How to cite this article: Melgar V, Espinosa E, Cuenca D, Valle V, Mercado M. Current diagnosis and treatment of acromegaly. Rev Med Inst Mex Seguro Soc. 2015 Jan-Feb;53(1):74-83.
Received: August 29th 2014
Accepted: October 6th 2014
Virgilio Melgar,a Etual Espinosa,a Dalia Cuenca,a Vanessa Valle,a Moisés Mercadoa
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
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
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
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
Figure 1 Axis of growth hormone/insulin-like growth factor-1. GHRH = growth hormone releasing hormone; GH = growth hormone; IGF-1 = Insulin-like growth factor-1
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
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
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
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
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
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.
Figure 2 Algorithm for drug treatment. GH = growth hormone; IGF-1 = insulin-like growth factor-1; CBG = cabergoline; MRI = magnetic resonance imaging
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
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.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.