Critical for normal growth to adult stature, growth hormone (GH) is secreted by the anterior pituitary under the influence of hypothalamic hormones.¹ Growth hormone-releasing hormone and somatostatin secreted by the hypothalamus stimulate and inhibit GH secretion, respectively, at the level of the pituitary gland. GH in turn acts peripherally, either directly on its target tissues or through its intermediary somatomedins (insulin-like growth factors), whose production it induces in the liver. The normal response to GH includes accelerated linear growth, increased lean body mass, and increased organ size.

GH hypersecretion occurs in the context of somatotropic adenomas, the second most common pituitary tumor after prolactinomas.² If such an adenoma develops before physeal closure, it results in excess linear growth known as gigantism. More commonly, however, such adenomas occur after physeal closure, leading to acromegaly whose constellation of symptoms includes expansion of the jaw and brow, enlargement of the hand and feet, and internal derangements such as organ swelling, hyperglycemia, hypertension, and osteoporosis.³ In addition to the increased size of the hands and feet, patients also frequently note an associated sponginess in the feet, especially in the heel pad, and may describe erythematous spots on the skin of the extremities.⁴

Cushing syndrome refers to elevated levels of glucocorticoids, primarily cortisol. Most commonly, this is because of exogenous administration of steroids, but other etiologies also exist.⁵,⁶ Cortisol is normally produced by the adrenal cortex under the influence of adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. Hypersecretion of ACTH by a pituitary adenoma or, more rarely, via ectopic production of ACTH by a nonpituitary carcinoma such as small cell lung cancer can lead to elevated levels of cortisol.⁷ Similarly, direct production of cortisol by an adrenal cortical adenoma or carcinoma can also rarely lead to elevated cortisol levels.

The clinical manifestations of Cushing syndrome include central weight gain with a characteristic round moon face and buffalo hump.⁸ Thinning of the skin with easy bruising, as well as reddish-purple striations on the trunk and legs, is also seen. Other features include proximal muscle weakness, acne, hirsutism, hypertension, hyperglycemia, and bone loss. Notably, in contrast to the observed truncal weight gain, the extremities may become quite thin secondary to associated muscle wasting, and slow healing of cuts and bruises may also occur. Matched cohort studies also underscore an elevated risk of thromboembolic disease and infections.⁹

Addison disease or primary adrenocortical deficiency is defined by loss of adrenal cortical function, most commonly because of autoimmune destruction.¹⁰ The resultant loss of glucocorticoid and mineralocorticoid production by the adrenal cortex can precipitate a life-threatening adrenal crisis marked by hypotension and volume depletion.¹¹ Many of the preceding symptoms are subtle, and include fatigue, nausea, orthostasis, salt craving, and muscle and joint pain. Notably, patients may also manifest skin hyperpigmentation due to the fact that both ACTH, which is elevated in the setting of low glucocorticoids, and melanocyte-stimulating hormone share the same hormone precursor.¹² Skin darkening occurs in sun-exposed areas, but also characteristically in palmar creases, recent scars, and pressure points such as the knees and knuckles.

Diabetes is generally divided into insulin-dependent and non-insulin-dependent varieties, or Type I and Type II, respectively. Type I, also known as juvenile onset, has a peak incidence in patients younger than age 14, but can also occur in adults.¹³ It is caused by selective autoimmune destruction
of the pancreas’ islets of Langerhans (beta cells), with resultant inability to produce insulin.¹⁴ In contrast, Type II occurs most often in middle age and is hallmarked by peripheral tissue resistance to insulin, particularly skeletal muscle but also hepatic and adipose cells.¹⁵ In the long run, Type II diabetes can also lead to loss of beta cells and hyperglycemia.

Elevated serum glucose can lead to blood vessel atherosclerosis through a number of mechanisms. Nonenzymatic glycosylation of critical proteins and lipids occurs in vessel wall endothelial cells, smooth muscle cells, and macrophages, which can lead to their dysfunction.¹⁶,¹⁷ In turn, receptor activation by glycosylated proteins can lead to oxidative stress and alterations in growth factor expression. Peripheral artery disease is a contributing component of an estimated 25% to 30% of diabetic ulcerations.¹⁸

Distal symmetric polyneuropathy also characterizes diabetes and is a significant source of morbidity. At least 50% of diabetics will develop neuropathy, which can be marked not only by decreased sensation, but also by “positive” symptoms such as burning and tingling.¹⁹ Its causes include a combination of direct nerve injury from hyperglycemia and ischemic insult from microvascular dysfunction. The loss of protective sensation contributes to almost all diabetic ulcerations, and over 60% of ulcerations result from a triad of neuropathy, minor foot trauma, and foot deformity.¹⁸,²⁰

Furthermore, decreased joint mobility occurs in both large and small joints due to stiffening of collagen-containing tissues.²¹,²² Decreased mobility of the ankle or 1st metatarsophalangeal joint directly correlates with the severity of diabetic neuropathy. This in turn increases plantar pressure, which can contribute to ulcerations.