cetrorelix and Genital-Diseases--Female

The effect of cetrorelix given in the early implantation period on rat pregnancy was investigated.. Forty-nine virgin Sprague-Dawley rats were randomized into six groups. At the 4th or 8th days of sperm plug, groups received 15, 75, 150 μg/kg cetrorelix or saline. Three subjects were randomly selected from each group and sacrificed at 11th gestational day for histomorphometric analysis. The remaining subjects were allowed to complete their pregnancy period. Volumes of total conceptus, labyrinth zone, transitional zone, giant cell zone, and exocoelomic cavity were calculated according to Cavalieri's principle.. Subjects receiving cetrorelix at 15 or 150 μg doses at the 4th day (D4) and those receiving cetrorelix at 150 μg dose at the 8th day (D8) of pregnancy delivered later than the controls. On necropsy examination at the 11th day, mean embryo weights of the cetrorelix 15 D4, 150 D4, 15 D8 and 75 D8 groups were found to be significantly lower than that of the controls (p<0.05). On histomorphometric evaluation, volumes of the fetuses and the amniotic sacs were decreased by cetrorelix at all doses studied dose dependently. Gross congenital anomalies were observed in the pups of three rats of the cetrorelix 150 D4 and D8 groups.. The results of this study suggest that cetrorelix in the early post-implantation period may lead to serious side effects in the rat.

Topics: Abnormalities, Drug-Induced; Amnion; Animals; Dose-Response Relationship, Drug; Embryonic Development; Female; Genital Diseases, Female; Gestational Age; Giant Cells; Gonadotropin-Releasing Hormone; Hormone Antagonists; Placenta; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley

Topics: Contraceptive Agents, Male; Female; Genital Diseases, Female; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Male; Prostatic Neoplasms; Reproductive Techniques

Inhibin and activin are structurally related dimeric peptide hormones and are members of the TGF-beta superfamily of proteins. In the accompanying paper, we describe transgenic mice that overexpress the inhibin alpha-subunit gene from a metallothionein-I promoter (MT-alpha) and examine the effects of the MT-alpha transgene on gonadotropin levels and fertility. To characterize the effects of increased inhibin alpha-subunit on gonadal morphology and function, in this report we investigate gonadal histology, steroid hormone levels, and the basis of ovarian cyst formation in MT-alpha transgenic mice. MT-alpha transgenic female mice develop large fluid-filled ovarian cysts of follicular origin as early as 3 months of age. By 12 months of age, more than 92% of female MT-alpha transgenic mice develop ovarian cysts compared with less than 25% of wild-type littermates. Ovarian cysts form unilaterally or bilaterally, and cystic ovaries often have a greatly expanded bursal sac. Additionally, the ovaries of MT-alpha transgenic mice contain polyovular follicles and have fewer mature antral follicles and corpora lutea. MT-alpha female mice exhibit abnormal steroid hormone production, with increased serum T levels and reductions in serum E with corresponding reductions in uterine mass. In the MT-alpha transgenic males, testis size was decreased by 20-40% compared with control males, and there is a corresponding reduction in seminiferous tubule volume. After a chronic treatment with a GnRH antagonist, MT-alpha female mice continued to develop ovarian cysts and bursal sac expansions, although the cysts were markedly reduced in size. These results indicate that the expression of the rat inhibin alpha-subunit in mice results in significant ovarian pathology, reduced testicular size, and altered ovarian steroidogenesis. The antagonist studies are consistent with a direct ovarian effect of the alpha-subunit transgene product mediated by changes in the inhibin-to-activin ratio in these mice.

Topics: Animals; Cysts; Estrogens; Female; Genital Diseases, Female; Genital Diseases, Male; Gonadotropin-Releasing Hormone; Hormone Antagonists; Inhibins; Male; Mice; Mice, Transgenic; Ovarian Diseases; Ovary; Rats; Testis; Testosterone