Inhibition of Aromatization Stimulates Luteinizing Hormone and Testosterone Secretion in Adult Male Rhesus Monkeys*

Abstract

Experiments were conducted to examine the role of aromatization in the control of LH and testosterone secretion in adult male rhesus monkeys. Treatment of male monkeys (n = 7) with sc Silastic packets containing the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) resulted in 1.5- to 3-fold elevations in serum LH and testosterone concentrations in six of seven animals. Concurrent treatment of ATD-treated monkeys with small quantities of estradiol-17 beta (n = 4) abolished the stimulatory effect of ATD. During ATD treatment, peripheral estradiol levels were reduced by 30% and hypothalamic aromatase activity, as determined in vitro, was reduced 80-90%. The lack of androgenic or antiandrogenic activity of ATD was demonstrated by its inactivity in either a mouse seminal vesicle bioassay or a highly sensitive penile spine bioassay. Furthermore, ATD did not react with rat prostatic or hypothalamic cytosol androgen receptors. 1,4,6-Androstatriene-17-ol-3-one, a possible metabolite of ATD in vivo, did react with prostatic and hypothalamic androgen receptors, but possessed no antiandrogenic activity in either bioassay. Thus, treatment of adult males with an aromatase inhibitor that inhibits both peripheral and central aromatization, and which has no apparent antiandrogenic activity, results in stimulation of LH and testosterone secretion. These data demonstrate that aromatization of androgens to estrogens plays an important role in negative feedback regulation of LH secretion and maintenance of normal testosterone levels in adult male primates.

Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility

“…The authors of that study concluded that both testosterone and oestradiol had a role in the negative feedback regulation of LH. This conclusion is consistent with the finding that suppression of aromatisation results in increases in LH concentrations in men, primates and dogs (Ellinwood et al 1984, Juniewicz et al 1988, Bhatnagar et al 1992, Trunet et al 1993, Plourde et al 1994. The situation in the rat was believed to be different, as short-term administration of non-steroidal aromatase inhibitors failed to alter serum LH concentrations; FSH concentrations were not measured in either study (Bhatnagar et al 1992, Plourde et al 1994.…”

“…Nevertheless, several studies involving the inhibition of aromatisation have shown a consistent and rapid increase in testosterone concentrations (50%) in humans (Bhatnagar et al 1992, Trunet et al 1993, Hayes et al 1999, primates (Ellinwood et al 1984, Dukes et al 1996, Shetty et al 1998 and dogs (Juniewicz et al 1988). In the present study, an increase in plasma testosterone concentrations occurred within 1 week of anastrozole treatment and was maintained for approximately 5 months but not beyond this time.…”

Evidence that oestrogen exerts an equivalent negative feedback action on LH secretion in male and female ferrets

“…Much evidence suggests that oestradiol, formed via aromatization of circulating testosterone, contributes to the regulation of LH secretion in males of several other species including the sheep (Schanbacher, 1984), dog (Worgul et al, 1981), and rhesus monkey (Ellinwood et al, 1984), but not the rat (Krey et al, 1982). Evidence from the ferret and rhesus monkey suggests that oestradiol produced by neural aromatization in the male may ultimately inhibit LH secretion as a result of its action on GnRH neurones in the hypothalamus.…”

Assessment of Circulating Hormones in Regulatory Toxicity Studies II. Male Reproductive Hormones

“…Primates, and macaques in particular, are more like dogs than rats in that their LH pulses are followed closely in time by a surge of T, and there are significant circadian differences in LH and T secretion, which are much higher at night than during the light hours (Plant 1981;Puri et al 1980;Steiner et al 1980;Steiner and Bremner 1981). Also like dogs, male macaques use E2 for the central feedback of peripheral hormones (Ellinwood et al 1984;Roselli and Resko 1990). The significant diurnal differences and the value of each experimental primate make it much more likely that blood will be sampled without terminating the animal.…”