Effect of the Antiandrogen Flutamide on Pituitary LH Content and Release

Abstract

Flutamide is a nonsteroidal antiandrogen that blocks androgen receptors, with a consequent increase in serum immunoreactive LH (I-LH) in the presence of high testosterone concentrations. Several studies suggested that the gonadal steroids also play an important role in the regulation of LH bioactivity (B-LH). Therefore, it seems difficult to understand how the blockade of pituitary androgen receptors leads to the increase in testosterone levels. The present study was designed to elucidate the effect of flutamide on serum I-LH, B-LH and testosterone, as well as on in vitro stimulation of pituitaries by gonadotropin-releasing hormone (GnRH), in intact and androgen-treated castrated rats. In intact animals, a dose of flutamide as low as 0.5 mg/day provoked a 7- to 8-fold increase in serum I-LH levels over the vehicle-injected controls, whereas B-LH and testosterone were unaffected. However, higher doses significantly increased serum B-LH to values similar to those obtained in vehicle-injected castrated animals, resulting in high testosterone levels. Flutamide treatment provoked a decrease in I-LH and B-LH pituitary content; this effect was significantly higher under in vitro GnRH stimulation. The releasable I-LH under GnRH stimulation was not affected by flutamide treatment; however, a marked decrease was observed in B-LH. The results presented here show that (1) the interference of androgen action by flutamide is as efficient as castration to affect I-LH and B-LH; (2) androgens may act directly at the pituitary level; (3) androgens modulate the action of GnRH in the pituitary gland, and (4) the effect of androgens on the pituitary can be observed at two distinct levels, depending on the androgen concentration, that is on LH synthesis and release, and on LH bioactivity. In addition, our results confirm that high doses of flutamide are not enough to abolish the biological action of androgens, due to the increase in LH bioactivity resulting in high androgen concentrations.

Morphologic and biochemical changes in male rat lung after surgical and pharmacological castration

“…Group I was sham operated and used as control, group II was subjected to castration by simple orchidectomy, group III was subjected to orchidectomy and received testosterone (100 µg/kg body weight) daily from day 2 until day 21 after castration by intramuscular (im) injection, and group IV was subjected to orchidectomy and received testosterone daily from day 15 to day 21 after castration. Group V consisted of sham-operated animals which received flutamide im (5 mg/250 g body weight) dissolved in 5% ethanol and mixed with gelatin twice a day (at 8:00 a.m. and 8:00 p.m.) from day 15 to day 21 after surgery (10). All animals were killed 21 days after surgery.…”

Hormonal programming of rat social play behavior: Standardized techniques will aid synthesis and translation to human health

“…This duality of mechanism highlights the complexity of effects that can be induced by EDCs, and sheds new light on data from Colbert et al (2005), which suggest that vinclozolin might have a variety of prenatal effects depending on which mechanism is activated. However, AR antagonists can increase plasma levels of testosterone, ultimately increasing T metabolites (Hellman et al, 1977;Sardanons et al, 1989). A substantial increase in the concentration of T and its metabolites could in fact outcompete antagonistic binding of AR or activate ER.…”

Flutamide as a tool to study the hormonal regulation of the reproductive tract in the golden hamster

“…This can be achieved by the use of non-steroidal antiandrogens such as flutamide (FLU), which are reported to block the negative feedback of testosterone on the hypothalamic-pituitary axis, without exhibiting progestational effects. Flutamide at low or moderate doses elevates LH and testosterone serum levels, also exerting a stimulatory action on testicular steroidogenesis and testicular weight, despite an important inhibition of reproductive accessory organs (Neri et al, 1972;Viguier-Martinez et al, 1983;Knuth et al, 1984;Roselli & Resko, 1984;Marchetti & Labrie, 1988;Gupta et al, 1989;Sardanons et al, 1989). Higher doses of FLU have been demonstrated to exert inhibitory effects on the testis (Singh, 1984).…”