The adrenal gland

Gabor Linthorst, M.D., Ph.D. and Stephan Kemp, Ph.D.

Adrenal anatomy

The adrenal glands are small triangular organs located above the kidneys. The adrenal gland consists of a medulla (the center of the gland) surrounded by a cortex. Epinephrine (adrenaline) and norepinephrine (noradrenaline) are produced by the medulla. The adrenal cortex is the source of a number of steroid hormones and is arranged in 3 major layers or zones, organized as concentric shells:

The zona fasciculata and the zona reticularis are regulated by ACTH (adrenocorticotropichormone), a hormone secreted by the pituitary gland. Excess or deficiency of this hormone alters the structure and function of these zones: when ACTH is deficient, they degenerate; when ACTH is excessive, hyperplasia and hypertrophy of these zones occur. ACTH, in turn, is regulated by the hypothalamus and the central nervous system (CNS) via neurotransmitters and corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP).

Biosynthesis of cortisol and adrenal androgens

The synthesis of cortisol and the androgens begins with cholesterol. Plasma lipoproteins are the major source of adrenal cholesterol, although synthesis from acetate also occurs within the adrenal gland. Low-density lipoprotein (LDL) accounts for approximately 80% of the cholesterol delivered to the adrenal gland. Cholesterol is stored as cholesterol esters in the lipid droplets within the adrenocortical cells.

The adrenal androgens dehydroepiandrosterone (DHEA), its sulfate ester DHEA-S, and androstenedione have minimal intrinsic androgenic activity but are converted in body tissues to the more potent androgens testosterone and dihydrotestosterone (male sex hormones) and estrogens (female sex hormones). DHEA and DHEA-S are the most abundant steroids produced by the adrenal cortex. DHEA and DHEA-S are easily interconvertible and will henceforth be referred to as DHEAs.

Control of cortisol secretion

Cortisol secretion is tightly regulated by ACTH, and plasma cortisol levels parallel those of ACTH. There are 3 mechanisms of neuroendocrine control:

Plasma ACTH and (subsequently) cortisol are secreted within minutes of the onset of stress, and these responses abolish circadian periodicity if the stress is prolonged.

Control of adrenal androgen secretion

DHEAs is the most abundant steroid produced in men. Under normal circumstances, DHEAs is secreted synchronously with cortisol in response to corticotropin-releasing hormone and ACTH. Due to its long circulating half-life and low clearance, the concentration of DHEAs shows little day-night variation.

In the human fetus, the so-called fetal zone of the adrenal cortex produces high levels of DHEA(S), and cortisol production does not begin until the end of pregnancy.

DHEA(S) shows a characteristic lifelong secretion pattern, with an increase during the prepubertal period (adrenarche, ~6 years), reaching a maximum at 25-35 years of age, followed by a continuous decline to steadily low levels with advancing age (adrenopause).

Circulation of cortisol and adrenal androgens

Cortisol and adrenal androgens are secreted into the blood in an unbound state; however, these hormones bind to plasma proteins as they enter the circulation. Cortisol binds primarily to corticosteroid-binding globulin (CBG) and to a lesser extent to albumin, whereas the androgens bind primarily to albumin. Under basal conditions, approximately 10% of circulating cortisol is free, approximately 75% is bound to CBG, and the remainder is bound to albumin.

Bound steroids are biologically inactive; the unbound or free fraction is active.

Biological effects of adrenal steroids

Adrenal steroids such as cortisol were originally called glucocorticoids because of their effect on glucose metabolism. Cortisol maintains fasting plasma glucose levels and raises plasma glucose levels during exercise or stress by stimulating gluconeogenesis and inhibiting glucose uptake in muscle and adipose tissue. Glucocorticoid receptors are present in virtually all tissues and have a variety of other effects. Cortisol has an inhibitory effect on the immune system and the inflammatory response. Through its effects on the central nervous system, cortisol affects mood, appetite, sleep, and memory.

Aldosterone helps maintain the right amount of sodium, potassium, and water in the body.

Pathophysiology

Loss of more than 90% of both adrenal cortices results in the clinical manifestations of adrenocortical insufficiency (often referred to as adrenal insufficiency). With progressive adrenocortical destruction, the initial phase is one of decreased adrenal reserve, i.e., basal steroid secretion is normal, but secretion does not increase in response to stress. Thus, an acute adrenal crisis may be precipitated by the stresses of surgery, trauma, or infection. With further loss of cortical tissue, even the basal secretion of mineralocorticoids and glucocorticoids becomes deficient, leading to manifestations of chronic adrenal insufficiency.

With decreased cortisol secretion, plasma levels of ACTH are elevated due to decreased negative feedback inhibition of its secretion. In fact, an increase in plasma ACTH is the earliest and most sensitive indication of suboptimal adrenocortical reserve.

Symptoms and signs

Treatment

The goal of treatment of adrenal insufficiency is to achieve levels of glucocorticoids and mineralocorticoids equivalent to those achieved in an age-matched individual with normal hypothalamic-pituitary-adrenal function under similar circumstances. Patients require lifelong glucocorticoid and mineralocorticoid therapy.

Treatment with glucocorticoid supplementation is similar to that of patients with other causes of primary adrenal insufficiency. Our experience is that mineralocorticoid supplementation is not necessary in all patients with ALD, as mineralocorticoid function seems to be preserved in some patients. Supplementation with androgens (DHEA and/or testosterone) is usually not necessary; clinical trials with DHEA have not shown a beneficial effect.

A prospective evaluation of adrenal function in a cohort of 49 neurologically presymptomatic boys (mean age 4 years) with ALD showed that 80% already had impaired adrenal function (Dubey et al. 2005). Therefore, endocrinologists should test for VLCFA in boys and men with adrenal insufficiency when tests for autoantibodies to the adrenal cortex are negative or when signs of myelopathy are present.

Last modified | 2024-06-24