Development of l-CDB-4022 as a Nonsteroidal Male Oral Contraceptive: Induction and Recovery from Severe Oligospermia in the Adult Male Cynomolgus Monkey (Macaca fascicularis)

• Published in: Endocrinology (Philadelphia) 2007-04, Vol.148 (4), p.1784-1796
• Main Authors: Hild, Sheri Ann, Marshall, Gary R, Attardi, Barbara J, Hess, Rex A, Schlatt, Stefan, Simorangkir, David R, Ramaswamy, Suresh, Koduri, Sailaja, Reel, Jerry R, Plant, Tony M
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Administration, Oral; Animals; Biological and medical sciences; Contraceptive Agents, Male - administration & dosage; Contraceptives; Dosage; Drug Evaluation, Preclinical; Epididymis; Epididymis - anatomy & histology; Epididymis - drug effects; Follicle Stimulating Hormone - blood; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gametocytes; Germ cells; Gynecology. Andrology. Obstetrics; Indenes - administration & dosage; Indenes - pharmacokinetics; Inhibin; Luteinizing Hormone - blood; Macaca fascicularis; Male; Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance; Males; Medical sciences; Metabolites; Models, Biological; Monkeys; Motility; Oligospermia - chemically induced; Oligospermia - rehabilitation; Oral contraceptives; Piperidines - administration & dosage; Piperidines - pharmacokinetics; Plasma levels; Recovery; Recovery of Function; Sex hormones; Sperm; Spermatids; Spermatocytes; Testes; Testis - anatomy & histology; Testis - drug effects; Testosterone; Testosterone - blood; Tubules; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-1487

The present study was undertaken to examine the antispermatogenic effect of l-CDB-4022 in the adult male cynomolgus monkey. Monkeys (four per group) were dosed via nasogastric tube for 7 d with l-CDB-4022 at 12.5 mg/kg·d or vehicle (d 0 = first day of dosing). Plasma levels of l-CDB-4022 and its deesterified metabolite were nondetectable prior to treatment and in all vehicle-treated monkeys. Peak levels of l-CDB-4022 and its metabolite were observed at 4 h after dosing with steady-state levels apparent around d 4. Sperm concentration and total sperm per ejaculate were decreased to levels below 1 × 106 sperm/ml or sperm/ejaculate in l-CDB-4022-treated monkeys by d 17 and remained suppressed through wk 6. Sperm motility also declined to 0% for 6 wk. Testicular volume was reduced in l-CDB-4022-treated monkeys through d 21. The left testis and epididymis were removed from all monkeys on d 24. At this time, the most mature germ cells in the seminiferous tubules of testes from l-CDB-4022-treated monkeys were either spermatocytes or round spermatids. Immature germ cells, but not mature sperm, were found in the efferent ducts and collapsed epididymal lumen of l-CDB-4022-treated monkeys. A steady recovery in sperm motility, concentration, and total sperm per ejaculate was observed in l-CDB-4022-treated monkeys such that these parameters were not different from those of vehicle-treated monkeys by wk 16. Volume of the remaining testis increased in vehicle- and l-CDB-4022-treated monkeys after hemicastration; however, the increase in l-CDB-4022-treated monkeys was delayed compared with that observed in the vehicle-treated monkeys. The morphology of the remaining testis and epididymis, which were removed on wk 17, was normal. Serum inhibin B levels were increased in l-CDB-4022-treated monkeys during the dosing interval; thereafter serum inhibin B levels declined such that there was no difference between the groups by wk 3. l-CDB-4022 treatment did not affect circulating levels of testosterone, LH, FSH, or estradiol. In conclusion, these data indicate that in the cynomolgus monkey, a representative higher primate, l-CDB-4022 exerts a selective antispermatogenic action, which was reversible under the conditions of this study and thus has potential as a nonhormonal oral male contraceptive.