The Journal of Steroid Biochemistry and Molecular Biology
Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments☆
Introduction
The crucial role of ovarian hormones in supporting pregnancy is largely recognized. The corpora lutea of the cycle are converted into those of pregnancy by a signal that emanates from the feto-placental unit. The chorionic gonadotropin secreted by the placenta assumes the role of maintaining the corpus luteum and directing placental steroidogenesis. Initially placental gonadotropins are luteotropic, facilitating a continuous secretion of estrogens and progesterone from the corpus luteum. Later in pregnancy, the placenta may assume total steroidogenic potential and the corpus luteum is no longer needed to bring fetal development to term.
The enzyme systems involved in the formation and transformation of steroid hormones evolve with the progress of pregnancy. There are significant differences in quality and quantity of enzymes between the fetal and placental compartments, although they remain complementary. The feto-placental unit has the capacity to biosynthesize all the active steroids (e.g. androgens, estrogens, gluco- and mineralocorticosteroids, progestins) which play an important biological role during gestation.
The steroid hormone receptors are present at an early age in the target tissues of the fetus. It is suggested that the hormone–receptor complex may be involved in the program mechanism for normal physiological, or for pathological, conditions in extra-uterine life.
Here we summarize the enzymes involved in the formation and transformation of steroid hormones in the feto-placental unit, their evolution and their possible biological role.
Section snippets
Formation and transformation of steroid hormones in the feto-placental unit
The major advances in understanding the biosynthesis and metabolism of steroids were carried out with the use of radioactive hormone precursors that made it possible to study hormonal formation and transformation in physiological conditions. Westin et al. [1] and Nyberg and Westin [2] were the pioneers in the use of human fetal perfusion techniques. The methods that made these studies possible include: in situ placental perfusion; in situ administration of the hormone or its precursors in the
Complementary enzyme activities in the fetal and placental compartments
The fetus lacks certain enzymes that are essential for steroidogenesis (e.g. 3β-hydroxysteroid dehydrogenase, 5-ene ↔ 4-ene isomerase, aromatase), while other enzymes present in the fetus (e.g. C17–C20 desmolase, hydrolases) are absent in the placenta. Table 1 summarizes the most important enzymatic functions in the placental and fetal compartments. The fetus is very active in converting acetate into cholesterol and in transforming pregnanes to androstanes by 16-hydroxylation, which is necessary
Steroid hormone receptors and biological responses in the fetus
The specific binding of different steroid hormones in various fetal organs of humans or animals is well established (for a general review see [15]). At mid-gestation, estrogen receptor (ER)-α was abundant in the fetal uterus and smaller quantities were detected in the ovary, testes, skin and gut. High levels of ER-β-mRNA were present in fetal ovaries, testes, adrenals and spleen. In the uterus, however, ER-α mRNA was more abundant, and ER-β mRNA was expressed only moderately [16]. In another
The fetal enzyme hypothesis: its possible role in breast cancer
As was indicated in the previous section, most of the estrogens (90–95%) in the fetal compartment circulate in the form of sulfate conjugates. These conjugates are biologically inactive and must be hydrolyzed by sulfatase before eliciting a biological response. Hence, the control over this enzyme during fetal life is of prime importance in regulating the action of estrogen. In a series of studies in our laboratory using human breast cancer cell lines it was shown that progesterone and various
Conclusions
Fetal hormonal biosynthetic potential appears early during gestation. With regard to steroid hormones, the adrenal cortex is capable of producing mineralo- and glucocortico-steroids, as well as DHEA, DHEA-sulfate, 16α-hydroxy-DHEA and its sulfate, and the testes testosterone. This steroidogenesis is regulated by the hypothalamic-pituitary axis. The placenta produces progesterone and estrogens. All the information indicates that there is complementary activity between the enzymes involved in
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Presented at the European Progestin Club Scientific Meeting Amsterdam, The Netherlands, 5 October 2004.