Contraceptive potential of an antiprogestin ZK 98.734: reversal of ZK 98.734--induced blockade of folliculogenesis with FSH and LH and their differential effects in bonnet monkeys.

Studies were undertaken in adult bonnet monkeys to investigate whether treatment with an antiprogestin ZK 98.734 at weekly intervals, starting from day one of menstrual cycle, could arrest ovulation and also to determine if ZK 98.734 induced blockade of ovulation could be reversed with gonadotropins. Adult animals have ovulatory menstrual cycles of normal duration were treated at weekly intervals with ZK 98.734 (25 mg/dose, sc, oil base) for 10 consecutive weeks and its effects on serum levels of estradiol, bioactive LH and progesterone, and endometrial histology were investigated. Following treatment with the antiprogestin they were treated with hMG or hFSH alone. Ovulation was blocked during treatment period in all the animals (n = 14). Typical follicular phase rise in estradiol levels was inhibited, mid cycle surge in the levels of bioactive LH was abolished and serum progesterone levels remained below 1 ng/ml throughout the treatment period. However, prolonged treatment had no significant effect on the basal levels of estradiol which were around 50 pg/ml. ZK 98.734 also had no significant effect on cortisol levels. In animals (n = 4) followed for recovery after the last dose, the treatment cycle length was increased to 117.8 + 6.8 days. In three animals the treatment cycles were anovulatory, whereas in one delayed ovulation with luteal insufficiency was observed. The endometrium had become atrophic. Treatment with hMG (Pergonal: 35 I.U. hLH and 35 I.U. hFSH) or hFSH (Metrodin, 35 I.U.) for 7 consecutive days initiated folliculogenesis and the animals ovulated either spontaneously or after a single im injection of hCG (100 I.U.) on day 8 in ZK 98.734 treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intranasal administration of norethisterone on folliculogenesis, cervical mucus, vaginal cytology, endometrial morphology and reproductive-endocrine profile in women.

The effects of intranasal administration of norethisterone (NET) on menstrual cycle length, folliculogenesis, serum levels of estradiol, FSH, LH and progesterone, vaginal cytology, cervical mucus and endometrial morphology were studied in 8 volunteers (age 28 to 39 years, weighing between 46 and 54 kg). The study period comprised 4 consecutive menstrual cycles. In the first cycle (pretreatment cycle), only the vehicle (alcohol, propylene glycol, water; 3:3:4) was sprayed intranasally (100 microliters in each nostril), using a metered nebulizer, once daily from day 3 to the last day of menstrual cycle. In the next two cycles (treatment cycles), NET (300 micrograms/day) was administered once daily, starting from day one of menstrual cycle, between 9 and 10 a.m. The fourth cycle was a post-treatment cycle in which the volunteers were monitored for recovery. Blood samples (about 5 ml each) were collected once daily from day 8 to 24 and thereafter on alternate days until the last day of cycle during all the 4 cycles. Levels of estradiol, FSH, LH and progesterone were measured in the serum samples by radioimmunoassay methods. Cervical mucus samples and vaginal smears were collected once daily starting from day 7 or 8 of each cycle until the mucus was very scanty. Serial pelvic ultrasonography was performed starting from day 7 or 8 until the growing follicle disappeared or throughout the cycle in case a growing follicular cyst was observed. Endometrial aspirates were collected once around day 22 in each cycle and processed for routine histological examination.

Gonadal and pituitary responses to progesterone antagonist ZK 98.299 during the follicular phase of the menstrual cycle in bonnet monkeys.

ZK 98.299 is a potent progesterone antagonist. Its effects on folliculogenesis, bioactive LH, ovulation and menstrual cycle (m.c.) length were studied in adult bonnet monkeys. ZK 98.299 (20 mg/day) was administered s.c., once daily on days 5 to 15 of m.c., to ten animals. The pretreatment m.c. was of 26.5 days (25 to 28 days, mean with 95% confidence limits) and on treatment it was significantly (p less than 0.001) prolonged to 46.9 days (39 to 54 days). The anticipated midcycle rise in estradiol and bioactive LH levels was completely blocked in six and attenuated in three animals during the treatment period. However, the levels did not drop below the early follicular phase levels. In one animal (#90), though the cycle length was prolonged by 5 days the midcycle rise in estradiol and bioactive LH levels was observed during the treatment period and this animal had normal luteal function. Seven animals had delayed ovulation whereas, two had anovulatory treatment cycles. The rise in estradiol and bioactive LH levels, prior to ovulation in the treatment cycles, was compatible with the midcycle rise observed in the pretreatment cycles. Serum progesterone levels during the luteal phase of the treatment cycles were normal in six animals whereas, in two they were indicative of luteal insufficiency. In two animals, the treatment cycles were anovulatory. ZK 98.299 had no effect on the duration of menses. The post-treatment cycles were of normal duration. This study suggests that the administration of ZK 98.299 during the follicular phase blocks estradiol and bioactive LH release and terminates the follicular phase in most of the animals. The follicular phase is reinitiated after the treatment is stopped.