Hypothalamic-pituitary-testicular function in rats after supraphysiological doses of a highly active LRH analogue (buserelin)

Abstract

Abstract. Male pre-pubertal rats (60 g) were treated with the LRH analogue, [D-Ser(But)6]LRH(1—9)-nonapeptide-ethylamide (buserelin, Hoe 766), during 4 weeks by daily sc injections of 5, 50 or 500 ng peptide (group I, II and III). At the end of treatment, hypothalamic LRH content and arylamidase activity (LRH degrading enzyme) were not changed. Pituitary arylamidase activity was reduced, but the pituitary LRH receptors (tested by analogue binding in vitro) were not diminished. Pituitary accumulation of [125I]buserelin 60 min after iv injection was not modified and organ distribution in liver and kidney was unchanged. Pituitary responsiveness to the analogue was reduced at the highest dose, but there was significant LH-release at all three dose levels. Testosterone production in vitro (stimulated by hCG) was unaltered in group I and dramatically reduced in group II and III. Testicular testosterone content and hCG binding by testes homogenates were dose-dependently reduced. Histology of the testes after 4 weeks treatment showed minimal impairment of spermatogenesis at the highest dose, whereas the epididymis was almost devoid of sperm. The results indicate, that low dose treatment with a highly active LRH analogue, buserelin, does not interfere with pituitary responsiveness (LRH receptors and LH-release) and testicular function (testosterone production, testosterone content, LH-receptor level). At higher doses, pituitary and testicular responsiveness are dose-dependently inhibited. At the pituitary level, LRH receptors were not reduced. The antifertility effect of supraphysiological doses at the testicular level is explained by an LH-dependent loss of LH-receptors.

Effects of an LHRH agonist on endocrine function, LHRH receptor and LH/hCG receptor in the pituitary-gonadal axis of male rats.

“…Similar findings were observed by Sandow et al (1980b), although they used pre-pubertal male rats. In our experiment, the plasma LH concentration reached a peak on day 7, whereas the pituitary LH content decreased to a minimum on day 3.…”

Anti-tumor and endocrine effects of chronic LHRH agonist treatment (Buserelin) with or without tamoxifen in premenopausal metastatic breast cancer

“…In our clinical study we found no clear indication for a direct anti-tumor effect of the Buserelin dose used, because the best responders had a complete castration indicating that 'pharmacological castration' may be the main mechanism of action in inhibiting tumor growth. However, one patient (6) showed an objective partial response in spite of the presence of peaks of estradiol.…”

“…In animals chronic treatment with supraphysiological doses of LHRH agonists causes: 1) 'partial hypophysectomy' with decreased gonadotropin (1,2) and prolactin secretion (2-5); 2) 'chemical castration' with a striking fall in plasma sex steroids followed by a reduction in weight of secondary sexual organs (1)(2)(3)(4)(5)(6); and 3) inhibition of the biological actions of sex steroids at their target organs (7)(8)(9). At least some of these endocrine effects have been suggested to be important in the treatment of hormone-dependent tumors such as breast (3,5,(10)(11)(12) and prostatic cancer (12,13) induced in animals.…”

Extrapituitary Actions of Gonadotropin-Releasing Hormone*

“…In immature rats chronic treatment with a GnRH agonist inhibits pubertal increases in Leydig cell steroidogenesis and LH receptor content, as well as inhibits maturation of the seminal vesicles (105,106).…”