Adrenal Androgen Response to Metyrapone, Adrenocorticotropin, and Corticotropin-Releasing Hormone Stimulation in Children with Hypopituitarism^*

Abstract

We determined the adrenal steroid responses to metyrapone, ACTH, and CRH in 12 ACTH-intact and 5 ACTH-deficient hypopituitary children to determine the mechanisms that control adrenal androgen secretion. Serum adrenal androgen concentrations [dehydroepiandrosterone (DHEA) and delta 4-androstenedione (delta 4-A)] rose in response to oral administration of metyrapone (450 mg/m2 X dose, every h for 7 doses) in ACTH-intact hypopituitary children with multiple or isolated pituitary hormone deficiencies [mean postmaryrapone level: DHEA, 225 ng/dL (range, 27-566); delta 4-A, 313 ng/dL (range, 105-651)], except in 2 young children in whom DHEA did not rise. These adrenal androgens did not rise in all ACTH-deficient hypopituitary children [mean postmetyrapone level: DHEA, 11.0 ng/dL (range, 3-16); delta 4-A, 6.2 ng/dL (range, 3-10)]. The increases in both serum cortisol and adrenal androgens, including DHEA sulfate, in response to short term ACTH infusion (40 U in 6 h) in ACTH-intact hypopituitary children were normal or above normal, while these steroid responses were significantly (P less than 0.05-0.01) lower in ACTH-deficient hypopituitary children compared to normal values. However, prolonged administration of ACTH (40 U/day, or im) for 6 days to 2 ACTH-deficient hypopituitary children resulted in normal DHEA responses to the 6-h ACTH stimulation test (DHEA levels after the first test, 14 and 30 ng/dL, after priming, 80 and 50 ng/dL). Furthermore, CRH administration to 4 ACTH-deficient patients caused a rise in serum DHEA and cortisol in patients with a normal ACTH response, while those with a poor ACTH response had a lesser rise in DHEA and cortisol. These data suggest that ACTH is the major tropic hormone for adrenal androgen secretion.

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

“…In many peripheral steroid tissues such as the prostate and mammary glands, DHEA can be converted into androgens and/or estrogens (45), which also have immunomodulatory functions. However, a role independent of its metabolic functions and, in particular, on immune regulation has been previously observed (31,46). For example, DHEA was shown to have immunomodulatory properties in androgen-unresponsive mice (47).…”

Regulation of murine lymphokine production in vivo II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells

“…This steroid is produced by the adrenals in response to stimulation by ACTH [23], and is uniquely sulfated by an adrenal sulfotransferase to DHEAS in humans (and to a lesser extent in rodents) prior to export into the plasma [24]. DHEAS represents the major secretory product of the human adrenal gland [28], and exhibits interesting and characteristic plasma levels throughout an individual's life-span.…”

“…production and secretion of the weak androgen steroid DHEA [23]. This knowledge, coupled to our present understanding about the molecular mechanisms that have been proposed to explain the transcriptional enhancing and transcriptional repressing influences of steroid hormones on steroid responsive genes [13-171, led us to question whether DHEA andor DHEAS could influence the ability of lymphocytes to produce TCGF.…”

“…It is well recognized that metyrapone treatment, by its capacity to inhibit the synthesis of functional GCS, causes an increased output of pituitary ACTH [23]. This results from an elimination of the normal feedback loop whereby GCS function to limit pituitary ACTH output.…”

Adrenal Androgens in Children with Short Stature

“…Both low [1][2][3][4] and normal [5][6][7][8][9] levels have been reported. Of particular interest is the study of Cohen et al [2] which demonstrated markedly reduced plasma concentrations of the AA dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S) and A4-androstenedione (A4A) in adolescent subjects with GH deficiency.…”