Ten analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 2 with D-amino acids and at 6 with either a D-amino acid or a nonasymmetric amino acid were synthesized by solid-phase methodology and assayed for antiovulatory activity. [D-Phe2]-LH-RH substituted in the 6 position with D-Ala, D-Leu, D-Arg, D-(Ph)Gly, D-Phe, or 2-Me-Ala possessed varying degrees of antiovulatory activity. [D-p-F-Phe2-D-Ala6]-LH-RH was one of the most active antiovulatory compounds, while the [D-p-Cl-Phe2-D-Ala6]-LH-RH analog was devoid of activity at a comparable dose.

Animals↗

PubMed1975

Post-coital contraceptive and uterotrophic effects of luteinizing hormone releasing hormone.

LRH, administered subcutaneously (s.c.) or orally (p.o.) to female rats, was capable of interfering with pregnancy when given on various days of gestation. A 100% inhibition of pregnancy was demonstrated at daily s.c. doses of 1000 mug/rat administered over days 1-7; LRH also was effective as an interceptive, terminating pregnancy in 100% of rats when delivered from days 7-12 of pregnancy at a daily dose of 1000 mug/rat s.c. or p.o. An 80% inhibition also was observed in rabbits administered LRH from days 1-7 at a total dose of 1000 mug/kg, s.c. Uterotrophic studies demonstrated that LRH, administered s.c. to intact immature mice, produces a dose-related increase in uterine and ovarian weight and initiates vaginal opening. The hypothalamic hormone also produced a dose-related increase in uterine weight in ovariectomized mice and hypophysectomized rats. The data suggest that LRH has a post-coital contraceptive effect, presumably acting via hyperstimulation of the hypophysial-ovarian steroid-uterine axis, and/or by a direct extrapituitary (uterine) effect.

Animals↗

PubMed1975

The differential effects of diestrous progestogen administration of proestrous gonadotrophin levels.

Progesterone or d-norgestrel, a totally synthetic progestogen, administered subcutaneously at 1330 h on diestrus (Day 2) of 4-day cyclic rats, inhibited ovulation and increased the vaginal cycle length in a dose-related manner. d-norgestrel was at least 5 times as potent as inhibitor of ovulation as progesterone. The dose-related inhibition of ovulation was directly related to suppression of the proestrous serum LH surge. Proestrous serum FSH levels were not depressed at the minimum dose of d-norgestrel that produced both a 100% reduction in ovulation (MED100) and a significant decrease in proestrous serum LH. However, progesterone produced a significant decrease in proestrous serum FSH at its anti-ovulatory MED100. Progesterone and d-norgestrel were equipotent (100 mug/100 g BW) with respect to significant suppression of proestrous serum FSH levels. Follicular growth was retarded, but only at the higher doses of either progestogen which suppressed FSH and LH. These data suggest that a) the increase in acute anti-ovulatory potency of a synthetic non-estrogenic progestogen over progesterone lies in its ability to reduced selectively serum LH levels at low doses, b) the progestational block of ovulation takes place via the hypothalamic-pituitary axis and not the ovary, and c) the retardation of follicular growth that accompanies ovulatory inhibition after diestrous administration of high doses of a progestogen takes place only when both serum FSH and LH are significantly reduced.

Animals↗

PubMed1975

Ihibition of the pre-ovulatory proestrous gonadotropin surge, ovulation and pregnancy with a peptide analogue of luteinizing hormone releasing hormone.

D-[PHE]-2-D[ALA]-6-LRH (Wy-18,185), an analogue of synthetic hypothalamic LRH, was evaluated for its anti-fertility properties. The compound dampens the preovulatory proestrous surge of serum LH and FSH in rats, is an active anti-ovulatory agent in both rats and rabbits and prevents pregnancy when administered pre-coitally to rats. Additionally, the compound suppresses the ovulatory event in rats only during the cycle in which it is acutely administered, does not interfere with the rat vaginal cycle and is devoid of any effects on body, ovarian and uterine weights when given acutely. The compound is a moderate LRH agonist in rats but does not induce ovulation in rats or rabbits.

Animals↗

PubMed1974