Acromegaly and gigantism are due to excess GH production, usually as a result of a pituitary adenoma. The incidence of acromegaly is 5 cases per million per year and the prevalence is 60 cases per million. Clinical manifestations in each patient depend on the levels of GH and IGF-I, age, tumor size, and the delay in diagnosis. Manifestations of acromegaly are varied and include acral and soft tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. Acromegaly is a disabling disease that is associated with increased morbidity and reduced life expectancy. The diagnosis is based primarily on clinical features and confirmed by measuring GH levels after oral glucose loading and the estimation of IGF-I. It has been suggested that the rate of mortality in patients with acromegaly is correlated with the degree of control of GH. Adequately treated, the relative mortality risk can be markedly reduced towards normal.
Acromegaly and gigantism are due to excess GH production, usually caused by a pituitary adenoma. The diagnosis is often preceded by around 10 years of active but unrecognized disease [
Some 25% of GH-secreting adenomas also secrete prolactin. These include dimorphic adenomas with GH and prolactin cells, monomorphic mammosomatotroph adenomas, and more primitive acidophilic cell adenomas. Multicellular or unicellular immunoreactivity is common, especially for the alpha subunit of glycoprotein hormones. The secretion of other hormones has very uncommon clinical consequences [
The manifestations of acromegaly are varied, including acral and soft tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. It has been suggested that the mortality rate in acromegalic patients is correlated with the degree to which GH hypersecretion is controlled. The decreased survival rate associated with acromegaly can be normalized by successful surgical and adjunctive therapy. The mortality rate of cancer can be stratified according to the level of GH treatment and may be similar to that of the general population. Analyzing mortality determinants, around 60% of acromegalic patients die from cardiovascular disease, 25% from respiratory causes, and 15% from neoplasias [
Clinical manifestations in each patient depend on the levels of GH and IGF-I, age, tumor size, and the delay in diagnosis. The typical features of acromegaly slowly develop over years; around 40% of acromegalic patients are diagnosed by internists, ophthalmologists if they have visual disturbances, dentists due to maxillary teeth separation, mandibular prognathism, and overbite, gynecologists due to menstrual irregularities and infertility, rheumatologists if they suffer form joint problems, or pulmonologist if they have obstructive sleep apnea [
Clinical manifestations of acromegaly.
Mass effects of the tumor |
Headache |
Visual field defects |
Hyperprolactinemia |
Pituitary stalk section |
Hypopituitarism |
Hypothyroidism, hypogonadism, hypocortisolism |
Systemic effects of GH/IGF-I excess |
Visceromegaly |
Soft tissue and skin changes |
Thickening of acral parts |
Increased skin thickness and soft tissue hypertrophy |
Hyperhidrosis/Oily texture |
Skin tags and acanthosis nigricans |
Cardiovascular features |
Hypertrophy (biventricular or asymmetric septal) |
Congestive Heart Failure (systolic and/or diastolic) |
Coronary disease |
Arrhythmias |
Hipertensión |
Cardiomyopathy |
Metabolic features |
Impaired glucose tolerance |
Diabetes mellitus |
Insulin resistance |
Respiratory manifestations |
Macroglossia |
Jaw malocclusion |
Upper airway obstruction |
Sleep disturbances |
Sleep apnea (central and obstructive) |
Ventilatory dysfunction |
Bone and joint manifestations |
Increased articular cartilage thickness |
Arthralgias and arthritis |
Carpal tunnel síndrome |
Osteopenia |
Other endocrine consequences |
Goiter |
Hypercalciuria |
Galactorrhea |
Decrease libido, impotents |
Menstrual abnormalities |
Modified from Cordero and Barkan [
The growth of the pituitary adenoma may compress local structures and cause neurological symptomatology and visual disturbances. Somatotroph adenomas grow slowly, and patients presenting these adenomas are usually older than 50 years. Changes in appearance derive from skeletal growth and soft tissue enlargement, which is subtle in the early stage of the disease. Visceromegalies are common, in the form of goiter, hepatomegaly, splenomegaly, and macroglossia. Facial changes include large lips and noses, frontal skull bossing and cranial ridges, mandibular overgrowth with prognathism, maxillary widening with teeth separation, jaw malocclusion, and overbite. Growth occurs on acral parts, with an increase in shoe and ring size [
The clinical manifestations of acromegaly include skin changes such as hyperhidrosis, oily skin, and unpleasant odor, which are due to the deposit of glycosaminoglycans. Pigmented skin tags over the trunk are common in patients with acromegaly; it is not clear whether GH/IGF-I excess causes skin tags directly, or whether they arise as a consequence of insulin resistance and dyslipidemia. Acanthosis nigricans develop in patients with severe acromegaly, where the skin in the axillae and back of the neck becomes dark, soft, and velvet-like with delicate folds and papillae. This phenomenon is caused by increased amounts of skin extracellular matrix, accompanied by edema. Cutaneous microcirculation is altered in patients with acromegaly. Rare manifestations include cutis verticis gyrate and psoriasis. These manifestations respond well to decreased GH level; although some changes are irreversible [
One of the most frequent clinical manifestations of acromegaly affects the joints, in approximately 70% of individuals at the time of diagnosis. Articular alterations are the most frequent and severe cause of morbidity and disability in these patients. The pathogenesis of arthropathy in acromegaly is comprised of two mechanisms: initial endocrine elevated GH and IGF-I levels promote growth of the articular cartilage and periarticular ligaments, subsequently leading to mechanical changes. Arthralgia is one of the most common complaints of acromegalic patients. Large joint arthropathy is a common feature of the disease, occurring in approximately 70% of patients, resulting from the thickening of cartilaginous and periarticular fibrous tissue, causing joint swelling, pain, and hypomobility followed by the narrowing of joint spaces, osteophytosis, and features of osteoarthritis with chronic disease [
The radiological appearance of arthropathy in acromegaly was studied in small noncontrolled groups of patients with the disease treated or untreated, but active. These studies have suggested that more severe radiological changes are associated with disease duration and activity. The most prevalent manifestation was axial osteoarthritis, affecting the cervical and lumbar areas, even at young ages. The characteristic radiological changes observed were wide joint spaces and severe osteophytosis. This study documents that the risk to develop osteoarthritis is predicted by IGF-I concentrations at the time of initial diagnosis. These associations were not caused by differences in age, gender, or BMI [
Although acromegaly is often included in lists of endocrinopathies associated with osteoporosis, due to increased bone turnover, some investigators have reported normal or increased bone mass in this disorder [
Chronic excess of GH and IGF-I typically affects the axial skeleton with the development of severe alterations to the spine morphology and function until features of diffuse idiopathic skeletal hyperostosis occur. An early diagnosis of acromegaly is mandatory in order to reduce the severity of spine abnormalities as they are significantly higher in patients with longer disease duration [
Cardiovascular manifestations occur in 60% of patients. Elevated growth hormone, hypertension, and heart disease are negative determinants for life expectancy in acromegaly. Therefore controlling GH, hypertension, and heart disease are relevant in decreasing mortality rate. Cardiac involvement in acromegaly, in the absence of other contributing factors, is called acromegalic cardiomyopathy, which is initially characterized by cardiac hypertrophy, followed by diastolic dysfunction and ultimately failure of systolic function [
Some authors have found an increased thickness of the intima-media layer, depending on factors such as smoking [
In acromegalic patients, the Framingham score was calculated and screening for calcification of the coronary arteries was carried out using computed tomography. The authors found a 40% risk [
Excess GH can cause insulin resistance, as it alters the ability of insulin to suppress glucose production and stimulates its use [
The possible association between intracranial aneurysms and pituitary adenoma has been frequently debated. A recent study documents an increased prevalence of intracranial aneurysms in acromegaly and the presence of intracranial aneurysms correlated with GH serum values at disease onset and showed a trend to a positive correlation with poor disease control [
Acromegaly alters the structure of the respiratory apparatus and impairs respiratory function. Patients with acromegaly develop a number of respiratory alterations, as a consequence of anatomical changes affecting the craniofacial bones and soft tissues, respiratory mucosa/cartilages, lung volumes, rib cage geometry, and the activity of respiratory muscles. This range of abnormalities results in two main respiratory dysfunctions, namely, sleep apnea and impaired respiratory function. Sleep apnea, the phenomenon of recurrent cessation or reduction of airflow to the lungs during sleep, is a common cause of snoring and daytime sleepiness in acromegaly. Impaired respiratory function is less frequently investigated in acromegaly and originates from multiple alterations involving the bone and muscle structure of the chest as well as lung elasticity. Lung volumes become increased in patients with acromegaly and they may develop subclinical hypoxemia. The impact of respiratory complications is high in acromegaly, and patients with this condition may have increased respiratory mortality [
Patients with acromegaly develop a barrel chest due to changes in their vertebral and costal morphology. Obstruction of the upper airways is a result of macroglossia, prognathism, thick lips, and hypertrophy of the laryngeal mucosa and cartilage; it can cause sleep apnea and excessive snoring and can complicate tracheal intubation during anesthesia. Hypoventilation and hypoxemia may also arise from central respiratory depression and kyphoscoliosis. The lungs show increased distensibility with normal diffusion capacity [
Moreover, using polysomnography, Attal and Chanson [
Hyperprolactinemia with or without galactorrhea develops in approximately 30% of patients due to of pituitary stalk compression or mixed tumor secretion of GH and PRL. Hypopituitarism, by mass compression of the normal pituitary tissue, occurs in approximately 40% patients; amenorrhea, impotence, or secondary thyroid or adrenal failure may develop. Goiter and thyroid abnormalities are common, potentially as a result of the stimulating effects IGF-I on thyrocyte growth. Hyperthyroidism rarely develops because of high levels of serum thyrotropin secreted from plurihormonal pituitary tumors. Hypercalcemia in acromegaly is reported in up to 8% of patients; it is usually secondary to coexistent hyperparathyroidism and does not resolve after treatment of excess GH. Reports indicate that hypercalciuria and nephrolithiasis may occur in 6–77% of patients with acromegaly. Proposed mechanisms of hypercalciuria include parathyroid hyperplasia, renal tubular acidosis, increased calcium absorption, and overproduction of 1, 25 (OH)2 D [
One study evaluated sleep characteristics in a small group of acromegalics; an astonishingly high number of patients were found to be affected by restless leg syndrome, a neurological disorder characterized by a compelling urge to move the limbs during the night, due to unpleasant paraesthetic sensory symptoms, which may lead to severe insomnia, consequent daytime sleepiness, and reduced quality of life. The study found that the prevalence and severity of restless leg syndrome is increased in patients with active acromegaly and impacts negatively on their physical performance, dramatically impairing quality of life [
The gastrointestinal manifestations associated with acromegaly are colon carcinoma, adenomatous polyps, and dolichocolon. In a recent study, colonic diverticular disease was found to be higher in patients with acromegaly when compared with controls, and diverticula were present at a significantly younger age. Diverticulosis in acromegaly was primarily associated with the duration of the active disease, which became even stronger when adjusted for excess GH and IGF-I. Dolichocolon and adenomatous polyps were increased in patients when compared with controls, both of which were associated with IGF-I concentrations at the time acromegaly was diagnosed [
Epidemiological studies have reported conflicting findings on cancer risk in acromegaly [
Patients with acromegaly have a higher prevalence of colorectal neoplasms. The pathogenic mechanisms are still unclear and may be related to a sustained increase in serum GH-IGF-I, hyperinsulinemia, altered IGFBP-3, increased IGF-II and IGFBP-2 levels, altered local immune response, and genetic susceptibility. Elevated levels of serum IGF-I are associated with increased proliferation in the superficial crypt cells. Colao et al. investigated the relationship of GH, IGF-I, and insulin levels to colonic lesions in a cohort of consecutive newly diagnosed patients with acromegaly and found that fasting insulin levels were associated with premalignant and malignant colonic lesions. It was also found that glucose tolerance and insulin levels were strongly associated with colonic adenomas and carcinomas. Diabetes or impaired glucose tolerance was a risk factor for the development of colonic lesions [
Considering all the prospective colonoscopy screening studies, an increased prevalence of colorectal cancer has been found in acromegaly when compared with controls. No increase was demonstrable if acromegaly was controlled, but if the disease was active, premalignant polyps were more frequent and increased their tendency to become malignant. Once developed, the cancer was more aggressive, with higher mortality. A positive correlation between mortality from colorectal cancer and disease activity was observed. Therefore, complete colonoscopy should be offered, and at least a baseline one at diagnosis colonoscopy assessment is required in all patients with acromegaly [
Acromegaly is an insidious disease, which is often diagnosed late (between 4 and more than 10 years after onset). The increase in morbidity and mortality associated with acromegaly is the result of the oversecretion GH and IGF-I and the direct mass effect of the pituitary tumor. An early diagnosis of the disease is mandatory, although none of these symptoms is sufficiently sensitive, especially during early stages of the disease. Physiognomic alterations and growth of the acral parts are the first manifestations of the disease in most cases; this is the reason for a medical visit in most patients. Growth of the acral parts is uncommon in adults without acromegaly and can be objectively evaluated by an increase in shoe and/or ring size. Therefore, familiarization of physicians with the phenotype of the disease may be more effective in order to increase the diagnosis and to permit early detection, rather than strategies addressing comorbidities, which are not always present, usually appear later, and are rarely seen in the absence of the acromegaly phenotype [
When there is clinical suspicion of the disease, biochemical confirmation is required to establish the diagnosis (Figure
Algorithm for the diagnosis of acromegaly (modified from: Cordero and Barkan [
GH levels are tonically elevated in acromegaly, so a random GH value of less than 0.04
IGF-I has been used as a marker of disease activity in acromegaly. It is mainly synthesized in the liver, although nearly all of the tissues contribute to the circulating concentration. It is an ideal screening test as it has a long half life of 18–20 hours and the levels remain stable throughout the day. IGF-I is affected by age and gender, decreasing by approximately 14% per decade during adult life. Some disorders including malnutrition, malabsorption, anorexia nervosa, liver cirrhosis, renal failure, type 1 diabetes mellitus, normal pregnancy, and adolescence show discrepancies between GH and IGF-I [
Biochemical diagnosis is made by determining of GH after OGTT with 75 g and determining the levels of IGF-I. The current international consensus for the diagnosis of acromegaly recommends a nadir GH equal to or greater than 0.4
In different situations IGF-I serves as a biomarker of the activity of acromegaly. IGF-I levels are relatively stable and correlate with clinical acromegaly and elevated GH levels. In order to accurately assess IGF-I levels, age-matched controls are required, as the levels of IGF-I decreased 14% per decade. In order to monitor disease activity, levels of GH and IGF-I are complementary. It has been suggested that in the presence of discordant serum IGF-I and GH levels, IGF-I is more predictive than GH in terms of insulin sensitivity and clinical symptom score [
As previously mentioned, pituitary GH-secreting tumors may cosecrete other hormones. Hyperprolactinemia may be due to cosecretion or pituitary stalk compression. Mass effect of the tumor may affect the secretion of the pituitary gland hormones, resulting in hypopituitarism. Therefore, other pituitary hormones and their target hormones should be evaluated.
Magnetic resonance imaging (MRI) with contrast administration is the best imaging technique to pinpoint the pituitary source of excess GH. This technique makes it possible to visualize and locate, in relation to surrounding structures, adenomas larger than 2 mm in diameter. At the time of diagnosis, over 75% show a macroadenoma (>10 mm in diameter), which grows into the cavernous sinus or suprasellar region. In rare cases, in patients with acromegaly and unremarkable pituitary MR imaging and no evidence of ectopic GH or GHRH production (CT or MRI thoracic and abdominal negative), a transsphenoidal pituitary exploration is a reasonable approach and may result in clinical improvement and biochemical cure in the hands of experienced surgeon [
As previously discussed, acromegaly is rarely caused by ectopic tumors that produce GHRH (only 0.5% of acromegalic cases) or GH [
It has been suggested that the mortality rate in patients with acromegaly is correlated with the degree of control of GH. The mortality rate from cancer can be stratified according to GH levels aftercare and may be similar to that of the nonacromegalic population. The standardized mortality rate for acromegaly is 1.72. Mortality is related to GH levels of over 2–2.5
Clinical and biochemical control is aimed at correcting tumor compression, controlling biochemical markers to normal levels, and reducing morbidity and mortality to the expected rate for the normal population. According to the 2010 consensus criteria, biochemical control of acromegaly is achieved when circulating IGF-I is reduced to an age- and sex-adjusted normal range and GH during OGTT is <0.4
Acromegaly is an uncommon disease, which in most cases is due to a pituitary tumor. It has a wide variety of clinical manifestations, including acral and soft tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. Acromegaly is usually diagnosed by increased IGF-I and GH after an OGTT. Its treatment reduces complications and mortality.
None of the authors have any conflict of interest related to this article.
This paper is supported in part by FIS del Instituto de Salud Carlos III PI070413, PI10/00088, and Xunta de Galicia PS07/12, INCITE08ENA916110ES, INCITE09E1R91634ES, IN845B-2010/187, 10CSA916014PR, Spain.