Dehydroepiandrosterone (DHEA) and aging

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid hormone in humans and can readily be converted to its parent steroid DHEA by tissue sulfatases. Yet, a biologic function for these steroids has not been defined. The link between DHEA and aging has been raised by: (1) its well documented age-related decline, and (2) a preventive effect of DHEA on numerous age-related illnesses: ischemic heart-disease, cognitive impairment, immunodeficiency, malignancies, osteoporosis. These effects have been suggested by epidemiological studies in humans. Animal studies support a protective effect of DHEA on these age-related diseases. However, it remains unknown whether these results in animals can be transposed in humans, because adrenal secretion of DHEA seems to be particular to primates. In humans, only a few studies have been performed. The effects of oral supplementation with DHEA have, so far, focused on the possible metabolic effects of DHEA. A few studies have shown: the absence of any side-effects; no change in body-weight; conflicting results on body-composition and lipids and no effect on insulin-tolerance. The latest study showed a beneficial effect on well-being but these results need to be confirmed.     

Dehydroepiandrosterone (DHEA) and systemic lupus erythematosus

Objective:

This study was performed to evaluate in vivo and in vitro dataon the effects of the adrenal steroid dehydroepiandrosterone (DHEA) with emphasis on its potential use in the treatment of systemic lupus erythematosus (SLE).

Methods:

The literature dealing with DHEA was reviewed.

Results:

Initially, research on DHEA focused on effects of DHEA in relation to obesity. Over the past decade, research stimulated by associations between the physiological decline in DHEA and aging, cardiovascular disease, changes in metabolism, brain function, and immune senescense have generated insight into the many effects that DHEA or its metabolites may have. In SLE a role for sex hormones in both the etiopathogenesis and disease activity is recognized. In SLE, as in aging, low DHEA levels are frequently found, especially with corticosteroid treatment.

Conclusions:

Research data in the elderly, on both hormonal and immunologiceffects, suggest that DHEA may become an adjunctive treatment for SLE patients.     

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg/kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca2+-activated potassium channel (BKCa)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.     

Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).     

Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT(1A), AT(1B) and AT(2) receptors

Angiotensin II (Ang II) AT(1) receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT(1A) mRNA in paraventricular nucleus. Repeated restraint increased AT(1A) mRNA and AT(1) binding in paraventricular nucleus and AT(1) binding in subfornical organ and median eminence. AT(1B) and AT(2) receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT(1A) mRNA and AT(1) binding and decreased AT(1B) mRNA. During repeated restraint, the increase in AT(1A) mRNA in the anterior pituitary was maintained, but AT(1B) mRNA and AT(1) binding returned to normal levels. In adrenal zona glomerulosa, AT(1B) mRNA, AT(1) binding, AT(2) mRNA and AT(2) binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT(2) mRNA. In adrenal medulla, AT(1A) mRNA increased and AT(2) mRNA decreased during acute restraint. AT(1A) mRNA remained increased during repeated restraint, while alterations in AT(2) mRNA were no longer present. Expression of AT(1A), AT(1B) and AT(2) receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT(1A) receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT(1A) receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT(1B) receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT(2) receptors during acute stress, possibly related to interaction or cross-talk with AT(1) receptors.     

Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans

Plasma dehydroepiandrosterone (DHEA) decreases ~80% between ages 25 and 75 yr. In a preliminary study, we found that 6 mo of DHEA replacement improved insulin action in elderly individuals. The purpose of the present larger, randomized double-blind study was to determine whether a longer period of DHEA replacement improves glucose tolerance. Fifty-seven men and 68 women aged 65 to 75 yr were randomly assigned to 50 mg DHEA or placebo once daily. Year one was a randomized, double blind trial. Year 2 was an open label continuation. DHEA replacement improved glucose tolerance in participants who had abnormal GT initially, reduced plasma triglycerides, and the inflammatory cytokines IL6 and TNFα.     

Dehydroepiandrosterone (DHEA) effects on HIV replication and host immunity: a randomized placebo-controlled study

Prior studies have indicated that dehydroepiandrosterone (DHEA) may have immunomodulatory properties as well as positive effects on mood, quality of life, and body composition. Preliminary data suggest that DHEA inhibits expression of human immunodeficiency virus 1 (HIV) in latently infected cells; thus, it might be a potential adjunct to currently available antiretroviral therapy. The objective was to determine DHEA's impact on latent HIV infection, persistent viral replication, immunity, and nonimmune aspects of health restoration. A randomized, double-blind, placebo-controlled 24-week outpatient intervention included 40 subjects with suppressed HIV viremia on a stable antiretroviral regimen. Participants were randomized with equal probability to receive either DHEA or placebo for 12 weeks, followed by open-label DHEA for an additional 12 weeks. Intensive virologic monitoring included plasma viral load assays (lower limits of detection 50 copies/ml and 2.5 copies/ml) and quantitative cultures of replication-competent virus reservoirs in blood cells. A full battery of immunologic measurements was performed. Measurements of hormones, body weight, and body composition were obtained. Quality of life was assessed using validated questionnaires. DHEA was bioavailable as ascertained by increased levels of DHEA, DHEA(S), and androstenedione in recipients' plasma compared to the control group. The titers of infectious HIV culturable from blood trended upward in the DHEA arm although there was no significant change in plasma HIV RNA level. No significant immune effects were observed with DHEA. There appeared to be no benefit with regard to lean muscle mass or bone density in the DHEA recipients. DHEA treatment had a positive impact on overall quality of life. DHEA supplementation in fully suppressed HIV patients was associated with an improvement in quality of life but appeared to have no beneficial antiviral, immunomodulatory, hormonal, or body composition effects, suggesting that it not be routinely used as an adjunctive therapy in this population.     

Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study

ObjectivesIt was previously shown that dehydroepiandrosterone (DHEA) reverses chronic hypoxia-induced pulmonary hypertension (PH) in rats, but whether DHEA can improve the clinical and hemodynamic status of patients with PH associated to chronic obstructive pulmonary disease (PH-COPD) has not been studied whereas it is a very severe poorly treated disease.Patients and methodsEight patients with PH-COPD were treated with DHEA (200 mg daily orally) for 3 months. The primary end-point was the change in the 6-minute walk test (6-MWT) distance. Secondary end-points included pulmonary hemodynamics, lung function tests and tolerance of treatment.ResultsThe 6-MWT increased in all cases, from 333 m (median [IQR]) (257; 378) to 390 m (362; 440) (P < 0.05). Mean pulmonary artery pressure decreased from 26 mmHg (25; 27) to 21.5 mmHg (20; 25) (P < 0.05) and pulmonary vascular resistance from 4.2 UI (3.5; 4.4) to 2.6 UI (2.5; 3.8) (P < 0.05). The carbon monoxide diffusing capacity of the lung (DLCO % predicted) increased significantly from 27.4% (20.1; 29.3) to 36.4% (14.6; 39.6) (P < 0.05). DHEA treatment did not change respiratory parameters of gas exchange and the 200 mg per day of DHEA used was perfectly tolerated with no side effect reported.ConclusionDHEA treatment significantly improves 6-MWT distance, pulmonary hemodynamics and DLCO of patients with PH-COPD, without worsening gas exchange, as do other pharmacological treatments of PH (trial registration NCT00581087).     

Growth Hormone Releasing Hormone (GHRH) and the GHRH Receptor

Reviews in Endocrine and Metabolic Disorders -     

Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement

OBJECTIVE: GH dose requirement is lower in ACTH replete compared with ACTH deficient hypopituitary patients suggesting that adrenal androgens may augment IGF-I generation for a given GH dose. This study aimed to determine the effect of dehydroepiandrosterone (DHEA) administration on GH dose requirements in hypopituitary adults. DESIGN: A double blind placebo controlled trial was conducted adding 50 mg DHEA to the standard replacement of hypopituitary patients, including GH, over an initial 6 months, followed by an open phase study of 6 months DHEA replacement and a final 2 month washout phase after DHEA withdrawal. The dose of GH was adjusted to achieve a constant serum IGF-I. PATIENTS: Thirty female and 21 male hypopituitary patients were enrolled. Data from 26 women and 18 men were analysed after patient withdrawal. MEASUREMENTS: The primary outcome objective was the GH dose required to achieve a stable serum IGF-I. Secondary outcome measures were lipoprotein profiles, insulin, insulin sensitivity, IGFBP-3, waist/hip ratio and indices of bone remodelling. RESULTS: DHEA replacement in female patients lead to a 14.6 +/- 20% reduction in the dose of GH for a constant serum IGF-I (P < 0.05, 95% CI: 1.8, 32.7). This was maintained for 12 months and there was a significant fall in serum IGF-I two months after withdrawal of DHEA. There was no change in the male group. CONCLUSIONS: DHEA replacement may reduce GH dose requirements in female hypopituitary patients.     

The somatostatin analogue octreotide modulates Iodothyronine deiodinase activity and pituitary neuromedin B.

Somatostatin inhibits growth hormone and thyrotropin (TSH) secretion. It also enhances the inhibitory effect of thyroid hormone (TH) on TSH by poorly understood mechanisms. We investigated the acute effect of the long-acting somatostatin analogue, octreotide (OCT), on anterior pituitary type 1 (D1) and 2 (D2) deiodinase activity, on liver D1, and on pituitary content of neuromedin B (NB), an autocrine inhibitor of TSH secretion, which is positively regulated by thyroid hormones. Euthyroid or hypothyroid rats were sacrificed at different times after a single subcutaneous injection of OCT (1 microg/kg body weight [BW]). D1 and D2 activities were measured by the release of 125I from 125I reverse triiodothyronine (rT3) under different assay conditions. NB, TSH, T3, and thyroxine (T4) were quantitated by radioimmunoassay (RIA). In euthyroid rats, liver and pituitary D1 activities were decreased (50%) 6 hours after OCT injection; pituitary D2 and NB remained unchanged. In hypothyroid rats, OCT increased near to the level of normal rats both pituitary D1 activity (but not liver) and NB content, at 24 hours and at 6 and 24 hours, respectively (p < 0.05). Pituitary D2, greatly increased by hypothyroidism, showed a small (25%) but significant reduction at 3 hours, persisting at 24 hours (p < 0.01), although it remained higher than that of euthyroid control. Serum thyroid hormones were not affected by OCT injection. The results show that octreotide acutely regulates pituitary deiodinases and NB content, both representing mechanisms that potentially can contribute to somatostatin and octreotide actions on pituitary growth hormone (GH) and TSH secretion and to modulate these cells sensitivity to thyroid hormone action.     

Growth hormone (GH)-releasing hormone (GHRH) and the GH secretagogue (GHS), L692,585, differentially modulate rat pituitary GHS receptor and GHRH receptor messenger ribonucleic acid levels.

The ability of synthetic GH secretagogues (GHSs) to elicit a maximal release of GH in vivo is dependent on an intact GH-releasing hormone (GHRH) signaling system. The role of GHRH in GHS-induced GH release has been attributed primarily to the ability of GHS to release GHRH from hypothalamic neurons. However, GHS also releases GH directly at the pituitary level. Several lines of evidence suggest that GHRH is necessary to maintain pituitary responsiveness to GHS by stimulating GHS receptor (GHS-R) synthesis. To test this hypothesis, male rats (250-290 g) were anesthetized with ketamine/xylazine (which does not alter pulsatile GH secretion) and infused i.v. with a GHRH analog ([des-NH2Tyr1,D-Ala15]hGRF-(1-29)-NH2; 10 microg/h) or saline for 4 h. Serum was analyzed for GH, pituitaries were collected, and GHS-R and GHRH receptor (GHRH-R) messenger RNA (mRNA) levels were determined by RT-PCR. GHRH infusion resulted in a 10-fold increase in circulating GH concentrations that were accompanied by an increase in GHS-R mRNA levels to 200% of those in saline-treated controls (P < 0.01). In contrast, GHRH reduced GHRH-R mRNA levels slightly, but not significantly (P < 0.07). The stimulatory effect of GHRH on GHS-R mRNA levels was independent of somatostatin tone, as pretreatment with somatostatin antiserum did not alter the effectiveness of GHRH infusion. In contrast, blockade of somatostatin actions up-regulated GHRH-R mRNA levels under basal conditions and unmasked the inhibitory effects GHRH on its own receptor mRNA. These observations suggest GHRH-R mRNA is tonically suppressed by somatostatin. The stimulatory effect of GHRH on GHS-R mRNA levels was independent of circulating GH, as GHRH infusion in spontaneous dwarf rats, which do not have immunodetectable GH, increased GHS-R mRNA levels to 150% of those in saline-treated controls (P < 0.05). To determine whether this effect occurred by a direct action on the pituitary, primary cell cultures from normal rat pituitaries were incubated with GHRH (0.01-10 nM) or forskolin (10 microM) for 4 h. These GH secretagogues did not alter GHS-R mRNA levels in vitro. However, GHRH and forskolin reduced GHRH-R mRNA levels by 40% (P < 0.05). To determine whether the synthesis of the GHS-R, like that of the GHRH-R, is negatively mediated by its own ligand, anesthetized rats were infused with the nonpeptidyl secretagogue, L-692,585 (100 microg/h) for 4 h. Neither circulating GH (at 4 h) nor GHRH-R mRNA levels were significantly altered by L-692,585, whereas GHS-R mRNA levels were reduced by 50% (P < 0.05). Taken together, these results indicate that GHRH-induced up-regulation of pituitary GHS-R synthesis in vivo is indirect and independent of both somatostatin and GH. They also demonstrate that GHS-R synthesis, like that of GHRH-R, can be rapidly down-regulated by its own ligand.     

Restoration of growth hormone-releasing hormone (GHRH) responsiveness in pituitary GH3 cells by adenovirus-directed expression of the human GHRH receptor

GH-secreting GH3 cells lack GH-releasing hormone (GHRH) receptors. In this study we used adenoviral vectors to transfer the human GHRH receptor to GH3 cells in an effort to restore GHRH responsiveness. A replication-deficient recombinant adenovirus (AdGHRH-R) was designed to allow cytomegalovirus promoter-driven expression of the GHRH receptor messenger RNA. COS-7 cells and GH-producing GH3 cells infected with AdGHRH-R showed GHRH receptor expression on their membranes and exhibited specific GHRH binding. The addition of GHRH to GH3 cells infected with AdGHRH-R increased cAMP levels, induced cAMP response element-binding protein phosphorylation and restored GH secretory responsiveness. GHRH treatment also caused activation of mitogen-activated-protein kinase, induction of c-fos, stimulation of GH promotor activity, and increased cellular proliferation. These findings indicate that adenoviral vectors carrying human GHRH receptor are useful for in vitro studies of GHRH receptor biology and represent a first step toward the development of gene therapy for dwarfism caused by GHRH receptor mutations.     

Estradiol reduces pituitary responsiveness to somatostatin (SRIF-14) and down-regulates the expression of somatostatin sst2 receptors in female goldfish pituitary

Sex steroid hormones have been shown to regulate somatostatin (SRIF) gene expression in goldfish brain, which in turn influences the regulation of GH secretion. In this study, the influences of sex steroids on pituitary responsiveness to SRIF-14 and the pituitary expression of a type two SRIF receptor (sst(2)) were examined. Results from in vitro perifusion of pituitary fragments show that pituitaries from estradiol-primed sexually regressed female fish have significantly lower GH release responsiveness to pulse exposure to SRIF-14 than pituitaries from control or testosterone-treated sexually regressed females. Results from in vitro static culture show that pituitaries from sexually mature female fish have lower GH release responsiveness to SRIF-14 than those from sexually regressed females. In addition, the sst(2) receptor mRNA levels in pituitaries from mature and recrudescent female fish are significantly lower than in sexually regressed female fish. Our results indicate that estradiol acts at the level of the pituitary to regulate GH secretion by influencing the responsiveness to SRIF-14. The underlying mechanism includes, in part, reduction of the expression of sst(2) receptors, presumably leading to the lower number of the receptors available for SRIF binding.