Acromegaly is a very insidious disease where changes occur over many years. Consequently, studies have reported that the diagnosis is often delayed for about nine years on average. Patients may seek care for dental problems, cardiac or rheumatological issues before being referred to endocrinology.

GH secreting pituitary adenomas are often big (> 1 cm) and can have compressive symptoms in the form of visual field deficits, ophthalmoplegia, and headaches which are out of proportion to the size of the tumor. Co-existent hyperprolactinemia can result in galactorrhea and symptoms of hypogonadism (irregular periods in females and decreased libido in males).

Acromegaly Characteristics

Increased size of extremities: Enlargement of the hands and feet is noted secondary to both bony expansion and soft tissue swelling. Patients often appreciate an increase in ring and shoe size. The extremities have a "dough" like consistency due to the soft tissue swelling. There is a decrease in the shoe size and ring size with the treatment of acromegaly due to the resolution of soft tissue swelling; the bony changes, however, are permanent.

Hyperhidrosis and skin tags are present in about 98% of cases of acromegaly; these features are a sensitive sign for the detection of acromegaly. Skin tags are due to the epithelial cell hyperproliferation induced by GH.

Acromegalic facies: Prominent supraorbital ridge, broad nose, acne, large lips, overbite, prognathism, tongue enlargement, and coarsening of facial features form the characteristic acromegalic facies. These changes, however, are very subtle and often go unrecognized by family members. A comparison of present and old photographs may show gradual changes and is an essential part of the assessment of acromegaly.

Musculoskeletal: Generalized weakness and lethargy are common symptoms. Elongation of the jaw can lead to teeth malocclusion, temporomandibular joint pain, and also a characteristic interdental separation. Carpal tunnel syndrome is seen about 60% of patients and is secondary to swelling of the median nerve rather than extrinsic compression. Early-onset osteoarthritis due to incongruent articular surfaces in the hips, knees, and spine may be seen. Kyphoscoliosis has also been reported in association with acromegaly.

Deep voice and obstructive sleep apnea can occur secondary to soft tissue swelling of the upper airway and large tongue.[7][8][9]

Gigantism

Gigantism is very rare and should be suspected when the patient's height is 3 standard deviations above normal mean height or 2 standard deviations above the adjusted mean parental height. Since gigantism is associated with various syndromes like neurofibromatosis, Carney complex and McCune Albright syndrome evaluation for neurofibromas, cafe au lait spots, optic gliomas, and skin lentigines should be done.[10]

Biochemical diagnosis: Measurement of IGF-1 level is the initial test for the diagnosis of acromegaly as it is a stable molecule with a half-life of 15 hours. It should be measured in cases where there is clinical suspicion of acromegaly and pituitary masses – normal IGF-1 rules out acromegaly. False-positive IGF-1 levels can be seen in pregnancy and adolescence, and false-negative levels may be seen with estrogen therapy. Furthermore, hepatic failure, renal failure, hypothyroidism, malnutrition, sepsis, and poorly controlled diabetes mellitus can also influence IGF-1 levels. All cases with elevated IGF-1 levels need to have an oral glucose tolerance test (OGTT) with GH measurement to confirm the diagnosis of acromegaly or gigantism. A GH level of 1 mcg/lt or less 2 hours after a 75 gms of oral glucose tolerance test rules out acromegaly. Plasma glucose needs to be measured before and after the administration of glucose to make sure hyperglycemia has been achieved.

Imaging: Pituitary Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis of acromegaly. The size, extent of the tumor, optic chiasmal compression, and cavernous sinus invasion can all be assessed on the MRI scan. Visual field testing is to be done in all cases where the tumor is in contact with the optic chiasma on the MRI scan.

Other tests: Prolactin levels need to be assessed especially in the presence of galactorrhea or symptoms of hypogonadism. Anterior pituitary hormonal assessment needs to be done based on the clinical picture. Rarely, in the presence of normal pituitary and biochemically confirmed acromegaly GHRH levels and imaging of the chest and abdomen need to be done to evaluate ectopic GH or GHRH secretion.[1]

The aims of treatment in acromegaly are:

1. Removal of the pituitary tumor to relive mass effects
2. Normalization of IGF-1 levels
3. Relief of acromegalic symptoms
4. Monitoring of acromegaly and associated comorbidities[4]

There are three main modalities available for the treatment of acromegaly each with its advantages and disadvantages, surgery, medical therapy, and radiation. The decision to use these modalities is made on a case by case basis.

Surgery

Surgical excision of the tumor is the preferred initial treatment unless the patient is deemed unfit for surgery. Surgery is also the preferred modality in recurrence as long as the tumor remains accessible. The transsphenoidal approach involves accessing the tumor by getting to the sphenoid sinus either through a nasal or sublabial approach and removing the sellar floor. Even tumors with suprasellar extension can be removed with this approach. Endoscopic transsphenoidal resection has better tumor clearance, decreased morbidity, and complications as compared to the microscopic approach. Post-surgical complications include diabetes insipidus and anterior pituitary deficiencies.[11][12]

IGF-1 and GH levels need to be measured 12 weeks after surgery. The goal is a normalization of IGF-1 and an undetectable GH level.

Medical Treatment

Various medical therapies are available for the management of acromegaly. They are used in the treatment of persistent disease after surgery.

• Dopamine agonists: Cabergoline is a D2 receptor agonist that can act on the D2 receptors in somatotrophs and decrease GH secretion. However, their efficacy is limited, with normalization of IGF-1 seen only in 34% of patients. Side effects of cabergoline include dizziness, nausea, vomiting, and postural hypotension.[13]
• Somatostatin receptor ligands (SRL): These mimic the action of somatostatin and inhibit the secretion of GH. Octreotide was the first SRL to be introduced, and it preferentially bound to human somatostatin receptor type 2. The dose was 100-200 mg by subcutaneous injection three times a day. Long-acting SRL has become available in the form of octreotide LAR and lanreotide. Both have similar efficacy in suppressing GH levels and normalizing IGF-1 levels. Octreotide LAR is given at a dose of 10 to 30 mg subcutaneously every four weeks while lanreotide is given at a dose of 120 mg subcutaneously every four weeks. Side effects of SRL include abdominal pain, nausea, flatulence, diarrhea, and hyperglycemia. The primary role of SRL is as an adjunct to radiation after surgery however in certain instances it may be used to decrease the size of the tumor or improve cardiovascular function preoperatively.[14][15] A second generation somatostatin analogue includes Pasireotide.
• GH receptor antagonists: GH binds to its receptor on two different sites and induced dimerization which activates the post-receptor signaling mechanisms. The novel GH receptor antagonist pegvisomant binds to the first binding site and prevents dimerization and post-receptor signaling. Van der Lely et al. followed 152 patients treated with pegvisomant for 18 months and found normalization of IGF-1 in 90% of patients. Pegvisomant is administered at a dose of 10 to 30 mg subcutaneously every day. Due to the high expense, its role is limited to patients who do not respond to SRL or have diabetes and worsening hyperglycemia with SRL.[16]

Radiation Therapy

Radiation is often used as an adjunct for the treatment of persistent disease after surgery; rarely it may be used as a first-line treatment in patients unfit for surgery. Two commonly used radiation therapy modalities are external irradiation and stereotactic single high dose irradiation.

• External irradiation: Using linear accelerators radiation is focussed on the pituitary fossa. CT or MRI are used for dosimetry to minimize radiation exposure to the surrounding tissues. The total radiation dose (around 4500 cGy) is divided into fractions (generally 25 fractions of 180 cGy) and given over 6 weeks, this fractionation helps minimize injury to surrounding tissues. About 60% of patients achieve normalization of IGF-1 with radiation in 10 years. Hypopituitarism is a known side effect of radiation and can occur years after cessation of radiation, therefore annual clinical and laboratory assessment for hypopituitarism should be done. With external irradiation, there is a resolution of even radiologically invisible disease.
• Stereotactic single high dose irradiation: Using a gamma knife or stereotactic multiple arc radiotherapy a high dose of radiation is delivered to a previously mapped area. Care should be taken to limit the exposure of radiation (< 8 cGy) to the optic chiasma. Since the radiation is delivered to a mapped area radiologically invisible disease will not be resolved. The rate of development of hypopituitarism is the same as that of external irradiation.[17][18]

Acromegaloidism: This is a condition where the patients have acromegaloid facial features or tall stature, however, laboratory assessment of GH and IGF-1 are normal. Imaging of pituitary in these cases is unremarkable.[19]

Soto's syndrome: This is a congenital overgrowth syndrome characterized by tall stature, acromegaloid facies, intellectual disabilities, macrocephaly, and advanced bone age.  Other clinical features include neonatal hypotonia, congenital heart defects, strabismus, scoliosis, and a predisposition to cancer. Soto syndrome is due to haploinsufficiency of NSD1 gene on chromosome 5. Laboratory assessment of IGF-1 and GH are normal. Genetic studies are needed to differentiate it from acromegaly.[20]

The prognosis depends on the stage at which the diagnosis is made as well as the response of hormone levels to treatment - surgical or non-surgical.

Cardiovascular Complications

• Hypertension is seen in about 40% of patients with acromegaly and is usually mild. Anti-hypertensive treatment is similar to non-acromegalic patients. Good control of blood pressure important irrespective of the modality used for acromegalic treatment.
• Cardiomyopathy is seen in most patients with acromegaly. Echocardiogram and electrocardiogram (ECG) should be done at baseline and repeated every year. Treatment of acromegaly improves cardiomyopathy; however, this depends on the age, duration of disease, and hypertension. In addition to echocardiogram and ECG, patients with gigantism will need Doppler of the peripheral arteries and veins.

Obstructive Sleep Apnea (OSA)

The prevalence of sleep apnea is 70% in patients with acromegaly. Prognathism, enlarged tongue, and soft tissue accumulation in the upper airways all predispose to having OSA. Clinical assessment (Epworth score) and if needed polysomnography should be done and baseline and repeated every year. Surgical correction of prognathism may help, and referral to the maxillofacial surgeon should be considered.

Arthropathy

Around 75% of patients with acromegaly are affected with arthropathy. Both small and large joints are affected. Bony expansion and soft tissue swelling can lead to nerve entrapment. Early diagnosis and aggressive treatment of acromegaly are essential to prevent arthropathy as these changes are irreversible.

Colon polyps

Colon length is increased in acromegaly, and so are the mucosal folds. There is an increased prevalence of colonic polyps with acromegaly; however, the risk of colon cancer may or may not be increased. Patients should get a colonoscopy at baseline and every 5 years.

Hypopituitarism can occur as a result of surgery or radiation. Annual assessment of pituitary hormones and replace hormones as needed.[21]

Patients should be educated on the importance of early diagnosis and adhering to the treatment. They should undergo regular endocrinology evaluation and check the blood pressure and blood sugar regularly.

• Acromegaly and gigantism are due to oversecretion of growth hormone. The most common cause is a GH secreting pituitary adenoma. Rarely, ectopic GH secretion or excess secretion of GHRH may be the cause.
• Gigantism is characterized by tall stature and should be suspected in children three standard deviations above the mean. Acromegaly is characterized by large hands and feet, coarse facial features, broad nose, acne, hyperhidrosis, underbite, and teeth separation.
• Laboratory assessment includes measurement of IGF-1, normal value rules out acromegaly.
• If IGF-1 is high, GH levels are assessed before and after OGTT to confirm the diagnosis.
• Surgery is the preferred initial modality of treatment. Residual or persistent can be treated medically or with radiotherapy.
• Medical treatment involves the use of the somatostatin analogs or GH receptor antagonists or dopamine receptor agonists.
• Radiotherapy involves either the use of external irradiation or stereotactic single high dose irradiation depending on the location and extent of residual disease.
• Mortality is increased in untreated acromegaly with cardiovascular disease being the major contributor.
• Besides control of GH management of acromegaly involves the management of acromegalic complications which include hypertension, cardiomyopathy, OSA, colonic polyps, hypopituitarism, and arthropathy.

The management of acromegaly and gigantism is with an interprofessional team that includes an endocrinologist, neurosurgeon, internist, cardiologist, rheumatologist, pulmonologist, and oncologist.  Untreated acromegaly has increased mortality as compared to the general population. The major contributors to mortality are cardiovascular disease (60%), respiratory disease (25%), and malignancies (15%). Mortality rates are similar to the general population in patients with controlled GH secretion. Besides, the level of GH presence of the cardiac disease is an important prognostic indicator. The presence of cardiac disease at diagnosis has a 100% mortality rate at 15 years. The mortality rate of patients with acromegaly and diabetes at 20 years is 80%.[22][23]