Dynamic tests and basal values for defining active acromegaly

Acromegaly is a rare disease caused by excess secretion of growth hormone (GH), usually from a pituitary somatotrope adenoma. The prevalence of acromegaly is 38-40 cases/1,000,000 subjects, while the annual incidence is 3 new cases/1,000,000 subjects. The increase in morbidity and mortality associated with acromegaly is the result of GH and insulin-like growth factor (IGF)-I oversecretion and the direct mass effect of the pituitary tumor. Once the disease is clinically suspected, laboratory evaluation is mandatory to establish diagnosis. The standard method for the diagnosis of acromegaly has been the measuring of GH nadir (GHn) during an oral glucose tolerance test (OGTT) which in normal individuals is undetectable, while acromegalics failed to suppress GH levels. Determination of IGF-I levels is useful as they correlate with clinical features of acromegaly and with the 24-hour mean GH levels. According to the more recent consensus, a random GH <0.4 microg/l and IGF-I in the age- and gender-matched normal range exclude the diagnosis of acromegaly. If either of these levels are not achieved, an OGTT should be performed, and then GHn <1 microg/l during OGTT excludes acromegaly. The therapeutic goals for acromegaly include the relief of sings and symptoms, the control of the tumor mass, the correction of the biochemical markers to normal levels, and the reduction in morbidity and mortality to the expected rate for the normal population. According to the 2000 consensus criteria, biochemical control of acromegaly is achieved when circulating IGF-I is reduced to an age- and sex-adjusted normal range and GHn during OGTT is <1 microg/l. There is debate in the literature whether GHn or IGF-I levels are more reliable to evaluate treatment of acromegaly. It has been reported that 15% of acromegalics with GHn <1 microg/l after treatment demonstrate abnormal IGF-I levels, while 15% of patients with normal IGF-I fail to suppress GH levels <1 microg/l during the OGTT. Probably, GHn and IGF-I levels represent two different aspects of disease activity in acromegaly. While IGF-I evaluates the secretory function of the somatotropes, GHn provides evidence of the presence or absence of functional autonomy of these cells.     

Cardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism

Chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess is associated with considerable mortality in acromegaly, but no data are available in pituitary gigantism. The aim of the study was to evaluate the long-term effects of early exposure to GH and IGF-I excess on cardiovascular and metabolic parameters in adult patients with pituitary gigantism. Six adult male patients with newly diagnosed gigantism due to GH secreting pituitary adenoma were studied and compared with 6 age- and sex-matched patients with acromegaly and 10 healthy subjects. Morphologic and functional cardiac parameters were evaluated by Doppler echocardiography. Glucose metabolism was assessed by evaluating glucose tolerance and homeostasis model assessment index. Disease duration was significantly longer (P<.05) in patients with gigantism than in patients with acromegaly, whereas GH and IGF-I concentrations were comparable. Left ventricular mass was increased both in patients with gigantism and in patients with acromegaly, as compared with controls. Left ventricular hypertrophy was detected in 2 of 6 of both patients with gigantism and patients with acromegaly, and isolated intraventricular septum thickening in 1 patient with gigantism. Inadequate diastolic filling (ratio between early and late transmitral flow velocity<1) was detected in 2 of 6 patients with gigantism and 1 of 6 patients with acromegaly. Impaired glucose metabolism occurrence was higher in patients with acromegaly (66%) compared with patients with gigantism (16%). Concentrations of IGF-I were significantly (P<.05) higher in patients with gigantism who have cardiac abnormalities than in those without cardiac abnormalities. In conclusion, our data suggest that GH/IGF-I excess in young adult patients is associated with morphologic and functional cardiac abnormalities that are similar in patients with gigantism and in patients with acromegaly, whereas occurrence of impaired glucose metabolism appears to be higher in patients with acromegaly, although patients with gigantism are exposed to GH excess for a longer period.     

Insulin-like growth factor-I: marker for diagnosis of acromegaly and monitoring the efficacy of treatment

Acromegaly is caused by chronic excess secretion of growth hormone (GH) and resultant persistent elevation in concentrations of insulin-like growth factor-I (IGF-I), also called somatomedin-C. A number of diagnostic tests are available to support the diagnosis of acromegaly, but those that rely on measurement of serum GH concentrations have important limitations. Concentrations of serum IGF-I, which is produced principally in the liver and mediates the actions of GH, have been shown to correlate with clinical and metabolic markers of disease activity. Additionally, normalisation of IGF-I levels in acromegaly is associated with the resolution of symptoms and normal life expectancy. Thus, serum IGF-I is an important marker of disease activity and a sensitive, practical, and reliable measure of integrated GH concentrations in patients with acromegaly.     

Acromégalie : améliorer la prise en charge: Acromegaly: improving care

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention.© 2019 Published by Elsevier Masson SAS. All rights reserved.Cet article fait partie du numéro supplément Les Must de l’Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.     

Insulin resistance and pseudoacromegaly: A case report

Patients with acromegaly have soft tissue overgrowth that induced characteristic clinical presentation. A growth hormone-secreting adenoma of the anterior pituitary gland is the most common cause of acromegaly. Metabolic and somatic features of acromegaly caused by high serum concentrations of insulin-like growth factor-I (IGF-I) and excess growth hormone (GH) production. we present a case of ‘pseudoacromegaly’ with an acromegaloid features, suppressed IGF-I levels and marked elevation of serum insulin. Endocrinologists should consider this diagnosis when assessing patients with clinical features of acromegaly and insulin resistance, in the absence of elevated levels of GH and IGF-I.     

Clinically silent somatotropinomas may be biochemically active

The diagnosis of acromegaly is suspected based on the typical clinical presentation and is subsequently confirmed biochemically by elevated GH and IGF-I concentrations. We report three female patients with pituitary tumors who presented without any signs or symptoms of acromegaly but with elevated IGF-I levels. Plasma GH was measured every 10 min for 24 h, and an oral glucose tolerance test was performed. All patients had abnormally elevated mean and trough plasma GH levels as well as post-glucose nadir GH concentrations. All patients had magnetic resonance imaging scans revealing pituitary tumors and underwent transsphenoidal surgery. Histologically, they had GH-producing pituitary tumors. Plasma IGF-I levels returned to normal in two patients after surgery. Some pituitary adenomas are true GH-secreting tumors despite not being accompanied by obvious clinical stigmata of acromegaly. Natural history of this disease is unknown because of the small number of reported patients and inconsistent results of biochemical testing. Based on the results of this and previous reports, we propose that all patients with known pituitary tumors, especially younger women with normal or mildly elevated prolactin level, be evaluated for GH excess.     

Mortality and pituitary disease

Outcome data from large series confirm increased mortality of patients with pituitary tumours, predominantly due to vascular disease. Control of cortisol secretion and growth hormone (GH) hypersecretion (together with cardiovascular risk factor reduction) is key in the normalisation of mortality rates in patients with Cushing's disease and acromegaly, respectively, though some excess mortality may persist even in "cured" patients.     

Pitfalls in the Biochemical Assessment of Acromegaly

The biochemical assessment for newly recognized acromegaly is in most, but not all patients straightforward. Although significant improvements in the methods of biochemical testing for acromegaly have recently been made, major pitfalls to the assessment of this disease still exist. A number of different schemes have been employed for the assessment of GH secretion in clinical practice. Random GH levels have been often used, but remain unreliable for the assessment of acromegaly. Mean GH levels are also frequently used to assess GH status, but are not specific for the diagnosis of acromegaly. Measurement of glucose suppressed GH levels is the preferred method for assessing GH secretion in acromegaly. However, it is essential to recognize that when using highly sensitive and specific GH assays, nadir GH levels can be < 1 microg/L after oral glucose in some patients with newly diagnosed acromegaly and postoperative patients with active disease. On the other hand, when using most clinically available commercial GH assays which are less sensitive and specific than those used in research studies, failure of GH suppression into the normal range set in these studies is not alone diagnostic of active acromegaly. In order to diagnose acromegaly, documentation of GH excess should be accompanied by elevation in levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). Consideration also needs to be given to the clinical context in which GH and IGF-I are being measured as both can be altered in a number of clinical settings other than acromegaly. Both IGF-I and GH evaluations are important and complimentary parts of the biochemical assessment of acromegaly.     

Cabergoline in acromegaly

Acromegaly, a rare disease due to growth hormone (GH) hypersecretion by a pituitary adenoma, is associated with severe comorbidity and premature death if not adequately treated. The usual first-line treatment is surgery. Various drugs, including somatostatin receptor ligands, dopamine agonists and GH receptor antagonists, are now available for use if surgery fails to suppress GH/IGF-I hypersecretion. Cabergoline, now the preferred dopamine agonist for treating hyperprolactinemia, is also used off-label for treating acromegaly. Cabergoline monotherapy is reported to normalize IGF-I levels in more than one-third of patients with acromegaly. When a somatostatin receptor ligand proves ineffective, cabergoline add-on therapy normalizes the IGF-I level in 40–50% of patients. Finally, when combined with the GH receptor antagonist pegvisomant in patients with mild uncontrolled disease, cabergoline helps to achieve normal IGF-I levels while avoiding the need for high-dose pegvisomant. Cabergoline is also inexpensive and well tolerated; in particular, it does not appear to promote heart valve disease.     

Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis and therapy

OBJECTIVE Early studies of acromegaly undertaken before the general availability of insulin-like growth factor I (IGF-I) assays have used arbitrary and varying growth hormone (GH) threshold levels for diagnosing and assessing outcome of treatment for this disease. We have undertaken a detailed study of GH secretion and its relationship to IGF-I levels to assess the usefulness of GH and IGF-I measurements in the assessment of acromegaly. PATIENTS Thirty acromegalic subjects (12 untreated and 16 previously treated) and 30 age and sex-matched normal subjects were studied. MEASUREMENTS Twenty-four-hour GH secretion was obtained from 20-minute sampling and serum IGF-I was measured. Comparisons were made of IGF-I, mean 24-hour GH concentration, and of the pulsatile and diurnal characteristics of GH secretion between the two groups. RESULTS IGF-I levels In untreated acromegaly were elevated and clearly separated from the normal range. Mean 24-hour GH concentrations in untreated and treated acromegalic subjects with elevated IGF-I (>40 nmol/l) were greater than (P < 0.01), and showed good separation from, those of normal subjects only after age-matching. From the 24-hour prollfes, nadir GH levels In normal subjects fell below the level of detectability while those in untreated acromegalic subjects did not. Pulse amplitude (P<0.01), ratio of pulsatile to non-pulsatile GH release and the night to daytime GH ratio (P<0 05) were significantly reduced in acromegaly. In the six patients who attained normal IGF-I levels after surgery, pulsatile characteristics remained abnormal in four. Mean 24-hour GH was significant related (r = 0.57) to IGF-I. A random GH concentration >2.5 μg/l (5 mlU/l) has a sensitivity of 77% and specificity of 95% In identifying acromegalic patients who have biochemically active disease (elevated IGF-I) after treatment. CONCLUSIONS Patients with active acromegaly secrete more GH than age-matched normal controls. GH secretion in acromegaly is characterized by marked blunting of pulsatile secretion and, in contrast to normal subjects, the failure of GH to fall to undetectable levels at any time during the 24-hour day. IGF-I measurement is a more practical alternative in the diagnosis of acromegaly and in the assessment of therapeutic outcome. Since abnormalities of GH regulation may persist despite normalization of IGF-I, a distinction between remission and cure should be made. Detailed post-treatment evaluation of GH secretion is necessary to define the nature of underlying GH regulation and to evaluate the risk of disease recurrence.     

The changing face of acromegaly-advances in diagnosis and treatment

Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly-such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities.     

Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly

INTRODUCTION: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established. PATIENTS AND METHODS: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57+/-1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2+/-7 years. RESULTS: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck. CONCLUSION: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.     

Serum IGF-I levels in the diagnosis and monitoring of acromegaly

Insulin-Like Growth Factor-I (IGF-I) is a reliable marker of disease activity and growth hormone (GH) status in acromegaly, but its clinical utility has been hampered over the years by various issues including a lack of robust reference range data and variability in assay sensitivity and specificity. In acromegaly IGF-I correlates well with GH activity and nadir GH on oral glucose tolerance test (OGTT) and is the most sensitive and specific test in diagnosis, where serum IGF-I is persistently seen to be elevated to a range that is distinct from that in healthy individuals. However it should not be relied on exclusively for diagnosis or used as the sole indication of disease severity and GH burden. Successful medical or surgical treatment of acromegaly is usually associated with normalisation of serum IGF-I but there is discordance between GH and IGF-I in some patients. Patients with a normal IGF-I but an abnormal GH suppression to OGTT are at risk of relapse and therefore it should not be used alone to establish disease remission. In contrast to the diagnosis of acromegaly, there is also considerable overlap in serum IGF-I with normality after primary treatment of disease, even in the presence of persisting GH excess. Gender, age and prior radiotherapy alters the relationship between GH and IGF-I and reliance on one marker of disease activity such as IGF-I is particularly precarious in certain disease states. However an elevated serum IGF-I has been shown to be associated with excess mortality and normalising IGF-I normalises mortality making it a useful marker. The tightening up of the assays means that establishing absolute concentrations as well as standard deviation scores are essential to allow cross-study comparisons. This becomes especially important in the use of Pegvisomant, where IGF-I becomes the sole biochemical marker of disease activity.     

Attenuated pulse size, disorderly growth hormone and prolactin secretion with preserved nyctohemeral rhythm distinguish irradiated from surgically treated acromegaly patients

BACKGROUND: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined. OBJECTIVE: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT). DESIGN: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls. SETTING/PARTICIPANTS: University setting. Fifteen subjects in each group. OUTCOME MEASURES: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations. RESULTS: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others. CONCLUSION: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.     

Cardiac Abnormalities in Acromegaly

Cardiovascular disease is claimed to be one of the most severe complications of acromegaly, contributing significantly to mortality in this disease. In fact, an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF-I) causes a specific derangement of cardiomyocytes, leading to abnormalities in cardiac muscle structure and function, inducing a specific cardiomyopathy. In the early phase of acromegaly the excess of GH and IGF-I induces a hyperkinetic syndrome, characterized by increased heart rate and increased systolic output. Concentric hypertrophy is the most common feature of cardiac involvement in acromegaly, found in more than two thirds of patients at diagnosis. This abnormality is commonly associated with diastolic dysfunction and eventually with impaired systolic function ending in heart failure, if the GH/IGF-I excess is left untreated. In addition, abnormalities of cardiac rhythm and of heart valves have also been described in acromegaly. The coexistence of other complications, such as arterial hypertension and diabetes mellitus, aggravates acromegalic cardiomyopathy. Successful control of acromegaly induces a decrease in left ventricular mass and an improvement in diastolic function, while the effects of GH/IGF-I suppression on systolic function are more variable. However, since cardiovascular alterations in young patients with short disease duration are milder than in those with longer disease duration, it is likely to be easier to reverse and/or arrest acromegalic cardiomyopathy in young patients with early-onset disease. In conclusion, careful assessments of cardiac function, morphology, and activity are required in patients with acromegaly. An early diagnosis and prompt effective treatment are important in order to reverse acromegalic cardiomyopathy.     

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl

OBJECTIVE: The use of a growth hormone (GH) receptor antagonist, pegvisomant has shown great promise in adults with acromegaly, but experience in paediatric patients is lacking. We aimed to describe the results of pegvisomant therapy in a 12-year-old girl with an aggressive GH-secreting pituitary tumour. DESIGN: To evaluate the ability of pegvisomant therapy to control the effects of peripheral GH excess in a case of pituitary gigantism. METHODS: Pegvisomant was introduced at 10 mg/day, given subcutaneously, and gradually increased to 20 mg/day until serum IGF-I was normal for age. RESULTS: A large pituitary adenoma with suprasellar extension was diagnosed in a 12-year-old girl with progressive tall stature (178 cm), GH hypersecretion without suppression during oral glucose loading (nadir serum GH, 90 mU/l), high serum IGF-I and serum prolactin levels. Surgical extirpation was not possible because tumour tissue was fibrous and adherent to the optical nerves. Histological examination showed a mixed GH- and prolactin-secreting adenoma with lymphocytic infiltration of B and T cells. Treatment with a dopamine agonist, cabergoline, normalized serum prolactin, but GH secretion was resistant to both somatostatin analogue, octreotide and cabergoline. Radiation followed by pegvisomant therapy titrated up in dose to 20 mg/day led to a marked reduction in GH secretion and normalization of IGF-I, and to growth arrest and improvement of well-being. CONCLUSIONS: We suggest that treatment in pituitary gigantism with pegvisomant is safe and may normalize IGF-I levels and effectively stop growing.     

Clinical use of a growth hormone receptor antagonist in the treatment of acromegaly.

The elucidation of the mechanisms by which growth hormone (GH) interacts with its receptor has facilitated the design of compounds that function as GH-receptor antagonists. One such compound, B2036, has been conjugated to polyethylene glycol to produce a drug, pegvisomant, that has a powerful ability to lower circulating concentrations of insulin-like growth factor I (IGF-I), the principal mediator of GH action, in patients with acromegaly and to improve the symptoms and signs associated with GH excess. This article describes the mechanism of action of GH-receptor antagonists, reviews the preclinical and clinical data on the use of pegvisomant and discusses some of the challenges that lie ahead in judging the efficacy of a treatment that, unlike established therapies for acromegaly, does not aim to modify the underlying cause of acromegaly, namely excess GH secretion, but aims to lower serum IGF-I levels to normal.     

Clinical utility of measurements of insulin-like growth factor 1

Plasma insulin-like growth factor 1 (IGF-I) concentrations are regulated by genetic factors, nutrient intake, growth hormone (GH) and other hormones such as T4, cortisol and sex steroids. The accuracy of IGF-I measurement in diagnosing GH deficiency or excess depends, in part, on the relative contributions of each of these variables. Since their respective influence may vary widely between individuals, the establishment of well-defined normal ranges is necessary, which requires adequate numbers of normal individuals, in order for IGF-I measurements to have maximum utility. In states of GH deficiency, the influence of these non-GH-related factors predominates. Although IGF-I levels have utility as a screening test in children and young adults, they cannot be used as a stand-alone test for the diagnosis of GH deficiency. By contrast, in acromegaly, GH is the predominant determinant of IGF-I levels and, therefore, measurement of IGF-I is a very useful diagnostic test. In acromegaly, IGF-I levels are useful for assessing the relative degree of GH excess, because changes in IGF-I correlate with changes in symptoms and soft-tissue growth. IGF-I is also very useful in monitoring the symptomatic response to therapy.     

Acromegaly

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 μg/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 μg/l (0.3 μg/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.     

Preserved thyroidal secretion of thyroxione in acromegalic patients with suppressed hypophyseal secretion of thyrotrophin

OBJECTIVE--We have assessed the mechanisms which maintain euthyroidism in acromegalic patients despite the suppression of thyrotrophin (TSH) secretion. MATERIALS--Fourteen untreated patients with acromegaly were analysed. Ten patients were also studied after pituitary surgery. METHODS--Thyroid hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and thyroidal uptake of radioactive iodine, thyrotrophin releasing hormone (TRH) test and basal metabolic rate (BMR) were measured before and after pituitary surgery. RESULTS--Nine patients had palpable goitres. The TSH response to TRH stimulation was suppressed in eight patients, who maintained normal serum levels of total T3, T4 and free T4. The patients with normal TSH response had lower levels of free and total T4 than controls. The response of TSH to TRH correlated inversely with the serum level of total and free T4, and also with the plasma level of IGF-I (r = -0.74, P less than 0.05, n = 9). After pituitary surgery, the serum levels of total and free T4 were elevated for at least up to 6 months, with a decrease in the T3/T4 ratio and the BMR. CONCLUSION--GH may have a direct stimulatory action on the thyroid secretion of T4 possibly via increased IGF-I, despite suppressed TSH secretion. The post-operative elevation of serum T4 suggests the persistent secretion of T4 from the thyroid gland, in spite of instantaneous normalization of the accelerated conversion of T4 to T3, even after reduction of excess GH secretion.