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Departments of Pediatrics and Cell Biology Duke University Medical Center Durham, North Carolina 27710
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Introduction |
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The transition from maternal dependence to independent life is not an easy one. The newborn infant must breathe freely in an air-filled environment, maintain body temperature at a relatively chilly 23 C, and sustain blood glucose concentrations after the cutoff of the placental glucose supply. At this critical juncture, the fetal adrenal gland plays a pivotal role. A surge of fetal glucocorticoid production near term (1) induces the expression of surfactant proteins B and C in fetal lung, reduces interalveolar wall thickness, increases airspace volume and lung compliance, and, through induction of pulmonary ß adrenergic receptors, potentiates the clearance of lung liquid by catecholamines (2). These changes prepare the fetus for independent respiration after birth. Glucocorticoids enhance the conversion of thyroxine (T4) to triiodothyronine (T3) and increase the activity of adrenomedullary phenylethanolamine N-methyltransferase, which catalyzes the methylation of norepinephrine to epinephrine. Striking increases in the thyroid hormones and catecholamines at birth activate lipolysis in brown and white adipose tissue, providing heat as well as energy for neonatal respiratory activity and muscular movement. In the fetal liver, glucocorticoids increase the storage of glycogen, which provides the major source of free glucose for the newborn infant immediately after delivery. Moreover, glucocorticoids induce expression of the gluconeogenic enzyme glucose-6-phosphatase (3), which maintains normoglycemia during periods of intermittent food intake. Finally, glucocorticoids accelerate the differentiation of fetal gastric epithelial cells and regulate the processing of lipoproteins in fetal jejunum (4), facilitating the shift to a high fat, milk-based oral diet.
In studies described in this and a previous issue of Endocrinology (5, 6), Phillips and his colleagues add a novel twist to an already complex tale. They demonstrate that glucocorticoids regulate the expression of the PRL receptor in the fetal lamb. The PRL receptor (PRLR) serves as a high affinity binding protein for mammalian PRLs and placental lactogens and for the primate GHs. The levels of the messenger RNAs (mRNAs) encoding the long and short forms of the PRLR in fetal sheep liver increase 4- to 6-fold between 90 and 144 days of gestation (term 147 ± 3 days). Surgical disconnection of the fetal hypothalamus and pituitary, which prevents the fetal cortisol surge in late gestation, reduces hepatic PRLR expression at 140 days of gestation to levels comparable with those found in the intact sheep fetus at 130 days of gestation, before the cortisol surge. And direct administration of hydrocortisone to the "disconnected" fetus at 140 days gestation up-regulates hepatic PRLR expression. Therefore, the increase in PRLR mRNA in the ovine fetal liver near term may be induced by the rise in fetal cortisol concentrations. On the other hand, the induction of PRLR expression between 90 and 130 days does not appear to be glucocorticoid dependent; its derivation remains obscure.
The results of these studies in the fetal sheep concord with previous studies in the rat (7, 8, 9, 10) and mouse (11), which revealed striking increases in PRLR mRNA, immunoreactivity, and lactogenic binding activity in the fetal liver and various other fetal tissues in late gestation. The induction of PRLR expression in rodent fetal tissues coincides with increases in fetal plasma ACTH and corticosterone levels, though the role of glucocorticoids in the regulation of PRLR expression in nonhepatic fetal tissues is unclear.
What is the physiological significance of PRLR induction in the late gestational fetus? In the fetal liver, lactogens stimulate ornithine decarboxylase activity, DNA synthesis, glycogenesis, and lipoprotein lipase activity (12, 13). These findings suggest that lactogenic hormones play roles in perinatal liver growth and hepatic carbohydrate and lipid metabolism. Hepatic bile secretory function is also lactogen dependent: in postpartum rats, PRL stimulates expression of the mRNA that encodes the Na-taurocholate cotransporter (14). In the fetal lung, lactogenic hormones may act synergistically with glucocorticoids to induce surfactant production (15). And lactogens likely play roles in perinatal insulin production (16) and in skeletal differentiation and maturation (10, 12, 17). PRLRs are expressed in the cortical periventricular neuroepithelium and in the sensory and efferent pathways of the fetal and neonatal olfactory system (8, 9), and lactogens stimulate the proliferation of neonatal rat astroglial cells in culture (18). Potential interactions between the glucocorticoids and the lactogenic hormones in the development of the central nervous system remain unexplored but clearly warrant study given the importance of glucocorticoid-lactogen interactions in the mammary gland, fetal lung and immune system (13).
Interestingly, glucocorticoids regulate the expression of the GH receptor as well as the PRLR in the fetal sheep liver near term (19). The rise in fetal cortisol levels in late gestation parallels increases in the levels of GH receptor mRNA in the fetal liver. The increases in GH receptor mRNA are prevented by fetal adrenalectomy and can be restored by intrafetal administration of cortisol.
Glucocorticoid induction of hepatic GH receptors in late gestation serves an important physiological role: it is the first step in a cascade of changes in the hormonal control of linear growth. Linear growth in the postnatal period is controlled by GH, which acts through its receptor to stimulate the production of insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) and to reduce the levels of IGFBP-2. Fetal growth, on the other hand, requires IGF-II as well as IGF-I (20) and is largely (though not entirely) independent of GH. A deficiency of GH production or an inactivating mutation in the GH receptor has variable and often negligible effects on fetal growth (12, 21), and low levels of IGF-I and IGFBP-3 prevail in the fetus despite high circulating concentrations of GH. In contrast, the levels of IGF-II in fetal blood and of IGF-II mRNA in fetal tissues are exceedingly high (22, 23).
The apparent resistance to GH in the fetus results, at least in part, from a relative paucity of GH receptors in fetal tissues (12). The emergence in late gestation of the GH receptor in fetal liver may explain the induction of hepatic IGF-I expression near term (19) and the subsequent rise in plasma IGF-I and IGFBP-3 levels and the fall in the levels of IGFBP-2 (22, 23). Placental hormones (24) and nutritional factors may contribute as well. Through negative feedback effects on hypothalamic GH-releasing hormone production, the rise in plasma IGF-I reduces plasma GH concentrations. Concurrently in sheep (25) and rodents, but not in humans (22, 23), the levels of IGF-II decline. Thus, through effects on GH receptor expression, the glucocorticoids may facilitate the transition from GH-independent fetal growth to GH-dependent postnatal growth.
The mechanisms by which glucocorticoids induce expression of the GH and PRL receptors in the fetal liver have not been elucidated. The GH receptor promoter bears two half-site glucocorticoid response elements (GREs), suggesting that cortisol has a direct effect on GH receptor gene transcription. On the other hand, no GREs have been identified in the PRLR gene, and glucocorticoids have no direct effects on PRL binding or PRLR mRNA in isolated hepatocytes, pancreatic islets or mammary epithelial cells. These findings suggest that the effects of glucocorticoids on PRLR expression in fetal liver may be mediated indirectly through the actions of other hormones or growth factors. In adult rat liver, PRLR mRNA and PRL binding activity are induced by estrogens in vivo but not in vitro. The effects of estradiol on PRLR expression are abolished by hypophysectomy and appear to be mediated by increases in the secretion of PRL and/or GH (26, 27). The effects of cortisol on fetal liver PRLR mRNA are unlikely to be mediated by PRL or other lactogens because the administration of glucocorticoids to the ovine fetus or to pregnant women has no effects on the levels of PRL or placental lactogen in fetal or maternal blood (6, 28, 29). In contrast, exogenous glucocorticoids accelerate the maturation of fetal pituitary somatotrophs and stimulate GH gene transcription (30). Nevertheless, a role for GH in glucocorticoid action in the fetus is uncertain because the late gestational induction of PRLR expression coincides with a fall in fetal plasma GH levels in humans as well as sheep (24). Interestingly, the administration of dexamethasone to fetal sheep near term increases the levels of 17-ß estradiol in fetal blood (31), suggesting that estrogens may mediate some of the biological effects of glucocorticoids in the fetus. The aforementioned studies of the induction of GH and PRL receptors in the ovine fetus (5, 6, 19) did not examine the effects of adrenalectomy or cortisol administration on fetal estrogen levels.
Major questions remain unanswered. Foremost among these is: What triggers the cortisol surge in late gestation? That problem has bedeviled investigators for more than a generation. The fetal hypothalamic-pituitary-adrenal axis may be activated directly by rising levels of fetal estrogens (32) or indirectly by estrogen-dependent reductions in the transplacental transfer of cortisol from the mother to the fetus (33). Alternatively, in humans and other primates, the major stimulus to fetal (and possibly placental) ACTH secretion may be the induction of placental CRH. In humans, the levels of CRH in maternal and fetal plasma rise markedly after 28 weeks of gestation (34). In contrast to hypothalamic CRH, the production of placental CRH is induced by cortisol (35). This positive feedback loop augments the fetal secretion of ACTH, which stimulates the growth and maturation of the fetal adrenal and its production of glucocorticoids. The effects of ACTH on primate fetal cortisol production are enhanced by the induction of ACTH receptors in the adrenocortical "transitional zone" near term (36, 37). Concurrently, there is a reduction in ACTH receptor expression (37) in the central "fetal zone", which in primates (but not rodents) produces dehydroepiandrosterone (DHEA).
ACTH is not the only factor that regulates the maturation and growth of the fetal adrenal. Other hormones and growth factors likely play important roles (36, 38). That the lactogenic hormones might regulate fetal adrenocortical growth and function has been a subject of longstanding controversy. In the early gestational human fetus and the mid-gestational fetal rat, the PRLR is expressed in the periadrenal mesenchyme and in a rim of capsular-like mesenchymal cells and neocortical-like parenchymal cells lying near the surface of the gland (10). Cells in this "definitive zone" have high mitotic activity and are thought to migrate centripetally to populate the developing "fetal zone". Thus lactogens may play roles in adrenal differentiation early in development. Subsequently, in mid-late gestation, the PRLR is expressed throughout the fetal adrenal cortex in humans and rodents (7, 8, 10, 39). Limited (40), and highly conflicting (38), evidence suggests that lactogens may stimulate production of DHEA and DHEA-sulfate in the primate fetus, thereby contributing to placental estrogen production. And lactogens stimulate the production of glucocorticoids in isolated adrenocortical cells of postnatal rats and human adults (39, 41). Given the rise in fetal PRL levels in the third trimester and the presence of placental lactogen in fetal serum (12), these findings raise the possibility that lactogenic hormones may synergize with ACTH to induce the fetal cortisol surge in late gestation.
The weight of evidence suggests a complex interplay of nutrients, hormones and growth factors in the biochemical and physiological changes that mark the transition from fetal to neonatal life. Future studies will no doubt explore the molecular mechanisms governing these interactions and will elucidate their roles in normal and pathologic pregnancies.
Received February 9, 1999.
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