Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause

Females live longer than males in many species, including humans, and estrogens are in part responsible for this protection against aging. We reported previously that estrogens can protect rats against oxidative stress, by inducing antioxidant and longevity-related genes. Thus, this study was aimed at confirming the ability of estrogens to upregulate antioxidant and longevity-related genes in humans. For this purpose, we selected 16 women of reproductive age (18-42 years old) undergoing a fertility treatment that includes a medically induced menopause, at the Valencian Infertility Institute. We took blood samples at each time point of the treatment (basal, induced menopause, estrogen, and estrogen plus progesterone replacement therapy). mRNA expression of antioxidant and longevity-related genes in peripheral blood mononuclear cells (PBMC) was determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Determination of reduced glutathione (GSH) in total blood was carried out using high-performance liquid chromatography (HPLC). As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood GSH levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of manganese superoxide dismutase (MnSOD), GPx, 16S rRNA, P53, P21, and TERF2 and restored blood GSH levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2 (SENS2), and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.

Efeito do estrogênio no risco cardiovascular: uma revisão integrativa

Objetivo: Analisar na literatura científica sobre a relação do estrogênio no risco cardiovascular. Métodos: Essa Revisão Integrativa utilizou plataformas, como PubMed, SciELO, Lilacs e Clinical Trials, para encontrar fontes relevantes para desenvolver este projeto. Descritores em Ciências da Saúde como “cardiovascular risk”, “cardiology”, “cardiology risk”, “estrogen”, “estrogen replacement”, “menopause”, “primary health care” e "hypertension" em associação com operadores booleanos foram usados para pesquisa nessas plataformas científicas, resultando em 2653 artigos. Dentro desses números, devido aos critérios de inclusão e exclusão, apenas 20 tornaram-se fontes oficiais. Resultados: Estudos mostram que o estrogênio tem papel importante na regulação do tônus vascular, evitando a remodelação vascular e, consequentemente, diminuindo o risco cardiovascular. Ainda, a deficiência de estrogênio contribui para o desenvolvimento de hipertensão durante a menopausa devido ao hormônio ovariano vasodilatador circulante reduzido, que causa colapso do sistema circulatório junto com a formação de placas ateroscleróticas. Por outro lado, a reposição hormonal durante a menopausa aumenta a chance de eventos trombóticos. Considerações finais: O estrogênio atua como fator protetor do risco cardiovascular, porém é muito importante considerar outros elementos de risco, como presença de comorbidades, tipos de reposição estrogênica e via de administração de medicamentos, para definir a conduta do paciente.

Findings from a feasibility study of estradiol for hypogonadal women with cystic fibrosis-related bone disease

Background Advancements in therapies for patients with cystic fibrosis (CF) have decreased mortality, leading to increased prevalence of chronic complications including bone disease. CF-related bone disease (CFBD) is characterized by low bone mineral density (BMD) and fragility fractures. Estrogen deficiency increases bone resorption, resulting in decreased BMD that can be restored with estrogen replacement. Current CF guidelines recommend treating female hypogonadal patients with CFBD with estrogen replacement, but no prospective study has investigated the effects of estrogen supplementation on CFBD. Estrogen is known to modulate inflammatory markers and autoimmune diseases. We proposed to test the hypothesis that estrogen status plays a critical role in optimizing bone health, modulating inflammation, preserving lung function, and maximizing quality of life in premenopausal women with CF. Methods We planned a randomized, placebo-controlled, investigator- and patient-blinded, pilot trial with two parallel arms. Eligible subjects were women with CF 18–50 years old with hypogonadism and low BMD who were not taking systemic glucocorticoids, had not had a prior transplant, and did not have contraindications to oral estradiol. Subjects would be block randomized to receive oral estradiol or placebo for 6 months. The primary outcome was feasibility metrics. Secondary outcomes included relative changes in estradiol, bone turnover markers, lung function, inflammatory markers, and quality of life metrics. The study was funded through departmental funds. Results Of 233 subjects screened, 86 subjects were women with CF 18–50 years old and none were eligible for participation. Most subjects were excluded due to absent DXA report (24%), normal BMD (22%), or use of systemic estrogen (16%). Due to difficulty recruiting the planned 52 subjects, the trial was closed for recruitment and no subjects were randomized. Conclusion This study was designed to investigate the feasibility of a safety and efficacy trial of estrogen therapy for women with CF. Unfortunately, due to eligibility criteria, the study was unable to recruit subjects. This feasibility study highlights the need for improved BMD screening in young women with CF. Future study designs may require the incorporation of a screening DXA as part of subject recruitment. Trial registration The study was registered on ClinicalTrials.gov (NCT03724955).

Pulsed administration for physiological estrogen replacement in mice

Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.

OCORRÊNCIA DOS CÂNCERES DE MAMA E ENDOMETRIAL EM MULHERES EM TERAPIA DE REPOSIÇÃO HORMONAL NA MENOPAUSA: UMA REVISÃO DE LITERATURA

INTRODUÇÃO: O uso da Terapia de Reposição Hormonal (THR) é prescrito para tratamento de alguns sintomas decorrentes da menopausa. O uso indiscriminado dessa terapêutica parece elevar os riscos de determinadas neoplasias. METODOLOGIA: Trata-se de uma revisão integrativa de literatura, com busca na base de dados Pubmed. Utilizou-se os descritores "Estrogen Replacement Therapy", "Hormone Replacement Therapy", “Menopause”, "Breast Neoplasms", "Breast Cancer", "Endometrial Neoplasms", "Endometrial Cancer", associados aos operadores booleanos AND e OR. Incluíram-se publicações entre 2016 e 2021 nos idiomas português, inglês e espanhol. RESULTADOS: Foram selecionados 20 artigos publicados em periódicos internacionais, sendo 17 estudos de Coorte, dois de Caso-Controle e um Ensaio Clínico Randomizado duplo-cego. DISCUSSÃO: Os estudos analisados sugerem boa resposta no controle dos sintomas pós menopausa pela TRH. Porém, apresenta associação com risco de desenvolvimento de neoplasias de mama e endométrio, ao passo que o uso de estrogênio isolado demonstrou pouca associação. Quando comparados em relação a raça, mulheres brancas apresentam maior risco em relação a negras e asiáticas. CONCLUSÃO: Houve associação do uso de TRH com desenvolvimento das neoplasias estudadas. A duração da terapia, o tipo de hormônio, o momento de início, a via de administração e a população submetida ao tratamento, parecem impactar neste desfecho.

Uterine Development During Induced Puberty in Girls with Turner Syndrome

ObjectiveMost girls and women with Turner syndrome (TS) require estrogen replacement therapy (ERT) to initiate or maintain pubertal development. Most likely, the most fundamental effect of ERT in hypogonadism is the promotion of uterine growth. The optimal ERT model is still being discussed. The present study aimed to assess uterine size in girls with TS in the prepubertal state during and after the induction of puberty and compare it to a healthy population.MethodsThe analysis encompassed 40 TS girls. The prepubertal and postpubertal control groups contained 20 healthy girls each. All patients with TS were treated with 17-ß estradiol. Uterine imaging was performed with two-dimensional (2D) transabdominal ultrasound. The uterine volume (UV) and fundocervical antero-posterior ratio (FCR) were calculated in patients with TS before the pubertal induction, after 6-12 months of estrogen replacement therapy (ERT), after ≥ 36 months of ERT or ≥ 12 months after menarche.ResultsThe average age of TS patients at estrogen introduction and at the last control visit, when the uterus was considered mature, was 12.9 years and 16.1 years, respectively. The UV in patients with TS at the beginning of ERT was 1.55 ± 1.22 cm3 and was not significantly different from the UV in the prepubertal controls. The mature UV in patients with TS was 31.04 ± 11.78 cm3 and was significantly smaller than the UV of the postpubertal controls (45.68 ± 12.51 cm3, p<0.001). The FCR in girls with TS did not differ significantly from that in the prepubertal and postpubertal control groups, respectively. No prognostic factors could be established for the final UV. By the last control visit, thelarche had advanced in most patients to Tanner 4 and 5 (37.5% and 40%, respectively).ConclusionsBefore the onset of ERT, patients with TS have a uterus similar in size to that in prepubertal healthy girls. Pubertal induction in patients with TS causes a significant increase in the UV that is detectable after 6-12 months of ERT. The mature uterus is smaller in patients with TS than in the age-matched healthy population.

In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P <0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P <0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.

Effect of Transdermal Estradiol and Insulin-Like Growth Factor-1 on Bone Endpoints of Young Women with Anorexia Nervosa

Context Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. Objective To assess the impact of estrogen replacement with/ without rhIGF-1 administration on bone outcomes. Design Double-blind, randomized, placebo-controlled 12-month longitudinal study. Participants Seventy-five adolescent and young adult women with AN age 14 - 22 years. Thirty-three participants completed the study. Intervention Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. Main Outcome Measures: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. Results Over 12 months, lumbar aBMD increased in AN-IGF-1- compared to AN-IGF-1+ (p=0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, vBMD, or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (p=0.042), while PTH increased in AN-IGF-1+ (p=0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. Conclusions We found no additive benefit of rhIGF-1 administration for 12-months over transdermal estrogen replacement alone in this cohort of young women with AN.

Liver Abnormalities in Turner’s Syndrome – Effects of Estrogen Replacement Therapy

BackgroundTurner’s syndrome is one of the most frequently reported sex chromosomal abnormality, affecting approximately 40 in every 100,000 live female births. Due to insufficient estrogen production, induction of puberty and sexual development requires hormone replacement. The syndrome affects several organ systems with diverse clinical features (cardiovascular, reproductive, hepato-biliary). There is also an increased risk of developing immune-mediated inflammatory diseases (IMID). Hepatobiliary alterations embrace a broad spectrum of possible manifestations, from asymptomatic mild hypertransaminasemia to overt hepatitis and even cirrhosis. Although exogenous estrogen hormones might cause liver dysfunction, in Turner’s syndrome hormone replacement can even alleviate the derangement of laboratory values and might prove beneficial in preventing the progression of hepatic architectural alterations.FindingsWe report two patients, in whom cessation of estrogen replacement therapy lead to worsening of hepatic and cholestatic enzyme values. These changes were later alleviated by recommencing estrogen hormone administration. We aim to summarize the available literature on estrogen hormone replacement therapy in Turner’s syndrome. We also provide a brief overview on the role of estrogen hormones in the pathology associated with the syndrome. ConclusionsOur findings are confirming, that estrogen replacement therapy has beneficial effects on hepatic enzymes and liver related laboratory studies in Turner’s syndrome. Therefore it is recommended for physicians not to withdraw estrogen replacement, even with elevated concentrations of liver and cholestatic enzymes in Turner’s syndrome patients.