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Mechanism of the Postcoital Contraceptive Effect of Luteinizing Hormone-Releasing Hormone: Ovarian Luteinizing Hormone Receptor Interactions^*

Endocrine Section, Wyeth Laboratories, Inc. Philadelphia, Pennsylvania 19101

Address requests for reprints to: Dr. Frederick Bex, Endocrine Section, Wyeth Laboratories, Inc., P. O. Box 8299, Philadelphia, Pennsylvania 19101.

Abstract

LHRH, via inducing inordinately high LH levels, can disrupt pregnancy in the rat. Based on studies indicating that LH can reduce gonadal content of its own receptor and thereby modify LH-dependent steroidogenesis, the effect of contragestational LHRH treatment on ovarian LH receptor dynamics was investigated. Pregnant rats were administered sc 200 ng LHRH/day during days 1–7 (pre- and periimplantation) or days 7–12 (postimplantation) of pregnancy. Vehicle-injected animals served as controls. At 1-day intervals, beginning the day after the first injection and continuing until the day after the final injection, animals were sacrificed for determination of pregnancy state, ovarian LH binding, and, in the postimplantational group, serum hormone levels.

LHRH treatment resulted in a marked decrease in the number of normal implantation sites as observed by day 6 in the preand periimplantational groups and by day 11 in the postimplantational group. Ovarian LH binding in both LHRH treatment groups was significantly decreased within 24 h after a single injection and continued to be depressed throughout the course of treatment. The degree of LH binding to isolated luteal homogenates from postimplantational animals autopsied on day 9 after 2 days of LHRH or vehicle treatment suggests that the differences seen using ovarian homogenates reflect changes in luteal LH binding. Scatchard analyses indicate that the decreased binding is due to a lower LH receptor concentration (LHRH, 0.2–0.7 x 10¹⁵ M/mg wet wt; controls, 3.9–4.4 x 10^-15 M/mg wet wt) rather than a change in receptor equilibrium constants (LHRH, Kd = 4.2–6.8 x 10^-10 M; controls, K_d = 8.3- 10.0 x 1O^-10 M).

In both LHRH groups, the progressive failure of pregnancy and depression of LH binding were associated with decreased serum progesterone levels.

The results from these experiments suggest that the mechanism by which LHRH terminates pregnancy involves a hypersecretion of LH which produces a decrease in ovarian LH receptor content (downregulation) resulting in a disruption of ovarian steroidogenesis, thereby removing gestational support. (Endocrinology 105: 139,1979)

Footnotes

^* This work was presented in part at the 60th Annual Meeting of The Endocrine Society, Miami, FL, June 1978.

Received October 9, 1978.