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Objectives: The good healing of the hysterotomy after cesarean section is important for subsequent pregnancies. However, the factors which improve this healing have not been completely described, yet. In this study, we focused on factors which may affect healing of hysterotomy within one year after delivery, such as menstruation, breastfeeding, and the use of the contraception. Material and methods: Following delivery, total of 540 women were invited for three consecutive visits at six weeks, six months, and 12 months postpartum. The presence of menstruation, frequency of breastfeeding and contraception use were recorded. The scar was evaluated by vaginal ultrasound as already described. The impact of menstruation, breastfeeding, and contraception method on presence of niche was evaluated. Results: The presence of menstruation increased odds to have niche by 45% (CI 1.046-2.018, p = 0.026). Secondarily, our results demonstrated a statistically significant protective effect of breastfeeding on the incidence of niche with OR 0.703 (CI 0.517-0.955, p = 0.024). Breastfeeding decreases odds to have niche by 30%. Also, the use of gestagen contraception lowered the odds by 40% and intrauterine device (IUD) or combine oral contraceptive (COC) by 46.5%. The other possibly intervening factors were statistically controlled. Conclusions: Amenorrhea, breast-feeding and progesterone-contraceptive decreases the risk of uterine niche within one year follow up. [ABSTRACT FROM AUTHOR]

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Objective: To identify the prevalence of hormonal contraceptive (HC) use, menstrual cycle disturbances, and self-perceived physical and emotional symptoms related to the menstrual cycle/pill cycle in elite female athletes. Methods: One hundred eighty-six Danish elite female athletes completed an online questionnaire to assess menstrual status and history, use of HCs, and self-perceived physical and emotional symptoms related to the menstrual cycle or HC use. Results: Fifty-seven percent of elite female athletes in Denmark use HC, with 74% using combined HCs and 26% using progestin only. Sixty percent of oral contraceptive users reported having manipulated their menstrual cycle by continuous oral contraceptive use. Forty-nine percent of non-HC users had a regular menstrual cycle, while 51% experienced menstrual disturbances, with 1 athlete being primary amenorrheic and 13 athletes having secondary amenorrhea. Menstrual disturbances were experienced by a larger proportion of endurance athletes (69%) compared with athletes performing power and technical disciplines. In endurance athletes amenorrhea was associated with a higher cardiovascular training volume (P <.001). Negative symptoms related to the menstrual/pill cycle were reported by both HC and non-HC users, whereas positive physical symptoms were experienced more often among the non-HC (14%) versus HC users (2%) (P <.01). Notably, 13% of the athletes reported that negative symptoms sometimes/always caused them to not participate in or complete the scheduled training. Conclusion: HC use is common among elite athletes, and continuation of HC is used to manipulate the menstrual cycle in relation to sport competitions. HC use does not abolish dysmenorrhea, but it may reduce emotional-related side effects. Menstrual disturbances are frequent in endurance athletes and are associated with cardiovascular training volume. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic inflammatory disease that occurs in women of reproductive age. Much of the treatment involves hormone therapy that suppresses the proliferation of endometriosis lesions. Objective To compare discontinuation rates of pharmacological treatment with estrogen-progestins and progestins medications. The secondary objective is to evaluate the main side effects of these drugs in patients with endometriosis. Methods This retrospective study analyzed data from 330 patients who attended the Hospital of the State Public Servant of São Paulo from August 1999 to September 2020 and received pharmacological treatment for endometriosis. The data were obtained by review of the files of medical appointments with specialized staff. Results The median treatment time was 18 months, ranging from 1 to 168 months, and 177 patients interrupted the proposed treatment. The combined contraceptives with estrogens and progestins were significantly linked to treatment interruption, with a relative risk of 1,99 (p = 0,005). The most important side effects that resulted in treatment interruption were pain persistence (p = 0,043), weight gain (p = 0,017) and spotting (p < 0,001). [ABSTRACT FROM AUTHOR]

Background: Wide range of ovulation distribution is the main restricting factor in establishing the pregnancy following oestrus synchronization (ES) and fixed time insemination (FTI) in sheep. Objectives: Determining the ovulation time (OVT) following ES with two different vaginal devices, its relation to progesterone and conception upon FTI with frozen/thawed semen. Methods: Oestrus was synchronized using either controlled internal drug release (CIDR) (ewe, n = 6; ewe lamb, n = 5) or vaginal sponge (ewe, n = 6; ewe lamb, n = 5) insertion for 12 days, plus Equine chorionic gonadotropin (eCG) at devices removal (Day 0). Sizes of the ovarian follicles were measured using transvaginal probe at −12, 0 and 30–33, 53 h and continued every 3–4 h until 75 h after eCG treatment. Serum progesterone amounts were measured at −12, 0, +2 and +11. Laparoscopic FTI was done at 60.5 ± 0.5 h. Results: The CIDR‐treated group initiated and completed ovulations earlier compared to sponge‐treated females (median: 64 vs. 71 h; p < 0.05). Ewe lambs were ovulated earlier compared to ewes in the sponge‐treated group (66.71 vs. 71.5; p = 0.017). Mean sizes of ovulatory follicles and corpora lutea were not affected by device types. Higher amounts of progesterone were observed in CIDR group compared to sponge‐treated group at device removal (2.68 ± 0.12 vs. 0.30 ± 0.01 ng/mL; p < 0.001). The conception was confirmed in 2/10, and 5/11 females of sponge and CIDR‐treated females, respectively. Conclusions: Types of progestogens influence the OVT, and consequently the result of FTI with frozen/thawed semen. The optimum timespan for FTI should be chosen according to the device types during non‐breeding season. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Timing of reproductive events can be crucial for a species' population growth and stability. Accurate detection of reproductive phenology presents a challenge to scientists studying wild species, including moose (Alces alces). Currently, there are several established methods for monitoring reproductive activity and events in domestic ruminants, including the use of biologging devices. The main objective of this study was to determine whether female moose display a distinct thermal and activity pattern associated with luteal activity during the estrous cycle, which could be used to determine the onset of their breeding season. We deployed biologging devices and collected fecal samples from 12 captive female moose on the Kenai Peninsula, Alaska, USA to explore variation in vaginal temperature and collar activity and the relationship between these variables and fecal progestagen concentrations. Fecal samples were collected from mid-August to mid-October and analyzed using radioimmunoassay to determine the concentration of fecal progestagens to classify luteal activity. Results: Captive female moose displayed an identifiable thermal pattern during the onset of luteal activity from mid-September to mid-October, associated with the initial estrous cycle of their breeding season. In contrast, we did not observe a distinct pattern in activity during this period. Recurring patterns in both vaginal temperature and activity were identified between mid-October and mid-November, however, which were likely associated with subsequent estrous cycles but not included in our fecal sampling period. Conclusions: This study supports that female moose display an identifiable pattern in vaginal temperature which is associated with luteal activity of the initial estrous cycle of the breeding season. An identifiable pattern was observed for both vaginal temperature and activity registrations at the presumed timing of subsequent estrous cycle of the breeding season. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Key content: Women receiving estrogen replacement require concomitant progestogen to prevent endometrial hyperplasia and carcinoma.A variety of progestogens are used in hormone replacement therapy (HRT), with different advantages and disadvantages and routes of administration.Progestogenic side effects may be mild but can be debilitating and lead to the discontinuation of HRT, so progestogens should be tailored to the individual woman.Combined HRT containing estrogen and progestogens may be associated with a small increase in the absolute risk of breast cancer, which is not seen in women taking estrogen alone. However, this risk is small, particularly when compared with other modifiable lifestyle risk factors.The addition of certain progestogens to estrogen in the long term may be associated with an increased risk of heart disease, breast cancer and dementia. Learning objectives: To understand relative advantages and disadvantages of the different progestogens, regimens and routes of administration.To be aware of current evidence for types, dose and routes of administration of different progestogens.To be able to prescribe progestogens safely in terms of side effect and risk profiles that are individualised to the patient. Ethical issues: Well‐informed counselling including absolute, individualised risks for women considering HRT with a progestogenic component is essential to allow patients to make well‐informed choices. [ABSTRACT FROM AUTHOR]

He considered himself to be a degradative chemist rather than a synthetic chemist exactly because of his interest in structure elucidation. Lacking financial resources (initially, his mother could work only as a physician's assistant), Djerassi worked for one year for CIBA as a junior chemist. Djerassi and his team wanted to develop a progesterone modification that would be orally consumable. [Extracted from the article]

Introduction: Menopausal hormone therapy (MHT) is used to alleviate the symptoms associated with menopause, despite the lack of recommendations for MHT in preventing dementia. Recent nationwide studies have explored the association between MHT and dementia risk, but the findings remain limited. This study aims to investigate the association between MHT and the incidence of Alzheimer's disease (AD) and non-AD dementia using national population data from Korea. Methods: We conducted a retrospective study using data from the National Health Insurance Service in Korea between January 1, 2002, and December 31, 2019. Women over 40 years were eligible for this study and classified into the MHT or non-MHT groups. The MHT group consisted of women who used Tibolone (TIB), combined estrogen plus progestin by the manufacturer (CEPM), estrogen, combined estrogen plus progestin by a physician (CEPP), and transdermal estrogen during menopause. We compared the risk of dementia between the MHT and non-MHT groups. Results: The study included 1,399,256 patients, of whom 387,477 were in the MHT group, and 1,011,779 were in the non-MHT group. The median duration of MHT was 23 months (range: 10-55 months). After adjusting for available confounders, we found that different types of MHT had varying effects on the occurrence of dementia. TIB (HR 1.041, 95% confidence interval (CI) 1.01-1.072) and oral estrogen alone (HR 1.081, 95% CI 1.03-1.134) were associated with a higher risk of AD dementia. In contrast, there was no difference in the risk of AD dementia by CEPM (HR 0.975, 95% CI 0.93-1.019), CEPP (HR 1.131, 95% CI 0.997-1.283), and transdermal estrogen (HR 0.989, 95% CI 0.757-1.292) use. The use of TIB, CEPM, and oral estrogen alone increased the risk of non-AD dementia (HR 1.335, 95% CI 1.303-1.368; HR 1.25, 95% CI 1.21-1.292; and HR 1.128, 95% CI 1.079-1.179; respectively), but there was no risk of non-AD dementia in the other MHT groups (CEPP and topical estrogen). Conclusion: Our findings indicate that MHT has varying effects on the incidence of AD and non-AD dementia. Specifically, TIB, CEPM, and oral estrogen alone increase the risk of non-AD dementia, while transdermal estrogen is not associated with dementia risk. It is essential to consider the type of MHT used when assessing the risk of dementia in women. [ABSTRACT FROM AUTHOR]

Simple Summary: Preclinical studies have shown an anti-neoplastic effect of progestins against adrenal cortical carcinoma. Progestins have a positive effect on patient cenesthesia and may make standard chemotherapy more tolerable. In this study, the addition of megestrol acetate to the etoposide, doxorubicin, cisplatin, and mitotane regimen (EDP-M) in patients with ACC and a low PS allowed the administration of EDP-M at adequate doses, and the efficacy was not inferior to that of EDP-M administered to patients with a good PS. Since a low PS is a predictive factor of poor efficacy of antineoplastic treatments in cancer patients, these results suggest a potentiating effect of megestrol acetate to EDP-M and provide the rationale for the ongoing randomized study at the Medical Oncology of Brescia. (1) Background: The standard first-line therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane). Progestins have shown cytotoxic activity both in vitro and in vivo on ACC; better EDP-M tolerability and efficacy have been hypnotized due to the association with progestins. (2) Methods: The feasibility and tolerability of EDP-M combined with oral megestrol acetate (EDP-MM) were tested in 24 patients (pts) affected by metastatic ACC with a low performance status (PS); the case group was compared with a 48 pts control group according to the propensity score. The secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). (3) Results: Thirteen pts (54.2%) in the EDP-MM population experienced progestin-related toxicities; in particular, five pts experienced vaginal bleeding (20.8%); four pts experienced weight gain (16.7%); and thromboembolic events, worsening of hypertension, skin rashes, and hyperglycemia were registered in one patient each (4.2%). This led to the discontinuation of megestrol acetate in four pts (16.7%). EDP-M-related toxicities were similar in both groups. No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) Conclusions: The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. Methods: A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Of 2342 cases reviewed, 74 met inclusion criteria. Sixty‐six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2–17.9) and 23.3 months (14.8–36.8), respectively. The PFS for patients with Grade 1–2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1–2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty‐four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy‐naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy‐naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. Conclusions: This real‐world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy‐naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy‐OS was 29.1 months (17.9, 61.1) for chemotherapy‐naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. This real‐world data on recurrent and metastatic endometrial carcinoma (RMEC) suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy‐naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following>=1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy‐OS was 29.1 months (17.9, 61.1) for chemotherapy‐naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. [ABSTRACT FROM AUTHOR]

Cyproterone acetate (CPA) is known to induce meningioma, and recently, nomegestrol acetate (NMA) and chlormadinone acetate (CMA) were also involved. Progestagen‐induced meningioma management starts with progestogen discontinuation and is either interventional (surgery and/or radiotherapy) or conservative (clinical and MRI radiological follow‐up). We performed a retrospective volumetric radiological outcomSe study of progestogen‐induced meningiomas diagnosed in our hospital. We analysed progestogen‐related meningiomas diagnosed until 30 June 2021, with at least one diagnostic and one follow‐up MRI results. Meningioma volumes were centrally retrospectively measured using a T1‐weighted 3D millimeter sequence with gadolinium injection on a postprocessing console. We analysed 98 meningiomas of 38 females and one transgender (male‐to‐female), of which 25 (64.1%) had taken CPA, seven (17.9%) NMA, three (7.7%) CMA, and four (10.2%) several progestogens. Eleven patients (24 meningiomas) underwent interventional management, seven patients had meningiomas followed by conservative or interventional management, and 21 patients (51 meningiomas) had only conservative management. Of these 21 patients, 17 had discontinued their progestogen less than 6 months before, of which 14 (82.3%) had decreased or stable meningioma(s) during a 24‐month median follow‐up (3 to 75) period. Overall, four of the 39 patients experienced meningioma progression (three during conservative treatment and one after surgery), including two patients who had continued NMA or CMA treatment several years after diagnosis. Our study confirms a generally favourable outcome of progestogen‐related meningioma after conservative treatment, especially for CPA. It also underlines the need for progestogen discontinuation at meningioma diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeting receptor activator of nuclear factor-κB ligand (RANKL) with the monoclonal antibody Denosumab decreases osteoclast-mediated bone resorption and is approved for the treatment of postmenopausal osteoporosis. Since RANKL is also implicated in mammary gland homeostasis and breast tumorigenesis, Denosumab is being currently pursued as a candidate for drug repurposing in oncology, including breast cancer, while its efficacy remains controversial. In this study, by developing a humanized transgenic mouse model of human RANKL overexpression, we demonstrated that RANKL mediated hormone-induced mammary carcinogenesis, while its prophylactic inhibition by Denosumab prevented tumorigenesis. Our humanized transgenic mice provide a unique genetic tool for investigating the involvement of human RANKL in breast cancer pathogenesis and can serve as a preclinical platform for anticancer therapies. Receptor activator of nuclear factor-κB ligand (RANKL) is critically involved in mammary gland pathophysiology, while its pharmaceutical inhibition is being currently investigated in breast cancer. Herein, we investigated whether the overexpression of human RANKL in transgenic mice affects hormone-induced mammary carcinogenesis, and evaluated the efficacy of anti-RANKL treatments, such as OPG-Fc targeting both human and mouse RANKL or Denosumab against human RANKL. We established novel MPA/DMBA-driven mammary carcinogenesis models in TgRANKL mice that express both human and mouse RANKL, as well as in humanized humTgRANKL mice expressing only human RANKL, and compared them to MPA/DMBA-treated wild-type (WT) mice. Our results show that TgRANKL and WT mice have similar levels of susceptibility to mammary carcinogenesis, while OPG-Fc treatment restored mammary ductal density, and prevented ductal branching and the formation of neoplastic foci in both genotypes. humTgRANKL mice also developed MPA/DMBA-induced tumors with similar incidence and burden to those of WT and TgRANKL mice. The prophylactic treatment of humTgRANKL mice with Denosumab significantly prevented the rate of appearance of mammary tumors from 86.7% to 15.4% and the early stages of carcinogenesis, whereas therapeutic treatment did not lead to any significant attenuation of tumor incidence or tumor burden compared to control mice, suggesting the importance of RANKL primarily in the initial stages of tumorigenesis. Overall, we provide unique genetic tools for investigating the involvement of RANKL in breast carcinogenesis, and allow the preclinical evaluation of novel therapeutics that target hormone-related breast cancers. [ABSTRACT FROM AUTHOR]

Summary : Pregnancy and lactation associated osteoporosis is a rare and often severe osteoporosis presentation. Little information is available about etiology, clinical characteristics, risk factors and predictors of severity. Using an anonymized questionnaire, we defined clinical characteristics and potential risk factors for disease severity in PLO including primiparity, heparin exposure and celiac disease. Purpose: Pregnancy and lactation associated osteoporosis (PLO) is a rare form of early-onset osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. Little information is available about etiology, clinical characteristics, risk factors and predictors of disease severity. Methods: PLO patients were recruited to complete an anonymized online questionnaire. Disease severity was defined as total number of fractures during or after the first pregnancy associated with a fracture(s). Analyses related disease severity to potential predictors including diseases/conditions or medication exposures. Results: 177 completed surveys were received between 5/29/2018 and 1/12/2022. Average age at initial PLO fracture event was 32 ± 5 years. The majority were primiparous with singleton pregnancy and 79% fractured during lactation. Subjects reported 4.7 ± 2.7 total PLO fractures, with 48% reporting ≥ 5 fractures. Vertebral fractures, reported by 164/177 responders (93%), were the most common fracture type. Conditions and medications most commonly reported included vitamin D deficiency, amenorrhea unrelated to pregnancy, nephrolithiasis, celiac disease (CD), oral steroid use, heparin products during pregnancy and progestin only contraceptive after pregnancy. CD and heparins exposure during pregnancy were significantly related to disease severity. Conclusion: This is the largest study characterizing clinical features of PLO to date. The large number of participants and broad range of clinical and fracture characteristics queried has yielded novel information on the characteristics of PLO and potential risk factors for its severity, including primiparity, exposure to heparin and CD. These findings provide important preliminary data that can help target future mechanistic investigations. [ABSTRACT FROM AUTHOR]

The residues of progestins in milk are significant risk factors for teenage acne and may cause hormone-dependent cancers in consumers, so the determination of these residues in milk is very important. However, an immunoassay or immunoassay-like method capable of determining multiple progestins in milk has not been reported so far. The present study, for the first time, synthesized a type of magnetic molecularly imprinted microsphere that was capable of simultaneously recognizing five progestins. At the same time, an enzyme labeled conjugate was synthesized by coupling progesterone 3-(o-carboxymethyl)oxime with streptavidinated horseradish peroxidase. The above two reagents were used to develop a semi-homogeneous method for the simultaneous detection of the residues of the five progestins in milk. During the experiments, biotinylated horseradish peroxidase was used to amplify the signal, so the sensitivity to the five drugs (limits of detection 0.04–0.1 pg/mL) was increased 44–75-fold. In addition, the magnetic molecularly imprinted microsphere could be regenerated four times by using simple elution. Through general comparison of its detection spectrum, sensitivity, simplicity, and reusability, the present method exhibited better performance than the previous immunoassays for the detection of progestins, and so it could be used as a routine tool for the screening of progestins residues in milk. [ABSTRACT FROM AUTHOR]

Introduction: Acute hepatic porphyrias (AHP) are a rare group of inherited disorders caused by abnormal functioning of the heme synthesis pathway. Patients often present with diffuse abdominal pain, neurologic dysfunction, and hyponatremia. Case Report: We present a case of a 25-year-old female who presented with AHP after implantation of progestin birth control. The patient was confused, markedly tachycardic and hypertensive, and complained of severe abdominal pain. Spot urine ordered during the emergency department workup was later found positive for porphyrins and porphobilinogen (PBG). Conclusion: Acute hepatic porphyrias typically present with nonspecific symptoms in young women and are often overlooked in the acute care setting. Spot urine testing for PBG and urine porphyrins should be initiated early in patients with clinical suspicion of AHP. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate within-cycle differences in nocturnal heart rate (HR) and heart rate variability (HRV) in naturally menstruating women (NM) and women using combined hormonal contraceptives (CU) or progestin-only hormonal contraceptives (PU). Methods: Physically active participants were recruited into three groups: NM (n = 19), CU (n = 11), and PU (n = 12). Participants' HR and HRV (with Bodyguard 2 HRV monitor) and blood hormones were monitored during one menstrual cycle (MC) (NM group) or for 4 wk (CU and PU groups). Estradiol, progesterone, and luteinizing hormone were analyzed from fasting blood samples collected four times in the NM (M1 = bleeding, M2 = follicular phase, M3 = ovulation, and M4 = luteal phase) and PU groups (M1 = lowest E2, M2 = M1 + 7 d, M3 = M1 + 14 d, and M4 = M1 + 21 d) and twice in the CU group (active and inactive pill phases). After every blood sample, nightly HR and HRV were recorded and examined as an average from two nights. Results: Hormonal concentrations differed (P < 0.05) between MC phases in the NM and PU groups, but not (P ≥ 0.116) between the active and the inactive phases in the CU group. In the NM and PU groups, some of the HRV values were higher, whereas in the NM group, HR was lower during M2 compared with M3 (P < 0.049) and M4 (P < 0.035). In the CU group, HRV values (P = 0.014–0.038) were higher, and HR was lower (P = 0.038) in the inactive phase compared with the first week of the active phase. Conclusions: The MC and the hormonal cycle phases influence autonomic nervous system balance, which is reflected in measurements of nocturnal HR and HRV. This should be considered when monitoring recovery in physically active individuals. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the application status and rationality of progestogens in outpatient and emergency patients in China based on big data analysis techniques, so as to provide support for promoting clinical rational drug use and ensuring drug safety for patients. METHODS: Data of progestogen prescriptions from 2016 to 2020 were extracted from 112 hospitals in 9 cities. The application status of progestogens in China was analyzed, the composition and selection of progestogen for typical diseases were analyzed, and the problem of off-label indications was discussed. RESULTS: Totally 540 184 prescriptions were enrolled, including 605 233 records of progestogens. Except for 2020, which may be affected by COVID-19, the overall use and frequency of progestogens were on the increase, and the defined daily cost of high-priced progestogens decreased significantly since 2017. Progestin and dydrogesterone were the most widely used, and the latter had an obvious trend of increasing in clinical selection. Drug combination of progestogens were common (10. 9%, 58 625 cases). The applications of progestogens in patients with typical diseases had their own characteristics, and the drug selection was basically rational. Off-label indications were also common, and the most common diagnoses were endometrial polyps, gynecological examination and vaginitis. CONCLUSIONS: Progestogens are widely used in China and show an increasing trend, and the clinical application is basically reasonable, yet the problem of off-label indication drug use and the lack of evidence for drug combination deserve attention. In the future, it is still necessary to carry out high-quality clinical studies with large samples to verify the safety, effectiveness and economy of the use of progestogens. [ABSTRACT FROM AUTHOR]

Objective: This study aims to compare treatment outcomes of a levonorgestrel-releasing intrauterine system (LNGIUS) or oral progestogens in women with non-atypical endometrial hyperplasia (EH). Additionally, the predictors for EH non-regression were determined. Methods: Medical records of women diagnosed with non-atypical EH between April 2016 and March 2022 at Tuen Mun Hospital were retrieved. These patients were offered LNG-IUS as the first-line option or oral progestogens if they refused or had LNG-IUS contraindications such as submucosal fibroid distorting endometrial cavity. The rate of EH non-regression at 12 months and the rate of EH relapse at 24 and 36 months between groups were compared. Univariate and multivariate analyses were conducted to identify predictors for EH non-regression. Results: The median follow-up duration was 24 months for the LNG-IUS group and 19 months for the oral progestogens group. The rate of EH regression at 12 months was higher in the LNG-IUS group (93.9% vs 71.2%, p<0.001). The rate of EH relapse was higher in the oral progestogens group at 24 months (21.1% vs 1.1%, p=0.003) and 36 months (33.3% vs 2.3%, p=0.014). The incidence of hysterectomy for treatment failure was higher in the oral progestogens group (13.7% vs 4.2%, p=0.005). No EH relapse occurred in either group after 36 months posttreatment. Predictors for EH non-regression were postmenopausal status (odds ratio=5.80, p=0.022) and oral progestogens treatment (odds ratio=7.51, p<0.001). Conclusion: In women with non-atypical EH, treatment with LNG-IUS leads to a higher regression rate at 12 months, a lower relapse rate within 36 months, and a lower rate of hysterectomy due to treatment failure, compared with treatment with oral progestogens. Postmenopausal status and treatment with oral progestogens are risk factors for treatment failure. Regular endometrial surveillance should be provided to women at risk. Hysterectomy is recommended for postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Abnormally changed steroid hormones during pregnancy are closely related to the pathological process of gestational diabetes mellitus (GDM). Our aim was to systematically profile the metabolic alteration of circulating steroid hormones in GDM women and screen for risk factors. Methods: This study was a case-control study with data measured from 40 GDM women and 70 healthy pregnant women during their 24-28 gestational weeks. 36 kinds of steroid hormones, including 3 kinds of corticosteroids, 2 kinds of progestins, 5 kinds of androgens and 26 kinds of downstream estrogens in serum were systematically measured using a combined sensitive UPLC-MS/MS method. The flux of different metabolic pathways of steroid hormones was analyzed. Logistic regression and ROC curve model analyses were performed to identify potential steroid markers closely associated with GDM development. Results: Serum corticosteroids, progestins and almost all the estrogen metabolites via 16-pathway from parent estrogens were higher in GDM women compared with healthy controls. Most of the estrogen metabolites via 4-pathway and more than half of the metabolites via 2-pathway were not significantly different. 16a-hydroxyestrone (16OHE1), estrone-glucuronide/sulfate (E1-G/S) and the ratio of total 2-pathway estrogens to total estrogens were screened as three indicators closely related to the risk of GDM development. The adjusted odds ratios of GDM for the highest quartile compared with the lowest were 72.22 (95% CI 11.27-462.71, Ptrend <0.001) for 16OHE1 and 6.28 (95% CI 1.74-22.71, Ptrend <0.05) for E1-G/S. The ratio of 2-pathway estrogens to total estrogens was negatively associated with the risk of GDM. Conclusion: The whole metabolic flux from cholesterol to downstream steroid hormones increased in GDM condition. The most significant changes were observed in the 16-pathway metabolism of estrogens, rather than the 2- or 4-pathway or other types of steroid hormones. 16OHE1 may be a strong marker associated with the risk for GDM. [ABSTRACT FROM AUTHOR]

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-1β, as markers of inflammation, and TGFβ, 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-1β, IL-6, and TNFα and inhibited TGFβ production, while P4 inhibited IL-6 (33% inhibition) and did not influence TGFβ 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. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does YAP1 inhibition alleviate progesterone resistance in endometriosis? SUMMARY ANSWER YAP1 inhibition reduces progesterone resistance in vitro and in vivo. WHAT IS KNOWN ALREADY Progesterone resistance not only causes treatment failure for endometriosis but also inhibits eutopic endometrial cell proliferation, dysregulates decidualization, and reduces the success rates of pregnancy. Hippo/yes-associated protein 1 (YAP1) signaling pathway plays an important role in the pathogenesis of endometriosis. STUDY DESIGN, SIZE, DURATION Paraffin-embedded tissues containing paired endometriotic and endometrial specimens (n = 42) and serum samples isolated from normal controls (n = 15) or endometriotic patients with (n = 25) or without (n = 21) prior dienogest treatment were analyzed. A mouse model of endometriosis was also used to evaluate the effects of YAP1 inhibition on progesterone resistance. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary endometriotic and endometrial stromal cells treated with YAP1 inhibitor or miR-21 mimic/inhibitor were used for the in vitro studies including decidualization induction, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation. Tissue specimens and serum from human and mouse were used for immunohistochemistry staining, exosome isolation, and microRNA (miRNA) quantification, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Herein, we report, by using ChIP-PCR and RNA-IP, that YAP1 inhibits progesterone receptor (PGR) expression through upregulation of miR-21-5p. Upregulation of miR-21-5p not only reduces PGR expression but also inhibits endometrial stromal cell decidualization. Indeed, levels of YAP1 and miR-21-5p are inversely correlated with the level of PGR in human endometrial samples. In contrast, knockdown of YAP1 or treatment with verteporfin (VP), a YAP1 inhibitor, reduces miR-21-5p expression, thus leading to an increase in PGR expression in ectopic endometriotic stromal cells. In the mouse model of endometriosis, treatment with VP increases PGR expression and enhances decidualization. More importantly, VP synergistically increases the treatment effect of progestin in causing the regression of endometriotic lesions and improves the decidualization capability of the endometrium. Interestingly, treatment with dienogest, a synthetic progestin, reduces YAP1 and miR-21-5p expression in human cells and in the mouse model of endometriosis. Patients who received dienogest treatment for 6 months show a significant decrease in serum extracellular vesicle-associated miR-21-5p level. LARGE SCALE DATA A public dataset (GSE51981) containing a large cohort of endometriotic tissues is available from the Gene Expression Omnibus (GEO). LIMITATIONS, REASONS FOR CAUTION A large cohort of clinical samples is needed to verify the current diagnostic value of miR-21-5p in future studies. WIDER IMPLICATIONS OF THE FINDINGS The reciprocal regulation of YAP1 and PGR suggests that combined YAP1 inhibitor and progestin may be a better therapeutic approach for treating endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Ministry of Science and Technology, Taiwan (MOST-111-2636-B-006-012, MOST-111-2314-B-006-075-MY3, and MOST-106-2320-B-006-072-MY3). The authors have no conflict of interest to disclose. [ABSTRACT FROM AUTHOR]

Estrogens are in the list of carcinogenic chemicals from the World Health Organization (WHO). However, estrogens require additional factors such as stromal factors or progestogens to increase the ratio of proliferation/apoptosis for initiation of replication errors and consequent mutations to occur. These mutations require at least 5–10 years to develop into clinically detectable cancer, whereby this review is focused on breast cancer. The US National Cancer Institute highlighted a second mechanism of carcinogenicity: certain estrogen metabolites are capable of inducing DNA damage, even in low concentration. They can be assessed in the tissue and circulation. However, those deleterious reactions require excessive unrestricted oxidative cell stress, for example in industrial areas with heavy pollution. We have shown that this can be avoided using transdermal instead of oral estradiol treatment, especially important in smokers. The spectrum of metabolites is also influenced by other exogenous factors such as nutrition, physical activity and certain diseases. Reduction of breast cancer risk as demonstrated in the Women's Health Initiative (WHI) was explained by pro-apoptotic estrogen effects working after a certain 'time gap'. In addition, certain estrogen metabolites are carcinoprotective, if no genetic polymorphisms would impair their beneficial activities. Thus, since additional factors are required for both main pathways of carcinogenicity and because estrogens can even have carcinoprotective effects, we cannot agree with the statement from the WHO. [ABSTRACT FROM AUTHOR]

The progestogen‐only pill (POP) is often a safe and effective option for women who prefer oral contraception but in whom combined hormonal contraception is unsuitable. This article outlines the choice of POPs available, their administration, efficacy and adverse effects. [ABSTRACT FROM AUTHOR]

Progestin is a term used to describe a synthetic progestogen. The activity and potency of synthetic progestins are mostly evaluated via parameters associated with their endometrial effects, which are related to their interactions with progesterone, estrogen, androgen, glucocorticoid, and mineralocorticoid receptors. The chemical structure of progestins is the key to understanding their interactions with these receptors and predicting the other effects associated with these drugs. Due to their endometrial effect, progestins are used for different gynecological conditions, such as endometriosis, contraception, hormonal replacement therapy, and artificial reproduction techniques. This review is focused on improving our knowledge of progestins (from their history and biochemical effects related to their chemical structures to clinical applications in gynecological conditions) in order to improve clinical practice. [ABSTRACT FROM AUTHOR]

• ALT, DRO, and MLA experienced abiotic-transformation in mineral suspensions. • The transformation of the progestins were sensitive to environmental variables. • Hydrolysis was the major transformation pathway for DRO and MLA on SiO 2 surface. • Oxidation was the major transformation pathway for ALT in MnO 2 suspension. • Transformation products identification is a priority for risk assessment. 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 MnO 2 , SiO 2 , 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 SiO 2 suspension and ALT in MnO 2 suspension (half-lives = 0.86 min – 9.90 day). ALT transformation was facilitated at higher MnO 2 loadings, while DRO and MLA transformations were inhibited at higher SiO 2 loadings. These data indicated that hydrophobic partitioning interaction was dominant at higher SiO 2 loadings rather than specific interaction, which limited subsequent surface-catalyzed transformation. ALT transformation rate decreased with increasing pH because MnO 2 reduction requires proton participation. In contrast, relatively high pH facilitated MLA and DRO transformation, indicating that base-catalyzed hydrolysis occurred in SiO 2 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. [Display omitted]. [ABSTRACT FROM AUTHOR]

The use of a progestin-releasing intrauterine device in premenopausal women with endometrial intraepithelial neoplasia has increased, and the progestin-releasing intrauterine device is associated with a lower rate of hysterectomy than oral progestins. OBJECTIVE: To estimate trends in use and outcomes of progestin therapy for premenopausal patients with endometrial intraepithelial neoplasia. METHODS: The MarketScan Database was used to identify patients aged 18–50 years with endometrial intraepithelial neoplasia from 2008 to 2020. Primary treatment was classified as hysterectomy or progestin-based therapy. Within the progestin group, treatment was classified as systemic therapy or progestin-releasing intrauterine device (IUD). The trends in use of progestins and the pattern of progestin use were examined. A multivariable logistic regression model was fit to examine the association between baseline characteristics and the use of progestins. The cumulative incidence of hysterectomy, uterine cancer, and pregnancy since initiation of progestin therapy was analyzed. RESULTS: A total of 3,947 patients were identified. Hysterectomy was performed in 2,149 (54.4%); progestins were used in 1,798 (45.6%). Use of progestins increased from 44.2% in 2008 to 63.4% in 2020 (P =.002). Among the progestin users, 1,530 (85.1%) were treated with systemic progestin, and 268 (14.9%) were treated with progestin-releasing IUD. Among progestin users, use of IUD increased from 7.7% in 2008 to 35.6% in 2020 (P <.001). Hysterectomy was ultimately performed in 36.0% (95% CI 32.8–39.3%) of those who received systemic progestins compared with 22.9% (95% CI 16.5–30.0%) of those treated with progestin-releasing IUD (P <.001). Subsequent uterine cancer was documented in 10.5% (95% CI 7.6–13.8%) of those who received systemic progestins compared with 8.2% (95% CI 3.1–16.6%) of those treated with progestin-releasing IUD (P =.24). Venous thromboembolic complications occurred in 27 (1.5%) of those treated with progestins; the venous thromboembolism (VTE) rate was similar for oral progestins and progestin-releasing IUD. CONCLUSION: The rate of conservative treatment with progestins in premenopausal individuals with endometrial intraepithelial neoplasia has increased over time, and among progestin users, progestin-releasing IUD use is increasing. Progestin-releasing IUD use may be associated with a lower rate of hysterectomy and a similar rate of VTE compared with oral progestin therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance. [ABSTRACT FROM AUTHOR]

Sex hormones are key determinants of gender-related differences and regulate growth and development during puberty. They also exert a broad range modulation of immune cell functions, and a dichotomy exists in the immune response between the sexes. Both clinical and animal models have demonstrated that androgens, estrogens, and progestogens mediate many of the gender-specific differences in immune responses, from the susceptibility to infectious diseases to the prevalence of autoimmune disorders. Androgens and progestogens mainly promote immunosuppressive or immunomodulatory effects, whereas estrogens enhance humoral immunity both in men and in women. This study summarizes the available evidence regarding the physiological effects of sex hormones on human immune cell function and the underlying biological mechanisms, focusing on gender differences triggered by different amounts of androgens between males and females. [ABSTRACT FROM AUTHOR]

The medical management of painful endometriosis is essentially based on anti-gonadotropic molecules and analgesics in the absence of a desire for pregnancy on the part of the patients, and constitutes the first therapeutic step. Dienogest, a recent treatment, has found its place in the management algorithm for painful endometriosis in view of its proven efficacy. It is recommended as a second-line treatment. The ANSM has very recently (March 2023) issued recommendations aimed at controlling the risk of meningioma for various progestogens including dienogest. Relugolix Combination Therapy, which combines a GnRH antagonist and an estrogen-progestin addback therapy in a single tablet, appears to be a promising treatment for painful endometriosis and the initial data on the safety of the treatment (after 6 months of use) are reassuring. Today, anti-aromatases, SERMs or selective inhibitors cannot be considered as an alternative therapy in the medical treatment of painful endometriosis. [ABSTRACT FROM AUTHOR]

Introduction and aim. Endometriosis is a common inflammatory disease affecting 6-10% of women of reproductive age. It is defined as the growth of endometrial-like tissue outside the uterine cavity. Dysmenorrhea, pelvic pain, dyspareunia and infertility are the main symptoms of endometriosis patients. Endometriosis treatment methods can be broadly divided into surgical and pharmacological. Currently, hormonal drugs are often used for women with endometriosis to relieve bothersome symptoms. The aim of this article is to review new publications presenting the effectiveness as well as side effects of the use of progestins and combined oral contraceptives in the hormonal treatment of endometriosis. Material and methods. A review of the literature regarding progestins and combined oral contraceptives in the treatment of endometriosis was performed using the PubMed database. In the end, 67 articles were included in this review. Analysis of the literature. Progestins and combined oral contraceptives significantly reduce dysmenorrhea, dyspareunia and pelvic pain in women with endometriosis. However, there is a risk of potential side effects, which should be taken into account when choosing a therapy for each patient individually. Conclusion. Endometriosis is a chronic disease that has a significant impact on the health-related quality of life of patients. When choosing a treatment, many aspects should be considered, primarily the patient's preferences, drug tolerance and safety. Further drug research is needed to determine the most effective treatment for endometriosis. [ABSTRACT FROM AUTHOR]

The present study was conducted to understand the changes in gonads and hematological parameters in climbing perch (Anabas testudineus) exposed to synthetic estrogen and progestogen [mixture of ethinylestradiol (EE2) and desogestrel (DES)]. Climbing perch were exposed to four different concentrations of EE2/DES mixtures, viz. 0 ng of EE2 and DES/L (T0), 3 ng EE2 and 15 ng DES/L (T3), 30 ng EE2 and 150 ng DES/L (T30), and 300 ng EE2 and 1500 ng DES/L (T300) for 60 days. On days 45 and 60, samples were taken to assess changes in somatic indexes, gonad histology, and hematological parameters. The gonadosomatic index (GSI) increased in both females and males with increasing concentrations of estrogen mixtures except for T30 females, which was the lowest among all\four treatments. The hepatosomatic index (HSI) was observed to be increased in males as estrogen content increased. However, compared to fish at T0, HSI in female individuals did not vary in T30 fish, where the value was the highest among all the treatments. On day 45, histological observations showed no feminization or intersexuality but several germ-cell deformities in the ovary (adhesion, degenerated oocyte wall, degenerated granulose layer, increased interfollicular space, atretic follicle, and cytoplasmic clumping) and testes (increased interstitial area, focal loss of spermatocyte, dilation of the lumen, breakage of tubular epithelium, and elongated seminiferous tubule) were observed in fish exposed to EE2 and DES. Fish reared at T30 had lower RBC count, hemoglobin (Hb), glucose, and hematocrit levels. On day 60, fish reared at T30 had the highest Hb content compared to fish raised in other treatment conditions. WBC was progressively higher with increasing EE2/DES concentrations. Significant erythrocyte cytoplasmic abnormalities and erythrocyte nuclear abnormalities were observed in fish exposed to higher EE2/DES concentrations. The present study provides insights into the adverse impacts of synthetic estrogens sourced from human contraceptive pills on fish physiology. [ABSTRACT FROM AUTHOR]

Objectives: Analysis of congenital adrenal hyperplasia (CAH) cases, gynaecological implications, referral reasons to gynaecologist and treatment. Material and methods: Retrospective, longitudinal, single-centre study with female CAH paediatric patients = 10 years-old, followed between 1998-2018 in gynaecology and endocrinology departments at a public university tertiary hospital. Results: 47 patients, 34.0% (n = 16) with classic, 66.0% (n = 31) with non-classic forms (NCAH), CYP21 deficit and 46,XX karyotype. We found a normal median menarche age [11.5 IQR 2 (6-15) years-old], but significantly earlier in NCAH (p = 0.003). Precocious puberty occurred in 48.9%, n = 23. Primary amenorrhea occurred in salt-wasting form (21.4%, n = 3). Oligomenorrhea and hirsutism were significantly more prevalent in NCAH (p = 0.018, p = 0.014 respectively) and acanthosis nigricans and virilization signs in classic forms (p = 0.05, p = 0.000 respectively). Sixteen patients (34.0%) were referred to gynaecology, mostly due to menstrual irregularities (50.0%, n = 8). Medical treatment with isolated or combined corticoids, oestrogen and progestogen were chosen in all but one case. Gonadotropin-releasing hormone analogues were used in 19.0% (n = 9). Surgery was performed in 34.0% (n = 16) patients, median age 2.0 IQR 2.5 (0.6-90) years-old. Conclusions: This paper highlights the importance of a multidisciplinary approach. Early treatment contributes to a phenotypical feminine differentiation and normalization of the hypothalamus-pituitary-ovarian axis, which is essential given the gynaecologic and obstetric consequences of untreated cases. [ABSTRACT FROM AUTHOR]

Pharmacovigilance data analysis can accelerate the identification of drug-related safety signals or reassure on the safety profile. This study evaluates the venous thromboembolism (VTE) risk of newer combined oral contraceptive (COC) formulations with natural estrogens, such as estradiol (E2) and estetrol (E4), using data from the EudraVigilance database. We conducted a disproportionality reporting rate analysis of VTE events associated with various COC formulations by extracting individual case reports from EudraVigilance database up to July 28, 2024. The study compared the proportionality reporting rate between natural estrogen-based COCs (E2 and E4) and conventional synthetic estrogen-based COCs (ethinylestradiol [EE]), with a comparison to EE-levonorgestrel. The analysis revealed that COCs containing natural estrogens exhibited significantly lower proportionality reporting rates for thrombotic events compared to EE-based COCs. Specifically, E4-drospirenone (E4-DRSP) showed the lowest proportionality reporting rate (0.12), similar to progestin-only pills. EE-DRSP had the highest proportionality reporting rate (2.25), suggesting an increased thrombotic risk. The study supports the safer thrombotic profile of natural estrogen-based COCs, particularly E2 and E4 formulations, over synthetic estrogen-based COCs containing EE. These findings support the hypothesis that E2- and E4-based pills are safer than EE-based pills, aligning with a shift toward safer contraceptive options in clinical practice. Natural estrogens such as E2 and E4 may emerge as safer alternatives to synthetic estrogens like EE, particularly when combined with progestins like DRSP. This multilevel evidence underscores the importance of evidence-based prescribing practices to enhance patient safety and minimize thrombotic risks associated with COC use. [ABSTRACT FROM AUTHOR]

We evaluated the effect of immediate postpartum use of depot medroxyprogesterone acetate (DMPA) on the timing of lactogenesis stage II (LS-II). The initial design randomly assigned adults who delivered a full-term infant in 2019–2021 to receive within 48 hours of delivery: (1) DMPA, (2) placebo injection, or (3) no injection. Due to low enrollment, we changed in 2021–2023 to a nonrandomized design using matching at recruitment for obesity and delivery method and propensity score weighting for analysis. We combined data from both designs to compare immediate postpartum DMPA use (N = 55) vs control (placebo or no injection) group (N = 95). We defined noninferiority a priori as being met if the upper bound of a two-sided 95% CI for mean difference in time to LS-II between groups was <6 hours. The unweighted mean time to LS-II was 57.8 hours in the DMPA group (SD, 29.4) and 64.1 hours in the control group (SD, 36.1). Using propensity score weighting to make the groups comparable with respect to age, race, delivery method, and previous live births, the mean time to LS-II was 5.5 hours shorter (95% CI, −16.4, 5.5) for women in the DMPA relative to control group. We found no evidence that DMPA use inhibits the onset of LS-II. Findings support immediate postpartum DMPA initiation among those intending to engage in human milk feeding. A controlled trial (N = 150) did not detect any difference in time to lactogenesis stage II ("milk let-down") between injectable contraception use within the first 48 hours postpartum and those without this exposure. [ABSTRACT FROM AUTHOR]

Maternal hormonal contraception use has been associated with childhood leukemia risk. However, studies are few and often based on self-reported information. Using registry data from Denmark, Norway, and Sweden, we identified 3,183,316 children (born 1996–2018) and followed them from birth until leukemia diagnosis, censoring (death, emigration, other cancer, 20th birthday) or study closure (December 31st, 2017, 2018 or 2020). We estimated hazard ratios (HRs) and 95 % confidence intervals (CIs) for childhood leukemia (any, lymphoid and non-lymphoid) associated with maternal recent use (≤ 3 months before or during pregnancy) or previous use (before recent use) of hormonal contraception overall and by type, compared to no use. During 29,455,528 person-years, 1701 children developed leukemia (no use: 518, previous use: 974, recent use: 209). Maternal recent use of hormonal contraception was associated with an increased leukemia risk in children (HR 1.22, 95 % CI 1.04–1.44; incidence rate per 1,000,000 person-years [IR] 65), compared to no use (IR 53). The association was strongest for non-lymphoid leukemia (HR 1.69, 95 % CI 1.20–2.37) and mainly driven by the oral combined products, both for any leukemia (HR 1.29, 95 % CI 1.05–1.59) and non-lymphoid leukemia (HR 1.75, 95 % CI 1.17–2.62). Additionally, non-lymphoid leukemia was associated with recent use of the non-oral progestin-only products (HR 2.10, 95 % CI 1.28–3.44). Although the absolute risk was low, maternal hormonal contraception use up to or during pregnancy was associated with an increased childhood leukemia risk, particularly non-lymphoid leukemia, and mainly driven by oral combined and non-oral progestin-only products. • Maternal hormonal contraception linked to higher childhood leukemia risk. • Association strongest when used close to or during pregnancy. • Risk increase mainly observed for non-lymphoid leukemia. • Primarily associated with oral combined and non-oral progestin-only contraceptives. [ABSTRACT FROM AUTHOR]

• High variety of progestagen receptors broadly distributed in the brain. • Progesterone influences emotional and cognitive amygdala reactivity. • Premenstrual mood symptoms improve upon progesterone receptor modulation. • Stress systems potentially implicated in adverse reactions to progestagens. • Progestagens are cerebroprotective following stroke. Progesterone is a highly lipophilic gonadal hormone that can influence behavior and mental health through its receptors in the brain. Fluctuations in progesterone levels across critical periods of a females life are associated with increased susceptibility to mental conditions. This review highlights the effects of progestagens, including progesterone and synthetic progestins, on the brain, mood, stress, and cognition in females. The primary focus is on experimental pharmacological research that teases out the distinct effects of progestagens from those of estrogens. Additionally, the key literature on puberty, the menstrual cycle, pregnancy, perimenopause, hormonal contraceptives, and menopausal hormone therapy is reviewed, although conclusions are limited by the nested effects of progestagens and estrogens. Single study-findings suggest an influence of progesterone on amygdala reactivity related to processing of emotional stimuli and memory. In patients with premenstrual dysphoric disorder, progesterone receptor modulation improves premenstrual mood symptoms and potentially enhances fronto-cingulate control over emotion processing. The interaction between progestagens and the systems involved in the regulation of stress seems to influence subjective experiences of mood and stress. Sparse studies investigating the effects of progestin-only contraceptives suggest effects of progestagens on the brain, mood, and stress. Progesterone and progestins used for contraception can influence neural processes as myelination and neuroprotection, exerting protective effects against stroke. Concerning menopausal hormonal therapy, the effects of progestins are largely unknown. Levels of progesterone as well as type, administration route, timing, dose regimen, metabolism, and intracellular activity of progestins in hormonal contraceptives and menopausal hormonal therapy are factors whose effects remain to be elucidated. Altogether, current knowledge highlights the potential role of progestagens in females health but also calls for well-designed pharmaco-behavioral studies disentangling the effects of progestagens from those of estrogens. [ABSTRACT FROM AUTHOR]

Sex-related differences characterize multiple sclerosis, an autoimmune, inflammatory and neurodegenerative disease displaying higher incidence in females as well as discrepancies in susceptibility and progression. Besides clinical specificities, molecular and cellular differences related to sex hormones were progressively uncovered improving our understanding of the mechanisms involved in this disabling disease. The most recent findings may give rise to the identification of novel therapeutic perspectives that could meet the urgent need for a treatment preventing the transition from the recurrent- to the progressive form of the disease. The present review is an update of our current knowledge about progestagens, androgens and estrogens in the context of CNS demyelination including their synthesis, the impact of their dysregulation, the preclinical and clinical data presently available, the main molecular dimorphisms related to these hormones and their age-related changes and relationship with failure of spontaneous remyelination, likely impacting the inexorable progression of multiple sclerosis towards irreversible disabilities. [ABSTRACT FROM AUTHOR]

The document is a correction to a systematic review on the use of progesterone for preventing preterm birth in singleton pregnancies. The authors clarify that the term "progesterone" should have been "progestogens" and "intramuscular progesterone" should have been "intramuscular 17α-hydroxyprogesterone caproate." They acknowledge the interchangeability of terms used in the text and apologize for any confusion. The article is open access and published by John Wiley & Sons Ltd on behalf of the Nordic Federation of Societies of Obstetrics and Gynecology. [Extracted from the article]

Reliable quantification of multiple steroid classes in biological fluids within a single method remains an analytical challenge despite many previously published methods. Crosstalk of positional isomers, overlap of stereoisomer fragmentation patterns, differing proton affinities, in-source fragmentation, varying stability of protonated ions in the gas phase across steroid classes, and non-existence of steroid-free matrix are the main challenges limiting the number of simultaneously profiled steroids. In this study, we focused on the development of a derivatization-free, achiral, high-throughput, and cost-effective UHPLC-MS/MS approach that allows simultaneous profiling of a spectrum of 38 steroids covering progestogens, androgens, corticosteroids, and estrogens, while properly addressing the hurdles of steroid analysis. Within a 20-min method, 16 stereoisomers and 15 positional isomers were fully resolved within a single run while separated from 7 additional non-interfering steroids and matrix interferences in rodent plasma. Protein precipitation (PP) and supported liquid extraction (SLE) methods using only 40 μL of sample were developed to achieve the lowest possible limits of quantification. Nevertheless, 5α-dihydroprogesterone and 3α,5α-THDOC could be only qualitatively assessed when using PP. In contrast, DHEA-S could not be quantified or identified when using SLE. A novel surrogate matrix-background subtraction approach, using rat plasma after the animal's adrenalectomy, has been implemented into the optimized PP-UHPLC-MS/MS workflow, successfully validated according to the unified ICH/EMA M10 guidelines, and compared to the traditional quantification strategies. Moreover, the validity of the newly adopted approach has been verified by the targeted profiling of multiple biologically active endogenous steroids in more than 500 samples of mouse plasma in total. Underestimation of hurdles associated with steroid analysis often compromises the accurate steroid quantification. Our comprehensive, fully validated UHPLC-MS/MS method targeting a wide spectrum of endogenous steroids, mitigating steroid crosstalk and using a minimal sample volume together with a novel surrogate matrix-background subtraction approach significantly advances steroid analysis for research and clinical applications covering multiple biological scopes. [Display omitted] • Multiple steroid classes analyzed in 20 min using a single UHPLC-MS/MS method. • Baseline separation of 15 stereo- and 17 positional isomers out of 38 steroids. • Post-column infusion selectively tunes MS response of individual structural classes. • Surrogate-matrix background subtraction approach replacing a steroid-free matrix. • Sensitive quantification achieved with LOQs ranging from 0.1 to 30 ng/mL. [ABSTRACT FROM AUTHOR]

Progestins (PGs) are a group of emerging contaminants with endocrine disrupting effects. Despite their large amounts of use and excretion, investigations have been limited to several compounds in the aqueous phase, and the occurrences and distribution of numerous PGs in different matrices remain unclear. In this study, water, suspended particulate matter and sediment samples from rivers in the Yellow River Delta (YRD), China were investigated over two seasons to elucidate the occurrences, sources, and ecological risks of 55 natural and synthetic PGs. 40 PGs were detected with concentrations varied from not detected (ND) to 146 ng/L in water, ND to 251 ng/g dry weight (dw) in SPM, and ND−173 ng/g dw in sediment. The less-studied natural metabolites were the predominant PGs in all samples. 54–96 % of the PGs were concentrated in the aqueous phase, and SPM was also an important carrier, especially for hydrophobic compounds. Anthropogenic activities and environmental conditions together affected the spatiotemporal distribution of PGs. Animal sources, including aquaculture and animal husbandry, contributed most (42.3 %) to the total PGs, followed by treated sewage (32.9 %) and industrial sources (24.7 %). The risk assessment suggested that PGs posed moderate to high risks to aquatic organisms, especially the fish. [Display omitted] • Occurrences, sources, and risks of fifty-five progestins were explored in the YRD. • Progestins were ubiquitous in water, suspended particulate matter and sediment. • Natural metabolites dominated the total concentration of progestins in all samples. • Aquaculture and animal husbandry were the main sources of progestins in the PRD. • Progestins posed moderate to high risks to aquatic organisms in surface water. [ABSTRACT FROM AUTHOR]