Perspectives The Unique Endocrine Milieu of The Fetus Delbert A. Fisher Department ofPediatrics, University of California, Los Angeles School ofMedicine, Harbor-UCLA Medical Center, Torrance, California 90509 Since the pioneering studies of Jost and colleagues four decades hormone precursor. DHAS is transported to the liver for 16- ago, there has been impressive progress in our understanding of hydroxylation and/or to the placenta, where it is hydrolyzed by the intrauterine endocrine milieu (1). Fetal endocrine physiology a steroid sulfatase and utilized as substrate for placental estrogen differs in many important ways from the endocrinology of post- biosynthesis. DHAS serves as substrate for placental estrone and natal life. It is characterized by a series of unique fetal endocrine estradiol production; 160H-DHAS is the major substrate for organs, by a number of hormones or metabolites uniquely placental estriol synthesis (1-6). Estriol is a hormone unique to prominent in the fetal compartment, by the adaptation of several pregnancy; it is not secreted by the ovary of nonpregnant women. fetal endocrine systems to special intrauterine functions, and by There is evidence that placental chorionic gonadotropin mechanisms to neutralize the biological actions of several potent (hCG) is an important stimulus to fetal adrenal function early hormones critical for normal postnatal development (Table I). in pregnancy; fetal pituitary adrenocorticotropin (ACTH) is es- The following discussion is intended to provide a brief perspective sential for maintenance of fetal zone function by midgestation of this unique environment. (4, 5, 7). Other pro-opiomelanocortin (POMC)-derived pep- tides-alpha-melanocyte-stimulating hormone (a-MSH), cor- Fetal endocrine adaptations ticotropin-like intermediate peptide (CLIP), and f,-endorphin- In several instances, fetal endocrine systems or hormones have seem to have only limited roles (4, 5). Preliminary evidence been transiently diverted to subserve singular gestational or de- suggests a possible role for epidermal growth factor (EGF) and velopmental roles. fibroblast growth factor (FGF) both at the adrenal gland and Fetal adrenal and estrogen production. The best-known pituitary levels (5, 8). and -characterized fetal endocrine gland is the fetal adrenal, The human placenta at term secretes 10-25 mg/d of estradiol adapted in utero to function in collaboration with the placenta and 40-50 mg/d of estriol (3-6); estrogen production in non- to produce estrogens. This system, the so-called fetoplacental pregnant women is less than 1 mg/d. Most of the estrogen is unit, has been reviewed in several recent publications (1-6). secreted into the maternal circulation, but fetal concentrations The fetal adrenal cortex is composed oftwo distinct anatomic and levels in amniotic fluid are quite high. To date, the signifi- zones, an inner "fetal" zone and an outer "definitive" zone. The cance of the enormous amounts of estrogen produced during fetal zone is deficient in A5,3l-01 dehydrogenase/A4,5,3-keto- pregnancy remains largely obscure both in the mother and fetus. steroid isomerase and has a high steroid sulfokinase activity (3- Estriol is a relatively weak estrogen in many biological systems, 5). Thus, the conversion ofpregnenolone to progesterone is lim- but is active and may have a role in maintenance of uteropla- ited and the major secretory product of the fetal adrenal is de- cental blood flow (5). It is of interest that estrogen production hydroepiandrosterone sulfate (DHAS),' an essentially inactive and circulating estrogen levels (especially estriol) may be mark- edly reduced in pregnancies in which the fetus (including pla- Dr. Fisher is Professor of Pediatrics and Medicine at the UCLA School centa) has x-linked steroid sulfatase deficiency, and the placenta of Medicine. is unable to convert DHAS to free DHA for estrogen biosynthesis; Address reprint requests to Dr. Fisher, Department of Pediatrics, the fetus in such instances seems otherwise normal (3). Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA Fetal adrenal and parturition. The fetal adrenal plays a sig- 90509. nificant role in the timing of parturition in some mammalian Receivedfor publication 3 February 1986. species (7, 9-12). The events of parturition have been best char- acterized in sheep, in which species a marked prenatal fetal cor- 1. Abbreviations used in this paper: AVT, pituitary arginine vasotocin; tisol surge, dependent on the fetal pituitary, initiates a cascade CAT, catecholamines; CLIP, corticotropin-like intermediate peptide; ofendocrine events (including decreased placental progesterone CRF, corticotropin-releasing factor, CT, calcitonin; 1,25D, 1,25-dihy- production, increased placental estrogen secretion, and droxyvitamin D; DHAS, dehydroepiandrosterone sulfate; EGF, epider- increased mal growth factor, FGF, fibroblast growth factor, FSH, follicle-stimulating production ofprostaglandins) which eventuate in parturition (4, hormone; GH, growth hormone; GnRH, gonadotropin-releasing hor- 5, 9-13). Fetal hypophysectomy prevents this sequence of events mone; GRF, growth hormone-releasing factor, hCC, human chorionic and delays parturition; however, the mechanism ofthe activation corticotropin; hCG, human chorionic gonadotropin; hCS, human cho- of the fetal adrenal remains unclear, ACTH does not increase rionic somatomammotropin; hCT, human chorionic thyrotropin; LH, in fetal blood prior to or during the rise in cortisol. The search luteinizing hormone; MIF, testicular mullerian inhibiting factor, NE, norepinephrine; NGF, nerve growth factor, OT, oxytocin; OVT, OT-AVT-like peptide; PGE and PGF, prostaglandins E and F; PNMT, phenylethanolamine N-methyl transferase; POMC, pro-opiomelanocor- J. Clin. Invest. tin; PRL, prolactin; rT3, reverse triiodothyronine; SRIF, somatotropin © The American Society for Clinical Investigation, Inc. release inhibiting factor, STH, second trophic hormone; T3, triiodoth- 0021-9738/86/09/0603/09 $ 1.00 yronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thy- Volume 78, September 1986, 603-611 roid-stimulating hormone; VP, vasopressin. Unique Endocrine Milieu ofthe Fetus 603 Table I. Features of the Fetal Endocrine Environment surfactant synthesis in lung tissue (14-17), (b) increase insulin, fl-adrenergic, and EGF receptors in fetal lung tissue (18-20), (c) Unique fetal endocrine adaptations increase adrenal medullary phenylethanolamine N-methyl Fetal adrenal transferase activity (to augment epinephrine biosynthesis from Estrogen production norepinephrine) (5, 16), (d) increase hepatic iodothyronine beta Parturition (outer) ring monodeiodinase (to augment thyroxine [T4] con- Fetal maturation version to triiodothyronine [T31) (21), (e) decrease sensitivity of Fetal testes the ductus arteriosus to prostaglandin (to facilitate ductal closure) Sex differentiation (22), (f) mature secretory function of the rat fetal pancreas (23), Neurohypophyseal system (g) induce maturation of numerous small bowel enzymes and Fetal water metabolism transport processes (24, 25), and (h) induce maturation of a Fetal stress variety of hepatic enzymes (5, 16). In some instances these events Parturition? involve stimulation by cortisol of synthesis of the specific protein Parathyroid-calcitonin system or enzymes; in other instances (e.g., the increased sensitivity of Placental calcium transport the ductus arteriosus to prostaglandin) the mechanism of the Bone mineral anabolism? cortisol effect remains obscure. Unique fetal endocrine systems Fetal testes and sexual differentiation. The fetal gonads have Paraaortic chromaffin system little or no metabolic role during fetal life. Instead the fetal testes, Fetal intermediate pituitary under the influence of the placenta, serve at a critical period of Placental progesterone system embryogenesis to induce male sexual differentiation (26, 27). Ectopic polypeptide hormones Human chorionic gonadotropin (hCG), a luteinizing hormone Extrahypothalamic neuropeptides (LH-like placental hormone, stimulates fetal testicular androgen Neutralization of hormone actions in the fetus production between 8 and 16-18 wk gestation. The testicular Production of inactive metabolites androgen, in turn, stimulates development of the embryonic Receptor/postreceptor immaturity wolffian duct system and the external genitalia to effect male differentiation. In addition, the fetal testes produce an inhibitor of mullerian for a second trophic hormone (STH) for the fetal zone con- duct differentiation, mullerian-inhibiting factor or MWF (28-30). tinues. Hormones considered include ACTH1I38, ACTH1I24, This substance, the existence of which was first proposed by ACTHI.13, ACTHI-38, ,B-endorphin, prolactin, estrogens, a- Jost, appears to be a glycoprotein with a monomer molecular MSH, CLIP, EGF, and FGF (4, 5, 13). However, the putative weight of 72,000 and multimer molecular weights ranging from STH remains elusive. 145,00 to 235,000 (27-30). The structure has not yet been char- In human and primate species a role for fetal cortisol as a acterized and information regarding its mechanism of action is trigger for parturition is less clear. Fetal cortisol levels do not limited. It has been shown that mullerian duct regression, in increase markedly, progesterone concentrations do not consis- vitro, requires a 24-36-h exposure to MIF, and that MIF acts tently fall, and changes in estrogen levels are variable (4, 5, 10). extracellularly by causing dephosphorylation of a membrane However,