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).
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 1x10(6) 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.
Hild
Sheri Ann
SA
Division of Reproductive Endocrinology and Toxicology, BIOQUAL, Inc., 9600 Medical Center Drive, Rockville, Maryland 20850, USA. shild@bioqual.com
Marshall
Gary R
GR
Attardi
Barbara J
BJ
Hess
Rex A
RA
Schlatt
Stefan
S
Simorangkir
David R
DR
Ramaswamy
Suresh
S
Koduri
Sailaja
S
Reel
Jerry R
JR
Plant
Tony M
TM
D000284:Administration, Oral; D000818:Animals; D003272:Contraceptive Agents, Male / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D004822:Epididymis / Q000033:anatomy & histology / Q000187:drug effects; D005640:Follicle Stimulating Hormone / Q000097:blood; D007192:Indenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007986:Luteinizing Hormone / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D009845:Oligospermia / Q000139:chemically induced* / Q000534:rehabilitation*; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020127:Recovery of Function; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000097:blood
C435918:CDB 4022; D003272:Contraceptive Agents, Male; D007192:Indenes; D010880:Piperidines; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone