Acromegaly is a rare endocrine disorder characterized by chronic pathological hypersecretion of growth hormone (GH) and consequently insulin-like growth factor-1 (IGF-1), almost always caused by a somatotroph adenoma of the anterior pituitary gland. When GH excess occurs before the closure of the epiphyseal growth plates, the result is gigantism; when it develops after skeletal maturity, the result is acromegaly. Due to its insidious and slowly progressive nature, the diagnosis is typically established an average of 7 to 10 years after the onset of symptoms.
Epidemiology
Acromegaly is a rare condition affecting 40 to 70 individuals per million population, with an annual incidence of 3 to 4 new cases per million. The mean age at diagnosis falls between 40 and 45 years, and the condition affects men and women with equal frequency. The true prevalence in the general population is thought to be underestimated due to the prolonged diagnostic delay that characterizes the disease.
Pathogenesis
In more than ninety-five percent of cases, the underlying cause is a somatotroph adenoma of the pituitary gland secreting excess GH. Based on tumor size, these are classified as microadenomas (below 10 mm) or macroadenomas (10 mm and above); approximately seventy percent of patients present with a macroadenoma at the time of diagnosis.
Rare causes include ectopic GH secretion from pancreatic, pulmonary, or ovarian tumors; ectopic GHRH secretion from carcinoid tumors or small cell lung cancer; and pituitary adenomas associated with multiple endocrine neoplasia type 1 (MEN-1).
GH stimulates hepatic secretion of IGF-1, and it is chronically elevated IGF-1 that is responsible for the majority of the clinical manifestations of acromegaly, including soft tissue overgrowth, bony expansion, organomegaly, and metabolic derangements.
Clinical Presentation
The clinical features of acromegaly can be organized into two broad categories: systemic effects of GH and IGF-1 excess, and local mass effects from the enlarging pituitary adenoma.
Somatic changes develop insidiously over years. Enlargement of the hands and feet is among the most common presenting complaints; patients typically notice progressively increasing glove and shoe sizes. Coarsening of facial features, frontal bossing, nasal broadening, lip thickening, and macroglossia are characteristic findings. Mandibular overgrowth producing prognathism and widening of interdental spaces are frequently observed.
Organomegaly may affect the heart, kidneys, liver, and thyroid gland. Cardiomegaly is the most clinically significant visceral complication, predisposing to cardiomyopathy, heart failure, and arrhythmias.
Musculoskeletal manifestations include arthralgia, arthropathy, and carpal tunnel syndrome. Chronic arthropathy represents a major source of long-term morbidity and significantly impairs quality of life.
Metabolic complications prominently include insulin resistance and impaired glucose tolerance; overt type 2 diabetes mellitus develops in approximately twenty percent of patients.
Sleep apnea is detected in more than half of patients as a consequence of soft tissue and tongue enlargement, and constitutes a major contributor to cardiovascular risk and daytime fatigue.
Hypertension is present in approximately one-third of patients and is one of the principal determinants of the elevated cardiovascular risk profile associated with the disease.
Colorectal polyp and colorectal cancer risk is significantly increased compared to the general population; colonoscopic surveillance is therefore recommended for all patients diagnosed with acromegaly.
Local mass effects of the enlarging adenoma include bitemporal hemianopia resulting from compression of the optic chiasm, headache, and hypopituitarism — deficiency of other pituitary hormones due to compression of normal pituitary tissue.
Diagnosis
Biochemical diagnosis rests on two principal tests. Failure to suppress GH below 1 ng/mL — or below 0.4 ng/mL with more sensitive contemporary assays — following a 75-gram oral glucose tolerance test (OGTT) is a cornerstone of diagnosis. An elevated serum IGF-1 level adjusted for age and sex is the most reliable single screening test; a value above the age-adjusted upper limit of normal on a single measurement is a strong indicator of disease activity.
Imaging of the pituitary gland with gadolinium-enhanced MRI is the modality of choice, allowing assessment of adenoma size, location, cavernous sinus invasion, and relationship to the optic chiasm.
Visual field testing by formal perimetry is mandatory when optic chiasm compression is suspected based on imaging or clinical findings.
Treatment
The primary goals of treatment are normalization of GH and IGF-1 levels, elimination or reduction of the tumor mass, and preservation of residual pituitary function.
Transsphenoidal surgery — endoscopic or microscopic — is the first-line treatment standard. In experienced centers, biochemical remission is achieved in more than eighty percent of microadenomas and in a significant proportion of selected macroadenomas. Invasive or very large macroadenomas frequently cannot be completely resected surgically.
Somatostatin receptor analogues (SRAs) — octreotide and lanreotide — suppress GH secretion and achieve biochemical control in approximately fifty percent of patients. Long-acting depot formulations are administered as monthly single injections. They are used as adjuvant therapy following incomplete surgical resection or as primary medical therapy in patients unfit for surgery.
Pegvisomant is a GH receptor antagonist and the most potent medical therapy available for normalizing IGF-1 levels. It is used in patients unresponsive or only partially responsive to SRAs and achieves IGF-1 normalization in more than ninety percent of treated patients.
Dopamine agonists — particularly cabergoline — may be used in mild disease or in combination with SRAs, although their efficacy as monotherapy is more limited compared to other agents.
Stereotactic radiosurgery and conventional radiotherapy are applied as secondary options in patients refractory to surgery and medical therapy; full biochemical control develops gradually over years following irradiation.
Prognosis
Untreated acromegaly is associated with a two- to threefold increase in mortality compared to the general population, driven primarily by cardiovascular disease, diabetes mellitus, and malignancy. With early diagnosis and effective treatment achieving normalization of GH and IGF-1 levels, mortality risk approaches that of the general population. Over the long term, complications such as joint damage, cardiomyopathy, and hypopituitarism may persist as sources of chronic morbidity even after biochemical remission is achieved.