Associations of LH and FSH with reproductive hormones depending on each stage of the menopausal transition.

INTRODUCTION: Associations of luteinizing hormone (LH) with androgens during the menopausal transition and associations between follicle-stimulating hormone (FSH) levels and various diseases related to reproductive hormones in postmenopause have received much attention. LH and FSH are also known to be associated with activities of enzymes related to reproductive hormones. We examined the associations of LH and FSH with androgens and estrogens in each stage of the menopausal transition according to a classification from menopausal transition to postmenopause. METHODS: This study was a cross-sectional design. We basically used the Stage of Reproductive Aging Workshop (STRAW) + 10. We divided the 173 subjects into 6 groups according to menstrual regularity and follicle-stimulating hormone level: mid reproductive stage (Group A), late reproductive stage (Group B), early menopausal transition (Group C), late menopausal transition (Group D), very early postmenopause (Group E) and early postmenopause (Group F). Levels of LH, FSH, dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and androstenediol were measured. RESULTS: In Group A, LH showed significant positive correlations with androstenedione and estrone. In Group D, LH was positively associated with T and free T and was negatively associated with estradiol. In Groups B, C, D and F, LH showed significant positive correlations with FSH, and there was a tendency for an association between LH and FSH in Group E. FSH was associated with estradiol but not with estrone in Groups C and D. CONCLUSION: The associations of LH and FSH with reproductive hormones are different depending on the stage of the menopausal transition. TRIAL REGISTRATION: Trial registration number 2356-1; Date of registration: 18/02/2018, retrospectively registered.

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.

Prenatal undernutrition suppresses sexual behavior in female rats.

Infectious, psychological and metabolic stresses in the prenatal and early neonatal period induce long-lasting effects in physiological function and increase the risk of metabolic disorders later in life. We examined the sexual behavior of female rats that were subjected to undernutrition in the prenatal period. Eight pregnant rats were divided into two groups: a maternal normal nutrition group (mNN; n = 4) and a maternal undernutrition group (mUN; n = 4), which received 50% of the daily food intake amount of the mNN group from gestation day 13 to delivery. Nine and seven female offspring were randomly selected from the mNN and mUN groups, respectively. Vaginal opening (VO), estrous cycle length, sexual behavior and mRNA expression levels of the factors that regulate sexual behavior were observed. In the mUN group, VO day was later, the estrous cycle was longer, and the lordosis quotient and lordosis rating were lower than in the mNN group; such differences were not seen in other sexual performances, such as ear wiggles, darts, kick bouts and box. The hypothalamic mRNA expression level of progesterone receptor (PR) A + B and oxytocin (OT) were significantly lower in the mUN group than in the mNN group. These findings indicated that prenatal undernutrition disrupted puberty onset, the estrous cycle, sexual behavior and hypothalamic mRNA expression of PR and OT in female rat pups.

Neurokinin B receptor agonist and Dynorphin receptor antagonist stimulated luteinizing hormone secretion in fasted male rodents.

Kisspeptin/neurokinin B (NKB)/dynorphin (Dyn) (KNDy) neuron in hypothalamic arcuate nucleus plays a key role in GnRH/LH pulsatile secretion. We aimed to determine whether stimulation of NKB/neurokinin 3 receptor (NK3R) signaling and inhibition of Dyn/kappa-opioid receptor (KOR) signaling recover LH secretion that is suppressed by acute fasting in male rats. Furthermore, we determined dose dependent effect of NKB/NK3R signaling on serum LH level under acute fasting condition in male mice. Mature male rats were injected saline (0.1 mL) and senktide (20 µg/kg), a NK3R agonist, or nor-BNI (800 µg/kg), a KOR antagonist intraperitoneally (ip) after 72 h fasting. And mature male mice were injected multiple doses of senktide, ip after 48 h fasting. Blood and brain sample were collected 90 min after injections for LH measurement and hypothalamic mRNA expressions. All three studies showed significantly lower LH concentration in fasted groups than non-fasted groups. Senktide did not recover LH suppressed by acute fasting in male rats, whereas nor-BNI injected male rats showed significantly higher LH than 72 h fasted male rats (p < 0.05). Mice study showed significantly higher LH concentration in higher doses senktide groups than 48 h fasted group and one of lower doses senktide group. These results suggest that stimulation of NKB/NK3R signaling and attenuation of Dyn/KOR signaling could recover suppressed LH secretion under acute fasting condition in male rodents.

Circulating dehydroepiandrosterone-sulphate decreases even with a slight change in oestradiol.

The aim of this study was to determine the effect of hormone replacement therapy (HRT) on changes in circulating dehydroepiandrosterone-sulphate (DHEA-S) with focus on the relationship between oestrogen level and change in DHEA-S. Forty-two women were enrolled in this longitudinal study. Nineteen women received oral oestradiol and twenty-three women received transdermal oestradiol continuously. Twenty women received progesterone continuously except for women who had undergone hysterectomy. Circulating oestradiol, follicle-stimulating hormone, luteinising hormone and DHEA-S levels before and at 3 months after commencement of HRT were measured. Circulating DHEA-S level was significantly decreased at 3 months (p < .001). Oestradiol level at 3 months ranged from 6.5 pg/ml to 159 pg/ml. There was no significant correlation of ΔDHEA-S (DHEAS level at 3 months-DHEA-S level at baseline) with Δoestradiol (r = 0.114, p = .471). Circulating DHEA-S level was significantly decreased at 3 months in all the four quartiles and divided according to Δoestradiol, and ΔDHEA-S did not show significant differences. In conclusion, circulating DHEA-S decreases even with a slight increase in oestradiol level. Impact statement What is already known on this subject: A transient increase in DHEA-S in women during the menopausal transition may be involved in the occurrence of menopausal symptoms and/or unfavourable metabolic changes. Hormone replacement therapy decreases circulating DHEA-S level. However, dose dependency of the change in DHEA-S on oestrogen has not been reported. What the results of this study add: Circulating DHEA-S decreases even with a slight increase in oestradiol level. What the implications are of these findings for clinical practice and/or further research: Adrenal function may respond to a small change in oestrogen.

Development-related changes in the expression of the ovarian Kiss1 and Kiss1r genes and their sensitivity to human chorionic gonadotropin in prepubertal female rats.

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.

Relationship between serum anti-Mullerian hormone and clinical parameters in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an ovulatory disorder that affects 6-10% of women of reproductive age. Serum AMH level may be an additional factor, or surrogate of PCOM, in the diagnostic criteria of PCOS. We evaluated the correlations between the serum AMH level and various endocrine and metabolic features in PCOS using the latest fully automated assay. Serum AMH level was compared between 114 PCOS patient (PCOS group) and 95 normal menstrual cycle women (Control group). Correlations between serum AMH level and various endocrine and metabolic factors were analysed in PCOS group. The serum AMH level was significantly higher in the PCOS group (8.35±8.19 ng/mL) than in the Control group (4.99±3.23 ng/mL). The serum AMH level was independently affected by age and the presence of PCOS on multiple regression analysis. Ovarian volume per ovary (OPVO) showed the strongest positive correlation (r=0.62) with the serum AMH level among related factors. On receiver operating characteristic (ROC) curve analysis, the cut-off value of AMH for the diagnosis of PCOS was 7.33 ng/mL, but this value did not have high efficacy (sensitivity 44.7%, specificity 76.8%). A cut-off value of 10 ng/mL had a high specificity of 92.6%, although the sensitivity was low (24.6%). The serum AMH level was elevated and reflected ovarian size in PCOS patients. The serum AMH level could be a surrogate for ultrasound findings of the ovaries in PCOS and might be useful for estimating ovarian findings without transvaginal ultrasound in the diagnosis of PCOS.

Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome.

Hypersecretion of luteinizing hormone (LH) is a common endocrinological finding of polycystic ovary syndrome (PCOS). This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of gonadotropin-releasing hormone (GnRH). We evaluated the relationship between the hypothalamic-pituitary-gonadal axis (HPG axis) and kisspeptin using a rat model of PCOS induced by letrozole. Letrozole pellets (0.4 mg/day) and control pellets were placed subcutaneously onto the backs of 3-week-old female Wistar rats. Body weight, vaginal opening and vaginal smear were checked daily. Blood and tissues of ovary, uterus and brain were collected at 12-weeks of age. An hypothalamic block was cut into anterior and posterior blocks, which included the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), respectively, in order to estimate hypothalamic kisspeptin expression in each area. The letrozole group showed a similar phenotype to human PCOS such as heavier body weight, heavier ovary, persistent anovulatory state, multiple enlarged follicles with no corpus luteum and higher LH and testosterone (T) levels compared to the control group. Kisspeptin mRNA expression in the posterior hypothalamic block including ARC was higher in the letrozole group than in the control group although its expression in the anterior hypothalamic block was similar between groups. These results suggest that enhanced KNDy neuron activity in ARC contributes to hypersecretion of LH in PCOS and might be a therapeutic target to rescue ovulatory disorder of PCOS in the future.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 µg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 µg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

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.

Changes of liver enzymes and triglyceride during the menopausal transition in Japanese women.

We examined detailed changes in liver enzymes as surrogate markers for metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) during the menopausal transition and the associations of liver enzymes with lipid profiles related to risk of metabolic syndrome and endocrinological hormones. We divided 393 women into seven stages by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of alanine aminotranferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, lipid parameters, glucose, and endocrinological hormones were measured. Both levels of AST and ALT increased towards early post-menopause. AST remained high in late post-menopause but ALT decreased. The AST/ALT ratio decreased towards late menopausal transition and very early post-menopause and increased thereafter. This ratio was negatively correlated with triglyceride. Significant changes in ALT and AST/ALT ratio during the menopausal transition, which were associated with triglyceride, might be involved in the occurrence of metabolic syndrome and NAFLD in Japanese women.

The effects of ovariectomy and LPS-induced endotoxemia on resistin levels in female rats.

Resistin is involved in the inflammatory response, as well as in insulin resistance. In rodents, resistin levels are partially regulated by ovarian hormones. Thus, ovariectomy-induced changes in resistin levels and their response to lipopolysaccharide (LPS)-induced septic stress were evaluated. Ovariectomized (OVX) rats exhibited higher serum resistin concentrations and visceral and subcutaneous white adipose tissue (WAT) resistin mRNA levels than sham-operated (sham) rats under the saline-injected (basal) conditions. The serum resistin levels of the gonadal intact male rats were higher than those of the sham rats, whereas the serum resistin levels of the male and OVX rats did not differ. In both the sham and OVX rats, the serum resistin concentration and the resistin mRNA levels of WAT were increased by LPS injection. At 24h after the LPS injection, no difference was detected in the serum resistin concentrations or WAT mRNA resistin levels between the sham and OVX rats. These results suggest that ovarian hormones partially regulate the basal resistin levels of female rats.

The effects of LPS-induced endotoxemia on the expression of adiponectin and its receptors in female rats.

Adiponectin (APN), secreted by white adipose tissue (WAT), acts as a protective factor against inflammatory conditions. However, the changes in the expression levels of endogenous APN and the two types of APN receptor (AdipoR1 and AdipoR2) induced by acute inflammatory conditions have not been fully elucidated. In this study, the changes in peripheral and/or central APN and AdipoR expression caused by lipopolysaccharide (LPS)-induced sepsis were examined in gonadal-intact (Sham) and ovariectomized (OVX) female rats. As it has been reported that APN and AdipoR suppress the production of inflammatory cytokines to prevent excessive inflammation, the mRNAs of these molecules were also examined. LPS injection induced increases in visceral WAT APN mRNA without affecting the serum APN level in both the Sham and OVX rats. OVX rats exhibited higher serum APN levels than Sham rats. LPS injection increased the subcutaneous WAT APN mRNA in OVX rats. In both Sham and OVX rats, LPS injection led to a decrease in hepatic AdipoR2 mRNA and an increase in hypothalamic AdipoR2 mRNA. Hypothalamic AdipoR2 mRNA was upregulated 24 h after LPS injection in OVX but not Sham rats. Serum TNF-α level at 6 h after LPS injection and hypothalamic and hepatic IL-6 and TNF-α mRNA at 24 h after LPS injection were significantly higher in Sham than OVX rats. These results suggest that APN and AdipoR play roles in modulating inflammation under septic conditions in female rats.

Different circulating levels of monocyte chemoattractant protein-1 and interleukin-8 during the menopausal transition.

OBJECTIVE: The aim of the present study was to clarify the changes in circulating cytokines and chemokines in women during the menopausal transition by using a detailed classification. MATERIALS AND METHODS: A total of 554 women were recruited for this study from the outpatient clinic of the Department of Obstetrics and Gynecology, Tokushima University Hospital. We divided the women into seven stages by menstrual regularity and FSH level: mid-reproductive stage, late reproductive stage, early menopausal transition, late menopausal transition, very early postmenopause, early postmenopause and late postmenopause. We measured serum concentrations of nine cytokines (IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, TNF-α, MIP-1ß and MCP-1). RESULTS: Serum IL-8 concentrations in postmenopausal women were significantly (p = 0.001) higher than those in women in the mid- or late reproductive stage and women in early or late menopausal transition. Serum MCP-1 levels in women in late menopausal transition and postmenopause were significantly (p < 0.001) higher than those in women in the mid- or late reproductive stage and women in early menopausal transition. MCP-1 level showed a significant positive correlation (r = 0.215, p < 0.01) with FSH level in women in menopausal transition. CONCLUSION: By using a detailed classification of menopausal transition, patterns of changes in IL-8 and MCP-1 levels during the menopausal transition were found to be different. IL-8 level showed a high level after menopause, while MCP-1 level showed a high level in menopausal transition. MCP-1 may be sensitive to hormonal change and may be involved in the development of estrogen deficiency diseases.

Correlations of androstenediol with reproductive hormones and cortisol according to stages during the menopausal transition in Japanese women.

Associations of androstenediol, which has both androgenic and estrogenic activities, with circulating reproductive hormones and stress hormone in women during the menopausal transition may be different depending on the menopausal stage. The aim of this study was to determine the changes in circulating androstenediol during the menopausal transition in Japanese women and the associations of androstenediol with estrogen, androgen and cortisol for each stage of the menopausal transition. We divided the 104 subjects into 6 stages by menstrual regularity and follicle-stimulating hormone level: mid reproductive stage, late reproductive stage, early menopausal transition, late menopausal transition, very early postmenopause and early postmenopause. Levels of dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and cortisol were measured. Serum androstenediol concentration was measured by using liquid chromatography mass spectrometry. There were no significant differences in androstenediol levels among the 6 stages. Levels of DHEA-S and testosterone showed significant and positive correlations with androstenediol in all stages. Estradiol levels showed negative correlations with androstenediol levels in the late menopausal transition and very early postmenopause (r=-0.452, p = 0.052 and r=-0.617, p = 0.006, respectively). Cortisol levels showed significant and positive correlations with androstenediol levels in the mid and late reproductive stages (r = 0.719, p = 0.003 and r = 0.808, p < 0.001, respectively).The associations of androstenediol with estradiol and cortisol were different depending on the stage of the menopausal transition. Androstenediol may play a compensatory role for estrogen deficiency from late menopausal transition to very early postmenopause.

Lipopolysaccharide promotes early endometrial-peritoneal interactions in a mouse model of 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. J. Med. Invest. 66 : 70-74, February, 2019.

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.

The sensitivity of adipose tissue visfatin mRNA expression to lipopolysaccharide-induced endotoxemia is increased by ovariectomy in female rats.

Visfatin plays an important role in inflammatory and metabolic conditions. In this study, the effects of septic stress on the serum, white-adipose-tissue (WAT), and liver visfatin levels of male and female rats were examined. Both gonadally intact (sham) and ovariectomized (OVX) female rats were used in order to evaluate the effects of the gonadal hormonal milieu on visfatin responses. Under the saline-injected conditions, the serum visfatin levels and the hepatic, subcutaneous, and visceral WAT visfatin mRNA levels of the OVX and sham rats did not differ. The serum visfatin levels and the subcutaneous, visceral WAT, and hepatic visfatin mRNA levels of both male and female rats were increased by the injection of a septic dose (5mg/kg) of LPS. At 6h after the injection of LPS, the WAT visfatin mRNA levels of the OVX rats were higher than those of the sham rats, whereas the serum visfatin levels and hepatic visfatin mRNA levels of the two groups did not differ. In the cultured visceral WAT, visfatin antagonist (FK-866) attenuated the LPS-induced up-regulations of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α). The pathophysiological roles of visfatin under septic conditions remain to be clarified. In addition, the precise mechanisms responsible for the increased WAT visfatin expression seen after ovariectomy and the effects of such changes should also be clarified.

Increase in circulating sclerostin at the early stage of menopausal transition in Japanese women.

OBJECTIVE: We examined the change in circulating sclerostin level during the menopausal transition and we investigated the associations of sclerositin with hormones and bone turnover markers according to each menopausal stage in cross-sectional and longitudinal studies. METHODS: We conducted a cross-sectional study in 200 healthy Japanese women and divided them into 4 stages (reproductive, menopausal transition, early postmenopause and late postmenopause) by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of sclerostin, bone turnover markers and reproductive hormones were measured. In addition, we examined changes in sclerostin level from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in a longitudinal study. RESULTS: In the cross-sectional study, sclerostin level gradually increased with progression of menopausal stages and showed a significant change during the menopausal transition. Sclerostin levels significantly increased from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in the longitudinal study. A negative correlation of sclerostin with estradiol was found in early postmenopause. Sclerostin levels were negatively correlated with bone-specific alkaline phosphatase levels in the reproductive stage and menopausal transition and with tartrate-resistant acid phosphatase-5b in menopausal transition. CONCLUSION: The change in sclerostin has already occurred in the early stage of menopausal transition and sclerostin level increases with progression of menopausal stages. Elevated sclerostin levels during the menopausal transition may be involved in relative decline in bone formation against increase in bone resorption.