Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation

Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women

Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts

In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production. We show, using a xenograft approach, that testosterone production is not reduced in human fetal testis following DES exposure. Human fetal testes (15-19 weeks' gestation, n = 6) were xenografted into castrate male nude mice which were then treated for 35 days with vehicle or 100 µg/kg DES three times a week. For comparison, similar treatment was applied to pregnant rats from e13.5-e20.5 and effects on fetal testes evaluated at e21.5. Xenograft testosterone production was assessed by measuring host seminal vesicle (SV) weights as an indirect measure over the entire grafting period, and single measurement of serum testosterone at termination. Human fetal testis xenografts showed similar survival in DES and vehicle-exposed hosts. SV weight (44.3 v 26.6 mg, p = 0.01) was significantly increased in DES compared to vehicle-exposed hosts, respectively, indicating an overall increase in xenograft testosterone production over the grafting period, whilst serum testosterone at termination was unchanged. In contrast intra-testicular testosterone levels were reduced by 89%, in fetal rats exposed to DES. In rats, DES effects are mediated via Estrogen Receptor α (ESR1). We determined ESR1 protein and mRNA expression in human and rat fetal testis. ESR1 was expressed in rat, but not in human, fetal Leydig cells. We conclude that human fetal testis exposure to DES does not impair testosterone production as it does in rats, probably because ESR1 is not expressed in human fetal Leydig cells. This indicates that DES exposure is likely to pose minimal risk to masculinization of the human fetus

Spatial Ecology and Habitat Selection of Eastern Hognose Snakes

The eastern hognose snake (Heterodon platirhinos) is a species of conservation concern, especially in the northeastern portion of its range. They remain relatively common at Cape Cod National Seashore, Barnstable County, Massachusetts, USA, where we studied their spatial ecology and habitat selection. We radio-tracked 17 adult snakes (10 F, 7 M) from May 2009 to November 2011, yielding 765 relocations. We conducted a use-availability analysis to investigate patterns of microhabitat selection using a subset of snake locations. We conducted a compositional analysis of habitat selection at multiple spatial scales within home ranges using a high-resolution (1-m pixel size) vegetation cover map of the study area. Snakes moved frequently and had large home ranges x = 35.4 ha) relative to other snake species of similar body size but exhibited variation in home range size among individuals (1–209 ha). Movements peaked at different times of year for each sex, and were most different between sexes in fall. In gravid females, movement was significantly greater in the 2-week post-oviposition period versus the 2-week pre-oviposition period. Estimates of home range and average daily movements x = 30.1 m/day) were lower than estimates from other studies of eastern hognose snakes, possibly because of a greater density of resources at our study area. Probability of snake habitat use increased with grass and leaf litter and decreased with open soil. Compositional analysis revealed a strong avoidance of open dune areas. A comparison of edge density between use and random locations within home ranges revealed an apparent preference for edge habitat. We recommend that resource managers should limit recreational disturbance to and maintain the patchy mosaic of early successional vegetation with abundant edge to ensure the persistence of appropriate habitat for the species. We identified the timing of peak seasonal movements and recommend that this information be used to help prevent road mortality for this important population

Surface Activity and Body Temperature of Eastern Hognose Snakes (Heterodon Platirhinos) At Cape Cod National Seashore, Massachusetts USA

Snakes, as ectotherms, rely heavily on environmental temperature to drive physiological processes. Activity in terrestrial snakes is influenced heavily by environmental temperature, but climatic, temporal, and ecological factors play a role as well. Understanding when and under what conditions a species is most likely to be active on the surface can be important when dealing with a cryptic species and a species that occurs at low densities. Surface activity, body temperature (Tb), and microclimatic data were collected during a study of 17 Heterodon platirhinos in an early-successional sand-dune ecosystem from 2009 to 2011 using temperature-sensitive radiotransmitters. Mean Tb (27.9°C, SE = 0.24) and Tb range (5.5-39.5°C) were similar to those reported in other studies of H. platirhinos. Females were generally more active than males, except in September when males may be searching for mates. Mixed-effects logistic regression was used to assess the relationship between snake surface activity and selected microclimatic and temporal variables. Hours postsunrise and relative humidity emerged as the top variables influencing surface activity in gravid females. Hours postsunrise and ambient air temperature emerged as the top variables influencing surface activity in males. Our data suggest that activity in H. platirhinos occurs as a function of several environmental, temporal, and ecological factors and varies on the basis of sex and reproductive class. When considering activity, future studies on terrestrial ectotherms should consider not only the relationships of sex, but of reproductive class as well

Smooth muscle cell-specific knockout of androgen receptor: a new model for prostatic disease

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease

The expression of aromatase in gonadotropes is regulated by estradiol and gonadotropin-releasing hormone in a manner that differs from the regulation of luteinizing hormone. Endocrinology 147, 4234– 4244. Gazzaley

THE REGULATION OF the anterior pituitary is achieved by the cell-specific and combined actions of central, peripheral, and local factors. It is established that estrogens are involved in the modulation of the hypothalamic-pituitary-gonadal axis. However, it is difficult to delineate the overall contribution of each site of action, particularly at the level of the pituitary gland. The biosynthesis of estrogens from androgens is catalyzed by the aromatase complex, which consists of cytochrome P450 aromatase (P450arom) and a flavoprotein, reduced nicotinamide adenine dinucleotide phosphate-cytochrome P450 reductase (1). The P450arom is encoded by a single copy gene, cyp19, composed of nine coding exons (exons II–X). The cyp19 gene expression is regulated by multiple tissue-specific promoters producing alternate 5�-untranslated exons I that are then spliced onto a common 3�-splice acceptor site in the exon II upstream of the translation start site (2). However, all transcripts contain a