Molecular biological examination of somatotroph pituitary adenomas related to clinical data from patients with acromegaly
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AbstractDefinition and epidemiology
The first historical description of acromegaly could be the story of David and Goliath described both in The Old Testament and in the Koran. Goliath was a giant, but David defeated him by sneaking up on him, maybe in his visual field defect, and hitting him with a stone in the forehead using a sling. The connection between gigantism and the pituitary, hence with the possibility of visual disturbances, was not recognized until 1884, published in a book by Fritzsche and Klebs. Two years later, Pierre Marie introduced the name acromegaly and a clinical description of the syndrome. He had several suggestions for the aetiology; none included the pituitary. Acromegaly is a clinical syndrome due to chronic exposure to supra-physiological levels of growth hormone (GH), in almost all cases caused by a GH producing somatotroph pituitary adenoma. When the GH overproduction occurs before the fusion of the growth plates, it results in increased and continuous length growth, termed gigantism. However, the disease usually develops later in life, with a median age of diagnosis at 40-50 years, men being a little younger than females. The incidence of acromegaly is reported to be 2-4 new cases per million inhabitants per year, but the prevalence is markedly higher, varying between 36 and 125 patients per million inhabitants in recent publications. The reports with the lowest numbers for both incidence and prevalence are from national registers of acromegaly, where the results from different regions are highly variable. This could be due to registration bias and underestimation in some of the regions, and hence an underestimation of total incidence and prevalence.
The clinical features and symptoms of acromegaly develop slowly, and the diagnosis is usually delayed by several years. The median time from start of symptoms to diagnosis has been reported to 4 to 6 years in recent studies. This diagnostic delay did not change in patients diagnosed between 1992 and 2003, compared to 1981 – 1991. A published patient’s journey is an illustrating example of how long the way to correct diagnosis can be. The symptoms of acromegaly are due to tumour mass or hormone hypersecretion. The symptoms caused by the expanding tumour mass are similar for all pituitary tumours, and include headache and compression of the optic nerve tract or chiasm causing visual field defects. In larger adenomas, various degrees of pituitary insufficiency can occur due to suppression of the other hormone producing cells in the pituitary. The elevated level of GH leads to increased production of insulin-like growth factor 1 (IGF-1), both in the liver causing increased systemic IGF-1, and locally. The effects of elevated GH and IGF-1 include acral and soft tissue hyperplasia, causing enlarged and swollen hands and feet, carpal tunnel syndrome, coarse facial features and macrognathia, macroglossia, sleep apnoea and deepening of the voice. Arthropathy with joint pain is common, developing to irreversible osteoarthritis in a later stage. Metabolic changes like increased insulin resistance causing impaired glucose tolerance or diabetes mellitus are not unusual. Commonly reported are also increased sweating, fatigue and physical weakness. A recent study reported higher incidence of affective disorders, particularly depressions, in patients with acromegaly, also compared to patients with other chronic diseases. Cardiac hypertrophy occurs even in patients shortly exposed to GH hypersecretion, and can develop further to cardiomyopathy and heart failure in untreated acromegaly. Arterial hypertension, arrhythmias and atherosclerosis are other manifestations. A schematic overview of symptoms is given in table 1.
Single GH measurements are not reliable in the diagnostic evaluation of acromegaly due to the normal pulsatile GH secretion. However, IGF-1 is a function of the integrated 24-h serum GH level and a single measure can be used as screening procedure. In acromegaly, serum IGF-1 will be elevated compared to the normal age related reference range. The diagnosis are confirmed with an oral glucose tolerance test (OGTT), where hyperglycaemia will fail to suppress GH sufficiently in the case of acromegaly. A magnetic resonance imaging (MRI) scan of the pituitary will usually identify the adenoma.
LIST OF PUBLICATIONS
Paper 1 Fougner SL, Borota OC, Berg JP, Hald JK, Ramm-Pettersen J, Bollerslev J. The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma. Clinical Endocrinology 2008 Mar;68(3):458-65. DOI: 10.1111/j.1365-2265.2007.03065.x
Paper 2 Fougner SL, Bollerslev J, Latif F, Hald JK, Lund T, Ramm-Pettersen J, Berg JP. Low levels of Raf kinase inhibitory protein (RKIP) in somatotroph pituitary adenomas correlate to poor clinical response to octreotide. J Clin Endocrinol Metab. 2008 Apr;93(4):1211-6. DOI: 10.1210/jc.2007-2272
Paper 3 Fougner SL, Lekva T, Borota OC, Hald JK, Bollerslev J, Berg JP. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness and to somatostatin analog response. Resubmitted after revision.J Clin Endocrinol Metab. vol 95(5), pages: 2334-2342 DOI: 10.1210/jc.2009-2197