This paper provides a detailed compilation of human prostatic development that includes human fetal prostatic gross anatomy, histology, and ontogeny of selected epithelial and mesenchymal differentiation markers and signaling molecules throughout the stages of human prostatic development: (a) pre-bud urogenital sinus (UGS), (b) emergence of solid prostatic epithelial buds from urogenital sinus epithelium (UGE), (c) bud elongation and branching, (d) canalization of the solid epithelial cords, (e) differentiation of luminal and basal epithelial cells, and (f) secretory cytodifferentiation. Additionally, we describe the use of xenografts to assess the actions of androgens and estrogens on human fetal prostatic development. In this regard, we report a new model of de novo DHT-induction of prostatic development from xenografts of human fetal female urethras, which emphasizes the utility of the xenograft approach for investigation of initiation of human prostatic development. These studies raise the possibility of molecular mechanistic studies on human prostatic development through the use of tissue recombinants composed of mutant mouse UGM combined with human fetal prostatic epithelium. Our compilation of human prostatic developmental processes is likely to advance our understanding of the pathogenesis of benign prostatic hyperplasia and prostate cancer as the neoformation of ductal-acinar architecture during normal development is shared during the pathogenesis of benign prostatic hyperplasia and prostate cancer.

Multiple sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiological conditions in women such as puberty, pregnancy, puerperium and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clinical evidence of sex hormone (estrogens, progesterone, prolactin and testosterone) impact on MS, and attempt to elucidate hormonal and immunological mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells, and provide new insights in the context of MS. Understanding these molecular mechanisms may contribute to the development of new and safer treatments for both men and women. This article is protected by copyright. All rights reserved.

Natural- or surgically-induced post-menopausal women are widely prescribed estrogen therapies to alleviate symptoms associated with estrogen loss and to lower the subsequent risk of developing metabolic diseases, including diabetes and non-alcoholic fatty liver disease. However, the molecular mechanisms by which estrogens modulate metabolism across tissues remain ill-defined. We have previously reported 17β-estradiol (E2) exerts anti-diabetogenic effects in ovariectomized (OVX) mice by protecting mitochondrial and cellular redox function in skeletal muscle. The liver is another key tissue for glucose homeostasis and a target of E2 therapy. Thus, in the present study we determined the effects of acute loss of ovarian E2 and E2 administration on liver mitochondria. In contrast to skeletal muscle mitochondria, E2 depletion via OVX did not alter liver mitochondrial respiratory function or complex I (CI) specific activities (NADH oxidation, quinone reduction, H2O2 production). Surprisingly, in vivo E2 replacement therapy and in vitro E2 exposure induced tissue-specific effects on both CI activity and on the rate and topology of CI H2O2 production. Overall, E2 therapy protected and restored the OVX-induced reduction in CI activity in skeletal muscle, whereas in liver mitochondria E2 increased CI H2O2 production and decreased ADP-stimulated respiratory capacity. These results offer novel insights into the tissue-specific effects of E2 on mitochondrial function.

The contamination of freshwater systems arises in many river basins due to industrialization and population growth, posing risks to ecosystems and human health. Despite these concerns, the fate and potential impact of many emerging pollutants are currently unknown, especially when the compounds are released into surface waters from populations distributed across large spatial scales. In order to address this shortcoming, a spatially-explicit contaminant fate model was developed as an extension of the global, vector-based river routing model HydroROUT. HydroROUT operates at very high spatial resolution (∼500 m), simulates river and stream chemical transport with in-stream removal, and contains links to a set of lakes and reservoirs, which act as a partial sink during the transport. The chemical fate model was applied to China and includes a consumption and release module based on county-level population demographics, considers point-source contributions from 2547 wastewater treatment plants, and accumulates contributions of rural and urban populations not connected to sewage treatment plants. As a case study, the sources and fates of the estrogens estrone (E1), 17β-estradiol (E2), estriol (E3), as well as the synthetic estrogenic steroid hormone 17α-ethinylestradiol (EE2) were modelled in Chinese surface water bodies. Preliminary validation of the results showed predictions to be within the ranges of concentrations reported in literature, with exception of EE2. The total estrogenic mass in the entire river and lake system amounted to 370 tonnes of estrogens, with about 1.3 tonnes per year discharged to the ocean, neighboring countries or to inland sinks. Under a selected baseline scenario, eco-toxicological risk-i.e., contaminant concentrations in excess of the predicted no effect concentration (PNEC)-is found in 23.6% of all analyzed rivers of China with an average flow > 0.1 m3/s. Out of these, about 4% of rivers showed a high level of risk of 10 times or more above PNEC. Medium-to-large rivers are disproportionally affected; for example, 23.6%, 37.3%, 29.0% and 21.6% of river length are at risk in rivers of 1-10, 10-100, 100-1,000, and 1,000-10,000 m3/s of discharge, respectively, whereas no risk was predicted in the largest rivers (i.e., >10,000 m3/s) of China. Wastewater treatment plants process 22.5% of the total hormone load and thus play an important role in water quality control by reducing the risk in substantial portions of the river network, which would otherwise show elevated risk. Releases from untreated population dominate by far the overall contribution to risk.

Diseases of the cardiovascular system are the leading cause of morbidity and mortality in men and women in developed countries, and CVD is becoming more prevalent in developing countries. Atherosclerotic cardiovascular disease (CVD) prevalence in men is greater than in women until menopause, when the prevalence of CVD increases in women until it exceeds that of men. Endothelial function is a barometer of vascular health and a predictor of atherosclerosis that may provide insights into sex differences in CVD, as well as how and why CVD risk drastically changes with menopause. Studies of sex differences in endothelial function are conflicting, with some studies showing earlier decrements in endothelial function in men compared to women, while others showing similar age-related declines between the sexes. Because the increase in CVD risk coincides with menopause, it is generally thought that female hormones, in particular estrogens, are cardioprotective. Further, it is often proposed that androgens are detrimental. In truth, the relationships are more complex. This review will first address female and male sex hormones and their receptors, and how these interact with the cardiovascular system, particularly the endothelium, in healthy young women and men. Second, we will address sex differences in sex steroid receptor-independent mechanisms controlling endothelial function, focusing on the vascular endothelin and the renin-angiotensin systems, in healthy young women and men. Finally, we will discuss sex differences in age-associated endothelial dysfunction, focusing on the role of attenuated circulating sex-hormones in these effects.

Halogenated estrogens are thought to be moderately potent endocrine-disrupting compounds that are formed during chlorine-based wastewater disinfection processes and may represent a significant fraction of the total amount of estrogen delivered from wastewater treatment plants to receiving waters. Yet we lack key information about the photochemical degradation of halogenated estrogens, a process that has important implications for UV-based wastewater treatment and environmental fate modeling. To better understand halogenated estrogen degradation in aquatic environments, we studied the direct photolysis of 17β-estradiol (E2), 2-bromo-17β-estradiol (monoBrE2), 2,4-dibromo-17β-estradiol (diBrE2), and 2,4-dichloro-17β-estradiol (diClE2) as well as the indirect photolysis of diBrE2 under natural solar irradiance. We found that direct photolysis rate constants increased with halogenation as pKa values decreased and molar absorptivity spectra shifted toward higher wavelengths. Compared to E2, quantum yields were threefold larger for monoBrE2, but 15-32% smaller for the dihalogenated forms. The rate of diBrE2 (pKa ∼ 7.5) photolysis was strongly influenced by pH. At pH 7, diBrE2 degraded on minute time scales due to the large red-shifted molar absorptivity values and greater quantum yields of the phenolate form. Degradation rates were only slightly different in the presence of Suwannee River Humic Acid (5 mg L-1), and quenching experiments pointed to excited triplet state dissolved organic matter (3DOM*) as the dominant reactive intermediate responsible for the indirect photolysis of diBrE2. Overall, our data suggest that halogenated estrogens are particularly susceptible to photochemical degradation at environmentally relevant pH values.

The importance of estrogens for glucose homeostasis has been demonstrated by clinical, pharmacological, and experimental studies. Male mice lacking the aromatase gene (ArKO mice), which encodes an enzyme involved in estrogen synthesis, develop glucose- and insulin-intolerance. However, it remains unclear whether insulin signaling is actually impaired in the liver and muscle of ArKO mice. We examined the effects of estrogen-deficiency on insulin signaling by quantifying phosphorylation levels of protein kinase B (Akt) in the liver and muscle and by examining the expression levels of insulin-target genes in the liver. Insulin administration enhanced phosphorylation levels of Akt in the liver and muscle of wild-type (WT) mice, ArKO mice, and ArKO mice supplemented with 17β-estradiol (E2), but insulin was less effective in ArKO mice. Gene expression analysis revealed that alterations induced by insulin in WT liver were also observed in ArKO liver, but the degree of altered expression in a subset of genes was smaller in ArKO mice than in WT mice. E2 supplementation improved the insulin responses of some genes in ArKO mice. Thus, these findings suggest that insulin signaling in the liver and muscle of ArKO mice is less efficient than in WT mice, which contributes to whole-body glucose intolerance in ArKO mice.