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Adrenal Hypertension: A Current Guide to DiagnosisLocated in the seclusion of the retroperitoneum, the small triangular shaped adrenal glands are critical to metabolic homeostasis. 

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Hypertension secondary to adrenal dysfunction is rare; however, it carries deleterious long-term effects and is often correctible. As such, it is essential to diagnose and treat. 

Adrenal anatomy and physiology

Weighing approximately 5 grams, the adrenal glands may either “cap” the kidney by sitting above its upper pole or “cradle” the renal unit by being located medially and just above the renal vessels.1-4 Embryologically and physiologically, the adrenal gland is two distinct organs—the cortex and the medulla. The cortex stems from the intermediate mesoderm, as do the kidneys, while the medulla originates from the neural crest cells of the sympathetic 
ganglia.2, 5, 6

It is important to note that despite anatomic proximity, adrenal and renal development are distinct embryologic processes and in cases of renal agenesis or malposition the adrenal glands are nearly always found in their usual orthotopic location.2

The adrenal cortex is stratified into three distinct layers: zona glomerulosa, zona fasiculata, and the zona reticularis. The endocrine function of each zone pivots on the ratios of its enzymes, which convert cholesterol to corresponding steroid hormone derivatives.7, 8. Zona glomerulosa, the outermost layer, primarily produces mineralocorticoid aldosterone (100-150 mcg/day), while zona fasiculata—the middle cortical layer—is responsible for production of the glucocorticoid cortisol (10-20 mg/day).

The innermost layer of the cortex, the zona reticularis, synthesizes adrenal androgens in excess of >20 mg/day.7 While corticosteroid and adrenal androgen production are under control of the hypothalamic-pituitary-adrenal (HPA) axis,9 secretion of aldosterone by the zona glomerulosa is under tight regulation of the renin-angiotensin-aldosterone-system.10

The adrenal medulla lies in the adrenal center and accounts for approximately 10% of the gland’s total mass. As a critical part of the autonomic nervous system, the medulla’s chromaffin cells are innervated by T-11 through L-2 sympathetic fibers. As such, the medulla secretes the catecholamines epinephrine (80%), norepinephrine (19%), and dopamine (1%).11, 12

Glucocorticoid, mineralocorticoid or catecholamine hypersecretion may result in significant physiologic perturbations, which often include hypertension. Etiology for such adrenal hypermetabolic activity are multifactorial and complex (Figure 1).

Cushing syndrome

Cushing syndrome is defined as hypersecretion of cortisol by the adrenal cortex and causes hypertension in 70 to 90% of patients who are diagnosed with the condition.13 14 Although the disease is rare, affecting approximately 3 of every million individuals per year, understanding of its multifactorial etiology and having a high index of suspicion for its presence are critical for urologists and nephrologists alike, given its deleterious short and long-term conseuquences.15, 16

Figure 1 summarizes etiologies of Cushing syndrome. Exogenous Cushing syndrome, which results from iatrogenic glucocorticoid intake is the most common cause of Cushinoid symptomatology and is important to rule out when obtaining the patient’s history. Endogenous Cushing syndrome is divided into ACTH-dependent and ACTH-independent disease. 

ACTH-dependent Cushing syndrome 

ACTH-dependent overproduction of cortisol by the adrenal is the most common cause of endogenous Cushing syndrome, accounting for up to 85% of cases.17. The vast majority (80%) of ACTH-dependent disease is due to hypersecretion of ACTH by the pituitary. Described by the early twentieth century neurosurgeon, Harvey Cushing, the condition stems largely from ACTH-secreting pituitary microadenomas and rarely from macroadenomas (1 cm or greater in size). If fact, Cushing syndrome that results from pituitary pathology is known as Cushing disease,18, 19 and females are diagnosed two times more frequently than males.20

ACTH-dependent Cushing syndrome can also be a result of ectopic production of corticotropin by non-pituitary tumors. Known as Ectopic ACTH Syndrome, and accounting for ~10% of endogenous hypercortisolemia, the condition can be caused by a number of malignancies with lung cancers being the primary culprits.18

ACTH-independent Cushing syndrome

ACTH independent secretion of excess cortisol by the adrenal glands accounts for approximately 10% of Cushing syndrome. Benign adenomas are the most common offenders; however, multifocal bilateral adrenal hyperplasia, adrenal carcinomas, ACTH-independent macronodular adrenal hyperplasia (AIMAH), and primary pigmented nodular adrenocortical disease (PPNAD) also account for rare cases of the condition.17, 21, 22