Acromegaly

 

Growth hormone (GH) is secreted by the pituitary in a pulsatile fashion and reaches its maximum rate during puberty and then declines over time. The pulsatile pattern of secretion is equally important to the amount of hormone for normal function. Secretion of GH is primarily regulated by GH-releasing hormone (GHRH) and somatostatin. Recently, the natural GH secretagogue ghrelin, produced in the stomach, has been discovered to have potent GH-releasing properties and may be involved in a separate pathway of GH regulation. GHRH stimulates the release of GH, whereas somatostatin has an inhibitory effect. The target of these regulatory factors is the GHRH receptor in the pituitary. The peripheral effects of GH are largely indirectly mediated through production of IGF-1 in the liver and stimulation of the IGF-1 receptor. GH contributes significantly to linear growth in children, increases protein synthesis, mobilizes stored triglycerides, and antagonizes the action of insulin .

 

ETIOLOGY AND PATHOGENESIS

 

Excessive production of GH is almost always due to a pituitary adenoma. In children, this results in pituitary gigantism, whereas in adults, excessive GH manifests as the clinical syndrome acromegaly. This syndrome is diagnosed in about 3 to 4 people per million every year.¹⁷¹ Very rarely, acromegaly is caused by a GH-producing tumor in the hypothalamus or by an ectopic non-endocrine tumor such as small cell lung cancer or carcinoid tumor.¹⁷² GH-producing adenomas are present in 8 percent of patients with Carney complex, an inherited disorder with multiple lentigines and multiple endocrine abnormalities.¹⁷³

 

GROWTH HORMONE AT A GLANCE

• Growth hormone plays a central role in longitudinal growth.
• In children, deficiency manifests as short stature while gigantism occurs from oversecretion of growth hormone before puberty, when the growth plates in long bones are still open.
• The disease acromegaly occurs in adults after the growth plates have closed.
• Acromegaly results from oversecretion of growth hormone, usually due to a pituitary adenoma.

CLINICAL FINDINGS: CUTANEOUS LESIONS

 The clinical manifestations of acromegaly include the overgrowth of bone and connective tissue, metabolic effects, and localized tumor mass effects. The onset is insidious, and the average age at the time of diagnosis is 40 to 45 years old, but often the condition has been present for many years before the diagnosis. The metabolic effects include diabetes, hypertension, and hyperlipidemia. There is a gradual coarsening of the features and increased head, hand, and foot size. This acral pattern of overgrowth may be noticed as increasing shoe, ring, glove, or hat size . Macroglossia can be seen. The skin becomes thickened, almost doughy, with deep grooves prominent on the forehead and around the nasolabial folds . On the scalp, cutis verticis gyrata may develop. Heel pads and the pads of the digits become thickened. Nails are thickened and brittle, and some patients develop hirsutism. Hyperhidrosis and malodor are common complaints. Many patients develop

acanthosis nigricans and multiple acrochordons with or without frank diabetes. Retinal angioid streaks can be seen in acromegaly (as well as in osteogenesis imperfecta and pseudoxanthoma elasticum) . Histologically, there is a dense deposition of GAGs in the papillary and superficial reticular dermis. Often, coarse collagen bundles with normal elastin and increased numbers of fibroblasts are seen in the dermis.

LABORATORY TESTS

Measurement of the serum GH level is highly variable and unreliable diagnostically because of the pulsatile pattern of secretion. Plasma IGF-1 levels are very much dependent on GH and fairly stable during any 24-hour period. Serum IGF-1 can be used as a surrogate measurement of GH. As a screening test for acromegaly, IGF-1 levels will be elevated. Further workup with assistance from a consulting endocrinologist may include an oral glucose tolerance test. In the proper clinical setting failure to suppress the GH level to < 1 ng/mL within 1 or 2 hours after 75 to 100 g of oral glucose is diagnostic for acromegaly.

TREATMENT

Because most cases of GH excess are due to a pituitary adenoma, surgical removal is the primary therapy. This is most commonly accomplished through a selective transsphenoidal resection.¹⁷⁶ Residual disease after surgery is more common in larger adenomas and may be higher than 30 percent for tumors larger than 1 cm. The inhibitory effect of somatostatin on GH secretion is harnessed for therapy. Somatostatin analogues, including octreotide, are used for the medical treatment of residual disease after surgery and are increasingly being considered as potential primary therapy. The somatostatin analogues alone have demonstrated the ability to reduce the size of tumors and to control IGF-1 levels in select patients. In resistant cases, radiation therapy can be considered.