From fallopian tube epithelium to high-grade serous ovarian cancer: A single-cell resolution review of sex steroid hormone signaling.

High-grade serous ovarian cancer (HGSOC) represents the most lethal subtype of ovarian cancer, largely due to being commonly diagnosed at advanced stages. The early molecular mechanisms underlying ovarian carcinogenesis remain poorly defined, posing challenges to the development of prevention and early detection strategies. Here we dissect the molecular mechanisms of sex steroid hormone signaling throughout the decades-long evolution of HGSOC precursor lesions, which predominantly originate from secretory epithelial cells of fallopian tubes (FT). We also discuss the prognostic significance of sex steroid receptor isoforms and steroid metabolizing enzymes in HGSOCs. Finally, we provide a comprehensive gene expression atlases of sex steroid receptors, steroidogenic, and steroid-metabolizing enzymes across different cell populations in pre- and postmenopausal FTs, and HGSOCs, using published single-cell RNA sequencing datasets. These atlases reveal that secretory epithelial cells and stromal populations in FTs express sex steroid receptors and enzymes responsible for the formation and inactivation of genotoxic estrogen metabolites. In HGSOC, epithelial cells express various HSD17B isoforms and steroid conjugating enzymes, suggesting an enhanced ability to finely regulate the levels of bioactive sex steroids.

Simultaneous measurement of 17 endogenous steroid hormones in human serum by liquid chromatography-tandem mass spectrometry without derivatization.

Mass spectrometric-based steroidomics is a valuable analytical approach that gives a comprehensive understanding of the interlinked steroid biosynthetic pathways. Here, we describe a rapid and versatile liquid chromatography-tandem mass spectrometry (LC-MS/MS) method designed to accurately quantify endogenous steroids in human serum. Sample preparation involved liquid-liquid extraction with methyl tert-butyl ether (MTBE) from 180 µL serum. The targeted steroids for quantification included androgens: dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), 11-oxyandrogens: 11ß-hydroxy-androstenedione (11OHA4), 11-keto-androstenedione (11KA4), 11ß-hydroxy-testosterone (11OHT), 11-keto-testosterone (11KT), progestogens: 17α-hydroxy-progesterone (17OHP4), progesterone (P4), 11ß-hydroxy-progesterone (11OHP4), 11-keto-progesterone (11KP4), mineralocorticoids: aldosterone, corticosterone, and glucocorticoids: 11-deoxycortisol, cortisol, and cortisone. The lower limits of quantification (LLOQ) were 0.05 ng/mL for A4, T, 11KA4, P4, and cortisone, 0.1 ng/mL for DHT, 11OHA4, 11OHT, 11KT, 17OHP4, 11OHP4, 11KP4, corticosterone, aldosterone, 11-deoxycortisol, and cortisol, and 0.5 ng/mL for DHEA. Accuracy, precision, reproducibility, and recovery fell within acceptable limits for bioanalytical method validation. Using serum samples from 29 premenopausal women in different menstrual phases, we demonstrated the clinical utility of our method, which showed sufficient sensitivity to reliably quantify all targeted steroids at levels typically found in circulation, except for 11OHP4 and 11KP4.

High enrichment factors in chemical analysis of progestins and in bioassays: insights beyond trace levels.

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.

Long-term therapy with dienogest or other oral cyclic estrogen-progestogen can reduce the need for ovarian endometrioma surgery.

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.

Preparation of a sustainable magnetic sorbent for the extraction and preconcentration of progestogens in natural water samples.

A film composed of agarose and graphene (G) and magnetic nanoparticles (G-MNPs) is proposed as a sorbent for the extraction and determination of medroxyprogesterone (MED), levonorgestrel (LEV), norethisterone (NOR) and progesterone (PRO) in natural water samples. Both the preparation of the film and the extraction procedure were optimized. The optimal extraction parameters were as follows: isopropyl alcohol as activation solvent, sample pH value of 3.0, extraction time of 30 min, 1.00 mL of acetonitrile as eluent, elution time of 5 min and sample volume of 100.00 mL. HPLC with photodiode array detector was used for the separation and determination. The method presented a linear range between 2.50 and 75.0 µg L-1 for all analytes, and the LODs were between 1.40 and 1.80 µg L-1. The method was applied to natural water samples, obtaining satisfactory recovery values (75-111 %). In conclusion, for the immobilization of the G-MNPs, agarose was used, which is a non-toxic, renewable and biodegradable material. The G-MNPs-agarose film was reused up to 70 times, without losing its extraction capacity significantly and presenting excellent sorbent properties, which allow the extraction and preconcentration of the progestogens under study.

Metabolism of progestogens used for contraception and menopausal hormone therapy.

A variety of progestogens are widely used by women for contraception and menopausal hormone therapy. The progestogens undergo extensive metabolism by oral and parenteral routes of administration to form many metabolites. Although a small number of metabolites have been shown to be biologically active, most have not been tested for biologic activity. The present review shows that we know most about progesterone metabolism, followed by the metabolism of levonorgestrel and norethindrone. Very few studies have been carried out on metabolism of most of the progestogens. The clinical significance of this deficiency is that those progestogen metabolites that bind to the progesterone receptors may also bind to other steroid receptors and be responsible for some of the well-documented side effects of administered progestogens. We also discuss how obesity and genetic polymorphisms alter progestogen metabolism, and how development of oral progestogen formulations that are targeted to the colon, where the concentration of steroid-metabolizing enzymes is much lower than in the proximal gut, may have a beneficial effect on progestogen metabolism.

The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women.

BACKGROUND: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized. OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. STUDY DESIGN: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state. CONCLUSION: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug's long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

Progestogens in women with threatened miscarriage or recurrent miscarriage: A meta-analysis.

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.

Progesterone Metabolism In Digitalis And Other Plants - 60 Years Research And Recent Results.

5ß-Cardenolides are pharmaceutically important metabolites of the specialized metabolism of Digitalis lanata. They were used over decades to treat cardiac insufficiency and supraventricular tachycardia. Since the 1960s, plant scientists have known that progesterone is an essential precursor of cardenolide formation. Therefore, plant progesterone biosynthesis was mainly analyzed in species of the cardenolide-containing genus Digitalis during the following decades. Today, Digitalis enzymes catalyzing the main steps of progesterone biosynthesis are known. Most of them were found in a broad range of organisms. This review will summarize the findings of 60 years of research on plant progesterone metabolism with a particular focus on the recent results in Digitalis lanata and other plants.

Proposal for targeted, neo-evolutionary-oriented secondary prevention of early-onset endometriosis and adenomyosis. Part II: medical interventions.

According to consistent epidemiological data, the slope of the incidence curve of endometriosis rises rapidly and sharply around the age of 25 years. The delay in diagnosis is generally reported to be between 5 and 8 years in adult women, but it appears to be over 10 years in adolescents. If this is true, the actual onset of endometriosis in many young women would be chronologically placed in the early postmenarchal years. Ovulation and menstruation are inflammatory events that, when occurring repeatedly for years, may theoretically favour the early development of endometriosis and adenomyosis. Moreover, repeated acute dysmenorrhoea episodes after menarche may not only be an indicator of ensuing endometriosis or adenomyosis, but may also promote the transition from acute to chronic pelvic pain through central sensitization mechanisms, as well as the onset of chronic overlapping pain conditions. Therefore, secondary prevention aimed at reducing suffering, limiting lesion progression, and preserving future reproductive potential should be focused on the age group that could benefit most from the intervention, i.e. severely symptomatic adolescents. Early-onset endometriosis and adenomyosis should be promptly suspected even when physical and ultrasound findings are negative, and long-term ovulatory suppression may be established until conception seeking. As nowadays this could mean using hormonal therapies for several years, drug safety evaluation is crucial. In adolescents without recognized major contraindications to oestrogens, the use of very low-dose combined oral contraceptives is associated with a marginal increase in the individual absolute risk of thromboembolic events. Oral contraceptives containing oestradiol instead of ethinyl oestradiol may further limit such risk. Oral, subcutaneous, and intramuscular progestogens do not increase the thromboembolic risk, but may interfere with attainment of peak bone mass in young women. Levonorgestrel-releasing intra-uterine devices may be a safe alternative for adolescents, as amenorrhoea is frequently induced without suppression of the ovarian activity. With regard to oncological risk, the net effect of long-term oestrogen-progestogen combinations use is a small reduction in overall cancer risk. Whether surgery should be considered the first-line approach in young women with chronic pelvic pain symptoms seems questionable. Especially when large endometriomas or infiltrating lesions are not detected at pelvic imaging, laparoscopy should be reserved to adolescents who refuse hormonal treatments or in whom first-line medications are not effective, not tolerated, or contraindicated. Diagnostic and therapeutic algorithms, including self-reported outcome measures, for young individuals with a clinical suspicion of early-onset endometriosis or adenomyosis are proposed.

Progestogens for endometrial protection in combined menopausal hormone therapy: A systematic review.

Menopausal women with an intact uterus choosing estrogens for menopausal symptom relief require a progestogen for endometrial protection. The aim of this systematic review was to evaluate the risks of endometrial hyperplasia resp. malignancy with different progestogens used in combined MHT. Overall, 84 RCTs were included. We found that 1) most studies were done with NETA, followed by MPA, MP and DYD and LNG, 2) most progestogens were only available as oral formulations, 3) the most frequently studied progestogens (oral MP, DYD, MPA, oral and transdermal NETA, transdermal LNG) were assessed in continuously as well as in sequentially combined MHT regimens, 4) FDA endometrial safety criteria were only fulfilled for some progestogen formulations, 5) most studies demonstrated endometrial protection for the progestogen dose and time period examined. However, 6) study quality varied which should be taken into account, when choosing a combined MHT, especially if off-label-use is chosen.

Effects of prenatal exposure to synthetic sex hormones on neurodevelopment: a biological mechanism.

Since the middle of the 20th century, synthetic sex hormones (estrogens and progestins) have been administered to millions of pregnant or not women worldwide, mainly to avoid miscarriage or for comfort, although their mode of action and their effects on the mother and fetus were ignored. Despite the alerts and the description of somatic and psychiatric disorders in children exposed in utero, synthetic estrogens were prohibited for pregnant women only in the 1970s and 1980s, but some progestins are still authorized. In this review, we summarize the psychiatric disorders described in children exposed in utero to such hormones, focusing particularly on schizophrenia, bipolar disorders, severe depression, eating disorders, suicide and suicide attempts. Moreover, only in 2017 the mechanism of action of these xenohormones has started to be deciphered. Some studies showed that in the fetus exposed in utero, they alter the DNA methylation profile (mainly hypermethylation), and consequently the expression of genes implicated in neurodevelopment and in regulating the sexual organ morphogenesis and also of the promoter of estrogen receptors, located in the amygdala. These deleterious effects may be transmitted also to the next generations, thus affecting the children directly exposed and also the following generations.

Combined oral contraceptives: update recommendations of the Latin American contraceptive association.

Background: In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users.Objective: To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety.Method: For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptives'.Results: Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman.Conclusion: Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health.

Real-world practice of estrogen and progestogen prescriptions in menopausal women in Japan: A descriptive study using a Japanese claims database.

AIM: This study aimed to investigate the real-world clinical practice of estrogen and progestogen prescriptions for menopausal women. METHODS: Using a health care database in Japan, we conducted a cross-sectional study on estrogen prescriptions and detailed analyses of newly initiated estrogens and concomitant prescriptions of progestogens. Data between January 2005 and December 2021 were analyzed. RESULTS: In 2021, the proportion of women aged 45-49 years receiving estrogens was 25.8 [95% confidence interval (CI): 25.3, 26.3] per 1000 women, while it was 6.4 [95% CI: 6.0, 6.7] for those aged ≥60 years. The prescription of estrogens gradually increased in women aged 50-59 years after 2009. In women without a history of hysterectomy, transdermal estradiol was the primary form of estrogens prescribed for ≥180 days, in women aged <60 years. The proportion of transdermal estradiol gradually increased each year, whereas that of oral-conjugated equine estrogens decreased. Among progestogen, the proportions of dydrogesterone and transdermal norethisterone acetate increased over time, while that of medroxyprogesterone acetate decreased. Approximately 30% of women prescribed estrogens for ≥180 days did not initiate progestogen concurrently. In women undergoing hysterectomy, progestogen was not initiated in >90% of cases, and transdermal estradiol was prescribed in approximately 80% of cases in 2021. CONCLUSIONS: This study reviewed the prescription of estrogens in menopausal women in Japan. A considerable number of women with a uterus are receiving estrogen therapy rather than estrogen-progestogen therapy (EPT), despite the guidelines recommending the use of EPT in these women.

Occurrence, tissue distribution, and risk assessment of progestins, androgens, estrogens, and phenols in wild freshwater fish species.

The presence of endocrine-disrupting chemicals (EDCs) in aquatic environments such as water, sediment, and sludge received more and more attention. However, the bioaccumulate properties of EDCs, particularly progestins and androgens, in various tissues of different wild freshwater fish species, as well as their effects on human health, have not been fully studied. The muscle, liver, and gills of three wild fish species obtained from the East Dongting Lake in southern China were examined for the presence of 19 EDCs (4 progestins, 5 androgens, 6 estrogens, and 4 phenols). Seventeen analytes were detected in all fish samples, and the concentrations of progestins, androgens, estrogens, and phenols ranged from ND-78.80 ng/g (wet weight, ww), ND-50.40 ng/g ww, ND-3573.82 ng/g ww, and ND-88.17 ng/g ww, respectively. The bioaccumulation of some EDCs in wild fish from East Dongting Lake was species-specific. Additionally, AND, EES, P4, and E2 were discovered in the liver at higher levels than in the muscle, suggesting that livers had a larger ability for enriching these EDCs than the muscle. Furthermore, the relationships between the fish sizes and the EDC concentrations indicated that total weight and length had a negligible impact on the bioaccumulation of EDCs in various fish species. Most importantly, the effects of EDCs on human health as a result of fish consumption were assessed. Although the estimated daily intakes (EDIs) of most EDCs were much lower compared with the corresponding acceptable daily intakes (ADIs) via consuming fish collected in this study, the EDI of EE2 in Silurus asotus was higher than the ADI of E2, indicating that Silurus asotus from East Dongting Lake should be eaten in moderation by local residents.

What now? A critical evaluation of over 20 years of clinical and research experience with 17-alpha hydroxyprogesterone caproate for recurrent preterm birth prevention.

Spontaneous preterm birth is multifactorial, and underlying etiologies remain incompletely understood. Supplementation with progestogens, including 17-alpha hydroxyprogesterone caproate has been a mainstay of prematurity prevention strategies in the United States in the last 2 decades. Following a recent negative confirmatory trial, 17-alpha hydroxyprogesterone caproate was withdrawn from the US market and is currently available only through clinical research studies. This expert review summarized clinical and research data regarding the use of 17-alpha hydroxyprogesterone caproate in the United States from 2003 to 2023 for recurrent prematurity prevention. In 17-alpha hydroxyprogesterone caproate. The history of the use, mechanisms of action, clinical trial results, and efficacy by clinical and biologic criteria of 17-alpha hydroxyprogesterone caproate are presented. We report that disparate findings and conclusions between similarly designed rigorous studies may reflect differences in a priori risk and population incidence and extreme care should be taken in interpreting the studies and making decisions regarding efficacy of 17-alpha hydroxyprogesterone caproate for the prevention of preterm birth. The likelihood of improved obstetrical outcomes after receiving 17-alpha hydroxyprogesterone caproate may vary by clinical factors (eg, body mass index), plasma drug concentrations, and genetic factors, although the identification of individuals most likely to benefit remains imperfect. It is crucial for the medical community to recognize the importance of preserving the decades-long efforts invested in preventing recurrent preterm birth in the United States. Moreover, it is important that we thoroughly and thoughtfully evaluate 17-alpha hydroxyprogesterone caproate as a promising contender for future well-executed prematurity studies.

Clinical Importance of PGRMC1 in Hormone Responsive Breast Cancer.

Background: For the development of PGRMC1, a multifunctional receptor belonging to membrane-associated progesterone receptor proteins (MAPR) family, as possible predictive marker for increased hormone-dependent breast cancer (BC) risk, a systematic research program has been performed, starting with different BC cells, continued with animal studies and finally with clinical studies with BC patients. Summary: In vitro studies showed dose- and time-dependent BC cell proliferations with all available synthetic progestogens (not with progesterone), but mostly significant only in the presence of PGRMC1. Different animal (xenograft) studies confirmed that synthetic progestogens, but not progesterone and dydrogesterone, increased the estradiol-induced tumor proliferation, although with dydrogesterone, a small time-dependent increase could be seen. Clinical studies with hormone replacement therapy (HRT) to confirm these results are still running. In patients with BC expression of PGRMC1 in BC tissue was correlated to tumor characteristics like diameter, grade, and metastatic status. BC patients with PGRMC1 in the tumors had poorer disease-free and overall survival. After developing of an assay, blood levels could be correlated to the expression in BC tissue showing PGRMC1 superior to tumor markers such as CEA, CA125, CA153, and TPS. Key Messages: This review is summarizing two different functions of PGRMC1: (1) to predict the prognosis of BC patients, already well demonstrated in BC patients and (2) being a possible predictive marker for BC risk during HRT as suggested from in vitro and animal research.

Baseline progestins characterization in surface waters of three main Portuguese estuaries.

Synthetic progestins are micropollutants of special concern, due to their growing use in human and veterinary therapies and their risks to aquatic life. Currently, there is a lack of environmental information on these compounds, worldwide. The main objective of this work was to characterize the levels of the most consumed progestins in Portugal. For that, Ria de Aveiro, Tagus estuary and Ria Formosa were sampled in a temporal perspective to evaluate levels of drospirenone (DRO), desogestrel (DSG), gestodene (GST) and levonorgestrel (LNG). Drospirenone and desogestrel were the most abundant progestins. In the North of Portugal, DSG was the most abundant (Aveiro: 193.9 ng L-1 in summer), while DRO was more representative in the South (Tagus: 178.9 ng L-1; Formosa: 125.7 ng L-1) and also in summer. These spatial differences can be associated with the hydrodynamics of each estuarine system as well as the distinct population and tourist levels associated with each site.

Occurrence and conversion of progestogens and androgens are conserved in land plants.

Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we show that the occurrence and biosynthesis of progestogens and androgens are conserved across the viridiplantae lineage. An UHPLC-ESI-MS/MS method allowed high-throughput analysis of the occurrence and chemical conversion of progestogens and androgens in 41 species across the green plant lineage. Dehydroepiandrosterone, testosterone, and 5α-dihydrotestosterone are plants' most abundant mammalian-like steroids. Progestogens are converted into 17α-hydroxyprogesterone and 5α-pregnane-3,20-dione. Androgens are converted into testosterone and 5α-dihydrotestosterone. 17,20-Lyases, essential for converting progestogens to androgens, seem to be most effective in monocot species. Our data suggest that the occurrence of progestogens and androgens is highly conserved in plants, and their biosynthesis might favor a route using the Δ4 pathway.

Comparison of dydrogesterone plus progesterone gel with subcutaneous aqueous progesterone plus progesterone gel for luteal phase supplementation of subsequent in vitro cycle in women after previous cycle failure.

OBJECTIVES: The luteal phase supplementation (LPS) of the in vitro fertilization (IVF) cycle is crucial to increase the chance of a live birth. There is no preferred progestogen for use in the general population. The optimal progestogen regimen in the event of prior IVF failure is unknown. The aim was to compare the live birth rate for dydrogesterone plus progesterone gel versus aqueous progesterone plus progesterone gel in LPS of the IVF cycle in women with at least one previous IVF failure. MATERIAL AND METHODS: A prospective randomized single-center study enrolled women with at least one previous IVF failure undergoing another IVF cycle. Women were randomly assigned in a 1:1 ratio to 2 arms depending on LPS protocol: dydrogesterone (Duphaston®) + progesterone in vaginal gel (Crinone®) vs aqueous progesterone solution in subcutaneous injection (Prolutex®) + progesterone in vaginal gel (Crinone®). All women underwent fresh embryo transfer. RESULTS: The live birth rate with one prior IVF failure was 26.9% for D + PG vs 21.2% for AP + PG (p = 0.54), and with at least two IVF failures: 16% for D + PG vs 31.1% for AP + PG (p = 0.16). There were no significant differences in live birth rates between protocols, regardless of the number of prior IVF failures. CONCLUSIONS: In light of the evidence from this study that neither of the two LPS protocols is more effective in women with prior IVF failure, other factors, such as potential side effects, dosing convenience and patient preference, should be considered when choosing a treatment.