Marek Demissie

Dehydroepiandrosterone replacement in healthy men with age-related decline of DHEA-S: effects on fat distribution, insulin sensitivity and lipid metabolism

Many animal and human studies show that supraphysiological doses of dehydroepiandrosterone (DHEA) can influence body composition and carbohydrate and lipid metabolism. Most studies have concentrated on women and have not been randomized, thus creating controversial results. With this in mind, we designed a cross-over double-blind placebo-controlled study of 12 men aged 59.0 ± 4.8 years, who received either 50 mg/24 h DHEA or placebo for 3 months to assess the influence of DHEA on the content and distribution of fat tissue and serum insulin, glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels, as well as testosterone, estradiol, DHEA-sulfate (S), prostate-specific antigen (PSA) concentrations and indexes of insulin sensitivity and resistance. Patients were recruited from university employees attending for periodic health checks, with normal hepatic and renal function with endogenous DHEA-S level < 1500 ng/dl. Our results did not reveal any significant changes in study parameters, apart from a statistically significant increase in DHEA-S levels after therapy with active substance.

Menopausal obesity – myth or fact?

Obesity, particularly with central fat distribution, and mortality from all causes are directly related in middle-aged women. Many studies have shown that women in their mid-life tend to gain weight, with a shift to visceral fat distribution. The etiology of perimenopausal obesity is not fully known, and it remains unclear whether excessive weight gain and changes in fat distribution at menopausal age result from climacteric changes or are related to the process of aging of the individual and/or to changing life-style factors. Obesity may have a genetic background. It is well established that an excessive amount of energy intake and too small an energy expenditure is crucial for the development of obesity. Diet composition also plays a role in the pathogenesis of obesity. Neuropeptides appear to be one of the factors that control food intake and nutrient balance. The aging process in women is associated with progressive declines in the levels of many hormones including estrogens, dehydroepiandrosterone (DHEA) and growth hormone-insulin-like growth factor I (GH–IGF-I). These endocrine perturbations may result in altered body composition and weight gain. Obesity in postmenopausal women is accompanied by many metabolic disturbances leading to increased mortality.

Serum adiponectin concentration and cardiovascular risk factors in climacteric women

Objective Adiponectin plays a significant role in the modulation of glucose tolerance and insulin sensitivity. We attempted to evaluate the relationship between adiponectin level and parameters of the menopausal metabolic syndrome: body mass index, waist-to-hip ratio, lipid profile and insulin resistance indices. Subjects and methods Thirty-two women and ten men aged 40–63 years were included. The percentage of body fat and of abdominal fat deposits were measured with dual-energy X-ray absorptiometry. Serum adiponectin, tumour necrosis factor-α (TNFα) and leptin were measured with commercially available radioimmunoassay kits. To exclude the influence of nutritional factors on adiponectin secretion, diet content was analysed in the preceding three days. Results Postmenopausal non-obese women had a non-significantly lower level of adiponectin compared with premenopausal women of corresponding body mass. Serum adiponectin level was significantly lower in postmenopausal obese women than in non-obese women (p = 0.0023). Men with similar age and body mass to the women had the lowest level of adiponectin (p = 0.06). Three months of estrogen replacement therapy in women with surgical menopause did not significantly change the serum level of adiponectin. We found a negative correlation of adiponectin with leptin, insulin resistance index and total cholesterol, and a positive correlation with high-density lipoprotein cholesterol. Adiponectin level was negatively correlated with free testosterone, but we did not find such a relationship with estradiol. There was no correlation of adiponectin level with TNFα; however, serum TNFα correlated positively with leptin. The dietary analysis showed no differences between the diets of obese and non-obese women over the preceding three days. Moreover, mean diastolic and systolic blood pressures were noted to be significantly lower in premenopausal women than in postmenopausal non-obese women (p = 0.05). Conclusions Our results suggest that adiponectin could be a marker of risk for developing menopausal metabolic syndrome. Moreover, it is possible that sex steroids have an influence on adiponectin secretion.

Expression and differential effects of the activation of glucocorticoid receptors in mouse gonadotropin-releasing hormone neurons

Prenatal exposure of rodents to glucocorticoids (Gc) affects the sexual development of the offspring, possibly interfering with the differentiation of the hypothalamic-pituitary-gonadal axis. Glucocorticoid receptors (GR) are present on gonadotropin-releasing hormone (GnRH) neurons in the rat hypothalamus, suggesting a direct effect of Gc in the control of the synthesis and/or release of the hormone. In this study, we demonstrate the colocalization of immunoreactive GR with GnRH in a subpopulation of mouse hypothalamic GnRH neurons, confirming the possible involvement of Gc in mouse GnRH neuronal physiology. Receptor-binding assay, RT-PCR, immunocytochemistry, and immunoblotting experiments carried out in GN11 immortalized GnRH neurons show the presence of GR even in the more immature mouse GnRH neurons and confirm the expression of GR in GT1-7 mature GnRH cells. In GN11 cells, the activation of GR with dexamethasone produces nuclear translocation, but does not lead to the inhibition of GnRH gene expression already reported in GT1-7 cells. Long-term exposure of GN11 cells to dexamethasone induces an epithelial-like phenotype with a reorganization of F-actin in stress fibers. Finally, we found that Gc treatment significantly decreases the migratory activity in vitro and the levels of phosphorylated focal adhesion kinase of GN11 immature neurons. In conclusion, these data indicate that GR are expressed in mouse hypothalamic GnRH neurons in vivo as well as in the immature GN11 GnRH neurons in vitro. Moreover, the effects of the GR activation in GN11 and in GT1-7 cells may be related to the neuronal maturational stage of the two cell lines, suggesting a differential role of Gc in neuronal development.

Influence of dietary and genetic factors on metabolic status in obese and lean postmenopausal women

This preliminary study addressed the possible associations between dietary ,genetic and hormonal factors that are involved in the development of menopausal obesity and its metabolic consequences. We performed anthropometrical ,hormonal and biochemical measurements and used a nutritional questionnaire on 43 postmenopausal women who were non-HRT-users (14 obese and 29 non-obese subjects ,mean age ± SD of 52.8 ± 4.6 years ,mean body mass 74.6 ± 4.6 kg). All of the women also had fat mass assessed by DPX-Lunar. From the 24-h dietary recall ,the nutrient intake in daily food rations was calculated using a computer program (Nutritionist IV ,San Bruno ,CA ,USA) based on our own database. Restriction fragment length polymorphism of the estrogen-receptor-α gene was determined with the PvuII restriction enzyme. Obese women widely under-reported their daily food intake. The analysis of body fat distribution showed that the total body weight and the percentage of total fat mass were significantly increased in the obese group (p = 0.001). We observed significantly higher leptin (20.56 ± 11.9 vs. 9.02 ± 2.8 ng/ml) and total cholesterol (but lower cholesterol HDL) ,triglycerides levels in the obese subjects (261.89 ± 48.8 vs. 248.23 ± 55.9; 52.17 ± 13.6 vs. 60.92 ± 13.04; 142.82 ± 61.02 vs. 106.61 ± 27.7 mg/dl). Except for diastolic blood pressure ,clinical variables were not significantly different between subjects with and without the PvuII ERα polymorphism. Allele frequencies of the ERα polymorphism did not differ from those previously reported (P-0.48 ,p-0.52) in our study. In this preliminary study we failed to find dietary and genetic factors involved in the pathogenesis of menopausal obesity. However ,our results provide support for the notion that the perimenopausal increase in visceral fat is a significant factor involved in the increased cardiovascular risk in postmenopausal women.

Metabolic and endocrine changes in climacteric women

Abstract The climacteric period is associated with gradual reduction of sex hormones secretion. Substantial evidence indicates that estrogen deficiency contributes to the long-term metabolic consequences. A range of age-related changes (e.g. a reduction in growth hormone (GH), dehydroepiandrosterone (DHEA), melatonin) may be involved in aggravation of described abnormalities. Our studies on plasma satiety and appetite-stimulating neuropeptides indicate that the modification of appetite preferences contributes to overconsumption of fat in postmenopausal women. It is known that 60% of postmenopausal women have central body obesity. This trend obviously favours insulin resistance, an atherogenic plasma lipid–lipoprotein profile, abnormal blood coagulation and the increase in prevalence of type 2 diabetes. This cluster of metabolic abnormalities may be described as menopausal metabolic syndrome. Importantly, the alterations that women suffer in the climacteric period are assumed to be a risk factor leading to a 26–30% increase in death due to coronary heart disease in the postmenopausal group.

Dexamethasone blocks the migration of the human neuroblastoma cell line SK-N-SH

Glucocorticoids (Gc) influence the differentiation of neural crest-derived cells such as those composing sympathoadrenal tumors like pheochromocytomas, as well as neuroblastomas and gangliomas. In order to obtain further information on the effects of Gc on cells evolving from the neural crest, we have used the human neuroblastoma cell line SK-N-SH to analyze: 1) the presence and the binding characteristics of Gc receptors in these cells, 2) the effect of dexamethasone (Dex) on the migration of SK-N-SH cells, and 3) the effect of Dex on the organization of the cytoskeleton of SK-N-SH cells. We show that: 1) receptors that bind [(3)H]-Dex with high affinity and high capacity (Kd of 9.6 nM, Bmax of 47 fmol/mg cytosolic protein, corresponding to 28,303 sites/cell) are present in cytosolic preparations of SK-N-SH cells, and 2) treatment with Dex (in the range of 10 nM to 1 microM) has an inhibitory effect (from 100% to 74 and 43%, respectively) on the chemotaxis of SK-N-SH cells elicited by fetal bovine serum. This inhibition is completely reversed by the Gc receptor antagonist RU486 (1 microM), and 3) as demonstrated by fluorescent phalloidin-actin detection, the effect of Dex (100 nM) on SK-N-SH cell migration is accompanied by modifications of the cytoskeleton organization that appear with stress fibers. These modifications did not take place in the presence of 1 microM RU486. The present data demonstrate for the first time that Dex affects the migration of neuroblastoma cells as well as their cytoskeleton organization by interacting with specific receptors. These findings provide new insights on the mechanism(s) of action of Gc on cells originating in the neural crest.

Familial hypopituitarism associated with mosaic form of Turner syndrome.

We present herein an unusual coincidence of familial hypopituitarism associated with a mosaic form of Turner syndrome in two adult sisters (51 and 43 years old). Both patients had hypopituitarism diagnosed in childhood. They have never been administered growth hormone, and remained short in stature. They were not given long-term estrogen–progestin treatment, despite lack of menstruation. Early in childhood both received thyroid hormone substitution. Pituitary imaging revealed pituitary hypoplasia with partial empty sella in one sister, and pituitary hypoplasia in the other. Very recently, during endocrinological evaluation, they were diagnosed with a mosaic form of Turner syndrome, additionally to their hypopituitarism. In this paper, we place special emphasis on the results of hormonal analyses and discuss the differential diagnosis.

POLYMORPHISM OF THE VITAMIN D RECEPTOR GENE, BONE MINERAL DENSITY, AND BONE TURNOVER IN POSTMENOPAUSAL WOMEN FROM LOWER SILESIA (POLAND)

Summary Objective Genetic factors are involved in determining bone mineral density (BMD) and in the pathogenesis of osteoporosis. There are relationships between various genetic polymorphisms and BMD or bone turnover. The aim of our study was to assess polymorphisms in the vitamin D receptor (VDR) gene ( BsmI ) in relation to BMD and bone turnover in a group of Polish postmenopausal women from the Lower Silesia region. Materials and Methods BMD at the lumbar spine and proximal femur, bone turnover (osteocalcin and carboxyterminal cross-linked telopeptide of type I collagen, ICTP), and restriction fragment length polymorphism (RFLP) of the VDR gene using the BsmI restriction enzyme were examined in 116 postmenopausal women. Results Despite the fact that we failed to detect statistically significant differences between the VDR genotypes in BMD, a trend towards higher BMD in women carrying allele b compared with wild-type subjects in our study is similar to previous reports. We also observed a higher allele b frequency in the control group (normal bone mass) compared with osteopenic/osteoporotic women (59.1% vs 40.0%). The lower activity of the resorption marker ICTP seen in allele b carriers could be involved. Conclusion We report an association between VDR gene polymorphism and decreased BMD in Polish postmenopausal women from the Lower Silesia region, but this requires further robust studies for confirmation.