Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats

Abstract

Our previous studies showed that treatment of female rats with large doses of Cetrorelix, an antagonist of luteinizing hormonereleasing hormone (LHRH), reduces levels of serum LH, estradiol, progesterone, and the concentration of pituitary LHRH receptors (LHRH-Rs) and their mRNA expression. Serum LH and testosterone levels and pituitary LHRH-R in male rats are also decreased by high doses of Cetrorelix. This approach can be used for therapy of sex hormone-dependent cancers. However, in conditions where an incomplete hormone deprivation is indicated, lower doses of Cetrorelix may suffice. Thus, we investigated the effect of a 30-day treatment with a low-dose depot formulation of Cetrorelix (20 -24 g per kg per day) on the pituitary-gonadal axis of male and female rats. In both sexes, lower serum LH levels were observed on day 4 after administration. In males, LH returned to control levels by day 10, whereas in females, a rebound LH elevation occurred. Testosterone levels in male rats were decreased up to day 20, but on day 30, the values were similar to controls. In females, serum estradiol was reduced on day 4; however, by day 10 it returned to normal. Progesterone levels were diminished through the entire period. Female rats showed diestrous smears during the first week of treatment and prolonged estrous periods thereafter. The weights of testes and ovaries were significantly lower, but not the weights of prostate, seminal vesicles, and uterus. Pituitary LHRH-R mRNA and LHRH-R protein levels were not significantly different from the controls. Thus, the treatment with low doses of Cetrorelix did not seriously impair gonadal functions. The results suggest that Cetrorelix in low doses induces only a partial pituitary-gonadal inhibition and might be indicated for treatment of endometriosis, leiomyomas, and benign prostatic hyperplasia.luteinizing hormone-releasing hormone analog ͉ luteinizing hormone-releasing hormone receptor L uteinizing hormone (LH)-releasing hormone (LHRH) exerts its effect on pituitary gonadotropes through the high-affinity G protein-coupled LHRH receptors (LHRH-Rs) and stimulates the release of LH and follicle-stimulating hormone, which in turn regulate reproductive functions and sex steroid secretion (1-7). The responses to LHRH vary under different conditions and depend on the mode of application and the doses delivered to gonadotrope cells. Prolonged exposure to high doses of LHRH or its agonists leads to an inhibition of pituitary responses and the suppression of serum LH, follicle-stimulating hormone, and sex steroid levels (8-10). This effect is the result of the downregulation of pituitary LHRH-Rs and inhibition of LHRH-R gene expression by mechanisms that have not been fully elucidated (11,12). Chronic administration of LHRH agonists can produce reversible medical castration and is used clinically for treatment of sex hormone-dependent cancers and various gynecologic conditions (2,6,7,10).However, in clinical situations, in which an immediate suppression of gonadotropins is desired, L...

Antagonistic and Agonistic GnRH Analogue Treatment of Precocious Puberty: Tracking Gonadotropin Concentrations in Urine

“…These results suggest an advantage over agonists in clinical conditions where a partial pituitary gonadal inhibition is desired [5, 11, 12]. In a recent study, Mardesic et al [14] showed in postmenarchal young women with hematological malignancies a rapid suppression of the pituitary-gonadal axis by combining of GnRH agonist and GnRH antagonist.…”

“…Multiple injections of these long-acting GnRH agonists over a period of time are necessary to forestall reactivation of the gonadotropin and gonadal steroid hormone secretion which reactivate soon after GnRH agonist treatment is discontinued [6]. GnRH antagonists offer theoretical advantages in treating precocious puberty, especially if an immediate suppression of gonadotropins is desired [5], but there are still no clinical data showing that GnRH antagonists are superior in treating precocious puberty compared to agonists in humans.However, experiments with rats indicate strong potential for the development and testing of long-acting depot preparations of GnRH antagonists (available for experiment use only) in treating precocious puberty, showing an immediate suppression of gonadotropin secretion by GnRH antagonist treatment [11]. Recently we were able to show in peripubertal female rats that a combination of antagonist and agonist could prevent the agonist ‘flare-up’, if the first injections of both were administered concurrently, while a sequential antagonist followed by agonist treatment was not effective [12], leading to the concurrent methodology used in this study.…”

Induction of Androgen Formation in the Male by a TAT-VDAC1 Fusion Peptide Blocking 14-3-3ɛ Protein Adaptor and Mitochondrial VDAC1 Interactions

“…injected into 60-64-dayold rats at 0.4 mg/day for 4 days as previously described. 33 T levels Figure 4 TVS167 administration modulates in vivo T production. (a) Testes dissected from adult Sprague-Dawley rats were cultured in media supplemented with or without TVG167 or TVS167 and/or hCG (120 minutes).…”

Identification of new gonadotrophin-releasing hormone partial agonists

“…There is no doubt that potent partial agonists may be useful in clinical practice, since they may provoke significant suppression of the hypothalamic-gonadotroph axis and allow endogenous oestrogen to remain at the level needed for maintenance of bone density and prevention of symptoms of oestrogen deficiency. For example, Horvath et al (2004) have approached this challenge using low doses of the GnRH antagonist, cetrorelix. Their results suggest that cetrorelix in low doses induces only a partial pituitary-gonadal inhibition and might be indicated for …”