Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats

Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone’s effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings

Androgen in postmenopausal women

Menopausal symptoms, bone loss, changes in lipid profiles and reduction of insulin sensitivity due to an abrupt decrease in circulating estrogen level are well known in women during the menopausal transition. On the other hand, the effect of androgen on women’s health has not been fully elucidated. Circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEA-S) gradually decrease with age in postmenopausal women, although transient increases have been observed during the menopausal transition. High testosterone level has been suggested to be associated with increased risk of cardiovascular disease, increased triglyceride, insulin resistance and increase in the risk of developing breast cancer in postmenopausal women. Circulating DHEA-S level does not affect the risk of cardiovascular disease, mortality or lipid profiles in women. Female androgen insufficiency, which is characterized by the presence of reduced androgen level in circulation, leads to an impairment in sexual drive, reduced libido, depressed mood, and signs and symptoms of limited androgen exposure such as decreased muscle mass, reduced bone density and decreased sense of well-being. An appropriate level of androgen may play important roles in metabolic, psychological and sexual functions in women. In addition, the roles of testosterone and DHEA-S in women’s health may be different

Androgen in postmenopausal women

Menopausal symptoms, bone loss, changes in lipid profiles and reduction of insulin sensitivity due to an abrupt decrease in circulating estrogen level are well known in women during the menopausal transition. On the other hand, the effect of androgen on women’s health has not been fully elucidated. Circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEA-S) gradually decrease with age in postmenopausal women, although transient increases have been observed during the menopausal transition. High testosterone level has been suggested to be associated with increased risk of cardiovascular disease, increased triglyceride, insulin resistance and increase in the risk of developing breast cancer in postmenopausal women. Circulating DHEA-S level does not affect the risk of cardiovascular disease, mortality or lipid profiles in women. Female androgen insufficiency, which is characterized by the presence of reduced androgen level in circulation, leads to an impairment in sexual drive, reduced libido, depressed mood, and signs and symptoms of limited androgen exposure such as decreased muscle mass, reduced bone density and decreased sense of well-being. An appropriate level of androgen may play important roles in metabolic, psychological and sexual functions in women. In addition, the roles of testosterone and DHEA-S in women’s health may be different

OVARIAN Kiss1 mRNA IN THE PREPUBERTAL PERIOD

Kisspeptin, which is encoded by the Kiss1 gene, and its receptor, the G protein-coupled receptor 54 (Kiss1r), play important roles in the regulation of reproductive functions in mammals. Several studies have shown that the Kiss1 and Kiss1r genes are expressed in the rat, primate, and human ovaries, and that the ovarian kisspeptin system plays a pivotal role in ovulation at the proestrous stage in adulthood. The purpose of this study was to evaluate development-related changes in the expression of ovarian Kiss1 and Kiss1r genes and in kisspeptin levels, and to identify the regulatory factors for these genes during the prepubertal period. The serum kisspeptin level was also measured to examine whether ovarian kisspeptin affects serum kisspeptin levels. Variations in the ovarian Kiss1 and Kiss1r mRNA levels were observed during the prepubertal period in female rats, with levels peaking around postnatal days 20 and 15, respectively. Nevertheless, the ovarian kisspeptin content per total protein level was stably maintained. Serum kisspeptin levels at postnatal days 30 and 35 were higher than those at earlier postnatal days. The pattern of the ovarian Kiss1 mRNA levels was similar to that of the serum luteinizing hormone (LH) levels, and the ovarian Kiss1 mRNA level increased after injection with human chorionic gonadotropin (HCG) on postnatal day 20, but not on postnatal days 10 and 30. These data indicate that ovarian Kiss1 and Kiss1r mRNA levels are increased on postnatal days 20 and 15, respectively, and that changes in the serum LH level and the ovarian sensitivity to LH may be involved in the alteration of ovarian Kiss1 mRNA levels

Clinical outcome of various metformin treatments for women with polycystic ovary syndrome

Aim: Polycystic ovary syndrome (PCOS) is an ovulatory disorder and insulin resistance and diabetes are involved in its pathophysiology. Metformin, an anti‐diabetic agent, has been reported to be useful to induce ovulation. Methods: Metformin treatment was classified into four types: (1) clomiphene–metformin combination treatment for clomiphene‐resistant patients; (2) clomiphene–metformin combination for clomiphene‐sensitive patients; (3) clomiphene–metformin combination for naïve patients; and (4) metformin monotherapy. The patients underwent physical, endocrinological, and clinical examinations for their ovulation rates, pregnancy rates, and follicular development. Results: The ovulation rates, pregnancy rates, and single follicular development were not significantly different among the clomiphene–metformin combination treatment groups. In the Body Mass Index (BMI) subanalysis, the pregnancy rate was higher in the BMI≥30 kg/m2 group than in the other three groups with a BMI of ≤30 kg/m2 in both cycles and cases. The ovulation rates and pregnancy rates were significantly higher in the group with a fasting insulin of ≥15 μU/mL than in the groups with a fasting insulin of <15 μU/mL in both cycles and cases. Conclusion: Clomiphene–metformin combination treatment appears to be useful, at least for clomiphene‐resistant patients, and a BMI of >30 kg/m2 and a fasting insulin of ≥15 μU/mL appear to be predictors of a good result with this treatment

Prenatal undernutrition disrupted the sexual maturation, but not the sexual behavior, in male rats

Purpose: Exposure to various stressors, including psychological, metabolic, and immune, in the perinatal period induces long‐lasting effects in physiological function and increase the risk of metabolic disorders in later life. In the present study, sexual maturation and sexual behavior were assessed in prenatally undernourished mature male rats. Methods: All the pregnant rats were divided into the maternal normal nutrition (mNN) group and the maternal undernutrition (mUN) group. The mUN mothers received 50% of the amount of the daily food intake of the mNN mothers. Preputial separation and sexual behavior were observed in randomly selected pups of the mNN and mUN groups. Results: The body weight of the mothers was significantly lighter in the mUN group than in the mNN group. Similarly, the pups in the mUN group showed a significantly lower body weight than those in the mNN group from postnatal day (PND) 1 to PND 15. The preputial separation day was significantly delayed in the mUN group, compared to the mNN group. Sexual behavior did not show any significant difference between the two groups. Conclusion: These findings indicated that prenatal undernutrition delayed sexual maturation, but did not suppress sexual behavior, in mature male rats

Effects of raloxifene on the production of cytokines in stimulated whole blood in ex vivo and in vitro studies

Purpose : The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. Methods :We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10-10-10-7 M and then stimulated with LPS or PHA. Concentrations of IL-1β, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. Results : In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1β, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (10-9 M) inhibited LPS-stimulated production of IL-1β, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. Conclusions : Raloxifene therapy decreases the production of IL-1β, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene

LPS proliferate the endometriosis

Purpose : The aims of this study were to clarify the effects of lipopolysaccharide (LPS) on the early development of endometriosis and on the production of cytokines and chemokines in the murine peritoneal cavity. Methods : Endometriotic lesions were induced in C57BL/6J adult female mice by intraperitoneal injection of endometrial fragments plus blood or endometrial fragments plus blood with LPS. On day 7, endometriotic lesions were assessed by gross and microscopic evaluations. Time-dependent changes in the secretion of TNF-α, IL-6, and CXCL2/MIP-2 in peritoneal lavage fluid after the intraperitoneal injection of LPS (50 µg/body) were measured by their respective enzyme-linked immunosorbent assays. Results : The areas of endometriotic lesions in the LPS group (10.8±8.6 mm2) were significantly larger than those in the control group (3.1±3.7 mm2). The levels of TNF-α and IL-6 peaked within 2 hours and the level of MIP-2 reached a maximum on day 1 after the injection of LPS. Conclusions : LPS promotes development of the early stages of murine endometriotic lesions

Differences in menopausal symptoms and coping strategies according to personality in Japanese nurses

We examined the associations of type A personality with menopausal symptoms and strategies for coping with menopausal symptoms in Japanese nurses. Valid responses to health questionnaires were obtained from 1174 nurses aged 45–60 years．Menopausal symptoms were assessed using Greene’s climacteric scale, and a type A behaviour pattern was assessed using the type A rating scale developed for the Japanese. The mean score of psychological symptoms in nurses with a type A personality was significantly higher than that in the nurses with a non-type A personality. The proportion of the nurses who received hormone replacement therapy in the nurses with a type A personality was significantly higher than that in the nurses with a non-type A personality. The nurses with a type A personality had a sufficient understanding of treatments for menopausal symptoms. In conclusion, there were differences in the menopausal symptoms and coping strategies between the nurses who had a type A personality and the nurses who had a non-type A personality.Impact statement What is already known on this subject? Menopausal symptoms have been shown to be affected by lifestyle and by socioeconomic status as well as oestrogen deficiency, but there have been few studies on the associations of personality with menopausal symptoms and coping with the menopausal symptoms. The type A personality is associated with a greater risk for the development of several diseases. However, the association of a type A behaviour pattern with menopausal symptoms has not been clarified. What do the results of this study add? There were differences in the menopausal symptoms and the coping strategies between women with a type A personality and women with a non-type A personality. Psychological symptoms were found more frequently in the Japanese nurses with a type A personality. The proportion of nurses who received hormone replacement therapy in the nurses with a type A personality was significantly higher than that in the nurses with a non-type A personality. There were no significant differences in the proportions of nurses in the two groups with other coping strategies. What are the implications of these findings for clinical practice and/or further research? The management for coping strategies according to the type of personality should be considered