SUMMARY The effects of seven amine oxidase inhibitors on pregnancy were investigated in mice. Four of the compounds were derivatives of hydrazine and three were not. All the derivatives of hydrazine and one of the other compounds tested produced toxic effects in early pregnancy but were relatively inactive later. The effect of one of the compounds investigated (HP 1325) was, to a great extent, reversed by either progesterone or prolactin, suggesting an interference with the hormonal mechanism responsible for the maintenance of pregnancy. HP 1325 (and 5-hydroxytryptamine) did not interrupt pseudopregnancy, indicating that luteal function is not completely inhibited. Evidence is adduced that the effects on pregnancy are not related to any particular chemical structure or to the amine-oxidase activity of the compound tested.

The action of 5-hydroxytryptamine (5-HT) on pregnancy in mice has been investigated. Deleterious effects have been observed at all stages. In advanced pregnancy a single dose may kill the foetuses within half an hour.The effect in early pregnancy can be antagonized by progesterone and by prolactin, as can the toxic effects of the drug on the experimental decidual reaction. In late pregnancy progesterone produces little, and prolactin no, reversal of the toxic action of 5-HT. It is suggested that in early pregnancy, 5-HT interferes with the hormonal mechanisms responsible for the maintenance of gestation, while later on its main toxic action is exerted directly on the uterine contents.Preliminary results (Poulson, Botros & Robson 1960a, b) have shown that 5-hydroxytryptamine (5-HT) has striking effects on pregnancy in mice and rabbits. The results in mice are reported in detail here, together with additional work under¬ taken to elucidate the mechanism of action. METHODSFemale mice of known fertility (having had at least one previous litter) and bred in the Animal House at Guy's Hospital Medical School were used. The first day of pregnancy was counted from the finding of the vaginal plug, which was looked for daily. 5-HT was injected in aqueous solution and the dose is expressed as that of the creatinine sulphate salt. Since preliminary experiments showed that intraperitoneal (i.p.) injection was no more effective than the subcutaneous (s.c.) route, all subsequent doses were given s.c. The drug was administered daily over different periods of pregnancy to try and determine whether it was effective before, during or after implantation, or at all these stages. In some experiments an amine oxidase inhibitor 2,2'-(^-phenylenedioxy)-di-(ethylhydrazinium (1 + )chloride) (HP 1325) was given together with 5-HT; HP 1325 was injected s.c. in aqueous solution. Pro¬ gesterone was given s.c. in oily solution, while prolactin (22-5 i.u./mg.) was given s.c.in aqueous solution, which was prepared fresh for each experiment and never stored in the refrigerator for more than 1 week.

The effects of 5-hydroxytryptamine and iproniazid on pregnancy in mice and rabbits were investigated. 5-Hydroxytryptamine can interrupt pregnancy at all stages in mice but is particularly effective early and late in pregnancy. Iproniazid exerts its action essentially in the first half of pregnancy. 5-Hydroxytryptamine produces striking hemorrhage in the placenta.

SUMMARY The effects of phenelzine and several of its derivatives in interrupting pregnancy, and on sexual development, were investigated in mice. At dose levels of one-fifth LD 50 given on days 1–6 of pregnancy, phenelzine had a low but significant activity and some derivatives were more active. There was no evidence that monoamine oxidase inhibitory activity was related to the anti-fertility activity of these compounds. The effects of two of the compounds investigated for this purpose (WL 27 and LON 41) were partially reversed by either progesterone or prolactin. WL 27 interrupted the normal oestrous cycle, delayed the onset of oestrus in immature female mice and depressed the weights of sex organs in immature and in non-pregnant adult mice, and in immature male mice. These effects suggest that these compounds produce a depression of pituitary gonadotrophic activity. However, the depression is not complete since WL 27 did not interrupt pseudopregnancy.

The subcutaneous injection of a single dose of 5-hydroxytryptamine into pregnant mice produced a large number of fetal abnormalities, mostly of the eyes, limbs, and tail; the skull and central nervous system were also sometimes affected. These effects could result from the action of the drug on placental function and blood supply.