Role of peripheral and central aromatization in the control of gonadotrophin secretion in the male sheep

Abstract

Both testosterone and its aromatized metabolite, oestradiol-17b, are known to act centrally on the secretion of GnRH, but the major site of aromatization is not clear as aromatase activities are found in numerous tissues including brain and testis. Here, we tested the importance of central aromatization of testosterone using a non-steroidal aromatase inhibitor, fadrozole. To distinguish between testicular and non-testicular sites, five intact and five testosterone-infused castrated rams (600 g kg –1 per 24 h for 3 days) were given four injections of fadrozole (i.m; 500 g kg –1 ) at 48, 52, 64 and 68 h relative to the start of testosterone infusion. Control rams (n = 5) received vehicle only. Fadrozole treatment decreased plasma oestradiol-17b concentrations and increased the LH pulse frequency in both intact rams and testosterone-treated castrates, suggesting that non-testicular sites of aromatization are important in the control of pulsatile LH secretion. To test the importance of central aromatization, intact rams (n = 5) were infused into the third ventricle with vehicle (artificial cerebrospinal fluid) or with fadrozole (20 and 200 g kg –1 per day). After two weeks, the same two doses of fadrozole were infused intravenously instead of intracerebrally. Central infusion of fadro-zole did not affect plasma oestradiol concentrations but increased LH pulse frequency. Only the highest dose increased LH pulse frequency when infused intravenously. In conclusion, central aromatization is involved in the control of pulsatile LH secretion in male sheep.

Brain aromatase: Roles in reproduction and neuroprotection

“…Clinical studies in men also confirm that hypothalamic aromatase is important for negative feedback [58]. In sheep, LH concentrations were elevated after brain aromatase was inhibited by intracerebral infusion of fadrozole [57]. These results provide direct proof for the concept that central aromatization is required for suppression of LH secretion by testosterone.…”

“…However, the importance of aromatase in these functions differs across species. For instance, a preponderance of evidence in men, non-human primates, sheep, and mice suggests that testosterone must be aromatized in the hypothalamus to completely exert negative feedback control over LH secretion, but no role for aromatase can be demonstrated in rats and guinea pigs [57][58][59][60]. The rat and mouse are excellent models to study the essential role of brain aromatase for the activation of male sexual behaviors [61,62].…”

Anatomic relationships between aromatase and androgen receptor mRNA expression in the hypothalamus and amygdala of adult male cynomolgus monkeys

“…Taken together, these data suggest that circulating T, as well as brain-derived estrogens and circulating estrogens, all contribute to the central feedback regulation of gonadotropin secretion in males (Resko et al, 1977). Although we do not completely understand the mechanism by which androgens and estrogens interact or the specifics of the hypothalamic circuitry involved, several studies have provided direct (Sharma et al, 1999) and indirect (Ellinwood et al 1984;Hayes et al, 2000;Scott et al, 1997) evidence that estrogens and, in particular, central aromatization is involved in the control of pulsatile LH secretion in males.…”

Inhibition of Luteinizing Hormone Secretion by Localized Administration of Estrogen, but not Dihydrotestosterone, Is Enhanced in the Ventromedial Hypothalamus During Feed Restriction in the Young Wether1

“…For example, testosterone may act directly on AR, but it may also be metabolized to the more potent androgen dihydrotestosterone (DHT) via 5␣-reductase or to estradiol via aromatase [34]. Although the role of DHT as a physiological inhibitor of LH is less characterized than the role of estradiol, DHT reduces pulsatile LH secretion [35] and the conversion of testosterone to DHT by 5␣-reductase is a physiologically important step in the inhibition of LH secretion by testosterone in male sheep [36].…”