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Environmental Science and Pollution... Jun 2024Concerns are growing about adverse effects of progestins on biota, even at ultra-trace concentrations. The enrichment factor (EF) from extraction of analytes in...
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 L/L) enabled the detection of more compounds compared to samples with lower sample EF (10,000 L/L). The matrix effect did not increase proportionally compared to lower EFs (10,000 and 16,666 L/L), and lower limits of quantification were achieved in WWTP effluents and surface waters. The results of bioassays have shown that relative EF of 25 L/L 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.
Topics: Progestins; Water Pollutants, Chemical; Chromatography, High Pressure Liquid; Biological Assay; Environmental Monitoring; Solid Phase Extraction; Wastewater
PubMed: 38806985
DOI: 10.1007/s11356-024-33714-y -
JAMA Network Open May 2024Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years.
OBJECTIVES
To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD.
DESIGN, SETTING, AND PARTICIPANTS
This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024.
INTERVENTION
Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age.
MAIN OUTCOMES AND MEASURES
The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment.
RESULTS
The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02133573.
Topics: Humans; Progesterone; Female; Heart Defects, Congenital; Male; Pregnancy; Double-Blind Method; Infant; Adult; Infant, Newborn; Child Development; Progestins; Neurodevelopmental Disorders
PubMed: 38805228
DOI: 10.1001/jamanetworkopen.2024.12291 -
The Lancet Regional Health. Europe Jul 2024Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC.
BACKGROUND
Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC.
METHODS
Observational cohort study using SNDS data (France). Women included had ≥ one dispensing of NOMAC between 2007 and 2017 (no dispensing in 2006). Exposure was defined as a cumulative dose >150 mg NOMAC within six months after first dispensing. A control group of women (cumulative dose ≤150 mg) was assembled. The outcome was surgery (resection or decompression) or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma.
FINDINGS
In total, 1,060,779 women were included in the cohort (535,115 in the exposed group and 525,664 in the control group). The incidence of meningioma in the two groups was 19.3 and 7.0 per 100,000 person-years, respectively (age-adjusted RRa = 2.9 [2.4-3.7]). The RRa for a cumulative dose of more than 6 g NOMAC was 12.0 [9.9-16.0]. In the event of treatment discontinuation for at least one year, the risk of meningioma was identical to that in the control group (RRa = 1.0 [0.8-1.3]). The location of meningiomas in the anterior and middle part of the skull base was more frequent with exposure to NOMAC.
INTERPRETATION
We observed a strong dose-dependent association between prolonged use of NOMAC and the risk of intracranial meningiomas. These results are comparable to those obtained for cyproterone acetate, although the magnitude of the risk is lower. It is now recommended to stop using NOMAC if a meningioma is diagnosed.
FUNDING
The French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI-PHARE.
PubMed: 38800110
DOI: 10.1016/j.lanepe.2024.100928 -
Cell Jun 2024Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain...
Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.
Topics: Humans; Progestins; Hydrogen; Gastrointestinal Microbiome; Female; Glucocorticoids; Pregnancy; Animals; Multigene Family; Feces; Pregnanolone; Mice
PubMed: 38795705
DOI: 10.1016/j.cell.2024.05.005 -
Molecules (Basel, Switzerland) May 2024Progesterone (PROG) and estrone (E) are typical reproductive hormones in dairy cows. Assessing the levels of these hormones in vivo can aid in estrus identification. In...
Progesterone (PROG) and estrone (E) are typical reproductive hormones in dairy cows. Assessing the levels of these hormones in vivo can aid in estrus identification. In the present work, the feasibility of the qualitative and quantitative detection of PROG and E using terahertz time-domain spectroscopy (THz-TDS) and metamaterial technology was preliminarily investigated. First, the time domain spectra, frequency domain spectra, and absorption coefficients of PROG and E samples were collected and analyzed. A vibration analysis was conducted using density functional theory (DFT). Subsequently, a double-ring (DR) metamaterial structure was designed and simulated using the frequency domain solution algorithm in CST Studio Suite (CST) software. This aimed to ensure that the double resonance peaks of DR were similar to the absorption peaks of PROG and E. Finally, the response of DR to different concentrations of PROG/E was analyzed and quantitatively modeled. The results show that a qualitative analysis can be conducted by comparing the corresponding DR resonance peak changes in PROG and E samples at various concentrations. The best R for the PROG quantitative model was 0.9872, while for E, it was 0.9828. This indicates that terahertz spectral-metamaterial technology for the qualitative and quantitative detection of the typical reproductive hormones PROG and E in dairy cows is feasible and worthy of in-depth exploration. This study provides a reference for the identification of dairy cow estrus.
Topics: Cattle; Animals; Progesterone; Female; Terahertz Spectroscopy; Estrone; Dairying
PubMed: 38792227
DOI: 10.3390/molecules29102366 -
International Journal of Molecular... May 2024Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent...
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients.
Topics: Animals; Adrenal Hyperplasia, Congenital; Disease Models, Animal; Steroid 21-Hydroxylase; Mice; Female; Male; Humans; Corticosterone; Aldosterone; Adrenal Glands; Mutation; Progesterone
PubMed: 38791102
DOI: 10.3390/ijms25105062 -
Cells May 2024There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the...
There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell-cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies.
Topics: Humans; Female; Endometrium; Epithelial Cells; Progestins; Estrogens; Cell Survival; Cell Movement; Cell Line; Estradiol; Stromal Cells; Coculture Techniques; Time Factors; Cell Adhesion
PubMed: 38786035
DOI: 10.3390/cells13100811 -
Journal of Controlled Release :... Jul 2024Vaginal drug delivery is often preferred over systemic delivery to reduce side effects and increase efficacy in treating diseases and conditions of the female...
Vaginal drug delivery is often preferred over systemic delivery to reduce side effects and increase efficacy in treating diseases and conditions of the female reproductive tract (FRT). Current vaginal products have drawbacks, including spontaneous ejection of drug-eluting rings and unpleasant discharge from vaginal creams. Here, we describe the development and characterization of a hypotonic, gel-forming, Pluronic-based delivery system for vaginal drug administration. The rheological properties were characterized with and without common hydrogel polymers to demonstrate the versatility. Both qualitative and quantitative approaches were used to determine the Pluronic F127 concentration below the critical gel concentration (CGC) that was sufficient to achieve gelation when formulated to be hypotonic to the mouse vagina. The hypotonic, gel-forming formulation was found to form a thin, uniform gel layer along the vaginal epithelium in mice, in contrast to the rapidly forming conventional gelling formulation containing polymer above the CGC. When the hypotonic, gel-forming vehicle was formulated in combination with a progesterone nanosuspension (ProGel), equivalent efficacy was observed in the prevention of chemically-induced preterm birth (PTB) compared to commercial Crinone® vaginal cream. Further, ProGel showed marked benefits in reducing unpleasant discharge, reducing product-related toxicity, and improving compatibility with vaginal bacteria in vitro. A hypotonic, gel-forming delivery system may be a viable option for therapeutic delivery to the FRT.
Topics: Female; Animals; Administration, Intravaginal; Gels; Poloxamer; Drug Delivery Systems; Vagina; Progesterone; Rheology; Mice; Vaginal Creams, Foams, and Jellies; Pregnancy
PubMed: 38782065
DOI: 10.1016/j.jconrel.2024.05.037 -
Domestic Animal Endocrinology Jul 2024The aim of the present study was to examine the influence of monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) on ovarian cell...
The aim of the present study was to examine the influence of monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) on ovarian cell functions. Rabbit ovarian granulosa cells were cultured with or without MCP-1 or PAI-1 (at 0, 0.1, 1, or 10 ng/ml). Cell viability, proliferation, cytoplasmic apoptosis and release of progesterone and estradiol were measured by Cell Counting Kit-8 (CCK-8), BrdU incorporation, and cell death detection assays and ELISA. The addition of either MCP-1 or PAI-1 increased cell viability and proliferation and decreased apoptosis. MCP-1 promoted, while PAI-1 suppressed, progesterone release. Both MCP-1 and PAI-1 reduced estradiol output. The present results suggest that MCP-1 or PAI-1 can be physiological promoters of rabbit ovarian cell viability and proliferation, inhibitors of apoptosis and regulators of ovarian steroidogenesis.
Topics: Animals; Female; Rabbits; Plasminogen Activator Inhibitor 1; Granulosa Cells; Chemokine CCL2; Apoptosis; Progesterone; Estradiol; Cell Survival; Cell Proliferation; Cells, Cultured
PubMed: 38781776
DOI: 10.1016/j.domaniend.2024.106856 -
American Journal of Physiology.... May 2024Oral contraceptive pills are used by approximately 250 million women worldwide, however a clear understanding of the concentrations of endogenous and exogenous hormones...
Oral contraceptive pills are used by approximately 250 million women worldwide, however a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day oral contraceptive pill pack is not well described. In our study of 16 female participants taking various monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle, challenging the previous assumption of hormonal stability in oral contraceptive users. The results from this study have wide ranging implications for research and treatment in women's health including: considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.
PubMed: 38775726
DOI: 10.1152/ajpendo.00418.2023