Acromegaly

Etiology

The causes of acromegaly can be divided into primary GH excess, ectopic or iatrogenic GH excess, and excess growth hormone-releasing hormone (GHRH).

Acromegaly is most commonly caused by a somatotroph GH-secreting adenoma of the anterior pituitary gland. The most commonly associated mutation involves activating the alpha subunit of the guanine nucleotide stimulatory protein gene.[5][6]

Other causes of primary GH excess include pituitary adenomas that secrete multiple hormones and GH-cell carcinomas. Important familial syndromes associated with acromegaly include Multiple endocrine neoplasia type 1, familial acromegaly, McCune-Albright syndrome, and Carney complex.

GH excess can also be ectopic and produced by other tumors such as lymphoma and pancreatic-islet cell tumors. GH excess can also be iatrogenic, resulting from excessive GH administration.

Rarer causes of acromegaly are related to GHRH excess. These can be further divided into central and peripheral causes. Central causes include hypothalamic hamartomas, choristoma, and ganglioneuroma. Peripheral causes include secretion of GHRH by bronchial carcinoid tumors, small cell lung cancer, adrenal adenoma, and even production by some medullary thyroid cancer or pheochromocytoma has been described.[7]

Epidemiology

Acromegaly has a worldwide prevalence of about 4,600 per million population, with about 116.9 new cases per million per year, and its incidence is increasing further.[8] The mean age of diagnosis is 40 for men and 45 for women.[9][10] Acromegaly usually presents in the third decade of life.[11]

History and Physical

Acromegaly is usually a slow-progressing disorder, with onset usually in the third or fourth decade of life. The presenting complaints can include the following:

• Joint pain due to hypertrophic arthropathy
• Wrist pain and numbness from carpal tunnel syndrome
• Snoring and sleep disorders related to sleep apnea
• Headaches and visual disturbances (bitemporal hemianopia) as a direct result of the pituitary adenoma
• Erectile dysfunction or low sex drive
• Abnormal menses in women
• Sweaty palms and soles (hyperhidrosis)
• Deepening of the voice

Signs upon physical examination can include the following:

General Examination

• Coarse facial features, prominent forehead, prominent brow, and prognathism (mandibular enlargement)
• Prominent forehead crease and nasolabial folds
• Macroglossia and widely spaced dentition[12]
• Thick eyelids, large nose, and large lower lip

Visual Field

• Bitemporal hemianopsia

Neck

• Possible thyromegaly or palpable nodules
• Raised JVP (in acromegalic cardiomyopathy)

Integumentary

• Thick and rough skin
• Skin tags
• Oily skin
• Abnormal or excess hair distribution, e.g., hirsutism(in women), hypertrichosis
• Hyperpigmentation
• Acanthosis nigricans, especially in the axillary areas

Breast

• Galactorrhea (this may be due to a combination of a GH-secreting adenoma co-secreting prolactin or pituitary stalk compression)
• Dry atrophic skin

Cardiovascular

• Features of acromegalic cardiomyopathy: may have displaced apex beat, the character may be sustained "pressure-loaded" in the hypertrophy stage, and if there is reduced systolic function, it may be diffuse
• Elevated blood pressure
• Cardiac murmur (evaluating for valvular disease)

Chest

• Potential dorsal kyphosis and lumbar hyperlordosis, prominence of the distal part of the sternum
• Bibasal crepitations in the case of congestive heart failure in a patient with acromegalic cardiomyopathy

Limbs

• Acral enlargement: large hands (with stubby fingers) and feet
• Proximal myopathy
• Carpal tunnel syndrome 
• Genu varum
• Rolling gait [13][14]

Evaluation

Acromegaly screening is appropriate in patients presenting with the typical phenotypic features but can also be considered in those patients with multiple disorders commonly associated with acromegaly, such as sleep apnea, hypertension, uncontrolled type 2 diabetes, debilitating arthropathy, and carpal tunnel syndrome. However, screening is not recommended in patients with isolated sleep apnea, type 2 diabetes, or hypertension because of the relative rarity of the syndrome.[15]

Screening is biochemical. IGF-1 is used as it does not vary with sleep patterns, exercise, or throughout the day like GH does. Increased IGF-1 level confirms GH excess, and imaging should be done next to localize the source. If the IGF-1 is normal, acromegaly can essentially be ruled out at this point.[16][17] If the test is equivocal, a GH suppression test should be performed. 75g of glucose is administered to the patient orally, and GH levels are measured before and 2 hours after the glucose load. The diagnosis of acromegaly is confirmed if GH concentration is >1ng/mL after the glucose load.[18] Other dynamic tests exist but are seldom necessary. They can be done if acromegaly is suspected, but the IGF-1 and GH suppression test with oral glucose tolerance test (OGTT) are both normal. Thyrotropin-releasing hormone (TRH) 500 mg can be given intravenously, and in about half of acromegalic patients, the GH level would increase by 50% within 30 minutes. This effect is not observed in the general population.[19]

The next step in evaluating these patients is obtaining imaging of the brain as a somatotroph adenoma is the most common cause of acromegaly. The imaging modality of choice is a pituitary MRI. Adenomas have a hypointense signal on T2-weighted images of the MRI.[20] If a mass is seen, proceed to the treatment options detailed below. If imaging does not identify a mass, the adenoma may be too small to be visualized or indicate an alternate GH excess source. At this point, alternative imaging should be done, including a CT of the chest and abdomen or DOTATE PET scan. This should be done in conjunction with serum measurement of GHRH, and elevated levels, usually > 300ng/mL, are suggestive of extra-pituitary sources.

Other tests to be done include evaluating other pituitary hormones. Adenomas can co-secrete more than one hormone and sometimes multiple hormones. Also, depending on the size of the adenoma, compression of the normal pituitary gland can result in deficiencies of other hormonal cell lines.[21] Prolactin can be elevated either due to stalk compression from the pituitary adenoma or due to a co-secreting adenoma. As appropriate, one should check ACTH, early morning cortisol, free T4, FSH, and LH with either testosterone or estradiol.

As a result of common comorbidities, a hemoglobin A1c should be measured for the screening of diabetes and a lipid panel, as these patients commonly have elevated triglyceride levels and low HDL. If they have symptoms suggestive of sleep apnea, they should be referred for a sleep study. Any concerning heart failure symptoms on physical examination should prompt referral to a cardiologist and an electrocardiogram and echocardiogram. Any visual concerns or adenomas close to or compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. Depending on the guidelines followed, a colonoscopy should be done at diagnosis (or age 40).[21] 

A SAGIT (Signs/Symptoms, Associated comorbidities, Growth hormone levels, IGF-1 levels, and Tumor features) evaluation has been developed, and it has been proven to be a valuable tool in recognizing the response in the treatment as well as giving potential information on the course and prognosis of the disease.[22]

Treatment / Management

The goals of acromegaly treatment include controlling biochemical parameters (GH and IGF-1 levels) and associated signs and symptoms, the local mass effect of the tumor, managing comorbidities, and improving mortality.[21]

Surgical Therapy

Surgery is the treatment of choice for all microadenomas as well as macroadenomas, causing a mass effect. Debulking of macroadenomas without mass effect can also be done and has been described as a modality to allow for better response to medical treatment, even if a surgical cure is not likely.[23] The best predictors of surgical cure include smaller tumor size, lower levels of GH/IGF-1, and absence of invasion of surrounding structures such as the cavernous sinus. Certain studies have also shown that neoadjuvant medical treatment with octreotide before surgery results in higher remission rates; however, larger studies are needed to ascertain whether this should be routinely done or which patient may benefit from this approach. In general, this type of surgery should be performed at a center with an experienced pituitary neurosurgeon who performs at least 50 cases per year.[24]

Surgical Techniques

• Endoscopic Transsphenoidal Surgery:  A minimally invasive surgery using an endoscope through a small incision in the nose or at the upper lip to remove the pituitary adenoma will promptly alleviate any pressure symptoms, as well as reduce the elevated growth hormone (GH) levels. The proposed benefit of using an endoscope is the enhanced ability to visualize the tumor in a panoramic fashion and not miss any residual tumor when resecting.[24]
• Transsphenoidal Microscopic Surgery:  The tumor is directly visualized using a microscope, which is the traditional method of transsphenoidal surgery. A meta-analysis compared endoscopic and traditional microscopic transsphenoidal surgeries. It found they have comparable endocrine remission and complication rates. As expected, microadenomas had higher remission rates regardless of the surgical technique used, and the endoscopic technique confers the theoretical benefit of better visualization and, thus, better outcomes for macroadenomas. But, further studies are required to directly compare these surgical modalities.[25]
• Craniotomy: This approach is reserved for those adenomas with suprasellar extension. Other reasons for choosing this approach include unfavorable para-sellar sinuses and internal or external carotid artery aneurysms.[24]
(A1)

Post-surgical Follow-up and Management

Immediately post-surgery, urine output monitoring and sodium levels are vital. Patients may either develop the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or, conversely, diabetes insipidus and necessitate desmopressin administration. The adrenal function should be monitored and treated appropriately immediately post-operatively. Patients with comorbid sleep apnea should not use their CPAP device post-operatively for a while to reduce the risk of pneumocephalus and infections as a result of the high nasal pressures. Thyroid and gonadal axes can undergo testing 6 to 12 weeks after surgery. Studies have shown that immediate day-one post-operative measurement of GH can be done to assess remission. However, the remaining normal pituitary gland may produce excess GH in response to surgical stress.

An OGTT can be done one week post-operatively. A GH value of <0.4ng/mL defines disease control. Serology of GH and IGF-1 can be measured by 3 to 6 months post-operatively as it can take this long for IGF-1 levels to normalize. Remission is then defined when normal IGF-1 levels are seen, and GH after OGTT is measured at <1ng/mL (although some recommend using <0.4ng/mL). If remission is confirmed, serology should be repeated at least annually, as relapse has been known to occur in some patients even as long as ten or more years later. Post-operative imaging should be done a minimum of 3 months after surgery as the fat and gel foam packing can take that long to be resorbed.[24]

If residual disease is noted, the patient may need further treatment with repeat surgery, if possible and appropriate, medical management or radiotherapy. Pathology specimens are helpful for further management and prognostication as, for example, when the tumor is densely granulated, this may predict response to octreotide.[26] Also, staining should be done for Ki67 and p21 as these levels have also shown to have prognostic value.[27] Also, if the adenoma stains positive for prolactin, this could predict a response to dopamine agonists. (B2)

Medical Therapy

This is considered for patients who do not desire surgery, are too high risk for surgery, are not a surgical candidate as the tumor may be unresectable, and those with recurrent disease after initial surgical management who do not qualify for repeat surgery. As described above, there may also be a role for neoadjuvant medical therapy before surgery. 

Medical Agents [28][29][30][31](A1)

• Somatostatin analogs (octreotide, Lanreotide, pasireotide): 
  • All of these drugs are synthetic somatostatin and bind to somatostatin receptors. This results in the suppression of growth hormone secretion from both normal pituitary gland and somatotroph adenomas; it also acts at the level of the liver inhibiting GH action by reducing GH binding to hepatocytes and reducing the production of IGF-1 from the liver. Thus, these drugs control hormonal overproduction as well as tumor growth.[32][33]
  • Also, Pasireotide is a second-generation somatostatin analog; it has been found to have a much higher affinity for the somatostatin receptor SSTR5 in addition to some action on SSTR2 and SSTR3. This is important as most somatotroph adenomas have high expression of both SSTR2 and SSTR5. Thus, with octreotide and lanreotide having effects predominantly via SSTR2 and pasireotide with the highest affinity for SSTR5, this can help with targeted therapy.[34] When pasireotide was compared to octreotide, pasireotide resulted in better control of both the hormonal profile and tumor size.[35]
  • Somatostatin analogs are usually administered as once-monthly intramuscular injections, although 3 to 4 times per day, subcutaneous injections are also available. Recently, an oral formulation of somatostatin has been FDA-approved. This came after the CHIASMA OPTIMAL trial. The primary endpoint was control of IGF-1 levels, and they met primary endpoints. 58% of patients with acromegaly taking the oral formulation of octreotide had controlled levels of IGF-1 as opposed to only 19% of those taking a placebo.[36][37]
  • Somatostatin analogs are generally well tolerated. Side effects that have been reported are mainly gastrointestinal such as diarrhea, vomiting, and abdominal pain, but they can also result in biliary sludge or cholelithiasis. These drugs can also affect glucose homeostasis resulting in hyperglycemia; this result seems more pronounced with pasireotide.[38]
  • Concerning monitoring, an IGF-1 level should be measured three months after administering a long-acting somatostatin analog. Treatment efficacy is described as one or a combination of the following: random GH level <2ng/mL, GH nadir <1ng/mL after OGTT, or normalization of IGF-1 levels.
• Dopamine receptor agonists (cabergoline, bromocriptine): 
  • These act on dopamine 2 receptors (D2R) in the pituitary gland and are less effective than somatostatin analogs. They are often used as adjuncts. Cabergoline is more potent than bromocriptine in lowering GH levels. Doses of cabergoline (up to 7mg weekly) are much higher than those used in prolactinomas to effectively reduce GH levels.
  • These drugs are considered for those patients with only mild biochemical abnormalities (GH >1 but <1.3ng/mL) and mild symptoms or in conjunction with somatostatin analogs. Studies have shown that cabergoline can reduce GH and IGF-1 levels in 40% of patients.[39] In general, a reduction in the tumor size in conjunction with control of IGF-1 levels only occurs in about 10 to 20% of people using bromocriptine. Another study showed only one-third of patients had both control of IGF-1 and tumor size with cabergoline.[40]
  • The most common side effects related to these drugs are nausea, abdominal pain, constipation, rarely dizziness, and orthostatic hypotension.
• GH-Receptor antagonist (pegvisomant): 
  • This novel drug is a human growth hormone analog and blocks endogenous growth hormone at the receptor level, lowering IGF-1 levels while GH levels can be increased.[41]
  • IGF-1 levels are the only biochemical marker used to monitor response to treatment.
  • This drug does not have anti-proliferative effects and thus does not affect tumor size.
  • Adverse reactions associated with this drug include diarrhea and nausea; it can also result in abnormal hepatic function tests, infections, and pain.
  • Of note, pegvisomant can have a beneficial effect on glucose homeostasis and can improve insulin sensitivity.[42]
(A1)

Combination medical therapy has also been described. Combining cabergoline with a somatostatin analog has been seen to be effective in a subset of patients, even in the absence of hyperprolactinemia. Another common combination is that of a somatostatin analog with Pegvisomant. A study demonstrated that by adding Pegvisomant to a somatostatin analog in patients seemingly resistant to the somatostatin analog, IGF-1 levels normalized in 95% of patients. Importantly, if this combination is used, one needs to monitor hepatic function, as liver derangement is more common with the combination of drugs than with Pegvisomant alone.[43]

A combination of a low-dose somatostatin analog with weekly pegvisomant is not an on-label or approved regimen for acromegaly; however, a study has shown promise for this novel dosing regimen to be effective in biochemical control in addition to being cost-effective in those requiring combination therapy for the management of their acromegaly.[44](A1)

Radiotherapy

Radiotherapy is considered in those patients in whom medical management is ineffective in controlling disease, recurrence after surgery, and, again, the failure of medical therapy. The patients treated with radiotherapy need to be closely monitored for hypopituitarism.

• Conventional fractionated radiotherapy is often administered as an adjunct to surgery to prevent relapse or when surgery cannot bring the acceptable lowering of GH levels. It is associated with the risk of irradiating adjacent brain tissues. It is provided at small daily doses five days a week, usually for 5 to 6 weeks duration. Remission can take up to 10 years, and these patients require medical management in the interim.
• Stereotactic radiosurgery: Precision radiotherapy directs high-dose radiation to the tumor and minimizes risk to nearby healthy brain tissues. It is a single high dose of radiation. The adenoma needs to be multiple millimeters away from the optic chasm to avoid damage to utilize this technique. The remission rate with this modality ranges from 17 to 50% in the absence of medical management for 2 to 5 years.[45]

Management of Acromegaly in Pregnancy [21]

GH secretion varies during normal pregnancy. GH-secreting tumors have estrogen receptors, particularly those that co-secrete prolactin. The concern is whether the pregnant state would increase the tumor size; however, in some studies, it has been found that tumor size does not change significantly during pregnancy in most women. But, given that the risk is still present, women need to be monitored closely with serial visual field monitoring. 

In a pregnant patient with acromegaly due to a microadenoma, the clinician should discontinue medical management, and these patients can just be closely monitored. The same applies to those with macroadenomas not affecting the optic chiasm with very close monitoring of visual fields. If a woman were to develop worsening symptoms related to acromegaly, medical management could be reinstituted to help alleviate those symptoms (no biochemical monitoring due to alterations of IGF-1 and GH during pregnancy). Bromocriptine has been used in pregnant women with acromegaly to manage the signs and symptoms without causing adverse fetal harm. However, cabergoline has not been extensively studied in pregnancy. Somatostatin analogs can cross the placenta and potentially decrease uterine blood flow, but longer use of octreotide does not seem to adversely affect the pregnancy or fetal development. Pegvisomant is not recommended as it has not been studied in pregnancy, and its use in pregnancy is limited to case reports. If visual complaints arise, an MRI is necessary to determine whether medical management or surgery is needed. 

Differential Diagnosis

• Carney complex
• McCune-Albright syndrome
• Multiple endocrine neoplasia type 1
• Genetic overgrowth syndromes:
  • Sotos syndrome
  • Beckwith-Wiedemann syndrome
  • Malan syndrome 
  • Tatton-Brown-Rahman syndrome[46] 
• Disorders with Tall stature (children):
  • Berardinelli–Seip lipodystrophy
  • Abnormalities of natriuretic peptide C pathway[47][46][47]
• Pachydermoperiostosis[48]
• Minoxidil use[49]

Prognosis

Acromegaly is associated with high mortality rates, chiefly due to malignancies and cardiovascular and respiratory disorders.[50] Individuals with acromegaly have 1.2 to 3.3 times the mortality rate compared to the general population as per the standardized mortality index. However, it has also been postulated that post-operative GH levels correlate the best with overall survival. Thus, if GH/IGF-1 levels are controlled, the life expectancy becomes the same as in age-matched controls.[51] Factors associated with a worse prognosis include high GH/IGF-1 levels, cardiomyopathy, and hypertension.[52] Morbidity related to the condition often remains despite normalizing GH/IGF-1 levels, but treatment can ameliorate the severity and partially improves the quality of life.[53][54]

Multiple factors influence the prognosis of acromegaly. Patient factors such as age, biochemical factors such as how high GH/IGF-1 levels are at diagnosis, tumor factors including tumor granularity, receptor expression (SSTR2, SSTR5, and D2), markers such as Ki67 and p21, specific mutations, how the tumor behaves in terms of its size and invasion and the T2 intensity of the tumor on MRI. Using this information, a classification of acromegaly into three subtypes has been proposed, guiding prognosis, predicting treatment responsiveness, and thus patient outcomes.[55][56]

• Type 1 (best prognosis): Older patients, fewer symptoms, and lower levels of IGF-1. They have densely granulated micro or macroadenomas that are less aggressive, as evidenced by lower Ki67 (a proliferation marker), high p21 (a marker of senescence), and very uncommonly have a suprasellar extension. Instead, they tend to exhibit extension laterally to the sphenoid sinuses, which are more accessible to surgery. Also, these tumors more frequently express SSTR2 predicting a better response to medical treatment.[55]
• Type 2 (intermediate prognosis): These macroadenomas can be either dense or sparsely granulated but do not demonstrate invasive features. Compared with type 1, IGF-1 levels are higher at diagnosis.[55]
• Type 3 (worst prognosis): These patients are young, experience severe symptoms, and have high levels of IGF-1 at diagnosis. Their tumors are macroadenomas and are sparsely granulated and more aggressive, as supported by low levels of p21. These tumors also extend to both the sphenoid sinus and the suprasellar region and frequently compress the optic chiasm. Low expression of SSTR2 may indicate poor response to medical therapy.[55]

Complications

Musculoskeletal Complications

Both GH and IGF-1 stimulate the production of periosteal bone formation. IGF-1 creates somatic growth by binding to the insulin-like growth factor-1 Receptor (IGF-1R), which is relatively ubiquitous. IGF-1R is a receptor tyrosine kinase that brings about phosphorylation and activation of several intracellular signaling pathways, one of which is the AKT pathway activation that results in somatic cell growth and proliferation. In the craniofacial region, this manifests as characteristic features such as prognathism, teeth separation, jaw thickening, frontal bossing, and nasal bone hypertrophy.[14]

The changes noted in the extremities are due to a combination of increased soft tissue, cartilage, bone overgrowth, and deformity. Cartilage hypertrophy results in the widening of joint spaces, and the widening of the phalanges occur due to the thickening of the base of the bone and the diaphysis. The spine is also affected by cartilage and bone overgrowth, the phenotype of which is dorsal kyphosis and lumbar hyperlordosis. Deformity due to overgrowth of the costochondral joints can cause splaying of the ribs. Bone mass can give differing results in these patients because acromegaly is associated with other endocrinopathies that may contribute to a low bone mineral density. An example of this would be hypogonadism. Peripheral arthralgias and myalgias are also common.[14]

Skin Manifestations

The major changes seen with the skin result from hyperhidrosis, and patients may complain of excessive sweating and general oiliness of their skin. Additional findings may include skin tags. Skin is also generally thickened as a result of glycosaminoglycan deposition and connective tissue overgrowth.

Neurologic Complication

Carpal tunnel remains the most common neuropathy. Interestingly, the mechanism is thought to be edema of the median nerve, not external nerve compression from soft tissue and bone overgrowth. Also, cerebral aneurysms have been reported with increased frequency in patients with acromegaly, often found incidentally on imaging during an evaluation, but they can also present as cerebral hemorrhage if they should rupture. 

Cardiovascular Complications

Hypertension is frequent in these patients. The pathophysiology seems multifactorial. Primarily, there is an increased plasma volume and perhaps an element of endothelial dysfunction as well. Secondary contributors to the development of hypertension include sleep apnea and insulin resistance. Myocardial biventricular hypertrophy can also occur directly from GH on the myocardium, leading to diastolic dysfunction. Histologically there is necrosis of myocardial cells, interstitial fibrosis, and infiltration of lymphocytes. Initially, this presents as a hyperkinetic heart, then evolving to biventricular hypertrophy and, eventually, diastolic and systolic dysfunction.[57] Arrhythmias can also occur but are seldom symptomatic. They occur due to the combination of fibrotic changes, cardiac remodeling, and associated cardiomyopathy. Valvular abnormalities can also occur with increased frequency in acromegalic patients. It has been postulated that this may, in part, be related to some fibrotic changes.

Metabolic Complications

Both insulin resistance and diabetes occur in acromegaly. This is because GH in excess causes insulin resistance at the level of the liver and peripheral tissues. There is an increase in beta-cell function as compensation attempts to maintain euglycemia. Physiologically, GH stimulates the hydrolysis of triglycerides into free fatty acids and glycerol. The combination of chronic insulin resistance and lipotoxicity results in beta-cell dysfunction and eventual apoptosis with the subsequent development of diabetes.[58]

Respiratory Complications

The most common respiratory complication is sleep apnea. Most acromegalic patients with sleep apnea have the obstructive kind due to craniofacial anatomic changes such as macroglossia, soft tissue overgrowth of the palate and uvula, and alterations of the jaw. However, one-third of patients do have central sleep apnea. Other abnormalities can occur again due to anatomic changes related to the ribcage, thus altering ventilatory mechanics.

Neoplastic Complications

The risk of colon cancer in acromegaly remains a very controversial topic. A large meta-analysis evaluating the presence of colorectal malignancy in acromegaly was published in 2008. It included around 700 patients with acromegaly compared to around 1500 controls. They found that the odds ratios of developing colon adenomas and colon cancer in patients with acromegaly were 2.5 and 4.3, respectively.[59] There remains no true consensus among different guidelines concerning colonoscopy surveillance. Some guidelines recommend screening at the time of diagnosis, and others starting at age 40. Repeat colonoscopies depend on the findings of the initial colonoscopy.[60] Thyroid nodules can also occur. Sometimes these patients can develop a multinodular goiter and become clinically thyrotoxic.