A Brief Account of the Discovery of the Fetal/Placental Unit for Estrogen Production in Equine and Human Pregnancies: Relation to Human Medicine

Abstract

The role of steroids in human medicine is well recognized, but the major contributions made by the large domestic animals as a source of material in the discovery, isolation, and determination of the structure of the steroid hormones is less well appreciated. After a brief reminder of the early efforts to obtain a reliable source of steroids for clinical use, the narrative here is to outline one example where success was ultimately achieved for estrogen replacement therapy. Whereas knowledge of the high concentrations of estrogens in urine of pregnant women and mares dates from the late 1920s, it was not until the 1940s that the latter was shown to be a practical source. Initially, the placenta was held to be responsible, but the involvement of the fetus in each case was eventually established. The remarkable enlargement of the human fetal adrenal glands and the fetal gonads in the horse, with characteristic features of steroid secreting tissues, suggested their participation. Ultimately, it was 16-hydroxylation by the fetal liver that resulted in estriol being the major estrogen type, by far, in late human pregnancy. In the mare, the pattern of estrogen production reflected that of the growth and later regression of the fetal gonads. The characteristic production ring-B, unsaturated estrogens in the mare is derived from an alternative pathway involving retention of the additional double bond in the biosynthesis of equilin.

Keywords: equilin; equine; estrone; fetal adrenals; fetal gonads; feto-placental unit; human; steroids.

Figure 1

Structure of estrogens formed by the placenta.

Figure 2

Urinary excretion of estrogens during normal pregnancy in four human subjects. (From Brown, 1956 [63]).

Figure 3

a. Patterns of total urinary estrogen excretion for four pregnant pony mares. (Ginther, 1992; adapted from Raeside and Liptrap, 1975 [64]). b. Mean plasma estrone and equilin concentrations in four pregnant mares. (Ginther, 1992; adapted from Cox, 1975 [64]).

Figure 4

Suggested scheme of the principal pathways of steroidogenesis in the human fetoplacental unit at midpregnancy. (Diczfalusy, 1955 [35]).

Figure 5

Plasma levels (ng/ml) of estrogens (open columns) and DHEA (solid columns) in maternal and fetal blood vessels in four mares carrying a female or male fetus. A, artery; V, vein; J, jugular; U, uterine; Um, umbilical; O, ovary; T, testis; L, left; R, right. (Raeside et al. 1979 [47]).

Figure 6

In vivo pathways of equilin and estrone biosynthesis in the pregnant mare, investigated by administration of radiolabeled precursor compounds. Broken arrows indicate negative results. (Bhavnani, 1988 [54]).