Acromegaly

DEFINITION, ETIOLOGY, PATHOGENESISTop

Acromegaly is a clinical syndrome resulting from excessive secretion of growth hormone (GH)/somatotropin, which leads to increased synthesis of insulin-like growth factor 1 (IGF-1) in the liver and peripheral tissues. This, in turn, stimulates cell division in target tissues and progressive growth of soft tissues, bones, and internal organs. If this occurs prior to epiphyseal closure in children or adolescents, it is termed gigantism. Excess GH also has negative effects on protein, fat, and carbohydrate metabolism. The worldwide incidence is ~3 to 4 million per year; the prevalence, 38 to 69 cases per million people; and mean age of diagnosis, 40 to 45 years.

Causes of acromegaly:

1) GH-secreting pituitary adenoma is the most common cause, present in >95% of cases. Most pure GH-secreting adenomas are macroadenomas (>1 cm in size) at the time of diagnosis. Some are caused by a tumor secreting both GH and prolactin (mixed GH and prolactin cell adenomas).

2) Familial syndromes: These could include GH-secreting pituitary adenomas as part of multiple endocrine neoplasia type 1 (MEN 1) syndrome (associated with primary hyperparathyroidism and pancreatic neuroendocrine neoplasms). Acromegaly can also be seen in McCune–Albright syndrome, Carney complex, familial acromegaly, or familial isolated pituitary adenoma (FIPA) with an aryl hydrocarbon receptor–interacting protein (AIP) mutation.

Causes such as growth hormone–releasing hormone (GHRH) excess from hypothalamic lesions or peripheral ectopic sources (neuroendocrine tumors [NETs]) are extremely rare. GH-secreting pituitary carcinomas and ectopic GH-releasing tumors are even more rare. Iatrogenic GH administration may also cause acromegaly.

CLINICAL FEATURES AND NATURAL HISTORYTop

The onset of symptoms is insidious, and progression is usually slow over many years. An average interval from symptom onset to diagnosis is 5 to 12 years. Symptoms usually include both direct effects of the pituitary tumor growth and distant clinical manifestations of GH and IGF-1. Of note, diseases of the cardiovascular and respiratory systems, complications related to diabetes and hypertension, and likely neoplastic diseases account for much of the morbidity and mortality.

1. Direct effects of pituitary tumor: Compressive symptoms including headaches and visual field defects from optic chiasm compression (classically bitemporal hemianopsia) and less commonly diplopia are present at the time of diagnosis. In 3% to 8% of cases, they can be the initial presenting symptoms.

2. Hypopituitarism: The adenoma can cause decreased secretion of other pituitary hormones through its size or expansion. The most often affected hormones are gonadotrophs causing lethargy, weakness, infertility, loss of libido, erectile dysfunction, oligomenorrhea, or amenorrhea; however, all anterior pituitary hormones can be affected. Additionally, it is important to ask the patient about hyperprolactinemia symptoms from cosecretion, including galactorrhea, gynecomastia, infertility, or menstrual irregularities.

3. Soft tissue and skin manifestations: Hyperhidrosis, macrognathia, frontal bossing, enlarged swollen hands and feet (resulting in an increase in ring or shoe size), splayed teeth with an enlarged jaw and macroglossia, skin thickening, skin tags, coarse facial features.

4. Bone and joint manifestations: Hypertrophic arthropathy or osteoarthritis with joint pain that can be debilitating and often irreversible, back pain and kyphosis, osteoporosis from hypogonadism.

5. Cardiovascular manifestations: Hypertension, left ventricular hypertrophy, cardiomyopathy (hypertrophic cardiomyopathy), heart failure, valvulopathy, arrhythmias, and accelerated atherosclerosis. Cardiovascular disease significantly increases morbidity and mortality in patients with acromegaly and structural changes are often irreversible.

6. Respiratory manifestations: Sleep apnea in up to 90% of patients as a result of enlargement of soft tissues in the pharynx and nasopharynx; upper airway obstruction.

7. Metabolic or hormonal manifestations: Impaired glucose tolerance or diabetes, hyperlipidemia, hypercalciuria, hyperphosphatemia, simple or nodular goiter, galactorrhea, symptoms of coexisting hyperparathyroidism or pancreatic tumor (MEN 1 syndrome).

8. Gastrointestinal manifestations: Constipation (due to elongation and widening of the large intestine), colonic polyps, and diverticula of the large intestine.

9. Neuropathy: Paresthesias, polyneuropathy, including carpal tunnel syndrome.

10. Malignancy risk: Increased risk of colon polyps. There may be an increased risk of colon, thyroid, breast, and prostate cancer, although this is controversial.

11. Nonspecific symptoms: Impaired cognitive function, anxiety, low mood and quality of life, fatigue or weakness.

12. Organomegaly: Enlargement of the heart, liver, spleen, thyroid, kidneys, or colon.

DIAGNOSISTop

1. Indications for screening with IGF-1 measurement:

1) Typical clinical manifestations of acromegaly, particularly acral and facial features.

2) Atypical clinical manifestations accompanied by a constellation of comorbidities including obstructive sleep apnea (OSA), type 2 diabetes, debilitating arthritis, carpal tunnel syndrome, hypertension, and hyperhidrosis.

3) A large sellar/pituitary mass.

2. Laboratory tests:

1) IGF-1 concentration measurement is the best single screening test for acromegaly. IGF-1 levels are elevated in virtually all individuals with acromegaly, and a normal IGF-1 level provides very strong evidence that the patient does not have acromegaly. The presence of typical clinical features and an unequivocally elevated IGF-1 level confirms diagnosis, but if the level is equivocal, then an oral glucose tolerance test (OGTT) should be done (described below). Keep in mind that there are certain conditions that can affect IGF-1 and GH levels. IGF-1 levels can be decreased at advanced age or due to oral estrogen administration, malnutrition, or systemic disease, hypothyroidism, poorly controlled diabetes, liver disease, kidney disease, and obesity. Increased IGF-1 levels are observed in pregnant women, during puberty, and in those with hyperthyroidism or hypogonadism. A GH decrease is seen in the elderly and in those with obesity, while increased GH levels can be found in patients receiving oral estrogen, with poorly controlled diabetes, liver disease, kidney disease, malnutrition, or systemic disease.

2) 75-g 2-hour OGTT: No inhibition of GH secretion after 2 hours in the 75-g OGTT to a concentration below the reference value (0.4-1.0 microg/L, depending on the assay used) is in keeping with the diagnosis of acromegaly.

3) GH concentration measurement: Basal GH concentration may be normal, as it is pulsatile and tends to fluctuate considerably. Normal GH levels neither exclude nor confirm acromegaly.

4) Other: The prolactin level should be measured to assess for cosecretion. The pituitary panel should also be performed to assess for hypopituitarism if macroadenoma has been detected or there is a clinical suspicion of it (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol/testosterone, thyroid-stimulating hormone [TSH], and free thyroxine [FT4], 8 am cortisol/adrenocorticotropic hormone [ACTH]). The metabolic panel (glycated hemoglobin [HbA1c], lipids) should be done and calcium concentration measured if MEN 1 is suspected. If there is a suspicion of ectopic GHRH NETs (very rare), the GHRH level should be measured.

2. Imaging: If biochemical diagnosis is established, proceed with the sellar magnetic resonance imaging (MRI) protocol to look for a pituitary adenoma. If an ectopic GHRH NET is suspected, computed tomography (CT) and Ga68 Dotatate positron emission tomography (PET) scans of the chest and abdomen may be considered.

3. Ophthalmologic examination: Formal visual field testing should be done (by referral to a neuro-ophthalmologist) to assess for visual field defects, especially if there is any suprasellar extension of a mass near or abutting the optic chiasm.

4. Other: Electrocardiography (ECG), sleep study, thyroid ultrasonography, colonoscopy, joint radiographic examination, bone mineral density (BMD) test, and echocardiography can be ordered as clinically indicated.

5. Genetic testing: Consider genetic testing in those who are young (<20-30 years), have a family history of the disease, or present with syndromes (eg, MEN 1).

TREATMENTTop

Treatment Goals

Goals of therapy are to improve symptoms and reverse or control metabolic comorbidities, lower IGF-1 and GH concentrations to a range considered normal according to the patient’s age and sex, restore and preserve pituitary function, and control adenoma size and mass effects, thus leading to improved survival and reduction in comorbidities. This often requires multidisciplinary approach engaging a wide range of specialties (eg, endocrinology, neurosurgery, cardiology, orthopedics, rheumatology, radiation oncology). It is also important to note that associated comorbidities (eg, type 2 diabetes, hypertension, OSA) should be managed appropriately and not overlooked.

Surgery

Surgery is a first-line therapy for pituitary acromegaly in most cases. There is a 60% to 80% chance of remission with surgery alone and it also allows for surgical debulking to relieve the mass effect. This is typically done by transsphenoidal pituitary resection. The probability of success is higher in centers with a high volume of procedures, in less invasive tumors, and in microadenomas. The success of surgery is assessed with IGF-1 and GH levels and/or a 75-g OGTT GH response at 12 weeks after the surgery (the closer to normal, the higher the probability of remission), as well as MRI 12 weeks after surgery. Postoperatively, the patient needs to be monitored for hypopituitarism, diabetes insipidus, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). For patients with residual disease or recurrence, further treatment with repeat surgery, medical therapy, or radiation may be needed.

Pharmacologic Treatment

Given the success of surgery, primary medical therapy is uncommonly used as a primary mode of treatment, unless surgery is contraindicated, the macroadenoma is unlikely to be meaningfully debulked without chiasmal compression, there is extensive cavernous sinus invasion, or the patient prefers pharmacotherapy. Medical therapy can also be used preoperatively in cases of significant delay in the timing of surgery, very large/invasive tumors, significant morbidity (CHF, severe OSA), or severe pharyngeal thickness. More commonly, pharmacotherapy is used postoperatively in patients who did not achieve biochemical control after surgery. At times combination medical therapy may be indicated.

1. Somatostatin analogues (SSAs) are used in moderate to severe disease, especially to lower IGF-1 levels by inhibiting GH secretion and reducing tumor size. Long-acting octreotide (Sandostatin LAR 10-40 mg, IM injection once a month) or lanreotide (Somatuline 60-120 mg, deep SC injection every 4-6 weeks) are the most commonly used first-generation SSAs. Pasireotide is a second-generation SSA. It is more effective than first-generation SSAs and can be used in patients inadequately controlled on other therapies. IGF-1 and GH levels are monitored for response every 3 to 6 months. Adverse effects to monitor with SSAs include hypoglycemia, hyperglycemia, cholestasis, sinus bradycardia, injection site reactions, and gastrointestinal adverse effects. With pasireotide, also monitor the QT interval on ECG.

2. GH receptor antagonists are very effective in moderate to severe disease when it comes to lowering IGF-1 levels by blocking GH receptors, provided that the tumor is not in close proximity to the chiasm or other vital structures (as they do not reduce tumor size). Daily subcutaneous injections of pegvisomant 10 to 40 mg are usually used in our setting. They are particularly helpful in patients at risk of or having diabetes, hyperintense areas on T2-weighted MRI, sparsely granulated histology, or in those inadequately controlled on other therapies. IGF-1 (not GH) levels are monitored every 3 to 6 months for response. The use of GH receptor antagonists requires serial liver function tests and periodic MRI due to a theoretical risk of increased tumor growth (not observed in most studies).

3. Dopamine agonists: Oral cabergoline can also be used in mild disease (IGF-1 level <2 x upper limit of normal [ULN]) since it is less effective than other medical therapies at doses of 1 to 4 mg/wk (biweekly to daily). Adverse effects include nausea, vomiting, and orthostasis.

Radiotherapy

Conventional or stereotactic radiotherapy is a complementary effective third-line treatment in cases of ineffective surgical treatment, pharmacologic treatment, or both. The normalization or reduction of IGF-1/GH concentration and tumor growth stabilization occur 6 months to 5 years after therapy (10-15 years for full effect); until then, treatment with medical therapy is necessary while awaiting the effects of radiation. Adverse effects include hypopituitarism, secondary cancers, radiation necrosis, vision damage, and infertility.

Monitoring (for Disease, Comorbidities, and Complications)

Patients should undergo frequent clinical reassessments and monitoring for recurrence as well as complications and associated conditions:

1) Clinical reassessment every 3 to 12 months.

2) Biochemical follow-up with IGF-1 and GH measurement every 3 to 12 months.

3) Clinical cardiovascular and metabolic reassessment every 3 to 12 months with HbA1c measurement, lipid profile, and echocardiography/cardiac testing and sleep study, as needed.

4) MRI every 3 to 12 months, as needed.

5) Formal visual field testing if any abutment of the optic chiasm is seen on MRI or if visual field changes have been noted by the patient.

6) Colonoscopy should be performed at the time of diagnosis. If polyps are detected, repeat colonoscopy every 5 years and, if the results are normal, then every 10 years.

If any palpable thyroid nodules are found on examination, perform thyroid ultrasonography.

PROGNOSISTop

The outcomes of acromegaly treatment depend on the size and location of the pituitary tumor (treatment effectiveness ranges from 80% for microadenomas to <50% for tumors >1 cm in diameter). Effective treatment, that is, maintaining GH levels <0.4 to 1.0 microg/L and IGF-1 levels within the normal range for sex and age, reduces mortality to the level observed in the general population and also reduces morbidity. In patients with untreated acromegaly, morbidity and mortality due to cardiovascular and/or respiratory system diseases, complications related to diabetes and hypertension, and possibly neoplastic diseases are 2 to 4 times higher than in the general population.