Clinical manifestations

Presentation and course

The clinical features of acromegaly develop insidiously, with most patients able to date symptoms back 15 years or longer (159). 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 (97).

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 (19).

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. Clinical signs and symptoms with the highest weighted mean prevalence at diagnosis include acral enlargement (90%), facial features (65%), oral changes (62%), headache (59%), fatigue/tiredness (53%; including daytime sleepiness: 48%), hyperhidrosis (47%), snoring (46%), skin changes (including oily skin [37%] and thicker skin [35%]), weight gain (36%), and arthralgia (34%) (176); the clinical signs and symptoms vary across studies by year of publication, reflecting changes in recognition, management, and probably variations in reporting.

Acromegalic individuals may present for orthodontic surgery because of mandibular prognathism (91).

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 (172).

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 (30).

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 (88; 86).

Growth hormone has a marked effect on the development of orofacial structures, including eruption and shedding patterns of teeth (09).

Hypertension (67%) and diabetes mellitus (24%) are common and a majority display insulin resistance (116). Secondary diabetes mellitus is encountered in from 23% to 55% of cases (116; 144). The presence of secondary diabetes is associated with increased cardiovascular morbidity, increased malignancy rate, and overall mortality (144). The pathophysiologic mechanism of secondary diabetes in acromegalics is increased insulin resistance due to excessive lipolysis, altered fat distribution, and dysfunctional adipose tissue (144). 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 (31). 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 (106). 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 (31). 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 (79); 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 (169). A proximal myopathy has also been described but is rare (117). 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 (177).

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.

Neuropathic foot ulcers in acromegalic gigantism are a common and significant problem, frequently impairing the daily activities of these individuals (61).

Neuropathies in these patients (with or without impaired fasting glucose or diabetes) can lead to hypoesthesia and hypoalgesia of the lower legs and feet, as well as neuropathic foot. Potential contributing factors include leg and foot deformities, muscle weakness, and poor-quality footwear.

Clinical vignette

Case 1. Acromegaly (85; 82). 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 (82). 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 (41; 31; 88). The overall standardized mortality ratio of patients with acromegaly is 1.48 (101; 113). 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 (88). 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 (119).

Psychological disturbances and poor quality of life are major consequences of acromegaly and the stigma associated with the disease (88; 126; 120; 130). 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 (120). Acromegalic patients exhibit critically high levels of perceived stigma, leading to psychological distress and disruptions in daily life (130). Among 171 adult acromegalic patients recruited in a cross-sectional Italian multicentric study, a very high proportion (up to 28%) were depressed (27).

Acromegaly is associated with significant medical morbidities (41; 118; 163; 75; 176). 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 (152; 151; 155; 70; 118; 124; 75; 176). Biochemical control of acromegaly reduces progression of left ventricular hypertrophy and improves other markers of structural cardiac dysfunction, including left ventricular ejection fraction (88).

Comorbidities more often present at diagnosis of acromegaly than in age- and sex matched controls and include hypertension, left ventricle hypertrophy, dia/systolic dysfunction, cardiac arrhythmias, (pre)diabetes, dyslipidemia, intestinal polyps, and malignancy (176); comorbidities vary across studies by year of publication, reflecting changes in recognition, management, and probably variations in reporting, although it is noteworthy that cardiovascular comorbidity was lower in more recent studies.

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 (88). 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 (69).

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 (88); 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 (88; 28; 35; 97).

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 (88). Patients with acromegaly are at increased risk of vertebral fractures, primarily because of deterioration in bone microarchitecture (124; 76; 161). Diagnostic delay in acromegaly has a significant adverse impact on vertebral fracture risk (38).

Neurologic complications can include headache, bitemporal hemianopsia, olfactory dysfunction (60), pituitary apoplexy (197), peripheral neuropathy, carpal tunnel or cubital tunnel syndrome (169; 191), and development of intracranial meningiomas (67). Most, but not all, patients with acromegaly-associated carpal tunnel syndrome show symptomatic improvement with acromegaly control (88). Rarely, pituitary apoplexy produces "autohypophysectomy" with a spontaneous resolution of acromegaly (77; 123; 04). Other rare complications include myelopathy due to ossification of posterior longitudinal ligament with resulting paraplegia (110).

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 (147).

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 (73). However, structural heart and joint changes are unlikely to resolve (73).

A metaanalysis of 19 studies showed that acromegalic patients have a modestly increased chance of cancer as compared to the general population (194). The overall incidence of cancer, as well as that of thyroid, gastrointestinal (gastric, small intestine, colorectal, anal, and pancreatic), brain/CNS, urinary, hematological, and connective tissue cancers was higher among patients with acromegaly than among the general population. No association between acromegaly and hepatobiliary, respiratory, reproductive, skin, breast, or prostate cancer was observed.

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) (15).

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 (139).

Acromegaly and gigantism are due to an overproduction of growth hormone (98%) most commonly by a benign pituitary adenoma (148). 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 (138; 196). 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) (168; 138; 16; 06;