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Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male
A S Bhatnagar1, P Müller, L Schenkel
1Department of Research and Development, Pharmaceuticals Division CIBA-GEIGY Limited, Basel, Switzerland.
Abstract:
Of the gonadal steroids in the male, testosterone is the most important regulator of gonadotrophin secretion. However, whether testosterone affects gonadotrophin secretion directly or whether it must first be aromatized to estrogens is controversial. We have reported extensively on the endocrine and anti-tumor effects of the non-steroidal aromatase inhibitors CGS 16949A and CGS 20267 in adult female rats. In these animals, both inhibitors potently and selectively inhibit estrogen biosynthesis. Thus these agents can be effectively used in studying estrogen-dependent processes. CGS 16949A was administered for 14 days to adult male rats, over a dose range which in females suppresses estradiol and elevates LH. In male rats a suppression of estradiol was seen, however, there was no significant effect on either serum LH or on the weights of androgen-dependent organs. CGS 16949A, when administered to healthy men at a dose of 1 mg b.i.d. for 10 days, causes a significant fall in plasma estradiol and significant elevations of plasma FSH and testosterone. Dose-dependent suppression of serum estradiol and an increase in serum testosterone and LH are seen after administration of single oral doses of CGS 20267. These results indicate that in the male rat, inhibition of aromatization of testosterone to estrogens does not influence gonadotrophin secretion whereas in men the negative feedback exerted by testosterone on gonadotrophin secretion is dependent on the aromatization of testosterone to estrogens.
Insights
Testosterone regulates gonadotrophin secretion, but whether it acts directly or via estrogens is debated. In male rats, aromatase inhibition didn't affect gonadotrophins, but in men, it revealed estrogen's crucial role in testosterone feedback.
Area of Science:
- Endocrinology
- Reproductive Biology
- Pharmacology
Background:
- Testosterone is the primary regulator of gonadotrophin secretion in males.
- The mechanism by which testosterone exerts this regulation—directly or via aromatization to estrogens—remains controversial.
- Aromatase inhibitors selectively block estrogen biosynthesis, offering a tool to study estrogen-dependent processes.
Purpose of the Study:
- To investigate the role of estrogen in mediating testosterone's negative feedback on gonadotrophin secretion in male rats and humans.
- To determine if testosterone affects gonadotrophin secretion directly or requires aromatization to estrogens.
Main Methods:
- Administration of non-steroidal aromatase inhibitors (CGS 16949A and CGS 20267) to adult male rats and healthy men.
- Measurement of serum hormone levels (estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone) and androgen-dependent organ weights.
- Dose-ranging studies and fixed-dose administration over specified durations.
Main Results:
- In male rats, CGS 16949A suppressed estradiol but did not significantly alter LH levels or androgen-dependent organ weights.
- In healthy men, CGS 16949A (1 mg b.i.d. for 10 days) significantly reduced plasma estradiol and elevated plasma FSH and testosterone.
- CGS 20267 administration in men showed dose-dependent suppression of estradiol and increases in testosterone and LH.
Conclusions:
- In male rats, the aromatization of testosterone to estrogens is not essential for regulating gonadotrophin secretion.
- In men, the negative feedback of testosterone on gonadotrophin secretion is dependent on its aromatization to estrogens.
- These findings highlight species-specific differences in the neuroendocrine regulation of reproduction.