Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0037315 (sleep apnea)
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Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5-1.0 microg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D(2) receptors using specific radiotracers such as (123)I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing's disease or Nelson's syndrome.
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PMID:New medical approaches in pituitary adenomas. 1097 Nov 10

The Rubinstein-Taybi syndrome (RTS) is a rare but well-defined condition characterized by growth and mental retardation, broad thumb-hallux, and distinctive facial features. Ten unrelated Taiwanese children (6 boys and 4 girls) with clinical features suggestive of RTS were evaluated. The associated anomalies included cryptochidism (6/6 males), microcephaly (9/10), congenital heart diseases (8/10), pectus excavatum (5/10), low IGF-I level (4/10), strabismus/nystagmus (4/10), epilepsy (3/10), glaucoma (2/10), cleft palate (2/10), web neck (2/10), limb hypoplasia (2/10), sleep apnea (1/10), and vesico-ureteral reflux (1/10). All of them had normal thyroid function. High-resolution chromosome studies by both G- and R-banding were applied to detect any microscopic chromosomal deletion, particularly over the 16p13 region (responsible for RTS locus). A panel of five cosmids spanning the human cyclic AMP-responsive element binding (CREB) binding protein (CREBBP or CBP) gene in terms of RT100, RT102, RT191, RT203 and RT166 (Leiden, the Netherlands) were used for fluorescence in situ hybridization on the metaphases of those patients. Three cases showed whole or partial deletion of one copy of the CBP gene. Thus, the rate for detecting interstitial submicroscopic deletion of this region by FISH was about 30% in these RTS patients. The disease severity seemed to be correlated with size of the deletion.
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PMID:Rubinstein-Taybi syndrome: clinical and molecular cytogenetic studies. 1623 61

Acromegaly is a slowly progressive disease characterized by 30% increase of mortality rate for cardiovascular disease, respiratory complications and malignancies. The estimated prevalence of the disease is 40 cases/1000000 population with 3-4 new cases/1000000 population per year. The biochemical diagnosis is based upon the demonstration of high circulating levels of GH and IGF-I. A random GH level lower than 0.4 microg/l and an IGF-I value in the age- and sex-matched normal range makes the diagnosis of acromegaly unlikely. In doubtful cases, the lack of GH suppressibility below 1 microg/l (0.3 microg/l according to recent reports) after an oral glucose load will confirm the diagnosis. A pituitary adenoma is demonstrated in most cases by CT scan or MRI. A negative X-ray finding or the presence of empty sella do not exclude the diagnosis. Cardiovascular complications (acromegalic cardiomyopathy and arterial hypertension) should be looked for and, if present, followed-up by echocardiography and 24h-electrocardiogram. Sleep apnoea, when clinically suspicious, should be confirmed by polisomnography. At the moment of diagnosis all patients should undergo colonscopy. Lipid profile should be obtained and glucose tolerance evaluated. Surgery, radiotherapy and medical treatment represent the therapeutic options for acromegaly. The outcome of transsphenoidal surgery is far better for microadenomas (80-90%) than for macroadenomas (less than 50%), which unluckily represent more than 70% of all GH-secreting pituitary tumours. Therefore, pituitary surgery is the first line treatment for microadenomas. Medical therapy is based on GH-lowering drugs (somatostatin receptor agonists and, in some cases, dopaminergic agents) and GH receptor antagonists (pegvisomant). The former are traditionally indicated after unsuccessful surgery and while awaiting the effectiveness of radiation therapy. However, GH-lowering drugs are also used as primary therapy when surgery is contraindicated or in the case of large GH-secreting macroadenomas which are not likely to be completely removed by surgery. These compounds may also be indicated in the preoperative management of some acromegalic patients in order to lower the risk of surgical and anaesthetic complications. For the moment pegvisomant is indicated for patients resistant to the GH-lowering drugs and there is no evidence for drug-induced enlargement of the pituitary tumour. In order to avoid this possibility, however, a combination of pegvisomant and GH-lowering compound can also be conceived. With pegvisomant, IGF-I plasma levels are the marker of therapeutic efficacy and normalize in 97% of patients. Radiotherapy is employed sparingly due to the number of side effects (80% of hypopituitarism). It is indicated after unsuccessful surgical and/or medical treatment and allows the control of hormonal secretion and tumour growth in approx. 40% and 100% of cases, respectively. Acromegaly is defined as controlled when, in the absence of clinical activity, IGF-I levels are in the age- and sex-matched normal range and GH is normally suppressible by the oral glucose load.
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PMID:Acromegaly. 1707 48

The approach to a patient with acromegaly and persistent disease after surgery requires a complex diagnostic assessment. Acromegaly is a chronic and insidious disease that is associated with multisystem comorbidities, including cardiovascular disease, hypertension, sleep apnea syndrome, colon polyposis, arthropathy, and metabolic complications including glucose intolerance and type 2 diabetes mellitus. Patients also have a variety of signs and symptoms, including headache, arthralgias, carpal tunnel syndrome, sweating, fatigue, and psychological issues that impact significantly on quality of life. The recommended approach to the evaluation of the postoperative patient includes a biochemical assessment, with measurement of serum IGF-I along with a glucose-suppressed GH value, radiological assessment to determine location of residual tumor and presence of mass effects, a physical examination for evidence of skeletal and soft tissue overgrowth and related signs of acromegaly, and a thorough clinical assessment for the presence of comorbidities. Repeat surgery is indicated if there is residual tumor that is surgically accessible and there may be a chance for surgical cure, or if there are persistent mass effects upon the optic chiasm. Otherwise, medical therapy is indicated, utilizing somatostatin analogs, dopamine agonists, and pegvisomant, a GH receptor antagonist. Radiation therapy is usually relegated to situations where medical therapy is ineffective or poorly tolerated or where patients would prefer not to sustain the cost of long-term medical therapy. The choice of therapy requires close dialog among endocrinologists, neurosurgeons, radiation therapists, and neuroophthalmologists for optimal care of patients.
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PMID:Approach to the patient with persistent acromegaly after pituitary surgery. 2082 64

In 2007 the Italian COM.E.T.A. (COMorbidities Evaluation and Treatment in Acromegaly) study group started to assess the application in a clinical setting of the Versailles criteria for management of acromegaly complications by a first questionnaire focusing on cardiovascular co-morbidities. A further questionnaire on sleep apnea syndrome (SAS) was delivered by the COM.E.T.A. study group to 107 endocrine centers in Italy. The results of our survey suggest that SAS is a well-known comorbidity even if its estimated prevalence is lower than in the literature. Polysomnography is the preferred tool for diagnosis. Control of SAS is considered relevant both for quality of life and co-morbidities. Continuous positive airway pressure is the cornerstone of therapy, but patients' acceptance may be critical. Control of GH/IGF-I secretion is important to improve SAS. Management of SAS requires cooperation between specialists.
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PMID:Assessment of the awareness and management of sleep apnea syndrome in acromegaly. The COM.E.TA (Comorbidities Evaluation and Treatment in Acromegaly) Italian Study Group. 2140 41

Diagnostic delay of acromegaly is still very relevant (6-8 years on average) without substantial changes in last twenty years. Clinical impact of this diagnostic delay is significant: tumor growth (2/3 of the patients at diagnosis bear a pituitary macroadenoma), development of irreversible complications (arthropathy, sleep apnea) and in all increased mortality. Reasons for this delay are related to the disease itself (facial and acral changes are very slow and subtle) but also to medical unawareness. Simple tools based on a few sufficiently sensitive and specific signs and symptoms which can trigger the diagnostic suspect would be useful in clinical practice. Global evaluation during follow-up (tumor volume, signs and symptoms, complications, circulating levels of growth hormone and its peripheral mediator IGF-I) has become crucial for the therapeutic decision making. In this regard, tools like SAGIT are now under validation and are expected to improve management of acromegaly. In fact, in the last 30 years there has been a relevant growth of the medical options to treat acromegaly and in the near future there will be an expansion of the medical options. This will greatly help the needed personalization of treatment which necessarily should consider patient convenience and preference and control of complications such as diabetes mellitus.
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PMID:[Acromegaly: reducing diagnostic delay]. 2757 62

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.
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PMID:Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Acromegaly - Part 1: Diagnostic and Clinical Issues. 3198 86

Background: Growth hormone (GH) stimulates the production of insulin-like growth factor 1 (IGF-1) in most tissues and together GH and IGF-1 profoundly impact adipose tissue deposition, glucose metabolism and cardiovascular function. A low serum IGF-I level has been reported as being associated with obstructive sleep apnea (OSA) and might be one of the mechanisms underlying cardio-metabolic risk in OSA patients. Methods: In a multicenter national study, 817 patients consulting for suspicion of OSA (OSA confirmed for 567 patients) underwent serum IGF-1 measurements. We analyzed the association between an IGF-1 level below the median value of the population and variables related to cardio-metabolic risk: body mass index (BMI) and waist circumference, apnea hypopnea index (AHI), cholesterol and triglycerides (expressed as median and divided into quartiles for continuous variables). Results: After adjustment for age and gender, low IGF-1 levels were associated with increased BMI and AHI (Odds ratios (OR) = 2.83; p < 0.0001 and OR = 3.03, p < 0.0001 for Quartile 4 vs. Quartile1, respectively), with elevated cholesterol levels (OR = 1.36, p = 0.0444), and elevated triglyceride levels (OR = 1.36; p = 0.0008). Conclusions: Both adiposity and sleep apnea synergistically predict low levels of IGF-1 and thus could together contribute toward cardio-metabolic risk. Further work are needed to confirm whether IGF-1 levels allow grading severity and predicting response to treatments to aim at a personalized medicine for patients suffering from OSA.
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PMID:The Somatotropic Axis in the Sleep Apnea-Obesity Comorbid Duo. 3265 94