Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity.
Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal-reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.
Zelinski-Wooten
M B
MB
Division of Reproductive Sciences, Oregon Regional Primate Research Center, Beaverton 97006, USA.
Slayden
O D
OD
Chwalisz
K
K
Hess
D L
DL
Brenner
R M
RM
Stouffer
R L
RL
D000818:Animals; D003271:Contraceptive Agents, Female / Q000008:administration & dosage*; D003338:Corpus Luteum / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D005298:Fertility / Q000187:drug effects; D005640:Follicle Stimulating Hormone / Q000097:blood; D006727:Hormone Antagonists / Q000008:administration & dosage*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008253:Macaca mulatta; D008597:Menstrual Cycle / Q000097:blood / Q000187:drug effects* / Q000502:physiology; D010053:Ovary / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000097:blood; D011372:Progestins / Q000037:antagonists & inhibitors*
D003271:Contraceptive Agents, Female; D006727:Hormone Antagonists; D011372:Progestins; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone