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Causes and clinical manifestations of acromegaly

Causes and clinical manifestations of acromegaly
Literature review current through: Sep 2023.
This topic last updated: May 29, 2020.

INTRODUCTION — Acromegaly is the clinical syndrome that results from excessive secretion of growth hormone (GH) [1]. Its annual incidence is six to eight per million people [2]. The mean age at diagnosis is 40 to 45 years.

The causes and clinical features of acromegaly will be reviewed here. The laboratory diagnosis and treatment of acromegaly are discussed separately. (See "Diagnosis of acromegaly" and "Treatment of acromegaly".)

CAUSES — The most common cause of acromegaly is a somatotroph (growth hormone [GH]-secreting) adenoma of the anterior pituitary. These adenomas account for approximately one-third of all hormone-secreting pituitary adenomas (table 1). GH excess that occurs before fusion of the epiphyseal growth plates in a child or adolescent is called pituitary gigantism. (See "Pituitary gigantism".)

An activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein (Gs-alpha) gene is found in approximately 40 percent of somatotroph adenomas [3-5]. These mutations result in constitutive activation of adenylyl cyclase, which may play a role in both cell division in and excessive GH secretion by these adenomas.

The pituitary tumor transforming gene is also overexpressed in most human somatotroph adenomas [6]. It also appears to play a role in tumor invasiveness since expression is increased in tumors that invade the sphenoid bone.

Microduplications on chromosome Xq26.3 have been associated with excessive GH in children with gigantism and in adults with acromegaly. In a study of 43 patients with gigantism due to GH excess, microduplications in the Xp26.3 region that includes the GPR101 (G protein-coupled receptor 101) gene were identified in 13 patients (termed X-linked acrogigantism [X-LAG]) [7]. All patients identified with this microduplication had disease onset before five years of age, and the G protein-coupled receptor was overexpressed in the patients' pituitary lesions (see "Pituitary gigantism" and "Sex chromosome abnormalities", section on 'Xq26.3 microduplication'). In the same study, a recurrent mutation in GPR101 was found in 11 of 248 adult patients with acromegaly (mostly in pituitary tumors). Other known causes of acromegaly, all very rare, are excess secretion of GH-releasing hormone (GHRH) by hypothalamic tumors, ectopic GHRH secretion by neuroendocrine tumors such as carcinoid tumors or small-cell lung cancers, and ectopic secretion of GH by neuroendocrine tumors [8-10].

CLINICAL MANIFESTATIONS

The clinical features of acromegaly are attributable to high serum concentrations of both growth hormone (GH) and insulin-like growth factor-1 (IGF-1), which is GH dependent. Excess GH and IGF-1 have both somatic and metabolic effects. The somatic effects include stimulation of growth of many tissues, such as skin, connective tissue, cartilage, bone, viscera, and many epithelial tissues.

The metabolic effects include nitrogen retention, insulin antagonism, and lipolysis.

In addition, the somatotroph adenoma itself may cause symptoms due to its size.

Insidious onset — The onset of acromegaly is insidious, and its progression is usually very slow. The average interval from the onset of symptoms until diagnosis is approximately 12 years [11], but determining the onset, which is usually done from old photographs, is very difficult. At diagnosis, most patients have macroadenomas (tumor diameter 10 mm or greater) [12], and some of the adenomas extend to the parasellar or suprasellar regions [13]. Overall, approximately 60 percent of patients eventually have headaches, and 10 percent have visual symptoms [1,14,15].

Direct effects of pituitary tumor

Headache/vision loss — Some patients with acromegaly and large tumors have symptoms due to direct compressive effects of the tumor mass, such as headache, visual field defects (classically bitemporal hemianopsia), and cranial nerve palsies. In a series of 310 patients with acromegaly, headache and visual defects were reported as the presenting features in 8 and 3 percent of patients, respectively [13]. However, approximately 60 percent of patients eventually develop headaches and 10 percent develop visual symptoms [1,14]. Headache, however, may be the direct result of the elevated serum GH concentration, as well as of the mass effect. (See "Causes, presentation, and evaluation of sellar masses", section on 'Clinical manifestations'.)

Pituitary function — A somatotroph macroadenoma, due to its size, can cause decreased secretion of other pituitary hormones, most commonly gonadotropins [14]. Many women with acromegaly have menstrual dysfunction, with or without galactorrhea, and some have hot flashes and vaginal atrophy as a result of estrogen deficiency. In a study of 47 women of reproductive age who had acromegaly, 29 (62 percent) had amenorrhea and seven (15 percent) had oligomenorrhea [16]. Men may have erectile dysfunction, loss of libido, decreased facial hair growth, and a decrease in testicular volume.

Hyperprolactinemia occurs in approximately 30 percent of patients. In some patients, it is due to cosecretion of prolactin and GH by a somatomammotroph adenoma, in which case the serum prolactin concentration may be over 200 ng/mL. In other patients, the cause is likely interference with hypothalamic-pituitary blood flow, in which case the serum prolactin concentration will likely be less than 200 ng/mL.

In a pilot study from a multicenter acromegaly registry (363 patients), hypogonadism was present in 53 percent of patients (49 percent of men and 57 percent of women) [17]. Prevalence of hypogonadism was similar in those with macroadenomas and microadenomas (54 and 38 percent, respectively). In macroadenoma patients, hypogonadism was more common in those with coexisting hyperprolactinemia. The cause of the hypogonadism in patients with microadenomas and normal serum prolactin concentrations is unknown. (See "Causes of secondary hypogonadism in males".)

Thyroid-stimulating hormone (TSH) and corticotropin (ACTH) deficiency occur less commonly than other pituitary hormonal deficiencies [18].

Effects of GH/IGF-1 excess — Long-term growth hormone (GH) and insulin-like growth factor-1 (IGF-1) excess results in overgrowth of many tissues, including connective tissue, cartilage, bone, skin, and visceral organs. Other systemic complications include cardiovascular disease, sleep apnea, metabolic disorders, and colon neoplasia.

Soft tissue and skin — Virtually all patients with acromegaly have acral and soft tissue overgrowth and skin thickening. The characteristic findings are an enlarged jaw (macrognathia) and enlarged, swollen hands and feet, which result in increasing shoe and glove size and the need to enlarge rings.

The facial features become coarse, with enlargement of the nose and frontal bones as well as the jaw, and the teeth become spread apart (picture 1A-B). Despite the prominence of these findings at the time of diagnosis, the rate of change is so slow that few patients seek care because their appearance had changed or for other symptoms related to acral enlargement (eg, only 13 percent of 256 patients in one series [13]).

Manifestations of soft tissue overgrowth include macroglossia, deepening of the voice, and paresthesias of the hands (eg, carpal tunnel syndrome in around 20 percent). Magnetic resonance imaging (MRI) studies suggest that the pathology of median neuropathy in acromegaly is increased edema of the median nerve, which resolves rapidly with reduction of serum GH and IGF-1 concentrations [19]. Other patients have a symmetric sensorimotor peripheral (rarely hypertrophic) neuropathy unrelated to entrapment.

Macroglossia and enlargement of the soft tissues of the pharynx and larynx lead to obstructive sleep apnea in approximately 50 percent of patients. (See 'Sleep apnea' below.)

The skin thickens, making it hard to puncture, and skin tags may appear. Hyperhidrosis is common (present in around 50 percent of patients), often making the patient malodorous. Hair growth increases, and some women have hirsutism (56 percent in one series) [16].

Bone and joints — When excess GH secretion occurs in children, eg, before the epiphyses of the long bones are fused, linear growth does increase; the result is pituitary gigantism. In contrast, adults with acromegaly do not become taller. (See "Pituitary gigantism".)

Synovial tissue and cartilage enlarge, causing hypertrophic arthropathy of the knees, ankles, hips, spine, and other joints [20]. Joint symptoms are a common presenting feature of the disease, and back pain (and kyphosis) is common (image 1A-B). Back pain may also be due to osteoporosis caused by concurrent gonadal insufficiency due to the enlarging pituitary tumor. (See "Rheumatologic manifestations of acromegaly".)

Bone density may be increased in both the spine and hip in acromegaly, at least in women [21], but not if the women are estrogen deficient. A meta-analysis of 41 studies reported a high prevalence of vertebral fractures in patients with active acromegaly [22]. A detailed discussion concerning bone disorders associated with acromegaly is located elsewhere. (See "Rheumatologic manifestations of acromegaly".)

Visceral enlargement — Many visceral organs are enlarged in acromegaly, including the thyroid, heart, liver, lungs, and kidneys. Reversible prostatic enlargement is also common, even in men with hypogonadism [23].

Thyroid — The thyroid enlargement may be diffuse or multinodular. In one study of 37 patients with acromegaly, 34 (92 percent) had an enlarged thyroid gland when assessed by ultrasonography; the mean thyroid size was more than five times normal [24]. In another report, 39 of 45 patients (87 percent) had palpable diffuse or multinodular goiter [25]. In one systematic review, 4 percent or patients with acromegaly also had thyroid cancer [26], higher than rates in the general population. It is unclear whether this association is due to increased GH/IGF-1 levels or enhanced ascertainment by the treating endocrinologists. Thyroid function is usually normal, but some patients with goiter have subclinical hyperthyroidism. A few patients have central hypothyroidism caused by their pituitary tumor. Thyroid function is usually normal in these patients.

Salivary gland enlargement has been described [27,28].

Cardiovascular disease — Cardiovascular abnormalities include hypertension, left ventricular hypertrophy, and cardiomyopathy [29,30].

The cardiomyopathy is characterized by diastolic dysfunction and arrhythmias [31]. The abnormalities are due both to hypertension (present in 43 percent of patients with active disease in one report) and to the acromegaly itself [32]. Reducing GH secretion improves some of the abnormalities of cardiac function [33-35]. A high plasma fibrinogen concentration occurs in acromegaly and is reduced when serum GH concentrations are lowered with octreotide [36].

Heart failure occurs in 3 to 10 percent of patients [37,38]. Compared with patients with acromegaly without heart failure, these patients had an increase in left ventricular mass index that was largely due to chamber dilation, a reduction in left ventricular ejection fraction (42 versus 66 percent), and a significant elevation in cardiac index (4.3 versus 3.5 L/min per m2) [37].

An increased prevalence of valvular heart disease has also been reported. In a series of 40 patients with acromegaly, echocardiography demonstrated significant aortic regurgitation in 30 percent and mitral regurgitation in 5 percent; the comparable values in a control group matched for age, sex, hypertension, and left ventricular systolic function were 7 and 0 percent, respectively [39]. The risk increased with the duration of GH excess, including inadequate therapy.

Sleep apnea — Obstructive sleep apnea may represent an additional risk factor for cardiovascular complications and excess mortality in patients with acromegaly. (See 'Cardiovascular disease' above and 'Mortality' below.)

The overall frequency of sleep apnea in patients with acromegaly is approximately 40 to 50 percent [40-42]. In most cases, craniofacial deformities, macroglossia, and enlargement of the soft tissues of the pharynx and larynx result in obstructive sleep apnea. Less commonly, patients develop central sleep apnea, which is thought to be due to altered respiratory control [40,43]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

Predictive factors for the development of sleep apnea include the severity of GH excess, duration of disease, obesity, older age, and male sex [41,42].

Sleep apnea symptoms gradually improve in some, but not all, patients after correction of the underlying GH excess with transsphenoidal surgery or medical therapy [41,42,44,45]. Thus, specific therapies for sleep apnea are necessary in many patients, although some require only transient therapy as the anatomic abnormalities induced by GH excess recede. (See "Treatment of acromegaly" and "Obstructive sleep apnea: Overview of management in adults".)

Metabolic — In addition to high serum GH and IGF-1 concentrations, uncontrolled acromegaly is also associated with hyperinsulinism, insulin resistance, overt diabetes in 10 to 15 percent of cases, and impaired glucose tolerance in a further 50 percent [46-49]. Some patients have hypertriglyceridemia or hypercalciuria.

Hyperphosphatemia occurs in approximately 70 percent of patients with acromegaly and is presumably due to direct stimulation of renal tubular phosphate reabsorption by IGF-1 [50]. The serum phosphate concentration usually does not exceed 5.5 mg/dL (1.8 mmol/L).

Colonic effects

Neoplasia — Conflicting evidence suggests that acromegaly is associated with an increased risk of colonic neoplasia [51-56]. However, colon cancer mortality does appear to be increased with uncontrolled GH or IGF-1 levels. Mechanisms thought to be involved in the apparent excess risk include a trophic IGF-1 effect on the proliferation of epithelial cells [57] and reduced expression of the peroxisome proliferator-activated receptor (PPAR) gene [58] (see "Molecular genetics of colorectal cancer", section on 'Modifier genes'). Many of these studies are confounded by the observed bowel loop complexity and increased length and megacolon [59,60].

A number of individual studies have reported an increased risk of adenomatous colonic polyps in patients with acromegaly [51-53,61]. As an example, a prospective colonoscopy study evaluated 103 patients with acromegaly and 138 nonacromegalic controls [51]. Adenomatous polyps were found in 22 percent of patients compared with 8 percent of controls. Patients with acromegaly who are over age 50 years, male, have three or more skin tags, or have a family history of colon cancer are more likely to develop polyps [61].

An excess risk of colon cancer has also been observed, but the magnitude of risk compared with controls has been highly variable, ranging from 2- to 14-fold [51-54,61,62]. The best estimate of risk in patients with acromegaly comes from a meta-analysis of nine studies that compared colon adenoma and cancer rates in 701 acromegalic patients and 1573 control subjects [55]. Results included the following:

In the eight studies with colon adenoma data, the frequency of adenomas was 2.5-fold higher in acromegaly patients than controls (23 versus 12 percent, pooled odds ratio [OR] 2.5, 95% CI 1.9-3.2).

In the three studies with colon cancer data, the frequency of cancer was increased more than fourfold in acromegaly patients (5 versus 1 percent, pooled OR 4.4, 95% CI 1.5-12.3).

Based upon these observations, we suggest that colonoscopy be performed at baseline and then every three to four years thereafter in patients over age 50 years, especially when GH levels are not strictly controlled. This recommendation is consistent with the 2009 guidelines from the Acromegaly Consensus Group [63].

Diverticula — Acromegaly also appears to be associated with an increased prevalence of colonic diverticula, as illustrated by a case-control study comparing 107 patients with cured or biochemically controlled acromegaly and 214 age- and sex-matched controls [64]. Diverticula were present on colonoscopy in 39 and 19 percent of patients with acromegaly and controls, respectively. Patients with the longest duration of active disease (>11 years), after adjustment for pretreatment concentrations of GH and IGF-1 (standard deviation scores), were the most likely to develop diverticula (OR 4.2).

Other tumors — In addition to an excess risk of colon polyps and cancer, acromegaly may be associated with other tumors [65-67]. In men, an excess number of malignant tumors including adenocarcinomas of the colon, stomach, esophagus, and melanoma were observed in a cohort of 1041 men with acromegaly (table 2) [65]. An increased frequency of thyroid cancers [68] and uterine leiomyomata have been reported in women [66].

Nonspecific symptoms — Fatigue and weakness can be prominent symptoms. They may result from sleep apnea, cardiovascular dysfunction, neuropathy, hypogonadism, hyperglycemia, or some combination of these factors as described in this section.

MORTALITY — The mortality rate of patients with acromegaly appears to be increased. Death is primarily from cardiovascular disease, a risk that may be reduced by strict biochemical control of the disease (table 3) [1,2,31,69-75].

The best estimate of all-cause mortality risk in patients with acromegaly and the effect of treatment comes from a meta-analysis of 16 studies published between 1970 and 2005 that compared mortality rates in acromegalic patients with those in the general population [70]. The mortality risk was reduced by therapy and may have been eliminated by cure, as illustrated by the following findings:

The overall weighted mean standard mortality ratio (SMR) was 1.72, which represents a 72 percent increase in mortality in acromegalic patients compared with the general population. Some studies have reported an average reduction in survival of as much as 10 years [31].

When only studies in which over 80 percent of patients underwent transsphenoidal surgery as primary therapy were included, there was a smaller increase in weighted mean SMR (1.32). However, transsphenoidal surgery is not synonymous with cure, as the cure rate is only 80 to 90 percent when performed by the most experienced surgeons. (See "Treatment of acromegaly", section on 'Transsphenoidal surgery'.)

There were four studies with postoperative biochemical data that could assess for surgical cure (serum growth hormone [GH] and insulin-like growth factor-1 [IGF-1]). When only patients considered to be cured were analyzed, there was no significant increase in mortality (weighted SMR 1.09, 95% CI 0.81-1.46).

Independent, yet significant, determinants of mortality in acromegaly include age, hypertension, GH levels, IGF-1 levels, history of prior irradiation, and coexisting corticotropin (ACTH) deficiency [76].

Although mortality is still increased in patients with acromegaly compared with control populations, rates have declined over time [77]. This is thought to be related to the more frequent use of pituitary surgery, more experienced pituitary surgeons, a decreased prevalence of hypopituitarism, and the availability of more medical treatment options. (See "Treatment of acromegaly", section on 'Medical therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acromegaly (The Basics)")

Beyond the Basics topics (see "Patient education: Acromegaly (Beyond the Basics)")

SUMMARY

Acromegaly is the clinical syndrome that results from excessive secretion of growth hormone (GH). Its annual incidence is six to eight per million people. The mean age at diagnosis is 40 to 45 years.

The most common cause of acromegaly is a somatotroph (GH-secreting) adenoma of the anterior pituitary. These adenomas account for approximately one-third of all hormone-secreting pituitary adenomas. An activating mutation of the alpha subunit of the guanine nucleotide stimulatory protein (Gs-alpha) gene is found in approximately 40 percent of somatotroph adenomas. These mutations result in constitutive activation of adenylyl cyclase, which may play a role in both cell division and excessive GH secretion by these adenomas. (See 'Causes' above.)

The clinical features of acromegaly are attributable to high serum concentrations of both pituitary-derived GH and liver-derived insulin-like growth factor-1 (IGF-1), which is GH dependent. Excess GH and IGF-1 have both somatic and metabolic effects. In addition, the somatotroph adenoma itself may cause local symptoms. (See 'Clinical manifestations' above.)

The onset of acromegaly is insidious, and its progression is usually very slow. The interval from the onset of symptoms until diagnosis is approximately 12 years. At diagnosis, approximately 75 percent of patients have macroadenomas (tumor diameter 10 mm or greater) and some of the adenomas extend to the parasellar or suprasellar regions. (See 'Insidious onset' above.)

Some patients with acromegaly and large tumors have symptoms due to compressive effects of the tumor, such as headache, visual field defects (classically bitemporal hemianopsia), and cranial nerve palsies. Overall, approximately 60 percent of patients eventually have headaches, and 10 percent have visual symptoms. Macroadenomas can also cause decreased secretion of other pituitary hormones, most commonly gonadotropins. (See 'Direct effects of pituitary tumor' above.)

Virtually all patients with acromegaly have acral and soft tissue overgrowth, and skin thickening. The characteristic findings are an enlarged jaw (macrognathia) and enlarged, swollen hands and feet, which result in increasing shoe and glove size and the need to enlarge rings. (See 'Soft tissue and skin' above.)

Cardiovascular abnormalities include hypertension, left ventricular hypertrophy, and cardiomyopathy. (See 'Cardiovascular disease' above.)

In addition to high serum GH and IGF-1 concentrations, uncontrolled acromegaly is also associated with hyperinsulinism, insulin resistance, overt diabetes in 10 to 15 percent of cases, and impaired glucose tolerance in a further 50 percent. (See 'Metabolic' above.)

Patients with acromegaly appear to be at increased risk for colon polyps, colon cancer, and other tumors. (See 'Colonic effects' above.)

The mortality rate of patients with acromegaly appears to be increased, especially if strict biochemical control is not achieved. Death is primarily from cardiovascular disease. However, mortality rates have begun to decline with improvements in therapy. (See 'Mortality' above.)

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Topic 6633 Version 22.0

References

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