Attenuation of Corpus Callosum Axon Myelination and Remyelination in the Absence of Circulating Sex Hormones

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone‐replaced gonadectomized animals were used. These groups were subjected to cuprizone diet‐induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol‐supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo‐treated ovariectomized or intact female levels during remyelination. In castrated males, the non‐aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.     

Benefits and risks of long-term low-dose oral continuous combined hormone therapy

OBJECTIVES: Current recommendations for hormone therapy (HT) are mainly based on findings from studies using standard dose regimens in older women who had a different health profile from those who start HT soon after the onset of menopause. METHODS: We, therefore, reviewed controlled trials assessing the efficacy, safety and tolerability of low-dose oral continuous combined HT (cc-HT) started for treatment of climacteric symptoms. This review is limited to oral cc-HT regimens over sequential regimens as most postmenopausal women prefer not to have a return of uterine bleeding, and to studies of at least 2 years in duration. RESULTS: Low-dose cc-HT is effective in alleviating climacteric symptoms and in maintaining bone density over prolonged periods, although no data were available regarding fracture risk. No increased risk of coronary heart disease, venous thrombo-embolism or stroke during the use of low-dose cc-HT was reported in the long-term studies and no definitive evidence for an increased risk of breast cancer was found. Breakthrough bleeding during the first months of use is less common than with standard dose HT and amenorrhoea is achieved in most women over time. These regimens are safe for the endometrium and are well tolerated, with a low incidence of adverse events compared with standard doses. CONCLUSIONS: Current evidence from controlled trials indicates that low-dose oral cc-HT appears effective and safe. This makes it a good choice for the alleviation of climacteric symptoms, and for this purpose long-term administration of low-dose cc-HT does not seem to impose serious health risks. However, more long-term study data and direct head-to-head comparisons between various low-dose preparations are needed to support or rectify the safety aspects.     

Adiposity and estrogen receptor-positive,postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case–cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case–control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m² compared to women with BMI 18.5–25 kg/m², the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05–2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43–2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11–2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68–1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity–breast cancer relationship but does not explain all of the association.     

The role of androgens on periodontal repair in female rats

1 Background

Testosterone replacement enhances cognitive function and musculoskeletal health in postmenopausal women. However, the biological role of testosterone on inflammation and bone metabolism in females is not well understood. Our objective was to measure the impact of androgens and their receptors on periodontal tissues during periodontal repair in female rats.

2 Methods

Seventy female Holtzman rats were divided into seven groups (n = 10/group): negative control; repair control; androgen receptor antagonist (flutamide, 50 mg/kg, every other day); estrogen receptor antagonist (fulvestrant, 1.5 mg/kg/day); testosterone supplementation (durateston, 250 mg/kg, weekly); aromatase inhibitor (anastrozole, 0.2 mg /kg/day); testosterone plus anastrozole. Cotton ligatures were kept for 13 days, when pharmacological treatment was initiated. On day 14, the ligatures were removed. The rats were euthanized on the 17^th or the 28^th day (n = 5/group/period) for the evaluation of markers related to inflammation and bone. The tissue and serum samples were evaluated using a multiplexed immunoassay for the inflammatory targets. Radiographic and histologic analyses were performed to assess changes in tissues.

3 Results

Blockage of androgen receptors had little effect on inflammatory cell count, although it tended to increase interleukin (IL)‐4, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) as well as decrease IL‐1β, tumor necrosis factor (TNF)‐α, and IL‐6. Flutamide also significantly impaired bone repair (P < 0.05) and had greater osteoclast count, although this last difference was not statistically significant. Testosterone supplementation significantly increased the inflammatory cell count, decreased the levels of IL‐4, IL‐10, IL‐1β, IL‐6, and TNF‐α; and increased VEGF and EGF.

4 Conclusion

The blockage of androgen receptors significantly impair bone repair in females through mechanisms that are different from those related to estrogen receptors.     

雌激素对成年SD大鼠缺血性脑损伤的认知保护作用

目的 探讨雌激素对成年SD大鼠缺血性脑损伤的认知保护作用及可能机制.方法 成年SD大鼠72只,随机分为雌激素处理组(A组)、安慰剂处理组(B组)、假手术组(C组)和正常对照组(D组),每组18只♀♂各半.除C、D组外其余大鼠均采用线栓法制备局灶性脑缺血/再灌注模型(MCAO),缺血2 h、再灌注22 h后观察神经功能评...     

性激素与原发性高血压

目的探讨性激素与高血压发病的关系。方法采用放射性免疫分析法检测５６例男性ＥＨ患者和２１例健康男性对照，４１例绝经后女性ＥＨ患者和２１例健康绝经后女性对照血清雌二醇（Ｅ２），孕酮（Ｐ）和睾酮（Ｔ）水平，进行对比研究。结果（１）男性ＥＨ组血清Ｔ水平明显低于对照组；（２）绝经后女性ＥＨ组Ｅ２水平明显低于对照组。结论血清性激素水平与男性及绝经后女性ＥＨ的发病有关。     

Estrogen-Induced Proliferation in Cultured Hepatocytes Involves Cyclin D1, P21CIP1 and P27KIP1

The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21^Cip1, and p27^Kip1. Male rat hepatocytes were cultured in presence of 17-β -estradiol (E₂) ± ICI-182780, a pure estrogen antagonist, and [³H]-thymidine, as required. DNA synthesis as well as p21^Cip1, p27^Kip1, and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E₂-increased DNA synthesis was correlated with cyclin D1 and p21^Cip1 (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27^Kip1protein levels progressively increased regardless of the presence of E₂ or ICI-182780. Our data confirm that estrogens’ stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21^Cip1 is probably related to the reentry of hepatocytes in the quiescent state. p27^Kip1protein is not able to arrest hepatocyte proliferation.     

Fibroblast growth factor-2 and epidermal growth factor modulate prolactin responses to TRH and dopamine in primary cultures

Fibroblast growth factor-2, (FGF-2) and epidermal growth factor (EGF) are expressed in most tissues of the organism including pituitary, FGF-2 increases PRL levels and PRL mRNA in GH3 cells and primary cultures, and it has been involved in the lactotroph proliferation and hyperplasia. EGF also increases PRL levels in vitro. However, the effects of these two factors in the responses of lactotroph cells to TRH and dopamine (DA) remain to be clarified. In the present work we have studied the modulator activity of FGF-2 and EGF on in vitro PRL in responses to TRH and DA in primary cultures from in vivo vehicle-or estrogen (E2)-treated rats. We have found that FGF-2 (2×10⁻¹¹ M) prevents the EGF-induced dose-dependent increase in PRL levels in control cells, and reversed the EGF-stimulating effects in cells from E2-treated rats. Both FGF-2 (2×10⁻¹¹ M) and EGF (6.6×10⁻⁹ M) significantly increase (>30% and >120%, respectively) the PRL levels in response to TRH (10⁻⁶ 10⁻⁵ M). FGF-2 blocked the inhibitory effects of low doses of DA (10⁻⁹ M). EGF was unable to do so, although markedly increased (>200%) the post-DA PRL rebound. In cells from in vivo E2-treated rats, FGF-2 increased (>50%) the PRL secretion in response to TRH, while EGF reduced responses to high doses of TRH (10⁻⁶, 10⁻⁵ M). In addition, FGF-2 reversed and EGF increased the inhibitory effects of DA. Both FGF-2 and EGF completely blocked the post-DA PRL rebound, in these cells. Taken together our data suggest that FGF-2 and EGF are important regulators of lactotroph responsiveness to TRH and DA in vitro, although their actions are highly dependent on estrogenic milieu.