Talk:Endocrine - Adrenal Development
|About Discussion Pages|
Cite this page: Hill, M.A. (2019, June 18) Embryology Endocrine - Adrenal Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Endocrine_-_Adrenal_Development
Impact of maternal pheochromocytoma on the fetus and neonate
Gynecol Endocrinol. 2019 Jan 6:1-7. doi: 10.1080/09513590.2018.1540568. [Epub ahead of print]
Iijima S1. Author information Abstract Pheochromocytoma during pregnancy is rare but potentially harmful to the mother and fetus. Fetal risks are mainly determined by the vasoconstrictive effects of maternal catecholamine on uteroplacental circulation, because the fetus is protected from the direct effects of high catecholamine levels at the placental interface. Uteroplacental insufficiency may lead to spontaneous abortion, fetal growth restriction, premature delivery, and fetal hypoxia, followed by fetal distress and/or birth asphyxia. Adrenalectomy is recommended during the second trimester. When a diagnosis is made during the late second or third trimester, appropriate medical treatment until term and planned delivery with concurrent or delayed adrenalectomy can result in good fetal outcomes. Moreover, when adrenalectomy is planned after delivery, there is concern regarding the potential of antihypertensive drugs to be transferred to breast milk. It is generally known that early detection and proper treatment of pheochromocytoma during pregnancy decrease maternal and fetal mortality. However, in recent case series, antenatal maternal pheochromocytoma diagnosis did not significantly decrease the risk of fetal and neonatal mortality and morbidity, contrary to the maternal death and complication rates. Although intrauterine ischemia and hypoxia due to uteroplacental insufficiency can affect the long-term outcomes of neonates, no systematic studies have been performed. KEYWORDS: Pheochromocytoma; antihypertensive; fetus; neonate; pregnancy PMID: 30614304 DOI: 10.1080/09513590.2018.1540568
Neuropilins guide preganglionic sympathetic axons and chromaffin cell precursors to establish the adrenal medulla
Development. 2018 Nov 2;145(21). pii: dev162552. doi: 10.1242/dev.162552.
Lumb R1,2, Tata M3, Xu X1, Joyce A3, Marchant C1, Harvey N1, Ruhrberg C3, Schwarz Q4.
The adrenal medulla is composed of neuroendocrine chromaffin cells that secrete adrenaline into the systemic circulation to maintain physiological homeostasis and enable the autonomic stress response. How chromaffin cell precursors colonise the adrenal medulla and how they become connected to central nervous system-derived preganglionic sympathetic neurons remain largely unknown. By combining lineage tracing, gene expression studies, genetic ablation and the analysis of mouse mutants, we demonstrate that preganglionic axons direct chromaffin cell precursors into the adrenal primordia. We further show that preganglionic axons and chromaffin cell precursors require class 3 semaphorin (SEMA3) signalling through neuropilins (NRP) to target the adrenal medulla. Thus, SEMA3 proteins serve as guidance cues to control formation of the adrenal neuroendocrine system by establishing appropriate connections between preganglionic neurons and adrenal chromaffin cells that regulate the autonomic stress response. KEYWORDS: Adrenal gland; Autonomic nervous system; Axon guidance; Chromaffin cell; Neural crest cell; Neuropilin PMID: 30237243 DOI: 10.1242/dev.162552
FASEB J. 2018 Sep 24:fj201801028RR. doi: 10.1096/fj.201801028RR. [Epub ahead of print]
Poli G1, Sarchielli E2, Guasti D2, Benvenuti S1, Ballerini L3, Mazzanti B3, Armignacco R1, Cantini G1, Lulli M4, Chortis V5, Arlt W5, Romagnoli P2, Vannelli GB2, Mannelli M1, Luconi M1.
The adrenal gland is a multiendocrine organ with a steroidogenic mesenchymal cortex and an inner catecholamine-producing medulla of neuroendocrine origin. After embryonic development, this plastic organ undergoes a functional postnatal remodeling. Elucidating these complex processes is pivotal for understanding the early bases of functional endocrine disorders and tumors affecting the mature gland. We developed an in vitro human adrenal cell model derived from fetal adrenal specimens at different gestational ages, consisting of neuroendocrine and cortical components and expressing the zona and functional markers of the original fetal organ. These cortical and neuroendocrine progenitor cells retain in vitro an intrinsic gestational-age-related differentiation and functional program. In vitro these cells spontaneously form 3-dimensional structure organoids with a structure similar to the fetal gland. The organoids show morphofunctional features and adrenal steroidogenic factor, steroid acute regulatory, cytochrome-P450-17A1, dosage-sensitive, sex-reversal, adrenal hypoplasia-critical region on chromosome X protein , NOTCH1, and nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3; stem (BMI1, nestin); and chromaffin (chromogranin A, tyrosine hydroxylase) markers similar to those of the populations of origin. This in vitro human adrenal system represents a unique but preliminar model for investigating the pathophysiological processes underlying physiologic adrenal remodeling and pathologic alterations involved in organ hypo- and hyperplasia and cancer. PMID: 30247985 DOI: 10.1096/fj.201801028RR
Adrenal gland size in growth restricted fetuses
J Perinat Med. 2018 Mar 15. pii: /j/jpme.ahead-of-print/jpm-2017-0339/jpm-2017-0339.xml. doi: 10.1515/jpm-2017-0339. [Epub ahead of print]
Heese S1, Hammer K1, Möllers M1, Köster HA1, Falkenberg MK1, Eveslage M2, Braun J1, Oelmeier de Murcia K1, Klockenbusch W1, Schmitz R1.
OBJECTIVE: To compare the adrenal gland size of fetal growth restricted (FGR) and normal control fetuses. STUDY DESIGN: In this prospective study the adrenal gland size of 63 FGR fetuses and 343 normal controls was measured between 20 and 41 weeks of gestation. The total width and the medulla width were measured in a new standardized transversal plane. The cortex width and a calculated ratio of the total and medulla width (adrenal gland ratio) were compared between both groups. RESULTS: The mean cortex width and the adrenal gland ratio in FGR fetuses were higher in comparison to the controls (P<0.001; P=0.036, respectively). The cortex width correlated positively with the gestational age (control group: P<0.001; FGR group: P=0.089) whilst the adrenal gland ratio showed no association with the gestational age (control group: P=0.153; FGR group: P=0.314). CONCLUSION: The adrenal gland cortex width and the adrenal gland ratio were increased in FGR fetuses compared to normal fetuses. KEYWORDS: Adrenal gland; fetal growth restriction; gestational age; prenatal ultrasound PMID: 29543592 DOI: 10.1515/jpm-2017-0339
Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla
Science. 2017 Jul 7;357(6346). pii: eaal3753. doi: 10.1126/science.aal3753.
Furlan A1, Dyachuk V2,3,4, Kastriti ME5, Calvo-Enrique L1, Abdo H1, Hadjab S2, Chontorotzea T5, Akkuratova N6,7, Usoskin D1, Kamenev D2, Petersen J5,8, Sunadome K5, Memic F1, Marklund U1, Fried K2, Topilko P9, Lallemend F2, Kharchenko PV10, Ernfors P11, Adameyko I12,8.
Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell-gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development. Copyright © 2017, American Association for the Advancement of Science.
PMID: 28684471 DOI: 10.1126/science.aal3753
Fetal development of the mesonephric artery in humans with reference to replacement by the adrenal and renal arteries
Ann Anat. 2015 Aug 22;202:8-17. doi: 10.1016/j.aanat.2015.07.005. [Epub ahead of print]
Hinata N1, Suzuki R2, Ishizawa A2, Miyake H3, Rodriguez-Vazquez JF4, Murakami G5, Fujisawa M3.
According to the classical ladder theory, the mesonephric arteries (MAs) have a segmental arrangement and persist after regression of the mesonephros, with some of these vessels becoming definitive renal arteries. To avoid interruption of blood flow, such a vascular switching would require an intermediate stage in which two or more segmental MAs are connected to a definitive renal artery. To examine developmental changes, especially changes in the segmental distribution of MAs, we studied serial paraffin sections of 26 human embryos (approximately 5-7 weeks). At 5-6 weeks, 1-2 pairs of MAs ran anterolaterally or laterally within each of the lower thoracic vertebral segments, while 2-5 pairs of MAs were present in each of the lumbar vertebral segments, but they were usually asymmetrical. The initial metanephros, extending along the aorta from the first lumbar to first sacral vertebra, had no arterial supply despite the presence of multiple MAs running immediately anterior to it. Depending on increased sizes of the adrenal and metanephros, the MAs were reduced in number and restricted in levels from the twelfth thoracic to the second lumbar vertebra. The elimination of MAs first became evident at a level of the major, inferior parts of the metanephros. Therefore, a hypothetical arterial ladder was lost before development of glomeruli in the metanephros. At 7 weeks, after complete elimination of MAs, a pair of symmetrical renal arteries appeared near the superior end of the metanephros. In conclusion, the MAs appear not to persist to become a definitive renal artery. Copyright © 2015 Elsevier GmbH. All rights reserved. KEYWORDS: Adrenal; Definitive kidney; Human embryo; Mesonephric artery; Metanephros; Renal artery
Fetal adrenal gland in the second half of gestation: morphometrical assessment with 3.0T post-mortem MRI
PLoS One. 2013 Oct 7;8(10):e75511. doi: 10.1371/journal.pone.0075511. eCollection 2013.
Zhang Z1, Meng H, Hou Z, Ma J, Feng L, Lin X, Tang Y, Zhang X, Liu Q, Liu S.
BACKGROUND: The morphometry of fetal adrenal gland is rarely described with MRI of high magnetic field. The purpose of this study is to assess the normal fetal adrenal gland length (AL), width (AW), height (AH), surface area (AS) and volume (AV) in the second half of gestation with 3.0T post-mortem MRI. METHODS AND FINDINGS: Fifty-two fetal specimens of 23-40 weeks gestational age (GA) were scanned by 3.0T MRI. Morphological changes and quantitative measurements of the fetal adrenal gland were analyzed. Asymmetry and sexual dimorphism were also obtained. The shape of the fetal adrenal gland did not change substantially from 23 to 40 weeks GA. The bilateral adrenal glands appeared as a 'Y', pyramidal or half-moon shape after reconstruction. There was a highly linear correlation between AL, AW, AH, AS, AV and GA. AW, AH, AS and AV were larger for the left adrenal gland than the right. No sexual dimorphism was found. CONCLUSIONS: Our data delineated the normal fetal adrenal gland during the second half of gestation, and can serve as a useful precise reference for anatomy or in vivo fetus.
A morphometric study of suprarenal gland development in the fetal period
Surg Radiol Anat. 2012 Mar 20. [Epub ahead of print]
Ozgüner G, Sulak O, Koyuncu E. Source Department of Anatomy, Faculty of Medicine, Suleyman Demirel University, 32260, Isparta, Turkey, firstname.lastname@example.org.
PURPOSE: The present study's purpose was to examine the morphometric development of the suprarenal gland using anatomic dissection methods during the fetal period. METHODS: This study was performed on 172 human fetuses (76 males and 96 females) and 344 fetal suprarenal glands obtained from ages 9-40 weeks of gestation with no external pathology or anomaly. Fetuses were divided into 4 groups between gestational ages as follows: Group 1, 9-12 weeks (first trimester); Group 2, 13-25 weeks (second trimester); Group 3, 26-37 weeks (third trimester); and Group 4, 38-40 weeks (full term). Also, the fetuses were grouped into monthly cohorts: 9-12 weeks 3rd month, 13-16 weeks 4th month, 17-20 weeks 5th month, 21-24 weeks 6th month, 25-28 weeks 7th month, 29-32 weeks 8th month, 33-36 weeks 9th month, and 37-40 weeks 10th month. The suprarenal glands were dissected in the abdominal cavity. The dimensions (width, length, and thickness), volumes and weights of the suprarenal glands were evaluated. The ratio of the fetal suprarenal gland weight/fetal body weight, the ratio of the fetal suprarenal gland volume/fetal kidney volume, and the ratio of the fetal suprarenal gland dimensions/fetal kidney dimensions were evaluated. RESULTS: Mean values and standard deviations of all parameters according to gestational weeks and trimesters were calculated. It is found that all parameters increase with gestational age. There was significant correlation between gestational age and all parameters (p < 0.001). No significant differences were observed between sexes for any of the parameters (p > 0.05). There was no difference between the right and left sides of parameters except the thickness of the suprarenal glands. The left suprarenal glands were thicker than the right. The ratio of suprarenal volumes to kidney volumes was determined, and we observed that the ratio decreased during the fetal period. CONCLUSIONS: We believe that the results obtained from this study will be beneficial in understanding the development of suprarenal glands and also contribute to future studies in obstetrics, perinatology, and fetopathology.
Normal sex differences in prenatal growth and abnormal prenatal growth retardation associated with 46,XY disorders of sex development are absent in newborns with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Biol Sex Differ. 2011 May 5;2:5.
Chalmers LJ, Doherty P, Migeon CJ, Copeland KC, Bright BC, Wisniewski AB. Source Department of Pediatrics, The University of Oklahoma College of Medicine-Tulsa, Tulsa, OK 74135, USA. email@example.com.
BACKGROUND: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common presentation of a disorder of sex development (DSD) in genetic females. A report of prenatal growth retardation in cases of 46,XY DSD, coupled with observations of below-optimal final height in both males and females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, prompted us to investigate prenatal growth in the latter group. Additionally, because girls with congenital adrenal hyperplasia are exposed to increased levels of androgens in the absence of a male sex-chromosome complement, the presence or absence of typical sex differences in growth of newborns would support or refute a hormonal explanation for these differences.
METHODS: In total, 105 newborns with congenital adrenal hyperplasia were identified in our database. Gestational age (weeks), birth weight (kg), birth length (cm) and parental heights (cm) were obtained. Mid-parental height was considered in the analyses.
RESULTS: Mean birth weight percentile for congenital adrenal hyperplasia was 49.26%, indicating no evidence of a difference in birth weight from the expected standard population median of 50th percentile (P > 0.05). The expected sex difference in favor of heavier males was not seen (P > 0.05). Of the 105 subjects, 44 (27%; 34 females, 10 males) had birth length and gestational age recorded in their medical chart. Mean birth length for this subgroup was 50.90 cm (63rd percentile), which differed from the expected standard population median of 50th percentile (P = 0.0082). The expected sex difference in favor of longer males was also not seen (P > 0.05).
CONCLUSION: The prenatal growth retardation patterns reported in cases of 46,XY disorders of sex development do not generalize to people with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Sex differences in body weight and length typically seen in young infants were not seen in the subjects who participated in this study. We speculate that these differences were ameliorated in this study because of increased levels of prenatal androgens experienced by the females infants.
The fetal and adult adrenal cortex
Mol Cell Endocrinol. 2011 Apr 10;336(1-2):193-7. Epub 2010 Dec 3.
Morohashi K, Zubair M.
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Abstract The orphan nuclear receptor AD4BP/SF-1 (adrenal-4-binding protein/steroidogenic factor-1 (NR5A1)) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/Sf-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. Our transgenic studies have identified the tissue-specific enhancers for the fetal adrenal cortex, ventromedial hypothalamus, and pituitary in Ad4BP/Sf-1 gene. The adrenal cortex forms morphologically distinct compartments, the inner (fetal) and outer (definitive or adult) zones. Despite considerable effort, the mechanisms that mediate the differential development of the fetal and adult adrenal cortex remain incompletely understood. It remained controversial whether a true fetal type adrenal cortex is present in mice, and this argument was complicated by the postnatal development of the so-called X-zone. Using transgenic mice with lacZ driven by the fetal adrenal enhancer (FAdE), we clearly identified a fetal adrenal cortex in mice, and the X-zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth. We combined the FAdE with the Cre/loxP system to trace cell lineages in which the FAdE was active at some stage in development. These lineage tracing studies establish definitively that the adult cortex derives from precursor cells in the fetal cortex in which the FAdE was activated before the organization into two distinct zones. The potential of these fetal adrenocortical cells to enter the pathway that eventuate in cells of the adult cortex disappeared by E14.5. Thus, these studies demonstrate a direct link between the fetal and adult cortex involving a transition that must occur before a specific stage of development.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Migration and distribution of neural crest-derived cells in the human adrenal cortex at 9-16 weeks of gestation: an immunohistochemical study
Inoue S, Cho BH, Song CH, Fujimiya M, Murakami G, Matsubara A. Okajimas Folia Anat Jpn. 2010 May;87(1):11-6.
Neural crest-derived cells are believed to migrate into the fetal adrenal cortex from the medially-located hilus. However, there appears to be a paucity of observations of the migration and distribution of medullary cells in humans. In sagittal as well as horizontal sections of human fetuses between 9 and 16 weeks of gestation, we identified chromaffin, ganglion and Schwann-like cells in the developing adrenal gland using immunohistochemistry. Cells showing tyrosine hydroxylase (TH) immunoreactivity (i.e., candidate ganglion cells) entered the fetal cortex mainly from the medial half of the adrenal, but the path of entry also included the ventral, dorsal and caudal aspects. These cells displayed linear arrangements, forming a connection between the peripheral and central areas of the gland. S100 protein-immunoreactive cells (i.e., Schwann-like cells) accompanied most (but not all) of the TH-positive cells. The distribution of chromogranin A-immunoreactive cells (i.e., chromaffin cells) was similar to and overlapped with that of TH-positive cells. Chromogranin A-positive cells were observed around the aorta as well as in the adrenal. The entry of neural crest-derived cells does not appear to be restricted to a hypothetical medial hilus, but occurs widely around the cortex, with or without the accompaniment of Schwann-like cells. These cells advance in lines through the fetal cortex in a cord-like arrangement without destruction of the cortical architecture. Some of the TH-positive cells very likely express chromogranin A before entry into the adrenal.
Development of the human adrenal zona reticularis: morphometric and immunohistochemical studies from birth to adolescence
J Endocrinol. 2009 Nov;203(2):241-52. doi: 10.1677/JOE-09-0127. Epub 2009 Sep 1.
Hui XG1, Akahira J, Suzuki T, Nio M, Nakamura Y, Suzuki H, Rainey WE, Sasano H.
Age-related morphologic development of human adrenal zona reticularis (ZR) has not been well examined. Therefore, in this study, 44 human young adrenal autopsy specimens retrieved from large archival files (n=252) were examined for immunohistochemical and morphometric analyses. Results demonstrated that ZR became discernible around 4 years of age, and both thickness and ratio per total cortex of ZR increased in an age-dependent fashion thereafter, although there was no significant increment in total thickness of developing adrenal cortex. We further evaluated immunoreactivity of both KI67 and BCL2 in order to clarify the equilibrium between cell proliferation and apoptosis in the homeostasis of developing human adrenals. Results demonstrated that proliferative adrenocortical cells were predominantly detected in the zona glomerulosa and partly in outer zona fasciculata (ZF) before 4 years of age and in ZR after 4 years of age, but the number of these cells markedly decreased around 20 years of age. The number of BCL2-positive cells increased in ZR and decreased in ZF during development. Adrenal androgen synthesizing type 5 17beta-hydroxysteroid dehydrogenase (HSD17B5 or AKR1C3 as listed in the Hugo Database) was almost confined to ZR of human adrenals throughout development. HSD17B5 immunoreactivity in ZR became discernible and increased from around 9 years of age. Results of our present study support the theory of age-dependent adrenocortical cell migration and also indicated that ZR development is not only associated with adrenarche, but may play important roles in an initiation of puberty.
Adrenal androgens in humans and nonhuman primates: production, zonation and regulation
Endocr Dev. 2008;13:33-54.
Nguyen AD, Conley AJ.
Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.
Abstract The synthesis and secretion of large quantities of the adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfoconjugate DHEA sulfate (DS), is a phenomenon that appears limited to humans and some nonhuman primates. Both hydroxylase and lyase activities of the enzyme 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17) are necessary for DHEA production and are differentially regulated during adrenal development. Production of DHEA and DS occurs in the zona reticularis (ZR) of adults and the fetal zone of fetal primate adrenal glands, which is the primary substrate for maternal estrogen production during pregnancy. The onset of adrenal androgen production in childhood, referred to as adrenarche, corresponds with the establishment of the ZR: but the process is poorly understood, largely due to the lack of accessible animal models. Several nonhuman primates have been used to study adrenal function and remodeling, though none completely recapitulates human adrenarche, developmentally, functionally or temporally. This review will summarize the variations in adrenal androgen production and adrenal zonation in humans and nonhuman primates throughout life. It is hoped that recent studies demonstrating adrenarche in the rhesus will put in proper context the significance of adrenal zonation in nonhuman primates as valid models for human adrenal development and function.
Study of migration of neural crest cells to adrenal medulla by three-dimensional reconstruction
J Vet Med Sci. 2004 Jun;66(6):635-41.
Yamamoto M, Yanai R, Arishima K.
Department of Veterinary Anatomy II, Azabu University, School of Veterinary Medicine, Japan.
Adrenal medullary cells are derived from the neural crest. To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland. The reconstructed images showed that TH-positive cells were present contiguously from the sympathetic chain ganglia through a group of TH-positive cells ventral to the adrenal gland into the adrenal cortex, and that the group of TH-positive cells ventral to the adrenal gland communicated with the preaortic ganglion present ventral and caudal to the adrenal gland. These results suggest that neural crest cells use the same pathway to migrate to the sympathetic chain ganglia dorsal to the adrenal gland, to the adrenal gland, and to the preaortic ganglion.
Childhood Adrenocortical Tumours
Inactivation of Dicer1 in Steroidogenic factor 1-positive cells reveals tissue-specific requirement for Dicer1 in adrenal, testis, and ovary
Development and function of the human fetal adrenal cortex
J Pediatr Endocrinol Metab. 2002 Dec;15 Suppl 5:1311-22.
Langlois D, Li JY, Saez JM.
INSERM U-369, Faculté de Médecine Laennec, Université Claude Bernard Lyon, Lyon, France.
The development and function of the primate adrenal cortex are characterized by rapid growth, high steroidogenic activity, and a particular morphological appearance. The fetal adrenal glands grow rapidly and exponentially and at term are similar in weight to adult adrenals. From birth to 1 year their mass is reduced as they undergo a process of differentiation. Growth then remains slow until age 7 years. Thereafter, growth accelerates and the adrenals reach adult weight by the end of puberty. In the first trimester of gestation, fetal adrenal growth is thought to be independent of adrenocorticotropic hormone (ACTH), but after 15 weeks, ACTH is absolutely required for normal morphological and functional development. Other factors of fetal and/or placental origin, acting independently of or in conjunction with ACTH, are also required. Basic fibroblast growth factor, epidermal growth factor/transforming growth factor beta, and insulin-like growth factor (IGF)-I and -II, all acting in an autocrine and/or paracrine fashion, have been postulated to stimulate fetal adrenal cell proliferation. Corticotropin-releasing hormone may also play an important role in primate fetal adrenal function, primarily at the end of gestation. Finally, the estrogens are also important in the development of the pituitary-adrenal axis in primates.