Control Of Adrenal Androgen Secretion Research Articles

Low-Dose Dexamethasone Therapy from Infancy of Virilizing Congenital Adrenal Hyperplasia

Objective. To assess the growth and control of adrenal androgen secretion in children with virilizing congenital adrenal hyperplasia (CAH) treated with dexamethasone. Method. We examined doses used, control of adrenal androgen secretion, and growth and skeletal maturation of 8 children with CAH treated with dexamethasone beginning in infancy. Results. 3 boys and 5 girls with classical CAH (17-hydroxyprogesterone at diagnosis >20,000 ng/dL) were treated with dexamethasone beginning at diagnosis (<10 days of age). Patients were also treated with fludrocortisone and sodium chloride. The average initial medication dose was 0.1 mg (0.28 ± 0.015 mg/m2); all doses were given in the morning using a dosing syringe to administer a 0.1 mg/mL elixir. The children were treated for 6.5 ± 2.0 years over which time the change in bone age to chronological age ratio (ΔBA/ΔCA) was 0.9 ± 0.06. Most recent height Z' scores were +0.5 ± 0.2, and body mass index (BMI) scores were 18 ± 0.2. Late afternoon levels of 17-hydroxyprogesterone, androstenedione, and testosterone were 780 ± 238 ng/dL (23.4 ± 7 nmol/L), 42 ± 10 ng/dL (1.4 ± 0.3 nmol/L), and 11.5 ± 3 ng/dL; (0.4 ± 0.1 nmol/L), respectively. Conclusions. These observations show that low doses of dexamethasone can be used to effectively treat CAH beginning in infancy.

Androgen secretion in ectopic ACTH syndrome and in Cushing's disease: modifications before and after surgery.

The role of ACTH in the control of adrenal androgen secretion is known, although the possible existence of other regulatory factors has been also suggested. While some data concerning Cushing's disease have been reported, only few studies concerned androgen levels in ectopic ACTH secretion. The aim of this study was to evaluate serum DHEA-S, androstenedione (A) and testosterone (T) levels in 36 women with ACTH-dependent Cushing's syndrome (30 with Cushing's disease and 6 with ectopic ACTH secretion) before and after surgery. Two men with ectopic ACTH production were also studied. In 30 women with Cushing's disease serum DHEA-S (9.6 +/- 0.9 micromol/l), A (15.2 +/- 1.2 nmol/l) and T (4.1 +/- 0.5 nmol/l) were higher than in controls (p < 0.01): elevated DHEA-S, A and T values were found in 8, 18 and 17 cases, respectively. After adenomectomy in 15 apparently cured patients DHEA-S, A and T levels were low at 1 - 3 months and at 6 - 12 months after surgery. At 18 - 24 months, DHEA-S remained low in spite of cortisol normalisation. In ectopic Cushing's syndrome, A levels were significantly higher (23.1 +/- 4.9 nmol/l) than in Cushing's disease (p < 0.05), while no differences were found in DHEA-S and T levels. Two patients had elevated DHEA-S values, 3 women had high T levels and 7 of the 8 patients had very high A concentration that was lowered in 3 operated cases. In conclusion, the pattern of adrenal androgen secretion is rather different in patients with pituitary or with ectopic Cushing's syndrome. While the frequency of DHEA-S and T alterations is similar, androstenedione secretion is greatly increased in the latter condition. It is suggested that in ACTH-secreting non-pituitary tumours, the production of a POMC-derived peptide, although unidentified, may lead to preferentially stimulated androstenedione secretion, without affecting other enzymatic pathways.

Effects of pro-opiomelanocortin-derived peptides on adrenal steroidogenesis in guinea-pig adrenal cells in vitro

The specific control of adrenal androgen secretion is unclear. This study was undertaken to investigate the effects of peptides derived from the ACTH precursor molecule pro-opiomelanocortin (POMC) on cortisol and androgen production using isolated guinea-pig adrenal cells. ACTH 10 −13−10 −9M, stimulated steroid production in a dose dependent manner, reaching a maximum of 12, 10 and 7 times basal levels for cortisol, androstenedione (A4) and dehydroepiandrosterone (DHEA), respectively, measured by specific radioimmunoassays. β-Lipotropin (β-LPH), 10 −10−10 −8M, also stimulated steroid production, reaching 6, 5 and 5 times basal levels of cortisol, A4 and DHEA, respectively. The N-terminal 16K fragment, λ 3- and β-MSH stimulated steroid production which reached statistical significance ( P < 0.05) only in the case of cortisol. Joining peptide, α-, β- and γ-endorphin resulted in no significant change in steroid production. Met- and leu-enkephalin resulted in significant inhibition of DHEA production. POMC-derived peptides altered the steroid response to ACTH. β-LPH and 16K fragment significantly increased the cortisol and A4 responses to a low concentration of ACTH. β-LPH reduced the maximum cortisol and A4 responses to a high concentration of ACTH. This study suggests that β-LPH may have a role in modulation of adrenal steroidogenesis but yielded no evidence to support a role for POMC-derived peptides in preferential stimulation of adrenal androgen production in guinea-pig adrenal cells.

Vasoactive Intestinal Peptide (VIP) stimulates androstenedione release in isolated perfused pig adrenals

The effect of the vasoactive intestinal peptide (VIP) on adrenal androstenedione release was investigated in isolated perfused pig adrenals. Our system allowed a direct comparison with the effect of ACTH, gonadotropins and proopiomelanocortin 79–96, which has been suggested to be the specific cortical androgen stimulating hormone (CASH). VIP 10 −8 M provoked a threefold increase of androstenedione release which was similar to the effect of ACTH at a physiological concentration of 10 −10 M. Gonadotropins at a perfusate concentration of 0.5 I.U. weakly but significantly increased androstenedione output, the response amounting to 32% of that elicted by ACTH or VIP. Perfusion of the adrenals with CASH at concentrations of 10 −11 to 10 −8 M did not affect the release of adrenal androstenedione. VIP appears to be a modulator of adrenal androgen release which might be involved in a local neuroendocrine control of adrenal androgen secretion.

Control of Adrenal Androgen Secretion

The human adrenal gland secretes large amounts of androgens and androgenic precursors as compared with the adrenal glands of other species. In part, this pattern of secretion is regulated by ACTH, analogous to the control of cortisol. However, in many instances, including adrenarche, puberty, aging, and severe illness, secretion of adrenal androgens and cortisol diverge for reasons which are not clear. Factors endogenous to the adrenal gland may have a role in the modulation of adrenal androgen secretion. These include the centripetal blood supply of the adrenal gland, availability of cofactors of steroidogenic enzymes, and intrinsic properties of adrenal cells or enzymes. However, these mechanisms may, in turn, be modified by factors exogenous to the adrenal gland. Possible evidence for a regulatory role for such known substances as growth hormone, IGF-1, gonadotropins, estrogens, angiotensins, prostaglandins, insulin, EGF, and POMC-related peptides is discussed. Furthermore, pituitary or extrapituitary substances, in addition to known hormones, may have a role in the control of adrenal androgen secretion. Several lines of evidence include the inability of ACTH to maintain a normal adrenal androgen/cortisol ratio in adrenally suppressed patients, or experimentally, in hypophysectomized chimpanzees. Evidence for such factors derived from fetal and adult human pituitary gland is discussed.

The control of adrenal androgen secretion

While it is well established that aldosterone arises exclusively from the zona glomerulosa of the adrenal gland under the dominant control of the renin-angiotensin system and that cortisol arises from both the zona fasciculata and zona reticularis under the almost exclusive control of adrenocorticotrophin (ACTH), the mechanisms controlling adrenal androgen secretion, predominantly from the zona reticularis, have not been established and are the subject of intense debate. Undoubtedly ACTH plays an important role in the stimulation of adrenal androgen secretion. However, the many instances of dissociation between cortisol and androgen secretion suggest that while ACTH is necessary for androgen biosynthesis, alone it is probably not sufficient. The fetal adrenal secretes Δ5 androgens in abundance; the steroid pattern changing in the early neonatal phase of life to favour Δ4 glucocorticoids with very little androgen production (De Peretti & Forest, 1976). This pattern is maintained into the second half of

Control of adrenal androgen production.

The major adrenal androgens are dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione (delta 4). Studies by Cutler et al in 1978 demonstrated that these androgens are detectable in blood of all domestic and laboratory animals studied, but that only 4 species show increase in one or more with sexual maturation: rabbit, dog, chimpanzee and man. Studies by Grover and Odell in 1975 show these androgens do not bind to the androgen receptor obtained from rat prostate and thus probably are androgens only by conversion to an active androgen in vivo. Thomas and Oake in 1974 showed human skin converted DHEA to testosterone. The control of adrenal androgen secretion is in part modulated by ACTH. However, other factors or hormones must exist also, for a variety of clinical observations show dissociation in adrenal androgen versus cortisol secretion. Other substances that have been said to be controllers of adrenal androgen secretion include estrogens, prolactin, growth hormone, gonadotropins and lipotropin. None of these appear to be the usual physiological modulator, although under some circumstances each may increase androgen production. Studies from our laboratory using in vivo experiments in the castrate dog and published in 1979 indicated that crude extracts of bovine pituitary contained a substance that either modified ACTH stimulation of adrenal androgen secretion, or stimulated secretion itself - Cortisol Androgen Stimulating Hormone. Parker et al in 1983 showed a 60,000 MW glycoprotein was extractable from human pituitaries, which stimulated DHA secretion by dispersed canine adrenal cells in vitro, but did not stimulate cortisol secretion. This material contained no ACTH by radioimmunoassay. In 1982 Brubaker et al reported a substance was also present in human fetal pituitaries, which stimulated DHA secretion, but did not effect cortisol.

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency.

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.