Systematic analysis of combined oral contraceptive prescription patterns in psychotropic drug users across twelve European countries.

OBJECTIVE: To investigate prescription patterns of combined oral contraceptives (COC) among psychotropic drug users compared to non-psychotropic drug users in routine clinical practice in Europe. STUDY DESIGN: A pooled analysis of three large, prospective, multinational cohort studies including women with a new prescription of COC from 12 European countries. We calculated standardized mean differences (SMD) to investigate whether the status of psychotropic drug use (use/no use) or the psychotropic drug class (psycholeptics/psychoanaleptics) is associated with the healthcare professional's choice of a specific type of COC progestin. RESULTS: Our analysis comprised 143,069 non-psychotropic drug users and 2174 psychotropic drug users. Progestins with the highest frequency in the cohorts were levonorgestrel (non-psychotropic drug users: 33.8%; psychotropic drug users: 32.4%), nomegestrol/nomegestrol acetate (non-psychotropic drug users: 19.1%; psychotropic drug users: 26.4%), and drospirenone (non-psychotropic drug users: 15.9%; psychotropic drug users: 14.8%). SMD analysis indicated no substantial differences in COC prescription patterns between the two cohorts. However, we observed association signals for users of the herbal antidepressant St. John's wort in that those individuals more often received a prescription for drospirenone and less frequently for nomegestrol/nomegestrol acetate compared to non-psychotropic drug users. CONCLUSIONS: Psychotropic drug user status does not seem to affect healthcare professionals' decisions when prescribing COC. However, limited evidence suggests that the risk for drug interactions might differ by progestin type, and some COC might be more suitable for psychotropic drug users than others. Specific guidelines should be conveyed to healthcare professionals to assist them in contraceptive counseling. IMPLICATIONS: With exception of St. John's wort, our analysis showed no differential prescription behavior of combined oral contraceptives in psychotropic drug users and non-users. However, healthcare professionals should carefully consider psychotropic drug use in contraceptive counseling as it is still unclear whether drug interactions exist when co-administered with certain oral contraceptives.

Progesterone-primed cycles result in slower embryos without compromising implantation potential and with the advantages of oral administration and potential cost reduction.

OBJECTIVE: To study the impact of the use of progesterone on embryo morphokinetics and on the outcomes of intracytoplasmic sperm injection cycles. DESIGN: Cohort study. SETTING: Private university-affiliated in vitro fertilization center. PATIENT(S): This study included 236 freeze-all intracytoplasmic sperm injection cycles and the resultant 2,768 injected oocytes cultured in a time-lapse imaging incubation system. Patients were matched by age and divided into groups depending on the protocol used to prevent the luteinizing hormone surge: progestin-primed (144 cycles and 1,360 embryos) and gonadotropin hormone-releasing hormone (GnRH) antagonist (144 cycles and 1,408 embryos) groups. INTERVENTION(S): The kinetic recorded markers were time to pronuclear appearance and fading, time to 2-8 cells, time to morulation, time to start of blastulation, and time to blastulation. The durations of cell cycles and time to complete synchronous divisions were calculated. The Known Implantation Data Score ranking was recorded. Morphokinetics and clinical outcomes were compared between the groups. MAIN OUTCOME MEASURE(S): Embryo morphokinetics and clinical outcomes. RESULTS: Slower time to pronuclear appearance, time to 2 cells, time to 7 cells, time to start of blastulation, and time to blastulation were observed in embryos derived from progestin-primed cycles than in those from the GnRH antagonist group. No significant differences were noted in any other morphokinetic milestone. Significantly higher cancellation and implantation rates were observed in the progestin-primed group. However, no significant differences were noted in the pregnancy and miscarriage rates. The expenses for treatment using premature GnRH antagonist and progestins were US$318.18 and US$11.05, respectively. CONCLUSIONS: Exogenous progesterone replaces the GnRH antagonist for the prevention of premature luteinizing hormone surge, in freeze-all cycles, with the advantage of oral administration and potential cost reduction.

Serum LH level prior to progestin administration is significant on pregnancy and live birth in programmed frozen-thawed embryo transfer cycles.

Purpose: To evaluate the impact of serum LH levels prior to progestin administration on the outcomes of programmed frozen-thawed embryo transfer (FET) cycles. Methods: Retrospective cohort study was conducted to compare the treatment outcomes between four groups based on the 25 percentiles of serum LH levels before progestin administration in 596 cycles of 518 patients undergoing artificial endometrial preparation protocols for FET. Primary outcome measures were ongoing and live birth rates. Secondary outcome measures were the pregnancy rates, clinical pregnancy rates, and pregnancy loss rates. Results: The trends in clinical pregnancy (CPR) and live birth rates (LBR) increased from the first to the fourth quartile (Q1 to Q4) of serum LH levels prior to progestin administration (37,0% to 48,3%, p = 0.042, and 22.6% to 39.5%, respectively, p = 0.003). Pregnancy loss rates (PLR) were higher in group Q1, although the difference was not statistically significant. Based on a multivariate logistic regression analysis, a low serum LH level before progestin initiation was found to be the most significant predictor associated with a negative effect on live birth (OR: 0,421, 95% CI 0,178 - 0,994, p=0,048). The day of estrogen initiation was significantly correlated with serum LH levels and quartiles of serum LH levels before progestin administration (r=0,200, p=0,015 and r=0,215, p=0,009, respectively). Conclusion: The serum LH level prior to progestin administration significantly affects pregnancy and live birth rates in patients undergoing an artificial endometrial preparation protocol for FET. LH monitoring should be incorporated into the follow-up, in addition to assessing endometrial thickness and morphology in artificial FET cycles.

Morphologic alterations of the fear circuitry: the role of sex hormones and oral contraceptives.

Background: Endogenous sex hormones and oral contraceptives (OCs) have been shown to influence key regions implicated in fear processing. While OC use has been found to impact brain morphology, methodological challenges remain to be addressed, such as avoiding selection bias between OC users and non-users, as well as examining potential lasting effects of OC intake. Objective: We investigated the current and lasting effects of OC use, as well as the interplay between the current hormonal milieu and history of hormonal contraception use on structural correlates of the fear circuitry. We also examined the role of endogenous and exogenous sex hormones within this network. Methods: We recruited healthy adults aged 23-35 who identified as women currently using (n = 62) or having used (n = 37) solely combined OCs, women who never used any hormonal contraceptives (n = 40), or men (n = 41). Salivary endogenous sex hormones and current users' salivary ethinyl estradiol (EE) were assessed using liquid chromatography - tandem mass spectrometry. Using structural magnetic resonance imaging, we extracted surface-based gray matter volumes (GMVs) and cortical thickness (CT) for regions of interest of the fear circuitry. Exploratory whole-brain analyses were conducted with surface-based and voxel-based morphometry methods. Results: Compared to men, all three groups of women exhibited a larger GMV of the dorsal anterior cingulate cortex, while only current users showed a thinner ventromedial prefrontal cortex. Irrespective of the menstrual cycle phase, never users exhibited a thicker right anterior insular cortex than past users. While associations with endogenous sex hormones remain unclear, we showed that EE dosage in current users had a greater influence on brain anatomy compared to salivary EE levels and progestin androgenicity, with lower doses being associated with smaller cortical GMVs. Discussion: Our results highlight a sex difference for the dorsal anterior cingulate cortex GMV (a fear-promoting region), as well as a reduced CT of the ventromedial prefrontal cortex (a fear-inhibiting region) specific to current OC use. Precisely, this finding was driven by lower EE doses. These findings may represent structural vulnerabilities to anxiety and stress-related disorders. We showed little evidence of durable anatomical effects, suggesting that OC intake can (reversibly) affect fear-related brain morphology.

Biotransformation of cyproterone acetate, drospirenone, and megestrol acetate in agricultural soils: Kinetics, microbial community dynamics, transformation products, and mechanisms.

The occurrence of biologically active synthetic progestins in agricultural soils is of growing concern due to their potential to disrupt the endocrine function of aquatic fish in nearby surface waters. This study investigated the biotransformation outcomes of cyproterone acetate (CPA), drospirenone (DRO), and megestrol acetate (MGA) in four agricultural soils. The biotransformation data were fitted to a first-order decay model (R2 = 0.93-0.99), with half-lives and first-order decay coefficients ranging from 76.2-217 h and 9.10 × 10-3-3.20 × 10-3 (h-1), respectively. Abundant biotransformation products (TPs) were generated during incubation, with the number and yields varying across the four soils. 1,2-Dehydrogenation was the main transformation pathway of DRO in the four soils (yields of 32.3-214 %). Similarly, 1,2-dehydrogenation was the most relevant transformation pathway of MGA in the four soils (yields of 21.8-417 %). C3 reduction was the major transformation pathway of CPA in soils B, C, and D (yields of 114-245 %). Hydrogenation (yield of 133 %) and hydroxylation (yield of 21.0 %) were the second major transformation pathway of CPA in soil B and C, respectively. In particular, several TPs exhibited progestogenic and antimineralocorticoid activity, as well as genotoxicity. The high-throughput sequencing indicated that interactions between microorganisms and soil properties may affect biotransformation. Spearman correlation and bidirectional network correlation analysis further revealed that soil properties can directly interfere with the soil sorption capacity for the progestins, thus affecting biotransformation. In particular, soil properties can also limit or promote biotransformation and the formation of TPs (i.e., biotransformation pathways) by affecting the relative abundances of relevant microorganisms. The results of this study indicate that the ecotoxicity of synthetic progestins and related TPs can vary across soils and that the assessment of environmental risks associated with these compounds requires special consideration of both soil properties and microbial communities.

The impacts of endogenous progesterone and exogenous progestin on vascular endothelial cell, and smooth muscle cell function: A narrative review.

Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone receptors are present on vascular endothelial and smooth muscle cells, and therefore it has been postulated that these compounds may affect vascular function. It has been well-established that estrogen is a vasoprotective compound, however, the effects of progesterone on vascular function are not well understood. This narrative review summarizes the current research investigating the impact of both endogenous progesterone, and exogenous synthetic progestin on vascular endothelial and smooth muscle cell function and identifies discrepancies on their effects in vitro and in vivo. We speculate that an inverted-U dose response curve may exist between nitric oxide bioavailability and progesterone concentration, and that the androgenic properties of a progestin may influence vascular function. Future research is needed to discern the effects of both endogenous progesterone and exogenous progestin on vascular endothelial and smooth muscle cell function with consideration for the impacts of progesterone/progestin dose, and progestin type.

In vitro chemo-preventive efficacy of synthetic progestin Norethindrone in human epithelial ovarian cancer.

Progestin-only based oral contraceptives are majorly used as 'minipill' to prevent unintended pregnancy and treat conditions like polycystic ovary syndrome, hirsutism, and acne. However, the dearth of literature has constrained our comprehension of the exogenous progestin in relation to ovarian cancer progression. Therefore, the aim of the present study was to evaluate the chemo-preventive potential of synthetic progestin Norethindrone (NET) in epithelial ovarian cancer in vitro. Briefly, SKOV3 cells were treated with 1, 10 and 100 µM concentrations of NET for seven days period. The assays for cell viability, wound-healing, cell cycle progression, detection of reactive oxygen species (ROS) and apoptosis were executed to illustrate the protective role of NET. To further clarify the underlying process, quantitative analysis of mRNA levels of oncogenes linked to angiogenesis, inflammation, proliferation, and metastasis (VEGF, HIF-1α, COX-2, and PGRMC1) and tumour suppressor (TP53) genes was conducted. Our study revealed that NET treatment significantly reduced SKOV3 cell growth by inducing cell cycle arrest at G2/M phase, elevating ROS levels, triggering cell death via apoptosis and necrosis, and inhibiting cell migration in a dose-dependent manner. Notably, NET also upregulated TP53 expression while concurrently downregulating VEGF, HIF-1α, COX-2, and PGRMC1 expression. Our results demonstrated that the chemo-preventive effect of Norethindrone may originate from the interaction of genes which exert a protective effect against ovarian carcinogenesis. The current findings also support further investigation, which may lead to changes in prescription practices or health-related advice for women.

The Effect of Progestins on Cytokine Production in the Peripheral Blood Mononuclear Cells of Menopausal Women and Their Luminol-Dependent Chemiluminescence.

Steroid hormones are the key regulators of inflammatory and autoimmune processes. The role of steroid hormones is mostly inhibitory in these processes. The expression of IL-6, TNFα, and IL-1ß, as markers of inflammation, and TGFß, as a marker of fibrosis, could be useful tools to predict the response of an individual's immune system to the different progestins suitable for the treatment of menopausal inflammatory disorders, including endometriosis. In this study, the progestins P4 and MPA, as well as the novel progestin gestobutanoyl (GB), which possess potent anti-inflammatory properties towards endometriosis, were studied at a fixed concentration of 10 µM. Their influence on the production of the above cytokines in PHA-stimulated peripheral blood mononuclear cells (PBMCs) during 24 h incubation was evaluated by ELISA. It was found that synthetic progestins stimulated the production of IL-1ß, IL-6, and TNFα and inhibited TGFß production, while P4 inhibited IL-6 (33% inhibition) and did not influence TGFß production. In the MTT-viability test, P4 also decreased PHA-stimulated PBMC viability by 28% during 24 h incubation, but MPA and GB did not have any inhibitory or stimulatory effects. The luminol-dependent chemiluminescence (LDC) assay revealed the anti-inflammatory and antioxidant properties of all the tested progestins, as well as some other steroid hormones and their antagonists: cortisol, dexamethasone, testosterone, estradiol, cyproterone, and tamoxifen. Of these, tamoxifen showed the most pronounced effect on the oxidation capacity of PBMC but not on that of dexamethasone, as was expected. Collectively, these data demonstrate that PBMCs from menopausal women respond differently to P4 and synthetic progestins, most likely due to distinct actions via various steroid receptors. It is not only the progestin affinity to nuclear progesterone receptors (PR), androgen receptors, glucocorticoid receptors, or estrogen receptors that is important for the immune response, but also the membrane PR or other nongenomic structures in immune cells.

Serotonin and the ventilatory effects of etonogestrel, a gonane progestin, in a murine model of congenital central hypoventilation syndrome.

Introduction: Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Methods: Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The influence of etonogestrel on respiratory variables under hypercapnia was investigated using whole-body plethysmographic recording. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized in the medulla oblongata by ultra-high-performance liquid chromatography. Results: We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and Phox2b mutant without restored chemosensitivity indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Finally, the increase in serotonergic signaling by the fluoxetine application modulated the respiratory effect of etonogestrel differently between Phox2b mutant mice and their WT littermates or WT OF1 mice, a result which parallels with differences in the functional state of serotonergic metabolic pathways between these different mice. Discussion: Our work thus highlights that serotonin systems were critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.

Progesterone and contraceptive progestin actions on the brain: A systematic review of animal studies and comparison to human neuroimaging studies.

In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.

The potent contraceptive gestodene exerts insulinotropic effects through its a-ring reduced metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.

PURPOSE: The contraceptive gestodene is a potent synthetic progestin used in several low-dose contraceptive formulations. Clinical studies reported a relationship between long-term use of combined oral contraceptives containing gestodene (GDN) and profound alterations in glucose metabolism in women. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether GDN may induce estrogen-like effects, even though GDN does not interact with estrogen receptors. The aim of this study was to investigate whether GDN affect pancreatic ß-cell activity, directly or through its conversion to other bioactive metabolites. METHODS: The effects of GDN and its two derivatives 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN on insulin 2 (Ins II) and glucokinase (Gk) expression and glucose-stimulated insulin secretion were determined in pancreatic islets from female rats. RESULTS: Gestodene did exert significant effects on islet ß-cells activity. The most striking finding was that 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN had greater stimulatory effects on Ins II and Gk expression than that observed with GDN, consistent with their effects on glucose-stimulated insulin secretion. The effects on gene expression induced by GDN-derivatives were abolished by ICI 182,780 and MPP. In addition, the presence of inhibitors of androgen and progestin-metabolizing enzymes eliminated gene expression induced by GDN. These results indicated that GDN is metabolized to A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect ß-cell activity. CONCLUSIONS: Altogether, the data suggest that 19-nortestosterone-derived contraceptives such as GDN, possess insulinotropic effects through their conversion into metabolites with intrinsic estrogen-like activity in pancreatic ß-cells.

The transcriptional activity of progestins used in contraception and menopausal hormone therapy via progesterone receptor A is dependent on the density of the receptor.

Studies directly comparing the efficacies and potencies of multiple progestins used in contraception and menopausal hormone therapy (MHT) in parallel via human progesterone receptor isoform A (PR-A) in the same model system are limited, and how these parameters are influenced by the density of PR-A are unclear. This is surprising as it is known that the expression levels of PR-A vary in different tissues and diseases. We thus determined for the first time the relative efficacies and potencies for transactivation of the natural PR ligand, progesterone (P4), the PR-specific agonist promegestone (R5020), and selected progestins from all four generations in parallel via different densities of PR-A overexpressed in the MDA-MB-231 breast cancer cell line. Comparative dose-response analysis showed that P4, R5020, the 1st generation progestins medroxyprogesterone acetate and norethisterone, 2nd generation progestin levonorgestrel, 3rd generation progestin gestodene, as well as 4th generation progestins nesterone, nomegestrol acetate and drospirenone display differential agonist efficacies and potencies via PR-A. Moreover, we showed that the agonist efficacies and potencies of the progestins via PR-A were modulated in a density- and progestin-specific manner. Our finding that the potencies of the progestins via PR-A, at all densities, do not exceed reported progestin serum concentrations in women, suggest that these progestins are likely to elicit similar effects in vivo. We are the first to report that P4 and the selected progestins display similar agonist activity for transrepression via PR-A, and that the density of PR-A enhances the transrepression activity of some, but not all progestogens. Collectively, our findings provide proof of concept that the effects of the selected progestins via PR-A is progestin-specific and dependent on the density of the receptor, suggesting differential progestin responses in women using these progestins in contraception and MHT.

Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study.

OBJECTIVES: Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN: In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS: A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS: During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS: In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

Dydrogesterone disrupts lipid metabolism in zebrafish brain: A study based on metabolomics and Fourier transform infrared spectroscopy.

Brain is a potential target for neuroprogestogens and/or peripheral progestogens. Previous studies reported that expression of genes about steroidogenesis, reproduction, cell cycle, and circadian rhythm in zebrafish brain could be affected by progestogens. However, there are limited information from metabolites or biomacromolecules aspects, leaving an enormous gap in understanding toxic effects of progestogens on fish brain. In this study, we exposed zebrafish embryos to 2.8, 27.6, and 289.8 ng/L dydrogesterone (DDG, a synthetic progestogen) until sexual maturity (140 days). LC-MS and GC-MS based untargeted metabolomics and Fourier-transform infrared (FTIR) spectroscopy were then performed to investigate the metabolic profiles and macromolecular changes of brain of these zebrafish. The results from multivariate statistical analysis of metabolite features showed a clear separation between different treatment groups of both female and male zebrafish brains. DDG exposure increased the levels of cholesterol, saturated fatty acids, and nucleoside monophosphates, but decreased the contents of polyunsaturated fatty acids (PUFAs), lysophosphatides, and nucleosides in dose-dependent manner. FTIR results indicated that DDG exposure led to accumulation of saturated lipids, reduction of nucleic acids and carbohydrates, and alteration of protein secondary structures. The findings from this study demonstrated that DDG could affect contents of metabolites and biomacromolecules of zebrafish brain, which may finally lead to brain dysfunctions.

Biotransformation kinetics and pathways of typical synthetic progestins in soil microcosms.

Gestodene (GES), altrenogest (ALT), and medroxyprogesterone acetate (MPA) are three potent synthetic progestins detected in agricultural soils; however, their biotransformation outcomes in soils remain unclear. This study explored the biotransformation of these progestins in five agricultural soils with different physicochemical properties. The biotransformation data were well-described by a first-order decay model (R2 = 0.83-0.99), with estimated half-lives ranging between 12.1 and 188 h. Amplicon sequencing indicated that the presence of progestins changed the bacterial richness and community structure in the soils. Linear correlation, canonical correlation, and two-way correlation network analysis revealed that soil properties can affect biotransformation rates by interfering with progestin-soil interactions or with keystone taxa in soils. The clustermap demonstrated the formation of abundant transformation products (TPs). Isomerization and C4(5) hydrogenation were the major transformation pathways for GES (yields of ∼ 13.7 % and ∼ 10.6 %, respectively). Aromatic dehydrogenation was the major transformation pathway for ALT (yield of ∼ 17.4 %). The C17 hydrolysis with subsequent dehydration and hydrogenation was the major transformation pathway for MPA (yield of ∼ 196 %). In particular, some TPs exhibited progestagenic, androgenic, or estrogenic activity. This study highlights the importance of evaluating the ecotoxicity of progestin and TP mixtures for better understanding their risks in the environment.

Abiotic transformation of synthetic progestins in representative soil mineral suspensions.

Altrenogest (ALT), drospirenone (DRO), and melengestrol acetate (MLA) are three highly potent synthetic progestins that can be released into agricultural soils, while their fate in soil minerals remains unclear. This study explored the transformation of these progestins in MnO2, SiO2, and ferrihydrite suspensions and identified their transformation products (TPs) via high resolution mass spectrometry and density functional theory calculations. Transformations were only observed for DRO and MLA in SiO2 suspension and ALT in MnO2 suspension (half-lives = 0.86 min - 9.90 day). ALT transformation was facilitated at higher MnO2 loadings, while DRO and MLA transformations were inhibited at higher SiO2 loadings. These data indicated that hydrophobic partitioning interaction was dominant at higher SiO2 loadings rather than specific interaction, which limited subsequent surface-catalyzed transformation. ALT transformation rate decreased with increasing pH because MnO2 reduction requires proton participation. In contrast, relatively high pH facilitated MLA and DRO transformation, indicating that base-catalyzed hydrolysis occurred in SiO2 suspension. The clustermap demonstrated the formation of abundant TPs. Lactone ring and acetoxy group hydrolysis was the major transformation pathway for DRO and MLA, with estimated yields of 57.7% and 173.2% at 6 day, respectively. ALT experienced C12 hydroxylation and formed the major TP 326g (yield of 15.4% at 8 hr). ALT also experienced allyl group oxidation and subsequent C5 hydroxylation, forming the major TP 344a (yield of 14.1% at 8 hr). This study demonstrates that TPs of metastable progestins are likely the main species in soils and that TP identification is a particular priority for risk assessment.

Effects of the synthetic progestin levonorgestrel on some aspects of thyroid physiology in common carp (Cyprinus carpio).

The objective of the present study was to assess the effects of levonorgestrel (LNG), a synthetic progestin, on early development and the thyroid system of carp using morphological, histological, immunohistochemical, and gene expression analysis. Fish were exposed to LNG at three levels (3, 31, and 310 ng L-1) from eggs to the onset of juvenile stage (47 days). LNG had no significant effect on early development in common carp or on the occurrence of morphological anomalies. No pathological alterations of the thyroid follicles were found. Immunohistochemical examination of the thyroid follicles using antibodies against thyroxin did not show any differences in fish exposed to 310 ng L-1 LNG compared to the controls. mRNA expression of iodothyronine deiodinases (dio1, 2, 3) was differentially affected by LNG treatment during carp development. Most importantly, dio3 was markedly downregulated in fish exposed to all three LNG levels compared to the controls at the conclusion of the experiment (47 days post-fertilization). A decrease in dio1 or dio3 or an increase in dio2 transcription observed at different time points of the study may be a sign of hypothyroidism. mRNA expression of genes npr, esr1, and esr2b in the body and npr and esr2b in the head of fish exposed to 310 ng L-1 LNG was significantly upregulated compared to the solvent control group at the end of the test. Together, these results show that levonorgestrel caused parallel changes in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonad axes.

The progestin-only pills drospirenone 4 mg and desogestrel 0.075 mg as an option for the management of dysmenorrhea and mastodynia.

INTRODUCTION: Dysmenorrhea and mastodynia are the most common gynecologic pain causes in women of all ages and races during their reproductive life. The following study aimed to show the influence of two POP´s in the development of dysmenorrhea and mastodynia after nine months of use. MATERIAL AND METHODS: A total of 858 women with 6691 drospirenone (DRSP) cycles and 332 women with 2487 desogestrel (DSG) cycles were analyzed. Women included in this study were all child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45. RESULTS: At screening, 168 (19.6%) of the 858 patients using DRSP and 64 (19,3%) of the DSG patients reported that they had suffered from dysmenorrhea within six cycles prior to the first visit before starting with the medication. 20,2% of the DRSP and 10,9% of the DSG group had a sever dysmenorrhea. After 9 cycles this was reduced to 0,6% and 3,1% respectively. In total, 96 women (11.2%) in the DRSP and 49 (14,8%) experienced mastodynia within six cycles before the screening. Of these 91.6% in the DRSP group and 91,8% in the DSG group had no or mild mastodynoa at follow-up. DISCUSSION: The progestins 4 mg and desogestrel 0,075 mg showed a marked effect in the non-contraceptive aspects of dysmenorrhea and mastodynia so that new possibilities are opened for these two benign gynecological diseases. Future studies must reaffirm these first data.

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.