Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.

Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A subgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.

Morales AJ ，Nolan JJ ，Nelson JC ，Yen SS ... -  《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》

Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women.

Attenuation of the GH and insulin-like growth factor I (IGF-I) axis in aging may be responsible for changes in body composition and metabolism. This relationship has been confirmed by studies of recombinant human GH replacement in aging men and women, but the adverse effects encountered limit its clinical utility. The use of GHRH or its analogs may be an alternative mode for restoring the GH-IGF-I axis in aging individuals. Here we report the endocrine-metabolic changes in response to a GHRH analog in age-advanced men and women. A single blind, randomized, placebo-controlled trial of 5 months duration was conducted. Ten women and 9 men between the ages of 55-71 yr self-injected placebo (saline) s.c. nightly for 4 weeks followed by 16 weeks of [Nle27]GHRH-(1-29)-NH2 at a dose of 10 microg/kg. Subjects underwent 12-h nocturnal (2000-0800 h) frequent blood sampling (10-min intervals) and 24-h urine collection at baseline, after 4 weeks of placebo injections, and after 16 weeks of GHRH analog administration. GH responses to GHRH analog and spontaneous GH pulsatility were assessed. Subjects were also monitored 2, 4, 8, and 12 weeks after commencement of GHRH analog treatment. Blood pressure, body weight, and fasting insulin and glucose levels were recorded at each visit. Serum concentrations of IGF-I, IGF binding protein-1 (IGFBP-1), IGFBP-3, GH-binding protein (GHBP), lipids, and safety laboratory tests (complete blood count and chemistry profile) were measured in fasting samples (0800-0900 h). Body composition was determined by dual energy x-ray absorptiometry scan, and skin thickness was measured at four sites, including the right and left hand and volar forearm, by Harpenden skin calipers. Insulin sensitivity was assessed by a frequently sampled i.v. glucose tolerance test. Quality of life parameters, including sleep, were evaluated through self-administered questionnaires. Nightly GHRH analog administration at 2100 h induced, within 10 min, an acute release of GH, which lasted for 2 h. The GH-releasing effect of GHRH analog was sustained during the course of the study. Compared with placebo, GHRH analog induced a significant increase in 12-h integrated nocturnal GH levels in women (P < 0.01) and men (P < 0.05). This was accompanied, within 2 weeks, by increased serum levels of IGF-I (P < 0.05) and IGFBP-3 (P < 0.001), but not IGFBP-1, which remained elevated for 12 weeks, returning toward baseline by 16 weeks in both genders. Within 4 weeks, GHBP concentrations were significantly increased (P < 0.01) in women, but not in men. Although blood pressure and body weight were unaffected, GHRH analog treatment resulted in a significant increase in skin thickness (P < 0.05) in both genders and increased lean body mass in men only (P < 0.05), with no other changes in body composition or bone mineral density in either gender. There was a trend for a positive nitrogen balance in both genders, which became significant (P = 0.03) when the data were combined. Fasting insulin and glucose levels were unaltered, but a significant increase in insulin sensitivity occurred in men (P < 0.05), but not in women. Assessment of quality of life parameters revealed a significant improvement in general well-being (P < 0.05) and libido (P < 0.01) in men, but not in women, and sleep quality was unaffected in both genders. The only adverse side-effect was transient hyperlipidemia, which resolved by the end of the study. We conclude that nightly administration of GHRH analog for 4 months in age-advanced men and women activated the somatotropic axis. Although an increase in skin thickness was found in both genders, increases in lean body mass, insulin sensitivity, general well-being, and libido occurred in men but not in women. These observations suggest that GHRH analog administration induced anabolic effects favoring men more than women. Further studies are needed to define the gender differences observed in response to GHRH analog administration.

Khorram O ，Laughlin GA ，Yen SS 《JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM》

The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.

The biological role of the adrenal sex steroid precursors--DHEA and DHEA sulphate (DS) and their decline with ageing remains undefined. We observed previously that administration of a 50 daily dose of DHEA for 3 months to age-advanced men and women resulted in an elevation (10%) of serum levels of insulin-like growth factor-I (IGF-I) accompanied by improvement of self-reported physical and psychological well-being. These findings led us to assess the effect of a larger dose (100 mg) of DHEA for a longer duration (6 months) on circulating sex steroids, body composition (DEXA) and muscle strength (MedX). Healthy non-obese age-advanced (50-65 yrs of age) men (n = 9) and women (n = 10) were randomized into a double-blind placebo-controlled cross-over trial. Sixteen subjects completed the one-year study of six months of placebo and six months of 100 mg oral DHEA daily. Fasting early morning blood samples were obtained. Serum DHEA, DS, sex steroids, IGF-I, IGFBP-1, IGFBP-3, growth hormone binding protein (GHBP) levels and lipid profiles as well as body composition (by DEXA) and muscle strength (by MedX testing) were measured at baseline and after each treatment. Basal serum levels of DHEA, DS, androsternedione (A), testosterone (T) and dihydrotestosterone (DHT) were at or below the lower range of young adult levels. In both sexes, a 100 mg daily dose of DHEA restored serum DHEA levels to those of young adults and serum DS to levels at or slightly above the young adult range. Serum cortisol levels were unaltered, consequently the DS/cortisol ratio was increased to pubertal (10:1) levels. In women, but not in men, serum A, T and DHT were increased to levels above gender-specific young adult ranges. Basal SHBG levels were in the normal range for men and elevated in women, of whom 7 of 8 were on oestrogen replacement therapy. While on DHEA, serum SHBG levels declined with a greater (P < 0.02) response in women (-40 +/- 8%; P = 0.002) than in men (-5 +/- 4%; P = 0.02). Relative to baseline, DHEA administration resulted in an elevation of serum IGF-I levels in men (16 +/- 6%, P = 0.04) and in women (31 +/- 12%, P = 0.02). Serum levels of IGFBP-1 and IGFBP-3 were unaltered but GHBP levels declined in women (28 +/- 6%; P = 0.02) not in men. In men, but not in women, fat body mass decreased 1.0 +/- 0.4 kg (6.1 +/- 2.6%, P = 0.02) and knee muscle strength 15.0 +/- 3.3% (P = 0.02) as well as lumbar back strength 13.9 +/- 5.4% (P = 0.01) increased. In women, but not in men, an increase in total body mass of 1.4 +/- 0.4 kg (2.1 +/- 0.7%; P = 0.02) was noted. Neither gender had changes in basal metabolic rate, bone mineral density, urinary pyridinoline cross-links, fasting insulin, glucose, cortisol levels or lipid profiles. No significant adverse effects were observed. A daily oral 100 mg dose of DHEA for 6 months resulted in elevation of circulating DHEA and DS concentrations and the DS/cortisol ratio. Biotransformation to potent androgens near and slightly above the range of their younger counterparts occurred in women with no detectable change in men. Given this hormonal milieu, an increase in serum IGF-I levels was observed in both genders but dimorphic responses were evident in fat body mass and muscle strength in favour of men. These differences in response to DHEA administration may reflect a gender specific response to DHEA and/or the presence of confounding factor(s) in women such as oestrogen replacement therapy.

Morales AJ ，Haubrich RH ，Hwang JY ，Asakura H ，Yen SS ... -  《CLINICAL ENDOCRINOLOGY》

Dehydroepiandrosterone supplementation in women with adrenal failure: impact on twenty-four hour GH secretion and IGF-related parameters.

In women, GH secretion is strongly influenced by oestrogen status, whereas the role of androgens is unclear. We, therefore, examined GH secretory dynamics during low vs. normalized androgen levels in women with adrenal failure. Ten females with adrenal failure (AF), mean age of 42 years (range 22-54 years). The effects of 8 days of oral dehydroepiandrosterone (DHEA; 50 mg/day) were studied in a double-blind placebo-controlled, cross-over design. A control group of healthy women was studied once without any treatment. Before and after each treatment period, blood was sampled for measurement of androgens, IGF-I, IGFBP-3 and GHBP. A 24-h GH profile with measurements every 20 min was performed at the end of each period. DHEA supplementation normalized the mean circulating levels of testosterone and androgen precursors. The secretory pattern of GH was unaltered during DHEA [placebo vs. DHEA; half-life 22.83 +/- 1.24 vs. 21.45 +/- 1.19 (min), P = 0.429; pulse frequency 9.9 +/- 0.7 vs. 10.5 +/- 0.5 (/24 h), P = 0.502; total production rate 62.27 +/- 13.44 vs. 52.61 +/- 7.06 (microg/l/day), P = 0.317]. Subgroup analysis, however, indicated that DHEA treatment increased GH secretion in patients not receiving oestrogen (n = 5), whereas the opposite was observed among patients receiving exogenous oestrogen derivatives (n = 5). Compared to the control group (CON), GH half-life was longer in AF (half-life CON: 16.48 +/- 0.91, P = 0.001). The additional features of GH secretion were similar. Unexpectedly, the levels of IGF-I, IGFBP-3 and GHBP were elevated in the patients as compared to controls, without significant effects of DHEA [AF vs. CON. IGF-I: 186 +/- 20 vs. 144 +/- 7 (microg/l), P = 0.04; IGFBP-3: 5196 +/- 224 vs. 3687 +/- 212 (microg/l), P = 0.001; GHBP: 2.27 +/- 0.25 vs. 1.41 +/- 0.13 (nmol/l), P = 0.002]. (1) Short-term DHEA administration in women with adrenal failure normalizes the circulating levels of androgens without uniformly affecting the GH-IGF axis; (2) The observation that exogenous oestradiol may mask a stimulatory effect of DHEA on GH secretion merits future investigation.

Christiansen JJ ，Gravholt CH ，Fisker S ，Svenstrup B ，Bennett P ，Veldhuis J ，Andersen M ，Christiansen JS ，Jørgensen JO ... -  《CLINICAL ENDOCRINOLOGY》

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

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. 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. Thirty female and 21 male hypopituitary patients were enrolled. Data from 26 women and 18 men were analysed after patient withdrawal. 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. 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. DHEA replacement may reduce GH dose requirements in female hypopituitary patients.

Brooke AM ，Kalingag LA ，Miraki-Moud F ，Camacho-Hübner C ，Maher KT ，Walker DM ，Hinson JP ，Monson JP ... -  《CLINICAL ENDOCRINOLOGY》