Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche.

In 104 normal boys, aged 7 to 14 years (bone ages 5 to 15 years), plasma dehydroepiandrosterone (DHEA) rose from 52.7 at 7 years, to 112.0 ng/100 ml at 10 years. A further rise occurred at 12 years (188 ng/100 ml). In relation to the bone age, DHEA increased from a mean plasma level of 31.1 at a bone age of 5 years to 77.1 ng/100 ml at one of 7 years. Further increases were observed with mean values of 163.2 at a bone age of 11 years, and of 221.2 at a bone age of 12 years, with a maximum of 333.4 ng/100 ml at bone ages of 14-15 years. The first significant increase of plasma testosterone (T) was noted at a bone age of 12 years (54.8 ng/100 ml). The major rise of T was preceded by the rise of plasma LH and was accompanied by the rise of plasma FSH. Plasma DHEA and T were also measured in 123 normal girls, ages 6 to 13 years (bone ages 5 to 15 years). DHEA rose significantly from a mean level of 44.7 at 6 years, to 80.9 ng/100 ml at 8 years, with further increases between 9 and 10 years and between 10 and 11 years. In relation to bone age, DHEA increased significantly from a mean plasma concentration of 30.9 at a bone age of 5 years, to that of 58.6 ng/100 ml at 7 years. Further increases were observed with values of 191.1 at a bone age of 10 years and 485.6 ng/100 ml at a bone age of 13 years. The first significant rise of testosterone (T) occurred at 10 years of both chronological and bone age. DHEA rose before the increase of gonadotropins. The major rise of T at a bone age of 10 years occurred concurrently with increases in plasma FSH and LH. Low levels of DHEA were observed in Addison's disease. In hypogonadotropin hypogonadism and in anorchia, DHEA levels were normal, suggesting that DHEA is produced primarily in the adrenal gland. In seven girls with early adrenarche, plasma concentrations of DHEA were in the upper range of normal values, whereas T levels were within the normal range. Conversely in girls with late adrenarche, plasms DHEA was lower than normal but T was within the normal limits. The elevation of DHEA prior to the first signs of puberty suggests that DHEA may play a role in the maturation of the hypothalamic-hypophysealgonadal axis. However, the mechanism that triggers the secretion of DHEA is not known.     

Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate

Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels. The present results demonstrate that circulating levels of the adrenal steroids DHEA and delta 4-dione comparable to those found in man cause an important stimulation of androgen-dependent gene expression in the rat, probably after their conversion to DHT in the prostatic tissue itself.     

Failure of dehydroepiandrosterone enanthate to promote growth

Adrenal androgens may promote pubertal growth. To assess this possibility, we administered dehydroepiandrosterone (DHEA) enanthate in monthly im injections in a dose of 70 mg/m2 for 1 yr to five boys with constitutional short stature (aged 11-13 4/12 yr) and one boy (aged 13 4/12 yr) with panhypopituitarism (coincidentally receiving T4 and human GH). All had bone age delay of at least 3 yr and subnormal levels of DHEA and DHEA sulfate (DHEA-S) for their chronological age. Pretreatment growth velocity ranged from 3-5 cm/yr. After DHEA enanthate injection, plasma DHEA levels were increased 10-fold after 8 days, 2.6-fold after 15 days, and 1.8-fold after 22 days. At the same times, plasma DHEA-S concentrations were 14-, 6-, and 4-fold increased, respectively. There was no rise in plasma testosterone and delta 4-androstenedione, which remained at prepubertal levels. During the year of therapy and for 1 yr after therapy, there was no significant change in growth velocity, and the rate of skeletal maturation assessed by x-ray was not affected. Three of the five boys with constitutional short stature entered puberty within 1 yr after discontinuation of therapy. These results demonstrate that this long-acting form of DHEA administered for 1 yr did not raise plasma testosterone above prepubertal levels and did not accelerate either growth or skeletal maturation. These findings do not support the possibility that DHEA plays a role in normal growth.     

Sex-dependent prepubertal gonadotrophin surges in the rat.

The concentrations of LH and FSH were measured by radioimmunoassay in sera from immature male and female rats of various ages. Fairly high levels of FSH were found in both sexes at birth but lh was not detected. FSH peaks appeared in the male at 13 and 19 days of age and in the female at 13 and 17-19 days of age. LH was undetectable in the male before 12 days of age, rose to a peak (440 plus or minus 60 (S.D.) ng/ml) at 13 days of age and fell below the detection level again between 15 and 25 days of age. A further increase then occurred which almost reached adult levels. LH was first detectable in the female rat at 11 days of age with a peak value of 130 plus or minus 35 ng/ml at 12 days. The hormone was undetectable on days 14 and 15, rose to a second peak on day (148 plus or minus 56 ng/ml), and was again absent between 19 and 25 days of age. The concentration rose, as in the male, between days 25 and 28 to a level similar to that of the adult. The results show sexual differences in prepubertal gonadotrophin surges. The LH peak at 12-13 days in both sexes appears to be light-dependent. The FSH peak at this time was affected by light but was not strictly light-dependent.     

Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood

In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.     

Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche.

Serum androgens testosterone (T), testosterone-like-substances (TLS), delta4-androstenedione (delta4), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) were measured in 85 normal girls and 101 normal boys grouped according to pubic hair development in Tanner stages I to IV/V. The pattern of change with puberty differed for each androgen. In boys T and TLS rose with the onset of puberty but showed a more abrupt rise later in puberty. DHT also was higher in boys in late puberty but did not demonstrate a steep rise. The other androgens did not show a sex difference at any stage of puberty. While delta4 steroids did not show an increase in the years before onset of puberty, DHEA was significantly higher in prepubertal children over 7 years than in those under 7 years (mean +/- SD 166 +/- 110 vs. 31 +/- 25, P less than 0.005). The most rapid increase of DHEA concentrations was observed with the appearance of pubic hair (Stage II) in boys and girls. This contrasted with the more gradual rise of delta4 in both sexes. The oldest boys and girls (Tanner stages IV/V) had mean concentrations of all androgens in the adult range except for DHT. Twenty-two girls with precocious adrenarche (PA) aged 3-8 years had mean concentrations of T, DHT, delta4 and DHEA that were significantly higher (P less than 0.05) than in prepubertal children, but similar to those of girls in stage II and significantly lower (P less than 0.02) than in late pubertal girls (stage IV/V). Longitudinal studies in 12 of the girls indicated fluctuation of androgen concentrations, especially DHEA, but in general no increase during the years of followup. Precocious adrenarche appears to be a non-progressive disorder associated with an advanced maturation of adrenal androgen to an early pubertal stage. A rise in all androgens measured was correlated with the development of sexual hair.     

Serum lipoproteins and endogenous sex hormones in early life: observations in children with different lipoprotein profiles

Relationships of endogenous testosterone, androstenedione, dehydroepiandrosterone, estradiol, and progesterone to lipoprotein cholesterol levels were examined concurrently in four groups of children (N = 375, age range 6 to 18 years) whose earlier VLDL-cholesterol and/or LDL-cholesterol levels were in the extreme quintiles or quartiles. In terms of significant correlations, estradiol related inversely with VLDL-cholesterol in prepubertal boys (-0.28) and pubertal girls (-0.34), while estradiol/testosterone ratios related inversely with LDL-cholesterol in pubertal girls (-0.27). HDL-cholesterol related negatively with testosterone in pubertal boys (-0.24) and positively with estradiol in pubertal girls (0.40). With respect to contrasting lipoprotein profiles, high LDL-cholesterol groups had significantly high progesterone/estradiol ratio (boys: 8.6 v 6.9; girls: 8.3 v 5.1), high progesterone (girls only: 0.40 v 0.29 ng/mL) and low estradiol/testosterone ratio (girls: 0.15 v 0.21; prepubertal boys: 0.09 v 0.21). Pubertal girls from high VLDL-cholesterol groups showed markedly low estradiol (71 v 120 pg/mL) and estradiol/testosterone ratio (0.11 v 0.19). These results emphasize the role of endogenous sex hormones in modulating lipoprotein concentrations as well as in the sexual divergence of lipoprotein profiles between males and females following puberty.     

Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens.

The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 +/- 5.1 yr; mean body mass index, 25.5 +/- 1.5 kg/m2) with serum DHEAS concentrations below 4.1 micromol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0-12 h (mean +/- SD) for DHEA, 108 +/- 22 vs. 252 +/- 45 vs. 349 +/- 72 nmol/L x h; AUC 0-12 h for DHEAS, 33 +/- 9 vs. 114 +/- 19 vs. 164 +/- 36 micromol/L x h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17beta-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men [placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0-12 h for 17beta-estradiol, 510 +/- 198 vs. 635 +/- 156 vs. 700 +/- 209 pmol/L x h (P < 0.0001); AUC 0-12 h for estrone, 1443 +/- 269 vs. 2537 +/- 434 vs. 3254 +/- 671 pmol/L x h (P < 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.     

Serum dehydroepiandrosterone and DHEA-sulfate in patients with adult T-cell leukemia and human T-lymphotropic virus type I carriers

The serum levels of dehydroeplandrosterone (DHEA) and DHEA-sulfate (DHEA-S) were determined by radioimmunoassay in 38 patients with adult T-cell leukemia (ATL). Levels of serum DHEA and DHEA-S were also measured in 60 human T-lymphotropic virus type I (HTLV-I) carriers, and did not differ from those in 60 healthy control subjects. Serum levels in patients with ATL were lower than those in the age- and sex-matched healthy controls and in HTLV-I carriers with statistical significance. Serum DHEA and DHEA-S in male patients with acute and lymphoma-type ATL were 1.06 ± 0.77 ng/ml and 245.8 ± 192.9 ng/ml, respectively. Levels in male patients with chronic and smoldering-type ATL were 1.69 ± 0.68 ng/ml and 477.6 ± 251.5 ng/ml, respectively. Serum levels of DHEA and DHEA-S in patients with acute and lymphoma-type ATL were significantly lower than those in patients with chronic and smoldering-type ATL (P < 0.05). These data suggest that a decrease in serum levels of DHEA and DHEA-S may be associated with patients who have some clinical subtypes of ATL. Moreover, androgens may have a therapeutic role in patients with ATL, as administered in patients with hairy-cell leukemia. Because there is at present no curative chemotherapy for ATL, a trial combination of androgens and standard chemotherapy may be a reasonable therapeutic option in such patients. © 1996 Wiley-Liss, Inc.     

Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography

Serum levels of DHEA sulfate are inversely associated with cardiovascular death in men, and urinary dehydroepiandrosterone (DHEA) levels are inversely associated with clinical manifestations of coronary artery disease. These observations may be related to the antiproliferative effects of DHEA, resulting in inhibition of atherosclerotic intimal hyperplasia. To examine the relation between these steroids and a direct measure of coronary atherosclerosis, plasma DHEA and DHEA sulfate levels were determined in 206 middle-aged patients (103 men, 103 women) undergoing elective coronary angiography. Plasma DHEA sulfate levels were lower in men with at least one stenosis greater than or equal to 50% compared with those without any stenosis greater than or equal to 50% (4.9 +/- 2.7 versus 6.1 +/- 3.5 nmol/ml, p = 0.05). Levels of DHEA sulfate were also inversely related to the number of diseased coronary vessels (r = -0.20, p = 0.05) and a continuous measure of the extent of coronary atherosclerosis (r = -0.25, p = 0.01) in men. The association between DHEA sulfate levels and extent of coronary artery disease was independent of age and other conventional risk factors for coronary disease. In women, there was no association between plasma DHEA or DHEA sulfate levels and coronary disease. These data demonstrate a consistent, independent, inverse, dose-response relation between plasma DHEA sulfate levels and angiographically defined coronary atherosclerosis in men. Plasma DHEA sulfate may be another important and potentially modifiable risk factor for the development and progression of coronary atherosclerosis.     

Short-term dehydroepiandrosterone treatment increases platelet cGMP production in elderly male subjects

OBJECTIVE: Several clinical and population-based studies suggest that dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S) play a protective role against atherosclerosis and coronary artery disease in human. However, the mechanisms underlying this action are still unknown. It has recently been suggested that DHEA-S could delay atheroma formation through an increase in nitric oxide (NO) production. STUDY DESIGN AND METHODS: Twenty-four aged male subjects [age (mean +/- SEM): 65.4 +/- 0.7 year; range: 58.2-67.6 years] underwent a blinded placebo controlled study receiving DHEA (50 mg p.o. daily at bedtime) or placebo for 2 months. Platelet cyclic guanosine-monophosphate (cGMP) concentration (as marker of NO production) and serum levels of DHEA-S, DHEA, IGF-I, insulin, glucose, oestradiol (E(2)), testosterone, plasminogen activator inhibitor (PAI)-1 antigen (PAI-1 Ag), homocysteine and lipid profile were evaluated before and after the 2-month treatment with DHEA or placebo. RESULTS: At the baseline, all variables in the two groups were overlapping. All parameters were unchanged after treatment with placebo. Conversely, treatment with DHEA (a) increased (P < 0.001 vs. baseline) platelet cGMP (111.9 +/- 7.1 vs. 50.1 +/- 4.1 fmol/10(6) plts), DHEA-S (13.6 +/- 0.8 vs. 3.0 +/- 0.3 micromol/l), DHEA (23.6 +/- 1.7 vs. 15.3 +/- 1.4 nmol/l), testosterone (23.6 +/- 1.0 vs. 17.7 +/- 1.0 nmol/l) and E(2) (72.0 +/- 5.0 vs. 60.0 +/- 4.0 pmol/l); and (b) decreased (P < 0.05 vs. baseline) PAI-1 Ag (27.4 +/- 3.8 vs. 21.5 +/- 2.5 ng/ml) and low-density lipoprotein (LDL) cholesterol (3.4 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l). IGF-I, insulin, glucose, triglycerides, total cholesterol, HDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and homocysteine levels were not modified by DHEA treatment. CONCLUSIONS: This study shows that short-term treatment with DHEA increased platelet cGMP production, a marker of NO production, in healthy elderly subjects. This effect is coupled with a decrease in PAI-1 and LDL cholesterol levels as well as an increase in testosterone and E(2) levels. These findings, therefore, suggest that chronic DHEA supplementation would exert antiatherogenic effects, particularly in elderly subjects who display low circulating levels of this hormone.     

Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men

In the present placebo-controlled, double-blind study, we assessed the effect of dehydroepiandrosterone (DHEA) supplementation (90 mg orally/d) on bone turnover in 43 healthy men, 56-80 yr old. Placebo or steroid was given for 6 months, followed by a 1-month washout period and then a further 6 months of the opposite agent. Serum samples were collected at baseline 3, 6, 7, and 13 months and assayed for procollagen peptide, bone-specific alkaline phosphatase, and osteocalcin, all markers of bone formation. Measurements were also made of serum cortisol, DHEA/DHEA-S, E2 and free and total T. First void, fasting urine was collected at baseline, 6, 7, and 13 months and assessed for deoxypyridinoline, a marker of bone resorption. Mean serum DHEA and DHEA-S levels in treated men were increased approximately 3-fold ( approximately 2.2 ng/ml to approximately 6 ng/ml) and 4.5-fold ( approximately 1000 ng/ml to approximately 4500 ng/ml), respectively, after 6 months and returned to baseline after washout. Similarly, circulating E2 concentrations were also increased 1.4-fold (from approximately 16-23 pg/ml; P < 0.001), a finding not observed with any other measured hormone. Bone marker levels remained remarkably constant at each sampling interval; procollagen peptide at approximately 8.0 ng/ml; bone-specific alkaline phosphatase at approximately 21.0 U/liter; deoxypyridinoline at approximately 4.5 nmol/mmol Cr. Osteocalcin showed a transient reduction from approximately 10.2- 6.2 ng/ml, P < 0.005 to P < 0.001, at 3 months, but this decline was observed in both treated and controls. Stratifying the marker levels by age or baseline DHEA/DHEA-S levels did not affect the findings. We conclude that oral DHEA does not affect bone turnover in middle-aged to elderly men when used for a 6-month period at doses targeted to restore circulating levels of the steroid to that seen in young adults.     

Blood pressure, body fat, and dehydroepiandrosterone sulfate variation in adolescence

Several significant interrelations among variation in blood pressure, body fat, and adrenal androgen levels, as assessed by serum dehydroepiandrosterone sulfate concentrations, were found in black male and female adolescents, aged 12 to 16 years. In girls, high levels of dehydroepiandrosterone sulfate were associated with significantly higher levels of blood pressure (alpha = 0.05), even after adjusting for the significant association between increased levels of dehydroepiandrosterone sulfate and body fat. The increased body fat (i.e., body mass index) found with higher levels of dehydroepiandrosterone sulfate in girls was related to significantly greater (alpha = 0.05) accumulations of fat in the upper trunk, as opposed to the limb. In boys, high levels of serum dehydroepiandrosterone sulfate, low body mass index, and significantly higher blood pressure were interrelated (alpha = 0.05). In addition to the interaction of increased body mass index or body fat and increased levels of dehydroepiandrosterone sulfate in association with higher blood pressure, high levels of the adrenal androgen, even in boys with low body mass index, were associated independently with relatively higher blood pressure. Body proportion analyses for these boys indicated that they were tall and thin, in contrast to the other boys with low body mass index, who were generally short and thin.     

Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial

Thirty-eight women, aged 25-65 yr, with androgen deficiency due to hypopituitarism were treated with oral dehydroepiandrosterone (DHEA; 30 mg/d if <45 yr of age and 20 mg if > or =45 yr of age) for 6 months in a randomized, placebo-controlled, double blind study, followed by a 6-month open treatment period. The administration of DHEA raised the serum levels of DHEAS to normal age-related reference ranges and increased androstenedione and T to subnormal levels. Androgen effects on skin and/or pubic and/or axillary hair were observed in 84% (32 of 38) of the women after all received 6 months of DHEA treatment. No such effects were observed after the placebo treatment. These effects after 6 months were correlated with the serum levels of DHEAS (r = 0.37; P = 0.03), androstenedione (r = 0.42; P = 0.01), and T (r = 0.37; P = 0.03). The percentages of partners who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (P < 0.05). According to the partners, sexual relations tended to improve compared with placebo (P = 0.06). After 6 months of treatment, increased sexual interest or activity was reported by 50% of the women taking 30 mg DHEA, by none taking 20 mg DHEA, and by two women taking placebo (P = NS). Compared with levels after placebo administration, high density lipoprotein cholesterol and apolipoprotein A-1 levels decreased after DHEA. Serum concentrations of IGF-I, serum markers of bone metabolism, and bone density did not change. In conclusion, oral administration of a low dose of DHEA to adult hypopituitary women induced androgen effects on skin and axillary and pubic hair as well as changes in behavior, with only minor effects on metabolism.     

Urinary markers of adrenarche: reference values in healthy subjects, aged 3-18 years

Information on the urinary excretion of dehydroepiandrosterone (DHEA) and its direct metabolites is scarce for healthy subjects during growth. We used gas chromatography-mass spectrometry urinary steroid profiling to noninvasively study adrenarchal metabolome in 400 healthy subjects, aged 3-18 yr. Urinary 24-h excretion rates of DHEA did not increase significantly before age 7-8 yr. However, DHEA together with its 16alpha-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 3beta,16alpha,17beta-androstenetriol (DHEA&M), as well as the DHEA metabolite, 5-androstene-3beta,17beta-diol (ADIOL), and the sum of major urinary androgen metabolites (C19) rose consistently from the youngest to the oldest age group. The significant increases (P < 0.01) observed for 24-h excretion rates of C19, ADIOL, and DHEA&M were 2- to 4-fold in boys and girls between age 3 and 8 yr. DHEA&M, for example, rose from about 20 to 80 microg/d (P < 0.0001) during this period. Until the age of 16 yr, DHEA&M excretion also increased to nearly 1000 microg/d. Patterns of steroidogenic enzyme activities were assessed (from definite ratios of urinary steroid metabolites) for 21-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and 5alpha-reductase. Our results indicate for healthy boys and girls that adrenarche is a gradual process starting much earlier than hitherto believed. Efficient metabolism of DHEA, especially to 16-hydroxylated steroids, may explain the almost constant levels seen for this steroid until age 7-8 yr. The established reference values for DHEA, DHEA&M, ADIOL, C19 (including androsterone and etiocholanolone), and urinary parameters of steroidogenic enzyme activities could be useful to identify nutritional, environmental, and pathophysiological interrelations with the progressive maturational process of adrenarche. Our data may also be used as reference data for the diagnosis of steroid-related disorders.     

Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human: the use of a sensitive radioimmunoassay.

A specific and sensitive radioimmunoassay for measuring unconjugated plasma dehydroepiandrosterone (DHA) has been developed and the results expressed in ng/100 ml. Mean values +/-1 SD were in mixed cord blood 593.3 +/- 186.5 in 21 females and 712.7 +/- 190.9 in 18 males. During the first day of life the peripheral plasma concentration of DHA was 917.6 +/- 317.8 in 22 female and 922.65 +/- 290 in 17 male neonates. During the first month of age, DHA levels decreased significantly and then more progressively throughout the first year of life. Mean levels observed between the first and 6th month of life were 147.1 +/- 53.6 in 15 girls and 151.6 +/- 62.7 in 28 boys. Between 6 and 12 months of age mean DHA levels were 90.9 +/- 43.3 and 68.14 +/- 30.9 in 11 girls and 24 boys, respectively. In 250 normal children, plasma DHA levels were very low between 1 to 6 years of age, but rising progressively thereafter without any sex difference long before any clinical sign of puberty. A circadian rhythm parallel to that of cortisol was observed as early as 5 years of age. Acute and chronic stimulation of ACTH confirmed the adrenal origin of DHA, while the results of hCG stimulation test and fluoxymesterone suppression test assessed the testicular participation to the DHA production.     

Free and solvolysable dehydroepiandrosterone and androsterone in blood of mammals under physiological conditions and following administration of dehydroepiandrosterone.

A gas chromatographic method has been empolyed for the determination of dehydroepiandrosterone (D), androsterone (A), dehydroepiandrosterone sulphate (DS) and androsterone sulphate (AS) in the peripheral blood of human subjects and in various mammals under physiological conditions and after the administration of D or DS. Unconjugated D has been isolated and the resting level determined in the rat, rabbit, dog , sheep, pig and cow, while DS was detectable in the peripheral circulation of the rat, dog and pig. Unconjugated A was present in blood of the rodents and domestic ungulates studied, while the parent sulphate could be demonstrated only in rat, dog, pig and cow. The plasma of lower mammals contained D in higher (0.8-10.9 microng/100 ml) and DS, if any, in lower level (1.5-5.7 microng/100 ml) than the human plasma samples (0.1-2.7 and 86-308 microng/100 ml, respectively). There was a more pronounced increase in D and A than in the DS and AS level in the rat and dog following administration of D. On the contrary, exogenous D hardly affected unconjugated D and appreciably enhanced the DS level in human plasma. The conclusion drawn for human subjects, that D is the metabolically active and DS the reserve hormone, does not seem to be valid for all the animals here studied.     

17-Hydroxyprogesterone responses to adrenocorticotropin in children with premature adrenarche

The adrenal secretory response to an iv bolus dose of ACTH was measured in 10 girls (4-8 yr of age), 5 boys (4-9 yr) with premature adrenarche (PA), and 20 normal children. The evening before the ACTH test, each subject took dexamethasone (1 mg at bedtime) to suppress the early morning surge of ACTH. The next morning, 2 serum samples were obtained before the administration of ACTH (Cortrosyn; 0.25 mg), and 2 samples were collected 30 and 45 min after ACTH administration. All samples were assayed for cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, 17-hydroxyprogesterone (17-OHP), and androstenedione. There was no significant difference in the dexamethasone-suppressed steroid levels between the children with PA and the normal children. After ACTH injection, cortisol, DHEA, 17-OHP, and androstenedione increased significantly. There was no significant change in DHEA sulfate. The mean 17-OHP response to ACTH in girls with PA was significantly higher than that in girls and women whose pubertal development was normal. This response was similar in magnitude to that in a group (n = 5) of obligate heterozygotes for congenital adrenal hyperplasia (CAH). These data suggest that many girls with PA have a mild adrenal steroid secretory defect that resembles the response in adult obligate heterozygotes for CAH due to 21-hydroxylase deficiency. In contrast to the girls, none of the boys with PA had an exaggerated 17-OHP response to ACTH. Thus, these boys had no evidence for an adrenal steroid secretory defect. In summary, although the clinical presentation of boys with PA is similar to that of girls with PA, there is a significant difference in the adrenal steroid secretory response to ACTH. Thus, the biochemical events that cause PA in boys may be different from the corresponding events in girls.     

Early activation of the inhibin B/FSH axis in obese Tanner stage G1PH1 boys

OBJECTIVE: To determine whether early activation of the inhibin B/FSH axis is detectable in prepubertal obese boys. METHODS: Thirty-five simple obese Tanner stage G1PH1 boys with body mass index over 25 aged 8-11 years old and 25 age-matched nonobese healthy prepubertal boys (G1PH1) were clinically examined and testicular size measured by ultrasound. Serum inhibin B, testosterone, LH, FSH, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and bone age were measured. GnRH-stimulating tests were performed in the obese children and the relationships between inhibin B and bone age, testicular volume, DHEA, DHEAS, and stimulated peak LH, FSH and testosterone were analysed. RESULTS: The majority of basal LH and testosterone levels were undetectable in both groups of G1PH1 children and no difference was apparent between the groups. However, testicular volume (left 1.21 ml vs 0.83 ml, right 1.15 ml vs 0.81 ml), bone age, DHEA and DHEAS levels were significantly higher in obese children. Inhibin B was detectable in all children. Basal levels were significantly higher in obese children (103.3 ng/l vs 60.95 ng/l, P < 0.001) and correlated with testicular volume (left: rs = 0.655, right: rs = 0.638, P < 0.001) and bone age (rs = 0.554, P < 0.05). Basal FSH levels did not correlate with inhibin B. However, after GnRH stimulation, a clear negative correlation between peak FSH and basal inhibin B was apparent (rs = -0.583, P < 0.001) consistent with early activation of the inhibin B/FSH axis. CONCLUSIONS: Activation of the inhibin B/FSH axis is apparent in obese Tanner stage G1PH1 boys and appears to represent an early hormonal change of puberty in these individuals.     

Adrenal steroid, cortisol, adrenocorticotropin, and beta-endorphin responses to human corticotropin-releasing hormone stimulation test in normal children and children with premature pubarche

To determine whether CRH affects adrenal androgen, beta-endorphin (B-E), and ACTH secretion in normal children during sexual maturation, 17-hydroxyprogesterone (17-OHP), androstenedione (D4-A), dehydroepiandrosterone (DHEA), DHEA sulfate (DS), cortisol, B-E, and ACTH were measured after an iv injection of 1 microgram/kg human CRH. Children with premature pubarche were similarly analyzed to establish whether this condition is accompanied by altered hormonal responses to CRH. CRH produced consistent increases in ACTH, B-EP, and cortisol blood levels, which were comparable at all age intervals in all groups. 17-OHP increased after CRH injection, but its response linearly with age. D4-A levels were not influenced, while DHEA and DS levels were only partially influenced by CRH. The stimulated D4-A to 17-OHP ratio increased with sexual maturation, whereas ratios of cortisol to 17-OHP and D4-A to DHEA remained constant. Children with premature pubarche had hormonal responses similar in magnitude to those of prepubertal children of comparable age. In conclusion, an increase in 17,20-desmolase efficiency occurs with postnatal maturation after CRH challenge. Moreover, CRH does not appear to play an important role in premature pubarche.