Adrenal androgens synthesis

Adrenal hormone production is controlled by the hypothalamus and pituitary gland. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus and stimulates secretion of adrenocorticotropic hormone (ACTH), also known as corticotropin from the anterior pituitary. ACTH, in turn, stimulates the adrenal cortex to produce cortisol. When sufficient or excessive cortisol levels are reached, a negative feedback is exerted on the secretion of CRH and ACTH, thereby decreasing overall cortisol production. The control of adrenal androgen synthesis also follows a similar negative-feedback mechanism. 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Ankie-wicz M, Hauffa BP, Malunowicz EM, Stewart PM, Shackleton CH (2004) Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis analytical study. Lancet 363 2128-2135... 

ACTH acts mainly on the cells of the zona fasciculata of the adrenal cortex to stimulate the synthesis and release of cortisol (Chapter 32). It also stimulates the secretion of adrenal androgens from the zona reticularis. Binding of ACTH to receptors activates formation of cAMP, which mediates cortisol formation and secretion and protein synthesis. Deficiency of ACTH leads to reduction in size and activity of adrenocortical cells in the inner two zones. 

Cyproterone acetate (CPA), the most widely nsed antiandrogen compound, is not available in the United States. It is a progestational agent that blocks the androgen receptors and also inhibits the synthesis of adrenal androgens. In Enrope and Canada, CPA is widely used in women for the treatment of acne, with or withont signs of hyperan-drogenism, and as an oral contraceptive formnlation (CPA 2 mg with ethinyl estradiol 35 meg or 50 meg). ... 

A. Androgenic phenotypes are commonly seen in Cushing syndrome because ACTH, frequently in excess, stimulates synthesis of adrenal androgens in addition to cortisol. 

Some antifungal drugs such as ketoconazole (see Chapter 48) inhibit CYPs and thereby block the synthesis of steroid hormones, including testosterone and cortisol. Because they may induce adrenal insufficiency and are associated with hepatotoxicity, these drugs generally are not used to inhibit androgen synthesis, but sometimes are employed in cases of glucocorticoid excess. 

Biosynthesis of adrenai corticosteroids. The primary precursor is acetyl-CoA and biosynthesis proceeds via cholesterol (see Terpenes, Steroids). The adrenal cortex also utilizes cholesterol which it receives as cholesterol esters from extra- adrenal sources (see Lipoproteins). The adrenal cortex is differentiated into 3 concentric layers. The outermost layer (zona glomerulosa) is primarily responsible for synthesis and secretion of aldosterone It contains the 18-hydroxylase and lacks the 17a-hydroxylase. The intermediate layer (zona fasciculata) and innermost layer (zona reticularis) are responsible for the synthesis of glucocorticoids (mainly cortisol) and adrenal androgens they possess the 17a-hydroxy-lase and lack the 18-hydroxylase. 

Cortisone Reductase DeGciency. In hirsutism and virilization in females, cortisone reductase deficiency has been described. Patients with this disorder convert all their cortisol into cortisone. This gives rise to an apparent cortisol deficiency. Adrenocorticotropic hormone increases and stimulates the adrenal steroid synthesis. The urinary steroid profile is characterized by a very high excretion of THE, cortolones, and adrenal androgens, and low excretion of THF and 5a-THF [33]. 

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