Effects of the thymic peptide thymulin on in vitro and in vivo testicular steroid concentrations in white composite and Meishan boars.
(17/967)
Immuno-peptides may have positive or negative effects on gonadal steroidogenesis, but few have been tested outside of rodent species or in vivo. In Exp. 1, thymulin, a secreted nonapeptide of the thymus, was incubated (1, 10, 100, or 1,000 ng/mL) with testicular minces (sampled at 3, 6, or 12 h) from Chinese Meishan boars of high gonadotropin/testicular steroidogenic function (n = 8) and White composite boars of European origin (n = 8 ) to test the hypothesis that thymulin could augment hCG stimulation of testicular androgen concentrations. Thymulin alone had few effects on androgen concentrations (testosterone, dehydroepiandrosterone+dehydroepiandrosterone sulfate [DHEA+DHEASO4]) in Meishan boar testicular incubates. In minces from White composites incubated with thymulin, testosterone concentrations were generally below control values (P<.05), but DHEA+DHEASO4 concentrations were unaffected. Thymulin had no effect on estrone concentrations in testicular incubates of White composite boars but stimulated estrone concentrations in Meishan testicular incubates. Thymulin plus hCG increased testosterone (3 and 6 h of incubation; P<.05) but not DHEA+DHEASO4 concentrations in White composite testicular incubates. Thymulin plus hCG did not alter androgen or estrogen concentrations from control values in Meishan testicular incubates. In Exp.2 with a protocol similar to that of Exp. 1 for testicular minces from White composite boars (n = 30), thymulin increased testosterone concentrations during the early incubation period (1 to 3 h; P<.05) and depressed testosterone concentrations at later times (6 h; P<.05). Thymulin synergized with hCG in stimulating increases in testosterone and DHEA+DHEASO4 concentrations (P<.05) but had no effect on estrone concentrations in vitro. Thymulin was tested in vivo in boars from three genetic lines selected for high, medium, or normal circulating LH concentrations (Meishan, select White composites, and control White composites, respectively). Injection of thymulin i.v. (4.4, 44.4, or 444.4 ng/kg BW) generally increased circulating testosterone concentrations (2 to 3 h later; P<.01), but the response was dependent on the boar's general circulating LH concentrations and dose of thymulin. Overall results from these studies support the hypothesis of a thymulin augmentation of LH stimulation of androgen increases in vitro and in vivo in the testis of boars. (+info)
The influence of age and gender on serum dehydroepiandrosterone sulphate (DHEA-S), IL-6, IL-6 soluble receptor (IL-6 sR) and transforming growth factor beta 1 (TGF-beta1) levels in normal healthy blood donors.
(18/967)
Dysregulation of IL-6 synthesis is thought to play a role in the development of a number of age-related conditions, such as rheumatoid arthritis, osteoporosis, atherosclerosis, Alzheimer's disease and B cell malignancies. Recently it has been suggested that the production of IL-6 is influenced by the adrenal hormone dehydroepiandrosterone (DHEA) and its sulphated derivative DHEA-S. In humans we investigated the relationship between DHEA-S, IL-6, IL-6 sR and TGF-beta1 in the serum of normal healthy male and female blood donors. Using immunoassay techniques we found that the serum levels of DHEA-S significantly (P = 0.0001) decreased with age in both males and females. Furthermore, mean DHEA-S levels in all age groups were significantly (P = 0.0001) higher in males. Such correlations were not apparent for IL-6 using a standard assay, but a high sensitivity assay revealed that serum IL-6 was significantly (P = 0.0018) positively correlated with age in males only. In addition, serum levels of DHEA-S were significantly (P = 0.048) negatively correlated with serum IL-6, again in male subjects only. In contrast, serum IL-6 sR and TGF-beta1 levels were not correlated with age in either males or females and were not significantly different between the sexes. However, a significant (P = 0.024) negative correlation between DHEA-S and IL-6 sR was found in males. These studies clearly highlight the complex nature of the relationship between these molecules in the ageing process in normal healthy blood donors and demonstrate the need to use high sensitivity assays when measuring IL-6 in apparently healthy individuals under the age of 70 years. (+info)
Apparent activities of 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase are impaired in adrenal incidentalomas.
(19/967)
OBJECTIVE: An increased response of 17-hydroxyprogesterone to ACTH stimulation has been observed in adrenal incidentaloma and linked to an impairment of either 21-hydroxylase or of 11beta-hydroxylase activity. To analyse this question further, we investigated the steroidogenic pathways in a series of 17 adrenal incidentalomas. DESIGN AND PATIENTS: 17 patients (7 women, 10 men; mean age, 62 +/- 12 years) with non-histologically analyzed adrenal incidentalomas were prospectively evaluated. METHODS: The following variables were investigated: 24-h urinary methanephrines and free cortisol excretion; plasma levels of ACTH and dehydroepiandrosterone; overnight dexamethasone suppression test; 1-24 ACTH stimulation test with measurement of: cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, 11-deoxycorticosterone, progesterone, 17-hydroxypregnenolone, Delta4-androstenedione, dehydroepiandrosterone and 21-deoxycortisol. RESULTS: Discordant features of subclinical hypercorticism were noted in one case. No patient had dehydroepiandrosterone sulfate levels in the normal range for his or her age. Peak 17-hydroxyprogesterone and peak 21-deoxycortisol disclosed impairment of 21-hydroxylase in 11 and 10 cases respectively. An increased 11-deoxycortisol/cortisol ratio identified reduced activity of 11beta-hydroxylase in 11 patients. Eight patients displayed features of mild 17,20-lyase impairment, which was related to 21-hydroxylase dysfunction. Whereas only 2 patients showed no enzyme modification, 9 displayed alterations of at least two pathways. CONCLUSION: In our hands, a combination of enzyme dysfunction was frequently observed. Shared biochemical mechanisms could explain combined 17,20-lyase and 21-hydroxylase alterations, whereas coexistence of 21-hydroxylase (particularly when based on peak 21-deoxycortisol) and 11beta-hydroxylase is more puzzling. (+info)
Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis.
(20/967)
OBJECTIVE: To examine the possibility that lower serum bioavailable testosterone concentrations, without increased LH release, in healthy older men, reflects hypothalamic GnRH deficiency. DESIGN: We used a randomized, double-blind, placebo-controlled design. METHODS: We treated each of five young (ages 20-34 years) and five older (ages 60-78 years) men with 2 weeks of randomized infusions of saline or pulsatile GnRH (100 ng/kg i.v. every 90 min). RESULTS: At baseline (saline infusion), older men had more LH pulses (young compared with old, 10 +/- 0.6 compared with 15 +/- 1, P = 0.0026) per 24h, reduced fractional LH pulse amplitude (219 +/- 17% compared with 167 +/- 40%, P = 0.0376), and more disorderly hormone release as judged by approximate entropy (ApEn) (LH, P < or = 0.0001; testosterone, P < or = 0.0047). In response to pulsatile i.v. GnRH infusions, serum 24-h LH concentrations (measured by immunoradiometric assay (IRMA)), increased equivalently in young and older men (to 7.3 +/- 1.2 and 7.2 +/- 1.8 IU/l respectively). GnRH treatment also normalized LH pulse frequency and amplitude, ApEn, and plasma biologically active LH (pooled) concentrations. In contrast, 24-h testosterone concentrations failed to increase equivalently in older men (young compared with old, 869 +/- 88 compared with 517 +/- 38 ng/dl, P = 0.0061), reflecting lower testosterone peak maxima (995 +/- 108 compared with 583 +/- 48 ng/dl, P = 0.0083) and interpeak nadirs (750 +/- 87 compared with 427 +/- 26 ng/dl, P = 0.0073). CONCLUSIONS: We have demonstrated that, in older men, successful reconstitution of 24-h pituitary (bioactive) LH output and pulsatile (IRMA) LH release patterns could be achieved by a fixed exogenous GnRH pulse signal, thereby implicating altered endogenous hypothalamic GnRH release in the relative hypogonadotropism of aging. The failure of testosterone concentrations to increase concomitantly points to a simultaneous Leydig cell defect. We conclude that aging in men is marked by a dual defect in the central nervous system-pituitary-Leydig cell axis. (+info)
Racial differences in the correlation between gonadal androgens and serum insulin levels.
(21/967)
OBJECTIVE: We previously demonstrated a direct correlation between serum insulin levels and gonadal androgens (testosterone and androstenedione) in a group of obese hyperandrogenic predominantly black women. Subsequent work by others in predominantly white women showed conflicting results. To examine these potentially important racial differences further, 14 premenopausal females from each ethnic group, of similar age, BMI, and waist-to-hip ratio, were studied. RESEARCH DESIGN AND METHODS: We measured baseline gonadal androgens, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and leutinizing hormone (LH)/follicle-stimulating hormone ratio. Serum glucose, insulin, and C-peptide were measured at baseline and during a 2-h oral glucose tolerance test (area under the curve [AUC]). Insulin sensitivity was measured by glucose decrement during the first 15 min of an intravenous insulin tolerance test. RESULTS: Simple correlation analysis revealed a significant direct correlation in blacks (but not whites) between gonadal androgens and AUC for glucose, insulin, and C-peptide. Race-by-covariate interaction models reinforced the simple correlation finding. Cholesterol level was also correlated to all androgens in blacks, but not in whites. We also found that whites had higher serum triglycerides and greater AUC glucose than blacks. CONCLUSIONS: We conclude that there is a significant direct correlation between gonadal androgens and stimulated glucose, insulin, and C-peptide in blacks but not in whites. Thus, the previously reported direct correlation between gonadal hyperandrogenism and hyperinsulinemia may be a race-dependent phenomenon, hitherto an unreported observation. The implications of these findings are discussed. (+info)
1. Sigma (sigma) receptors have recently been cloned, though their endogenous ligand(s) remain unidentified. However, some neuroactive steroids, such as progesterone, have a high affinity for these receptors. Some sigma ligands, such as DTG, (+)-pentazocine and DHEA, act as sigma 'agonists' by potentiating the neuronal response to NMDA. Others, such as haloperidol, NE-100 and progesterone, act as sigma 'antagonists' by reversing the potentiations induced by sigma 'agonists'. 2. We compared the effects of sigma 'agonists' in four series of female rats: in controls, at day 18 of pregnancy, at day 5 post-partum, and in ovariectomized rats following a 3-week treatment with a high dose of progesterone. 3. In pregnant rats and following a 3-week treatment with progesterone, 10 fold higher doses of DTG, (+)-pentazocine and DHEA were required to elicit a selective potentiation of the NMDA response comparable to that obtained in control females. Conversely, at day 5 post-partum and following the 3-week treatment with a progesterone and after a 5-day washout, the potentiation of the NMDA response induced by the sigma 'agonist' DTG was greater than in control females. 4. The present data suggest that endogenous progesterone acts as an 'antagonist' at sigma receptors. The resulting changes in the function of sigma receptors during pregnancy and post-partum may be implicated in emotional phenomena occurring during these periods. (+info)
DHEA deficiency syndrome: a new term for old age?
(23/967)
Dehydroepiandrosterone (DHEA) is a steroid secreted by the adrenal cortex, with a characteristic, age-related, pattern of secretion. The decline of DHEA concentrations with age has led to the suggestion that old age represents a DHEA deficiency syndrome and that the effects of ageing can be counteracted by DHEA 'replacement therapy'. DHEA is increasingly being used in the USA, outside medical supervision, for its supposed anti-ageing effects. This commentary weighs the evidence for the existence of a DHEA deficiency syndrome and considers the value of DHEA 'replacement therapy'. (+info)
Suppression of Delta(5)-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells.
(24/967)
Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-Adiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-diol; no. 6, 17alpha-ethynyl-androstene-diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the Adiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the Adiol-induced AR transactivation. Reporter assays further showed that these four anti-Adiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-Adiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth. (+info)