Adrenal glands are small triangular organs located on top of the kidneys. The adrenal gland consists of a medulla (the center of the gland) surrounded by the 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 as 3 major layers or zones, organized as concentric shells:
The zona fasciculata and the zona reticularis are regulated by ACTH (Adreno Cortico Tropic Hormone), a hormone secreted by the pituitary gland. Excess or a deficiency of this hormone alters the structure and function of these zones: when ACTH is deficient they degenerate; when ACTH is present in excess, hyperplasia and hypertrophy of these zones occur. ACTH in turn is regulated by the hypothalamus and central nervous system (CNS) via neurotransmitters and corticotropin-releasing hormone (CRH) and arginine vasopressine (AVP).
Synthesis of cortisol and the androgens begins with cholesterol. Plasma lipoproteins are the major source of adrenal cholesterol, though synthesis within the adrenal gland from acetate also occurs. Low-density lipoprotein (LDL) accounts for about 80% of 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 the tissues of the body to the more potent androgens testosterone and dihydrotestosterone (male sex hormones) and to estrogens (female sex hormone). DHEA and DHEA-S are the most abundantly produced steroids by the adrenal cortex. DHEA and DHEA-S are readily interconvertible and will from now on be called DHEAs.
Cortisol secretion is closely regulated by ACTH, and the plasma cortisol levels parallel those of ACTH. There are 3 mechanisms of neuroendocrine control:
Plasma ACTH and cortisol are secreted within minutes following the onset of stress and these responses abolish circadian periodicity if the stress is prolonged.
DHEAs is the most abundantly produced steroid in men. Under normal circumstances, DHEAs is secreted synchronously with cortisol in response to corticotropin-releasing hormone and ACTH. DHEAs concentration demonstrates only limited day-night variation due to its long circulating half-life and lower clearance.
In the human fetus the so-called fetal zone of the adrenal cortex produces DHEA(S) in high quantities and cortisol production only starts at the end of pregnancy.
DHEA(S) displays a characteristic secretion pattern over a lifetime, with a surge 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).
Cortisol and adrenal androgens are secreted into the blood in an unbound state; however, these hormones bind to plasma proteins upon entering the circulation. Cortisol binds mainly to corticosteroid-binding globulin (CBG) and to a lesser extent to albumin, whereas the androgens bind mainly to albumin. Under basal conditions, about 10% of the circulating cortisol is free, approximately 75% is bound to CBG and the remainder to albumin.
Bound steroids are biologically inactive; the unbound or free fraction is active.
Adrenal steroids like cortisol were originally called glucocorticoids because of their influence on glucose metabolism. Cortisol maintains the plasma glucose levels during fasting and increases plasma glucose during 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. By its effects on the central nervous system cortisol influences mood, appetite, sleep and memory.
Aldosterone maintains the right amount of sodium, potassium and water in the body.
Loss of more than 90% of both adrenal cortices results in the clinical manifestations of adrenocortical insufficiency (often also called adrenal insufficiency). With gradual adrenocortical destruction, the initial phase is that of decreased adrenal reserve; i.e., basal steroid secretion is normal, but secretion does not increase in response to stress. Thus, acute adrenal crisis can be precipitated by the stresses of surgery, trauma or infection. With further loss of cortical tissue, even basal secretion of mineralocorticoids and glucocorticoids becomes deficient, leading to manifestations of chronic adrenocortical insufficiency.
With decreased cortisol secretion, plasma levels of ACTH are increased because of decreased negative feedback inhibition of their secretion. In fact, an elevation of plasma ACTH is the earliest and most sensitive indication of suboptimal adrenocortical reserve.
The aim of the treatment of adrenocortical insufficiency is to produce levels of glucocorticoids and mineralocorticoids equivalent to those achieved in an age-related individual with normal hypothalamic-pituitary-adrenal function under similar circumstances. Patients require lifelong glucocorticoid and mineralocorticoid therapy.
Treatment by means of glucocorticoid supplementation is similar to that of patients with other causes of primary adrenal insufficiency. Experience in our institute is that supplementation of mineralocorticoids is not necessary in all patients with ALD, as mineralocorticoid function seems preserved in some patients.
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. Therefore, endocrinologists should test for VLCFA in boys and men with adrenal insufficiency when tests for autoantibodies to adrenal cortex are negative, or when signs of myelopathy are present.