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Protection by Steroid Contraceptives against Procarbazine-induced Sterility and Genotoxicity in Male Rats¹

Equipe "Interactions Cellulaires et Contróle de la Fertilité Male" URA CNRS 256, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France

Several recent morphological studies in various mammals have suggested that partial protection of the seminiferous epithelium against cancer therapeutic agents could be obtained by treatments using gonadotropin-releasing hormone analogues or steroids. However, considering that anticancer drugs can induce genetic lesions in germ cells that may transmit abnormalities to offspring (M. Auroux and E. Dulioust, Behav. Brain Res., 16: 25–36, 1985; M. G. Horstman et al., Cancer Res., 47: 1547–1550, 1987), we believe that the assessment of a possible protection of testicular function must necessarily include tests that would detect qualitative damage of germ cells and abnormalities of the progeny. This study in adult rats aims at: (a) obtaining objective data on testicular effects of a contraceptive regimen (medroxyprogesterone acetate plus testosterone) at daily s.c. doses of 8 and 1 mg/kg, respectively, for 55 days and of an anticancer drug (procarbazine) at an i.p. dose of 150 mg/kg on Days 40, 47, and 55 of the experiment: (b) assessing the possible paternally mediated effects of these compounds on the outcome of pregnancy; and (c) attempting to prevent the possible quantitative and qualitative effects of procarbazine on treated animals and on their offspring by combining the contraceptive preparation and the anticancer drug treatments.

Starting 5 days after the last injection, nine to 12 treated rats taken from each of the experimental groups were individually placed with two mature virgin females for serial mating trials. Every 20 days, and after a resting period of 5 days, the females were changed and, following parturition, fertility parameters were determined (percentage of fertile males, litter size, pre-, post-, and total implantation losses). In addition, on Days 1, 75, and 100 posttreatment, rats from each group (six to 12/group) were killed to determine testicular histology, body and reproductive organ weights, serum follicle-stimulating hormones luteinizing hormone and testosterone, and the number of spermatozoa in the cauda epididymides.

Our results provide the first evidence that: (a) procarbazine induces both quantitative (histology, sperm reserves) and qualitative (fertility, postimplantation losses) damage to germ cells and, in particular, to spermatogonia which, when this does not lead to sterility, is transmitted as impaired implantation and development abilities to the male progeny; and (b) medroxyprogesterone acetate plus testosterone can successively be used as a contraceptive regimen in the adult rat which can protect testicular function against impaired spermatogenesis as well as against genetic damage in germ cells (normal fertility parameters of the male offspring).

¹ This work was supported by l'Association pour le Développement de la Recherche sur le Cancer (Villejuif, France; Grant 6339), by l'Institut National de la Santé et de la Recherche Médicale (Grant 844019/844004), and by Roche Products (Neuilly sur Seine, France).

² Recipient of a studentship from l'Association pour le Développement de la Recherche sur le Cancer.

³ To whom requests for reprints should be addressed, at Université de Rennes I, URA CNRS 256, Campus de Beaulieu, 35042 Rennes Cedex, France.

Received 4/ 7/89. Revised 10/10/89. Accepted 10/31/89.

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