Embryological and Molecular Development of the Adrenal Glands
IAN L. ROSS1* AND GRAHAM J. LOUW2
1 Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, Republic of South Africa
2Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, Republic of South Africa
In this mini review, the embryological and functional development of the adre- nal glands is presented from a molecular perspective. While acknowledging that this is a highly complex series of events, the processes are described in simple and broad strokes in a single text for the reader who is interested in this field but is not an active researcher. The origin of the adrenal glands is in the mesodermal ridge as early as the fourth week of gestation. Between the eighth and ninth weeks of gestation, the adrenal glands are encapsulated and this results in the presence of a distinct organ. There have been great strides in deciphering the very complicated molecular aspects of adrenal gland devel- opment in which multiple transcription factors have been identified, directing the adrenogonadal primordium into the adrenal cortex, kidney, or bipotential gonad. Adrenocorticotrophic hormone is critical for early development of the hypothalamic-pituitary adrenal axis. Several mutations in transcription factors, responsible for normal adrenal gland development have been found to induce the familial syndrome of congenital adrenal hypoplasia or neoplasia. Clin. Anat. 00:000-000, 2014. @ 2014 Wiley Periodicals, Inc.
Key words: molecular development; transcription factors; adrenogonadal primordium; genetics of adrenal tumors
INTRODUCTION
The adrenal glands have been a focus of attention for certain scientists and researchers for many centu- ries (Carmichael, 2014) and considerable advance- ments in knowledge about the structure and function of these glands have been made in relatively recent times as a result of improvements in technological expertize. The adrenal glands are small triangular glands; one located above each kidney. The left adre- nal gland is crescent-shaped and the right gland is pyramidal in shape (Fig. 1). Both glands are sur- rounded by a firm fibrous capsule that often merges with perinephric capsules. The adrenal glands are sup- plied by arterial branches arising from the inferior phrenic artery, the abdominal aorta, and renal arteries (Donnellan, 1961). The veins draining the adrenal glands are the shorter right adrenal and the left longer adrenal veins. Variations of venous drainage and arte- rial supply are known to occur, and one case of the
right middle adrenal artery arising from the right renal artery was recently documented (Cimen et al., 2007). The major lymph vessels drain the medulla and sub- scapular adrenal cortex and culminate in the para- aortic, paracaval, and perirenal lymph nodes (Wilkins, 2001). The adrenal gland is richly innervated by the autonomic nervous system. The capsule contains nerve plexuses of fibers originating from the greater splanchnic nerve and associated abdominal plexuses
*Correspondence to: Ross IL, J 47 Old Main Building, Groote Schuur Hospital Observatory Cape Town 7925. E-mail: Ian.Ross@uct.ac.za
I.L.R. and G.J.L. have no conflicts of interest.
Received 10 April 2014; Revised 12 May 2014; Accepted 13 May 2014
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ca.22422
Inferior phrenic arteries
Superior suprarenal arteries
Left suprarenal gland
Right suprarenal gland
Middle suprarenal artery
Inferior suprarenal artery
Left kidney
Right kidney
Abdominal aorta
Inferior vena cava
of the sympathetic autonomic nervous system, com- bined with parasympathetic contributions from the phrenic and vagal nerves (Li et al., 1999).
The adrenal glands have a larger outer cortex and a smaller inner medulla. The glands measure between 3 and 4 cm at their longest diameters, have a mass of between 5 and 7 g, and have a yellow color imparted by the rich lipids within the cortices. The adrenal medulla, by contrast is reddish-brown (Kemp, 1937). In most mammals, the adrenal cortex consists of an outer zona glomerulosa, intervening zona fasciculata and an inner zona reticularis. A narrow population of stem cells surround zona glomerulosa, facilitating pro- gressive development. This population of cells may ultimately give rise to adrenocortical neoplasia (Par- viainen et al., 2007).
EMBRYOLOGICAL DEVELOPMENT OF THE ADRENAL GLANDS
The urogenital ridge of mesoderm on either side of the midline in the thoracolumbar region of the embryo gives rise to the gonads, mesonephros, and adrenal cortices, which helps to explain the close anatomical proximity between the kidneys and adrenal glands. At around the fourth week of gestation, the celomic epi- thelial cells and the underlying mesonephric mesen- chymal cells migrate from the mesonephros to form the most rudimentary steroid producing tissue (Fig. 2;
Ferraz-de-Souza and Achermann, 2008). By day 25, bilateral adrenal primordia develop as cords of large polyhedral cells of celomic mesothelium. Primitive sympathetic cells migrate with nerve tracts to form the adrenal medulla, which is, therefore, of ectoder- mal origin. In the seventh week in utero, the paragan- glionic cells replicate and differentiate by the eighth week, discreet fetal gonadal and adrenal tissues are discernible, which then develop as separate entities thereafter. Between the eighth and the ninth weeks of gestation, adrenal glands are encapsulated, which results in a distinct organ cranial to the kidney (Ferraz-de-Souza and Achermann, 2008).
The human fetal adrenal gland comprises two dis- tricts zones; the fetal zone and the definitive zone. The former accounts for 80-90% of the adrenal cor- tex at term and is responsible for the elaboration of mainly androgens, especially dehydroepiandrosterone (DHEA). The definitive zone is responsible for produc- ing cortisol. A transitional zone exists between two zones and is capable of glucocorticoid production in the third trimester (Mesiano and Jaffe, 1997). The adrenal cortex development in mice is a persistent postnatal player adjacent to the medulla known as the X zone. In many respects, the X zone is similar to that of fetal adrenal tissue. The development of the adre- nal cortices is different in mice and humans as 17x- hydroxylase (CYP17) is expressed only transiently in the former, explaining why mice adrenal glands pro- duce primarily corticosterone rather than androgens
~ 4 weeks
~ 4 weeks
~ 5 weeks
~ 8-9 weeks
coelomic epithelium
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adrenal primordium
adrenal gland
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mesonephros
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gonadal primordium
gonad
capsule
.
0
9
9
A
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0
O
intermediate mesoderm
kidney
metanephros
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b
C
d
(Parviainen et al., 2007). At birth the significant reduction in the volume of the adrenal glands is matched by a rapid reduction in the levels of andro- gens. A specific molecular clock has been proposed to direct the number of cell divisions that facilitates invo- lution of the fetal zone. Fetal pituitary adrenocortico- trophic hormone (ACTH) is responsible for the phenomenal growth of the fetal zone (Coulter, 2005), while insulin-like growth factor (IGFII), fibroblast growth factor and epidermal growth factor (EGF) mediate growth of the fetal adrenal gland (Coulter, 2004). The development of the vascular network may be facilitated by vascular endothelial growth factor and angiopoietins (Shifren, 1998).
MOLECULAR ASPECTS OF ADRENAL GLAND DEVELOPMENT
The molecular underpinnings of the development of the adrenal gland are highly complex and knowledge about these mechanisms is rapidly expanding. A Pubmed search revealed that between 1970 and 1991, there were seven published articles that described the embryological development of the adre- nal glands from a molecular biological perspective, whereas there were 36 such articles published between 1992 and 2002, and 45 articles in the decade ending in 2013. A search on molecular mechanisms of the development of the adrenal gland indicated that 176 articles appeared in the last decade, and a total of 312 in the same decade were published on gene expression in this process. The formation of the primi- tive adrenogonadal primordia (AdP), occurs under the influence of transcription factors empty spiracles2 (Emx2), Lin 11 Islet 1 and Mec-3 homeobox gene 1 (Lim1), Wilms tumor 1 (Wt-1), and wingless-type MMTV integration site family member 4 (Wnt4; Runge, 2006). Figure 3 demonstrates the various combina-
primordia develop as separate entities. d) Between 8 and 9 weeks, the adrenal gland becomes encapsulated and already exhibits a fetal and definitive zone. Reproduced with permission from Ferraz-de-Souza and Achermann, Endocr Dev, 2008, 13, 19-32. [Color figure can be viewed in the online issue, which is available at wileyonlineli- brary.com.]
tions of transcription factors that direct the develop- ment of undifferentiated primordial cells to form the adrenal cortex, kidney, bipotential gonad, and internal reproductive tract primordia.
The AdP has its origins at the primitive urogenital ridge (Zubair et al., 2008) and its formation is crit- ically dependent on the expression of the nuclear receptor steroidogenic factor (Sf1; Zubair et al., 2006). Both these primitive organs appear to arise from a single group of cells because they stain immuno-histochemically strongly positive for Sf1 (Zubair et al., 2008). The bilateral AdP then divide into fetal adrenal and the gonadal primordia. Wnt4 is critical for the separation of the AdP.
Fetal zone specific Sf1 enhancer (FadE) is specific for adrenal gland development as it is absent in the gonadal primordium (Zubair et al., 2008). The AdP expresses Wt-1 and Wnt4, which have been found to be crucial in the differentiation of both adrenocortical and gonadal stromal cells (Luo et al., 1994; Keegan and Hammer, 2002). The Wnt pathway regulates pro- liferation, specification of cell fate, stem cell mainte- nance and differentiation. Wt-1 is responsible for the molecular specification of the adrenal primordia by upregulation of Sf1. Development of the adrenal pri- mordia is directed through the upregulation of Sf1 by Wt-1, transcriptional coactivator CREB-binding pro- tein/P 300-interacting transactivator, with ED-rich tail, 2 (Cimen et al., 2007). As the adrenal primordia sepa- rate from AdP, they are subject to the action of a tran- scription complex containing the homeobox protein [(PKNOX1, homeobox gene 9B and pre-B-cell leuke- mia homeobox 1 (Pbx1)] and their principal function is to maintain Sf1 fetal zone expression (Zubair et al., 2006; Kim et al., 2009).
It has been suggested that stem cells within the capsule give rise to the definitive cortex in response to a number of morphogenetic signals (Kim et al., 2009). Simultaneous with the transcriptional cascade,
primitive mesoderm
coelomic epithelium
DAX1 Sf1 Wnt4 Wt-1 FadE
EmX2 Lim1 Wt-1 Wnt4
cKit/steel
adrenal cortex
migration of primordial germ cells
Adrenogonadal primordium
Wt-1 Wnt4 EmX2 Lim1 Pax2/8
Wnt4 HoXa13 EmX2
Sf1 Wt-1 EmX2 Lim1 Lhx9 M33
kidney
internal reproductive tract primordial
bipotential gonad
mesenchymal cells that are Sf1 negative coalesce to form a capsule around the fetal cortex (Fig. 4). As soon as the capsule is complete, the adult cortex develops in the intervening tissue between the cap- sule and fetal cortex. Following various mitogenic stimuli, the capsule undergoes symmetrical division, developing another capsule cell, which in turn pro- duces a subcapsular progenitor cell. The capsule and subcapsular population of cells play a critical role in adrenocortical growth and maintenance. These cells are also receptive to ACTH and angiotensin II signals, which direct the differentiation of these cells to pro- ducing steroids (Kim et al., 2009).
Sf1/adrenal 4-binding protein (Ad4BP) like other nuclear hormone receptors, has an N- terminal zinc fin- ger DNA-binding domain, a ligand-binding domain, and a C-terminal AF-2 activating domain (Fujieda et al., 2003). Sf1 actively promotes a variety of steroidogenic enzymes following ACTH stimulation and is essential not only for providing the subcapsular cells with their ability to proliferate but is also essential in interacting with other transcription factors (Kim et al., 2009).
Sf1 also interacts with transcription factors cyclic AMP response element binding protein and ß-catenin. Pbx1 is a downstream mediator of Sf1-dependent pro-
tive tract primordia. Factors highlighted in bold are involved in human development. Abbreviations used: DAX1, dosage-sensitive-sex-reversal-adrenal hypoplasia congenital locus on the X-chromosome gene 1; Emx2, empty spiracles 2; Hoxa1, homeobox A1; Lhx9, lim homoeobox gene 9; Lim, 1 Lin11 Islet 1 and Mec-3 homeobox gene 1; Sf1, steroidogenic factor 1; Wt-1, Wilms tumor 1; Wnt4, Wingless-type MMTV integration site family member 4; FadE, fetal zone specific Sf1 enhancer. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
liferation of subcapsular cells. DAX1 (dosage-sensitive- sex-reversal, adrenal hypoplasia congenita critical region, on chromosome X gene 1) positive together with Sf1 positive progenitor cells are responsible for transiently amplifying nonsteroidogenic cells (Kim et al., 2009). Investigation of patients with adrenal hypoplasia congenita has revealed that nuclear recep- tors Sf1, DAX1, and the Pbx1 play pivotal roles in the development of the adrenal cortex (Fujieda et al., 2003). The homeobox genes induce the Ad4BP/Sf1 expression in the intermediate mesoderm and interact with Pbx1, critical in the early phase of adrenal gland development (Zubair et al., 2006). FadE functions to fine-tune expression of the Ad4BP/Sf1. The amount of Ad4BP/Sf1 expressed will ultimately determine the size of the mature adrenal gland (Zubair et al., 2006). Inter- estingly, DAX1 and Sf1 mutations produce a similar clinical picture of X-linked adrenal hypoplasia congen- ita, suggesting their interaction. The DAX1 gene prod- uct acts as a repressor of Sf1 transactivation, preventing transcription. By contrast, ACTH stimulation inactivates DAX1 and initiates steroidogenesis (Kim et al., 2009).
Wnt signaling is crucial in the canonical and planar polarity pathway (Fig. 2). In the absence of Wnt
ligands, ß-catenin is found predominantly in the cell membrane and cellular adherence junctions. Following binding of ligands to Wnt, ß-catenin accumulates in the cytoplasm and nucleus, resulting in the activation of various genes including Sf1 and DAX1, suggesting that -catenin has an important role to play in adrenal cortex development through proliferation, specifica-
tion of cell fate, stem cell maintenance and differen- tiation (Schimmer and White, 2010; Kim et al., 2008). As Wnt4 is a secreted protein with a critical role in female genital and adrenal gland development, dis- ruption of this protein in a mouse model resulted in abnormal differentiation of the adrenal cortex and sex reversal (Bernard and Harley, 2007). Aberrant
capsular stromal cell
Wnt
Wnt
Shh
stem cell
Gli
Shh Subcapsular progenitor cell
multipotency
GATA 4
ß-Catenin
GATA 4
ACTH
FSH/LH
O
O
AR
Sf1
DAX1
GR
+
multipotency
GC
multipotency
+
E/T
ß-Catenin
GATA 4
Sf1
GATA 6 endocrine signals
inhibin
gonadal fate ®
+
adrenal fate
Sf1
Sf1
steroidogenic enzyme genes
steroidogenic enzyme genes
granulosa cell
theca cell
diferentiated adrencortical cells
migration of adrenocortical cells into the developing gonad was observed in the absence of Wnt4 (Jeays- Ward et al., 2003).
Very large quantities of inhibin-a are produced by the fetal adrenal gland, which ensures adrenal specifi- cation and unresponsiveness to human chorionic gonadotropin-mediated variant development (Kim et al., 2009).
All GATA transcription factors are zinc fingers that bind to specific DNA sequences. GATA-4 has been detected exclusively in the fetal adrenal gland and has been shown to work in concert with Sf1 for adrenocor- tical development (Parviainen et al., 2007). GATA-4 plays an essential role in upregulating inhibin-a, 17a- alpha hydroxylase (CYP17), and steroidogenic acute regulatory protein (StAR). Ad4BP/Sf1 is expressed in three zones of the adrenal cortex and is critical for the regulation of the genes encoding the steroid hydroxy- lases (Tanaka et al., 2007).
Sonic hedgehog (Shh) is a signaling glycoprotein that is known to have a key morphogenetic function in organogenesis including limb development (Ishibashi et al., 2005). It binds to a receptor of Patched 1 (PTCH1) and Smoothened (SM0), which in turn acti- vates the downstream pathway of glioma associated oncogene homologue (Gli)1, Gli2, and Gli3. Shh is expressed by relatively undifferentiated steroidogenic cells and is involved in the expansion of the progenitor pool in the adrenal capsule. Sf1 positive adrenocorti- cal cells expand the cortex by producing Shh on the adrenal capsule (Huang et al., 2010). The subcapsular cells gain Sf1 expression but have limited steroido- genic potential. They continued to proliferate and migrate toward the corticomedullary boundary and mature acquiring full steroidogenic activity (Kim et al., 2009).
FETAL PRODUCTION OF CORTISOL AND DHEA
StAR, 11 beta-hydroxylase, 17 «-hydroxylase, 3 ß- hydroxysteroid dehydrogenase, and 21-hydroxylase enzymes have been detected by immunohistochemis- try at 50-52 days postconception. The presence of
high concentrations of transient nerve growth factor IB-like (NGFI-B) through its regulation of type 2 3 - hydroxysteroid dehydrogenase, along with early ACTH secretion from the pituitary in the first trimester may be responsible for the early production of cortisol (Goto et al., 2006), whereas EGF may be responsible for promoting adrenocortical growth (Coulter et al., 1996). Taken together it appears as although the combination of NGFI-B and ACTH are critical in the early development of a functioning hypothalamic- pituitary axis, but the mechanisms that regulate NGFI-B expression in the precise order in which con- trol occurs remain uncertain (Goto et al., 2006). The volume of steroid hormones produced is influenced by the arterial perfusion of the adrenal gland which in turn is affected by the prevailing partial pressure of oxygen, endothelin, and nitric oxide. ACTH exerts a vasodilator action on the arteries, which supply the adrenal cortex. The zone glomeruloza is able to release epoxyeicosatrienoic acids (EETs) in response to ACTH secretion. These EETs induce vascular smooth muscle relaxation and ultimately lead to growth of the adrenal cortices (Zhang et al., 2007). Concomitantly the human corticotrophs produce ACTH (Hanley and Arlt, 2006). DHEA has been detected as early as the onset of the second trimester. Large vol- umes of verse secreted during the second and third trimesters by the adrenal cortices (Goto et al., 2006; Parker, 1999).
CLINICAL EXAMPLES OF TRANSCRIPTION FACTOR MUTATIONS AS A CAUSE FOR PRIMARY HYPOADRENALISM
Mutations in transcription factors responsible for normal adrenal gland development have been found to induce familial syndrome of adrenal hypoplasia con- genita. These include mutations of any of the follow- ing: DAX1, critical region on the X chromosome gene- 1, nuclear receptor subtype and family 0 group B, member 1 (NR0B1)/AHC] and steroidogenic factor-1 (Sf1), nuclear receptor subfamily 5 group A member
Fig. 4. Molecular aspects of adrenal cortical cell development. Reproduced with permission from Kim et al., Endocr Rev, 2009, 30, 241-263. Stem cells within the capsule give rise to the definitive cortex. Mesenchy- mal cells negative for Sf1 (steroidogenic factor-1) coa- lesce to form a capsule around the fetal cortex. Following mitogenic stimuli, the capsule produces another capsule cell, which in turn produces a subcapsular progenitor cell. ACTH and angiotensin II direct the differentiation of these cells to produce steroids. The DAX1 gene product acts as a repressor of Sf1 and prevents transcription, while ACTH inactivates the former. Sf1 interacts with other transcrip- tion factors for adrenocortical development. Wnt signal- ing is crucial in the canonical and planar polarity pathway. Wnt4 is involved in female genital development. Large quantities of inhibin-a ensure adrenal gland rather than
ovarian development. GATA-4 plays a role in upregulating inhibin-a, CYP17, and StAR (steroidogenic acute regula- tory protein) and is thus critical for upregulating the genes encoding the steroid hydroxylases. Shh (Sonic hedgehog) is a glycoprotein and has a key morphogenic function. Shh is expressed by relatively undifferentiated steroidogenic cells then expands the progenitor pool in the adrenal capsule. The subcapsular cells gain Sf1 expression but have limited steroidogenic potential. They continue to proliferate and migrate toward corticomedul- lary boundary acquiring full steroidogenic activity. Abbre- viations used: E, oestrogen; T, testosterone; AR, androgen receptor; GR, glucocorticoid receptor; GC, glu- cocorticoid; FSH, follicle stimulating hormone; LH, lutei- nising hormone. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
1 (NR5A1), and Ad4BP (Nawata et al., 1999; Habiby et al., 1996). Males with adrenal hypoplasia congenital usually present in infancy or early childhood with salt- losing primary adrenal failure, recognized by profound hyponatraemia, global glucocorticoid deficiency in infancy, and arrested puberty, because of associated hypogonadotrophic hypogonadism (Habiby et al., 1996). Duplication of the NR0B1 induces a 46, XY dis- order of sex development resulting in XY “sex reversal” females (Skinningsrud et al., 2009).
CARCINOMA OF THE ADRENAL GLAND
The impact of genetics and genomics on clinical medicine is becoming increasingly important. Endocri- nology pioneered the development of molecular medi- cine, and studies of adrenal tumors had a great impact in this field. Particularly important was the detection of genetics of tumors derived from the adre- nal medulla, as well as that of those derived from the sympathetic and parasympathetic paraganglia (Opocher et al., 2009). The identification of mutations in one of the several pheochromocytoma/paragan- glioma susceptibility genes may indicate a specific clinical management drive. Less well understood is the genetics of adrenal cortex tumors, in particular adrenocortical carcinoma (ACC). There are only a few examples of hereditary transmission of ACC, but the analysis of low penetrance genes by genome wide association study may enable us to discover new genetic mechanisms responsible for adrenocortical- derived tumors (Opocher et al., 2009).
Adrenal tumors are common, with an estimated incidence of slightly more than seven per hundred in autopsy cases, while ACCs are rare, with an estimated prevalence of 4-12 per million population (Soon et al., 2008) but are particularly aggressive (Opocher et al., 2009). Because the prognoses for adrenocortical adenomas and ACCs are vastly different, it is impor- tant to be able to accurately differentiate the two tumor types. Advancement in the understanding of the pathophysiology of ACCs is essential for the devel- opment of more sensitive means of diagnosis and treatment, resulting in better clinical outcome. Adre- nocortical tumors (ACTs) occur as a component of several hereditary tumor syndromes, which include the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, Carney complex, and congenital adrenal hyperplasia (Soon et al., 2008). The genes involved in these syndromes have also been shown to play a role in the pathogene- sis of sporadic ACTs. The adrenocorticotropic hor- mone-cAMP-protein kinase A and Wnt pathways are also implicated in adrenocortical tumorigenesis. In their review article, the authors examined the molecu- lar mechanisms involved in adrenocortical tumorigen- esis, such as comparative genomic hybridization, loss of heterozygosity, and microarray gene-expression profiling studies (Soon et al., 2008).
Progress into the elucidation of the genes and path- ways involved in the pathogenesis of ACC has been slow largely because of the rarity of this tumor. The TP53, IGF2, H19, p57kip2, and MEN1 genes are
involved in adrenocortical carcinogenesis, as are the ACTH-CAMP-PKA and Wnt pathways (Soon et al., 2008). Studies on comparative genomic hybridization and loss of heterozygosity, however, have implicated the involvement of many chromosomal regions in which oncogenes or tumor suppressor genes have yet to be identified (Soon et al., 2008).
THE ENDOCRINE ROLE OF THE FETAL ADRENAL GLANDS
The paradox of human fetal adrenal function is that steroidogenesis is programmed largely toward the production of inactive products (Melmed et al., 2011). The gland is maximally stimulated to maintain fetal cortisol levels and ACTH feedback homeostasis but is programmed by the steroidogenic enzyme expression pattern to produce inactive DHEA and pregnenolone and their sulphate conjugates (Melmed et al., 2011; Jameson and De Groot, 2010). Much of the DHEA is converted to 16-hydroxy-DHEAS by the fetal adrenal gland and fetal liver. This programming is designed to provide DHEA substrate for placental oestrone and oestradiol production. Both fetal and maternal oestriol levels increase progressively to term (Melmed, 2011; Jameson and De Groot, 2010; Mesiano and Jaffe, 2004; Winter, 2004). Studies of fluctuations of hor- mone levels in anencephalic fetuses have revealed the complex nature of fetal and placental hormone pro- duction and control (Melmed et al., 2011; Mesiano and Jaffe, 2004; Winter et al., 2004).
CONCLUSIONS
Major advances in our understanding of the embryological development of the adrenal glands have occurred as a result of molecular biological tech- niques. This has provided insight into the various causes of congenital adrenal gland hypoplasia and the pathogenesis of adrenal cortical neoplasia.
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