J.R.M. Franckson

Control of circadian and episodic variations of adrenal androgens secretion in man

The 24-h profiles of plasma cortisol (F), 11-β-hydroxyandrostenedione (11OHAD), androstenedione (AD), dehydroisoandrosterone (DHEA) and testosterone (T) were obtained simultaneously in 11 normal males sampled at 15-min intervals. The data were submitted to a detailed quantitative analysis including the estimation of the circadian rhythm and of the episodic variations as well as the evaluation of the concomitance of episodic pulses of different hormones. A bimodal circadian rhythm was detected in the various individual profiles. The major acrophase occurred in the morning earlier for T (around 04:00 h) than for the hormones of totally or partially adrenal origin (around 07:00 h); the secondary acrophase (around 17:00 h) and the main midnight nadir were common to all hormones. The amplitude of the rhythm was highest for purely adrenal hormones (F and 11OHAD), averaging 79 and 75%, respectively, lower for hormones of mixed origin (DHEA and AD), averaging 44 and 42%, respectively, and minimal for T (22%). The possible relationship between the circadian and pulsatile variations of the various steroids was estimated in each individual by calculating Pearson’s standard coefficient of variation on all pairs of hormonal profiles. A very tight relationship (r > 0.75; p < 0.001) was found between the 4 adrenal hormones in each individual; a looser but significant correlation (r > 0.30; p< 0.001) was also detected between T and its partial precursors (AD and DHEA) and between T and the purely adrenal hormones: F and 11OHAD (r > 0.30; p < 0.01). The pulsatility of the corticotrophic axis was readily transmitted to the secretory pattern of 11OHAD, DHEA and AD. Ninety-six percent of the F pulses were reflected in at least one other hormonal profile. Finally, we showed that concomitant pulses common to the five adrenal and gonadal patterns were more frequent than would be expected on the basis of chance. These results: (1) demonstrate a total parallelism between the long-lasting secretory events and the episodic bursts of the 4 adrenal hormones showing that the reticular and fascicular zones of the adrenal respond to pituitary control as an homogeneous structure; (2) demonstrate the existence of a partial synchronization of adrenal and testicular pulsatile variations; (3) suggest that, throughout the afternoon, a common mechanism may influence the slow variations of adrenal hormones and of testicular testosterone.

Enhanced ACTH and blunted cortisol responses to corticotropin-releasing factor in idiopathic panhypopituitarism

ADM IN 1STRATION of corticotropin-reteasing factor has been shown to stimulate the release of ACTH and cortisol in normal humans? -4 In one patient with hypothalamic anterior pituitary failure, Miiller et al? found a normal ACTH response without cortisol elevation. The purpose of our study was to assess the characteristics of the pituitaryadrenal responsiveness to CRF in a group of six patients with nontumoral idiopathic panhypopituitarism. METHODS Six patients (five males) with nontumoral idiopathic panhypopituitarism, aged 12 to 29 years, were examined, with informed consent. All patients had delayed growth and bone maturation. All were shown to have blunted responses of hGH and of cortisol to both insulin intravenously and glucagon intramuscularly 5 and absence of an increase of plasma l l-deoxycortisol or urinary 17hydroxysteroids after metyrapone. Serum dehydroepiandrosterone sulfate concentration ~was <100 ng/ml in all patients. All had tertiary hypothyroidism as assessed by TSH response to TRH, and gonadotropin deficiency as assessed by lowered LH and FSH responses to LH-RH and absence of spontaneous pubertal development. Skull radiographs were normal. All patients had been receiving hormonal substitutive therapy for several years. The two oldest patients (patients 4 and 5) were not receiving growth hormone treatment at the time of the study. Corticoid treatment had been stopped for 2 years in patient 4 and at

Partial 17, 20-desmolase and 17α-hydroxylase deficiencies in a 16-year-old boy

Thirteen plasma steroids as well as ACTH, LH and FSH were measured by specific RIAs under basal and dynamic conditions in a 16-year-old boy (normal external genitalia, 46, XY karyotype) who presented slowness and unachievement of pubertal development. On the Δ4-pathway: basal levels of testosterone and dihydrotestosterone were low — with a normal ratio-, Δ4-androstenedione and 11β-hydroxyandrostenedione were in the low normal range. Meanwhile, 17α-hydroxyprogesterone and progesterone levels were markedly elevated. On the Δ5-pathway: dehydroepiandrosterone was extremely low while 17α-hydroxypregnenolone and pregnenolone were almost normal; dehydroepiandrosterone sulfate was subnormal while pregnenolone sulfate was normal. Cortisol, aldsoterone were normal while ACTH was moderately increased. Basal and responsive levels of LH and FSH were markedly increased. ACTH stimulation induced asubnormal rise of Cortisol and 11 β-hydroxyandrostenedione, a low or absent rise of dehydroepiandrosterone, 17α-hydroxypregnenolone, androstenedione and 17α-hydroxyprogesterone contrasting with a marked rise of pregnenolone and progesterone. After hCG stimulation, responses were low for testosterone, extremely high for 17α-hydroxyprogesterone with a normalisation of the 17α-hydroxyprogesterone/progesterone ratio. Fluoxymesterone dramatically reduced the pathologically high basal levels of progesterone and 17α-hydroxyprogesterone. Dexamethasone induced only a minute decrease in the A4-progestagens, a marked decrease in pregnenolone, with a more than 80% reduction of 17α-hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. These data suggest a defect involving the cytochrome P450 common to both 17α-hydroxylase and 17,20-desmolase activities. In the testis, the alteration is already present in basal state and mainly expressed in its 17,20-desmolase activity whereas in the adrenal, it is only expressed in its 17a-hydroxylase component. The different behavior of adrenals and testes regarding this common defect is probably due to local factors affecting specifically the tissue expression of the enzyme.

Quantitative characterization of ACTH and adrenocortical episodic secretion in man: An introduction

Publisher Summary This chapter presents an introduction to quantitative characterization of ACTH and adrenocortical episodic secretion in man. A quantitative characterization of hormonal episodic variations aims at the estimation of the number of secretory episodes over a determined period of time. In a study described in the chapter, blood was sampled simultaneously every 5 min from the vena cava superior and from an antecubital vein, over a total period of 245 min. Plasma cortisol was measured by the radioimmunoassay method. Central and peripheral cortisol patterns were identical. Preliminary analysis of data obtained in normal subjects, using 15-min intervals sampling of peripheral blood for 24 h, showed excellent temporal and quantitative correlations between episodic variations of ACTH, cortisol, 11β-hydroxyandrostenedione, and androstenedione. In 15 nyctohemeral profiles, more than 80% of ACTH secretory bursts were accompanied by cortisol peaks. In three other patterns, more than 75% of secretory episodes of cortisol, 11β-hydroxyandrostenedione, and androstenedione occurred simultaneously. The chapter also describes the correlations between simultaneous peak values of ACTH and cortisol in three normal subjects.

163. Detection of heterozygote carriers of congenital adrenal hyperplasia

Heterozygote carriers of 21-hydroxylase deficiency (21-OHD) cannot be detected by measurements of basal adrenal secretion. Attempts were made to reveal the latent metabolic block by ACTH stimulation and determination of plasma 17-hydroxyprogesterone (17-OHP). Overlapping of the response curves between normals and carriers prevented their use for individual prediction purposes. The test sensitivity was improved as follows: endogenous ACTH interference was suppressed by dexamethasone prior to I.V. injection of ACTH: plasma 17-OHP, cortisol (F), progesterone (P), corticosterone (B) and androstenedione (AD) were measured (during the 1 h duration of the test): parameters analyzed were the ratio of plasma increments between precursors and end-products (Δ17-OHP/ΔF, ΔP/ΔB, Δ17-OHP/ΔAD) at corresponding times: data were analysed by a stepwise discriminant analysis. The test was performed in 22 normal adults and 14 parents of children with 21-OHD. The following results were obtained: significant alterations in the metabolic pathways of F and B but not in the conversion of 17-OHP to AD were demonstrated in carriers; addition of ΔP/ΔB results did not improve the discriminant potency of statistical analysis performed in the Δ17-OHP/ΔF data; within the limits imposed by the number of subjects studied, the discriminant analysis applied to the Δ17-OHP/ΔF data revealed a combination of variables which lead to a 91% correct classification for normals and carriers.