UNSW Embryo- Development of the Endocrine System- Adrenal PubMed References Back to Endocrine Notes Links: PubMed Link About PubMed Note: A Selected List of References from PubMed March 1999 search results for adrenal dev/review is available for computers within School of Anatomy without Internet access. Access to abstracts from these computers is not available. See also Review Articles Internet access computers will be able to get abstract directly from PubMed (when available) by clicking Author's name below.

The regulation and role of fetal adrenal development in human pregnancy. Jaffe RB, Mesiano S, Smith R, Coulter CL, Spencer SJ, Chakravorty AEndocr Res 1998 Aug-Nov;24(3-4):919-26 The rapid growth of the human fetal adrenal gland, which is primarily a reflection of the growth of the unique fetal zone, is regulated by ACTH acting indirectly to stimulate the expression of locally produced growth factors, of which IGF-II and bFGF appear to play key roles. Through most of gestation, the outer definitive zone appears to function as a reservoir of progenitor cells which move centripetally to populate the rest of the gland. At the end of pregnancy, the fetal zone undergoes senescence through an apoptotic process. Activin and TGF-beta are capable of inducing apoptosis in the fetal zone. Corticotropin-releasing hormone, which is produced by the placenta in markedly increased amounts at the end of gestation, may orchestrate a variety of processes, including direct stimulation of fetal adrenal steroidogenesis, culminating in the initiation of parturition. PMID: 9888597, UI: 99103672    Role of growth factors in the developmental regulation of the human fetal adrenal cortex. Mesiano S, Jaffe RB Steroids 1997 Jan;62(1):62-72 Development of the human fetal adrenals is characterized by rapid growth and high levels of steroidogenic activity during the latter two-thirds of pregnancy. By midgestation, the human fetal adrenals are composed of two distinct cortical zones: the predominant fetal zone, which occupies 80-90% of the cortical volume and produces large amounts of the delta 5-steroid dehydroepiandrosterone sulfate, and the narrow definitive zone, which surrounds the fetal zone. Late in gestation, the peripheral portion of the fetal zone develops into a third, functionally distinct compartment, the transitional zone, which is the likely site of cortisol synthesis. Soon after birth, the adrenal cortex is remodeled and the fetal zone disappears. The adult cortical zones are thought to arise from the definitive zone, which persists postnatally. Development of the human fetal adrenals is regulated primarily by corticortropin (ACTH) secreted from the fetal pituitary. However, as ACTH is not a mitogen per se, its proliferative actions on human fetal adrenal cortical cells are thought to be mediated by autocrine/paracrine growth factors produced by adrenal cortical cells in response to ACTH. In addition, these growth factors appear to modulate the functional response of fetal adrenal cortical cells to ACTH. The roles of several growth factors, including the insulin like growth factors I and II (IGF-I and IGF-II), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), activin, inhibin, and the transforming growth factors alpha and beta (TGF-alpha and TGF-beta) have been examined. In cultured human fetal adrenal cortical cells, EGF, bFGF, and IGF-I and -II are mitogenic, whereas activin and TGF-beta inhibit proliferation. IGF-II, activin, and TGF-beta also modulate ACTH-stimulated steroidogenesis. Human fetal adrenal cortical cells express IGF-II, bFGF and the activin/inhibin subunits, and the abundance of mRNAs for each of these factors is up-regulated by ACTH, suggesting that these growth factors are autocrine/paracrine mediators of ACTH action. Thus, although human adrenal development is primarily regulated by ACTH, its actions appear to be mediated/modulated by a cohort of locally expressed growth factors, the net effect of which results in the unique growth and steroidogenic activity of the human fetal adrenal cortex. PMID: 9029717, UI: 97181556    Basic fibroblast growth factor expression is regulated by corticotropin in the human fetal adrenal: a model for adrenal growth regulation. Mesiano S, Mellon SH, Gospodarowicz D, Di Blasio AM, Jaffe RB Proc Natl Acad Sci U S A 1991 Jun 15;88(12):5428-32 Human fetal adrenal growth after midgestation is very rapid and appears to be dependent upon pituitary adrenocorticotropin (ACTH) in vivo. We hypothesized that the regulation of fetal adrenal growth by ACTH is mediated by ACTH-stimulated local growth factor production. As we have found basic fibroblast growth factor (bFGF) to be a potent mitogen for human fetal adrenal cells in culture, we conducted studies to determine whether bFGF is synthesized by the human fetal adrenal gland and whether bFGF gene expression in primary cultures of human fetal adrenal cells is regulated by ACTH. Bioassayable bFGF-like activity was detected in extracts of whole human fetal adrenal glands and primary cultures of human fetal adrenal cells. Northern blot analysis of total RNA from whole human fetal adrenal glands revealed a characteristic 7-kilobase bFGF mRNA, indicating that the fetal adrenal bFGF bioactivity was most likely due to local synthesis. Slot blot and ribonuclease protection analysis showed that bFGF mRNA was present in very low amounts in total RNA from primary cultures of unstimulated human fetal adrenal cells but was increased 2- to 3-fold in cells exposed to 10 nM ACTH-(1-24) or 1 mM 8-bromoadenosine 3',5'-cyclic monophosphate for 24 hr. bFGF mRNA was localized to adrenocortical cells and not fibroblasts by in situ hybridization. bFGF mRNA was barely detectable in unstimulated cells, whereas it was markedly increased in cells exposed to either ACTH or 8-bromoadenosine 3',5'-cyclic monophosphate. These data support our hypothesis that the regulation of human fetal adrenal growth by ACTH at midgestation may be mediated by the stimulation of local growth factor production, and we suggest that bFGF may play a major role in this process. PMID: 1711231, UI: 91271402   The development of the ovine fetal adrenal gland and its regulation. Naaman Reperant E, Durand PReprod Nutr Dev 1997;37(1):81-95 In mammalian species, the fetal adrenal gland plays a key role during late gestation since fetal glucocorticoids are involved in the maturation of the fetus and in the adaptation of the neonate to extra-uterine life. Moreover, in domestic ruminants as well as in the pig, the onset of parturition is triggered by an increased level of fetal plasma glucocorticoids. This prepartum rise of fetal glucocorticoids, which conveys growth and differentiation of adrenocortical cells, is not only under pituitary control but also involves local regulations. We review the actual knowledge of the modalities of fetal adrenal development in the sheep and its regulation by the adrenocorticotropic hormone (ACTH) and other factors.   Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. Seron-Ferre M, Lawrence CC, Jaffe RB It has been suggested that hCG is a trophic hormone for the fetal zone of the human fetal adrenal gland. To test this hypothesis, the isolated fetal zones of adrenals from eight fetuses (12-17-week gestation age) were superfused in the presence or absence of hCG. Dehydroepiandrosterone sulfate (DHAS) was measured in the superfusion effluent. A significant increase in DHAS production was observed in the presence of hCG. DHAS secretion decreased during the first 60 min in the control and experimental superfusions from 83 +/- 10.0 (mean +/- SE) to 71 +/- 8.0, and from 90 +/- 9.0 to 70 +/- 6.0 ng/100 mg/ml, respectively. In the presence of hCG (250 ng/ml), DHAS secretion increased significantly (P less than 0.01) over the controls to 116 +/- 12.0 at 120 min, and remained above the controls thereafter. These results support the hypothesis that hCG is one of the regulators of DHAS production by the human fetal adrenal gland early in gestation. As we found that ACTh stimulated DHAS secretion in a previous study and as there is indirect evidence for a role of ACTH in DHAS regulation late in pregnancy, these observations suggest dual regulation by hCG and ACTH early in pregnancy, and a possible transition to ACTH regulation of the fetal zone of the human fetal adrenal after midgestation. PMID: 162472, UI: 82053361   Steroid production by definitive and fetal zones of the human fetal adrenal gland. Seron-Ferre M, Lawrence CC, Siiteri PK, Jaffe RBJ Clin Endocrinol Metab 1978 Sep;47(3):603-9 This study was performed to assess the relative contributions of the fetal and definitive zones of the human fetal adrenal gland to "corticoid" (cortisol and perhaps other corticosteroids) and dehydroepiandrosterone sulfate (DHAS) production, and the possible regulatory role of ACTH and the fetal pituitary in the secretion of of these steroids. Corticoid and radioimmunoassayable DHAS or total aromatizable androgen secretion by the isolated definitive and fetal zones of the human fetal adrenal gland between 10-20 weeks gestation has been studied in a superfusion system. Different functional capacities of the two zones were seen; corticoids were found to be secreted primarily by the definitive zone, while DHAS was found to be the main secretory product of the fetal zone. Addition of ACTH (250 ng/ml) or fetal pituitary homogenate produced a 2- to 5-fold stimulation of corticoid production by the definitive zone at all gestational ages studied. DHAS secretion by the fetal zone was also stimulated by ACTH. These results indicate that the definitive and fetal zones of the human fetal adrenal gland at midgestation have the capacity to respond to ACTH with increased corticoid or DHAS secretion, respectively. PMID: 263313, UI: 83186533   Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland. Mesiano S, Mellon SH, Jaffe RB J Clin Endocrinol Metab 1993 Apr;76(4):968-76 Polypeptide growth factors may play an important role in the regulation of human fetal adrenal cortical growth by mediating the tropic actions of ACTH. The abundance of mRNA encoding insulin-like growth factor-II (IGF-II) is high in the human fetal adrenal gland and is stimulated by ACTH in cultured fetal adrenal cortical cells. Therefore, we studied the mitogenic action, regulation, and localization of IGF-II and a closely related peptide, IGF-I, in primary cultures of human fetal adrenal cortical cells and whole human fetal adrenal glands. Recombinant human IGF-I and IGF-II stimulated proliferation of fetal adrenal cortical cells in a dose-dependent fashion (1-1000 ng/mL; 0.133-133 nM). At 1000 ng/mL (133 nM), both peptides increased cell number 1.8- to 2-fold. Combinations of IGF-I or -II (100 ng/mL; 13.3 nM) with basic fibroblast growth factor (bFGF; 0.1 ng/mL; 6 pM) or epidermal growth factor (EGF; 1.0 ng/mL; 0.17 nM) had a greater effect on proliferation than bFGF, EGF, or either of the IGFs alone, suggesting an additive interaction. IGF-II mRNA was detected in cultured adrenal cortical cells by in situ hybridization analysis, and its abundance was stimulated by ACTH. In contrast, IGF-I mRNA was not detected in cultured fetal zone cells and was not regulated by ACTH. In whole human fetal adrenal glands, IGF-II mRNA was detected in the definitive and fetal zones and in the capsule, whereas IGF-I mRNA was detected only in the capsule and not in the two cortical zones. Using Northern blot analysis, we found that mRNA encoding IGF-II was present in high abundance in fetal adrenal glands (16-22 weeks) and barely detectable in adult adrenals, whereas mRNA encoding IGF-I was present in very low abundance in the fetal adrenal, but was high in adult human adrenals. As IGF-II expression is high in the human fetal adrenal cortex and is regulated by ACTH, we propose that it is the dominant of the two IGFs regulating human fetal adrenal growth. The cooperative mitogenic effect of IGF-II with bFGF and EGF and the regulation of its expression by ACTH support the hypothesis that IGF-II may act as a mediator, in concert with bFGF and possibly EGF, of the tropic action of ACTH in regulating the rapid growth of the human fetal adrenal cortex during midgestation. PMID: 8473412, UI: 93232170   Growth hormone stimulates adrenal steroidogenesis in the fetus. Devaskar UP, Devaskar SU, Voina S, Velayo N, Sperling MA Nature 1981 Apr 2;290(5805):404-5 The 'surge' of corticosteroid in fetal plasma during late gestation has been implicated in the initiation of parturition and the maturation of enzyme systems in organs such as the lung, liver, adrenal medulla and thyroid. But in all species studied, the mechanism responsible for increased secretion in the fetus remains unclear. The hormone adrenocorticotropin (ACTH) is well established as the primary regulator of adrenocortical cellular growth and secretory function during fetal and adult life. However, no increase in fetal plasma ACTH has been observed before the corticosteroid surge in sheep or humans, although differential responsiveness of the fetal adrenal cortex to ACTH at various gestational ages and a possible role of extra-adrenal inhibitory factors have been proposed. The possible steroidogenic effect of alpha-melanocyte-stimulating hormone (alpha MSH) on fetal adrenocortical function is controversial, and we could not demonstrate any such action in fetal lamb or rabbit. Prolactin and growth hormone (GH) potentiate the steroidogenic effect of ACTH in adult rats but prolactin had no such effect in fetal lamb. We have investigated the steroidogenic properties of GH, and report here that it stimulates adrenal steroidogenesis in the fetal but not maternal rabbit in vitro and in fetal but not maternal sheep in vitro as well as in vivo. PMID: 7219525, UI: 81173036   J Med Primatol 1998 Oct;27(5):234-9   Fetal growth in the baboon during the second half of pregnancy.   Tame JD, Winter JA, Li C, Jenkins S, Giussani DA, Nathanielsz PW College of Veterinary Medicine, Department of Physiology, Cornell University, Ithaca, NY 14853-6401, USA. The normal growth profile of critical fetal organs through the last third of gestation has not been documented in detail in human fetuses or the fetus of any nonhuman primate species. Recent epidemiological studies in human pregnancy suggest that fetal growth plays a major role in the programming of life-long health by modifying cardiovascular, pancreatic, brain, and liver growth. The present study aimed to produce a detailed database of individual organ growth in the fetal baboon in late gestation. Fetal organ weights were obtained from 43 baboon fetuses between 121 and 177 days of gestation. Various organs (brain, heart, kidney, femur, intestines, and spinal cord) showed no sign of slowed growth in late gestation while growth of others (lung, liver, stomach, and bladder) accelerated in late gestation. The fetal adrenal and thymus showed a decrease in growth rate over the final 20 and 10 days of gestation respectively. These observations provide a database that will permit analysis of factors responsible for regulation of normal and altered fetal organ development in this important experimental species. PMID: 9926978, UI: 99124168 Placental corticotropin-releasing hormone: function and regulation. Majzoub JA, Karalis KPAm J Obstet Gynecol 1999 Jan;180(1 Pt 3):S242-6 Corticotropin-releasing hormone is a neuropeptide placentally expressed among mammals only in primates. Its expression increases as much as 100 times during the last 6 to 8 weeks of pregnancy and is paradoxically stimulated by glucocorticoids. Increasing evidence suggests that placental corticotropin-releasing hormone may have evolved in primates to stimulate fetal adrenocorticotropin release and adrenal steroidogenesis, thus satisfying the high demand for synthesis of dehydroepiandrosterone, the predominant source of placental estradiol. Concomitant stimulation by placental corticotropin-releasing hormone of fetal cortisol and dehydroepiandrosterone would couple the glucocorticoid effects on fetal organ maturation with the timing of parturition, an obvious benefit in postnatal survival. PMID: 9914625, UI: 99115184     Developmental and functional biology of the primate fetal adrenal cortex.   Mesiano S, Jaffe RB Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143-0556, USA. The unique characteristics of the primate (particularly human) fetal adrenal were first realized in the early 1900s when its morphology was examined in detail and compared with that of other species. The unusual architecture of the human fetal adrenal cortex, with its unique and disproportionately enlarged fetal zone, its compact definitive zone, and its dramatic remodeling soon after birth captured the interest of developmental anatomists. Many detailed anatomical studies describing the morphology of the developing human fetal adrenal were reported between 1920 and 1960, and these morphological descriptions have not changed significantly. More recently, it has become clear that fetal adrenal cortical growth involves cellular hypertrophy, hyperplasia, apoptosis, and migration and is best described by the migration theory, i.e. cells proliferate in the periphery, migrate centripetally, differentiate during their migration to form the functional cortical zones, and then likely undergo apoptosis in the center of the cortex. Consistent with this model, cells of intermediate phenotype, arranged in columnar cords typical of migration, have been identified between the definitive and fetal zones. This cortical area has been referred to as the transitional zone and, based on the expression of steroidogenic enzymes, we consider it to be a functionally distinct cortical zone. Elegant experiments during the 1950s and 1960s demonstrated the central role of the primate fetal adrenal cortex in establishing the estrogenic milieu of pregnancy. Those findings were among the first indications of the function and physiological role of the human fetal adrenal cortex and led Diczfalusy and co-workers to propose the concept of the feto-placental unit, in which DHEA-S produced by the fetal adrenal cortex is used by the placenta for estrogen synthesis. Tissue and cell culture techniques, together with improved steroid assays, revealed that the fetal zone is the primary source of DHEA-S, and that its steroidogenic activity is regulated by ACTH. In recent years, function of the human and rhesus monkey fetal adrenal cortical zones has been reexamined by assessing the localization and ontogeny of steroidogenic enzyme expression. The primate fetal adrenal cortex is composed of three functionally distinct zones: 1) the fetal zone, which throughout gestation does not express 3 beta HSD but does express P450scc and P450c17 required for DHEA-S synthesis; 2) the transitional zone, which early in gestation is functionally identical to the fetal zone but late in gestation (after 25-30 weeks) expresses 3 beta HSD, P450scc, and P450c17, and therefore is the likely site of glucocorticoid synthesis, and 3) the definitive zone, which lacks P450c17 throughout gestation but late in gestation (after 22-24 weeks) expresses 3 beta HSD and P450scc, and therefore is the likely site of mineralocorticoid synthesis. Indirect evidence, based on effects of P450c21 deficiency and maternal estriol concentrations, indicate that the fetal adrenal cortex produces cortisol and DHEA-S early in gestation (6-12 weeks). However, controversy exists as to whether cortisol is produced de novo or derived from the metabolism of progesterone, as data regarding the expression of 3 beta HSD in the fetal adrenal cortex early in gestation are conflicting. During the 1960s, Liggins and colleagues demonstrated that in the sheep, cortisol secreted by the fetal adrenal cortex late in gestation regulates maturation of the fetus and initiates the cascade of events leading to parturition. Those pioneering discoveries provided insight into the mechanism underlying the timing of parturition and therefore were of particular interest to obstetricians and perinatologists confronted with the problems of preterm labor. However, although cortisol emanating from the fetal adrenal cortex promotes fetal maturation in primates as it does in sheep, its role in the regulation of primate parturition, unlike that in sheep PMID: 9183569, UI: 97326748   Early Hum Dev 1982 Apr;6(2):121-4   Growth of the adrenal gland of the normal human fetus during early gestation.   Carr BR, Casey ML The weights of 182 adrenal glands obtained from presumably normal human fetuses delivered by elective abortion between 6 and 17 weeks post-conceptional gestational age were measured. There was little increase in adrenal weight between 6 and 12 weeks gestation. Thereafter, the rate of increase in adrenal weight was rapid. There were no significant differences between the adrenal gland of male and female abortuses of similar gestational ages. PMID: 7094849, UI: 82235534     Functional maturation of the primate fetal adrenal in vivo: I. Role of insulin-like growth factors (IGFs), IGF-I receptor, and IGF binding proteins in growth regulation.   Coulter CL, Goldsmith PC, Mesiano S, Voytek CC, Martin MC, Han VK, Jaffe RB Reproductive Endocrinology Center, University of California, San Francisco 94143, USA. The rapid growth of the primate fetal adrenal from midgestation until term is regulated by ACTH secreted by the fetal pituitary. Previous studies suggest that the trophic actions of ACTH are mediated by insulin-like growth factor II (IGF-II) synthesized by fetal adrenal cortical cells. To characterize further the role of IGF-II in the regulation of fetal adrenal growth, we investigated the expression of the messenger RNAs (mRNAs) encoding IGF-I, IGF-II, IGF-I receptor (IGF-IR) and IGF binding protein (IGFBP) 1-6 in the fetal rhesus monkey adrenal in vivo from 109 days of gestation until term (165 +/- 5 days) using in situ hybridization. To assess the role of ACTH in the regulation of expression of the IGF system in vivo, we administered metyrapone (3-7 days) to late gestation fetal rhesus monkeys (n = 4) in utero to increase fetal pituitary ACTH secretion. IGF-II mRNA was abundant in the definitive, transitional and fetal zones of the adrenal cortex from 109 days until term. IGF-IR mRNA was expressed in the definitive, transitional and fetal zones and decreased to nondetectable levels at term. IGFBP-2 and IGFBP-6 mRNAs were expressed in the definitive, transitional, and fetal zones, whereas IGFBP-1, -3, -4, and -5 were not detected in adrenal cells. The effects of increasing ACTH secretion on the growth of the specific zones of the adrenal were determined using morphometric techniques. Metyrapone treatment approximately doubled adrenal weight, which was due to an increase in the area of the definitive, transitional, and fetal zones with decreased cell density of the definitive, transitional, and fetal zones compared with controls and not due to a change in total cell number. Therefore, the increase in adrenal weight after metyrapone treatment was due to hypertrophy of the three cortical zones; there was no effect on adrenal medullary growth. The relative abundance of the mRNAs encoding IGF-II and the IGF-IR was increased after metyrapone treatment, whereas the localization and relative abundance of IGFBP 1-6 mRNAs were not altered by metyrapone treatment. We conclude that the ontogenetic increase in adrenal growth may be regulated, at least in part, by locally synthesized IGF-II, and the cessation of adrenal growth that occurs at term may be mediated by the decrease in the IGF-IR. The adrenal cortical expression of IGFBP-2 and IGFBP-6 suggests that these IGFBPs may modulate the IGF-IGF-IR interaction. Metyrapone treatment, which likely increased fetal pituitary ACTH secretion, causes a coordinated increase in expression of IGF-II and IGF-IR in fetal adrenal cortical cells, which may be an important mechanism of regulation of fetal adrenal cortical growth. PMID: 8828511, UI: 96426217   Regulation of corticotropin responsiveness in human fetal adrenal cells.   Rainey WE, McAllister JM, Byrd EW, Mason JI, Carr BR Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas 75235-9032. The human fetal adrenal gland exhibits a high rate of steroidogenesis during fetal development and produces the majority of steroids used by the placenta for estrogen synthesis. Corticotropin appears to be the principal hormonal regulator of steroidogenesis in the fetal adrenal gland. However, little is known concerning the regulation of corticotropin receptors. In this study we examined the long-term regulation of corticotropin responsiveness as measured by the ability of human fetal adrenal gland cells to produce cyclic adenosine monophosphate after corticotropin treatment for 3 hours. We also examined the regulation of corticotropin receptors as determined by iodine 125-labeled corticotropin binding to fetal adrenal cells. Fetal adrenal glands were obtained from second-trimester abortuses. The two distinct zones of the fetal adrenal gland, the definitive zone and the fetal zone, were separated and the tissue mechanically dispersed. Freshly isolated cells responded to corticotropin with a sevenfold to tenfold increase in the production of cyclic adenosine monophosphate, indicating a functional corticotropin receptor-adenylate cyclase coupling. However, when either fetal zone or definitive zone cells were grown and passed in monolayer culture, corticotropin stimulation of cyclic adenosine monophosphate production dropped to only twofold. The loss of corticotropin stimulation of cyclic adenosine monophosphate production occurred with a loss of the steroid-metabolizing enzyme 17 alpha-hydroxylase (P-450(17 alpha]. Because P-450(17 alpha) expression can be stimulated after treatment of fetal adrenal gland cells with corticotropin or forskolin, we attempted to increase the ability of corticotropin to stimulate cyclic adenosine monophosphate production in a similar manner. After cells were pretreated with corticotropin (0.1 to 100 nmol/L) or forskolin (0.1 to 100 mumol/L) for 4 days, their ability to produce cyclic adenosine monophosphate in response to corticotropin was examined. Pretreatment with both corticotropin and forskolin caused a dose-dependent increase in the ability of corticotropin to stimulate the production of cyclic adenosine monophosphate. Cells stimulated with corticotropin after pretreatment with forskolin exhibited a 35- to 50-fold increase in cyclic adenosine monophosphate production compared with nontreated cells (approximately twofold). Corticotropin pretreatment increased responsiveness to a lesser extent than forskolin pretreatment. The increase in corticotropin responsiveness occurred along with an induction of P-450(17 alpha) enzyme levels. The effect of pretreatment with corticotropin and forskolin on the binding of iodine 125-labeled corticotropin to definitive zone cells was also investigated. Corticotropin pretreatment increased corticotropin receptor binding 2.8 times; forskolin pretreatment increased corticotropin binding by seven times. PMID: 1661068, UI: 92087809   Regulation of the primate fetal adrenal cortex. Pepe GJ, Albrecht ED Endocr Rev 1990 Feb;11(1):151-76 Significant advances in our understanding of the regulation of fetal adrenal growth, differentiation, and steroidogenesis have been made in the past several years. In vitro studies employing molecular biological techniques have demonstrated that the placenta and several fetal tissues synthesize growth factors and/or oncogene-related products, which have the capacity to modulate growth and maturation of the fetal adrenal. Moreover, there is evidence that the fetal adrenal itself produces IGF-I and IGF-II and that the mRNAs for these growth factors are responsive to ACTH and perhaps other peptides originating in the fetal pituitary and/or the placenta. Most fascinating are the studies demonstrating that growth factors may also regulate the pattern of steroidogenesis elicited by the fetal adrenal. For example, TGF beta modulates binding, internalization, and degradation of LDL-cholesterol in adult adrenals while IGF-I increases fetal adrenal steroidogenesis by mechanisms that do not involve induction of P-450scc or enhanced metabolism of LDL. These studies, coupled with the observation that activation of protein kinase C by EGF or bFGF can block ACTH and/or other cAMP-induced increases in the activity of P-450(17 alpha), provide new insight into the subcellular mechanisms that underlie the regulation of fetal adrenal function. However, in vivo investigations must be aggressively pursued because the latter provide a major and perhaps exclusive means to elucidate the complex and multiple mechanisms that are apparently operative in utero in the regulation of fetal adrenal development. Moreover, in vivo studies remain the only valid means to delineate whether the factors that have been shown to modulate fetal adrenal function in vitro are indeed operable in vivo. Thus, in vivo investigations have shown that a multifactorial regulation of the fetal adrenal exists in utero in which PRL and perhaps other peptides as well as ACTH selectively stimulate fetal adrenal androgen production. Moreover, in vivo studies have demonstrated that a feedback mechanism operates in utero whereby estrogen produced in the placenta from androgen precursors of fetal adrenal origin feeds back to modulate the responsivity of the fetal adrenal to tropic peptides perhaps by regulating peptide binding to cell membrane receptors and/or other mechanisms. Evidence has also been provided from in vivo studies to support the concept that the placenta via metabolism of maternal cortisol and cortisone regulates fetal pituitary production of ACTH by modulating the extent to which maternal cortisol arrives at the fetus. PMID: 2180686, UI: 90200941   Hormonal regulation of fetal growth. Evain-Brion D Horm Res 1994;42(4-5):207-14 The regulation of fetal growth is complex and poorly known. During the first trimester of pregnancy, no strict endocrine mechanisms are involved, but embryonic growth might be controlled at the level of the individual organs by supply of nutrients and by locally active growth factors. Later on, fetal growth depends essentially upon the maternoplacental cooperation in delivering nutrients to the fetus. Therefore, the major role of hormones in fetal growth is to mediate the utilization of available substrate. In late gestation, placental size and fetal growth rate are well correlated, pointing to a key role of the placenta in the regulation of fetal growth. It is therefore important to understand the molecular mechanisms involved in regulating placental development and endocrine functions. TGF alpha and EGF might play major roles as suggested by the modulation of their receptors with placental development, and by the specific alterations of EGF receptors in intrauterine growth retardation. In addition, human placenta specifically secretes placental growth hormone, the level of which is significantly decreased in the sera of pregnant women bearing a fetus with intrauterine growth retardation. PMID: 7868075, UI: 95172537   Ultrasonographic identification and measurement of the human fetal adrenal gland in utero. Hata K, Hata T, Kitao M Int J Gynaecol Obstet 1985 Oct;23(5):355-9 Ultrasonographic studies on the fetal adrenal gland were performed in utero on 100 fetuses 22-42 weeks of gestation. The correlations of the area of fetal adrenal gland (FAGA) with gestational age (r = 0.95, P less than 0.001) were high. The circumference of the fetal adrenal gland (FAGC) correlated well with the gestational age (r = 0.86, P less than 0.001) as did the length of this gland (FAGL) (r = 0.70, P less than 0.001). Ultrasonographic identification and measurement of the fetal adrenal gland in utero is thus an useful indicator to assess the growth and maturation of the fetal adrenal gland, and for detecting of congenital adrenal hyperplasia and hypoplasia. PMID: 2866985, UI: 86082666   Endocrine regulation of fetal growth. Fowden AL Reprod Fertil Dev 1995;7(3):351-63 Hormones have an important role in the control of fetal growth. They act on both tissue accretion and differentiation and enable a precise and orderly pattern of growth to occur during late gestation. In part, their actions on growth may be mediated by other growth factors such as the insulin-like growth factors (IGFs). Insulin stimulates fetal growth by increasing the mitotic drive and nutrient availability for tissue accretion. It has little effect on tissue differentiation. In contrast, the main effects of cortisol in utero are on tissue differentiation and maturation. Cortisol appears to act directly on the cells to alter gene transcription or post-translational processing of the gene products. Cortisol may also initiate the transition from the fetal to the adult modes of growth regulation by inducing the switch from IGF-II to IGF-I gene expression in the fetal liver. Thyroxine affects both tissue accretion and differentiation in the fetus by a combination of metabolic and non-metabolic mechanisms. Pituitary growth hormone, on the other hand, appears to have little part in the control of fetal growth, unlike its role postnatally. Fetal hormones, therefore, promote growth and development in utero by altering both the metabolism and gene expression of the fetal tissues. These hormonal actions ensure that fetal growth rate is commensurate with the nutrient supply and that prepartum maturation occurs in preparation for extrauterine life. PMID: 8606944, UI: 96187468   Development of the fetal pituitary-adrenal axis in the sheep. Brieu V, Cathiard AM, Darbeida H, Naaman E, Saez JM, Durand P Reprod Nutr Dev 1988;28(4B):1129-44 In the ovine fetus, plasma levels of corticosteroids are very low between 60 and 130 days of gestation, then increase dramatically before birth. ACTH appears to be an important regulating hormone for the fetal adrenal cortex, the sensitivity of which to this hormone increases during late gestation. However, the relationship between immunoreactive ACTH and corticosteroids in the fetus is unclear. We review herein recent work performed in our laboratory on the regulation of ACTH secretion by ovine fetal pituitary cells and on the biochemical modifications responsible for the enhancement of the steroidogenic response to ACTH of fetal adrenal cells. It is suggested that qualitative together with quantitative changes in the pituitary drive to the fetal adrenal has to be taken in account to explain the rise of corticosteroids in prepartum animals. Also extra pituitary hormones may be operating during intrauterine life to regulate fetal adrenal function. PMID: 3072626, UI: 89221919     J Clin Endocrinol Metab 1996 Jan;81(1):340-5   Localization and regulation of corticotropin receptor expression in the midgestation human fetal adrenal cortex: implications for in utero homeostasis.   Mesiano S, Fujimoto VY, Nelson LR, Lee JY, Voytek CC, Jaffe RB Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143-0556, USA. Developmental changes in the responsiveness of the fetal adrenals to corticotropin (ACTH) play an important role in the regulation of the fetal hypothalamic-pituitary-adrenal axis. Responsiveness of adrenal cortical cells to ACTH is dependent on the extent of ACTH receptor expression. Therefore, we examined the localization and regulation of ACTH receptor expression in the midgestation (16-24 weeks) human fetal adrenal cortex. In situ hybridization analysis was used to localize messenger RNA (mRNA) encoding the ACTH receptor in sections of human fetal adrenal glands. Messenger RNA encoding the ACTH receptor was localized in cells from all cortical zones; abundance was higher in definitive zone than in fetal zone cells and was least abundant in the more central portions of the cortex. Regulation of ACTH receptor expression was studied using Northern blot analysis of total RNA extracted from primary cultures of fetal and definitive zone cells. Two major (1.5 and 3.5 kilobases) and, upon stimulation with ACTH, 3 minor (4.0, 6.0 and 10.0 kb) ACTH receptor mRNA transcripts were detected in RNA from fetal and definitive zone cells. In both cell types, ACTH-(1-24) increased the abundance of mRNA encoding the ACTH receptor 10- to 20-fold compared with untreated cells. The effects of ACTH-(1-24) on ACTH receptor expression in fetal zone cells were time- and dose-dependent. The ED50 for the stimulation of ACTH receptor expression by ACTH-(1-24) was 1-10 pM, and maximal response to 0.1 nm ACTH-(1-24) was detected after 12-16 h. Eight-bromoadenosine cAMP and forskolin also stimulated ACTH receptor expression in fetal zone cells and closely mimicked the effects of ACTH-(1-24). In contrast, stimulation of protein kinase C with 12-O-tetradecanoyl phorbol 13-acetate had no effect on ACTH receptor expression. Changes in ACTH receptor expression in response to ACTH-(1-24), cAMP and forskolin were paralleled by changes in expression of the P450 cholesterol side chain cleavage (P450scc) enzyme. These data demonstrate that expression of the ACTH receptor by the human fetal adrenal cortex is up-regulated by its own ligand and that this effect is mediated by a cAMP-dependent mechanism. In addition, the coordinate stimulation of ACTH receptor and P450scc expression by ACTH indicates that the gene for the ACTH receptor is one of a specific cohort of genes regulated by ACTH that are required to facilitate fetal adrenal cortical response to ACTH. ACTH regulation of its own receptor may represent a mechanism by which fetal adrenal responsiveness to ACTH is maintained and possibly enhanced during fetal development. PMID: 8550775, UI: 96142010   Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Pepe GJ, Albrecht EDEndocr Rev 1995 Oct;16(5):608-48 It is clear that steroid hormones of placental and fetal adrenal origin have critically important roles in regulating key physiological events essential to the maintenance of pregnancy and development of the fetus for extrauterine life. Thus, progesterone has suppressive actions on lymphocyte proliferation and activity and on the immune system to prevent rejection of the developing fetus and placenta (see Fig. 9). Progesterone also suppresses the calcium-calmodulin-MLCK system and thus activity of uterine smooth muscle, thereby promoting myometrial quiescence to ensure the maintenance of pregnancy. Estrogen enhances uteroplacental blood flow and possibly placental neovascularization to provide optimal gas exchange and the nutrients required for the rapidly developing fetus and placenta. In turn, estrogen has specific stimulatory effects on the receptor-mediated uptake of LDL by, and P-450scc activity within, syncytiotrophoblasts, thus promoting the biosynthesis of progesterone. Moreover, there is an estrogen-dependent developmental regulation of expression of the LDL receptor and NAD-dependent 11 beta-HSD in the placenta, processes reflecting functional/biochemical differentiation of the trophoblast cells with advancing gestation. The increase in 11 beta-HSD causes a change in transplacental corticosteroid metabolism, which results in activation of the HPAA in the fetus. As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, e.g. 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland. In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor. At midgestation, estrogen also selectively feeds back on the fetal adrenal to suppress DHA and maintain physiologically normal levels of estrogen. Preparation of the breast for lactation and nourishment of the newborn appears to involve a multifactorial system of regulation that includes estrogen. It is apparent, therefore, that autocrine/paracrine, as well as endocrine, systems of regulation are operative within the fetoplacental unit during primate pregnancy. A major goal of this review has been to illustrate the critically close functional communication existing between the developing placenta and fetus in the biosynthesis and the actions of steroid hormones during primate pregnancy. The functional interaction of the human fetal adrenal and placenta with respect to the biosynthesis of estrogen was demonstrated many years ago. However, the recent studies presented in this review show that the endocrine interaction between the fetus and placenta is more extensive, involving complex physiological regulatory mechanisms. Thus, as illustrated in Fig. 9, estrogen, acting via its receptor within the placenta and other reproductive tissues, orchestrates the dynamic interchange between the placenta and fetus responsible for the developmental regulation of the biosynthesis of the various steroid and peptide hormones and their receptors necessary for the maintenance of pregnancy and development of a live newborn. It would appear, therefore, that the immediate and long range challenges in this area of reproductive endocrinology are to employ in vitro molecular and in vivo experimental approaches simultaneously to elucidate the nature of these complex interactions and define the cellular and molecular mechanisms underlying these important regulatory events. PMID: 8529574, UI: 96119902   Prog Growth Factor Res 1991;3(2):103-13   Growth factor regulation of adrenal cortex growth and function.   Feige JJ, Baird A Unite INSERM 244 DBMS/BRCE, CENG, 85X Grenoble, France. The control of adrenal cortex growth in vivo during development or under certain stress conditions is still very poorly understood at the molecular level. Some information can be collected however from in vitro experiments. Acidic and basic FGF appear to be the most potent mitogens, so far, for primary cultures of adult adrenocortical cells, whereas EGF can also stimulate growth of fetal cells. Several growth factors have emerged in the recent years as multifunctional molecules that play important regulatory functions on adrenocortical steroidogenesis. These include EGF, IL-1, insulin, IGF-1 and TGF beta. In certain cases (e.g. IGF-1, TGF beta), these factors participate in autocrine loops of regulation. The differential expression, release and activation of these factors might locally regulate the steroidogenic action of the hormonal signals delivered through the hypothalamo-pituitary-adrenal axis. Publication Types: Review Review, academic PMID: 1663405, UI: 92127006     Ultrasonographic identification and measurement of the human fetal adrenal gland in utero: clinical application.   Hata K, Hata T, Kitao M Department of Obstetrics and Gynecology, Shimane Medical University, Izumo, Japan. The size of the fetal adrenal gland was determined using ultrasonography in 346 fetuses with no complications at 28-40 weeks of gestation and in 12 fetuses of abnormal pregnancies (8 intrauterine growth retardations, 2 anencephalies, 1 intrauterine fetal death and 1 fetus of a mother who had been on steroids for treatment of systemic lupus erythematosus). The fetal adrenal gland area (FAGA), circumference (FAGC) and length (FAGL) were calculated. In 12 abnormal fetuses, FAGA values always fell below the mean +/- 2 SD. Deviations from the normal values were seen in 9 out of 12 cases (75%) in FAGC and in 4 out of 12 cases (33.3%) in FAGL. Of these pregnancies, 4 (33.3%) resulted in intrauterine fetal or neonatal death, and 2 neonates (16.6%) had to be admitted to the neonatal intensive care unit. Measurement of the fetal adrenal gland, especially of the FAGA, should be a pertinent diagnostic tool for perinatologists to manage and control high-risk pregnancies. PMID: 3277902, UI: 88138139     J Clin Endocrinol Metab 1999 Mar;84(3):1110-5   Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling.   Spencer SJ, Mesiano S, Lee JY, Jaffe RB Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 94143-0556, USA. After 10-15 weeks of gestation, the human fetal adrenal cortex undergoes rapid growth due to enlargement of a specialized cortical compartment known as the fetal zone (FZ). Soon after birth, the FZ regresses and the adult zonation pattern develops at least in part from cells derived from the persistent definitive zone (DZ), a thin layer of tightly packed cells surrounding the FZ. We postulated that growth of the fetal adrenal cortex involves zone-specific cellular hyperplasia, whereas the postnatal involution of the FZ is due to apoptosis. Therefore, we investigated the pattern of cellular proliferation and death in the FZ and DZ of the human fetal and postnatal adrenal cortex using immunohistochemical staining for proliferating cell nuclear antigen as a marker of mitosis and in situ detection of DNA fragmentation as a marker of apoptosis. Between 10-14 weeks' gestation, the mitotic indexes (percentage of proliferating cell nuclear antigen-positive cells) in the DZ (26.46 +/- 2.95%) and in the FZ (21.26 +/- 2.57%) were not significantly different. Between 15-20 weeks gestation, the mitotic index increased significantly (P < 0.05) in both zones (FZ, 33.84 +/- 5.21%; DZ, 67.45 +/- 7.58%) relative to levels before 15 weeks. This increase persisted between 21-24 weeks gestation (FZ, 39.5 +/- 4.22%; DZ, 58.63 +/- 6.83%). Interestingly, after 14 weeks, the mitotic index of the DZ was significantly greater (P < 0.05) than that of the FZ. In adrenal specimens obtained from infants born prematurely and treated in utero with glucocorticoid, the mitotic indexes in the FZ and DZ were significantly decreased. At all stages of gestation, no apoptotic nuclei were detected in the DZ. However, scattered apoptotic nuclei were detected in the central portions of the FZ. The number of apoptotic nuclei in the inner FZ increased with advancing gestation and was maximal during the first postnatal month. To identify factors that may regulate apoptosis, primary cultures of midgestation FZ cells were treated with activin A and transforming growth factor-beta (TGFbeta). Activin A and TGFbeta both induced apoptotic cell death, as assessed by internucleosomal DNA cleavage (DNA laddering). Induction of apoptosis by activin A was prevented by concomitant addition of follistatin, an activin-binding protein. Taken together, these data indicate that 1) growth of the human fetal adrenal cortex involves cellular hyperplasia, mainly in the DZ and to a lesser extent in the FZ, which is probably dependent on ACTH; and 2) apoptosis occurs predominantly in the inner cortical compartment and may be responsible for the rapid regression of the FZ after birth, a process that may be regulated by activin A and/or TGFbeta. PMID: 10084603, UI: 99182094       Reprod Fertil Dev 1995;7(3):323-31   Implication of inhibin and related proteins in fetal development.   Jenkin G, McFarlane JR, de Kretser DM Department of Physiology, Monash University, Clayton, Vic, Australia. Initial studies on inhibin, activin and follistatin focussed on their role as regulators of adult gonadal function via feedback regulation of anterior pituitary hormones and via intragonadal control of steroid hormones. The discovery of isoforms of follistatin which are either secreted or retained on the cell surface and which bind activin and, to a lesser extent, inhibin adds a further dimension to the regulation of these peptides. More recently, the cloning of inhibin and activin, and the observation of their close homology to the transforming growth factor-beta family of peptides, has led to an interest in their possible role as growth and differentiation factors. Activin, inhibin and follistatin are expressed in embryonic and fetal tissues, as well as in the placenta. However, although activin is a potent regulator of growth and differentiation in a number of cell types, their role in embryonic and fetal development has yet to be established. High concentrations of inhibin have been observed in the fetal gonads, particularly the testes, and in the fetal adrenals of a number of species and a sex difference in fetal plasma concentrations has also been observed. Although the stimulus for high concentrations of inhibin in the fetus is not know, they are associated with decreased testicular testosterone and a decrease in the concentration of circulating follicle-stimulating hormone (FSH); this suggests that, as in the adult, inhibin may be involved in the regulation of fetal testicular androgen and pituitary FSH secretion during late gestation. The recent reports of elevated concentrations of inhibin and, particularly, activin in amniotic fluid during late gestation and its ability to stimulate the production of prostaglandin E2 by fetal membranes provides yet another potential role for this hormone in the regulation of events leading to parturition. Publication Types: Review Review, tutorial PMID: 8606941, UI: 96187465       Am J Obstet Gynecol 1993 Nov;169(5):1205-10   Transvaginal ultrasonographic measurements of the fetal adrenal glands at 12 to 17 weeks of gestation.   Bronshtein M, Tzidony D, Dimant M, Hajos J, Jaeger M, Blumenfeld Z Department of Obstetrics and Gynecology A, Rambam Medical Center, Haifa, Israel. OBJECTIVE: Our purpose was to compile normative data of fetal adrenal gland measurements between 12 and 17 weeks' gestation with transvaginal ultrasonography. STUDY DESIGN: Transvaginal ultrasonographic measurements of the fetal adrenal length and adrenal-to-kidney length ratio calculations were performed on 100 normal fetuses at 12 to 17 weeks' gestation. The diameters of the fetal adrenals and kidneys on each side were measured, and nomograms were generated. These parameters were also measured in two fetuses whose mothers were treated for congenital adrenal hyperplasia. RESULTS: The measurements of the maximal longitudinal axis of the right and left fetal adrenal glands showed a linear increase with fetal age between 12 and 17 weeks of gestation. The adrenal-to-kidney length ratio decreased linearly between these gestational ages. In maternal congenital adrenal hyperplasia treated with glucocorticosteroids the fetal adrenals were small. CONCLUSION: Fetal adrenal gland measurements in the early second trimester show a linear progressive growth between 12 and 17 weeks' gestation. PMID: 8238184, UI: 94056586     J Dev Physiol 1991 Feb;15(2):71-9   The trigger for parturition in sheep: fetal hypothalamus or placenta?   Thorburn GD, Hollingworth SA, Hooper SB Department of Physiology, Monash University, Clayton, Victoria, Australia. The fetal pituitary-adrenal axis plays a pivotal role in the mechanisms leading to parturition in sheep. Fetal cortisol concentrations gradually increase in the last 15 days before term, with a marked increase occurring in the last 3-4 days. Some mechanism causes a marked increase in the stimulatory drive to the fetal pituitary resulting in increased secretion of ACTH from the pituitary, and subsequent cortisol secretion from the adrenal gland. In this paper we discuss the roles of the hypothalamus and placenta in triggering the onset of labour in sheep. We have shown that prostaglandin E2 can stimulate the release of ACTH and cortisol in the intact fetus and we believe that this could be mediated by the release of CRH and AVP. Although CRH and AVP are present in the fetal hypothalamus and are capable of being released, these factors may not be released until approximately 135 days of gestation. One fundamental question in relation to parturition remains unanswered: how are the high concentrations of cortisol in fetal plasma sustained given that cortisol has an inhibitory feedback effect on the release of CRH and ACTH secretion? We discuss the possibility that the placenta provides an additional trophic drive to both the pituitary and adrenal glands which contributes towards the sustained elevated cortisol concentrations needed to initiate parturition. The placenta may initiate the hypothalamus and PGE2 and/or CRH, secreted by the placenta, may stimulate pituitary ACTH release. Publication Types: Review Review, tutorial PMID: 1865094, UI: 91324668 Ot     Cell Tissue Res 1976 May 26;168(4):549-59   Ultrastructural study on the hypothalamic-hypophysial-adrenal axis in fetal rats.   Daikoku S, Kinutani M, Sako M The adrenal glands of decapitated and encephalectomized fetal rats were investigated electron microscopically and compared to those of normal intact fetal rats. Although the adrenal cortices did not show three zones (zona glomerulosa, fasciculata, and reticularis) on the 16.5th day of gestation when the decapitation or encephalectomy was carried out in utero, the zonation was recognized in fetuses operated on the 21.5th day of gestation. The same was true for normal control fetuses. However, cytoplasmic characteristics suggesting steroidogenesis in the cortical cells were reduced to various degrees in the encephalectomized or decapitated fetuses, especially in the latter ones. The change in cytoplasmic appearance was more conspicuous in the inner portion of the cortex. This result suggests that for the maintenance of normal adrenocortical function the hypothalamus may be indispensable even during the prenatal life of rats. PMID: 945131, UI: 76208330     Ciba Found Symp 1981;86:43-65   The development of fetal adrenal function.   Challis JR, Manchester EL, Mitchell BF, Patrick JE The response profiles of fetal sheep adrenals to tropic stimulation have been examined ih vivo and in vitro. Isolated adrenal cells from sheep fetuses in early pregnancy (Day 50) reduced cortisol in response to ACTH, dibutyryl cyclic AMP and GTP. The response was minimal on Day 100, but reappeared near term. 17 alpha-Hydroxyprogesterone was converted to cortisol by adrenals of all ages, but pregnenolone and progesterone were converted to cortisol only in early and late, but not mid-pregnancy. These studies suggested that the mid-gestation loss of fetal adrenal responsiveness was associated with post-receptor/adenylate cyclase events and involved loss of 17 alpha-hydroxylase activity. Fetal adrenal function was activated by exogenous ACTH in vivo, and was reflected in an increase in the ratio of cortisol to corticosterone in fetal plasma and in augmented cortisol output in vitro from dispersed fetal adrenal cells. The results were consistent with an effect of ACTH administration on 17 alpha-hydroxylation. Fetal pituitary cells, prostaglandin E2, alpha-MSH and term placental extract are other potential (sources of) corticotropins, although further studies are required to delineate the nature and origin of the active substances, and/or their primary sites of action. PMID: 6279366, UI: 82164163 J Steroid Biochem Mol Biol 1995 Jun;53(1-6):227-31   Steroid-protein interaction in human placenta.   Petraglia F, de Micheroux AA, Florio P, Salvatori M, Gallinelli A, Cela V, Palumbo MA, Genazzani AR Department of Gynecological, Obstetric and Pediatric Sciences, University of Modena, School of Medicine, Italy. Human placenta produces a large variety of bioactive substances with endocrine and neural competence: pituitary and gonadal hormones, hypothalamic-like releasing or inhibiting hormones, growth factors, cytokines and neuropeptides. The most recent findings indicate that locally produced hormones regulate the secretion of other placental hormones supporting a paracrine/autocrine regulation. In placental endocrinology, a particular relevance is played by steroid hormones. In fact, a specific gonadotropin-releasing hormone (GnRH)-human chorionic gonadotropin (hCG) regulation of placental steroidogenesis has been proposed as a placental internal regulatory system acting on steroids production from human placenta. In addition, activin and inhibin have been proposed as further regulatory substances of the synthesis and secretion of steroids; the addition of activin A to placental culture augments GnRH, hCG and progesterone, and this effect can be significantly reduced by the addition of inhibins. Finally, a steroid-steroid interaction is suggested by the evidence that placental estrogen has a positive role in the regulation of progesterone biosynthesis. Other steroid-protein interactions have been observed in human placenta. In fact, recent data indicate that progesterone inhibits placental corticotropin-releasing factor (CRF) and estrogens act on placental conversion of cortisol to cortisone, activating cortisol secretion by the fetal adrenal and enhancing fetal adrenal function with advancing gestation. PMID: 7626460, UI: 95352455 Effect of placental factors on growth and function of the human fetal adrenal in vitro. Riopel L, Branchaud CL, Goodyer CG, Zweig M, Lipowski L, Adkar V, Lefebvre Y Biol Reprod 1989 Nov;41(5):779-89 Conditioned medium from human placental monolayer cultures (PM) had a marked stimulatory effect on proliferation (3H-thymidine uptake) of human fetal zone adrenal cells in primary monolayer culture, even in the absence of serum. Epidermal growth factor (EGF) and fibroblast growth factor (FGF) also significantly stimulated fetal adrenal cell growth. However, the effects of PM differed from those of EGF and FGF in several respects: 1) maximal response to PM was 2-5 times greater; 2) mitogenic effects of EGF and FGF were suppressed by adrenocorticotropic hormone (ACTH), whereas that of 50% PM was not; 3) PM inhibited ACTH-stimulated steroidogenesis (dehydroepiandrosterone sulfate and cortisol), but EGF and FGF did not. Preliminary characterization studies have indicated that approximately half of the placental growth-promoting activity is heat resistant and sensitive to bacterial proteases, and that 50-60% of the activity is lost after dialysis with membranes having a molecular weight cutoff of 3500. These findings suggest a role for the placenta in the growth and differentiated function of the human fetal adrenal gland. PMID: 2560404, UI: 90167148