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.

Lessons from KEEPS: the Kronos Early Estrogen Prevention Study.

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17ß-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of ß-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.

Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice.

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.

Hormone Therapy in Menopause.

As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).Local vulvovaginal and urinary symptoms, now termed genitourinary syndrome of menopause (GSM), are seen in 50% of postmenopausal women, and it negatively impacts quality of life. Estrogen remains the most effective treatment for both VMS and GSM, for osteoporosis prevention, and for symptom relief as well as chronic disease prevention in women who experience premature menopause whether from primary ovarian insufficiency (POI) or iatrogenic etiologies. For women who have contraindications to estrogen therapy or who personally object, a panoply of nonhormonal modalities can be offered to treat both systemic and local menopausal symptoms. A historical review of estrogen studies reveals why its persona has vacillated from hero to villain (after the WHI) and back to hero. The "timing hypothesis" and its underlying mechanism shed light on the pleiotropic nature of estrogen. Finally reviewed is the compelling argument from notable thought-leaders that estrogen, in those without contraindications, should be considered for primary prevention of cardiovascular disease as well as the prevention of chronic disease.

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.

Effect of a tissue selective estrogen complex on breast cancer: Role of unique properties of conjugated equine estrogen.

The Women's Health Initiative studies reported that the menopausal hormone therapy (MHT) regimen containing conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased, whereas CEE alone reduced breast cancer incidence. These observations suggest the possibility that CEE might exert unique actions on breast and also suggest the need to eliminate the progestogen from MHT regimens. A MHT regimen called a tissue selective estrogen complex (TSEC), containing CEE plus bazedoxifene (BZA), to avoid the need for a progestogen, was developed and FDA approved. Our study addressed two questions regarding this TSEC: (i) whether CEE exert effects on breast cancer which differ from those of estradiol (E2 ) and (ii) whether BZA antagonize the effects of E2 and CEE on breast cancer? Two rodent models (NMU and ACI) were used to compare the effect of CEE with E2 on mammary tumor formation, proliferation and apoptosis. In both the NMU and ACI models, E2 significantly increased tumor incidence and multiplicity whereas in striking contrast CEE did not, even though the estrogenic effects of CEE and E2 on uterine weight were identical. Mechanistically E2 blocked whereas CEE stimulated apoptosis (cleaved caspase-3) in ACI animals and only E2 stimulated proliferation (Ki67). BZA exerted highly potent anti-estrogenic effects on tumors by completely blocking palpable tumor formation. These data suggest that the CEE/BZA TSEC may be a safer, breast-antagonistic, MHT agent for women and might have potential to prevent breast cancer while relieving menopausal symptoms.

Effects of different menopausal hormone replacement regimens on body composition in Chinese women.

PURPOSE: The aim of this study was to determine the effects of different menopausal hormone therapy regimens on body composition in healthy postmenopausal Chinese women. MATERIALS AND METHODS: One hundred and twenty-three healthy postmenopausal Chinese women were randomly assigned to either group A (0.625 mg conjugated equine estrogens [CEE] plus 100 mg micronized progesterone [MP]), group B (0.3 mg CEE plus 100 mg MP), or group C (0.625 mg CEE plus 10 mg dydrogesterone). Body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: One hundred and two women completed the trial at 1 year. A small but significant gain in lean body mass (619 ± 1019 g, p = 0.002) and a decrease of fat mass in all separate regions was observed in group A. A significant shift from gynoid to android fat distribution was observed in group B and group C (android/gynoid fat percentage ratios increased by 0.06 ± 0.08, p = 0.000 and 0.03 ± 0.08, p = 0.018, respectively), whereas no significant change was observed in group A (0.02 ± 0.06, p = 0.103). CONCLUSIONS: In healthy postmenopausal Chinese women, 0.625 mg of CEE combined with 100 mg of MP was associated with a more favorable fat distribution compared with 0.3 mg CEE plus 100 mg MP or 0.625 mg CEE plus 10 mg dydrogesterone.

Vaginal Health During Breast Cancer Treatment.

There are increasing numbers of breast cancer survivors. Chemotherapy or endocrine therapy result in effects on vaginal health that may affect quality of life. These effects may impact sexual function, daily comfort, or the ability to perform a pelvic examination. Vulvovaginal atrophy, or genitourinary syndrome of menopause, may be treated with nonhormonal or hormonal measures. Breast cancer survivors who are menopausal and/or on endocrine therapy should be screened for issues with vaginal health and counseled about treatment options.

Metabolism of endogenous and exogenous estrogens in women.

Estrogens regulate important processes in reproductive, skeletal, cardiovascular, and central nervous systems that impact women's overall health. Understanding endogenous and exogenously administered estrogen metabolism is vital to determining therapeutic estrogen levels. The present review provides an overview of estrogen metabolites formed in non-pregnant and pregnant women, and those resulting from exogenous estrogen administration. There are four principal endogenous estrogens: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). E4, which is produced only in pregnancy, has emerged recently as an estrogen with significant therapeutic potential. E1, E2, and E3 undergo extensive metabolism primarily through phase I (hydroxylation, oxidation, reduction) and phase II (primarily conjugation) reactions, whereas E4 undergoes only phase II reactions. Exogenous estrogens commonly used for menopausal treatment and/or contraception, including micronized E2, conjugated equine estrogens, and ethinyl estradiol, also undergo phase I and phase II reactions, but differ widely in the types of metabolites formed. The mechanisms by which estrogen metabolites are formed and their excretion in urine, bile, and feces, are still poorly understood. We highlight areas that require further research to foster a better understanding of how estrogen metabolism impacts dosing of oral estrogens for therapeutic use, as well as the physiological regulation of endogenous estrogens.

Developmental toxicity and transcriptome analysis of equine estrogens in developing medaka (Oryzias latipes) using nanosecond pulsed electric field incorporation.

Equine estrogens (EQs) are steroidal hormones isolated from the urine of pregnant mares and are used in the formulation of human medications. This study initially investigated the embryonic developmental toxicity of equilin (Eq) and equilenin (Eqn) in medaka (Oryzias latipes). Malformations were observed in embryos exposed to nominal concentrations of 1 and 10 mg/L of Eq and Eqn. Delayed hatching was observed at 1 mg/L of Eq. To further investigate the molecular mechanism of developmental toxicity caused by Eq and Eqn, transcriptome and bioinformatics analyses were performed. Among 2016 and 3855 total differentially expressed genes (DEGs), 1117 DEGs overlapped between Eq. (55.4 % of total DEGs) and Eq. (29.0 % of total DEGs). Gene ontology indicated effects in terms related to blood circulation and cell junctions. Pathway analyses using DEGs revealed that both Eq and Eqn treatments at 10 mg/L affected various KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, such as neuroactive ligand-receptor interaction, mitogen-activated protein kinase signaling, retinol metabolism, and cytokine-cytokine receptor interaction. These results suggest that the disruption of these KEGG pathways is involved in the developmental toxicity of EQs in medaka embryos.

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.

[Menopause hormone therapy and cognition. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. / Traitement hormonal de la ménopause et cognition. RPC Les femmes ménopausées du CNGOF et du GEMVi.

The results of the WHI, which reported a doubling of the risk of Alzheimer's disease (AD) and a decline in cognitive function in women who were given menopause hormone therapy (MHT), have raised concerns on the deleterious impact of MHT on the central nervous system. Such as for the cardiovascular system, the very late age of initiation of treatment and the nature of the molecules have led to conclusions that cannot be extended to women in their fifties, at the onset of their menopause which is the usual age of MHT initiation. The molecules, which are used in France, 17-beta estradiol and natural progesterone (or its isomer, dydrogesterone) are very different from the equine conjugated estrogens and medroxyprogesterone acetate used in the WHI. It can now be stated that if MHT is started within the window of opportunity (i.e. before the age of 60 or within the first 10years after the beginning of menopause) no deleterious effect on cognition is observed. Moreover, cognition remains relatively stable at the beginning of menopause since the cognitive reserve as well as the different compensation circuits allow compensation for estrogen deficiency. This does not in any way prejudge a possible positive effect of MHT on AD, which is very difficult to demonstrate, as the age of onset of this dementia is very late, 20 or 30years after the initiation of treatment.

Hormone Therapy and Effects on Sporadic Alzheimer's Disease in Postmenopausal Women: Importance of Nomenclature.

Numerous observational studies have suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and Alzheimer's disease (AD). However, because of the significant disparity between results, especially those between observational and randomized controlled trials (RCT), this postulate remains unproven. A significant contributing factor to these inconsistencies is the loose use of the generic definitions of estrogens and progestogens with most studies not delineating the clear differences between non-endogenous and endogenously identical (bioidentical) hormones, their molecular binding affinities and actions, and resultant metabolites. This is highlighted by the generalized terminological use of HT, which is often used to encompass significantly disparate hormonal formulations without clear demarcation. This has impacted and continues to significantly influence interpretations of data, meta-analyses, observational studies, etc., relevant to AD. To progress forward and allow unbiased interpretation, it is no longer acceptable to group HT formulations together as a homogenous group. This will also allow differentiation between compounds that exhibit beneficial actions and those that do not and whether these effects are specific or generalized. The role of the endogenous hormones, 17 beta-oestradiol (E2) and progesterone (P4), in the development of sporadic AD in postmenopausal women is also examined.

Human versus non-human sex steroid use in hormone replacement therapies part 1: Preclinical data.

Prior to 2002, hormone replacement therapy (HRT) was considered to be an important component of postmenopausal healthcare. This was based on a plethora of basic, epidemiological and clinical studies demonstrating the health benefits of supplementation with human sex steroids. However, adverse findings from the Women's Health Initiative (WHI) studies that examined the 2 major forms of HRT in use in the US at that time - Premarin (conjugated equine estrogens; CEE) and Prempro (CEE + medroxyprogesterone acetate; MPA), cast a shadow over the use of any form of HRT. Here we review the biochemical and physiological differences between the non-human WHI study hormones - CEE and MPA, and their respective human counterparts 17ß-estradiol (E2) and progesterone (P4). Preclinical data from the last 30 years demonstrate clear differences between human and non-human sex steroids on numerous molecular, physiological and functional parameters in brain, heart and reproductive tissue. In contrast to CEE supplementation, which is not always detrimental although certainly not as optimal as E2 supplementation, MPA is clearly not equivalent to P4, having detrimental effects on cognitive, cardiac and reproductive function. Moreover, unlike P4, MPA is clearly antagonistic of the positive effects of E2 and CEE on tissue function. These data indicate that minor chemical changes to human sex steroids result in physiologically distinct actions that are not optimal for tissue health and functioning.

Safety and benefit considerations for menopausal hormone therapy.

INTRODUCTION: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile. Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported. Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women's Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens.

Preclinical breast effects of a tissue selective estrogen complex (TSEC) including conjugated estrogen with bazedoxifene.

The first tissue-selective estrogen complex (TSEC), consisting of a combination of a conjugated equine estrogen (CEE) and bazedoxifene (BZA), has been approved for treatment of the menopause in the USA and European Union. We have postulated that this TSEC might block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer growth. This manuscript, representing a presentation at a Festschrift honoring Evan Simpson, reviews our published data BZA blocked the in vitro effects of both estradiol and CEE on cell growth and gene expression in MCF-7 cells. BZA completely blocked CEE- or E2-stimulated ductal and terminal end bud growth of immature murine mammary glands and the growth of experimental breast cancers. These findings provide a rationale for future clinical studies to determine whether this TSEC prevents the growth of occult breast cancer in women.

Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action.

Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50-59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD. CEE is a natural formulation of an extract prepared from pregnant mares' urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17ß-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17ß-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor ß and not the estrogen receptor α. All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17ß-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins. Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer's disease in both aging women and men. This article is part of a Special Issue entitled 'Menopause'.

Estrógeno tópico vaginal y dehiscencia de la cúpula vaginal en pacientes con histerectomía total laparoscópica / Topical vaginal estrogen and vaginal vault dehiscence in patients rather than a laparoscopic total hysterectomy

Resumen OBJETIVO: Comparar la frecuencia de dehiscencia de la cúpula vaginal en pacientes tratadas con y sin estrógenos equinos conjugados por vía vaginal antes de la histerectomía total laparoscópica. MATERIALES Y MÉTODOS: Ensayo clínico controlado, comparativo, ciego simple, efectuado en pacientes atendidas entre enero de 2013 y agosto de 2016 en el Hospital Civil de Culiacán con indicación de histerectomía total laparoscópica por enfermedad benigna. Criterios de inclusión: haber recibido durante tres semanas previas al procedimiento estrógenos equinos conjugados por vía vaginal (grupo de estudio) o crema lubricante vaginal como placebo (grupo control). Criterios de exclusión: pacientes con diabetes mellitus tratadas con esteroides y antecedente de un evento tromboembólico reciente. Se evaluó la frecuencia de dehiscencia de la cúpula vaginal a los 7 y 30 días posteriores a la cirugía. Se utilizó la prueba t de Student para comparar medias y la χ2 para la comparación de proporciones, con cálculo de riesgo relativo para evaluar el riesgo de dehiscencia de la cúpula vaginal. RESULTADOS: Se estudiaron 236 pacientes con edad promedio, en ambos grupos, de 47.1 y 47.7 años, respectivamente (p > .05). Los antecedentes ginecoobstétricos y las indicaciones para histerectomía fueron similares en ambos grupos (p = .340). La incidencia total de dehiscencia de la cúpula vaginal fue de 4.6% (n = 11/236) con frecuencia de 6.8% (n = 8/118) en las pacientes del grupo tratado con lubricante vaginal y de 2.5% (n = 3/118) en el grupo tratado con estrógenos equinos conjugados por vía vaginal, sin diferencias entre ambos grupos (p = .123; RR=.359; IC95%: .093-1.387). CONCLUSIONES: El riesgo de dehiscencia de la cúpula vaginal fue similar entre el grupo que recibió lubricante y el de estrógenos tópicos vaginales, pero con una tendencia menor en la frecuencia de dehiscencia de la cúpula vaginal en el grupo tratado con estrógenos tópicos.

Abstract OBJECTIVE: To compare the frequency of vaginal cuff dehiscence in patients managed with and without conjugated equine estrogens vaginally prior to total laparoscopic hysterectomy (TLH). MATERIALS AND METHODS: In a single-blind controlled clinical trial, 236 patients with indications for laparoscopic total hysterectomy for benign pathology at the Hospital Civil de Culiacán and who agreed to participate in the study were randomly assigned to receive vaginally conjugated equine estrogens (study group) or vaginal lubricating cream as a placebo (control group) for 3 weeks prior to the procedure. Patients with diabetes mellitus, treated with steroids and history of a recent thromboembolic event were excluded. The frequency of vaginal cuff dehiscence was evaluated at 7 and 30 days after surgery. The student's t-test was used to compare means and the Chi-square test was used to compare proportions, with relative risk (RR) calculation to evaluate the risk of vaginal cuff dehiscence. RESULTS: We studied 236 patients with average age, in both groups, 47.1 and 47.7 years, respectively (p > .05). The mean age of the patients was similar between the groups (47.1 vs 47.7 years, p>.05). The gynecological-obstetric history and indications for hysterectomy were similar between both groups (p = .340). The incidence of vaginal cuff dehiscence was 2.5% (n = 3) in the group treated with conjugated equine estrogens vaginally and 6.8% (n = 8) in the patients of thse group treated with vaginal lubricant (p= .123; RM= .359; IC95%: .093-1.387). CONCLUSIONS: The risk of presenting vaginal cuff dehiscence was similar between the group of lubricant and topical vaginal estrogens, but with a lower tendency in the frequency of vaginal cuff dehiscence in the group of topical estrogens.

Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice.

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Women's Health Initiative Hormone Therapy Trials: New insights on Cardiovascular Disease from Additional Years of Follow up.

Debate and controversy surrounding the benefits and risks of menopausal hormone therapy (MHT) for prevention of cardiovascular disease has continued in the decade since the cessation of the Women's Health Initiative (WHI) hormone therapy interventions. As a result, many women and their physicians have been reluctant to turn to MHT for relief of vasomotor and other menopausal symptoms. However, several follow-up studies of WHI participants provide additional insight into clinical characteristics of women who are more likely to have favorable outcomes and lower rates of adverse events associated with MHT. This report focuses on those studies that identify characteristics and biomarkers helpful in stratifying risk for an individual. Incorporation of these factors into a benefit:risk model could assist in patient-oriented decision making regarding use of MHT. Personalizing treatment offers the potential to minimize risk and improve health outcomes.