Peripheral sensitivity to steroids revisited.

Resistance to steroid hormones presents a serious problem with respect to their mass use in therapy. It may be caused genetically by mutation of genes involved in hormonal signaling, not only steroid receptors, but also other players in the signaling cascade as co-regulators and other nuclear factors, mediating the hormone-born signal. Another possibility is acquired resistance which may develop under long-term steroid treatment, of which a particular case is down regulation of the receptors. In the review recent knowledge is summarized on the mechanism of main steroid hormone action, pointing to already proven or potential sites causing steroid resistance. We have attempted to address following questions: 1) What does stay behind differences among patients as to their response to the (anti)steroid treatment? 2) Why do various tissues/cells respond differently to the same steroid hormone though they contain the same receptors? 3) Are such differences genetically dependent? The main attention was devoted to glucocorticoids as the most frequently used steroid therapeutics. Further, androgen insensitivity is discussed with a particular attention to acquired resistance to androgen deprivation therapy of prostate cancer. Finally the potential causes are outlined of breast and related cancer(s) resistance to antiestrogen therapy.

Vitamin D supplementation changed relationships, not levels of metabolic-hormonal parameters in autoimmune thyroiditis.

In women with chronic autoimmune thyroiditis and vitamin D deficiency we have found reference levels of relevant metabolic-hormonal parameters except for parathormone and total calcium. Three months supplementation with vitamin D (4300 IU/day, cholekalciferol) did not lead to significant changes of investigated hormonal parameters, while the levels of parathormone and calcium reached normal levels. However, a correlation analysis revealed marked changes in mutual relations. First, an inverse correlation of vitamin D with parathormone, insulin secretion (C peptide, insulin) and its efficiency (HOMA IR) disappeared. Relationships of vitamin D to hepatic insulin resistance (insulin/C peptide), to DHEA (both negative), and to DHEAS/DHEA ratio (positive) were newly found. Second, a positive correlation of CRP with insulin secretion remained, while its relation to insulin efficiency (HOMA IR, insulin/C peptide) was newly observed. Analogical positive correlations appeared also among anti TPO and insulinemia, insulin/C peptide, HOMA IR, and anti Tg to C peptide. A relationship of the CRP with anti TPO became significant (+). Third, out of glucose metabolism parameters only insulin/C peptide and glycemia did not correlate with vitamin D during its deficiency, while after supplementation insulin/C peptide alone correlated positively with both DHEAS and DHEA, and negatively with vitamin D.

Daily profiles of steroid hormones and their metabolites related to food intake.

The aim of this study was to look for changes in the daily profile of steroid hormones after standardized food intake. Eight young women not taking contraceptives were followed from 5:30 a.m. till 9:30 p.m. before and 1 and 2 h after eating breakfast, snack, lunch, the second snack and dinner. The differences in steroid levels before and after meals were evaluated. As expected, glucose, C-peptide and ghrelin levels changed postprandially. The steroid hormones cortisol, progesterone, pregnenolone and dehydroepiandrosterone showed a decrease after main meals, whereas testosterone and dihydrotestosterone showed no significant dependence on food intake. Estrogen levels did not exhibit a significant nycthemeral rhythm, but estradiol decreased after main meals. In our study the known nycthemeral rhythm of LH, FSH, cortisol, progesterone and pregnenolone after food intake were confirmed, but significant changes after meals were also observed in the levels of cortisol, dehydroepiandrosterone, estradiol and SHBG.

The steroid spectrum during and after quitting smoking.

Addiction to tobacco results in an imbalance of endocrine homeostasis in both sexes. This can also have impacts on fertility problems. The male reproductive system is less susceptible than that of females, with a worsening spermiogram in smokers, the most cited effect in the literature. However, the literature is inconsistent as to the effects of smoking on steroid hormone levels in men, and there is very little data on the effects of quitting smoking in men. In this study we followed 76 men before quitting smoking, and then after 6, 12, and 24 weeks and 1 year of abstinence. We measured basic anthropomorphic data and steroid hormone levels along with steroid neuroactive metabolites using GC-MS. We demonstrate lower androgen levels in men who smoke, and these changes worsened after quitting smoking. There was a drop in SHBG already in the first week of non-smoking, and levels continued to remain low. Male smokers have lower androgen levels compared to non-smokers. The lower the initial level of androgen, the lower the likelihood of success in quitting smoking. Changes in steroid hormones proved to be a promising marker for the prediction of success in quitting smoking.

DHEA, DHEAS and prolactin correlate with glucose control parameters in women of fertile age with type-1 diabetes mellitus.

The aim of our work was to provide data from women of fertile age with type 1 diabetes mellitus about the endogenous androgens and on their relations to the parameters of diabetes control. Forty-two women were examined, they did not use contraceptives for at least three months prior to the examination. A multivariate regression analysis showed that the daily insulin dose, the fasting glycemia and the HbA1c values and patient's age correlated negatively with dehydroepiandrosterone sulfate, dehydroepiandrosterone and prolactin levels. The testosterone/dehydroepiandrosterone sulfate ratio correlated positively with daily insulin dose and patient's age. In contrast to adrenal androgens the values of other hormones, including total and free testosterone, androstenedione, dihydrotestosterone, estradiol, LH, FSH, 17-OH-P, progesterone and cortisol revealed no significant correlation. To conclude, significant relations between the glucose control parameters and the adrenal androgens and prolactin were demonstrated. These relationships should be considered as an important factor influencing diabetes control so the additional cardiovascular risk in women with DM1.

Vitamin D and thyroid diseases.

In this review we summarize recent opinions on the possible role of vitamin D in the risk of thyroid diseases development. It may be concluded from the available data that vitamin D deficiency, particularly levels below 12.5 ng/ml should be considered as an additional, but important risk factor for development of thyroid autoimmunity, both chronic autoimmune thyroiditis and Graves' disease. A higher risk of Graves' disease development is also associated with several polymorphisms in the gene encoding for vitamin D binding protein and for the specific receptor of active form of vitamin D - 1,25-(OH)(2)D(3) in the respective target cells. Important for development of thyroid cancer appeared polymorphisms of genes encoding for vitamin D receptors and of genes encoding for the participating hydroxylating enzymes in thyroid tissue, leading to a diminished local 1,25-(OH)(2)D(3) formation capacity with following alteration of antiproliferatory, antiapoptotic and prodifferentiating efficacy of the latter. Whether supplementation with high doses of vitamin D or its analogues possesses preventive or therapeutic effect is an object of intensive studies.

Effects of smoking cessation on hormonal levels in men.

Chronic smoking can cause imbalance in endocrine homeostasis and impairment of fertility in both sexes. The male reproductive system is more resilient, still the literature provides conflicting results about the influence of smoking on the steroid hormone levels. The data about smoking cessation are limited; there has not yet been a study primarily focused on changes in steroids levels. In our study, we analyzed levels of testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), cortisol and sex hormone-binding globulin (SHBG) in male smokers and during smoking cessation. Monitored analytes were determined by RIA. The free testosterone index was calculated. Basal samples of men successful and unsuccessful in smoking cessation did not differ and monitored hormones could hardly predict success of smoking cessation. After one year without smoking, a significant BMI increase and SHBG decrease in former smokers was observed. The decrease in total testosterone was non-significant. Changes in SHBG and testosterone did not correlate with BMI, presumably due to the direct effect of smoking cessation.

T2D risk haplotypes of the TCF7L2 gene in the Czech population sample: the association with free fatty acids composition.

The association of transcription factor 7-like 2 (TCF7L2) gene variants with the pathogenesis of T2D, gestational diabetes and polycystic ovary syndrome (PCOS) was examined. The study involved 1460 individuals: 347 T2D patients (D); 261 gestational diabetics (G); 147 offspring of T2D (O); 329 women with PCOS, and 376 controls (C). The SNPs: rs7901695; rs7903146; rs12255372 in the TCF7L2 gene were genotyped. Anthropometric and biochemical parameters, oGTT derived indices were assessed. In addition, free fatty acids (FFAs) were evaluated in 183 non-diabetic women. The CTT haplotype showed the strongest association with T2D with OR 1.57, p=0.0003. The frequency of the CTT/CTT haplotype was decreasing in following order: D 10.6, O 9.5, G 6.1, C 5.3 and PCOS 4.9 [%]. Among CTT carriers, significantly decreased levels of oGTT-stimulated insulin and C-peptide as well as proportions of fasting PUFAs were observed. The carriership of CTG/TCG was associated with gestational diabetes, OR 2.59, p=0.036. The association of TCF7L2 haplotypes with T2D and gestational diabetes but not with PCOS was confirmed. Novel association of TCF7L2 with FFAs composition was found.

Evaluation of hepatic 11 beta-hydroxysteroid dehydrogenase activity by cortisone acetate test in young adults with diabetes mellitus type 1.

Cortisone acetate test was performed in twelve young adult patients with diabetes mellitus type 1, after dexamethasone administration to suppress endogenous cortisol production. Previous screening revealed that all of the subjects had peak cortisol responses in the range from subnormal to normal, as determined by a low-dose Synacthen test. The aim was to find out whether these patients would exhibit different conversion of cortisone to cortisol by 11beta-hydroxysteroid dehydrogenase. Using multifactorial ANOVA the following significant relationships were obtained between cortisol or cortisol/cortisone ratio measured during the test and other parameters examined a) before dexamethasone suppression and b) during the test: a) Cortisol at 120(th) minute negatively correlated with daily insulin dose and positively with basal aldosterone. Cortisol/cortisone ratio at 60(th), 120(th), 180(th), and 240(th) minute negatively correlated with basal aldosterone/plasma renin activity ratio, urinary free cortisol/24 hours and positively with basal dehydroepindrosterone sulphate. b) Cortisol at 120(th) minute negatively correlated with suppressed basal serum glycemia; cortisol/cortisone ratio during the whole test negatively correlated with supressed basal ACTH. The examination of peripheral metabolism of cortisol using cortisone acetate test in patients with diabetes mellitus type 1 showed adaptive changes of 11beta-hydroxysteroid dehydrogenace activity associated with altered cortisol tissue supply.

Metabolic profile and sex hormone binding globulin (SHBG) in different reproductive phases of Czech women and their relations to weight, body composition and fat distribution.

In our study, 213 healthy Czech women aged 20 to 65 years were examined and divided into fully reproductive, premenopausal, menopausal and postmenopausal groups. In all subjects body composition was determined by classical anthropometry and metabolic profile was assessed. A total of 146 subjects completed 3-year longitudinal study. Total and LDL cholesterol increased and ratio HDL/total cholesterol decreased with age (p<0.001), most significantly in menopause. Triacylglycerols increased only up to menopause. HDL had a very slight trend to decrease in menopause and postmenopause. Fasting blood glucose level increased progressively (p<0.001), in postmenopause frequently exceeded normal range. Higher BMI, total fat mass and central fat indices were associated with higher total and LDL cholesterol, triacylglycerols, C-peptide, insulin and fasting blood glucose level (p<0.001; fasting blood glucose level to waist-to-hip ratio: p<0.01) and lower HDL cholesterol (p<0.001). Higher C-peptide and insulin were associated with lower HDL cholesterol and higher triacylglycerols (p<0.001). Fasting glucose correlated with LDL cholesterol (p<0.01). Higher SHBG was associated with higher HDL and lower LDL cholesterol (p<0.001). Hormone replacement treatment was related to lower fasting blood glucose level in postmenopausal women (p<0.01). Oral contraception is suggestive of a positive influence on lipid spectrum by increasing the ratio HDL/total cholesterol. Markers of lipid and carbohydrate metabolism are not only age-related, but they are also related to BMI, total fat mass and central fat indices. Therefore, preventive programs should be focused above all on menopausal women.

Comparison of total and salivary cortisol in a low-dose ACTH (Synacthen) test: influence of three-month oral contraceptives administration to healthy women.

The objective of this study was to evaluate the influence of low-dose combined oral contraception (COC) on basal and stimulated (1 microg ACTH test) levels of serum and salivary cortisol (F), cortisone and on basal serum cortisol binding globulin (CBG), adrenocorticotropic hormone (ACTH), dehydroepiadrosterone (DHEA) and calculated free cortisol in healthy young women. Three-month administration of COC resulted in 1) significant increase of basal (454.0+/-125.0 to 860.9+/-179.7 nmol/l) and ACTH-stimulated serum cortisol in 30th min (652.3+/-60.5 to 1374.1+/-240.6 nmol/l); 2) no significant change of basal (15.4+/-7.3 to 18.9+/-8.5 nmol/l) and ACTH-stimulated salivary cortisol at the 30th min (32.4+/-8.8 to 32.9+/-9.0 nmol/l); 3) no significant change of basal serum cortisone (38,8+/-7.68 to 45.2+/-24.2 nmol/l) and ACTH-stimulated cortisone at the 30th (34.8+/-10.9 to 47.0+/-35.7 nmol/l); 4) significant increase of basal ACTH (17.2+/-9.0 to 38.2+/-29.4 ng/l), CBG (991.0+/-161.0 to 2332.0+/-428.0 nmol/l), and 5) no significant change of basal DHEA (24.6+/-15.7 to 22.6+/-11.7 micromol/l) and calculated basal value for free cortisol (22.8+/-14.9 to 19.2+/-6.9 nmol/l). In conclusions, higher basal and ACTH-stimulated serum cortisol were found after three-month administration of COC, while basal and stimulated salivary cortisol were not significantly affected. Therefore, salivary cortisol can be used for assessment of adrenal function in women regularly using COC.

TRH test in patients with diabetes mellitus type 1 and/or autoimmune thyroiditis. Changes in the pituitary-thyroid axis, reverse T3, prolactin and growth hormone levels.

The response of the pituitary- thyroid axis, reverse triiodothyronine (rT3), prolactin, and growth hormone (GH) levels following TRH stimulus (Relefact TRH 200 microg 2 amp. i.v.) was examined in patients with autoimmune diabetes type 1 (DM1, n=30), with autoimmune thyroiditis (AT, n=25), and with concurrent DM1 and AT (n=22) to evaluate the influence of DM1 and AT of autoimmune pathogenesis on the above-mentioned hormonal parameters. Statistical analysis (ANOVA) showed that: a) the response of TSH did not differ from control groups (C); b) free triiodothyronine (fT3), free thyroxine (fT4) and their ratio in DM1, DM1+AT and C rose in 120 and 180 min, while a similar increase was not seen in AT (p<0.000001); c) rT3 was not present in any group, with rT3 levels higher in AT (p<0.00002) and lower in DM1 (p<0.02); d) the response of GH had a paradoxical character in some patients in all groups, most often in DM1 (52 %, DM1 vs C, p <0.01). The characteristic response difference was not in the peak GH level, but the delayed return to basal levels in DM1 (p<0.0001) and an abrupt one in AT (p<0.0001). The major findings in DM1 were the differences in GH response, while significant impairment of pituitary-thyroid axis and PRL response to TRH was absent. AT was associated with impairment of TRH stimulated fT3, fT4, fT3/fT4 response and changes in rT3 levels, in spite of preserved TRH-stimulated TSH secretion. GH response in AT patients was also altered.

Fasting insulin pulsatile secretion in lean women with polycystic ovary syndrome.

The aim of our study was to evaluate rapid insulin pulses and insulin secretion regularity in fasting state in lean women with polycystic ovary syndrome (PCOS) in comparison to lean healthy women. PCOS (n=8) and controls (n=7) underwent every minute blood sampling for 60 min. Insulin pulsatility was assessed by deconvolution and insulin secretion regularity by approximate entropy methodology. PCOS had higher testosterone (p<0.02), prolactin (p<0.05) and lower sex hormone binding globulin (SHBG) (p<0.0006) levels than controls. Approximate entropy, insulin pulse frequency, mass, amplitude and interpulse interval did not differ between PCOS and controls. PCOS had broader insulin peaks determined by a common half-duration (p<0.07). Burst mass correlated positively with testosterone (p<0.05) and negatively with SHBG (p 0.0004) and common half-duration correlated positively with prolactin (p<0.008) and cortisol levels (p<0.03). Approximate entropy positively correlated with BMI (p<0.04) and prolactin (p<0.03). Lean PCOS patients tended to have broader insulin peaks in comparison to healthy controls. Prolactin, androgens and cortisol might participate in alteration of insulin secretion in PCOS-affected women. Body weight and prolactin levels could influence insulin secretion regularity.

PPARgamma2 Pro12Ala polymorphism in relation to free fatty acids concentration and composition in lean healthy Czech individuals with and without family history of diabetes type 2.

Free fatty acids (FFAs) are natural ligands of the PPARgamma2 receptor. FFA plasma concentration and composition may represent one of the factors accounting for high heterogeneity of conclusions concerning the effect of the Pro12Ala on BMI, insulin sensitivity or diabetes type 2 (DM2) susceptibility. Our objective was to investigate the relation and possible interactions between the Pro12Ala polymorphism and FFA status, metabolic markers, and body composition in 324 lean nondiabetic subjects (M/F: 99/225; age 32+/-11 years; BMI 23.9+/-4.0 kg/m(2)) with and without family history of DM2. Family history of DM2 was associated with lower % PUFA and slightly higher % MUFA. The presence of Pro12Ala polymorphism was not associated with fasting plasma FFA concentration or composition, anthropometric or metabolic markers of glucose and lipid metabolism in tested population. However, the interaction of carriership status with FFA levels influenced the basal glucose levels, insulin sensitivity and disposition indices, triglycerides, HDL-cholesterol and leptin levels, especially in women. The metabolic effects of 12Ala carriership were influenced by FFA levels - the beneficial role of 12Ala was seen only in the presence of low concentration of plasma FFA. Surprisingly, a high PUFA/SFA ratio was associated with lower insulin sensitivity, the protective effect of 12Ala allele was apparent in subjects with family history of DM2. On the basis of our findings and published data we recommend the genotyping of diabetic patients for Pro12Ala polymorphism of the PPARgamma2 gene before treatment with thiazolidinediones and education of subjects regarding diet and physical activity, which modulate metabolic outcomes.

Dehydroepiandrosterone in relation to adiposity, glucose tolerance and lipid spectra in Czech non-diabetic population.

This study aimed to examine relationships between DHEA(S), anthropometric parameters, oral glucose tolerance test derived data and lipid spectra in a Czech non-diabetic population. 380 healthy volunteers both with and without a family history of diabetes type 2 (DM2) were enrolled into the study (women: n=235, age 28.9+/-9.4 years, BMI 22.3+/-4.5 kg/m(2), men: n=145, age 32.3+/-10.0 years, BMI 24.7+/-3.6 kg/m(2)). Spearman's correlations (both without and with the adjustment for age, age and BMI), as well as ANCOVA were used. Non-adjusted data showed many "beneficial" correlations between DHEA(S) and both anthropometric and metabolic variables. Statistical analysis revealed that almost all correlations of DHEA(S) to adiposity and fat distribution in men as well as in women disappeared after the adjustment. There are, however, differences between men and women in the correlation of DHEA(S) to insulin sensitivity and lipid levels. The use of hormonal contraceptives (COC) is also an important factor in this relationship. In men and also in women using COC, DHEA-S after adjustment correlated positively with fasting and stimulated glucose, insulin and C-peptide, and negatively with insulin sensitivity. In this respect, the benefit of DHEA(S) supplementation seems -- at least in terms of its alleged antiobesity and antidiabetogenic effects -- to be more than controversial.

Family history of diabetes mellitus determines insulin sensitivity and beta cell function in polycystic ovary syndrome.

OBJECTIVE: To examine the impact of family history of diabetes mellitus 2 (DM 2) on insulin sensitivity and secretion in lean women with polycystic ovary syndrome (PCOS). Thirteen healthy women (C), 14 PCOS without family history of DM 2 (FH-) and 8 PCOS with family history of DM 2 (FH+) were examined using euglycemic hyperinsulinemic clamp and an arginine secretion test (insulin and glucagon at fasting glycemia (AIR(FG) and AGR(FG)) and at hyperglycemia (AIR(14) and AGR(14)). FH+ women were more insulin resistant than FH- with lower insulin sensitivity index corrected per lean body mass (p 0.05). They had significantly higher triglycerides (p 0.05) and lower HDL-cholesterol (p 0.05) than C or FH- women. Concerning insulin secretion, AIR(FG) was increased in FH+ women comparing FH- women (p 0.05). Disposition indices derived from AIR(FG) or AIR(14) and insulin sensitivity index did not differ between FH+ or FH-. Thus, women with PCOS with the concomitant family history of DM 2 have lower insulin sensitivity than healthy control women. Insulin resistance observed in these women with PCOS is compensated by increased insulin secretion.

[Autoimmune polyglandular syndromes: clinical aspects]. / Autoimunitní polyglandulární syndromy: klinické aspekty.

The history of autoimmune polyglandular syndromes (APS) and the basic characteristics of types 1 and 2 are briefly introduced. The clinical aspects of the more common type 2 are discussed in more detail from the point of view of the endocrinological and diabetological practice. The diagnosis aspects of preclinical, subclinical and manifestation stage of the main diseases occurring along with APS are briefly mentioned as well as the treatments and their challenges cause by the combination of various endocrine and non-endocrine autoimmune diseases. It is emphasized that care for there patients is a life-long process and that the health condition of these patients is usually very complicated. In some cases the combination of various disease conditions can make these patients completely disabled.

Weight, body composition and fat distribution of Czech women in relation with reproductive phase: a cross-sectional study.

A sample of 213 healthy Czech women was classified into four groups according to their reproductive phase: fully reproductive, premenopausal, menopausal and postmenopausal women. Changes in body weight, body composition and fat distribution were studied in those four groups using the classical anthropometric method. Body weight rises till the menopause with no further increase. A decrease in relative contribution of muscle and bone mass was observed. The progressive increase in fat mass with age was clearly demonstrated, both the fat mass weight (r = 0.38, p < 0.001) and its percentage contribution (Matiegka r = 0.40, p < 0.001, Parízkovi r = 0.42, p < 0.001). There is a stronger correlation of central fat indices as WHR (r = 0.57, p < 0.001), abdominal (r=0.56, p < 0.001) and waist circumference (r = 0.50, p < 0.001) than for hip circumference (r = 0.27, p < 0.001) to the age. WHR and waist increase most when fully reproductive and premenopausal women were compared (p < 0.001); less when premenopausal to menopausal women are compared (NS) and the least when menopausal to postmenopausal women were compared (NS). The mean values of 14 skinfolds thickness are shown, the skinfold at the abdomen shows the strongest correlation to the age (r = 0.49, p < 0.001). The results are consistent with the hypothesis of progressive fat centralisation.

The UCP1 gene polymorphism A-3826G in relation to DM2 and body composition in Czech population.

UNLABELLED: Mitochondrial uncoupling contributes to the control of energy expenditure. The brown fat specific uncoupling protein 1 (UCP1) mRNA was detected in intraperitoneal and extraperitoneal adipose tissue in adult humans. The A-3826G polymorphism in the UCP1 gene promoter region was found to be associated with reduced mRNA expression indicating that the polymorphism is of functional importance. OBJECTIVE: To determine allelic frequencies and genotypic distribution of the A-3826G polymorphism and to study its possible association with anthropometric parameters and biochemical markers of glucose and lipid metabolism in type 2 diabetes mellitus (DM2) patients (n=295), in offspring of DM2 patients (n=113), and in healthy adults without family history of DM2 (n=120). RESULTS AND DISCUSSION: In the whole cohort of 528 subjects, the G allele was observed with a frequency of 0.26. Genotypic distribution did not differ between diabetics and controls. However, in the offspring of DM2 patients, significantly higher BMI and a trend towards higher waist to hip ratio, waist to height ratio, waist circumference, and subcutaneous fat mass was observed in the AG genotype compared with the wild-type. Similar tendency was evident in the control group. This indicates possible involvement of the A-3826G polymorphism in the regulation of body composition.