Luteinizing Hormone-Releasing Hormone (LHRH) and LHRH Agonist Termination of Pregnancy in Hypophysectomized Rats: Extrapituitary Site of Action*

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Abstract
LHRH or agonist analogs terminate pregnancy when administered pre- or postimplantationally. Also, LHRH can exert this effect independent of the pituitary after day 12 (D12) of pregnancy in the rat, when the pituitary is unnecessary for gestational support. The present study, using LHRH and the potent agonist, D-AlaB6-des-Gly10-Pr9-NHEt-LHRH (Wy- 18,481), confirms this extrapituitary antifertility activity and describes associated changes in placental and luteal function, as determined by serum rat placental lactogen (rPL) and serum progesterone (P), respectively. An initial study in intact pregnant rats indicated that the administration of 500 fig LHRH/day between D7–12 produced a decrease in serum rPL which was associated with the termination of pregnancy induced by this treatment and coincident with a fall in P. In an effort to determine whether the inhibition of rPL represented a direct effect of the LH-releasing peptide, daily sc administration of 500 μg LHRH or 50 jug Wy-18,481 was begun immediately after hypophysectomy (hypx) on either D12 or D13 of pregnancy and was continued until D16. Determination of pregnancy state and blood collection were performed at autopsy on D18. Pregnancy was disrupted (characterized by resorbing fetal sites) in 19% of the D12 hypophysectomized (hypx) control rats and 0% of the D13 hypx rats. LHRH or Wy-18,481 treatment markedly inhibited pregnancy in 87% and 94%, respectively, of the D12 hypx rats and in 79% and 100%, respectively, of those hypx on D13. D18 serum rPL levels were not significantly different in control rats hypx on D12 or D13 from intact controls (811 ± 75, 799 ± 93, and 1091 ± 229 ng/ml, respectively). Although serum rPL was depressed below the sensitivity of the assay (92 ng/ml) in 35–50% of the D12 and D12 hypx animals receiving LHRH and in 50–100% receiving Wy- 18,481, there were a number of animals with failing pregnancies exhibiting normal levels of rPL. In contrast, serum P was significantly reduced in all rats receiving either compound. Concurrent daily administration of 5 mg P reversed the antipregnancy effects of LHRH in both D12 and D12 hypx animals. An ectopic pituitary graft was also found to protect against LHRH-induced pregnancy termination in hypx rats. The results of these experiments demonstrate that the antipregnancy mechanism of LHRH and its agonistic analogs in hypx rats involves an inhibition of luteal progesterone production which is reflected, but not initiated, by reduced rPL secretion. Although the ovary appears to be the extrapituitary site for the antipregnancy effects produced by these peptides, an action on placental production of hormones other than rPL, possibly rCG, necessary for luteal function may be involved as well.