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.

Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives.

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.

Is the multinational, surveillance PRO-E2 study informative for all countries? The Italian data on VTE and contraceptive effectiveness.

PURPOSE: To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. MATERIALS AND METHODS: Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. RESULTS: Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21-6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4-14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06-0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08-0.26) cohorts. CONCLUSION: Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. SHORT CONDENSATION: This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill.

Effects of Transdermal 17ß-Estradiol + Norethisterone Acetate on Cardiovascular Disease Risk Factors in Postmenopausal Women: A Meta-analysis of Data From Randomized, Controlled Trials.

PURPOSE: To date, no study has demonstrated the role of transdermal 17ß-estradiol + norethisterone acetate on all of the risk factors for cardiovascular disease in postmenopausal women. To overcome this knowledge gap, a systematic review and meta-analysis were conducted to determine the effects of this combination treatment on BMI, body weight, waist/hip ratio, fibrinogen, factor VII, lipoprotein(a), fasting blood sugar, insulin, HbA1c, TG, LDL-C, HDL-C, and TC in postmenopausal women. METHODS: PubMed/Medline, SCOPUS, Web of Science, Embase, and Google Scholar were searched for relevant articles published between the inception of each database and April 6, 2023. The sample size and mean (SD) were used to calculate overall effect size using a random-effects model. FINDINGS: A total of 10 articles with 14 arms were included in the meta-analysis. On pooled analysis of effect size, fibrinogen (weighted mean difference [WMD], -0.18 g/L; 95% CI, -0.25 to -0.10), factor VII (WMD, -9.58; 95% CI, -12.51 to -6.64), LDL-C (WMD, -13.09 mg/dL; 95% CI, -18.48 to -7.71), and TC (WMD, -12.61 mg/dL; 95% CI, -18.11 to -7.12) were significantly affected with the use of transdermal 17ß-estradiol + norethisterone acetate (all, P < 0.001), but effects on lipoprotein(a), TG, HDL-C, fasting blood sugar, insulin, HbA1c, BMI, body weight, and waist/hip ratio were not significant. IMPLICATIONS: Based on the findings from the present systematic review and meta-analysis, it was concluded that transdermal administration of 17ß-estradiol + norethisterone acetate had beneficial impacts on fibrinogen, factor VII, LDL-C, and TC, suggesting a possible application in the reduction of cardiovascular disease risk.

Association Between the Route of Administration and Formulation of Estrogen Therapy and Hypertension Risk in Postmenopausal Women: A Prospective Population-Based Study.

BACKGROUND: Hypertension is the leading global cause of cardiovascular disease and premature mortality in women. The effects of postmenopausal hormone therapy (HT) on blood pressure are uncertain but may be related to route of estrogen administration and formulation of estrogen. We sought to determine the association between route of administration and formulation of estrogen HT and hypertension risk in postmenopausal women. METHODS: Population-based cohort study with women aged ≥45 years who filled ≥2 consecutive prescriptions for estrogen-only HT, identified from linked provincial health administrative data from Alberta, Canada, between 2008 and 2019. The primary outcome, incident hypertension, was identified using standardized International Classification of Diseases, Ninth and Tenth Revision. Cox proportional hazard models were used to calculate hazard ratios (HRs) for hypertension in women using oral HT compared with nonoral HT (transdermal, vaginal, or intramuscular). RESULTS: In total, 112 240 women used an estrogen-only form of HT. Oral estrogen was associated with a higher risk of hypertension compared with both transdermal (HR, 1.14 [95% CI, 1.08-1.20]) and vaginal (HR, 1.19 [95% CI, 1.13-1.25]) estrogens. Conjugated equine estrogen was associated with an increased risk of hypertension compared with estradiol (HR, 1.08 [95% CI, 1.04-1.14]) but not estrone (HR, 1.00 [95% CI, 0.93-1.10]). Duration of estrogen exposure and cumulative dose of estrogen was positively associated with risk of hypertension. CONCLUSIONS: Oral estrogen-only HT use was associated with an increased risk of hypertension in women. In women using estrogen-only HT, nonoral estradiol at the lowest dose and for the shortest time-period is associated with the lowest risk of hypertension.

Central nervous system tumours among users of vaginal oestradiol tablets: A nationwide population-based study.

BACKGROUND AND PURPOSE: It is currently unknown whether vaginal oestradiol is associated with development of meningioma and glioma. The aim of this study was to examine associations between cumulative use and treatment intensity of vaginally administered oestradiol tablets and incidence of meningioma and glioma in a nationwide, population-based study. METHODS: We conducted a nested case-control study within a nationwide cohort of Danish women followed from 2000 to 2018. The cohort consisted of 590,676 women aged 50-60 years at study start, without prior cancer diagnosis or use of systemic hormone therapy. Information on cumulative dose, duration, and intensity of vaginal oestradiol tablet use was assessed from filled prescriptions. Conditional logistic regression provided adjusted hazard ratios (HRs) for the association between vaginal oestradiol use and diagnosis of meningioma or glioma. RESULTS: We identified 1108 women with meningioma and 835 with glioma. Of these, 19.8% and 14.0% used vaginal oestradiol tablets, respectively. The HRs in those with ever-use of vaginal oestradiol tablets was 1.14 (95% confidence interval [CI] 0.97-1.34) for meningioma and 0.90 (95% CI 0.73-1.11) for glioma. The corresponding HRs for new users exclusively were 1.18 (95% CI 0.99-1.40) for meningioma and 0.89 (95% CI 0.71-1.13) for glioma. Intensity of vaginal oestradiol tablet use according to duration and user status yielded slightly elevated HRs for meningioma without an apparent dose-response pattern, while the HRs for glioma were generally below unity. Among new users, the HR with high intensity of current or recent vaginal oestradiol tablet use for 2+ years was 1.66 (95% CI 1.09-2.55) for meningioma and 0.77 (95% CI 0.41-1.44) for glioma. CONCLUSION: Use of vaginal oestradiol tablets was associated with a slightly increased incidence of meningioma but not of glioma. Owing to the observational nature of the study, residual bias cannot be ruled out.

High Fat Diet Exaggerate Metabolic and Reproductive PCOS Features by Promoting Oxidative Stress: An Improved EV Model in Rats.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent multifactorial endocrinopathy affecting women in the reproductive period, often associated with infertility and metabolic disorders. The use of animal models helps to better understand etiopathogenesis, enabling the examination of the effects of certain drugs in order to discover the best possible therapeutic approach. We tried to investigate the additional effect of estradiol-valerate (EV) and high-fat diet (HFD) in female rats to explore PCOS-related alterations with special focus on oxidative stress. Materials and Methods: Animals were divided into three groups: control group (CTRL, n = 6), estradiol-valerate group (EV, n = 6), and estradiol-valerate group on HFD (EV + HFD, n = 6). PCOS was induced by single subcutaneous injection of long-acting EV in a dose of 4 mg/per rat. We tried to improve the metabolic characteristics of the PCOS animal model by adding HFD, so the CTRL and EV group had a regular diet, while the EV + HFD group had HFD during the induction period of 60 days. Results: We observed alterations of anthropometric parameters and hormonal disturbances, along with estrus cycle impairment reassembly to obese-type PCOS phenotype. Moreover, glucose metabolism was impaired after addition of HFD to EV protocol, contrary to EV administered alone. Histological analysis confirmed more numerous cystic follicles after the combination of EV and HFD protocol. The alterations of oxidative stress markers could be related to and serve as the mechanistic base for development of PCOS-related endocrine, reproductive, and metabolic properties. Conclusions: The additive effect of EV and HFD was obvious in the majority of the parameters observed. Our study strongly demonstrated metabolic as well as reproductive properties of PCOS in rats.

Intravaginal Drug Delivery Systems to Treat the Genitourinary Syndrome of Menopause: Towards the Design of Safe and Efficacious Estrogen-loaded Prototypes.

Estrogens locally delivered to the vagina by tablets, capsules, rings, pessaries, and creams are the most common and highly recommended platforms to treat the genitourinary syndrome of menopause (GSM). Estradiol, an essential estrogen, is routinely administered alone, or in combination with progestins, to effectively alleviate the symptoms associated with moderate to severe menopause when non-pharmacological interventions are not indicated. Since the risk and side effects of estradiol use depends on the administered amount and duration of use, the lowest effective dose of estradiol is recommended when long-term treatment is required. Although there is a wealth of data and literature comparing vaginally administered estrogen-containing products, there is a lack of information revealing the effect of the delivery system used and formulation constituent's attributes on the efficacy, safety, and patient acceptability of these dosage forms. This review therefore aims to classify and compare various designs of commercially available and non-commercial vaginal 17ß-estradiol formulations and analyze their performance in terms of systemic absorption, efficacy, safety, and patient satisfaction and acceptance. The vaginal estrogenic platforms included in this review are the currently marketed and investigational 17ß-estradiol tablets, softgel capsules, creams, and rings for the treatment of GSM, based on their different design specifications, estradiol loads, and materials used in their preparation. Additionally, the mechanisms of the effects of estradiol on GSM have been discussed, as well as their potential impact on treatment efficacy and patient compliance.

Efficacy and safety of ultra-low-dose estradiol and norethisterone in postmenopausal Brazilian women.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of oral ultra-low-dose continuous combination of 17ß-estradiol (17ß-E2) and norethisterone acetate (NETA) in postmenopausal Brazilian women. METHODS: Postmenopausal women (age 45-60 years) with amenorrhea >12 months and intact uterus, with moderate to severe vasomotor symptoms, were included. The vasomotor symptoms and endometrial bleeding were evaluated by a daily diary for 24 weeks, and the women were assessed at baseline and endpoint. RESULTS: A total of 118 women were included. The group treated with 0.5 mg 17ß-E2/0.1 mg NETA (n = 58) showed a percentage reduction of 77.1% in the frequency of vasomotor symptoms versus 49.9% in the placebo group (n = 60) (p = 0.0001). The severity score showed a reduction in the treatment group when compared to the placebo (p < 0.0001). The adverse events were comparable between the groups; however, in the 0.5 mg 17ß-E2/0.1 mg NETA group there were more complaints of vaginal bleeding; despite that, in most cycles in both treatment groups, more than 80% of women experienced amenorrhea. CONCLUSIONS: The combination of 0.5 mg 17ß-E2/0.1 mg NETA in a continuous combination regimen was shown to be effective in reducing the frequency and severity of vasomotor symptoms in Brazilian postmenopausal women.

Effects of Rosa damascena on reproductive improvement, metabolic parameters, liver function and insulin-like growth factor-1 gene expression in estradiol valerate induced polycystic ovarian syndrome in Wistar rats.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. The present study aimed to evaluate the effects of Rosa damascena (RD) extract in estradiol valerate (EV) induced polycystic ovary syndrome rats. METHODS: Adult female Wistar rats were divided into control (n = 12) and PCOS groups (n = 36). The PCOS model was induced using EV (4 mg/kg/day), which was confirmed in 6 rats in each control and PCOS group by observation of irregular estrous cycles in vaginal smears and ovarian multiple cystic. Then, the rest of the control group (n = 6) and PCOS rats (n = 30 in 5 divided groups) were treated orally for 28 days with metformin (MET) as a positive control (200 mg/kg/day) and RD extract (400, 800, and 1200 mg/kg/day, respectively). Body and ovary weights, biochemical and histological parameters, and expression of the IGF-1 gene were measured. RESULTS: Compared to the PCOS group, metformin and higher doses of RD extract (800 and 1200 mg/kg/day) significantly reduced BW, HOMA-IR, FBS, FINS, TG, LDL, TT, E2, LH, TC, and liver enzymes, and increased HDL and FSH levels. In addition, ovarian weight and CFs decreased, and the findings showed an increment in PFs, CLs, PAFs, AFs, and GFs. IGF-1 gene expression levels were significantly decreased (p < 0.001). CONCLUSION: RD extract seems to have the potential therapeutic effect of alleviating PCOS complications, and IGF-1 signaling may be involved in the beneficial effects of RD on PCOS.

Effects of Isoflavone Supplementation on the Response to Medroxyprogesterone in Premenopausal Women with Nonatypical Endometrial Hyperplasia: A Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: The purpose of this study was to evaluate the impact of isoflavone supplementation compared with placebo on endometrial histology and serum estradiol levels in premenopausal women with nonatypical endometrial hyperplasia. Materials and Methods: The present double-blindplacebo-controlled clinical trial was conducted on 100 women with nonatypical endometrial hyperplasia in the age range of 30 to 45 years. Participants were randomly assigned to receive 50 mg of isoflavone (n = 50) or placebos (n = 50) daily for three months. Both groups received the standard treatment of nonatypical endometrial hyperplasia. Endometrial biopsy and blood samples were taken at the baseline and three months after the intervention. The incidence of drug side effects was assessed as well. Results: After three months, 88.4% of isoflavone-administered subjects had a significant histological improvement compared to 68.9% subjects in the placebo group (P=0.02). There were no significant differences between the two groups in the changes of serum estradiol levels and the incidence of drug side effects. Conclusion: The findings of the present study demonstrated that the coadministration of 50 mg of isoflavones and medroxyprogesterone acetate increases the treatment efficacy in women with nonatypical endometrial hyperplasia. Clinical Trial Registration. This trial was registered on the Iranian website for clinical trial registration (https://www.irct.ir/trial/53553).

Nasturtium officinale L. and metformin alleviate the estradiol- induced polycystic ovary syndrome with synergistic effects through modulation of Bax/Bcl-2/p53/caspase-3 signaling pathway and anti-inflammatory and anti-oxidative effects.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, which is associated with metabolic, hereditary and hormonal disorders. The aim of this study was to evaluate the therapeutic effects of Nasturtium officinale L. (N. officinale) on biochemical and molecular parameters in estradiol-induced PCOS in rats. Seventy Wistar rats in 7 groups (n = 10) were randomly assigned to normal (NC), PCOS, metformin (MET - 300 mg/kg), N. officinale (50 and 100 mg/kg) and co-treatment with MET and N. officinale groups. After 21 days of treatment, biochemical parameters levels of estrogen, LH and FSH along with serum levels of (IL-6 and IL-1ß cytokines) and serum antioxidant parameters (enzymatic activity of catalase and superoxide dismutase) were measured. Finally, by measuring the expression of apoptosis related genes (Bax/Bcl-2/p53/caspase-3) with the help of real-time PCR and the expression of p53 with the help of immunohistochemistry in ovarian cells. N. officinale modulates hormones through its hypothalamic-pituitary-gonadal pathway with its synergistic effects along with MET. Also, in co-treatment groups (MET and N. officinale), the activity of serum antioxidant enzymes increased and also the serum level of inflammatory cytokines decreased. N. officinale, along with MET, amplified the Bax/Bcl2/p53/caspase-3 pathways, which eventually increased the number of p53 positive cells. These findings indicate that N. officinale extract along with MET can improve the physiological function of the ovaries in PCOS-induced disorders. PRACTICAL APPLICATIONS: Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women, which is associated with metabolic, hereditary and hormonal disorders. The extract of Nasturtium officinale L. was able to intensify mitochondrial apoptotic pathway in cystic follicles and prevent their formation. It seems that pro-drugs containing N. officinale along with effective commercial drugs in PCOS can help ovulation and fertility in woman with this disease.

Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor ß and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor ß-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.

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.

Effects of estradiol- and ethinylestradiol-based contraceptives on adrenal steroids: A randomized trial.

OBJECTIVES: Ethinylestradiol (EE)-based combined oral contraceptives (COC) affect adrenal function by altering steroid and corticosteroid-binding globulin (CBG) synthesis that may contribute to adverse effects related to these drugs. The effects of COCs containing natural estrogens remain unclear. We compared the effects of COCs containing estradiol valerate (EV) and EE on cortisol and other adrenal steroid hormones. STUDY DESIGN: A spin-off study of a randomized, open-label trial. Fifty-nine healthy women were allocated to groups that engaged in the continuous use of EV+dienogest (DNG), EE+DNG, or DNG only for 9 weeks. We measured changes in adrenal steroids, CBG, and the free cortisol index (FCI). RESULTS: Treatment with EE+DNG increased total cortisol (mean increment 668 nmol/L, p < 0.001) and cortisone (10 nmol/L, p= 0.001) levels, whereas the change from the baseline was insignificant for the EV+DNG and DNG-only groups. Dehydroepiandrosterone sulfate decreased by 24% in the EE+DNG group but remained unchanged in the EV+DNG and DNG-only groups. Aldosterone and 17-hydroxyprogesterone levels did not differ between the groups. All preparations increased CBG, but the increase in the EE+DNG group (median increment 42 µg/mL, p < 0.001) was 9- and 49-fold higher than that in the EV+DNG and DNG-only groups, respectively. The FCI remained unchanged in all study groups, indicating that cortisol and CBG mainly increased in parallel, although some individuals demonstrated larger alterations in the cortisol-CBG balance. CONCLUSION: In COCs, EV had a milder effect on circulating CBG and adrenal steroid levels than EE; however, further research is necessary to determine the long-term effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02352090 IMPLICATIONS: EV-based COC had reduced effects on circulating CBG and adrenal steroids compared to EE, probably due to a lower hepatic impact. Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated. These results encourage further research and development of contraceptives containing natural estrogens.

Menopausal hormone therapy with conjugated equine estrogen is associated with a higher risk of hemorrhagic stroke than therapy with estradiol: a retrospective population-based cohort study.

BACKGROUND: Several studies have shown that menopausal hormone therapy (MHT) reduces the risk of hemorrhagic stroke (HS), but there are no studies comparing the effect of different estrogen types (conjugated equine estrogen [CEE] and estradiol [E2]). METHODS: This retrospective cohort study included menopausal women aged 40-65 years diagnosed between 2000 and 2016 who received MHT with oral CEE or E2 and were registered in Taiwan's National Health Insurance Research Database. The primary outcome was HS. Propensity score matching with menopausal age and comorbidities was performed. Cox proportional hazard regression models were used to calculate the incidence and hazard ratios (HRs) of HS. RESULTS: A total of 14,586 pairs of women were included. The mean menopausal ages of the CEE and E2 groups were 50.45 ± 5.31 and 50.31 ± 4.99 years, respectively. After adjusting for age and comorbidities, the incidence of HS was 1.23-fold higher in women treated with CEE than in those treated with E2 (8.04 vs. 6.49/10,000 person-years), with an adjusted HR of 1.50 (95 % confidence interval [CI] 1.04-2.17). MHT with CEE initiated within 5 years of menopause was associated with a higher risk of HS than MHT with E2 (HR = 1.47, 95 % CI: 1.01-2.14). CONCLUSIONS: In postmenopausal Taiwanese women, MHT with CEE was associated with an increased risk of HS compared to MHT with E2, a risk that women using CEE should discuss with their clinicians. Further large-scale investigations of this population are warranted.

Oestrogen therapy for postpartum depression: efficacy and adverse effects. A double-blind, randomized, placebo-controlled pilot study.

BACKGROUND: Postpartum depression (PPD) is detrimental to the mother and the family as a whole. Early initiation of appropriate treatment is important. The aim of this pilot study was to evaluate the efficacy and adverse effects of oestradiol treatment. METHODS: We performed a pilot double-blind, randomized, placebo-controlled study. Major depression was diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), and the severity of depression was evaluated using the Edinburgh Postnatal Depression Scale (EPDS). The duration of treatment with sublingual oestradiol hemihydrate (1-3 mg/day) was 12 weeks. RESULTS: The treatment group consisted of 16 mothers and the placebo group of 14 mothers. Thirteen mothers in the treatment group and ten in the placebo group recovered from depression during the treatment period as measured with the EPDS (<10). There was no evidence to suggest that oestradiol was more effective than placebo. More mothers in the treatment group than in the placebo group (eight vs. one) received gestagen treatment for irregular bleeding. Oestradiol did not disturb breastfeeding. The mean number of other adverse effects per mother was lower in the treatment group, and these were mostly somatic symptoms. CONCLUSION: Our findings warrant further studies on oestrogen therapy for PPD with and without antidepressant and gestagen therapy, and on adverse effects (including effects on vaginal bleeding and breastfeeding).

Vaginal estrogen and association with dementia: A nationwide population-based study.

INTRODUCTION: Use of systemic hormone therapy has been positively associated with development of dementia. Little is known about the dose-dependent effect of vaginal estradiol on dementia risk. METHODS: We assessed associations between cumulative dose of vaginal estradiol tablets and dementia in a case-control study nested in a nationwide Danish cohort of women aged 50 to 60 years at study initiation, who did not use systemic hormone therapy. Each case was age-matched to 10 female controls. RESULTS: A total of 4574 dementia cases were matched to 45,740 controls. Cumulative use of vaginal estradiol tablets was not associated with all-cause dementia; adjusted hazard ratio 1.02 (95% confidence interval [CI] 0.89-1.18) for low dose (< 750 mcg), 1.07 (0.94-1.21) for medium dose (750-2000 mcg), and 0.93 (0.84-1.03) for high dose (> 2000 mcg). Similarly, Alzheimer's disease (AD) only was not associated with vaginal estradiol. DISCUSSION: Exposure to vaginal estradiol tablets was not associated with all-cause dementia or AD only.