17-n-n-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one and formestane

The effect of several synthetic steroids belonging either to the 4-aza-3-oxo-steroid family or to androstene and androstane derivatives was investigated "in vitro" on the epididymal as well as prostatic 5 alpha-reductase activity. For this purpose rat caput epididymis and prostate were incubated with the different steroidal compounds at molar concentrations of 10(-7), 10(-6), and 10(-5) in the presence of labelled testosterone as substrate. The steroids 4-MA (17 beta, N,N-diethyl-carbamoyl-4-aza-5 alpha-androstan-3-one) and 4-OH-A (4-hydroxy-androstenedione), already known to be effective 5 alpha-reductase inhibitors at the level of the prostate, have been used as reference molecules. The 5 alpha-reductase activity was evaluated by measuring pg of dihydrotestosterone (DHT) formed in 2 h of incubation by mg of tissue. The steroids A, B, C, F, G and I inhibit the formation of DHT in the rat epididymis although to different extents; they are also equally effective on the formation of DHT in the rat prostate. The steroids D, E, H and L are devoid of any inhibitory property on the formation of DHT in both the rat epididymis and prostate. The most interesting results were obtained with compound M which exhibits a dose-dependent and significant inhibitory effect on the formation of DHT in the epididymis, but it is inactive at the level of the prostate. These findings suggest that it is possible (a) to selectively interfere with the 5 alpha-reductase of the epididymis without affecting that present in the prostate, and (b) consequently to envisage new ways to regulate male fertility.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Androstenedione; Animals; Azasteroids; Dihydrotestosterone; Epididymis; In Vitro Techniques; Male; Molecular Structure; Pyrazoles; Rats; Rats, Inbred Strains; Steroids

Although testosterone (T) stimulates aggressive and reproductive behaviors in males of many vertebrate species, it is now known that the full expression of T action in the brain requires aromatization to estradiol (E2) and subsequent interaction of locally formed E2 with nuclear estrogen receptors. In experiments reported here, we used a behavioral test which quantifies the response of an individual male Japanese quail (Coturnix coturnix japonica) to the visual stimulus of a conspecific. We have called this behavior aggression because it shares many features in common with traditional measures of aggression, e.g., predicting dominance and subordinance. Nevertheless, the behavior probably also combines a complex steroid-sensitive masculine behavior. The advantage of this test is that it allows the discrimination of individual differences in masculine behavior but avoids fighting and sexual encounters per se, thereby reducing effects of learning, a problem with previous tests of avian aggression. In addition, this test has been applied usefully to identify neuroendocrine correlates to male behavior. Using this test, the arousal of reproductively inactive males (hereafter referred to as aggression) is activated by administration of T or estradiol benzoate (EB), but not by 5 alpha-dihydrotestosterone (DHT). T-induced aggression was blocked by the aromatase inhibitor 4-hydroxyandrostenedione (OHA), an effect partially reversed by treatment with EB. In addition, OHA or the estrogen receptor blocker CI-628 reduced aggressiveness of reproductively active males whereas the androgen receptor blocker flutamide had no effect. Results with the 5 alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 alpha-carboxyamide (4-MA) were equivocal. Additionally, treatment of reproductively inactive quail with T or E2 but not DHT increased aromatase activity in the hypothalamus-preoptic area (HPOA). We conclude, therefore, that T to E2 conversion is essential for the activation of aggressiveness in this species. Although locally formed estrogen exerts its effects on aggression in part by increasing activity of aromatase per se, analysis of the time course of behavioral induction or suppression by the various treatments suggests that the response has multiple components, including both short latency, receptor-independent and long latency, receptor-dependent events.

Topics: 5-alpha Reductase Inhibitors; Aggression; Androstenedione; Animals; Aromatase; Aromatase Inhibitors; Azasteroids; Behavior, Animal; Coturnix; Dihydrotestosterone; Estradiol; Female; Flutamide; Hypothalamus; Male; Motor Activity; Nitromifene; Preoptic Area; Quail; Testosterone

Newborn female Albino Swiss rats received testosterone propionate, dihydrotestosterone benzoate or oestradiol benzoate for 4 days after birth. The neonatal administration of all three hormones maintained neurones of the spinal nucleus of bulbocavernosus (SNB) complex in adulthood at levels intermediate between those found in normal females (approximately 40 neurones) and those found in normal males (approximately 220 neurones). Dihydrotestosterone benzoate was the most effective treatment. Oestradiol benzoate, while as potent as testosterone propionate in maintaining SNB neurone numbers, could not maintain the perineal muscles which are their normal target. Dihydrotestosterone benzoate and testosterone propionate maintained both neurones and muscles. Newborn male Albino Swiss rats received either the aromatase inhibitor 4-OH-androstenedione, or the 5 alpha-reductase inhibitor aza-steroid 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one(4-MA). Only neonatal treatment with 4-MA led to reduced SNB neurone numbers in adulthood, but the reduction was modest (-16%). The results of the two experiments suggest that several hormones can maintain SNB neurone numbers in Albino Swiss rats, but that 5 alpha-reduced metabolites of testosterone may be particularly effective.

Topics: Androgen Antagonists; Androstenedione; Animals; Azasteroids; Dihydrotestosterone; Estradiol; Female; Gonadal Steroid Hormones; Male; Motor Neurons; Muscles; Organ Size; Perineum; Rats; Rats, Inbred Strains; Sex Characteristics; Testosterone

To determine the effects of 4-hydroxy-4-androstene-3,17-dione (4-OH-A) on the in vitro conversion of testosterone (T) to 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone, DHT), 5 alpha-androstan-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta, 17 beta-diol (diols), human benign hypertrophic prostatic (BPH) tissue was incubated with 4-14C-T as substrate, in the presence of 4-OH-A (10(-8) to 10(-6) M); the amounts of the 5 alpha-reduced metabolites formed were quantitated. The effects of 4-OH-A were compared with those of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), a known inhibitor of the 5 alpha-reductase. In the absence of 4-OH-A and 4-MA, human BPH tissue converted T to DHT and the diols readily. Both 4-OH-A and 4-MA induced significant and dose-related decreases in the formation of both DHT and the diols. The degree of inhibition induced by the different concentrations of 4-OH-A and 4-MA were 31, 41, 72% and 57, 87, 97%, respectively. The decreased formation of the diols was a consequence of the decreased availability of DHT (the immediate precursor of the diols) and was not due to direct effects of the inhibitors on the 3-hydroxysteroid dehydrogenases; both 4-OH-A and 4-MA were totally unable to modify the conversion of DHT to the diols, when 4-14C-DHT was used as substrate. Thus, 4-OH-A inhibits the process of 5 alpha-reduction of T in BPH tissue. This molecule might represent a potential new agent for the prevention and/or treatment of human BPH.

Topics: 5-alpha Reductase Inhibitors; Aged; Androstane-3,17-diol; Androstenedione; Aromatase Inhibitors; Azasteroids; Dihydrotestosterone; Humans; In Vitro Techniques; Male; Middle Aged; Prostatic Hyperplasia; Testosterone