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Received: August 29^th 2014
Accepted: October 6^th 2014

Current diagnosis and treatment of acromegaly

Virgilio Melgar,^a Etual Espinosa,^a Dalia Cuenca,^a Vanessa Valle,^a Moisés Mercado^a

^aServicio de Endocrinología, Unidad de Investigación Médica en Endocrinología Experimental, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Moisés Mercado
Telephone: (55) 5281 3029
Email: mmercadoa@yahoo.com; moises.mercado@endocrinologia.org.mx

Acromegaly is a rare condition characterized by the excessive secretion of growth hormone (GH), usually by a pituitary adenoma. The clinical manifestations of acromegaly include enlarged hands, feet and face, headaches, arthralgias, fatigue and hyperhydrosis. This condition is also associated with comorbidities such as hypertension and diabetes in a significant proportion of patients and frequently compromises life quality and life expectancy. The biochemical diagnosis of acromegaly rests on the demonstration of an autonomous secretion of GH by means of the measurement of glucose-suppressed GH levels and the serum concentration of insulin like growth factor type 1 (IGF-1). The localizing method of choice is magnetic resonance image of the selar area, which in 70 % of the cases reveals the presence of a macroadenoma. Even though the primary treatment is usually the transsphenoidal resection of the adenoma, the majority of patients require a multimodal intervention that includes radiotherapy, as well as pharmacological therapy with somatostatin analogs and dopamine agonists. The latter approach has resulted in a significant reduction in mortality and in an improvement in the quality of life.

Keywords: Acromegaly; Pituitary adenoma; Growth hormone; IGF-1

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Acromegaly is a chronic multisystem disease of relatively low prevalence (30-60 cases per million inhabitants), caused by excess growth hormone (GH), which in over 98% of cases results from a benign epithelial tumor of pituitary gland somatotroph.¹ According to the Programa Epidemiológico Nacional de Acromegalia, through 2014 there have been about 2,000 reported cases, indicating a significant degree of under-diagnosis in our country. The average age at diagnosis is around 40 years and there is no gender predominance.²

Physiological basis of the GH/IGF-1 system

The hypothalamus regulates GH secretion by two main factors: GH-releasing hormone (GHRH) is secreted in pulses which stimulate GH secretion, and somatostatin is secreted tonically and inhibits GH secretion. By acting on specific receptors in the pituitary somatotroph, these hypothalamic peptides result in pulsatile GH secretion, which happens predominantly overnight. GH secretion is also stimulated by ghrelin, an orexigenic hormone, produced mainly by the gastric fundus, which interacts with a receptor on the somatotroph different from the GHRH receptor.3 GH thus secreted circulates in plasma about 50% bound to the GH binding protein (GHBP, an extracellular portion of the GH receptor) and reaches its target cells, where it interacts with specific receptors, which are distributed in all tissues but predominantly in the liver and cartilage of bone epiphysis.4 As a result of the interaction of GH with its receptor, insulin-like growth factor 1 (IGF-1) is produced, which is the mediator of most of the trophic effects of this hormone. IGF-1, in turn, inhibits GH secretion by a negative feedback mechanism that occurs both in the hypothalamus and pituitary. IGF-1 circulates in plasma bound predominantly to six binding proteins produced in the liver, of which IGFBP1 and IGFBP3 are the most important. IGFBP3, whose synthesis is dependent on GH, is the most abundant and transports more than 90% of the IGF-1; IGFBP1 is insulin-dependent and negatively regulates the biological actions of IGF-1 (Figure 1).^3,4

GH secretory pulses are "cushioned" by GHBP, which ensures proper delivery of GH to its target tissues, where it interacts with its receptor. GH receptor (GHR) belongs to the family of cytokines/prolactin/growth factor receptors, which consist of an extracellular portion that binds to the ligand, a transmembrane portion which is involved in dimerization of the molecule, and an intracellular portion, which the signal translation depends on. A GH molecule interacts with two molecules of GHR, which is found in the cell membrane prior to dimerization. The arrival of GH reinforces the functional dimerization of the receptor, which initiates the signal translation. The first step in this signaling is the attraction and phosphorylation of two kinase molecules called JAK2 (Janus associated kinase). This results in the phosphorylation of STAT5b (signal transducers and transcription activators), which in turn activates the transcription of several genes, particularly that of IGF-1, which, as mentioned above, is the mediator of the growth effects of GH. The metabolic effects of GH (gluconeogenesis, glycogenolysis, lipolysis), moreover, appear to be independent of the generation of IGF-1 and involve inositol triphosphate.⁵

Glucose regulates GH secretion by increasing (hyperglycemia) or decreasing (hypoglycemia) synthesis of somatostatin in the hypothalamus. Exercise and amino acids such as arginine also stimulate the secretion of GH. IGF-1 concentrations vary with age, reaching their highest levels in puberty, and decrease progressively as part of the process called "somatopause". Estrogens produce a state of relative resistance to GH, which explains why eugonadal women have lower levels of IGF-1 than men of the same age. Malnutrition, poorly-controlled diabetes, hypothyroidism, and kidney failure reduce IGF-1 concentrations.⁶

Classification and pathogenesis of GH-producing tumors

GH-producing adenomas are, like the rest of pituitary adenomas, benign epithelial neoplasms. They may originate from the somatotroph, the mammosomatotroph, or the acidophilic stem cell. As for their staining, they are generally acidophilic, while by immunohistochemistry most of them immunostain only for GH (somatotropic adenomas) and 20% may co-secrete GH and prolactin (mammosomatotrophic adenomas). As for their ultrastructure, they are classified as rare and densely granulated. The first is associated with a more aggressive biological behavior and its pattern of immunostaining with cytokeratin (CAM 5.2) is perinuclear (so-called fibrous bodies); the second immunostain diffusely for cytokeratin and are typically less invasive and more sensitive to treatment with somatostatin analogues (SA).⁷

Pituitary oncogenesis involves a complex network of molecular, genetic, and epigenetic events. These events include the activation of oncogenes, the inactivation of tumor suppressor genes, and action of trophic factors such as GHRH. Mutations activating oncogene GSP alpha or GNAS are the best-known of these mechanisms. The alpha subunit of the Gs protein associated with the GHRH receptor has capacity for autohydrolysis, ensuring signal completion. Point mutations of the alpha subunit, which impede such autohydrolysis, result in constitutive activation of the GHRH receptor, which results in unrestricted hormonal hypersecretion and excessive cell proliferation. These mutations occur in about 40% of cases of sporadic acromegaly in Caucasians, in 15-20% of cases in mixed-race populations such as Mexicans, and in less than 10% of Asian populations.^3,8 There is the notion that patients whose tumors are carriers of these mutations usually have smaller, less invasive, and more SA-treatable tumors.⁹ The underexpression of the protein GADD 45 gamma (growth arrest and DNA damage inducible protein) and the overexpression of PPTG1 (Pituitary Tumor Transforming Gene) are other molecular alterations that have been described in GH-producing tumors.^3,8

While over 95% of acromegaly cases occur sporadically, the oncogenic mechanisms are known best when the disease occurs in syndromic and hereditary context. Multiple endocrine neoplasia type 1 (MEN1) encompasses tumors of the parathyroid glands, the endocrine pancreas, and the pituitary gland, of which the adenomas which are the second greatest GH producers after prolactinomas. MEN1 results from inactivating mutations of the menin gene, located on the short arm of chromosome 11. Although even rarer, acromegaly can be part of the Carney complex, which in turn is caused by inactivating mutations in the regulatory region of the kinase A protein.¹⁰ More recently, inactivating germline mutations have been found in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in more than half of patients with isolated familial acromegaly. In sporadic acromegaly, the frequency of this alteration in AIP can reach 8% if patients younger than 30 years are studied.¹¹

GH-producing carcinomas, with metastasis well-documented as a diagnostic criteria for malignancy, are rare. Rarely, acromegaly arises because of GHRH-producing neuroendocrine tumors, which are located in the lung, thymus, or the endocrine pancreas. GHRH excess produces pituitary hyperplasia and this, in turn, produces more GH.¹² The least common causes of acromegaly are ectopic pituitary adenomas, in which the presence of pituitary tissue is seen in places like the sphenoidal sinus or the clivus.¹³ There is only one reported case of GH-producing lymphoma in world literature.¹⁴

Clinical manifestations of acromegaly

Acromegaly develops insidiously over years and even decades. It has been estimated that the average delay in diagnosis is 8-10 years after the onset of the first symptoms. The signs and symptoms are commonly attributed to the aging process. Clinical manifestations may be related to hormonal excess or to compressive effects of the tumor.^15,16

1. 1. Local tumor effects: headache results from increased intracranial pressure by the tumor or may be secondary to the GH hypersecretion itself. Occasionally, the tumor can invade areas lateral to the sella turcica, such as the cavernous sinus, and can generate alterations in the cranial nerves, including nerves III, IV, and VI. To be clear, effect on cranial pairs by a pituitary adenoma is extremely rare, and their presence should prompt a search for alternative diagnoses, such as infiltrative and metastatic diseases of the sellar area. Visual field defects are common in macroadenomas that extend to the top of the sella turcica and compress the optic chiasma. Compression of this structure creates different combinations of homonymous hemianopia or bitemporal quadrantanopia, although it can cause any type of syndrome of the chiasma.^15,16
2. Consequences of excess GH and IGF-1


• Bone and skin changes: excess GH before closure of the bone epiphysis in puberty leads to an increase in linear growth resulting in gigantism. When the patient is an adult, the hormone excess results in acral growth (increasing the size of the fingers and hands, foot and shoe size, nose, cheekbones, jaw, and frontal bones). The soft tissues of the hands and feet thicken. The skin becomes thick due to deposit of glycosaminoglycans and collagen production. There is seborrhea and hyperhidrosis in 60% of patients; they can also have skin tags and acanthosis nigricans.^16,17
• Musculoskeletal system and calcium metabolism: acromegaly is associated with hipercalciuira and hyperphosphatemia and an increase in bone turnover; on balance, increased mineral density of cortical bone and decreased trabecular bone. Generalized arthralgias occur in up to 80% of patients, and degenerative osteoarthritis is more common than in the general population. There is numbness in hands and feet, painful proximal myopathy, and nerve entrapment (carpal tunnel syndrome) in a high percentage of cases.^16,18
• Cardiovascular system: there is hypertension in 30% of patients. Hyperaldosteronism with low renin levels and the increase in sodium reabsorption play an important role in the pathogenesis of hypertension, although other factors are also involved, such as the increase in sympathetic tone. Echocardiography can find hypertrophy of the left ventricle or septum, as well as diastolic dysfunction. 15% of patients develop symptomatic heart disease (coronary artery disease, heart failure, or arrhythmias). Some patients, even without hypertension, present cardiac abnormalities, so the existence of acromegalic cardiomyopathy has been proposed, which is mainly characterized by the presence of extensive myocardial fibrosis.¹⁹
• Respiratory system: Most patients present snoring and a high percentage of them have sleep apnea with central and obstructive components, with the typical consequences of this syndrome, such as hypertension and cerebrovascular events.¹⁶
• Abnormalities in glucose and lipid metabolism: excessive GH secretion generates insulin resistance and impaired glucose tolerance, which is reported between 30 and 50% of patients with acromegaly. The main mechanism by which the changes are generated in the glucose metabolism is increased hepatic glucose production. 30% of patients have fasting hyperglycemia. Patients may have a lipid profile associated with hypertriglyceridemia, elevated IDL (intermediate density lipoproteins) and lipoprotein (a), which also generate atherosclerosis.^4,20
• Neoplasms: There is a slightly increased risk of adenomatous colonic polyps and colon adenocarcinoma. In patients with premalignant polyps and uncontrolled acromegaly, there is a greater risk of recurrence. Today the malignancy most commonly associated with acromegaly is well-differentiated thyroid cancer.²¹
• Associated endocrine abnormalities: patients with acromegaly may have a euthyroid goiter that does not require further treatment. When there are very large adenomas that compress the normal pituitary gland, there may be variable hormone deficiencies, which can also occur after surgical or radiation treatment. Menstrual disorders in women are common, and sexual dysfunction in men occurs in 20 to 30% of patients. Hyperprolactinemia can be caused by co-secretion of prolactin (PRL) by the pituitary adenoma, or by compression of the pituitary stalk, which disrupts the descending dopaminergic pathway. Although rare, acromegaly can occur in the context of multiple endocrine neoplasia or McCune Albright syndrome; in these cases, other hormonal changes are presented that are related to the specific disease and not the pituitary tumor.^8,16

Biochemical diagnosis

GH is secreted in a pulses, so that random determinations are not useful for diagnosis. The gold standard is the measure of GH after an oral glucose load of 75 g every 30 minutes for two hours. Current guidelines indicate that with this stimulus, GH should be suppressed to less than 0.4 ng/dL using ultrasensitive tests. If there is no suppression, acromegaly is diagnosed; however, there are situations where the suppression of the hormone may be altered, such as pregnancy, puberty, the use of oral contraceptives, uncontrolled diabetes, and kidney and liver failure.^1,22

IGF-1 determination reflects the integrated GH concentrations in 24 hours and correlates with clinical activity. There are specific ranges of IGF-1 that change according to age and sex, so the assessment is made relative to the specific group corresponding to each patient. Also due to variations in the tests, each laboratory should establish normal values ​​for their tests. GHRH, because it is expensive and not available in most laboratories, is required only when there is suspicion of an ectopic source.^1,22,23

Imaging

Pituitary magnetic resonance imaging (MRI) contrasted with gadolinium allows the visualization of lesions 2 or 3 mm in diameter or more. The tumors are visualized as hypointense lesions in the T1 sequence, and they remain hypointense with the administration of paramagnetic contrast. Like other pituitary adenomas, lesions can be microadenomas (less than 1 cm) or macroadenomas (over 1 cm) that, in turn, range from intrasellar to highly invasive (para-, infra-, and suprasellar invasion) or giant (over 4 cm). The hyperintense lesions on T2 are associated with a poor response to SA. High-resolution tomography is a useful alternative though it is less sensitive. When these images are negative there should be suspicion of an ectopic GHRH source and in that case one must request a high-resolution scan of the chest and abdomen.^1,22,23

Treatment

The decision of which treatment modality to use depends not only on the clinical characteristics of the patient (age, comorbidities) and biological nature of the tumor (adenoma size and location), but also on issues such as the availability of a capable neurosurgeon or the financial resources to sustain costly long-term drug treatment. Notwithstanding this, the treatment goals of acromegaly are the same: 1) reduction of the tumor mass and its pressure effects, particularly on the optic chiasma, 2) control of symptoms such as headache, joint pain, hyperhidrosis, and acral growth, 3) hormonal control: basal GH < 1 ng/mL, post-glucose GH < 0.4 ng/mL, and normalization of IGF-1, 4) control of comorbidities such as diabetes and hypertension, 5) reduced mortality rate. In addition, it should be considered as a goal to achieve all of this while preserving pituitary function.^1,22,23 Here we present the treatment to be given to patients with acromegaly. 

1. Surgery: microscopic or endoscopic transsphenoidal surgery remains the primary treatment of choice, as long there is a competent neurosurgeon. It is estimated that a good pituitary neurosurgeon should perform at least 50 transsphenoidal procedures per year. The cure rate ranges between 80 and 90% for microadenomas, between 40 and 50% for noninvasive macroadenomas, and < 10% for invasive adenomas when the most stringent healing criteria are used. Transcranial surgery is reserved for macroadenomas larger than 4 cm with posterior or parasellar extension. Although there is no absolute chance of cure, the use of surgery to reduce the size of the tumor allows drugs and radiation to have better effect and improves symptoms from tumor compression. The mortality of transsphenoidal surgery is less than 0.6%, while the risk in transcranial surgery is around 7%. The most common complications include cerebrospinal fluid leak, meningitis, hemorrhage, and transient diabetes insipidus. GH levels are reduced in the first postoperative week, IGF-1 levels take several weeks or months, and the image of the scan can take months to be correctly evaluated.^1,22,23
2. Drug treatment


• The SA are the most commonly used drugs for acromegaly. They inhibit GH secretion and somatotropic growth through their interaction with specific receptors linked with Gi proteins (SSTR). The SA used today preferentially bind to SSTR2 and to a lesser extent SSTR5; in fact, these receptors are the most commonly expressed in GH-producing tumors. SA currently used in the treatment of acromegaly are LAR (long acting repeatable) octreotide and lanreotide autogel; both are deposit drugs administered every four weeks. LAR octreotide is for intramuscular administration and is used in doses of 10 to 40 mg/month, and lanreotide autogel is for deep subcutaneous administration and is used in doses of 60 to 120 mg/month. In patients with good control the dose can be spaced at 6 to 8 weeks, which reduces the cost of treatment. These SA are generally used as secondary treatment when the disease persists after surgery. They can also be used in primary forms when there are contraindications to surgery, when no surgeon is available, for invasive tumors, or just when that is the preference of the patient or physician. In both cases hormonal control is achieved in 25-35% of patients, but tumor shrinkage up to 70% can be achieved in patients with primary treatment. Patients who have hormone levels lower than the diagnosis and with more receptors 2 and 5 are more likely to respond to drug treatment. Adverse effects are related to gastrointestinal effects, alopecia, and gallstones in 20% of patients.^1,22,23
• Pegvisomant: This is a GH mutant that prevents functional dimerization of the GH receptor, so it acts as a competitive antagonist. It is administered subcutaneously at a rate of 10 to 30 mg daily. Its use reduces IGF-1 in 70% of patients. Since Pegvisomant drastically reduces levels of IGF-1, it eliminates the negative feedback that this exerts at pituitary level, so there is the risk that tumor growth will be induced, similar to what happens with Nelson syndrome. Although the possibility of tumor growth is only 3%, caution is advised when using the GH receptor antagonist in cases where the adenoma is within 3 mm of the optic chiasma. This can increase liver aminotransferases and is extremely expensive, so it is not recommended as first-line treatment. Pegvisomant administered weekly has been used with reasonable success in combination with SA administered monthly, a strategy that seems to reduce the cost of treatment.^1,22,23
• Dopamine agonists: dopamine agonists decrease the secretion of GH and IGF-1. Although initially recommended only for prolactin co-secreting tumors, studies have shown that they are also useful in tumors that only produce GH. Bromocriptine was used for several years because of its usefulness and cost; however, it is poorly tolerated. Cabergoline in an average dose of 2 mg per week has shown better tolerability and effectiveness in biochemical control in 20-30% of patients. It has a synergistic effect with somatostatin analogues and has allowed over 25% of patients to achieve significant additional hormone reductions. At the doses used in GH-secreting adenomas, cabergoline does not produce clinically significant heart valve abnormalities (Figure 2).^22,24




Figure 2 Algorithm for drug treatment. GH = growth hormone; IGF-1 = insulin-like growth factor-1; CBG = cabergoline; MRI = magnetic resonance imaging



• Radiation therapy: External radiation therapy and radiosurgery are indicated in patients with persistent disease, who have a remaining tumor, and who are intolerant or resistant to drug treatment. It has the disadvantage that its effect may take years to become evident. There is biochemical control in 20 to 60% of cases, and it is associated with hypopituitarism in more than 50% of patients at 10 years of follow up. Some studies have found that radiation therapy is associated with an increase in mortality from cerebrovascular disease; however, not all studies support this notion. Radiosurgery cannot be used in tumors less than 3 mm from the optic chiasma because of potential damage to the optic nerve. The doses of external fractionated radiation therapy are 45-65 Gy divided into daily doses over a period of 4 to 6 weeks. Stereotactic or gamma knife radiation surgery administers a similar dose of radiation in a single dose but does not seem more effective compared to conventional external radiotherapy.^22,25

Prognostic

In the past, life expectancy in acromegaly was markedly limited and standardized mortality ratios (SMR) could be up to 2 or 3 times that in the general population. With the advent of better surgical techniques to address the sella turcica, the emergence of effective drug therapies such as SA and Pegvisomant, and refinement in radiation therapy techniques, the prognosis of this disease has improved dramatically. Currently, the multimodal treatment of acromegaly and careful management of comorbidities have improved the quality of life of these patients and managed to bring down the mortality figures found in the general population.^26-28

Conclusions

Although acromegaly is a rare condition, its multisystem nature and etiopathogenic and pathophysiological basis have led to significant progress in understanding the interaction of the somatotropic axis and the intermediate metabolism, vascular endothelial damage, and tumorigenesis mechanisms. Currently, the treatment of acromegaly should include not only surgery, radiation therapy, and drugs to manage the issues of GH-producing adenoma; it should also consider the careful treatment of comorbidities. For this it is essential to recognize the reality of the specific site where a patient has to be managed. On the one hand, pituitary surgery should be practiced only by professionals with the expertise to ensure reasonable outcomes; on the other, drug treatment with SA and GH receptor antagonists is very expensive. Proper use of radiation therapy is crucial in controlling many patients, although there are authorities in the field who have relegated this therapeutic modality to a third level. In Mexico, health institutions such as the Instituto Mexicano del Seguro Social (IMSS) and the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE) have all the tools needed to address these patients with a multimodal approach that without doubt leads to an improvement in their quality of life and life expectancy.

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