Adrenal Maturation Research Articles

The reproductive endocrine system of nonhuman primates—A model for prediction of toxicity

Summary The following statements summarize our present judgements of the areas of reproductive endocrinology in which rhesus monkeys and chimpanzees can appropriately serve as surrogates for man. In many cases these conclusions are based on preliminary data and may be altered by subsequent experiments. Because of different patterns of steroid synthesis and metabolism, the rhesus monkey is not a good model for human pregnancy. Endocrine relationships in the three species are similar during the neonatal period, but due to the lack of a detectable adrenal maturation process the rhesus monkey may not be an appropriate model for studies during puberty. Control of the menstrual cycle appears to be similar in each of the three species. While post-menopausal rhesus monkeys have been found and their hormone patterns are similar to those of postmenopausal humans, menopause has not yet been documented in chimpanzees. Studies of the relationship of the hypothalamus to the pituitary in rhesus monkeys would be difficult since they do not uniformly respond to GnRH. Preliminary results of our initial attempts to utilize the reproductive endocrine system of primates as a means of predicting toxicity have been presented. While sufficient information is not yet available to enable a definitive outline of all the facets of the primate endocrine system which are liable to specific toxic intervention, we hope this presentation will elicit the interest of both toxicologists and endocrinologists in a fruitful marriage of the two disciplines.

Androgens and gonadotropins levels in precocious puberty (PP) and premature adrenarche (PA) in girls

Testosterone (T), androstenedione (A), dehydroepiandroste rone (DHA), DHA-sulfate (DHA-S), FSH and LH were measured in 45 girls with PP and 35 with PA. In PP, plasma levels, ng/ml, (x ± sem) of T (0.14 ± 0.03) and A (0.47 ± 0.05) were higher than in normal girls of same age (p 0.4, p > 0.8). DHA (1.06 ± 0.12) was high in respect of age, but lower than normal P2 level (p 0.4, p > 0.8). DHA (2.78 ± 0.37) was higher than normal P2 level (p < 0.05) and far higher than in PP (p < 0.00001). DHA-S (212-3800 ng/ml) was also higher than in normal girls at P2 (p < 0.04). FSH (1.08 ± 0.14 mIU/ml) and LH (0.68 ± 0.07 mIU/ml) were lower than in normal girls at P2 (p < 0.01, p = 0.05). These results are consistent with a lack of adrenal maturation in PP and a lack of gonadotropic maturation in PA, suggesting that adrenal and ovarian pubertal maturations are relatively independant.

196 SERIAL PLASMA CORTICOSTEROIDS IN THE FETAL GROWTH RETARDED LAMB (FGR)

Growth retarded fetuses are considered to be under chronic stress due to lack of oxygen and nutrients. Since FGR lambs have proportionally a large adrenal weight and a small thymus, both suggestive signs of increased adrenal activity, we measured the total corticosteroid levels in this syndrome. Growth retardation was produced in 7 chronically catheterized fetal lambs by embolization of the maternal uterine bed with non radioactive microspheres. Fetal femoral artery pH was (mean±SE) 7.38±0.008; PO2 18.41±0.61 torr; PCO2 46.62±1.19 torr and hematocrit 36.64±0.68%. Total corticosteroid was measured by RIA serially in fetal femoral arterial plasmas from 113 to 141 days gestation. Mean corticosteroid concentration (ng/ml) in FGR lambs were 4.92±1.0 (n=10), 7.44±1.3 (n=11), 20.75±5.42 (n=17) at 110-120, 121-130 and 131 to 141 days gestation respectively. These values are not significantly different from control animals, (5.21±1.02, n=10; 7.22±0.75, n=5; 13.75±3.12, n=4; respectively). These results indicate that placental embolization enough to cause fetal growth retardation is not a stimulus for enhanced fetal adrenal activity nor accelerates fetal adrenal maturation.

Development of fetal pituitary-adrenal function

The factors responsible for the growth of the fetal adrenal, and its increase in cortisol secretion during late pregnancy have been examined in experimental studies in sheep. The fetal pituitary is necessary for these changes to occur. However, the increase in cortisol secretion at term is not preceded by an increase in ACTH in fetal plasma. Prolactin increases in parallel with fetal cortisol. ACTH is elevated in fetal plasma during late pregnancy, despite the demonstration of a negative feedback relationship with cortisol, suggesting an overriding stimulus to ACTH. Comparison of fetal ACTH levels during Synacthen (β1–24 ACTH) infusion into intact and hypophysectomized fetal lambs demonstrates endogenous ACTH release at this time. The possible mechanisms by which negative feedback may be overridden are discussed. Studies in vivo and in vitro show that there is a maturation of fetal adrenal sensitivity during late pregnancy. In vivo at days 120–130, ACTH provokes little or no increase in the fetal adrenal secretion of cortisol, whereas intra-fetal infusion of prostaglandin E 2, but not PGF 2α, provokes a rapid 300% increase in the cortisol concentration in fetal plasma. These findings indicate that the fetal adrenal has the pathway necessary for cortisol production by day 130 p.c., and suggest that adrenal maturation is a key factor in the release of cortisol which precedes parturition.

13 Plasma 17-Ketosteroid Levels During Adolescence

To study adrenal maturation at adolescence, pooled blood was collected from prepubertal males, age 6–9 years, and from pubertal boys, age 12–14 years. Plasma steroid sulfates were extracted in the form of methyl green salts, which were solvolyzed and then successively subjected to purification by means of the Girard T-reagent, digitonin, thin-layer chromatography, and gas-liquid chromatography (free steroid, acetate, trimethylsilyl ether) on the phases SE-52 and QF-1. In the 6–9 year-old pool the level of androsterone sulfate (AS), corrected for 80 % recovery, was 8.6 μg%; and of dehydroepiandrosterone sulfate (DHAS), corrected for 65% recovery, 13.5 μg%. In the 12–14 year-old male pool the level of AS was 56.7 μg % and of DHAS 80.3 μg %. In adult males, studied for comparison, plasma levels of AS were 40–53 μg % and of DHAS 89–209 μg%. No etiocholanolone sulfate or free 17-ketosteroid was detected.The dramatic rise of plasma DHAS and AS during adolescence appears to occur simultaneously wih beginning testicular maturation. Since ACTH secretion is not known to change at the time of adolescence, these observations suggest that beginning adrenal production of DHAS at this age is not directly related to ACTH stimulation, but rather that it is promoted by some other trophic factor. (SPR)