioassays. The results showed that HPLC-APCI/APPI-HRMS coupled with solid-phase extraction and a high EF (33,333 Lwater/Lextract) enabled the detection of more compounds compared to samples with lower sample EF (10,000 Lwater/Lextract). The matrix effect did not increase proportionally compared to lower EFs (10,000 and 16,666 Lwater/Lextract), and lower limits of quantification were achieved in WWTP effluents and surface waters. The results of bioassays have shown that relative EF of 25 Lwater/Lbioassay appears high enough to detect progestogenic activity in treated waste water. Our study is one of the first to provide insights into sample pre-concentration in analysis of progestins and progestogenicity in aquatic environments. [ABSTRACT FROM AUTHOR]

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The article presents a case study of a 34-year-old woman seeking counseling about the first over-the-counter progestin-only oral contraceptive (Opill). It discusses her medical history, including a previous deep vein thrombosis (DVT) and her preference for avoiding intra-uterine devices (IUDs) and progestin implants.

The article presents a case study of a 34-year-old woman seeking counseling about the first over-the-counter progestin-only oral contraceptive (Opill). It discusses her medical history, including a previous deep vein thrombosis (DVT) and her preference for avoiding intra-uterine devices (IUDs) and progestin implants.

Background: Almost 10% of women in reproductive age are diagnosed with ovarian endometriomas and can experience symptoms and infertility disorders. Ovarian endometriomas can be treated with medical or surgical therapy. Objective: To assess whether long-term therapy with dienogest or oral cyclic estrogen-progestogens is effective in reducing the size of ovarian endometriomas, alleviating associated symptoms, and reducing the requirement for surgery. Design: Prospective non-interventional cohort study. Methods: We enrolled childbearing women diagnosed with ovarian endometriomas. We collected demographic, clinical, and surgical data, including the evaluation of ovarian endometrioma-associated symptoms and pain using the visual analog scale. We grouped the women according to treatment regimen into dienogest, estrogen-progestogens, and no-treatment. Patient's assessment was performed at baseline and after 12 months evaluating the largest ovarian endometrioma diameter (in millimeters) and the associated symptoms. Furthermore, we analyzed the impact of hormonal treatment in a sub-group of women fulfilling at baseline the criteria for a first-line surgical approach (ovarian endometrioma > 30 mm with visual analog scale > 8 or ovarian endometrioma > 40 mm before assisted reproductive treatments or any ovarian endometrioma(s) > 60 mm). Results: We enrolled 142 patients: 62, 38, and 42 in dienogest, estrogen-progestogens, and no-treatment groups, respectively. No significant differences were found regarding baseline characteristics. After 12 months, the mean largest ovarian endometrioma diameter increased in the no-treatment group (31.1 versus 33.8; p < 0.01), while a significant reduction was registered in the dienogest (35.1 versus 25.8; p < 0.01) and estrogen-progestogens (28.4 versus 16.7; p < 0.01) groups; no significant difference in ovarian endometrioma diameter reduction between these two latter groups was noted (p = 0.18). Ovarian endometrioma-associated symptoms and pain improved in dienogest and estrogen-progestogens groups, with a significantly greater effect for dienogest than for estrogen-progestogens for dysmenorrhea (74% versus 59%; p < 0.01). In the sub-group of women eligible for first-line surgery at baseline, long-term treatment with dienogest and estrogen-progestogens reduced surgical eligibility by 30%. Conclusions: Decreased mean largest ovarian endometriomas'diameter after 12 months and reduction of the need for surgical treatment by 30% were observed in dienogest and estrogen-progestogens groups. Long-term treatment with dienogest had a greater effect in alleviating dysmenorrhea and pain. [ABSTRACT FROM AUTHOR]

Naked mole-rats (Heterocephalus glaber) live in large colonies with one breeding female (queen), one to three breeding males (BMs) and the remainder are non-reproductive subordinates. The animals have a linear dominance rank with the breeders at the top of the hierarchy. We investigated how dominance rank in naked mole-rats differs with exploration (the propensity to explore a novel environment) and related endocrine markers. Exploration behaviour, faecal progestagen metabolite (fPM), faecal glucocorticoid metabolite (fGCM), faecal androgen metabolite (fAM) and plasma prolactin concentrations were quantified in breeding, high-, middle- and low-ranked females and males from five naked mole-rat colonies. There were no significant differences between the dominance rank and exploration behaviour. Interestingly, the queens and high-ranking females had higher fGCM and fAM concentrations compared with middle- and low-ranked females. The queens had significantly higher fPM concentrations than all other ranked females, since they are responsible for procreation. In the males, the BMs had higher fGCM concentrations compared with high- and low-ranked males. In addition, BMs and middle-ranking males had overall higher prolactin levels than all other ranked males, which could be linked to cooperative care. Overall, the results suggest that physiological reproductive suppression is linked to high dominance rank. [ABSTRACT FROM AUTHOR]

Hormonal contraceptive (HC) users have a different ovarian hormonal profile compared to eumenorrheic women. Due to the prevalence of HC use amongst sportswomen, there has been increased research efforts to understand their impact on exercise performance. The aim was to audit this research. Studies identified were assessed for HC type, athlete calibre, performance outcome, study design, and quality of methodological control regarding ovarian hormonal profiles. Sixty-eight different HCs were reported across 61 studies. Monophasic combined oral contraceptive (OCP) pills represented 60% of HCs, followed by other pills [34%, phasic-combined, progestogen-only, and un-specified], phasic and long acting reversible contraceptives [5%, vaginal ring, patch, implant, injection, intrauterine system] and unspecified HCs (1%). Eleven percent of participants using HCs were classified as highly trained or elite/international with no participants being classed as world class. Whilst the number of studies involving HCs has increased two-fold over the past decade, the number of studies ranked as gold standard has not increased (HC; 2003–57%, 2011–55%, 2022–43%. OCP; 2003–14%, 2011–17%, 2022–12%). Future research assessing HCs and exercise performance should adopt high-quality research designs and include a broader range of HCs in highly trained to world-class populations to increase the reach and impact of research in this area. [ABSTRACT FROM AUTHOR]

Background We conducted a systematic review and meta-analysis to examine outcomes of patients with endometrial intraepithelial neoplasia treated with oral progestins or a levonorgestrel-releasing intrauterine device (IUD). Methods We conducted a systematic review across 5 databases to examine outcomes of progestational treatment (oral progestins or levonorgestrel-releasing IUD) for patients with endometrial intraepithelial neoplasia. The primary outcome was the best complete response rate within 12 months of primary progestational treatment. Sensitivity analyses were performed by removing studies with extreme effect sizes. Secondary outcomes included the pooled pregnancy rate. Results We identified 21 eligible studies, including 824 premenopausal patients with endometrial intraepithelial neoplasia, for our meta-analysis. Among these, 459 patients received oral progestin, and 365 patients received levonorgestrel-releasing IUD as a primary progestational treatment. The pooled best complete response proportion within 12 months was 82% (95% confidence interval [CI] = 69% to 91%) following oral progestin treatment and 95% (95% CI = 81% to 99%) following levonorgestrel-releasing IUD treatment. After removing outlier studies, the pooled proportion was 86% (95% CI = 75% to 92%) for the oral progestin group and 96% (95% CI = 91% to 99%) for the levonorgestrel-releasing IUD group, with reduced heterogeneity. The pooled pregnancy rate was 50% (95% CI = 35% to 65%) after oral progestin and 35% (95% CI = 23% to 49%) after levonorgestrel-releasing IUD treatment. Conclusions This meta-analysis provides data on the effectiveness of oral progestins and levonorgestrel-releasing IUD treatment within 12 months of treatment among premenopausal patients with endometrial intraepithelial neoplasia. Although based on small numbers, the rate of pregnancy after treatment is modest. These data may be beneficial for selecting progestational therapies that allow fertility preservation for patients with endometrial intraepithelial neoplasia. [ABSTRACT FROM AUTHOR]

Summary: Sheehan's syndrome (SS) is a rare but well-characterized cause of hypopituitarism. Data on skeletal health is limited and on microarchitecture is lacking in SS patients. Purpose: We aimed to explore skeletal health in SS with bone mineral density (BMD), turnover, and microarchitecture. Methods: Thirty-five patients with SS on stable replacement therapy for respective hormone deficiencies and 35 age- and BMI-matched controls were recruited. Hormonal profile and bone turnover markers (BTMs) were measured using electrochemiluminescence assay. Areal BMD and trabecular bone score were evaluated using DXA. Bone microarchitecture was assessed using a second-generation high-resolution peripheral quantitative computed tomography. Results: The mean age of the patients was 45.5 ± 9.3 years with a lag of 8.3 ± 7.2 years prior to diagnosis. Patients were on glucocorticoid (94%), levothyroxine (94%), and estrogen–progestin replacement (58%). None had received prior growth hormone (GH) replacement. BTMs (P1NP and CTX) were not significantly different between patients and controls. Osteoporosis (26% vs. 16%, p = 0.01) and osteopenia (52% vs. 39%, p = 0.007) at the lumbar spine and femoral neck (osteoporosis, 23% vs. 10%, p = 0.001; osteopenia, 58% vs. 29%, p = 0.001) were present in greater proportion in SS patients than matched controls. Bone microarchitecture analysis revealed significantly lower cortical volumetric BMD (vBMD) (p = 0.02) at the tibia, with relative preservation of the other parameters. Conclusion: Low areal BMD (aBMD) is highly prevalent in SS as compared to age- and BMI-matched controls. However, there were no significant differences in bone microarchitectural measurements, except for tibial cortical vBMD, which was lower in adequately treated SS patients. [ABSTRACT FROM AUTHOR]

To explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA) We describe 3 cases of adolescents and young adults who developed HA while on norethindrone (NET), as well as their management. In addition, we provide a comprehensive literature review on the association between progestins and HA. Since 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on NET and 5 on a prodrug of NET (4 on norethindrone acetate [NETA] and 1 on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: 4 experienced a size reduction, and 3 had complete resolution of their HA. Among our patients, 1 ceased NET and instead had a levonorgestrel intrauterine device inserted, and another swapped from NET to oral medroxyprogesterone acetate. Both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. These cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared with the levonorgestrel intrauterine device. There are no case reports relating to other forms of progestins, such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities. [ABSTRACT FROM AUTHOR]

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Background: Decidualization of endometrial cells is the prerequisite for embryo implantation and subsequent placenta formation and is induced by rising progesterone levels following ovulation. One of the hormone receptors contributing to endometrial homeostasis is Progesterone Receptor Membrane Component 1 (PGRMC1), a non-classical membrane-bound progesterone receptor with yet unclear function. In this study, we aimed to investigate how PGRMC1 contributes to human decidualization. Methods: We first analyzed PGRMC1 expression profile during a regular menstrual cycle in RNA-sequencing datasets. To further explore the function of PGRMC1 in human decidualization, we implemented an inducible decidualization system, which is achieved by culturing two human endometrial stromal cell lines in decidualization-inducing medium containing medroxyprogesterone acetate and 8-Br-cAMP. In our system, we measured PGRMC1 expression during hormone induction as well as decidualization status upon PGRMC1 knockdown at different time points. We further conferred proximity ligation assay to identify PGRMC1 interaction partners. Results: In a regular menstrual cycle, PGRMC1 mRNA expression is gradually decreased from the proliferative phase to the secretory phase. In in vitro experiments, we observed that PGRMC1 expression follows a rise-to-decline pattern, in which its expression level initially increased during the first 6 days after induction (PGRMC1 increasing phase) and decreased in the following days (PGRMC1 decreasing phase). Knockdown of PGRMC1 expression before the induction led to a failed decidualization, while its knockdown after induction did not inhibit decidualization, suggesting that the progestin-induced 'PGRMC1 increasing phase' is essential for normal decidualization. Furthermore, we found that the interactions of prohibitin 1 and prohibitin 2 with PGRMC1 were induced upon progestin treatment. Knocking down each of the prohibitins slowed down the decidualization process compared to the control, suggesting that PGRMC1 cooperates with prohibitins to regulate decidualization. Conclusions: According to our findings, PGRMC1 expression followed a progestin-induced rise-to-decline expression pattern during human endometrial decidualization process; and the correct execution of this expression program was crucial for successful decidualization. Thereby, the results of our in vitro model explained how PGRMC1 dysregulation during decidualization may present a new perspective on infertility-related diseases. [ABSTRACT FROM AUTHOR]

The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration was granted in 1960. However, it took several years to realize that OCs presented an important but not frequent risk of venous thrombosis. Several reports ignored this dangerous effect and only in 1967 the Medical Research Council clearly stated this as an important risk. Later, research led to the formulation of second-generation OCs containing progestins, which nevertheless presented an increased thrombotic risk. In early 1980s, OCs containing third-generation progestins were introduced into the market. Only in 1995, it became clear that these new compounds induced a higher thrombotic risk than that related to the second-generation progestins. It appeared clear that the modulating action of progestins was against the procoagulant activity of estrogens. Lastly, at the end of the 2000s, OCs containing natural estrogens and a fourth-generation progestin (dienogest) became available. The prothrombotic effect of those natural products was not different from that of preparations containing second-generation progestins. Moreover, research over the years has produced much data on risk factors associated with OCs use such as age, obesity, cigarette smoking, and thrombophilia. These findings allowed us to better assess the individual thrombotic risk (both arterial and thrombotic) of each woman before offering an OC. Furthermore, research has shown that in high-risk people the use of single progestin is not dangerous as far as thrombosis is concerned. In conclusion, the OCs road has been long and difficult but has led to a great and unthinkable scientific and social enrichment since the 1960s. [ABSTRACT FROM AUTHOR]

Objectives: Endocrinal variations within an individual impact the electrolyte composition, pH, and flow‐rate (FR) of saliva. The aim of this study was to evaluate the gender‐specific differences and the effect of combined estrogen‐progestin oral contraceptives (COCs) on FR, pH, and electrolyte concentrations in the parotid saliva (PS) of a group of healthy adults. Material and Methods: Stimulated PS was collected from 20 healthy adults using a Lashley cup; 11 males, 8 females, and 1 female undertaking combined contraceptive therapy (levonorgestrel/ethinyloestradiol 0.1 mg + 0.02 mg). FR and pH were recorded for each saliva sample. Electrolytes concentrations (Na+, Ca2+, K+, Mg2+) were measured using inductively coupled plasma optical emission spectrometer (ICP‐OES). Statistical analysis was performed, and the significance level was set at p <.05. Results: PS FR varied from 0.13 to 0.42 mL/min in females not taking any medication and from 0.08 to 0.5 mL/min in males not taking any medication. PS pH of females and males not taking any medication ranged from 6.23 to 7.50 and from 6.15 to 7.55. PS pH and FR of the female taking COCs were 6.5 and 0.1 mL/min. PS pH, FR, and electrolytes concentrations (Ca2+, Na+, K+, Mg2+) were not statistically significantly different between females and males not taking any medication. PS concentrations of Ca2+ and Na+ were significantly higher in the females taking COCs than in the females not taking any medication. Whereas, concentrations of K+ and Mg2+ did not differ significantly between the females taking COCs and the females not taking any medication. Conclusions: There are no significant gender‐specific differences in PS flow rate, pH, and electrolyte concentrations of Na+, Ca2+, Mg2+, and K+. Combined hormonal oral contraceptive has a significant effect on PS flow rate, pH, Ca2+, and Na+ concentrations. Whereas the PS concentration of K+ and Mg2+ are not influenced by COCs. These results warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Medical management of adenomyosis is an emerging perspective in modern gynecology. Though levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG) effectively relieve symptoms in adenomyosis, neither has been approved for the same indication. Our study aims to compare the efficacy and safety of these progestins in treating adenomyosis. Objective: To study the efficacy and safety of LNG-IUS versus DNG in patients with symptomatic adenomyosis. Design: Open-labeled, parallel, single-centered, randomized clinical trial. Methods: Patients with adenomyosis-associated pain with or without abnormal uterine bleeding were randomly allocated to either LNG-IUS group or DNG group. The primary outcome was a reduction in painful symptoms after 12 weeks of treatment measured by visual analog scale (VAS) score. Changes in menstrual blood loss (MBL), improvement in quality of life (QoL), and adverse drug reactions were also analyzed. Results: The VAS score significantly decreased from baseline in both groups. The baseline and post-treatment VAS scores in the LNG-IUS group were 6.41 ± 1.07 and 3.41 ± 1.04 (p = <0.001) and in the DNG group, were 6.41 ± 0.95 and 3.12 ± 1.40 (p = <0.001), respectively. A significantly greater proportion of patients in the LNG-IUS group experienced lighter MBL as compared to the DNG group [27/30 (90%) in the LNG-IUS group versus 17/22 (77.2%) in the DNG group (p = 0.006)]. Both the groups had improvement in QOL scores calculated by the World Heath Organisation QOL scale (WHOQOL BREF) questionnaire; however, it was more pronounced in the DNG group [(28.76 ± 30.47 in the LNG-IUS group versus 48.26 ± 44.91 in the DNG group (p = 0.04)]. Both the agents were safe as there were no reported major adverse drug reactions. Conclusion: DNG can be an effective and safe alternative to LNG-IUS for the medical management of adenomyosis. Trial registration: The trial was prospectively registered at the clinical trial registry – India (CTRI) vide CTRI number CTRI/2020/05/025186. Plain language summary: Comparison of effectiveness and safety of Mirena (LNG-IUS) with dienogest for treatment of adenomyosis Adenomyosis is a condition affecting women, typically aged 40–50, but its incidence is rising in younger women, impacting fertility. It causes painful symptoms like dysmenorrhea, dyspareunia, chronic pelvic pain, and heavy menstrual bleeding. Managing symptoms is crucial, and medical approaches include levonorgestrel intrauterine system (LNG-IUS) and dienogest (DNG). LNG-IUS is reversible contraception, approved for eight years, effectively treating symptoms. DNG, a newer progestin, is effective for endometriosis, but evidence for adenomyosis is limited. This single-center, open-label randomized clinical trial compared LNG-IUS and DNG in treating adenomyosis. Women over 20 with pelvic pain were diagnosed using ultrasound and met specific criteria. After informed consent, participants were assigned randomly to LNG-IUS or DNG groups. Treatment outcomes, including pelvic pain, quality of life (QoL), and adverse effects, were assessed over 12 weeks. Out of 84 assessed, 74 women were recruited, with 34 in each group analyzed. After 12 weeks, both groups showed significantly reduced pelvic pain (VAS scores), but no significant difference was found between the groups. LNG-IUS resulted in a significantly greater reduction in heavy menstrual bleeding (HMB), whereas DNG showed better improvement in overall QOL. Adverse effects were similar in both groups, with hot flushes reported in the DNG group. This study is one of the few comparing LNG-IUS and DNG for adenomyosis, finding both effective for symptom relief. Although LNG-IUS was superior in reducing HMB, DNG showed better overall improvement in QoL. Safety profiles were similar. Previous studies support the efficacy of DNG in reducing adenomyosis symptoms. To conclude, both LNG-IUS and DNG effectively alleviate adenomyosis symptoms, with LNG-IUS superior in reducing heavy menstrual bleeding and DNG showing better overall improvement in QOL. DNG is a viable and effective alternative to LNG-IUS. [ABSTRACT FROM AUTHOR]

This document provides recommendations for the use of hormonal contraceptives in women with systemic arterial hypertension (SAH). It emphasizes the importance of monitoring blood pressure regularly and considering the suspension of hormonal contraceptives if there is a significant increase in blood pressure. The document suggests using non-hormonal contraceptives, progestin-only pills, levonorgestrel intrauterine devices, and subdermal implants as safer alternatives. Further research is needed to understand the safety profiles of non-oral hormonal preparations in women with SAH. [Extracted from the article]

Context Although many physicians have been concerned that the menopausal hormones used currently in clinical practice may affect the risk of breast cancer, there are currently few informative updated studies about the associations between menopausal hormone therapy (MHT) and the risk of breast cancer. Objective This study aims to evaluate the association between the risk of breast cancer and MHT using the National Health Insurance Database in South Korea (HISK) cohort between 2002 and 2019 retrospectively. Methods Postmenopausal women over 40 years of age from 2003 to 2011 were selected as the subject population, and their follow-up data were collected until 2019. We analyzed the risk and mortality of breast cancer according to the type of MHT received, namely, tibolone, combined estrogen plus progestin by manufacturer (CEPM), oral estrogen, combined estrogen plus progestin by physician (CEPP), or topical estrogen. Results The risk of breast cancer increased in the CEPM group [hazard ratio (HR) 1.439, 95% CI 1.374-1.507, P -value <.001] in comparison with the non-MHT group. However, no significant associations were found between the use of tibolone, oral estrogen, CEPP, or topical estrogen and breast cancer risk in comparison with the non-MHT group (HR 0.968, 95% CI 0.925-1.012; HR 1.002, 95% CI 0.929-1.081; HR 0.929, 95% CI 0.75-1.15; HR 1.139, 95% CI 0.809-1.603). The mortality rate from breast cancer is lower in the MHT group in comparison with the non-MHT group, indicating that significant associations were found for tibolone, CEPM, and oral estrogen (HR 0.504, 95% CI 0.432-0.588; HR 0.429, 95% CI 0.352-0.522; HR 0.453 95% CI 0.349-0.588, P -value <.001). Conclusions This study suggests that the risk of breast cancer is increased by drugs in the CEPM group but not by tibolone, oral estrogen, CEPP, or topical estrogen. The mortality rate from breast cancer is lower with MHT (tibolone, CEPM, oral estrogen) than without MHT. [ABSTRACT FROM AUTHOR]

Obtaining endocrinological profiles using non-invasive methodologies by the measurement of hormone fecal metabolites is a widely used method to monitor ovarian activity and pregnancy in wild species. These tools allow the obtention of physiological information without causing capture-related stress on the individuals. In this research, we aimed to 1) biologically validate a non-invasive method to assess fecal progestagens and estrogens fluctuations during gestation in guanacos (Lama guanicoe) and 2) apply this technique to assess pregnancy in a wild free-ranging population. Fecal samples were collected through the gestation period (~12 months) of female guanacos in a 6.5-ha paddock. An increase in fecal metabolites of both hormones was detected. Progestagens increased gradually, in contrast to estrogens, which remained at basal values for most of the gestation period and peaked only a few days before calving. To assess pregnancy in wild free-ranging animals, fecal samples were collected from a population of La Payunia provincial reserve (Mendoza, Argentina) during the beginning of gestation and at the end of gestation. Through the first months of possible gestation, pregnant females represented between 40 and 80% of the population; at the end of gestation, only 20–40% of the females had confirmed pregnancies. Our results demonstrated that the polyclonal antisera and sexual hormone metabolite assays used here detect variations in the metabolites excreted through feces in guanacos and provide the possibility of non-invasive hormone monitoring of female reproductive status. Also, the findings in wild conditions suggest that natural abortions could have occurred during the first months of gestation. Although some abortions may be natural, the harsh environmental conditions that challenge the support of such a long gestational process may be another relevant factor to consider. The results obtained here enhance our understanding of the reproductive physiology of one of the most emblematic ungulates in South America. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What are the odds of achieving pregnancy when adopting progestin-primed ovarian stimulation (PPOS)-related protocols combined with repetitive frozen-thawed transfer (FET) cycles in patients with different clinical characteristics? SUMMARY ANSWER The cumulative live birth rates (CLBRs) of women undergoing different PPOS-related protocols can be significantly and consistently enhanced within six FET cycles when the female age is <40 years (or even <45 years) and when >5 oocytes are retrieved, regardless of antral follicle count (AFC). WHAT IS KNOWN ALREADY There have been numerous studies on the live birth rate of the first FET cycle in patients with PPOS-related protocols. These studies have focused mainly on comparing pregnancy outcomes with those of other stimulation protocols. However, owing to the unique features of the PPOS-related strategy, such as its flexible timing of oocyte retrieval and repeated transfer of frozen embryos, studies using the CLBR as an overall indicator of success and investigating which types of patients would benefit from this protocol are lacking. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 18 593 women who underwent PPOS-related protocols (dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, and luteal-phase ovarian stimulation protocol) from 1 March 2011 to 31 September 2022 in our centre. PARTICIPANTS/MATERIALS, SETTING, METHODS The population was categorized by female age, number of oocytes retrieved, and AFC in the analysis of CLBR within six FET cycles. The age groups (Groups 1–5, respectively) were <30, 30–34, 35–39, 40–44, and ≥45 years. The number of oocytes retrieved was grouped as 1–5, 6–10, 11–15, 16–20, and >20. AFC was grouped as <5, 5–10, 11–15, and >15. The Kaplan–Meier analysis (optimistic method), which hypothesized that patients who did not continue treatment had the same chance of achieving a live birth as those who continued, and the competing risk method (conservative method) which hypothesized they had no chance of achieving a live birth, were applied. In further analyses, the Cox model and Fine–Gray model were adopted: the former corresponds to the optimistic scenario, and the latter corresponds to the pessimistic scenario. MAIN RESULTS AND THE ROLE OF CHANCE CLBR had a declining trend with female age over six FET cycles (Groups 1–5, respectively: optimistic: 96.9%, 96.6%, 91.4%, 67.3%, and 11.7%; conservative: 87.3%, 85.0%, 74.0%, 41.3%, and 7.5%), requiring more FET cycles to achieve a success rate of at least 50% (Groups 1–5, respectively: optimistic: 2, 2, 2, 4, and >6 cycles; conservative: 2, 2, 2, >,6 and >6 cycles). CLBR showed an increasing trend with the number of oocytes retrieved (Groups 1–5, respectively: optimistic: 93.8%, 94.3%, 95.8%, 96.0%, and 95.6%; conservative: 66.2%, 78.3%, 85.6%, 88.9%, and 91.0%). All groups needed the same number of FET cycles to achieve a success rate of at least 50% (Groups 1–5, respectively: optimistic: 2, 2, 2, 2, and 2 cycles; conservative: 2, 2, 2, 2, and 2 cycles). Furthermore, the CLBR within six FET cycles had an increasing trend with AFC number (Groups 1–4, respectively: optimistic: 89.2%, 94.8%, 95.9%, and 96.3%; conservative: 67.4%, 78.2%, 83.9%, and 88.1%), with all four groups achieving a success rate of at least 50% by the second FET cycle. LIMITATIONS, REASONS FOR CAUTION The current research is limited by its retrospective design and single-centre nature, which may restrict the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS This work describes two models (the Kaplan–Meier analysis and the competing risk method) to evaluate the clinical outcome of patients using PPOS-related protocols, which are especially useful for patients of advanced age or those with diminished ovarian reserve. Our findings encourage patients below 45 years old, especially younger than 40 years, and patients with lower AFCs and fewer retrieved oocytes to try this new protocol. Moreover, this study demonstrates the degree of improvement in the CLBR within six FET cycles for patients with different clinical characteristics, providing a valuable point of reference to determine whether to continue ART after a transfer failure. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by grants from the National Natural Science Foundation of China (82071603 to L.W. 82001502 to Y.L.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Progestin-only injectable contraceptives, mainly depo-medroxyprogesterone acetate intramuscular (DMPA-IM), are the most widely used contraceptive methods in sub-Saharan Africa. Insufficient robust data on their relative side-effects and serum concentrations limit understanding of reported outcomes in contraception trials. The WHICH clinical trial randomized HIV-negative women to DMPA-IM (n = 262) or norethisterone enanthate (NET-EN) (n = 259) at two South African sites between 2018–2019. We measured serum concentrations of study and non-study progestins at initiation (D0) and peak serum levels, one week after the 24-week injection [25 weeks (25W)], (n = 435) and investigated associations between study progestin levels, and BMI and weight of participants. Peak median serum concentrations were 6.59 (IQR 4.80; 8.70) nM for medroxyprogesterone (MPA) (n = 161) and 13.6 (IQR 9.01; 19.0) nM for norethisterone (NET) (n = 155). MPA was the most commonly quantifiable non-study progestin at D0 in both arms (54%) and at 25W in the NET-EN arm (27%), followed by NET at D0 in both arms (29%) and at 25W in the DMPA-IM arm (19%). Levonorgestrel was quantifiable in both arms [D0 (6.9%); 25W (3.4%)], while other progestins were quantifiable in ≤ 14 participants. Significant negative time-varying associations were detected between MPA and NET concentrations and weight and BMI in both contraceptive arms and a significant increase was detected for peak serum progestin concentrations for normal weight versus obese women. Contraceptive-related reported outcomes are likely confounded by MPA, more so than NET, with reported DMPA-IM effects likely underestimated, at sites where DMPA-IM is widely used, due to misreporting of contraceptive use before and during trials, and 'tail' effects of DMPA-IM use more than six months before trial enrolment. Peak serum levels of MPA and NET are negatively associated with BMI and weight, suggesting another source of variability between trial outcomes and a potential increase in side-effects for normal weight versus overweight and obese women. Trail registration: The clinical trial was registered with the Pan African Clinical Trials Registry (PACTR 202009758229976). [ABSTRACT FROM AUTHOR]

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action. [ABSTRACT FROM AUTHOR]

Background: abnormal uterine bleeding is a very frequent reason for referral to gynaecologists and can deeply influence the quality of life. Once organic causes requiring surgical treatment are ruled out, clinicians should be able to manage these patients conservatively in the most effective way. Materials and methods: a search in PubMed/MEDLINE database was conducted in order to find relevant and recent meaningful sources for this narrative review. Results: LNG-IUS 52 mg is the first-line treatment for non-organic causes. Nevertheless, it could be contraindicated or declined by the patient. Combined oral contraceptives (COC) and progestinonly pills inhibit the hypothalamic-pituitary-ovarian axis, preventing ovulation, and induce endometrial atrophy. Consequently, they are effective in treating AUB. Moreover, brand new pills containing a combination of oestrogens, progestins and GnRH antagonists are now available for the management of AUB related to uterine fibroids. Conclusions: In daily clinical practice, oral hormonal therapies are convenient and reversible tools to manage AUB when LNG-IUS 52 mg is contraindicated or turn down by the patient. Many oral hormonal therapies are prescribed to treat AUB, but only a few have been approved with this specific indication, therefore further large well-designed studies are necessary in order to compare the efficacy of different pills for treating AUB. [ABSTRACT FROM AUTHOR]