John W. Reynolds,     Department of Pediatrics, University of Oregon Health Sciences Center, Portland, Oregon

Publisher Summary

This chapter discusses the development and function of the human fetal adrenal cortex. The adrenal cortex of human beings undergoes extensive anatomical and biochemical changes during fetal life and during the first few months of postnatal life. In contrast to the changes in other fetal organs, many of these developmental changes cannot be understood through the study of animal models because distinctive features of human fetal adrenal glands are not seen in nonhumans other than the high primates. From early embryologic development, there is a separation of the adrenal cortex into permanent and fetal zones. The fetal zone is the inner portion of the gland and is composed of cells with small nuclei and large amounts of cytoplasm. The outer, permanent zone is made up of cells with relatively small amounts of cytoplasm. The two zones of the fetal adrenal cortex differ by way of histochemical and biochemical properties, as well as structural features. In the human fetus, organs other than the adrenal cortex play important roles in adrenal steroid metabolism and in determining the characteristic patterns of the circulating steroids. Many of the distinguishing features of human fetal adrenal cortical function are the results of steroidogenic activities of the fetal zone.

INTRODUCTION

The adrenal cortex of human beings undergoes extensive anatomical and biochemical changes during fetal life and during the first few months of postnatal life. In contrast to the changes in other fetal organs, many of these developmental changes cannot be understood through the study of animal models because distinctive features of human fetal adrenal glands (e.g., large fetal zone and high Δ5–3β–hydroxysteroid production) are not seen in nonhumans other than the high primates. However, in contrast to the secretory products of other fetal organs (which cannot be assessed by examination of maternal fluids), the secretory products of the fetal adrenal cortices are precursors to certain maternal steroids and the course of fetal maturation can be followed through an examination of the end products in the maternal circulation. As is the case with many other organs in the newborn, there is no abrupt change from fetal to postnatal modes of functioning, but rather there is a transition period lasting days to weeks, during which there is a blending of fetal patterns into postnatal patterns. The study of this transition can provide important insights into fetal steroid metabolism. As in all areas of human developmental biology, deviations from normal development and “experiments of nature” are particularly useful for the unique views they may provide of developmental processes. In the study of fetal adrenal cortical function, particularly valuable data have been gained from examinations of women bearing anencephalic, growth–retarded, or postmature fetuses; women with placental sulfatase deficiency; and newborns with prematurity, respiratory distress syndrome, intrauterine growth retardation, or postmaturity syndrome.

ANATOMICAL DEVELOPMENT

From early in embryologic development, there is a separation of the adrenal cortex into permanent and fetal zones. The fetal zone is the inner portion of the gland and is composed of cells with small nuclei and large amounts of cytoplasm. The outer, permanent zone is made up of cells with relatively small amounts of cytoplasm. Early in development, the fetal zone constitutes over 80% of the gland; at the time of birth it makes up about 77% of the gland in premature infants and 73% in full–term infants. The adrenal glands of the human newborn are large; the mean combined weight is 10.3 g in term infants. Within a few days after birth, the fetal zone begins to involute. By day 14 the entire fetal zone shows degenerative changes, and by week 6 it has decreased to about 20% of its initial weight. In contrast, the permanent zone shows a rapid increase in size in the first month and by 6 weeks of age has increased to about 175% of its initial weight (Benner, 1940).

On the basis of ultrastructural features, Johannisson (1979) has concluded that the permanent zone is germinative and not steroidogenic during the first trimester. The fetal zone shows signs consistent with steroid biosynthesis. The permanent zone does not show signs of differentiation and steroidogenic function until midpregnancy, but the fetal zone shows such signs throughout the second trimester. On the basis of both in vivo and in vitro enzymatic studies, the fetal adrenals have been found to be capable of carrying out the complete set of reactions in the conversion of acetate to cortisol and aldosterone by week 20 of gestation. The enzymatic activities appear sequentially in the cortex. Hydroxylating enzyme activities for various positions on the steroid ring appear in the order 17α, 11β, 21, and 18.

BIOCHEMICAL DEVELOPMENT

The two zones of the fetal adrenal cortex differ in histochemical and biochemical properties, as well as in their structural features. The activity of 3β–hydroxysteroid dehydrogenase (3β–HSD), the enzyme system necessary for the conversion of Δ5 − 3β–hydroxysteroids to Δ4 − 3 ketosteroids (e.g., pregnenolone to progesterone, or dehydroepiandrosterone [DHA] to androstenedione), is almost completely localized to the permanent zone according to histochemical evidence (Goldman et al., 1966) and biochemical data on the separate cortical zones (Shirley and Cooke, 1969; Cooke and Taylor, 1971). The differences are also evident in a superfusion system, in which isolated midgestation permanent zone produces essentially only cortisol and isolated fetal zone produces minimal cortisol, but more dehydroepiandrosterone sulfate (DHAS) (Serón–Ferré et al., 1978). These findings confirm that 3β–HSD activity is present in the permanent zone but presumably low in the fetal zone. The overall low activity of the 3β–HSD enzyme system in the adrenal cortex persists into the neonatal period, as shown by incubation studies (Villee and Loring, 1965) and by analysis of the types of steroids extractable from the glands (Matsumoto et al., 1968).

In the human fetus, organs other than the adrenal cortex plan important roles in adrenal steroid metabolism and in determining the characteristic patterns of the circulating steroids. The liver has high 16α–hydroxylase activity for a large numer of Δ5 − 3β–hydroxysteroids (Reynolds, 1966a); this activity leads to the prominence of 16α–hydroxy–dehydroepiandrosterone sulfate (16α–OH–DHAS) and 16α–OH–pregnenolone sulfate in the fetal blood. The fetal adrenals and liver are active in sulfurylating steroids, both Δ5 − 3β– hydroxysteroids and 4 − 3 keto corticosteroids. The sulfatase enzyme activities are low in the fetus; thus, most circulating fetal steroids are sulfate–conjugated. The fetal tissues in general are strongly oxidative in relation to the cortisol–cortisone equilibrium (Murphy, 1979). An exception at midgestation is the chorion, which begins to reduce activity cortisone to cortisol. Also, the fetal lungs may begin to convert cortisone to cortisol in the third trimester (Smith et al., 1973). At term, the cortisol–to–cortisone conversion in all tissues is much less prominent (Murphy, 1979).

The placenta, also an organ of fetal origin, is particularly active with regard to steroid biosynthesis and metabolism. The fetus, placenta, and placental membranes, acting in concert, constitute the fetoplacentalsteroidogenic unit and produce the large amounts of estrogens characteristic of human pregnancy (Telegdy and Diczfalusy, 1971). The fetal adrenals produce DHAS from circulating cholesterol; it is 16α–hydroxylated in the fetal liver and then transported to the placenta, where the active placental sulfatases remove the conjugate and placental aromatizing enzymes convert the 16α–OH–DHA into estriol. The fetus lacks the sulfatase and aromatizing activities needed for the transformation of 16α–OH–DHAS to estriol, and the placenta lacks the 17α–hydroxylase and 17–20 desmolase activities necessary for the cholesterol–to–DHA conversion. Thus, fetal adrenal cortical function cannot be assessed in isolation from the functions of many other fetal organs.

MAINTENANCE OF THE FETAL ZONE

As has been evident from the preceding discussion, many of the distinguishing features of human fetal adrenal cortical function, and by extension fetoplacental unit function, are the results of steroidogenic activities of the fetal zone. To interpret the clinical meaning of deviations in fetoplacental steroid metabolism, one should have an understanding of factors critical in the growth of the...