Menopause status is associated with circadian- and sleep-related alterations.

OBJECTIVE: The aim of the study was to investigate whether postmenopausal women show differences in circadian-related variables and sleep characteristics compared with premenopausal women, and to analyze potential associations between these circadian-related variables and abdominal fat distribution or metabolic syndrome (MetS) components. METHODS: A total of 177 women were studied (127 premenopausal, 50 postmenopausal). Sixty percent of the total population was overweight/obese, with no significant differences between premenopausal (60%) and postmenopausal women (62%) (P = 0.865). Wrist temperature (WT) and rest-activity cycles were measured during 8 consecutive days, and sleep and food diaries collected. MetS characteristics and daily patterns of saliva cortisol were analyzed. Sleep characteristics were assessed with domiciliary polysomnography. RESULTS: Postmenopausal women showed a less robust rhythm in WT with lower amplitude (°C) (0.8 ±â€Š0.4 vs 0.9 ±â€Š0.5) (P < 0.05) and lower mean temperature values at the midpoint of sleep than premenopausal women. Postmenopausal women were also more morning-type than premenopausal women, showing a phase advance of approximately 1 hour in WT and rest-activity rhythms, and more morning-type habits (earlier sleep onset/offset and breakfast intake) (P < 0.05). Postmenopausal women showed higher levels of activity in the morning and lower in the evening compared with premenopausal women (P < 0.05). Daily variability in cortisol was significantly reduced in postmenopausal women compared with premenopausal women (P < 0.05). Postmenopausal women had increased frequency of sleep-related breathing abnormalities (P < 0.0001). In the women studied, abdominal fat and MetS were associated with an increase in circadian alterations (high fragmentation and low amplitude of the rhythm) (P < 0.05). CONCLUSIONS: Postmenopausal women exhibit loss of circadian robustness and an increase in sleep abnormalities compared with premenopausal women.

Differential effect of oral dehydroepiandrosterone-sulphate on metabolic syndrome features in pre- and postmenopausal obese women.

OBJECTIVE: To analyze the effect in obese pre- and postmenopausal women of a daily dose of 100 mg dehydroepiandrosterone-sulphate (DHEA-S) provided over a period of 3 months as replacement therapy against metabolic syndrome. CONTEXT: Although DHEA-S appears to be effective against certain features of metabolic syndrome, its usefulness against this syndrome as a whole has not been evaluated to date. DESIGN/PATIENTS: A randomized, double-blind placebo-controlled trial was conducted involving 61 postmenopausal women, who received DHEA-S (n = 41) or placebo (n = 20) for 3 months. The effect of DHEA-S treatment on the same postmenopausal women was compared with the effects observed in a group of premenopausal women (n = 20). MEASUREMENTS: Anthropometric measurements were taken at the beginning and at the end of the treatment. Similarly, different parameters that define metabolic syndrome and other cardiometabolic variables were determined. RESULTS: Dehydroepiandrosterone-sulphate replacement produced weight loss in the obese women studied. Moreover, waist circumference, glucose and systolic and diastolic blood pressure, among other metabolic syndrome parameters, improved in the postmenopausal group, who showed a significant reduction in the total metabolic syndrome score (P < 0·05). In contrast, in premenopausal women, the effect of DHEA-S was limited to obesity parameters, and no effect was observed on metabolic syndrome components. No significant changes were evident in the placebo group. CONCLUSIONS: An oral dose of DHEA-S is useful for weight loss. In obese postmenopausal women, the hormone significantly improves plasma biochemical levels and anthropometric characteristics, leading to a better metabolic profile, which highlights the usefulness of this therapy against metabolic syndrome in this group of women.

Influence of menopause on adipose tissue clock gene genotype and its relationship with metabolic syndrome in morbidly obese women.

Menopausal women exhibit a loss of circadian coordination, a process that runs parallel with a redistribution of adipose tissue. However, the specific genetic mechanisms underlying these alterations have not been studied. Thus, the aim of the present study was to determine whether the development of menopause induces an alteration of the genes that control biological rhythms in human subcutaneous (SAT) and visceral (VAT) adipose tissue, and whether changes in clock gene expression are involved in the increased risk of developing metabolic syndrome (MetS), which is frequently associated with menopause. To this end, VAT and SAT biopsies were taken in pre- (n = 7) and postmenopausal (n = 7) women at similar hours in the morning. RNA was extracted, and a microarray analysis was made. Data were confirmed by quantitative real-time polymerase chain reaction. Western blot and immunohistochemical analysis were also performed. When clock gene expression was compared between both groups of women, data in SAT showed that expression of the core clock gene period3 was significantly higher in postmenopausal women, while casein kinase-1δ, E1A-binding protein and cAMP-responsive element were preferentially expressed in the premenopausal group. In VAT, period2 (PER2) and v-myc myelocytomatosis viral oncogene expressions were significantly higher in the postmenopausal group. Western blot analysis indicated that PER2 and PER3 protein expression was also increased in postmenopausal women. In addition, several genes, including PER2, were differentially expressed depending on whether or not the patient met the MetS criteria. We conclude that menopause transition induces several changes in the genotype of the adipose tissue chronobiological machinery related to an increased risk of developing MetS.

Profile of adipose tissue gene expression in premenopausal and postmenopausal women: site-specific differences.

OBJECTIVES: Menopause increases the risk of several pathologies, probably due to enlarged levels of visceral fat. Apart from morphological and endocrine changes, a cluster of genes, still not fully defined, may be involved in these alterations. The objectives of the present study, therefore, were to analyze differences in adipose tissue gene expression between premenopausal and postmenopausal women and to ascertain whether any differences were depot specific. METHODS: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) biopsies were taken from 7 premenopausal and 7 postmenopausal women undergoing surgery because of morbid obesity. RNA was extracted, and the overall gene expression profile was analyzed by microarray analysis. RESULTS: In general, SAT genes were overexpressed, whereas VAT genes were down-regulated in premenopausal compared with postmenopausal women. We found 724 differentially expressed genes in SAT and 327 in VAT. These differences suggest that several biological processes, such as the immune system and other metabolic processes, were altered based on menopause status. Regarding individual genes, neurexin 3, metallothionein 1E, and keratyn 7 showed the most pronounced differences. Interestingly, the expression of these genes was related to body fat distribution. CONCLUSIONS: Our results reveal that menopause influences the adipose tissue expression of many genes, especially of neurexin 3, metallothionein 1E, and keratyn 7, which are associated with the alteration of several key biological processes, such as the immune system and cell metabolism. Gene expression in adipose tissue could be used for diagnosis and the development of new therapeutic strategies against obesity and related alterations, depending on menopause status.

Circadian rhythm of clock genes in human adipose explants.

To analyze in severely obese women the circadian expression of the clock genes hPer2, hBmal1, and hCry1 in explants from subcutaneous (SAT) and visceral (VAT) adipose tissue (AT), in order to elucidate whether this circadian clockwork can oscillate accurately and independently of the suprachiasmatic nucleus (SCN) and if glucocorticoid metabolism-related genes such as glucocorticoid receptor (hGr) and 11beta-hydroxysteroid dehydrogenase 1 (h11 beta Hsd1) and the transcription factor peroxisome proliferator activated receptor gamma (hPPAR gamma) are part of the clock controlled genes. AT biopsies were obtained from morbid obese patients (BMI > or =40 kg/m(2)) (n = 7). Anthropometric variables were measured and fasting plasma lipids and lipoprotein concentrations were analyzed. In order to carry out rhythmic expression analysis, AT explants were cultured during 24 h and gene expression was performed at the following times (T): 0, 6, 12, and 18 h, with quantitative real-time PCR. Clock genes oscillated accurately and independently of the SCN in AT explants. Their intrinsic oscillatory mechanism regulated the timing of other genes such as hPPAR gamma and glucocorticoid-related genes. Circadian patterns differed between VAT and SAT. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome (MetS) revealed that subjects with a higher sagittal diameter showed an increased circadian variability in hPer2 expression (r = 0.91; P = 0.031) and hBmal1 (r = 0.90; P = 0.040). Data demonstrate the presence of peripheral circadian oscillators in human AT independently of the central circadian control mechanism. This knowledge paves the way for a better understanding of the circadian contribution to medical conditions such as obesity and MetS.