Clinical manifestations

Presentation and course

The clinical features of acromegaly develop insidiously, with most patients able to date symptoms back 15 years or longer (143). Common symptoms and signs include enlargement of the skull, hands, feet, nose, lips, and ears; lower jaw protrusion (prognathism) and macroglossia with consequent difficulty biting or chewing food; arthralgias (especially cervical); headaches; hypertrichosis, hyperpigmentation, and hyperhidrosis with an oily texture of the skin; skin tags; generalized weakness; carpal and cubital tunnel syndromes; paresthesias; decreased libido; and amenorrhea. The most common symptoms at the time of diagnosis are acral enlargement (81%), headaches (29%), macroglossia (29%), and visual field defects (19%). Affected people must progressively enlarge their rings, hats, gloves, and shoes. Other manifestations can include loud snoring, nocturnal coughing fits, and obstructive sleep apnea (86).

Men present slightly earlier on average than do women. In addition, hypogonadism and greater IGF-1 values were more frequently observed in men with acromegaly (18).

Physical examination reveals prominent supraorbital ridges; prognathism with teeth separation due to continued growth of the mandible; macroglossia; large, doughy and sweaty hands; goiter; osteoarthritis; increased anterior-posterior diameter of the chest; spinal and thoracic deformities; cardiomegaly; hepatomegaly; and skin tags.

Acromegalic individuals may present for orthodontic surgery because of mandibular prognathism (82).

In one such case, histological examination showed a highly vascularized pituitary adenoma with a diffuse (solid) growth pattern. Higher magnification showed uniform cells with broad eosinophilic cytoplasm and round-to-oval nuclei.

The proliferation index was very low, with approximately 3% of cells showing immunoreactivity against MiB-1.

The MiB-1 monoclonal antibody recognizes the Ki-67 protein, which is expressed over the entire cell cycle except for the G0 phase; it has been used as an operational marker of cell proliferation for various types of tumors. Some tumor cells showed immunopositivity for prolactin in the peripheral areas of the cytoplasm.

However, no immunoreactivity was evident for human growth hormone.

Absence of immunostaining for growth hormone is found in a subset of patients with acromegaly (155).

Temporally, the earliest observed signs and symptoms tend to be enlarged hands and feet, hypertension, and carpal or cubital tunnel syndrome, which may precede diagnosis by years. Morphologic changes, snoring, and fatigue are all present in about 80% of patients at the time of diagnosis (27).

The acral manifestations of acromegaly may be asymmetric, although this is uncommon.

In severe acromegaly, acanthosis nigricans can occur involving the axillae and back of the neck, where the skin becomes dark, soft, and velvety with delicate folds and papillae. Rare manifestations include cutis verticis gyrata (ie, visible folds, ridges, or creases of the scalp resulting from thickening of scalp tissues) and psoriasis.

In patients with advanced disease, large-joint and axial arthropathy develops that may include thickened articular cartilage, periarticular calcifications, osteophyte overgrowth, synovitis, degenerative osteoarthritis, scoliosis, kyphosis, and vertebral fractures (79).

Growth hormone has a marked effect on the development of orofacial structures, including eruption and shedding patterns of teeth (08).

Hypertension (67%) and diabetes mellitus (24%) are common and a majority display insulin resistance (104). Cardiac findings include left ventricular hypertrophy, asymmetric septal hypertrophy, cardiomyopathy, hypertension, and congestive cardiac failure.

Neurologic manifestations develop as a consequence of both the endocrine disturbance and the local mass effect of the underlying pituitary adenoma, but most neurologic complications are neuromuscular (28). At least one abnormal finding in the peripheral nervous system is found in most patients (88%) (05). A mild (often subclinical) peripheral polyneuropathy is present in approximately half of patients and is independent of associated diabetes (95). Paresthesias in the lower extremities, as well as sensory loss, hyporeflexia, and weakness, may be seen in a length-dependent distribution. Nerve biopsy indicates an increase in fascicular connective tissue elements and some loss of myelinated and unmyelinated nerve fibers. Peripheral nerve (median and ulnar) enlargement has been reported and appears to correlate with disease control, IGF-1 levels, and duration of disease (28). A prospective observational study (using dynamometers to measure muscle strength) found that patients with acromegaly tend to have increased muscle bulk, normal proximal strength, and reduced grip strength (71); grip strength improved after biochemical treatment was achieved.

Carpal tunnel syndrome may develop due to enlargement of the transverse carpal ligament, and surgical release may precede the diagnosis of underlying acromegaly by years (152). A proximal myopathy has also been described but is rare (105). Very rarely, a compressive myelopathy may occur secondary to overgrowth of spinal bony and soft tissue.

Neurocognitive dysfunction has been documented, with acromegaly patients manifesting worse executive functioning than normal controls (159).

Obstructive sleep apnea secondary to the associated anatomic changes of the air passages may produce lethargy and hypersomnolence.

Features of hypopituitarism, visual field loss, (ie, bitemporal defects including bitemporal hemianopsia) and ophthalmoplegia (due to compression of cranial nerves III, IV, and VI in the cavernous sinus) may be seen when a pituitary tumor enlarges to compress adjacent neural tissue.

Pituitary apoplexy (due to ischemic necrosis or hemorrhage into the tumor) or cerebrospinal fluid leakage may also occur.

Case 1. Acromegaly (77; 74). In 1899, Senior Assistant Physician to the Edinburgh Royal Infirmary GA Gibson reported a case of acromegaly. MC, a 42-year-old Scottish woman, was hospitalized with complaints of weakness and stiffness in the back and limbs and "enlargement of the body" for 17 years. There was no family history of similar problems. She was healthy until the age of 25, when her hands, particularly the phalangeal joints, began to swell and become painful, especially at night. Soaking them in hot water helped some. Several months later, she stopped having menstrual periods. By her late 20s, she felt languid, "perspired very freely," fatigued easily with mild exertion, and developed daytime somnolence. Her hands, then feet, and then jaw began to steadily enlarge, and her somnolence and languor increased so much that she "finally took to bed" in her late 30s. She developed a mild goiter. Her tongue became thickened and enlarged and "protruded a good deal between the lips," so she had difficulty with distinct articulation and developed hypogeusia. Next, her lower lip increased in size, her face "became very large and swelled in appearance," her nose and ears increased in size, and her hair became much coarser and thicker.

Her entire body slowly increased in size, with severe enlargement of the face and mandible, and she became so weak that she was bedridden. Around the age of 40, she accidentally discovered that her right eye was blind. Her skin became very pale, which she described as a "deadly whiteness." She developed transient nausea and lightheadedness when she sat up, which was occasionally accompanied by vomiting, and two or three times she had syncope while sitting. With administration of "thyroid gland," her goiter decreased; her tongue diminished in size, and she was able to keep it in her mouth; her hypogeusia improved; and her weight decreased (from 180 pounds to 146 pounds). She returned home, was again able to do simple tasks with significantly improved exertional tolerance, felt less languid and sleepy, and was able to walk with difficulty using a stick.

By the age of 42, her right eye was blind, and she had a right esotropia (divergent squint) affecting her blind eye. There had been significant progression of facial changes, and numerous acneiform lesions were apparent on her face. Her mandible had markedly enlarged, which was particularly evident in profile and was emphasized in a lateral radiograph. Her hands and feet had also enlarged.

By the age of 49, the 24th year of her disease, there had been continued progression of facial changes since her photograph at the age of 42, and the right esotropia (divergent squint) was worse. She died in Edinburgh the following year, in 1907, and a postmortem photograph was taken to show her facial and hair changes at the end of her illness.

In 1911, 4 years after her death, British physician and anatomist Auckland Campbell Geddes (1879–1954) reported further concerning her skeletal abnormalities (74). He referred to her simply as "EAS 07" (for "Edinburgh Acromegalic Subject 1907"). Among other prestigious positions, Geddes was later Professor of Anatomy at McGill University in Montreal, but his academic career was interrupted by World War I, during which he served as a Brigadier General in the War Office. He was elected to Parliament in 1917 and was appointed British Ambassador to the United States in 1920. From 1924 to 1947, he was the Chairman of the Rio Tinto Company and Rhokana Corporation. He returned to public service during World War II, when he served as Commissioner for Civil Defence for the South-East Region from 1939 to 1944 and for the North-West Region from 1941 to 1942. In 1942, he was raised to the peerage as Baron Geddes.

Among the bony photographs of MC, Geddes focused on the skull and mandible. In particular, Geddes noted (1) the antero-posterior reduction in the size of the foramen magnum and (2) the great size of the pituitary fossa, which measured 31 mm in its antero-posterior diameter, 39 mm in its transverse diameter, and 26 mm in depth.

Prognosis and complications

Historically, patients with acromegaly and gigantism rarely lived past their mid-50s, with some dying as young as their early 20s from complications of their disease. Even today, acromegaly is associated with a 2- to 3-fold increase in mortality, particularly from cardiovascular and cerebrovascular disease (36; 28; 79). The overall standardized mortality ratio of patients with acromegaly is 1.48 (90; 101). In longitudinal studies, multivariate analyses indicate that growth hormone levels of less than 2.5 µg/L, younger age, shorter duration of disease, and the absence of hypertension independently predict longer survival. Hypertension is a major contributor to cardiovascular mortality in acromegaly (79). Untreated or uncontrollable acromegaly has a high mortality rate usually due to cardiopulmonary complications and diabetes mellitus. Quality of life remains poor over the long-term despite biochemical control (107).

Psychological disturbances and poor quality of life are major consequences of acromegaly and the stigma associated with the disease (79; 114; 108; 118). Mental state and quality of life are the most important determinants of biopsychosocial complexity in patients with acromegaly, whereas the biochemical normalization is of lesser importance (108). Acromegalic patients exhibit critically high levels of perceived stigma, leading to psychological distress and disruptions in daily life (118). Among 171 adult acromegalic patients recruited in a cross-sectional Italian multicentric study, a very high proportion (up to 28%) were depressed (24).

Acromegaly is associated with significant medical morbidities (36; 106; 147; 67). More than 50% of patients have coexisting cardiac, metabolic, and endocrine disturbances, and only 5% of patients do not suffer from any of these diseases. Medical comorbidities in acromegalic patients include impaired glucose tolerance, diabetes mellitus, hypocortisolism, hypothyroidism, hyperprolactinemia, hypertension, left ventricular hypertrophy, hypogonadism, obstructive sleep apnea, arthropathy and arthropathy-associated pain, vertebral deformities, osteoporosis, vertebral and other fractures, and growth of benign and malignant neoplasms (137; 136; 139; 62; 106; 112; 67). Biochemical control of acromegaly reduces progression of left ventricular hypertrophy and improves other markers of structural cardiac dysfunction, including left ventricular ejection fraction (79).

Impaired glucose tolerance and diabetes mellitus are the most frequent metabolic comorbidities associated with acromegaly and are present in 30% to 50% of affected patients at diagnosis (79). Excess growth hormone stimulates gluconeogenesis and lipolysis, causing hyperglycemia and elevated free fatty acid levels. In addition, excess growth hormone leads to both hepatic and peripheral insulin resistance, with compensatory hyperinsulinemia, whereas conversely IGF-1 increases insulin sensitivity. The presence of diabetes in patients with acromegaly is associated with increased overall mortality as well as increased cardiovascular mortality and morbidity (61).

Pituitary dysfunction in acromegaly may also be manifest as hypocortisolism, hypothyroidism, hyperprolactinemia, and hypogonadism. Hyperprolactinemia in acromegalic patients may result either from co-secretion of growth hormone and prolactin by the tumor or from pituitary stalk compression. Hypogonadism is detected in approximately 50% of patients and results from tumor mass effect or the normal portion of the pituitary gland on concomitant hyperprolactinemia (79); hypogonadism may compromise sexual function, fertility, muscle function, bone health, and well-being.

Obstructive sleep apnea is present in 50% to 80% of newly diagnosed acromegaly patients and results mainly from the pharyngeal soft-tissue swelling that occurs with the disease (79; 25; 32; 86).

Arthropathy-associated pain is one of the most prominent symptoms negatively affecting quality of life in patients with acromegaly and can result in significant deterioration of functional abilities over time, potentially compromising independent functioning (79). Patients with acromegaly are at increased risk of vertebral fractures, primarily because of deterioration in bone microarchitecture (112; 68; 145). Diagnostic delay in acromegaly has a significant adverse impact on vertebral fracture risk (34).

Neurologic complications can include headache, bitemporal hemianopsia, olfactory dysfunction (53), pituitary apoplexy, peripheral neuropathy, carpal tunnel or cubital tunnel syndrome (152; 169), and development of intracranial meningiomas (59). Most, but not all, patients with acromegaly-associated carpal tunnel syndrome show symptomatic improvement with acromegaly control (79). Rarely, pituitary apoplexy produces "autohypophysectomy" with a spontaneous resolution of acromegaly (69; 111; 04). Other rare complications include myelopathy due to ossification of posterior longitudinal ligament with resulting paraplegia (98).

Although the frequency of hyperostosis frontalis interna is 22% in patients with acromegaly, apparently neither excess growth hormone nor hyperprolactinemia plays a role in its etiopathogenesis because acromegalic individuals with and without hyperostosis frontalis interna have similar basal growth hormone, IGF-1, and prolactin levels; IGF-1 index; diagnosis lag time; and insulin resistance (132).

Biochemical control remains the strongest predictor of patient outcomes and specifically produces improvements in glucose metabolism, obstructive sleep apnea, cardiovascular disease, and bone mineral density and fracture risk (65). However, structural heart and joint changes are unlikely to resolve (65).

Acromegaly should be treated as early as possible to prevent development of irreversible adverse outcomes and then relieve selected comorbidities (eg, hypertension and type-2 diabetes) (14).

Biological basis

Etiology and pathogenesis

Growth hormone is a 191-amino acid polypeptide, secreted in a pulsatile fashion by somatotroph cells of the anterior pituitary. Growth hormone-releasing hormone and somatostatin, both released by the hypothalamus, have opposing effects on release of growth hormone; growth hormone-releasing hormone induces the synthesis and secretion of growth hormone whereas somatostatin suppresses the secretion of growth hormone. Growth hormone release is also known to be influenced by age, nutritional state, and sleep. Insulin-like growth factor-1 (IGF-1) mediates most of the growth-promoting effects of growth hormone. The development and proliferation of somatotrophs are largely determined by a gene called the Prophet of Pit-1 (PROP1), which controls the embryonic development of cells of the Pit-1 (POU1F1) transcription factor lineage as well as gonadotroph hormone-secreting cells (126).

Acromegaly and gigantism are due to an overproduction of growth hormone (98%) most commonly by a benign pituitary adenoma (133). Growth hormone-cell adenoma make up 60%, whereas mixed growth hormone-cell and prolactin-cell adenoma constitute 25% and mammosomatotroph-cell adenoma 10%, with the rest comprised of the rare causes including plurihormonal adenoma, GGGH-cell carcinoma, multiple endocrine neoplasia, ectopic pituitary adenoma, and extra pituitary neuroendocrine tumors (125; 172). Acromegaly develops when somatotrophs (cells in the anterior pituitary gland that produce growth hormone) proliferate and over-secrete the hormone. When tumors arise in pituitary somatotroph cells, aberrant secretion of growth hormone leads to the distinctive features of acromegaly. Somatotroph adenomas make up some 20% of functioning pituitary adenomas. If the overproduction begins early, before epiphyseal closure, long bone growth accelerates, leading to linear growth of up to 1 foot per year with heights of 8 feet or above being recorded (gigantism). Increased growth hormone after puberty leads to widening of the bones, excess tissue growth at the ends of bones, and then arthritic changes (acromegaly).

Rarely, acromegaly is caused by ectopic secretion of either growth hormone or growth hormone-releasing hormone (GHRH) (151; 125; 15; 06; 21; 73; 142; 110; 140; 172). Ectopic growth hormone secreting tumors have been reported, for example, with a pituitary adenoma in the sphenoid sinus (142), an islet cell tumor (127), and non-Hodgkin lymphoma (15). A case has also been reported with secretion of both growth hormone and IGF-1 from a pulmonary neuroendocrine tumor (NET) (110). Ectopic GHRH-secreting tumors are usually extracranial (79%) (125; 21; 73; 172). Most patients with ectopic GHRH-induced acromegaly have hyperplastic pituitaries (140). Histopathological evaluation of 121 tumors showed that 98% were neuroendocrine tumors with only two exceptions (a pituitary diffuse large B-cell lymphoma and an adenoid cystic carcinoma of the lung) (172). Most extracranial GHRH-secreting tumors originate in the lung or pancreas (50% and 35%, respectively) (172); bronchial carcinoid is the most common histopathological diagnosis (151; 06; 172), but cases are also reported with a variety of malignant tumors, including pancreatic islet cell tumors (163). The most common GHRH-secreting tumor of the para-sellar region is mixed gangliocytoma-pituitary adenoma (78% of intracranial cases) (172). GHRH secretion rarely occurs with other tumors, including pheochromocytoma, lymphoma, paraganglioma, and thymoma (172).

The clinical picture of acromegaly is influenced by many factors, including the levels of growth hormone and insulin-like growth factor (IGF-I), age, tumor size, and the time to diagnosis (122).

Genetics of acromegaly and gigantism

Growth hormone-secreting pituitary tumors are the most genetically determined type of pituitary tumor (19). Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as in some currently unknown genes (ie, as indicated by familial cases with no mutations in known genes) (19).

A genetic basis can be identified in half of the cases of gigantism (19).

Hereditary growth-hormone-secreting pituitary adenoma can manifest as isolated tumors, familial isolated pituitary adenoma, including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG), or it can be a part of systemic diseases like multiple endocrine neoplasia types 1 or 4, McCune-Albright syndrome, Carney complex, and the so-called "3P association" of pituitary adenoma and pheochromocytoma/paraganglioma (83; 19).

The vast majority of symptomatic pituitary tumors occur sporadically and are not part of syndromic disorders (117). However, germline mutations in genes known to predispose individuals to familial pituitary adenomas can be found in a small percentage of patients with sporadic pituitary adenomas. Mutations in the AIP gene are the most frequently observed germline mutations, occurring in about 4% of patients with sporadic pituitary adenomas, but the prevalence can increase to 8% to 20% in young adults with macroadenomas or gigantism and also in affected children. Germline mutations in MEN1 (encoding menin) on the long arm of chromosome 11 (at the 11q13 locus) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas.

Fifteen to twenty percent of familial isolated pituitary adenomas occur in association with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; 50% to 80% of cases with AIP mutation exhibit a somatotropinoma. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family (135). Many somatotrophic tumors are monoclonal, arising from a single cell (87; 57). In up to half of the somatotroph adenomas associated with acromegaly, a mutation in the alpha-subunit of the stimulatory G protein is a consequence of the presence of an oncogene (160); this mutation results in increased stimulation of cyclic adenosine monophosphate, leading to somatotroph hyperplasia and elevated circulating growth hormone levels.

An extraordinary example of familial gigantism due to a mutation in AIP was that of Irish giant Charles Byrne (1761-1783), who was shown in 2011 to have a mutation in AIP (33). On its way to be buried at sea, Byrne's skeleton was snatched by agents of Scottish anatomist John Hunter (1728-1793), against Byrne's expressed wishes before death. Byrne's 2.31-meter (7 foot, 7 inch) skeleton was subsequently purchased in 1799 by the Hunterian Museum of the Royal College of Surgeons in London, where it has been displayed for over 2 centuries.

It remains an issue of contention and controversy today (121). American neurosurgeon Harvey Cushing opened Byrne's skull with Scottish anatomist and anthropologist Sir Arthur Keith (1866-1955) in 1909 at the Museum of the Royal College of Surgeons of England, at a time when Cushing was marshalling evidence for endocrine functions of the pituitary. Oddly, Keith misattributed the source of the skeleton to another Irish giant, Patrick Cotter O'Brien (1760-1806), also known as the Bristol Giant. In 1911, Keith presented drawings of Byrne's pituitary fossa and sella turcica and a lateral view of his skull (both misattributed to O'Brien) (103); these show remarkable enlargement of the pituitary fossa with erosion of the sella turcica.

X-linked acrogigantism is a form of early-onset growth hormone excess resulting from the germline or somatic duplication of the GPR101 gene on chromosome Xq26.3 (166; 47; 99). The GPR101 gene codes for a G protein-coupled receptor that is normally expressed in the central nervous system and at particularly high levels in the hypothalamus. During development before birth and again at adolescence, the GPR101 protein is predominantly expressed in the pituitary gland, where it is thought to be involved in the growth of cells in the pituitary gland, in the release of growth hormone from the gland, or both. Histopathology in X-linked acrogigantism shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia (93). Although affected females present with germline mutations, the sporadic male patients have been somatic mosaics. No differences in the clinical phenotype have been observed between patients with germline or somatic duplication.

Epidemiology

Pituitary tumors account for about 15% of primary intracranial neoplasms (96; 76).

Pituitary gigantism is very rare, particularly among children younger than 3 years of age (134).

Acromegaly is a rare clinical entity occurring equally among men and women, although a single-center experience may show gender differences (94). The estimated prevalence is 50 to 70 cases per million and the annual incidence is three to four cases per million population. In a meta-analysis of 22 studies, the pooled prevalence was 5.9 (95% CI: 4.4-7.9 per 100,000 persons), whereas the incidence rate was 0.38 cases per 100,000 person-years (95% CI: 0.32-0.44 per 100,000 person-years) (41).

Acromegaly carries an increased risk of malignancy, particularly colon and thyroid cancer. Prospective, controlled studies of colonoscopy screening indicate that the risk of colon cancer in patients with acromegaly is about twice that of the general population (144), which may reflect an effect of trophic insulin growth factor-1 (IGF-1) on the proliferation of epithelial cells (30). The prevalence of thyroid cancer is also strikingly elevated compared to the prevalence in the general population, affecting 5.6% versus 0.093%, respectively, in one study (164). Sustained exposure to high serum IGF-1 levels likely plays a role in the development of thyroid cancer in this disease, in combination with the autocrine/paracrine action of locally produced IGF-1.

Hypertension is more frequent than in the general population (162).

Carpal tunnel syndrome can be seen in 50% of patients (05). Compared with the general population, patients with acromegaly have a 6-fold higher incidence of carpal tunnel syndrome surgery before the diagnosis of acromegaly (169).

Increased soft-tissue swelling, nasal polyps, macroglossia, and pneumomegaly lead to obstructive sleep apnea in 50% to 80% of patients with acromegaly (79; 25; 32).

Achieving biochemical control is associated with improvements in treatment costs, quality of life, and mortality but not to the level of the general population (170).

Prevention

In 2006, germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were found to predispose to development of pituitary adenoma (168). The AIP gene helps regulate the proliferation and differentiation of cells and acts as a tumor suppressor. AIP mutations are rare in individuals with sporadic acromegaly but occur more commonly in individuals with pituitary gigantism, familial isolated pituitary adenomas, and macroadenomas diagnosed by age 30 years (46; 44; 148; 45); targeted genetic screening for AIP mutations is recommended in these latter three groups of patients with pituitary adenoma. AIP mutations are most prevalent in patients with pituitary gigantism (29%) but occur in 15% to 25% of cases of familial isolated pituitary adenoma. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, with resultant improved outcomes (148).

Acromegaly may occasionally be identified by screening members of families with multiple endocrine neoplasia type 1, which results from mutations in the MEN1 gene.

In addition, because acromegaly is a significant risk factor for the development of colon and thyroid cancers, acromegalic patients should have regular colonoscopy screening and monitoring of thyroid function and morphology.

Patients with acromegaly should also be screened for obstructive sleep apnea because of the extremely high incidence (50%-80%) in this group (79).

Differential diagnosis

Confusing conditions

Because of the typically insidious nature of the clinical syndrome, acromegaly is often underrecognized, with a long delay from disease onset to diagnosis.

Similar facial features or acral enlargement may be seen in severe hypothyroidism, pachydermoperiostosis, and some forms of leprosy.

Gigantism also occurs in androgen-deficient states, such as Klinefelter syndrome, and other genetic syndromes like Simpson-Golabi-Behmel syndrome, Sotos syndrome, Marfan syndrome, homocystinuria, and fragile X syndrome (109).

Sotos syndrome is a genetic disorder that presents with acromegalic features, mental retardation, advanced bone age, and typical oral features, including premature eruption of teeth; high, arched palate; pointed chin; and, rarely, prognathism (141).

The local effects of a somatotrophic pituitary adenoma are similar to those of other tumors in the region of the sella.

Associated or underlying disorders

Acromegaly occurs as a symptom of several syndromes, such as multiple endocrine neoplasia type 1 (MEN-1), McCune-Albright syndrome, and NAME syndrome (Carney complex type I) (102).

McCune-Albright syndrome results in hypersecretion of hormones in peripheral endocrine tissues (35). This can be expressed as precocious puberty, mainly in girls, primary hyperthyroidism, growth hormone or prolactin excess, hyperparathyroidism, and hypercortisolism. The incidence of growth hormone excess among patients with McCune-Albright syndrome has been assessed as up to 21%. The diagnosis often relies heavily on the physician recognizing the distinctive physical features of the disease.

Diagnostic workup

Unfortunately, the diagnosis of acromegaly is delayed in most patients, allowing development of irreversible disease-related complications (55). Once a patient with suggestive physical features has been identified, the diagnosis of acromegaly is relatively straightforward.

Laboratory studies

Measurement of insulin-like growth factor-1 (IGF-1) levels is the most important laboratory test in the diagnosis and monitoring of acromegaly, but basal and nadir growth hormone levels following oral glucose tolerance test (OGTT) are also useful (02; 12; 60). The IGF-1 level (a marker of growth hormone output) is positively correlated with the severity of the disease, only reaching a plateau when growth hormone levels reach 20 µg/L.

Random growth hormone levels are not recommended for screening because they may be raised in renal failure and diabetes and sometimes even in normal controls, especially if monitored around the time of sleep. In addition, measurements of growth hormone are confounded by heterogeneity in reference standards and technical differences among assays (161), altered hypothalamic activity associated with initiation of sleep, and the age and nutritional status of the patient (88).

The glucose-suppressed growth hormone level (60 to 120 min after 100 mg of oral glucose) is less than 2 µg/L in normal individuals but is always greater than 10 µg/L in acromegaly patients. However, occasionally disorders other than acromegaly can also be associated with failure of normal growth hormone suppression, including chronic renal insufficiency, liver failure, active hepatitis, hyperthyroidism, diabetes mellitus, anorexia nervosa, and other forms of malnutrition.

Awareness of limitations of current growth hormone and IGF-1 assays, as well as interpretation of growth hormone testing in conjunction with serum IGF-1 levels within the appropriate clinical context, will help to avoid potential pitfalls to the diagnostic assessment of acromegaly (70).

Preoperative evaluation of pituitary function in acromegalic patients should include the following (165):

Imaging

All individuals with biochemical or clinical evidence of acromegaly should have a contrast-enhanced MRI of the brain. Most acromegalic patients have readily visible pituitary adenomas as over 65% of growth hormone-secreting adenomas are either invasive or macroadenomas, although growth hormone secreting microadenomas also occur (128).

Diffuse pituitary enlargement without a discrete adenoma should raise suspicion of an ectopic source of growth hormone-releasing hormone or growth hormone in the lung, pancreas, or gastrointestinal tract.

MRI also is useful for surgical planning and assessing chiasmal compression, cavernous sinus invasion or compression, the extent of extrasellar growth, and the position of the carotid arteries (100).

In the absence of a pituitary tumor detected on MRI, an extra-pituitary source of growth hormone needs to be excluded (eg, ectopic production of GHRH with resultant growth hormone hypersecretion). Localization of neuroendocrine tumors (that ectopically secrete growth hormone) can be facilitated with In-111 DPTA octreotide scintigraphy (156).

Acromegaly with an empty sella on MRI is rare; this combination should raise consideration of prior pituitary apoplexy or an extra-pituitary source of growth hormone (49).

Other studies

For individuals older than 50 years of age, an electrocardiogram, echocardiograph, and colonoscopy are recommended as part of the initial workup (65).

Management

Acromegaly ultimately becomes a life-threatening condition that requires aggressive treatment. The goals of treatment are to return the levels of circulating growth hormone and insulin-like growth factor-1 (IGF-1) to normal, and to reduce the size of a compressive pituitary tumor while attempting to preserve pituitary function and relieve the signs and symptoms. Growth hormone levels of less than 2 µg/L with normal IGF-1 levels are reasonable criteria for an endocrine "cure." Normalization of both growth hormone and IGF-1 levels can normalize life expectancy in patients with acromegaly but does not relieve all symptoms (78).

Therapeutic modalities for the treatment of pituitary gigantism are the same as those for acromegaly (75).

Surgery

Surgical excision of the adenoma (usually by means of a transsphenoidal approach), leaving the normal pituitary as intact as possible, is potentially curative and is the first line of therapy (113; 128; 40; 76; 80; 42; 60). There is a rapid therapeutic response following surgery: growth hormone levels may drop within hours and a reversal of soft tissue abnormalities begins soon thereafter.

Preoperative hormone replacement should include the following (165):

The most important predictors of the likelihood of achieving surgical remission are invasiveness of surrounding structures (particularly the cavernous sinus), tumor size, and preoperative growth hormone levels (81; 01; 80; 38). Smaller, less invasive tumors and tumors with lower preoperative levels of growth hormone and IGF1, have better remission rates (81; 01; 38). Metabolic complications (eg, impaired blood sugar control) and facial features (eg, nose width) also improve (39; 58).

Signal intensity on T2-weighted MRI has been proposed as another prognostic factor (03). In a surgical series of 124 patients, total resection was achieved in 69% of the T2-hyperintense group, 77% of the T2-hypointense group, and 69% of the T2- isointense group. The surgical remission rates for the T2-hyper-, hypo-, and isointense groups were 55%, 81%, and 69%, respectively.

Growth hormone nadir lower than 1 μg/L after oral glucose tolerance test was defined by a Consensus Group in 2000 as a marker of postsurgical remission and later revised in 2020 to 0.4 μg/L based on use of ultrasensitive growth hormone assays (80).

IGF-I levels measured 6 weeks postoperatively can be also used to assess remission, although patients with mildly elevated IGF-I levels may not normalize until 3 to 6 months postoperatively (79; 65). Endocrine remission is seen in 65% to 90% of microadenomas but in less than 50% of macroadenomas greater than 1 cm in diameter following excision (81). Other studies have reported postoperative remission rates from 30% to 85% (150). In specialized referral centers, remission can be achieved in 80% to 90% of microadenomas and about 50% to 75% of macroadenomas (80). Preoperative treatment of macroadenomas with a somatostatin analogue may improve postoperative remission rates (11).

In one study, outcomes of endoscopic endonasal transsphenoidal surgery for pituitary tumor removal were at least equivalent to that of the standard traditional transnasal transsphenoidal approach, with an excellent postoperative course (26). Postsurgical hospital stay was significantly shorter after endoscopy as compared to the transnasal transsphenoidal approach (26).

Postoperative endocrine evaluation should include the following (165):

Medical management

In a cross-sectional study, medical treatment achieved a quality of life comparable to surgery, and it may also be associated with better quality of life in physical subdomains (07). Primary medical therapy is a reasonable option, especially for elderly patients with acromegaly (31).

The mainstays of medical therapy have been treatment with dopamine agonists and somatostatin analogues.

Dopamine agonists (eg, bromocriptine, capergoline) bind to D2 receptors and suppress growth hormone hypersecretion but their clinical effectiveness is modest (54; 80). Cabergoline, a relatively long-acting dopamine agonist, has the advantages of limited cost and an oral route of administration compared to somatostatin receptor ligands (80). Cabergoline therapy is effective in normalizing IGF-I levels, even in patients with normoprolactinemic acromegaly, when IGF-I levels are mildly or moderately elevated during somatostatin receptor ligand therapy (85).

There are currently four medical therapies approved by the U.S. Food and Drug Administration (FDA) for patients with acromegaly: octreotide (Sandostatin LAR) and pasireotide (Signifor), lanreotide (Somatuline Depot injection), and pegvisomant (Somavert).

Octreotide, a somatostatin analogue, effectively lowers growth hormone levels in up to 50% of patients with acromegaly and causes modest tumor regression, but the injectable form of the drug must be given several times a day by subcutaneous injection and there is a significant risk of cholelithiasis (128). A more effective and practical approach is the use of a longer-acting preparation of octreotide or lanreotide, which is administered as depot intramuscular injections. Overall, the octreotide long-acting release formulation (octreotide-LAR) is well tolerated and is an effective agent in alleviating symptoms, suppressing growth hormone, normalizing IGF-1, and inducing tumor shrinkage in many patients with acromegaly. It is recommended for patients who are not cured by surgery, and it should also be considered as primary therapy for selected unoperated cases with a low probability of surgical cure (97).

Oral octreotide capsules that combine octreotide with a transient permeability enhancer technology were approved by the U.S. Food and Drug administration in 2020 and are the first and only oral somatostatin receptor ligands approved in the United States for acromegaly. Oral octreotide capsules are a treatment option for patients with acromegaly who previously responded to injectable somatostatin receptor ligands (149; 171). In four clinical trials involving 238 patients with acromegaly, oral octreotide capsules produced effective suppression of serum growth hormone and insulin-like growth factor 1 (IGF-1) levels, maintained disease control and biochemical response, and had a safety profile comparable to injectable somatostatin receptor ligands.

Pasireotide long-acting release is a multi-somatostatin receptor-ligand that is now also approved for acromegaly and appears to be more effective than octreotide in both treatment-naive patients and those already on octreotide (37; 72). This agent has a higher affinity for the receptor than first-generation drugs such as somatostatin. About half of the patients who are refractory to a first-generation somatostatin analogue experience normalization of IGF-1 levels on the drug, although many patients experience a decline in their glucose control (157; 02). Pasireotide may be an effective monotherapy option in patients who were controlled on both a long-acting somatostatin analogue and pegvisomant previously (130).

Lanreotide is a long-acting analogue of somatostatin. Lanreotide is available in two formulations: a sustained-release formulation (trade name Somatuline LA), which is injected intramuscularly every 10 or 14 days, and an extended-release formulation (trade name Somatuline Autogel in the UK, or Somatuline Depot in the US), which is administered subcutaneously once a month. Extended-dosing intervals (greater 4 weeks) for 120 mg lanreotide may be effective among selected patients previously controlled with long-acting somatostatin receptor ligands (SRLs) (65). The main side effects are injection site pain and gastrointestinal disturbances (eg, diarrhea, nausea, and vomiting). Primary treatment with lanreotide 120 mg provides early significant tumor shrinkage with rapid improvement of visual symptoms at the end of the first month in approximately half of patients (13). Lanreotide use over long periods of time has been associated with development of gallstones. Older age, female sex, lower IGF-I levels, and tumor T2 hypointensity on MRI at baseline predict more favorable long-term biochemical responses to primary lanreotide therapy (65).

Pegvisomant blocks growth hormone action at peripheral receptors, normalizes IGF-1 levels in most patients, reduces signs and symptoms, and corrects metabolic defects (36; 80; 66). It has relatively few serious adverse effects and is the most effective drug treatment for acromegaly in normalizing IGF-1 and producing a clinical response (66). Abnormal liver function can occur early, and consequently liver function studies should be monitored (80; 66). Pegvisomant is the most likely agent to achieve maximal improvement in glucose tolerance and insulin sensitivity; it is, therefore, the preferred medical therapy for patients with preexisting hyperglycemia or diabetes mellitus who do not respond to octreotide LAR/lanreotide (80; 65). It is also the preferred agent in patients resistant to or intolerant of somatostatin analogs: in patients resistant to somatostatin analogues, beginning pegvisomant early facilitates improvement in glucose control (138). It is effective in controlling acromegaly in 60% to 90% of patients (78). Because higher rates of control may be achieved as the dose is escalated, pegvisomant treatment should be started at a low dose and gradually increased as tolerated until control is achieved (80). Patients with diabetes mellitus and those who are obese require higher doses of pegvisomant and more rapid up-titration to achieve IGF-I normalization (65). Over a period of 10 years, the drug was well-tolerated and produced normalization of IGF-1 levels in 73% of subjects (23).

Combination therapy with a somatostatin receptor ligand plus pegvisomant is recommended for patients with acromegaly who do not reach hormonal targets after a maximizing dose on monotherapy (65). In patients who do not reach hormonal targets with first-generation depot somatostatin analogs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with somatostatin analogs) should be offered (40). A regimen incorporating low-dose somatostatin receptor ligand therapy plus weekly pegvisomant is a novel dosing option for achieving cost-effective biochemical control in patients with uncontrolled acromegaly requiring combination therapy (20).

In general, medical treatment can produce a rapid clinical and endocrine response but causes only minimal tumor shrinkage and growth hormone levels immediately rise again after stopping the drug (10). Medical treatment alone is seldom sufficient to achieve an adequate response and is most often useful as an adjunct to other treatment modalities.

Primary medical treatment should be offered to patients who are either not surgical candidates because of comorbidities or complications of their illness, or who refuse surgery (40).

All treated patients with acromegaly require radiographic and endocrine monitoring for recurrence.

Given the frequency of bony abnormalities and particularly of fractures, as well as the frequency of associated hypogonadism, imaging studies to assess bone morphometry are suggested in all patients at diagnosis, regardless of disease status (79a). Note, though, that bone mineral density is not a good reflection of bone quality in patients with acromegaly and may be normal as assessed on standard dual energy x-ray absorptiometry studies (79a).

Because of the risk of colon and thyroid cancers, acromegalic patients should have regular colonoscopy screening and monitoring of thyroid function and morphology (as determined by physical examination). Some authors have suggested that patients with acromegaly undergo screening colonoscopy at diagnosis, although there are no conclusive data linking screening frequency to colon cancer mortality rates in patients with this disease (79a). Current evidence does not support routine screening for thyroid cancer at acromegaly diagnosis, although thyroid ultrasound and consideration of fine-needle aspiration are recommended in those with palpable thyroid nodules and other risk factors for thyroid cancer (79a).

Radiotherapy

Radiotherapy is a third-line option for management of acromegaly but nevertheless continues to have a role in the management of these patients (80).

Radiation therapy may be used to augment partial surgical resection or as a moderately effective primary mode of treatment in those patients who cannot be managed surgically or who have failed medical therapy (40). The full benefit of radiation therapy may develop slowly over a period of years, and medical treatment is required in the intervening period. Postradiation hypopituitarism is common, and most patients require lifelong hormonal replacement therapy.

Stereotactic Gamma knife radiosurgery is replacing conventional external-beam radiotherapy administered over a period of several weeks (29). Gamma knife delivers a single radiation fraction to a small tumor target, minimizing radiation scatter and vulnerability of adjacent structures, including optic tracts (29). Gamma knife radiosurgery is most commonly applied as an adjuvant treatment; in this regard, Gamma knife radiosurgery is generally safe and effective in controlling growth hormone and IGF-1 levels, increasing remission rates, improving endocrine control, and reducing tumor diameter in persistent active acromegaly patients after surgery (167). The lowest complication rates of Gamma knife radiosurgery are associated with accurate MRI-based treatment planning and single stereotactic radiosurgery treatment, whereas more than one radiation treatment (stereotactic radiosurgery or fractionated radiotherapy) is associated with increased visual complications (158).

Approximately half of the patients treated with stereotactic Gamma knife radiosurgery or fractionated radiotherapy achieve and maintain biochemical control (65). However, up to one third of such patients with otherwise normal pituitary function ultimately develop hypopituitarism, confirming the need for ongoing monitoring (65).

Special considerations

Pregnancy

Pregnancy in women with acromegaly is frequently associated with disease control with fetal and maternal outcomes comparable to women without acromegaly. A retrospective study found that active acromegaly did not have an evident adverse bearing on pregnancy outcomes (48). A systematic review and meta-analysis of 19 studies encompassing a total of 273 pregnancies in 211 women with acromegaly found that the overall frequency of acromegaly control of during pregnancy was 62%, and of tumor growth was 9% (09). There were no fetal or maternal deaths. The overall frequency of worsening of previous diabetes or development of gestational diabetes was 9%, and of previous hypertension or preeclampsia/eclampsia was 6%. Among adverse pregnancy outcomes, the overall frequencies were as follows: premature labor 9%, spontaneous miscarriage 4%, small for gestational age 5%, and congenital malformations 1%.

Anesthesia

Special care should be taken with intubation in patients with acromegaly due to the abnormal anatomy of the air passages in response to growth hormone. In addition, positioning of the neck during surgery should take into account the high incidence of cervical arthritis.