Endocrinological Studies on TAP-144-SR, a Sustained-Release Formulation of a Potent GnRH Agonist (D-Leu6-(des-Gly10-NH2)-GnRH Ethylamide), in male Rats.

Abstract

The paradoxical effects of TAP-144-SR, a biodegradable sustained-release formulation of a potent GnRH agonist (TAP-144, leuprolide acetate) were evaluated in male rats by comparing its potency with that of TAP-144 solution.A single sc injection of TAP-144-SR (equivalent to 0.1 mg/kg/day as TAP-144), prepared by encapsulating the agonist in microcapsules of copoly (DLlactic/glycolic acid), suppressed serum levels of androgens, and the levels remained suppressed for 4 weeks.The potency of the paradoxical effects of TAP-144-SR was evaluated 4 weeks after treatment by comparing it with that of TAP-144 solution administered daily for 4 weeks. Both daily injections of TAP-144 solution and a single injection of TAP-144-SR (equivalent to 0.02, 0.2 or 2 mg/kg/day as TAP-144) decreased the weight of the testes, prostates and seminal vesicles in a dose-dependent manner in a 4-week assay in male rats. TAP-144-SR was more effective than TAP-144 solution in reducing these organ weights. Serum and pituitary concentrations of LH and FSH and serum testosterone levels were also lower in TAP-144-SR-treated than in TAP-144 solution-treated rats. These results indicate that the paradoxical effects were more extensive upon TAP-144-SR treatment, suggesting that maintaining constant serum TAP-144 levels results in more extensive desensitization of the pituitary and testes. These results also suggest advantages of TAP-144-SR over TAP-144 solution in both efficacy and convenience as an anti-prostatic tumor agent.

Gonadotropin-releasing hormone agonist has the ability to induce increased matrix metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea, and structural luteolysis in rats

“…However, an earlier study using GnRHa revealed that desensitization of the pituitary actually occurred because pituitary concentrations of LH and FSH were suppressed and additional treatment with GnRHa did not stimulate gonadotropin release from the already stimulated pituitary (Sudo et al 1990). Curious effects of GnRHa on the PMSG-hCGinduced luteinization process of superovulated rats have been reported (Harwood et al 1980b).…”

“…The treatment seemed not to cause desensitization of the pituitary gland, although changes in bioactive LH concentrations were not determined. However, a study using GnRHa revealed that densensitization of the pituitary actually occurred because pituitary concentrations of LH and FSH were suppressed, and additional treatment with GnRHa did not stimulate gonadotropin release from the already stimulated pituitary (Sudo et al 1990).…”

Gonadotropin-releasing hormone agonist administration reduced vascular endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of the ovaries of hyperstimulated rats

“…Treatment with GnRH-a, especially long-term treatment, clearly reduced VEGF, VEGFR-1, and VEGFR-2 expression in the ovaries of hyperstimulated rats. We chose the amount of GnRH-a treatment to cause the desensitization of the pituitary in accordance with previously published reports (14,26).…”

Effects of TAP-144-SR, A Sustained-Release Formulation of a Potent GnRH Agonist, on Experimental Endometriosis in the Rat.

“…This discrepancy in the effects of the two dosage formulations on gonadotropin levels has also been observed in male rats [19]. Pituitary concentrations of LH and FSH are also lower in TAP-144-SR-treated than in TAP-144-solutiontreated male rats.…”

“…These results indicate that at the highest dose, the sustainedrelease formulation of TAP-144 is more effective than TAP-144 solution in suppressing ovarian hormone-dependent tissue growth. TAP-144-SR is also more effective than TAP-144 solution in suppressing testicular hormone-dependent accessory sex organ weight in male rats [19]. The reason why TAP-144-SR is more efficient than TAP-144 solution at the highest dose, and the reverse is true at the lowest dose may be explained as follows.…”