Gigantism and Acromegaly

Gigantism

Gigantism is a nonspecific term that refers to any standing height more than 2 standard deviations above the mean for the person's sex, age, and Tanner stage (ie, height Z score >+2). These disorders are placed along a spectrum of IGF-I hypersecretion, wherein the developmental stage when such excess originates determines the principal manifestations. The onset of IGF-I hypersecretion in childhood or late adolescence results in tall stature (see the image below). (See Presentation and Workup.)

Scientific breakthroughs in the molecular, genetic, and hormonal basis of growth hormone (GH) excess have provided important insights into the pathogenesis, prognosis, and treatment of this exceedingly rare disease. (See Prognosis, Treatment, and Medication.)

Acromegaly

Acromegaly is a rare, insidious, and potentially life-threatening condition for which there is good, albeit incomplete, treatment that can give the patient additional years of high-quality life.[10] (See Prognosis, Treatment, and Medication.)

Symptoms develop insidiously, taking from years to decades to become apparent. The mean duration from symptom onset to diagnosis is 5-15 years, with a mean delay of 8.7 years. Excess GH produces a myriad of signs and symptoms and significantly increases morbidity and mortality rates. Additionally, the mass effect of the pituitary tumor itself can cause symptoms. Annual new patient incidence is estimated to be 3-4 cases per million population per year. The mean age at diagnosis is 40 years in males and 45 years in females. (See Presentation.)

Growth hormone and insulinlike growth factor

GH is necessary for normal linear growth. Its secretion from the pituitary gland is controlled by combined hypothalamic regulation, with secretion being stimulated by GHRH and inhibited by somatostatin (also called GH release–inhibiting hormone). Several tissues, including the endocrine pancreas, produce somatostatin in response to GH. (See Pathophysiology and Etiology.)

GH acts indirectly, by stimulating the formation of IGF hormones (also called somatomedins). IGF-I (somatomedin C), the most important IGF in postnatal growth, is produced in the liver, chondrocytes, kidneys, muscles, pituitary gland, and gastrointestinal tract.

Once released into the circulation, GH stimulates the production of IGF-I. The main source of circulating IGF-I is the liver, though it is produced in many other tissues. IGF-I is the primary mediator of the growth-promoting effects of GH.

It is characterized by increased and unregulated GH production, usually caused by a GH-secreting pituitary tumor (somatotroph tumor). Other causes of increased and unregulated GH production, all very rare, include increased GH-releasing hormone (GHRH) from hypothalamic tumors; ectopic GHRH from nonendocrine tumors; and ectopic GH secretion by nonendocrine tumors.

Causes of excess IGF-I action can be divided into the following three categories:

• Release of primary GH excess from the pituitary

• Increased GHRH secretion or hypothalamic dysregulation

• Hypothetically, the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I

By far, most people with gigantism or acromegaly have GH-secreting pituitary adenomas or hyperplasia. Other causes of increased and unregulated GH production, all very rare, include increased GHRH from hypothalamic tumors; ectopic GHRH from nonendocrine tumors; and ectopic GH secretion by nonendocrine tumors.

Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such as the following:

• Multiple endocrine neoplasia (MEN) type I

• McCune-Albright syndrome

• Neurofibromatosis

• Tuberous sclerosis

• Carney complex[11]

Approximately 20% of patients with gigantism have McCune-Albright syndrome (the triad of precocious puberty, café au lait spots, fibrous dysplasia) and may have either pituitary hyperplasia or adenomas. (See the image below.)

More than 95% of acromegaly cases are caused by a pituitary adenoma that secretes excess amounts of GH. Histopathologically, tumors include acidophil adenomas, densely granulated GH adenomas, sparsely granulated GH adenomas, somatomammotropic adenomas, and plurihormonal adenomas.

Ectopic production of GH and GHRH by malignant tumors accounts for other causes of IGF-I excess. (Ectopic GHRH-producing tumors, usually seen in the lung or pancreas, may occasionally be evident elsewhere, such as in the duodenum as a neuroendocrine carcinoma.)[12, 13]

Of these tumors, up to 40% have a mutation involving the alpha subunit of the stimulatory guanosine triphosphate (GTP)–binding protein. In the presence of a mutation, persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs results in excessive GH secretion.

The pathologic effects of GH excess include acral overgrowth, insulin antagonism, nitrogen retention, increased risk of colon polyps/tumors, and acral overgrowth (ie, macrognathia; enlargement of the facial bone structure, as well as of the hands and feet; and visceral overgrowth, including macroglossia and enlargement of the heart muscle, thyroid, liver, and kidney).[14]

Pathologic studies on acromegalic hearts have shown extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy.

GH/IGF-I excess

Despite diverse pathophysiologic mechanisms, the final common abnormality in gigantism and acromegaly is IGF-I excess. Elevated tissue levels of free IGF-I, which is produced primarily in hepatocytes in response to excess GH, mediate most, if not all, growth-related outcomes in gigantism. Transgenic mice that overexpressed GH, GHRH, or IGF-I were found to have dramatically accelerated somatic growth compared with control litter mates.

One acromegalic patient had low serum GH levels and elevated serum total IGF-I levels; this finding implicates IGF-I as the key pathologic factor in this disease. Serum levels of IGF-I are consistently elevated in patients with acromegaly and, therefore, are used to monitor treatment success. The conditions described below can cause IGF-I oversecretion.

Primary pituitary GH excess

In most individuals with GH excess, the underlying anomaly is a benign pituitary tumor composed of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH-secreting and prolactin-secreting cells) in the form of a pituitary microadenoma (< 1 cm) or macroadenoma (>1 cm). The adenomas are most characteristically well-demarcated and confined to the anterior lobe of the pituitary gland. In some people with GH excess, the tumor spreads outside the sella, invading the sphenoid bone, optic nerves, and brain. GH-secreting tumors are more likely to be locally invasive or aggressive in pediatric patients than in adults.

Gs-alpha (Gsa) mutation

G proteins play an integral role in postligand signal transduction in many endocrine cells by stimulating adenyl cyclase, resulting in an accumulation of cyclic adenosine monophosphate (cAMP) and subsequent gene transcription. About 20% of patients with gigantism have McCune-Albright syndrome and pituitary hyperplasia or adenomas.

Activating mutations of the stimulatory Gsa protein have been found in the pituitary lesions in McCune-Albright syndrome and are believed to cause the other glandular adenomas observed. Point mutations found in several tissues affected in McCune-Albright syndrome involve a single amino-acid substitution in codon 201 (exon 8) or 227 (exon 9) of the gene for Gsa. Somatic point mutations have been identified in the somatotrophs of less than 40% of sporadic GH-secreting pituitary adenomas. The resulting oncogene (gsp) is thought to induce tumorigenesis by persistently activating adenyl cyclase, with subsequent GH hypersecretion.

Loss of band 11q13 heterozygosity

Loss of heterozygosity at the site of a putative tumor-suppressor gene on band 11q13 was first identified in tumors from patients with MEN type I and GH excess. Loss of heterozygosity at band 11q13 has also been observed in all types of sporadically occurring pituitary adenomas. It is associated with an increased propensity for tumoral invasiveness and biologic activity.

Isolated familial somatotropinoma, a rare disease, refers to the occurrence of two or more cases of acromegaly or gigantism in a family in whom the features of Carney complex or MEN type 1 are absent.[15] It appears to be inherited as an autosomal dominant disease with incomplete penetrance. Although an association exists between isolated familial somatotropinoma and loss of heterozygosity on 11q13, the responsible gene remains unknown.

Abnormality at Carney loci on chromosomes 2 and 17

The Carney complex, which is characterized by myxomas, endocrine tumors, and spotty pigmentation, is transmitted as an autosomal dominant trait. About 8% of affected individuals have GH-producing pituitary adenomas. The causative gene for this disease was mapped to bands 2p16 and 17q22-24. Germline mutations in PRKAR1A (which encodes for the protein kinase A type I-alpha regulatory subunit, an apparent tumor-suppressor gene on chromosome arm 17q) were detected in several families with Carney complex.

Secondary GH excess

Causes of secondary GH excess include increased secretion of GHRH due to an intracranial or ectopic source and dysregulation of the hypothalamic-pituitary-GH axis.

GHRH excess

Hypothalamic GHRH excess is postulated as a cause for gigantism, possibly secondary to an activating mutation in hypothalamic GHRH neurons. Excess GHRH secretion may be due to an intracranial or ectopic tumor. Several well-documented incidents of hypothalamic GHRH excess demonstrated intracranial gangliocytomas associated with gigantism or acromegaly.

Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet-cell, and bronchial neoplasms. Prolonged tumoral secretion of GHRH leads to pituitary hyperplasia, with or without adenomatous transformation, that increases levels of GH and other adenohypophyseal peptides.

Disruption of somatostatin tone

Tumoral infiltration into somatostatinergic pathways are hypothesized to be the basis for GH excess in rare incidents of gigantism associated with neurofibromatosis and optic glioma or astrocytomas.

Gigantism is extremely rare, with approximately 100 reported cases to date. Although still rare, acromegaly is more common than gigantism, with a prevalence of 36-69 cases per million and an incidence of 3-4 cases per million per year.[16]

Gigantism may begin at any age before epiphyseal fusion. X-linked acrogigantism (X-LAG) caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, is a severe infant-onset gigantism syndrome with onset as early as 2-3 months of age (median, 12 months).[4] Other genetic causes of gigantism include familial isolated pituitary adenoma (FIPA) caused by aryl hydrocarbon receptor interacting protein (AIP) gene mutations, multiple endocrine neoplasia type 1 (MEN1), McCune-Albright syndrome (MAS), and Carney complex with onset during prepubescence.[5]

The mean age for onset of acromegaly is in the third decade of life; the delay from the insidious onset of symptoms to diagnosis is 5-15 years, with a mean delay of 8.7 years. The mean age at diagnosis for acromegaly is 40 years in males and 45 years in females.

Because of the small number of people with gigantism, mortality and morbidity rates for this disease during childhood are unknown.

In acromegaly, a severe disease that is often diagnosed late, morbidity and mortality rates are high, particularly as a result of associated cardiovascular, cerebrovascular, and respiratory disorders and malignancies.[1]

Because IGF-I is a general growth factor, somatic hypertrophy in acromegaly occurs across all organ systems. Associated complications include the following[17] :

• Acromegalic heart

• Increased muscle and soft tissue mass

• Increased kidney size

• Articular overgrowth of synovial tissue and hypertrophic arthropathy

• Joint symptoms, back pain, and kyphosis: Common presenting features

• Thick skin

• Hyperhidrosis (often malodorous)

• Carpal tunnel syndrome and other entrapment syndromes

• Macroglossia: May result in sleep apnea

• Cerebral aneurysm and increased risk of cerebrovascular accident: Less common[18]

The prevalence of gastritis, duodenitis, peptic ulcer and intestinal metaplasia may be enhanced in acromegaly as compared to a normal healthy population.[19]

Early diagnosis of acromegaly, however, results in early transsphenoidal pituitary microsurgery, and currently, patients are more likely to be cured than in the past.

Reversal of excessive GH produces the following:

• Decreased soft tissue swelling

• Diminished sweating

• Restoration of normal glucose tolerance

No studies have established, however, that the treatment of acromegaly leads to a reduction in morbidity and mortality rates, although successful treatment, with normalization of IGF-I levels, may be associated with a return to normal life expectancy.

Remission depends on the initial size of the tumor, the patient’s GH level, and the skill of the neurosurgeon. Remission rates of 80-85% and 50-65% can be expected for microadenomas and macroadenomas, respectively.

The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration of greater than 5 ng/dL.

Metabolic and endocrine complications

Diabetes mellitus occurs in 10-20% of patients with acromegaly. A 2009 study suggests that in patients with acromegaly, insulin resistance and hyperinsulinemia are positively correlated with the level of disease activity.[20] Hypertriglyceridemia is found in 19-44% of patients. Multinodular goiter also is often present in acromegaly.

Hypopituitarism may develop in patients with acromegaly, as a result of the pituitary mass or as a complication of surgery or radiation therapy. Treat pituitary failure with appropriate hormone-replacement therapy.

Respiratory complications

In acromegaly, respiratory complications occur as follows:

• Increased lung capacity: 81% of men and 56% of women

• Small airway narrowing: 36% of patients

• Upper airway narrowing: 26% of patients

• Acute dyspnea and stridor

• Sleep apnea: As a significant cause of morbidity, sleep apnea may be both obstructive and central; curing acromegaly does not necessarily correct the disorder

Cardiovascular complications

A study by Berg et al found an increased prevalence of cardiovascular risk factors in patients with acromegaly compared with controls.[1] Cardiovascular complications include the following:

• Hypertension

• Acromegalic cardiomyopathy (with dysfunction and arrhythmias)

• Left ventricular hypertrophy

• Increased left ventricular mass

Disorders of calcium and bone metabolism

The following calcium and bone metabolism disorders can be found in acromegaly:

• Hypercalciuria

• Hyperphosphatemia

• Urolithiasis

Neuromuscular complications

In acromegaly, these include the following:

• Weakness (although with muscular appearance)

• Nerve root compression

• Radiculopathy

• Spinal stenosis

• Carpal tunnel syndrome

Cancer risks

Patients with acromegaly may be at increased risk for colorectal cancer and premalignant adenomatous polyps. Most studies suggest that as many as 30% of patients may have a premalignant colon polyp at diagnosis and that as many as 5% may have a colonic malignancy.[21] In studies, polyps were generally multiple and proximal to the splenic flexure, making them less likely to be discovered during sigmoidoscopy. However, the long-term effect of colonic lesions on morbidity and mortality has not been established.

Patients with acromegaly may also have an increased risk of developing breast and prostate tumors, although no clear evidence supports this; the risk of thyroid cancer is increased in males.[14] However, the prevalence of cancers in patients with acromegaly remains controversial, although patients might be advised to undergo screening colonoscopy and thyroid ultrasonography.[21, 22, 23]

For individuals with acromegaly, the mortality rate is 2-3 times that of the general population, with cardiovascular and respiratory complications being the most frequent causes of death. Transgenic mouse models of acromegaly demonstrate cardiac and vascular hypertrophy but normal function, raising the concern that hypertrophic cardiomyopathy may contribute to the increased mortality.[24]

A study by Bates et al suggested that the extent of a patient’s GH excess impacts mortality. The investigators found that acromegaly patients with a GH concentration of greater than 10 ng/mL had double the expected mortality rate, whereas patients with a GH concentration of less than 5 ng/mL approached normal mortality.[16] These results underscore the necessity to reduce GH and IGF-I concentration in patients with acromegaly.

Researchers disagree on whether malignancy is a significant cause of increased mortality in acromegaly. Although benign tumors (including uterine myomas, prostatic hypertrophy, and skin tags) are frequently encountered in acromegaly, documentation for overall prevalence of malignancies in patients with acromegaly remains controversial.

Refer patients to the Hormone Health Network for additional information.

For patient education information, the Thyroid & Metabolism Center, as well as, Acromegaly, Acromegaly FAQs, and Acromegaly Medications.

Gigantism

The presentation of patients with gigantism is usually dramatic, unlike the insidious onset of acromegaly in adults. Reasons for this difference include the close monitoring of growth in children and their relatively responsive growth-plate cartilage. Children with gigantism have few soft tissue effects (eg, peripheral edema, coarse facial features), because of their rapid linear growth. Features of gigantism include the following:

• Longitudinal acceleration of linear growth secondary to insulinlike growth factor I (IGF-I) excess is the cardinal clinical feature

• Tumor mass may cause headaches, visual changes due to optic nerve compression, and hypopituitarism

• Hyperprolactinemia is a common finding; it results from pituitary growth hormone (GH) excess, which manifests in childhood because mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism

Acromegaly

Acromegaly can be an insidious disease. Symptoms, which may precede diagnosis by several years, can be divided into the following groups:

• Symptoms due to local mass effects of an intracranial tumor

• Symptoms due to excess of GH/IGF-I

Symptoms due to local mass effects of tumor

These symptoms depend on the size of the intracranial tumor. Headaches and visual field defects are the most common symptoms.

Visual field defects depend on which part of the optic nerve pathway is compressed. The most common manifestation is a bitemporal hemianopsia caused by pressure on the optic chiasm.

Tumor damage to the pituitary stalk may cause hyperprolactinemia due to loss of inhibitory regulation of prolactin secretion by the hypothalamus. Damage to normal pituitary tissue can cause deficiencies of glucocorticoids, sex steroids, and thyroid hormone.

Loss of end-organ hormones results from diminished anterior pituitary secretion of corticotropin (ie, adrenocorticotropic hormone [ACTH]), gonadotropins (eg, luteinizing hormone [LH], follicle-stimulating hormone [FSH]), and thyrotropin (ie, thyroid-stimulating hormone [TSH]).

Symptoms due to excess of GH/IGF-I

These include the following:

• Soft tissue swelling and enlargement of extremities

• Increase in ring and/or shoe size

• Hyperhidrosis

• Coarsening of facial features

• Prognathism

• Macroglossia

• Arthritis

• Increased incidence of obstructive sleep apnea

• Increased incidence of glucose intolerance or frank diabetes mellitus, hypertension, and cardiovascular disease

• Hyperphosphatemia, hypercalcuria, and hypertriglyceridemia possible

• Increased incidence of congestive heart failure, which may be due to uncontrolled hypertension or to an intrinsic form of cardiomyopathy attributable to excess GH/IGF-I

• Increased incidence of colonic polyps and adenocarcinoma of the colon

In comparison with acromegalic patients with GH–secreting adenomas alone, patients who have hyperprolactinemia as well tend to have an earlier onset of disease, lesser acromegalic features, and lower GH levels, but also larger tumors.[25] Women with GH-prolactin–secreting adenomas tend to have higher incidences of menstrual disorders and galactorrhea.

Gigantism

Gigantism affects all growth parameters, although not necessarily symmetrically. Over time, insulinlike growth factor–I (IGF-I) excess is characterized by progressive cosmetic disfigurement and systemic organ manifestations. Manifestations of gigantism include the following:

• Tall stature

• Mild to moderate obesity (common)

• Macrocephaly (may precede linear growth)

• Soft tissue hypertrophy

• Exaggerated growth of the hands and feet, with thick fingers and toes

• Coarse facial features

• Frontal bossing

• Prognathism

• Hyperhidrosis

• Osteoarthritis (a late feature of IGF-I excess)

• Peripheral neuropathies (eg, carpel tunnel syndrome)

• Cardiovascular disease (eg, cardiac hypertrophy, hypertension, left ventricular hypertrophy): Occurs if IGF-I excess is prolonged

• Benign tumors (uterine myomas, prostatic hypertrophy, colon polyps, and skin tags, which are frequently found in acromegaly)

• Endocrinopathies (eg, hypogonadism, diabetes and/or impaired glucose tolerance, hyperprolactinemia)

Acromegaly

Signs and symptoms of acromegaly include the following:

• Doughy-feeling skin over the face and extremities (one of the earliest signs in acromegaly is swelling of soles and palms)

• Thick and hard nails

• Deepening of creases on the forehead and nasolabial folds

• Noticeably large pores

• Thick and edematous eyelids

• Enlargement of the lower lip and nose (the nose takes on a triangular configuration)

• Wide spacing of the teeth and prognathism

• Cutis verticis gyrata (ie, furrows resembling gyri of the scalp): Acromegaly may be first evident as cutis verticis gyrata.[6]

• Small sessile and pedunculated fibromas (ie, skin tags): An association between skin tags and polypoid lesions has been described in the literature, but currently, no conclusive studies exist to substantiate this finding

• Hypertrichosis (found in approximately one half of acromegaly patients): Unlike virilizing disorders, hypertrichosis of acromegaly does not affect the beard area

• Oily skin (acne is not common)

• Hyperpigmentation (40% of patients)

• Acanthosis nigricans (a small percentage of patients): Results from excessive stimulation of keratinocytes and fibroblasts in the skin

• Excessive eccrine and apocrine sweating

• Breast tissue becoming atrophic; galactorrhea

• High blood pressure

• Mitral valvular regurgitation

• Mild hirsutism (in women)

Skin changes are considered to be a classic feature of acromegaly; as activity of the disease diminishes, the skin changes become stationary and regress.

In a study assessing a 30-year experience with acromegaly at a major Canadian center, the most common presenting features included acral enlargement, coarse facial features, and sweating or oily skin.[26]

Patients with active acromegaly have abnormal dynamics of GH secretion. Before immunoassays for insulinlike growth factor I (IGF-I) were developed, growth hormone (GH) measurement was the only method used in the biochemical assessment of the disease.[27] (A simple diagnostic approach is to measure serum GH 1 hour after oral administration of 100 g of glucose.)[28]

IGF-I, however, has been the most reliable biochemical indicator of acromegaly, because of an excellent linear dose-response correlation between serum IGF-I levels and 24-hour integrated GH secretion.

Oral glucose

Because GH secretion is inhibited by glucose, measurement of glucose nonsuppressibility may be useful, although there is debate as to what value of GH is considered “normal” after a 1.75g/kg oral glucose challenge (not to exceed 75 g oral glucose load). A paradoxic rise in GH concentration is seen in 15-20% of patients with acromegaly following oral glucose administration.

Two baseline GH levels are obtained prior to ingestion of 75 or 100 g of oral glucose, and additional GH measurements are made at 30, 60, 90, and 120 minutes following the oral glucose load.

With newer assays for GH using the immunoradiometric assay (IRMA), acromegaly is thought to be present when a criterion of less than 1 mcg/L is used following oral glucose ingestion.

Growth hormone

Patients with active acromegaly have abnormal dynamics of GH secretion. A simple diagnostic approach is to measure serum GH 1 hour after oral administration of 100 g of glucose. Clearly elevated GH levels (>10 ng/mL) after oral glucose, combined with the clinical picture, secure the diagnosis of acromegaly, while a normal GH level (< 5 ng/mL) after oral glucose essentially excludes the diagnosis.

Only a small percentage of patients investigated for acromegaly have a postglucose GH level that is intermediate (5-10 ng/mL). In these patients, other tests can be used to define their status.

Before immunoassays for IGF-I, GH measurement was the only method used in the biochemical assessment of acromegaly,[27] and the availability of supersensitive GH has changed many aspects of the interpretation of the GH value. Hypersecretion and abnormal neuroregulation characterize acromegaly. GH can be measured in many ways to give useful information on diagnosis, therapy, and prognosis. Measuring GH in the management of acromegaly complements the information IGF-I values provide.

Random GH measurements, however, often are not diagnostic, because of the episodic secretion of GH, its short half-life, and the overlap between GH concentration in individuals with acromegaly and individuals without the condition.

GHRH

GH-releasing hormone (GHRH) concentration may be obtained if clinically indicated. Levels higher than 300 pg/mL usually indicate an ectopic source of GHRH. In pituitary disease (GHRH independent), GHRH concentration is normal or suppressed.

Prolactin

Because as many as 20% of GH-secreting pituitary adenomas co-secrete prolactin, the prolactin level also may be elevated. However, a rise in prolactin may result from stalk compression or from co-secretion from a pituitary adenoma. Pituitary adenomas may be associated with deficiencies of other pituitary hormones. Consider evaluation of the adrenal, thyroid, and gonadal axes.

Insulinlike growth factor I

As previously stated, IGF-I has been the most reliable biochemical indicator of acromegaly. An excellent linear dose-response correlation between serum IGF-I levels and 24-hour integrated GH secretion has been demonstrated. Elevated IGF-I values in a patient whose symptoms prompt appropriate clinical suspicion almost always indicate GH excess. IGF-I is useful not only in diagnosis, but also in monitoring the efficacy of therapy.

Measurement of IGF binding protein 3 (IGFBP-3), the primary binding protein for circulating IGF, is increased in acromegaly and may be useful in its diagnosis. It also may be helpful for monitoring the activity of the disease during treatment.

Factors altering IGF-I levels

Starvation, obesity, and diabetes mellitus decrease IGF-I concentration, while pregnancy increases it. In addition, IGF-I concentrations vary with age, which means an assay is required in which the normal ranges have been stratified to account for this discrepancy.

Potential confusion may arise in the evaluation of healthy adolescents, because IGF-I levels can be substantially higher during puberty than during adulthood. Always compare the patient's measurement with age-matched and sex-matched IGF-I reference ranges published in the literature or established for the specific testing laboratory.

MRI

Because of the relatively high incidence of nonfunctioning, incidentally discovered pituitary adenomas, imaging studies should be obtained only after a firm biochemical diagnosis of acromegaly has been made.

The sella turcica should be imaged first, since GH-secreting pituitary adenoma is the most common cause of acromegaly. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) scanning for this purpose and provides detailed information about surrounding structures (eg, optic chiasm, cavernous sinuses).

CT scanning

If MRI findings of the sella are negative, appropriate studies to localize tumors causing ectopic secretion of GH or GHRH may be obtained.

CT scans of the abdomen/pelvis can be used to evaluate for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH. Use chest CT scans to evaluate for bronchogenic carcinoma secreting GH/GHRH.

Radiography

Radiographic studies show the following:

• Increase in length and thickness of the mandible

• Underbites resulting from mandible enlargement

• Thickened calvaria

• Exaggerated bony ridges and muscle attachments

• Enlarged frontal, mastoid, and ethmoid sinuses

• Elongated ribs resulting from proliferation at the cartilage-bone junction

• Deep barrel chest, which, as a result of continued costal growth, is often pronounced in long-standing acromegaly

• Periosteal growth of the vertebrae and osteophytic proliferation of the articular margins of joints

• Cartilage proliferation of the larynx

• Cortical thickening and distal tufting

• Deformities of the skull

Although testing with an intravenous administration of thyrotropin-releasing hormone (TRH) is not necessary to make the diagnosis, 50-80% of patients with GH excess have a paradoxic rise in GH levels after the challenge.

Circulating GHRH blood levels may confirm peripheral ectopic GHRH secretion in the presence of an ectopic tumor. However, in the presence of a hypothalamic GHRH-secreting tumor, circulating GHRH levels may be normal.

Surgical specimens from pituitary tumors demonstrate a variety of histologic findings, such as the following:

• Densely granulated somatotrope adenoma

• Sparsely granulated somatotrope adenoma

• Mixed somatotrope-lactotrope adenoma

• Acidophilic stem cell adenoma

• Mammosomatotroph adenoma

• Plurihormonal adenoma producing GH and one or more glycoprotein hormones, principally alpha

• Somatotrope carcinoma

• Somatotrope hyperplasia

• No distinct morphologic change

Skin biopsy may demonstrate the following:

• Slight thinning of the epidermis

• Papillary and upper reticular dermis (may appear edematous and myxoid)

• Separation of the collagen fibers

• Slightly increased number of fibroblasts

• Fibrous component normal (qualitatively and quantitatively)

• Dense glycosaminoglycan deposit (most consistent abnormality)

• Infiltration by glycosaminoglycans (most prominent in the papillary, the upper reticular dermis, and in the vicinity of sweat glands)

Mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism. Coexistence of GH and prolactin in the secretory granules of the tumor cells is clearly demonstrated on immunohistochemical staining.

Most experts define cure, or adequate control, of growth hormone (GH) excess as a glucose-suppressed GH concentration of less than 2 ng/mL, as determined by radioimmunoassay (1 mcg/L by IRMA), and normalization of the serum insulinlike growth factor I (IGF-I) concentration.

However, no single treatment modality consistently achieves control of GH excess. For pituitary adenomas, transsphenoidal surgery is usually considered the first line of treatment, followed by medical therapy for residual disease.[7] Radiation treatment usually is reserved for recalcitrant cases. The cost of providing care for acromegaly may need to be considered.[29] Surgery may lower it by avoiding lifelong pharmacological therapy.

Radiotherapy and medical treatment are important because in long-term studies, surgery has been found to cure only approximately 60% of patients with acromegaly.[30] Slow-release formulations of somatostatin are now widely used (including as a primary treatment) and appear to be safe and effective in 50-60% of the patients. A GH-receptor blocking agent, pegvisomant, appears to normalize IGF-I levels in almost all patients.

Guidelines released by the Endocrine Society (ENDO) in 2014 address important clinical issues regarding the evaluation and management of acromegaly.[31, 32] Recommendations include the following:

• For most patients with acromegaly, surgical removal of the pituitary gland tumor should be considered the primary treatment

• An imaging study should be performed at least 12 weeks postsurgery to determine whether any residual tumor tissue is present

• Patients should be evaluated for any damage caused by the pituitary tumor and for the development of hypopituitarism

• Medical therapy should be administered only to patients with persistent postoperative disease

The guidelines also address the management of women with acromegaly who are pregnant or trying to conceive.

The goals of medical therapy for GH excess are as follows:

• Remove or shrink the pituitary mass

• Restore GH secretory patterns to normal

• Restore serum total IGF-I and IGF binding protein 3 (IGFBP-3) levels to normal

• Retain normal pituitary secretion of other hormones

• Prevent recurrence of disease

Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment for GH excess and are generally used when primary surgery fails to induce complete remission.

Somatostatin analogues

The most extensively studied and used somatostatin analogue, octreotide, binds to the somatostatin receptor subtypes II and V, inhibiting GH secretion. Octreotide suppresses the serum GH level to less than 2.5 mcg/L in 65% of patients with acromegaly and normalizes circulating IGF-I levels in 70% of patients. Tumor shrinkage, although generally modest, is seen in 20-50% of patients. Consistent GH suppression was achieved with a continuous subcutaneous pump infusion of octreotide in a pubertal boy with pituitary gigantism.

Studies of patients with GH excess for longer than 14 years have demonstrated that the effects of octreotide are well sustained over time. An anaphylactic reaction to octreotide has been described.[33]

Primary treatment with depot octreotide and lanreotide has been found to induce tumor shrinkage in newly diagnosed acromegaly.[9]

Long-acting formulations, including long-acting octreotide, lanreotide, and pasireotide, have been demonstrated to produce consistent GH and IGF-I suppression in patients with acromegaly with once-monthly or biweekly intramuscular depot injections. (Sustained-released preparations have not been formally tested in children with gigantism.)

In two Japanese studies by Shimatsu et al, the sustained-release lanreotide Somatuline Depot (or lanreotide Autogel) was found to control elevated GH and IGF-I levels within the first weeks of treatment, as well as over a long-term period of administration. In an open-label, parallel-group, dose-response study, which included 29 patients with acromegaly and 3 with pituitary gigantism, 5 injections of lanreotide Autogel were administered over a 24-week period, in dosages of 60, 90, or 120 mg.[34]

At week 4, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels were found in 41% and 31% of patients, respectively. At week 24, the investigators found that serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been attained in 53% and 44% of patients, respectively.[34]

In the second investigation, an open-label, long-term study of 30 patients with acromegaly and 2 with pituitary gigantism, lanreotide Autogel injections were administered every 4 weeks for a period of 52 weeks (13 injections). Patients initially received a 90-mg dose, which was subsequently adjusted based on clinical response. At week 52, serum GH levels of below 2.5 ng/mL and normalized IGF-I levels had been achieved in 47% and 53% of patients, respectively.[34]

Pasireotide’s approval was based on two multicenter, phase 3 studies, one in medically naive patients with acromegaly who had prior surgery or in whom surgery was not an option, and the other in patients inadequately controlled on first-generation somatostatin analogs (ie, octreotide, lanreotide).[35, 36]

The risk for hyperglycemia needs to be considered with use of pasireotide. In one open-label, multicenter safety study, hyperglycemia-related adverse events were reported in 45.5% of patients but were typically manageable.[37, 38]

Dopamine-receptor agonists

Dopamine-receptor agonists (eg, bromocriptine, cabergoline) bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although their precise mechanism of action remains unclear.

Prolactin levels are often adequately suppressed with these agents. However, circulating GH and IGF-I levels rarely normalize with this therapy. Less than 20% of patients achieve GH levels of less than 5 ng/mL, and less than 10% achieve normal IGF-I levels. Tumor shrinkage occurs in a few patients.

Dopamine-receptor agonists are generally used as adjuvant medical treatments for GH excess, and their effectiveness may be added to that of octreotide.

Although long-acting formulations are available, no data about the long-term control of GH and IGF-I with these agents are available.

Bromocriptine

Bromocriptine has an adjunctive role in the treatment of patients with GH excess who fail to achieve a cure by surgical treatment or who are to be treated with radiation. It has limited effectiveness, however, reducing the circulating GH level to less than 5 ng/mL in only 20% of patients with acromegaly and normalizing IGF-I concentration in only 10% of these patients. Shrinkage in tumor size also occurs, albeit in fewer than 20% of patients. Patients in whom prolactin is elevated are more likely to have a favorable response to bromocriptine.

Cabergoline

Cabergoline, another dopamine-receptor agonist, is somewhat more effective than bromocriptine in reducing GH levels, with response rates of 46%. A meta-analysis found that cabergoline used as single-agent therapy in patients with acromegaly normalized IGF-I levels in one third of patients.[39] In those cases in which a somatostatin analogue has failed to control acromegaly, cabergoline adjunction normalized IGF-I levels in about 50% of cases.

GH-receptor antagonists

Tests of pegvisomant (Somavert), a novel hepatic GH-receptor antagonist, demonstrated effective suppression of GH and IGF-I levels in patients with acromegaly due to pituitary tumors or ectopic GHRH hypersecretion. However, pegvisomant does not have direct antiproliferative effects on the underlying pituitary adenoma.[40]

Normalization of IGF-I levels occurs in as many as 90% of patients treated daily with this drug for 3 months. Patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring.[41]

In the interim analysis of ACROSTUDY, a global noninterventional surveillance study of 1288 patients with acromegaly treated with pegvisomant for a mean period of 3.7 years (2.1-y mean follow-up), 63.2% of subjects had normal IGF-1 levels at a mean dose of 18 mg/day. The reported incidence of transaminitis, lipodystrophy, and increase in pituitary tumor size was low.[42]

Combination therapy with pegvisomant and cabergoline or somatostatin analogues is also being investigated for efficacy.[43, 44]

Pegvisomant has not been formally tested in children; however, a case study described normalization of IGF-1 in a 12-year-old girl with pituitary gigantism treated with pegvisomant 20 mg/day.[45]

Radiation Therapy

In general, radiation therapy is recommended if GH hypersecretion is not normalized with surgery. Radiation prevents further growth of the tumor in more than 97% of patients after surgical resection.[46] However, radiation treatment takes years to reduce/normalize GH/IGF-I levels.[47] About 60% of patients have a GH concentration of less than 5 ng/mL 10 years after radiotherapy.

Hypopituitarism is a predictable outcome of radiation treatment, occurring in 40-50% of patients within 10 years after irradiation.[46] Some studies suggest that radiation is associated with the development of secondary tumors.

Newer modalities (eg, stereotactic fractionated radiotherapy, proton beam therapy) may have the advantage of a better target dose-conformation, but long-term outcome data are lacking at this time.[48]

Stereotactic gamma-knife radiosurgery for recurrent or residual pituitary adenomas, when combined with microsurgery, is often effective in controlling pituitary adenoma growth and hormone hypersecretion.[49] Results are influenced by many factors, including adenoma histology, adenoma volume, and radiation dose.

The primary goal of surgery is to normalize GH levels. For well-circumscribed pituitary adenomas, transsphenoidal surgery to completely remove the tumor is the treatment of choice, and it may be curative. The procedure can also rapidly improve symptoms caused by mass effect of the pituitary tumor. The following should be kept in mind concerning surgical treatment:

• The likelihood of a surgical cure greatly depends on the surgeons' expertise and on the size and extension of the mass

• Intraoperative GH measurements can improve the results of tumor resection

• Transsphenoidal surgery to resect tumors is as safe in children as it is in adults

• A transcranial approach is sometimes necessary

As determined by using the GH assays available to date, GH levels should be normalized (< 1 ng/mL for ≥50% of the points measured during the day) in all patients. Because this change is impractical to test, however, GH levels (< 1 ng/mL within 2 h after a glucose load) and serum IGF-I levels (within 2 standard deviations of the reference range adjusted for age, sex, and Tanner stage) are the best measures of a biochemical cure.

A remission rate of 80-85% can be expected for microadenomas and 50-65% for macroadenomas.

The postoperative GH concentration may predict remission rates. According to the results of one study, a postoperative GH concentration of less than 3 ng/dL was associated with a 90% remission rate, which declined to 5% in patients with a postoperative GH concentration of greater than 5 ng/dL.

A significant proportion of acromegalic patients who have undergone surgery have been found to have a change in biochemical status upon long-term follow-up. Most of these changes have occurred within the first postoperative year and were more likely to occur if the initial GH postglucose and IGF-I levels were discordant.[50]

If surgery does not normalize GH secretion, options include pituitary radiation and medical therapy.

All patients with a history of GH excess require periodic, lifelong evaluation. In one series, the long-term recurrence rate for GH-secreting adenomas in children was 13.3% after surgery.[39]

In a majority of cases of acromegaly, multimodal treatment with surgery, medical therapy, and radiotherapy provides biochemical control as defined by Endocrine Society (ENDO) guidelines as a reduction of GH levels to < 1.0 ng/ml and normalization of IGF1 levels.[31] Biochemical control is associated with reduced mortality, and patients require long-term monitoring of GH and IGF1 levels for early identification and treatment of recurrent disease.[51]

IGF-I levels appear to correlate better with clinical activity than do GH levels and should therefore be monitored. Patients should also be evaluated for severe GH deficiency, which may occur in more than half of all patients treated for acromegaly (even those who have been cured by surgery alone).[52]

An association exists between acromegaly and regurgitant valvular heart disease. Patients with acromegaly require adequate cardiac evaluation and follow-up to establish whether valvular disease is present and, if so, to determine the extent and progression of valvular involvement.[53] Echocardiography may document a cardiomyopathy with left ventricular hypertrophy, diastolic and systolic dysfunction, aortic and mitral regurgitation, and increased aortic root diameters.[54] Other cardiovascular complications include concentric biventricular hypertrophy and cardiomyopathy, hypertension, arrhythmias, atherosclerosis, coronary artery disease, and cardiac dysfunction.[55] Sleep apnea is also common in patients with acromegaly and may exacerbate cardiovascular dysfunction.[56] Because cardiorespiratory complications are not reversed with biochemical control, patients should be screened periodically for the common cardiovascular and respiratory manifestations of acromegaly.[55, 56]

Guidelines for the diagnosis and treatment of acromegaly have been released by the following organizations:

• American Association of Clinical Endocrinologists (AACE) (2011) ^[16]
• The Endocrine Society (ENDO) (2014) ^{[31, 32]}
• Acromegaly Consensus Group ^[57]

Endocrine Society (ENDO) Guidelines

Diagnosis

Recommendations for diagnostic testing include[31] :

• Measurement of IGF-1 levels in patients with typical clinical manifestations of acromegaly
• Measurement of IGF-1 in patients without the typical clinical manifestations of acromegaly, but who have several of these associated conditions: sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis, and hypertension.
• Measurement of serum IGF-1 to rule out acromegaly in a patient with a pituitary mass
• Use of random GH levels to diagnose acromegaly is recommended against
• In patients with elevated or equivocal serum IGF-1 levels, diagnosis should be confirmed by a finding of lack of suppression of GH to <  1 μg/L following documented hyperglycemia during an oral glucose load
• Following biochemical diagnosis of acromegaly, an imaging study should be performed to visualize tumor size and appearance, as well as parasellar extent  
• Magnetic resonance imaging (MRI) is the imaging modality of choice, followed by computed tomography (CT) scan when MRI is contraindicated or unavailable

Management of comorbidities and mortality risk

The following additional testing is recommended after diagnosis[31] :

• Evaluation for associated comorbidities: hypertension, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnea
• All comorbidities should be monitored and rigorously managed
• Screening colonoscopy for colon cancer
• Thyroid ultrasound if there is palpable thyroid nodularity
• Assessment for hypopituitarism and hormone deficits

Treatment goals

Recommended therapeutic goals are as follows[31] :

• Age-normalized serum IGF-1 value
• Random GH <  1.0 μg/L

Surgical Intervention

Key recommendations for surgical treatment include[31] :

• Transsphenoidal surgery as the primary therapy in most patients
• Repeat surgery should be considered if residual intrasellar disease is present following initial surgery
• In select patients, preoperative medical therapy with somatostatin receptor ligands (SRLs) to reduce surgical risk from severe comorbidities
• In a patient with parasellar disease making total surgical resection unlikely, surgical debulking to improve subsequent response to medical therapy
• Measurement of IGF-1 level and a random GH at 12 weeks or later post-surgery; measure a nadir GH level after a glucose load in a patient with a GH greater than 1 μg/L
• Perform an imaging study at least 12 weeks post-surgery to visualize residual tumor and adjacent structures; MRI is the preferred study followed by CT scan when MRI is contraindicated or unavailable

Medical therapy

Key adjuvant medical therapy recommendations include[31] :

• Patient with significant disease (ie, with moderate-to-severe signs and symptoms of GH excess and without local mass effects) should receive either a somatostatin-receptor ligand (SRL) or pegvisomant as the initial adjuvant medical therapy
• Patient with only modest elevations of serum IGF-1 and mild signs and symptoms of GH excess should receive a trial of a dopamine agonist, usually cabergoline, as the initial adjuvant medical therapy
• Patients who cannot be cured by surgery, have extensive cavernous sinus invasion, do not have chiasmal compression, or are poor surgical candidates should receive SRL as primary therapy
• For patients with inadequate response to an SRL, pegvisomant or cabergoline should be added

Radiotherapy (RT)/Stereotactic Radiotherapy (SRT)

Recommendation for the use of radiation therapy include[31] :

• Radiation therapy in the setting of residual tumor mass following surgery, and if medical therapy is unavailable, unsuccessful, or not tolerated
• Stereotactic radiotherapy (SRT) should be performed over conventional radiation therapy unless the technique is not available, there is significant residual tumor burden, or the tumor is too close to the optic chiasm resulting in an exposure of more than 8 Gy

Management during pregnancy

The guidelines include the following recommendations for treatment during pregnancy[31, 57] :

• Discontinue long-acting SRL formulations and pegvisomant approximately 2 months before attempts to conceive; use of short-acting octreotide as necessary until conception
• During pregnancy, medical therapy only for tumor and headache control.
• Monitoring GH and/or IGF-1 levels during pregnancy is not recommended

Somatostatin analogues are the most effective medical therapies for growth hormone (GH) excess. After transsphenoidal surgery, these agents are generally a first-line treatment, followed by a dopamine-receptor agonist or GH receptor antagonist.[58]

The most extensively studied and used somatostatin analogue, octreotide, binds to the somatostatin receptor subtypes II and V, inhibiting GH secretion.

Prolactin levels are often adequately suppressed with dopamine-receptor agonists. However, circulating GH and insulinlike growth factor ̶ I (IGF-I) levels rarely normalize with these agents.

Class Summary

Like natural somatostatin, octreotide inhibits the secretion of GH, insulin, and glucagon. After an intravenous administration, basal serum GH, insulin, and glucagon levels fall. Octreotide also inhibits prolactin release by means of vasoactive intestinal peptide (VIP) ̶ and thyrotropin-releasing hormone (TRH) ̶ mediated secretion of prolactin. Octreotide is used to treat acromegaly and several hormone-secreting tumors.

Octreotide (Sandostatin, Mycapssa)

Octreotide acts primarily on somatostatin receptor subtypes II and V, inhibiting GH secretion. It also has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and gastrointestinal peptides.

The SC product is administered 3 times per day. The long-acting somatostatin analogue given IM every 4 weeks. It results in similar improvements in GH/IGF-I concentration as octreotide but is associated with fewer adverse effects. A trial of short-acting somatostatin analogue is necessary to confirm the patient's ability to tolerate this compound.

Do not administer octreotide LAR in the deltoid area, because of significant discomfort at the injection site. Gluteal injection sites should be alternated.

An oral twice daily product is also available.

Lanreotide (Somatuline Depot)

Lanreotide, an octapeptide analogue of natural somatostatin, is indicated for long-term treatment of acromegaly in patients who experience inadequate response to other therapies. It inhibits a variety of endocrine, neuroendocrine, exocrine, and paracrine functions. Lanreotide elicits high affinity for human somatostatin receptors 2, 3, and 5.

It inhibits basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide and markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Lanreotide also significantly decreases prostaglandin E1–stimulated jejunal secretion of water, sodium, potassium, and chloride and reduces prolactin levels in acromegalic patients undergoing long-term treatment.

Pasireotide (Signifor LAR)

Pasireotide is a cyclohexapeptide somatostatin analog that binds to human somatostatin receptors 1, 2, 3, 4 and 5. It is indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

Class Summary

Dopamine-receptor agonists make up another pharmacologic option. They have modest effects if used as single agents and are usually added to somatostatin analogues if complete remission has not been achieved. Cabergoline is well tolerated.

Bromocriptine (Parlodel, Cycloset)

This is the dopamine-receptor agonist that is most often used to treat GH and prolactin excess. It is safe when administered to a child for extended period.

Cabergoline

Cabergoline is a potent dopamine-receptor agonist with a prolonged duration of action. It inhibits prolactin secretion more effectively than bromocriptine.

Class Summary

GH-receptor agonists are the newest class of drugs used to decrease excessive GH effect. It blocks GH binding to receptors, thus decreasing IGF-I, IGF binding protein 3 (IGFBP-3), and acid-labile subunit.

Pegvisomant (Somavert)

Pegvisomant is a recombinant deoxyribonucleic acid (DNA) analogue of human GH that has been structurally altered to act as a GH receptor antagonist. It selectively binds to GH receptors on cell surfaces, blocking endogenous GH binding. By interfering with GH signal transduction, it decreases levels of IGF-I, IGFBP-3, and acid-labile subunit.