Metabolism of the sex steroids in the hypothalamus and its role in the neuroendocrine regulation of reproduction

Abstract

Physiological active metabolites of the sex steroids are formed in the hypothalamus, the limbic complex, and other brain structures in the course of 5a-reduction reactions, aromatization of androgens, and hydroxylation of the estrogens. These metabolites, which differ from the primary hormones in a number of new biological properties, are involved in the neuroendocrine regulation of the secretion of gonadotropins, behavior, and sexual maturation. Various aspects of this problem have been investigated in our laboratory. The inverse relationships between the aromatase and 5a-reductase complexes of the hypothalamus in sexually mature males. Using radioisotope techniques and two-dimensional thin layer chromatography, the activity of the aromatase and the 5a-reductase of the C19-steroids in the 1000g fraction of homogenates of the hypothalamus of sexually mature male rats under conditions of the inhibition of the aromatization of 1,4,6-androstatrien-3,17-dione (ATD) was studied. The material for the investigation was collected 12 h following the termination of the administration of the ATD (25 mg each per 1 kg of body weight intramuscularly, twice, with a 12-h interval). (1,2,6,7-3H)-T.estosterone was used as the substrate. The activity of the aromatase was expressed in terms of the quantity of 3H-estradiol 173, and that of the 5areductase as the quantity of SH-5a-dihydrotestosterone (DHT), formed during 1 h of incubation at 27~ per 1 g of protein. The activity of the enzymes induced by the ATD changed in opposite directions: a twofold decrease in aromatase activity along with almost as marked an increase in the formation of DHT (Fig. 1). Since the intensity of the formation of DHT was greater by an order of magnitude than that of eslradiol, it is diff~ult to hypothesize that the increase in the rate of 5a-reduction of the androgen was associated with greater accessibility of the substrate. Most probably the activation of the 5a-reductase is explained by the actuation of unknown regulatory mechanisms. Role of Estrogenic Metabolites of Testosterone (T) in the Physiological Regulation of the Secretion of LH. According to contemporary notions, the regulation of the secretion of gonadotropins and androgens in males takes place according to the negative feedback principle. T and its metabolites effect tonic inhibition of the corresponding neuroendocrine center. The inhibitors of the aromatase of the steroids are convenient pharmacological instruments for studying the role of the estrogens formed from endogenous androgens in the physiological regulation of the gonadotropic function of the hypophysis in males. The content of bioactive LH and T in the blood plasma of rats receiving ATD was studied in experiments performed conjointly with P. V. Sinitsyn. The LH was determined on the basis of the steroidogenic reaction of a suspension of Leydig cells from mouse testes; the T was determined radioimmunologicaUy. A pronounced reaction of the hypophysis-testes system was observed in the hypothalamus against the background of the above-described changes in the metabolism ofT. A twofold (from 5.9 + 0.34 IU/liter in the control, up to 11.1 + 0.96 IU/liter in the experiment; p < 0.01) increase in the level of LH in the plasma and a threefold increase in the level of T (from 18.29 + 1.74 to 55.56 + 4.20 nmole/liter; p < 0.001) took place in the sexually mature males. An increase in the secretion of LH and T had been previously demonstrated under the influence of aromatase inhibitors in rats [4], male dogs [10], and monkeys [5]. However, the conclusions of the authors regarding the significance of the process of conversion of endogenous androgens into estrogens in the neuroendocrine regulation of the secretion of LH could not be endorsed unequivocally, since they did not take into account possible changes in the intensity of the formation of 5a-reduced products of the metabolism of T in the hypothalamus. It is known, meanwhile, that DHT exerts a stronger inhibitory influ