Sex-Specific Effects of Estradiol and Progesterone in Ischemic Kidney Injury.

The positive effects of female sex hormones, particularly estradiol and progesterone, have been observed in treatment of various pathologies. Acute kidney injury (AKI) is a common condition in hospitalized patients in which the molecular mechanisms of hormone action are poorly characterized. In this study, we investigated the influence of estradiol and progesterone on renal cells during ischemic injury. We performed both in vivo experiments on female and male rats and in vitro experiments on renal tubular cells (RTCs) obtained from the kidneys of intact animals of different sexes. Since mitochondria play an important role in the pathogenesis of AKI, we analyzed the properties of individual mitochondria in renal cells, including the area, roundness, mitochondrial membrane potential, and mitochondrial permeability transition pore (mPTP) opening time. We found that pre-treatment with progesterone or estradiol attenuated the severity of ischemia/reperfusion (I/R)-induced AKI in female rats, whereas in male rats, these hormones exacerbated renal dysfunction. We demonstrated that the mPTP opening time was higher in RTCs from female rats than that in those from male rats, which may be one of the reasons for the higher tolerance of females to ischemic injury. In RTCs from the kidneys of male rats, progesterone caused mitochondrial fragmentation, which can be associated with reduced cell viability. Thus, therapy with progesterone or estradiol displays quite different effects depending on sex, and could be only effective against ischemic AKI in females.

Progesterone hypersensitivity: a cyclical history.

Hypersensitivity reaction to progesterone is rare, with less than 200 cases reported. It occurs mainly in women in their third decade of life and can have a heterogeneous presentation (cutaneous and/or systemic), with temporal relation to serum levels of progesterone. Diagnosis is based on history and physical examination, supported by skin tests. We describe the case of a woman in her late 20s with pruritic erythema on the chest that manifested in the luteal phase of the menstrual cycle, with spontaneous resolution in less than 5 days, without secondary scarring. The histological diagnosis was non-specific, with evidence of interface dermatitis, but positive skin tests supported the diagnosis of autoimmune progesterone dermatitis. It is intended to alert to the manifestations of a pathology that is rare and difficult to diagnose but with a great impact on daily life.

Navigating a plethora of progesterone receptors: Comments on the safety/risk of progesterone supplementation in women with a history of breast cancer or at high-risk for developing breast cancer.

Progesterone and progestin agonists are potent steroid hormones. There are at least three major types of progesterone receptor (PR) families that interact with and respond to progesterone or progestin ligands. These receptors include ligand-activated transcription factor isoforms (PR-A and PR-B) encoded by the PGR gene, often termed classical or nuclear progesterone receptor (nPR), membrane-spanning progesterone receptor membrane component proteins known as PGRMC1/2, and a large family of progestin/adipoQreceptors or PAQRs (also called membrane PRs or mPRs). Cross-talk between mPRs and nPRs has also been reported. The complexity of progesterone actions via a plethora of diverse receptors warrants careful consideration of the clinical applications of progesterone, which primarily include birth control formulations in young women and hormone replacement therapy following menopause. Herein, we focus on the benefits and risk of progesterone/progestin supplementation. We conclude that progesterone-only supplementation is considered safe for most reproductive-age women. However, women who currently have ER + breast cancer or have had such cancer in the past should not take sex hormones, including progesterone. Women at high-risk for developing breast or ovarian cancer, either due to their family history or known genetic factors (such as BRCA1/2 mutation) or hormonal conditions, should avoid exogenous sex hormones and proceed with caution when considering using natural hormones to mitigate menopausal symptoms and/or improve quality of life after menopause. These individuals are urged to consult with a qualified OB-GYN physician to thoroughly assess the risks and benefits of sex hormone supplementation. As new insights into the homeostatic roles and specificity of highly integrated rapid signaling and nPR actions are revealed, we are hopeful that the benefits of using progesterone use may be fully realized without an increased risk of women's cancer.

Lack of evidence that progesterone in ovulatory cycles causes breast cancer.

A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.

Menopausia quirúrgica en pacientes con mutación BRCA, el papel de la terapia hormonal / Surgical Menopause in Patients with BRCA Mutation, the Role of Hormone Therapy

Introducción: las mujeres con mutación BRCA1/2 (mBRCA) tienen un riesgo aumentado de desarrollar cáncer de mama (CM) y ovario (CO). La salpingo-oforectomía bilateral (SOB) se asocia con la reducción del riesgo del 80% para CO y un 50% para CM. Se recomienda realizarla entre los 35 y 40 años. Como consecuencia se produce una menopausia prematura, con un impacto negativo sobre la calidad de vida por la presencia de síntomas climatéricos, aumento del riesgo de enfermedad cardiovascular, osteoporosis y riesgo de alteración cognitiva. La terapia hormonal (THM) es el tratamiento más eficaz para la prevención de estos síntomas. Estado del arte: distintos estudios han demostrado un mayor riesgo de CM en mujeres posmenopáusicas que reciben THM en particular con terapia combinada, estrógeno + progesterona (E+P). Según el metanálisis de Marchetti y cols., en las mujeres portadoras de mBRCA que recibieron THM, no hubo diferencias en el riesgo de CM comparando E solo con E+P. En el estudio de Kotsopoulos, incluso se encontró un posible efecto protector en aquellas que usaron E solo. Otro estudio en portadoras sanas demostró que, en las mujeres menores de 45 años al momento de la SOB, la THM no afectó las tasas de CM. Sin embargo, en las mujeres mayores de 45 años, las tasas de CM fueron más altas. Como el esquema de E+P se asocia con un mayor riesgo relativo (RR) de CM, las dosis de progestágenos utilizados se deberían limitar, eligiendo derivados naturales de progesterona, de uso intermitente para disminuir la exposición sistémica. Según diferentes guías internacionales, a las portadoras de mBRCA sanas que se someten a una SOB se les debe ofrecer THM hasta la edad promedio de la menopausia. Conclusión: la menopausia prematura disminuye la expectativa de vida; es por ello que una de las herramientas para mejorar y prevenir el deterioro de la calidad de vida es la THM. El uso de THM a corto plazo parece seguro para las mujeres portadoras de mBRCA que se someten a una SOB antes de los 45 años, al no contrarrestar la reducción del riesgo de CM obtenida gracias a la cirugía. (AU)

Introduction: women with BRCA1/2 (mBRCA) mutation have an increased risk of developing breast (BC) and ovarian (OC) cancer. Bilateral salpingo-oophorectomy (BSO) is associated with an 80% risk reduction for OC and 50% for BC. The recommended age for this procedure is 35 to 40 years. The consequence is premature menopause, which hurts the quality of life due to the presence of climacteric symptoms, increased risk of cardiovascular disease, osteoporosis, and a higher risk of cognitive impairment. Hormone therapy (MHT) is the most effective treatment for preventing these symptoms. State of the art: different studies have shown an increased risk of BC in postmenopausal women receiving MHT, particularly with combined therapy, estrogen + progesterone (E+P). According to the meta-analysis by Marchetti et al., in women carrying mBRCA who received MHT, there was no difference in the risk of BC compared to E alone with E+P. In the Kostopoulos study, there was also a possible protective effect in those who used E alone. Another study in healthy carriers showed that in women younger than 45 years at the time of BSO, MHT did not affect BC rates. However, in women older than 45 years, BC rates were higher. As the E+P scheme is associated with a higher RR of BC, the doses of progestogens should be limited, choosing natural progesterone byproducts of intermittent use to decrease systemic exposure. According to various international guidelines, healthy mBRCA carriers undergoing BSO should be offered MHT until the average age of menopause. Conclusion: premature menopause decreases life expectancy, which is why one of the tools to improve and prevent deterioration of quality of life is MHT. Short-term use of MHT appears safe for women with mBRCA who undergo BSO before age 45 as it does not counteract the reduction in the risk of MC obtained by surgery. (AU)

Progestogen Hypersensitivity.

Progestogen hypersensitivity (PH) is a heterogeneous disease characterized by diverse cutaneous manifestations, bronchospasm, and/or anaphylaxis. Possible triggers include ovarian progesterone and exogenous progestogens. The timing of symptoms is critical to diagnose PH: during the luteal phase of the menstrual cycle for the endogenous form and after exposure to progestins for exogenous PH. Diagnostic modalities such as progesterone skin testing have low sensitivity and specificity for PH. When exogenous PH is suspected, the allergist should consider a progestogen challenge. Treatment strategies should be tailored for each patient, including symptom-directed therapies, ovulation suppression, and progesterone desensitization. Future studies should explore the mechanisms of PH, validation of diagnostic criteria, and standardization of treatment strategies.

O uso de métodos contraceptivos hormonais em pacientes com asma: repercussões clínicas / The use of hormonal contraceptives methods in patients with asthma: clinical repercussions

Objetivo: Analisar o uso dos contraceptivos hormonais em mulheres com asma e a escolha desses métodos contraceptivos para essa população, com avaliação de eventuais repercussões sobre novos episódios de asma e sibilos. Métodos: Foram selecionados estudos longitudinais, ensaios clínicos, revisões sistemáticas e metanálises. As plataformas consultadas foram PubMed, Embase, Cochrane e SciELO, com a utilização dos descritores: "contracepção", "contracepção hormonal", "sistema intrauterino liberador de levonorgestrel" e "asma". Resultados: Dois grandes estudos demonstraram que o uso de contraceptivos hormonais esteve associado à redução do risco de novos episódios de asma. Uma revisão sistemática concluiu que os resultados para o uso de contraceptivos hormonais para mulheres com asma foram mistos, com aumento ou redução dos seguintes riscos: novo episódio de asma e aumento da frequência das crises e dos sibilos. O uso da contracepção hormonal em pacientes obesas portadoras de asma é controverso. Conclusão: Os resultados para o uso de contraceptivos hormonais em mulheres com asma são inconsistentes, com relatos de aumento ou de redução do risco de novos episódios. O uso do método contraceptivo deve ser discutido individualmente, levando-se em consideração outros fatores de risco associados e o desejo da mulher. A paciente deverá ser orientada se houver piora dos sintomas clínicos de asma na vigência do uso de qualquer método contraceptivo hormonal.

Objective: To analyze the use of hormonal contraceptives in women with asthma and the choice of this contraceptive method for this population, evaluating possible repercussions on new episodes of asthma and wheezing. Methods: Longitudinal studies, clinical trials, systematic reviews and meta-analyses were selected. Platforms consulted: PubMed, Embase, Cochrane, SciELO, using the descriptors: "contraception", "hormonal contraception", "levonorgestrel-releasing intrauterine system" and "asthma". Results: Two large studies demonstrated that the use of hormonal contraceptives was associated with a reduced risk of new episodes of asthma. A systematic review concluded that the results for the use of hormonal contraceptives for women with asthma were mixed, with increased or decrease in the following risks: new asthma episodes, increased frequency and wheezing. The use of hormonal contraception in obese patients with asthma is controversial. Conclusion: The results for the use of hormonal contraceptives in women with asthma are inconsistent, with reports of increased or reduced risk of new episodes. The use of the contraceptive method should be discussed individually, taking into account other associated risk factors and the woman's desire. The patient will be advised if there is a worsening of the clinical symptoms of asthma while using any hormonal contraceptive method.

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.

PURPOSE: The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. METHODS: A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. RESULTS: 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). CONCLUSION: This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

Effect of Parquetina nigrescens (Afzel.) Leaves on Letrozole-Induced PCOS in Rats: a Molecular Insight into Its Phytoconstituents.

Polycystic ovarian syndrome (PCOS) is one of the common causes of female infertility in women of reproductive age. P. nigrescens is a plant used in the treatment of various diseases including menstrual disorders. This study investigated the effect of ethanolic extracts of P. nigrescens leaves on the estrous cycle, fasting blood glucose, and hormonal and lipid profile in letrozole-induced PCOS rats and also evaluated the molecular mechanism of the active constituents using computational methods. After the induction of PCOS with letrozole, rats were treated orally for 14 days with distilled water (1 mg/kg/day), clomiphene citrate (2 mg/kg/day), metformin (7.14 mg/kg/day), and ethanolic extract of P. nigrescens (50 and 100 mg). Thereafter, selected biochemical parameters were assayed to determine the extract's effect on the estrous cycle. Molecular docking and molecular dynamics simulation (MDS) were carried out to determine the binding affinity and relative stability of the ligand-receptor complexes. Letrozole-induced PCOS rats showed irregular estrous cyclicity, elevated (p > 0.05) triglycerides, low-density lipoprotein cholesterol (LDL), total cholesterol, insulin, testosterone, and luteinizing hormone (LH) concentration, low (p > 0.05) progesterone, low follicle-stimulating hormone (FSH), high-density lipoprotein cholesterol (HDL), and high fasting blood glucose concentration compared to that of the control group. The reproductive, biochemical, and structural alterations were reversed by the administration of ethanolic extract of P. nigrescens leaves (50 mg/kg) which restored the estrous cycle after 14 days of treatment. However, the ethanolic extracts of P. nigrescens (100 mg/kg) significantly increased (p > 0.05) FSH, HDL, and progesterone concentrations but decreased the LH, progesterone, and total cholesterol. Of all 44 compounds identified in GCMS analysis of an ethanolic extract of P. nigrescens leaves, only 2-ethylbutyl heptyl ester (CID 91705405) had a higher binding affinity for hormonal receptors and enzymes responsible for hepatic gluconeogenesis compared to standard drugs used in the study. CID 91705405 was also relatively stable over 100 ns of MDS. This compound is therefore revealed to have the potential to modulate both endocrine and metabolic pathways involved in PCOS. The ethanolic extract of P. nigrescens leaves can therefore be considered in the management/treatment of the reproductive and metabolic disorders related to PCOS subject to further experimental validation.

Vaginal Progesterone Is Associated with Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: The frequency of intrahepatic cholestasis of pregnancy (ICP) peaks during the third trimester of pregnancy when plasma progesterone levels are the highest. Furthermore, twin pregnancies are characterized by higher progesterone levels than singletons and have a higher frequency of cholestasis. Therefore, we hypothesized that exogenous progestogens administered for reducing the risk of spontaneous preterm birth may increase the risk of cholestasis. Utilizing the large IBM MarketScan Commercial Claims and Encounters Database, we investigated the frequency of cholestasis in patients treated with vaginal progesterone or intramuscular 17α-hydroxyprogesterone caproate for the prevention of preterm birth. STUDY DESIGN: We identified 1,776,092 live-born singleton pregnancies between 2010 and 2014. We confirmed second and third trimester administration of progestogens by cross-referencing the dates of progesterone prescriptions with the dates of scheduled pregnancy events such as nuchal translucency scan, fetal anatomy scan, glucose challenge test, and Tdap vaccination. We excluded pregnancies with missing data regarding timing of scheduled pregnancy events or progesterone treatment prescribed only during the first trimester. Cholestasis of pregnancy was identified based on prescriptions for ursodeoxycholic acid. We used multivariable logistic regression to estimate adjusted (for maternal age) odds ratios for cholestasis in patients treated with vaginal progesterone, and in patients treated with 17α-hydroxyprogesterone caproate compared with those not treated with any type of progestogen (the reference group). RESULTS: The final cohort consisted of 870,599 pregnancies. Among patients treated with vaginal progesterone during the second and third trimester, the frequency of cholestasis was significantly higher than the reference group (0.75 vs. 0.23%, adjusted odds ratio [aOR]: 3.16, 95% confidence interval [CI]: 2.23-4.49). In contrast, there was no significant association between 17α-hydroxyprogesterone caproate and cholestasis (0.27%, aOR: 1.12, 95% CI: 0.58-2.16) CONCLUSION: Using a robust dataset, we observed that vaginal progesterone but not intramuscular 17α-hydroxyprogesterone caproate was associated with an increased risk for ICP. KEY POINTS: · Previous studies have been underpowered to detect potential association between progesterone and ICP.. · Vaginal progesterone was significantly associated with ICP.. · Intramuscular 17α-hydroxyprogesterone was not associated with ICP..

Oral estradiol/micronized progesterone may be associated with lower risk of venous thromboembolism compared with conjugated equine estrogens/medroxyprogesterone acetate in real-world practice.

OBJECTIVES: The Women's Health Initiative study reported an increased risk of venous thromboembolism among menopausal women treated with conjugated equine estrogens/medroxyprogesterone acetate (CEE/MPA) versus placebo. Newer hormone therapies may have a lower venous thromboembolism risk. The study compared the risk of venous thromboembolism between women treated with the combined oral product 17ß-estradiol/micronized progesterone (E2/P4) and those treated with oral CEE/MPA regimens. STUDY DESIGN: In a retrospective longitudinal study using real-world claims data from April 2019 to June 2021, women aged 40 years or more treated with oral E2/P4 or oral CEE/MPA who did not have a venous thromboembolism diagnosis before first dispensing claim of CEE/MPA or E2/P4 identified on or after May 1st 2019 (index date) were observed for 6 months or more after the index date. Oral E2/P4 and oral CEE/MPA had been prescribed by the treating physician in real-world practice and were observed through pharmacy dispensing records. MAIN OUTCOME MEASURES: Venous thromboembolism risk was compared between women receiving oral E2/P4 versus oral CEE/MPA. RESULTS: The study included 36,061 women treated with oral E2/P4 or oral CEE/MPA. In the analyses weighted by the inverse probability of treatment for control of potential confounding factors, the incidence of venous thromboembolism was significantly lower for oral E2/P4 compared with oral CEE/MPA (37/10,000 women-years for oral E2/P4 vs 53/10,000 women-years for oral CEE/MPA; incidence rate ratio 0.70, 95 % confidence interval: 0.53-0.92). CONCLUSIONS: Real-world evidence suggests that the risk of venous thromboembolism is significantly lower among women treated with oral E2/P4 compared with oral CEE/MPA.

B-cell lymphoma 6 expression significantly differs by the uterine preparation method used for frozen embryo transfer.

OBJECTIVE: To determine whether B-cell lymphoma 6 (BCL6), an endometriosis-associated marker postulated to predict poor pregnancy outcomes, is differentially expressed in the window of implantation with various uterine preparation regimens commonly used for frozen embryo transfers. DESIGN: A retrospective cohort study. SETTING: An academic center. PATIENT(S): Patients with infertility who underwent endometrial biopsy for BCL6 evaluation INTERVENTION(S): Exogenous estradiol and/or progesterone. MAIN OUTCOME MEASURE(S): Endometrial BCL6 histological score (HSCORE) and overexpression (HSCORE >1.4) RESULT(S): Two hundred and forty-four patients were included in the analysis: 76 patients were sampled in a natural menstrual cycle without exogenous hormone exposure (NC), 25 under a modified natural cycle embryo transfer protocol with choriogonadotropin alfa injection followed by luteal phase vaginal progesterone supplementation (mNC), and 143 under a programmed cycle embryo transfer protocol, with estradiol administration followed by addition of intramuscular progesterone-in-oil injections (PC). Median HSCORE (interquartile range) was the highest in NC (3.0 [1.8-3.6]). BCL6 expression was significantly lower in mNC (1.1 [0.4-2.1]) and PC groups (0.8 [0.3-1.3]) compared with NC. In addition, BCL6 overexpression (HSCORE >1.4) was observed in 80.3% of NC, 40.0 % of mNC, and 23.1 % of PC. After adjusting for covariates, the endometrium exposed to exogenous progesterone had significantly lower odds of BCL6 overexpression than that of a natural menstrual cycle (adjusted odds ratio, 0.12 [95% CI 0.04-0.35] for mNC; and odds ratio, 0.08 [95% CI 0.04-0.17] for PC). CONCLUSION(S): BCL6 expression differs by the type of uterine preparation method, with lower levels observed with exogenous progesterone exposure. The validity and utility of BCL6 testing under medicated endometrial state warrants further investigation.

Society for Maternal-Fetal Medicine Statement: Response to the Food and Drug Administration's withdrawal of 17-alpha hydroxyprogesterone caproate.

On April 5, 2023, the US Food and Drug Administration withdrew the approval of 17-alpha hydroxyprogesterone caproate, effective immediately, because of the lack of evidence that it reduces the risk of recurrent spontaneous preterm birth. This decision withdraws approval for all formulations of 17-alpha hydroxyprogesterone caproate (both intramuscular and subcutaneous) and applies to both brand name (Makena) and generic versions of the medication. We agree with the Food and Drug Administration determination and discourage continued prescribing of 17-alpha hydroxyprogesterone caproate, including through compounding pharmacies. We do not recommend changing indications for cerclage, indications for vaginal progesterone in patients with a short cervix, or recommendations against activity restriction based on the Food and Drug Administration withdrawal of 17-alpha hydroxyprogesterone caproate from the market. We recommend that discussion of the use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length or in those with a cervical length of ≥25 mm includes a shared decision-making process, especially if a progesterone formulation for preterm birth prevention was received in a previous pregnancy. The Food and Drug Administration determined that it would be inappropriate to delay the effective date of the withdrawal to allow patients currently receiving 17-alpha hydroxyprogesterone caproate to finish treatment. We agree with the Food and Drug Administration that there is no evidence of benefit with continued treatment. Patients currently receiving 17-alpha hydroxyprogesterone caproate can be counseled that the Food and Drug Administration's Center for Drug Evaluation and Research has not identified evidence of harm from discontinuation before 37 weeks of gestation.

Effects of Estradiol/Micronized Progesterone vs. Conjugated Equine Estrogens/Medroxyprogesterone Acetate on Breast Cancer Gene Expression in Healthy Postmenopausal Women.

Recent studies suggest estradiol (E2)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if differences in the regulation of breast cancer-related gene expression could provide some explanation. This study is a subset of a monocentric, 2-way, open observer-blinded, phase 4 randomized controlled trial on healthy postmenopausal women with climacteric symptoms (ClinicalTrials.gov; EUCTR-2005/001016-51). Study medication was two 28-day cycles of sequential hormone treatment with oral 0.625 mg CEE and 5 mg of oral medroxyprogesterone acetate (MPA) or 1.5 mg E2 as percutaneous gel/day with the addition of 200 mg oral micronized P. MPA and P were added days 15-28/cycle. Material from two core-needle breast biopsies in 15 women in each group was subject to quantitative PCR (Q-PCR). The primary endpoint was a change in breast carcinoma development gene expression. In the first eight consecutive women, RNA was extracted at baseline and after two months of treatment and subjected to microarray for 28856 genes and Ingenuity Pathways Analysis (IPA) to identify risk factor genes. Microarray analysis showed 3272 genes regulated with a fold-change of >±1.4. IPA showed 225 genes belonging to mammary-tumor development function: 198 for CEE/MPA vs. 34 for E2/P. Sixteen genes involved in mammary tumor inclination were subject to Q-PCR, inclining the CEE/MPA group towards an increased risk for breast carcinoma compared to the E2/P group at a very high significance level (p = 3.1 × 10-8, z-score 1.94). The combination of E2/P affected breast cancer-related genes much less than CEE/MPA.

Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study.

BACKGROUND: Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. METHODS: The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. RESULTS: Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (Phomogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. CONCLUSION: Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies.

The Risk of Breakthrough Bleeding Justifies the Use of Combined Hormonal Contraception Over Progesterone-Only Pills While Breastfeeding.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP-even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

PDE4 inhibitor Roflumilast modulates inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis in vitro.

This study was implemented to address the role of Roflumilast in polycystic ovary syndrome (PCOS) as well as to discuss its reaction mechanism in vivo and in vitro. In vivo, mice were administrated with 6 mg dehydroepiandrosterone (DHEA) per 100 g body weight and fed with 60% high fat diet to induce PCOS. The expression of phosphodiesterases 4 (PDE4) was assessed with RT-qPCR. The ovary pathology was observed by hematoxylin and eosin staining and follicles were counted. Enzyme-linked immunosorbent assay was adopted for the estimation of progesterone, testosterone and inflammatory factors and lipid accumulation was observed by Oil Red O staining. With the application of reverse transcription-quantitative PCR (RT-qPCR) and western blot, the messenger RNA (mRNA) and protein expressions of low-density lipoprotein receptor (LDLR) was resolved. In vitro, Cell counting kit-8 and flow cytometry analysis were applied for the assessment of cell proliferation and apoptosis. The proliferation- and apoptosis-related proteins were appraised with western blot. Additionally, the expressions of PDE-4 at both mRNA and protein levels were tested with RT-qPCR and western blot. Here, it was discovered that PDE4 was greatly elevated in PCOS mice and DHEA-induced ovarian granulosa cells (KGN). In PCOS mice, PDE4 was negative correlated with progesterone and had positive correlation with testosterone. Roflumilast could enhanced progesterone expression, increased the number of primary follicles, preantral follicles and antral follicles but reduced testosterone and decreased the number of cystic follicles in PCOS mice. It was also testified that Roflumilast could inhibit the release of inflammatory factors and lipid accumulation in PCOS mice. Besides, the proliferation of DHEA-induced KGN cells was enhanced while the apoptosis was declined by Roflumilast, accompanied by elevated contents of PCNA, Ki67 and antiapoptotic protein Bcl-2. Collectively, Roflumilast inhibited inflammation and lipid accumulation in PCOS mice to improve ovarian function and reduce DHEA-induced granulosa cell apoptosis.

Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis.

Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle (CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3) were validated by RT-qPCR. Specifically, these seven DEGs were increased in EPT compared to ET (p < 0.05) and had higher expression levels in breast cancer than adjacent normal tissues (p < 0.05). Next, we found that estrogen receptor (ER)-positive breast cancer patients with a higher CNNE2 expression have a shorter overall survival time (p < 0.05), while this effect was not observed in the other six DEGs (p > 0.05). Interestingly, the molecular docking results showed that CCNE2 might bind to 17ß-estradiol (−6.791 kcal/mol), progesterone (−6.847 kcal/mol), and medroxyprogesterone acetate (−6.314 kcal/mol) with a relatively strong binding affinity, respectively. Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT.