The adrenal gland
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 glomerulosa produces mineralocorticoids (most notably aldosterone) and cannot produce cortisol or androgens (male sex hormones).
- The zona fasciculata is the thickest layer of the adrenal cortex, comprising about 75% of the cortex. It produces glucocorticoids (cortisol) and androgens.
- The inner zona reticularis surrounds the medulla and also produces cortisol and androgens.
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:
- Circadian (day and night) rhythm of ACTH.
- Stress response of the hypothalamic-pituitary-adrenal (H-P-A) axis.
- Feedback inhibition of ACTH secretion by cortisol.
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
- The main presenting symptoms of adrenal insufficiency are hyperpigmentation, weakness, fatigue (unusual tiredness), dizziness on standing, loss of appetite, weight loss, anorexia, and gastrointestinal disturbances (nausea, diarrhea, stomach pain, and vomiting). Many of these symptoms are nonspecific and therefore diagnosis is often delayed.
- Generalized hyperpigmentation of the skin and mucous membranes is one of the earliest signs of adrenal insufficiency. It is increased in sun-exposed areas and accentuated over pressure areas such as the knuckles, toes, elbows, and knees. It is accompanied by an increased number of black or dark brown freckles. The classic hyperpigmentation of the buccal (cheek) mucosa and gums is preceded by generalized hyperpigmentation of the skin; adrenal insufficiency should also be suspected when there is increased pigmentation of the palmar creases, nail beds, nipples, areoles, and perianal mucosa. Scars formed after the onset of ACTH excess become hyperpigmented, whereas older scars do not.
- An increase in gastrointestinal symptoms during acute adrenal crisis may confuse the diagnosis by suggesting a primary intra-abdominal process.
- Hypotension (low blood pressure) occurs in approximately 90% of patients and is associated with orthostatic (standing) symptoms and occasionally syncope (fainting).
- Salt craving occurs in 20% of patients.
- Severe hypoglycemia may occur in children. This finding is uncommon in adults, but may be precipitated by fasting, fever, infection, or nausea and vomiting, especially in acute adrenal ccrisis.
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