Physiology of the Adrenal Gland

Published on 25/03/2015 by admin

Filed under Pediatrics

Last modified 25/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 4 (1 votes)

This article have been viewed 1577 times

Chapter 568 Physiology of the Adrenal Gland

568.1 Histology and Embryology

Perrin C. White

The adrenal gland is composed of two endocrine tissues: the medulla and the cortex. The chromaffin cells of the adrenal medulla are derived from neuroectoderm, whereas the cells of the adrenal cortex are derived from mesoderm. Mesodermal cells also contribute to the development of the gonads. The adrenal glands and gonads have certain common enzymes involved in steroid synthesis; an inborn error in steroidogenesis in one tissue can also be present in the other.

The adrenal cortex of the older child or adult consists of three zones: the zona glomerulosa, the outermost zone located immediately beneath the capsule; the zona fasciculata, the middle zone; and the zona reticularis, the innermost zone, lying next to the adrenal medulla. The zona fasciculata is the largest zone, constituting about 75% of the cortex; the zona glomerulosa constitutes about 15% and the zona reticularis about 10%. Glomerulosa cells are small, with a lower cytoplasmic : nuclear ratio, an intermediate number of lipid inclusions, and smaller nuclei containing more condensed chromatin than the cells of the other two zones. The cells of the zona fasciculata are large, with a high cytoplasmic : nuclear ratio and many lipid inclusions that give the cytoplasm a foamy, vacuolated appearance. The cells are arranged in radial cords. The cells of the zona reticularis are arranged in irregular anastomosing cords. The cytoplasmic : nuclear ratio is intermediate, and the compact cytoplasm has relatively little lipid content.

The zona glomerulosa synthesizes aldosterone, the most potent natural mineralocorticoid in humans. The zona fasciculata produces cortisol, the most potent natural glucocorticoid in humans, and the zona fasciculata and zona reticularis synthesize the adrenal androgens.

The adrenal medulla consists mainly of neuroendocrine (chromaffin) cells and glial (sustentacular) cells with some connective tissue and vascular cells. Neuroendocrine cells are polyhedral, with abundant cytoplasm and small, pale-staining nuclei. Under the electron microscope, the cytoplasm contains many large secretory granules that contain catecholamines. Glial cells have less cytoplasm and more basophilic nuclei.

The primordium of the fetal adrenal gland can be recognized at 3-4 wk of gestation just cephalad to the developing mesonephros. At 5-6 wk, the gonadal ridge develops into the steroidogenic cells of the gonads and adrenal cortex; the adrenal and gonadal cells separate, the adrenal cells migrate retroperitoneally, and the gonadal cells migrate caudad. At 6-8 wk of gestation, the gland rapidly enlarges, the cells of the inner cortex differentiate to form the fetal zone, and the outer subcapsular rim remains as the definitive zone. The primordium of the adrenal cortex is invaded at this time by sympathetic neural elements that differentiate into the chromaffin cells capable of synthesizing and storing catecholamines. Catechol O-methyltransferase, which converts norepinephrine to epinephrine, is expressed later in gestation. By the end of the 8th wk of gestation, the encapsulated adrenal gland is associated with the upper pole of the kidney. By 8-10 wk of gestation, the cells of the fetal zone are capable of active steroidogenesis.

In the full-term infant, the combined weight of both adrenal glands is 7-9 g. At birth, the inner fetal cortex makes up about 80% of the gland and the outer “true” cortex, 20%. Within a few days the fetal cortex begins to involute, undergoing a 50% reduction by 1 mo of age. Conversely, the adrenal medulla is relatively small at birth and undergoes a proportionate increase in size over the first 6 mo after birth. By 1 yr, the adrenal glands each weigh <1 g. Adrenal growth thereafter results in adult adrenal glands reaching a combined weight of 8 g. The zonae fasciculata and glomerulosa are fully differentiated by about 3 yr of age. The zona reticularis is not fully developed until puberty.

Adrenocorticotropic hormone (ACTH) is essential for fetal adrenal growth and maturation; feedback regulation of ACTH by cortisol is apparently established by 8-10 wk of gestation. Additional factors important in fetal growth and steroidogenesis include placental chorionic gonadotropins and a number of peptide growth factors produced by the placenta and fetus.

Several transcription factors are critical for the development of the adrenal glands. The three that are associated with adrenal hypoplasia in humans are steroidogenic factor-1 (SF-1; NR5A1), DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, X chromosome; NR0B1), and the GLI3 oncogene. Disruption of SF-1, encoded on chromosome 9q33, results in gonadal and often adrenal agenesis, absence of pituitary gonadotropes, and an underdeveloped ventral medial hypothalamus. In-frame deletions and frameshift and missense mutations of this gene are associated with 46,XX ovarian insufficiency and 46,XY gonadal dysgenesis. Mutations in the DAX1 gene, encoded on Xp21, result in adrenal hypoplasia congenita and hypogonadotropic hypogonadism (Chapter 569.1). Mutations in GLI3 on chromosome 7p13 cause Pallister-Hall syndrome, other features of which include hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly. Postnatally, both SF-1 and DAX-1 play important roles in regulating steroidogenesis by modulating transcription of steroidogenic enzymes.

Bibliography

Ferraz-de-Souza B, Achermann JC. Disorders of adrenal development. Endocr Dev. 2008;13:19-32.

Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology. 2005;146:1018-1024.

Kempna P, Fluck CE. Adrenal gland development and defects. Best Pract Res Clin Endocrinol Metab. 2008;22:77-93.

Lourenco D, Brauner R, Lin L, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009;360:1200-1210.

568.2 Adrenal Steroid Biosynthesis

Perrin C. White

Cholesterol is the starting substrate for all steroid biosynthesis (imagesee Fig. 568-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com). Although adrenal cortex cells can synthesize cholesterol de novo from acetate, circulating plasma lipoproteins provide most of the cholesterol for adrenal cortex hormone formation. Receptors for both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are expressed on the surface of adrenocortical cells; the receptor is termed scavenger receptor class B, type I (SR-BI). Patients with familial hypercholesterolemia who lack LDL receptors have unimpaired adrenal steroidogenesis, suggesting that HDL is the more important source of cholesterol. Cholesterol is stored as cholesteryl esters in vesicles and subsequently hydrolyzed by cholesteryl ester hydrolases to liberate free cholesterol for steroid hormone synthesis.

image

Figure 568-1 Steroid biosynthesis and metabolism during gestation. Conversions within the fetal adrenal cortex, fetal liver, male (i.e., testosterone-exposed) genital skin, and placenta are denoted by arrows; the enzyme mediating each conversion is also shown. Enzymatic conversions in the adrenal cortex are the same postnatally as prenatally, but cortisol and aldosterone biosynthesis are more prominent, and normally little testosterone is synthesized. Many of the involved enzymes are cytochromes P450 (CYPs). Adrenal enzymes include CYP 11A, cholesterol side chain cleavage enzyme (P450scc); HSD3B2, 3β-hydroxysteroid dehydrogenase/Δ5,Δ4 isomerase type 2; CYP 17, 17β-hydroxylase/17,20-lyase (P450c17); CYP 21, 21-hydroxylase (P450c21); CYP 11B1, 11β-hydroxylase (P450c11); CYP 11B2, aldosterone synthase (P450aldo; this enzyme mediates successive 11β-hydroxylase, 18-hydroxylase, and 18-oxidase reactions in the zona glomerulosa for the conversion of deoxycorticosterone to aldosterone). Other enzymes important in the fetoplacental unit include ARSC1, arylsulfatase; CYP 19, aromatase (P450arom); HSD3B1, 3β-hydroxysteroid dehydrogenase/Δ5,Δ4 isomerase type 1; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; HSD17B1 and HSD17B5 are two different 17-hydroxysteroid dehydrogenase enzymes; SRD5A2, steroid 5α-reductase type 2; SULT2A1, steroid sulfotransferase.

The rate-limiting step of adrenal steroidogenesis is importation of cholesterol across the mitochondrial outer and inner membrane. This requires several proteins, particularly the steroidogenic acute regulatory (StAR) protein. StAR protein has a very short half-life, and its synthesis is rapidly induced by trophic factors (corticotropin); thus, it is the main short-term (min to hr) regulator of steroid hormone biosynthesis.

At the mitochondrial inner membrane, the side chain of cholesterol is cleaved to yield pregnenolone. This is catalyzed by cholesterol side-chain cleavage enzyme (cholesterol desmolase, P450scc, CYP11A1), a cytochrome P450 (CYP) enzyme. Like other P450s, this is a membrane-bound hemoprotein with a molecular mass of about 50 kd. It accepts electrons from an NADPH-dependent mitochondrial electron transport system consisting of 2 accessory proteins, adrenodoxin reductase (a flavoprotein) and adrenodoxin (a small protein containing nonheme iron). P450 enzymes use electrons and O2 to hydroxylate the substrate and form H2O. In the case of cholesterol side-chain cleavage, 3 successive oxidative reactions are performed to cleave the C20,22 carbon bond. Pregnenolone then diffuses out of mitochondria and enters the endoplasmic reticulum. The subsequent reactions that occur depend on the zone of the adrenal cortex.

Zona Glomerulosa

In the zona glomerulosa, pregnenolone is converted to progesterone by 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), an NAD+-dependent enzyme of the short chain dehydrogenase type. Progesterone is converted to 11-deoxycorticosterone by steroid 21-hydroxylase (P450c21, CYP 21), which is another P450. Like other P450s in the endoplasmic reticulum, it uses an electron transport system with only one accessory protein, P450 oxidoreductase.

Deoxycorticosterone then reenters mitochondria and is converted to aldosterone by aldosterone synthase (P450aldo, CYP11B2), a P450 enzyme structurally related to cholesterol desmolase. Aldosterone synthase also carries out 3 successive oxidations: 11β-hydroxylation, 18-hydroxylation, and further oxidation of the 18-methyl carbon to an aldehyde.

Zona Fasciculata

In the endoplasmic reticulum of the zona fasciculata, pregnenolone and progesterone are converted by 17α-hydroxylase (P450c17, CYP17) to 17-hydroxypregenolone and 17-hydroxyprogesterone, respectively. This enzyme is not expressed in the zona glomerulosa, which consequently cannot synthesize 17-hydroxylated steroids. 17-Hydroxypregnenolone is converted to 17-hydroxyprogesterone and 11-deoxycortisol by the same 3β-hydroxysteroid and 21-hydroxylase enzymes, respectively, as are active in the zona glomerulosa. Thus, inherited disorders in these enzymes affect both aldosterone and cortisol synthesis (Chapter 570). Finally, 11-deoxycortisol reenters mitochondria and is converted to cortisol by steroid 11β-hydroxylase (P450c11, CYP11B1). This enzyme is closely related to aldosterone synthase but has low 18-hydroxylase and nonexistent 18-oxidase activity. Thus, under normal circumstances the zona fasciculata cannot synthesize aldosterone.

Zona Reticularis

In the zona reticularis and to some extent in the zona fasciculata, the 17-hydroxylase (CYP 17) enzyme has an additional activity, cleavage of the 17,20 carbon-carbon bond. This converts 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA). DHEA is converted to androstenedione by HSD3B. This may be further converted in other tissues to testosterone and estrogens.

Fetoplacental Unit

Steroid synthesis in the fetal adrenal varies during gestation (Figs. 568-1 and 568-2). Shortly after the fetal adrenal gland forms (wk 8-10), it efficiently secretes cortisol, which is able to negatively feed back on the fetal pituitary and hypothalamus to suppress ACTH secretion. This is critical time for differentiation of the external genitalia in both sexes (Chapter 570.1); to prevent virilization, the female fetus must not be exposed to high levels of androgens of adrenal origin, and placental aromatase activity must remain low during this time to minimize conversion of testosterone to estradiol in male fetuses, which would interfere with masculinization. After wk 12, HSD3B activity in the fetal adrenal gland decreases and steroid sulfokinase activity increases. Thus, the major steroid products of the midgestation fetal adrenal gland are DHEA and DHEA sulfate (DHEAS) and, by 16α-hydroxylation in the liver, 16α-hydroxy DHEAS. Aromatase activity increases in the placenta at the same time, and steroid sulfatase activity is high as well. Thus, the placenta uses DHEA and DHEAS as substrates for estrone and estradiol and 16α-OH DHEAS as a substrate for estriol. Cortisol activity is low during the 2nd trimester, which might serve to prevent premature secretion of surfactant by the developing fetal lungs; surfactant levels can affect the timing of parturition. As term approaches, fetal cortisol concentration increases as a result of increased cortisol secretion and decreased conversion of cortisol to cortisone by 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Low levels of aldosterone are produced in mid gestation, but aldosterone secretory capacity increases near term.

image

Figure 568-2

Related posts:

Gonadal and Germ Cell Neoplasms Hypopigmented Lesions Menstrual Problems Anesthesia, Perioperative Care, and Sedation Goiter Default ThumbnailGynecologic Care for Girls with Special Needs