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Extensive animal research has shown that endogenous estrogens and progestins play a vital role in controlling the course of normal pregnancy and fetal development. The balance of the 2 types of hormones must be maintained, a relative excess of deficiency of either being detrimental to the offspring. Information on this topic is presented from a review of the animal study literature. The effect of sex steroids in the following areas of pregnancy and fetal development is discussed: 1) interruption of gestation; 2) antifertility effects; 3) prolonged gestation; 4) maintenance of pregnancy; 5) fetal masculinization; 6) fetal feminization; 7) teratogenic effects; 8) postnatal effects of steroids on males and females; 9) steroid transfer through milk; and 10) female sterility induction through early postnatal administration of steroids.

DAVIS Hart (1930 and1930a) have shown that the blood serum of mares contains a gonad-stimulating hormone between the 45th and the 150th days and small amounts of oestrin during the last half of pregnancy. According to Zondek (1930), tremendous amounts of oestrin are present in the urine of the mare between the 74th and 260th days. The concentration of these hormones at the various stages of pregnancy has not, however, been systematically studied. Many problems might be more easily solved if exact information on this point were available. For example, one question concerns the sources of these hormones. Does the fetus with its attending membranes initiate an unusual activity of the hypophysis and ovary or are the hormones in question vicariously produced during this phase of reproduction? Another problem concerns the fate of the gonad-stimulating hormone. It is not excreted in the urine unchanged for only rarely can it be detected there. Thus it must be eliminated with other body excretions or destroyed within the mare. In addition, several interesting gonadal phenomena characteristic of this species may be partly explained by a study of hormonal concentrations. Another objective in our experiments was to ascertain in what period of gestation these hormones are most abundant.In this study we have not attempted to fractionate the serum into several components having specific ovarian effects. Publications by Fevold, et al. (1931), Leonard (1931), and Evans, et al. (1931, indicate that such an investigation might be fruitful. Our tests have shown, however, that at all stages of pregnancy in which the serum gives an ovarian response it will bring about the maturation of follicles, oestrus, ovulation, and the development of normal corpora lutea in the rat, mouse, sow, cow, and ewe. Furthermore, some, at least, of these phenomena may be produced in the bitch, rabbit, and mare.tWe have taken frequent samples, therefore, from a few individuals and have studied the concentration of gonad-stimulating hormone and oestrin. This paper will not discuss in detail the theoretical considerations pertaining to the source of these two hormones or to the disposition of the former, but may serve in the direct attack upon these attractive problems.

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The natural hormone, progesterone, has long served as the standard for the production of endometrial changes in the uterus. In 1944 Allen and Ehrenstein' reported that norprogesterone was more active than the natural hormone, a finding that has since been confirmed by Tullner and Hertz2 Recently it has also been demonstrated that the nor derivative of ethynyltestosterone is more potent as a progestational agent than the methylated parent compound, both in animals and man.3, Studies in this laboratory have encompassed a wide variety of steroid structures. Particular attention has been paid to the study of 17-substituted derivatives of 17-hydroxyestrenones with the double bond in either the 5(10) or the 4(5) position. In the series with the double bond in the 5(10) position, the most interesting substance has been norethynodrel, which shows a mixture of both estrogenic and progestational a~tivities.~ With the double bond in the 4(5) position, estrogenic activity is absent and more nearly pure progestational effects are obtained. However, some of this latter group also have androgenic and anabolic activities.6 Inasmuch as the properties in these two series do differ, the endocrine effects of the A6(lU) compound, norethynodrel, will be discussed first, and the progestational activity of the A4(6) steroids second. MethodsProgesteronelike activity, Clauberg assay.7 Immature female rabbits weighing about 1 kg. were treated for 6 days with 5 fig. of estradiol daily. Starting on the following day they received the test compound in oil, subcutaneously, daily for the next 5 days. On the day after the last injection they were sacrificed and the uteri were fixed for later histological study. Sections of the uterus were graded from 1 to 4 on the basis of glandular development.* Further studies were conducted using the technique described by McGinty et aL9 I n this assay the compound in oil was injected into a segment of the uterus in the ovariectomized rabbit, previously primed with estrogen. Uterine sections were examined histologically and graded as above. Estrogenic activity was determined by the uterine weight technique of Rubin et in immature mice and by the vaginal smear technique of Allen and Doisy17 employing castrated rats and scoring according to the method of Biggers and C1aringbold.l' Norethynodrel Norethynodrel has four main properties: (1) It is progestational under certain conditions; (2) it has estrogenic activity; (3) it can inhibit the pro-516 Progesteronelike activity, intrauterine assay. Estrogenic activity. Saunders & Drill: 17-Ethynyl and 17-Alkyl Derivatives 517 CH 111 C FIGURE 1. Structural formula of norethynodrel.duction or release of pituitary gonadotropin; and (4) during treatment it prevents conception.Detailed data illustrating the biological activities of the pure compound, 17a-ethynyl-17hydroxy-5 (lO)-estren-3-one, called norethynodrel, are presented below.The condition of the uterus of an estrogen-primed control rabbit in the Clauberg assay is shown in FIGURE 2. Glandular crypts are lacking. ...

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