Commencing growth hormone replacement in adults with a fixed low dose. Effects on serum lipoproteins, glucose metabolism, body composition, and cardiovascular function.

The safety and effects of a fixed low dose of growth hormone (GH), 0.17 mg/day was evaluated for 3 months, on glucose metabolism, serum lipids, body composition and cardiac function in 53 GH deficient adults aged 18-78 years. Body composition was determined by dual energy X-ray absorptiometry and total body water was determined by bioelectrical impedance. Echocardiography was used to assess cardiac function and bicycle ergonometry was used to determine exercise capacity. All investigations were performed at baseline and after 3 months. At 3 months, serum levels of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and lipoprotein (a) and lean body mass were increased (P<0.05). Total and low density lipoprotein cholesterol levels and fat mass were reduced (P<0.05). There was an increase in the serum glucose value at 120 min after an oral glucose tolerance test performed at 3 months (P<0.05), no other changes in glucose metabolism or in cardiac function were noted. Side-effects were few and mild. This fixed low-dose regime resulted in improvements in body composition and lipid profile, without causing serious side effects. This is therefore a valid method to institute GH replacement in adults.

Inhibition of the rise in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-deficient adults.

To test the hypothesis that GH-induced insulin resistance is mediated by an increase in FFA levels we assessed insulin sensitivity after inhibiting the increase in FFA by a nicotine acid derivative, Acipimox, in nine GH-deficient adults receiving GH replacement therapy. The patients received in a double blind fashion either Acipimox (500 mg) or placebo before a 2-h euglycemic (plasma glucose, 5.5 +/- 0.2 mmol/liter) hyperinsulinemic (serum insulin, 28.7 +/- 6.3 mU/liter) clamp in combination with indirect calorimetry and infusion of [3-(3)H]glucose. Acipimox decreased fasting FFA by 88% (P = 0.012) and basal lipid oxidation by 39% (P = 0.015) compared with placebo. In addition, the insulin-stimulated lipid oxidation was 31% (P = 0.0077) lower during Acipimox than during placebo. Acipimox increased insulin-stimulated total glucose uptake by 36% (P = 0.021) compared with placebo, which mainly was due to a 47% (P = 0.015) increase in glucose oxidation. GH induced insulin resistance is partially prevented by inhibition of lipolysis by Acipimox.

Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease.

Although a specific GH deficiency (GHD) syndrome in the adult and the response to GH replacement therapy are well recognized, there are few data available on the effect of GH replacement therapy in elderly GH-deficient patients. We studied the effect of GH therapy on body composition and bone mineral density measured by dual energy x-ray absorptiometry, markers for bone metabolism, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in 31 patients (6 women and 25 men; aged 60-79 yr; mean, 68 yr) with multiple pituitary hormone deficiencies. The GH response to arginine or insulin was below 3 microg/L (9 mU/L) in all subjects. They were randomized to GH (Humatrope, Eli Lilly & Co.) or placebo for 6 months, followed by 12 months of open treatment. The dose was 0.05 IU/kg x week for 1 month, and after that it was 0.1 IU/kg x week divided into daily sc injections (0.75-1.25 IU/day). There were no changes in any of the measured variables during placebo treatment. GH treatment normalized serum IGF-I in a majority of the patients and increased IGFBP-3 and -5 as well as IGFBP-4 and IGF-II to values within normal range. Lean body mass was increased, and the increase at 6 and 12 months correlated with the increase in IGF-I (r = 0.46; P = 0.010 and r = 0.54, respectively; P = 0.003). GH treatment caused a modest, but highly significant, reduction of total body fat. Mean bone mineral density was not different from that in healthy subjects of the same age and did not change during the observation period. Markers for bone formation (bone-specific alkaline phosphatase activity, osteocalcin, and procollagen I carboxyl-terminal peptide in serum) increased within the normal range, and levels were sustained throughout the study. The bone resorption marker (pyridinoline in urine) was significantly elevated for 12 months. Side-effects were mild, mostly attributed to fluid retention. In two patients with normal glucose tolerance at the start of the study, pathological glucose tolerance occurred in one patient and was impaired in one. In conclusion, elderly patients with GHD respond to replacement therapy in a similar manner as younger subjects, with an improvement in body composition and an increase in markers for bone metabolism. Side-effects are few, and elderly GHD patients can be offered treatment. As long-term risks are unknown, GH doses should be titrated to keep IGF-I within the age-related physiological range.

Early postoperative growth hormone levels: high predictive value for long-term outcome after surgery for acromegaly.

OBJECTIVES: To explore the prognostic value of early - within 1 week - postoperative growth hormone (GH) measurements with regard to outcome after surgery for acromegaly in a short- and a long-term perspective. DESIGN: Retrospective study of patients operated on between 1987 and 1998, including follow-up for up to 60 months. SETTING: University hospital. SUBJECTS: Sixty-eight patients with acromegaly. INTERVENTION: Pituitary surgery aiming at adenomectomy with preservation of pituitary function. MAIN OUTCOME MEASURES: The effect of the operation was evaluated after 3 months, mostly by means of an oral glucose load or by insulin-like growth factor 1 (IGF-1). The specificity, sensitivity and the predictive values of an early postoperative mean GH concentration 4.8 mU L-1 had a 77.8% predictive value for persistent or recurrent disease, compared with 85.7% for persistently increased SmC/IGF-1 and 68.8% for an abnormal GH release after TRH 3 months after surgery. In the short-term perspective, the specificity and the predictive value of an early GH 4.8 mU L-1 had a 94.4% sensitivity but a predicative value of only 63.0% for an unsatisfactory effect. CONCLUSION: Measurement of GH within 1 week after surgery is highly predictive for outcome of surgery for acromegaly. Specifically, an early mean GH 4.8 mU L-1 have a high sensitivity for persistent or recurrent disease in both the short- and long-term perspectives, but lower predictive value. The usefulness of the TRH test can be questioned.

Effect of 6 months of GH treatment on myosin heavy chain composition in GH-deficient patients.

OBJECTIVE: To investigate the effect of GH on myosin heavy chain (MHC) isoform composition, physical fitness and body composition in GH-deficient (GHD) patients. DESIGN: Twenty-two GHD patients were randomized in a double blind manner and half were treated with recombinant human GH (rhGH) and half were treated with placebo for 6 months. Twelve age-matched controls were also included in the study. METHODS: MHC isoform composition in biopsies obtained from the vastus lateralis muscle was determined using SDS-PAGE. Physical fitness was determined on a bicycle ergometer and body composition was determined using bioelectrical impedance analysis. RESULTS: More MHC IIX (28.9 +/- 4.1% and 10.0 +/- 3.1% in GHD and controls respectively (means +/- S.E.M.)) and less MHC I (36.2 +/- 2.4% and 51.7 +/- 3.9% in GHD and controls respectively (means +/- S.E.M.)) were present in the GHD patients compared with the controls. No significant difference in the amount of MHC IIA was detected. Linear regression was used to determine the relationship between variables. There were no significant relationships between the concentration of insulin-like growth factor-I (IGF-I) or the body composition and the MHC composition. Maximal oxygen uptake (VO(2)max) per kg body weight (BW) (litres/min per kg) correlated significantly with the amount of MHC I (r=0.60) and MHC IIX (r=-0.72) but not with the amount of MHC IIA (r=0.35). Treatment of GHD patients with rhGH for 6 months increased the concentration of IGF-I, lean body mass and decreased fat mass but had no effect on MHC composition and physical fitness. CONCLUSIONS: We conclude that a major part of the differences in MHC composition between GHD patients and age-matched controls can be explained by variation in physical fitness. The severity of the GHD and the body composition does not seem to be important for the MHC composition. Furthermore, treatment with GH for 6 months does not affect MHC composition in GHD patients.

[Hypophyseal incidentaloma is a common finding requiring investigation. The question is: surgery, medication or wait-and-see?]. / Incidentalom i hypofysen ses ofta, måste utredas. Frågan är: operera, medicinera eller bara följa utvecklingen?

The advent of new radiological methods such as CT (computerised tomography) and MRI (magnetic resonance imaging) has resulted in the detection of increasing numbers of anatomical changes in the pituitary. When discovered in patients without evidence of pituitary disease, they are called pituitary incidentalomas. They defy classification on a radiological basis. Micro-incidentalomas (< 10 mm in diameter) do not usually cause pituitary insufficiency, but may be associated with low-grade overproduction of prolactin, growth hormone, or adrenocorticotropic hormone (which may be cyclic). Although micro-incidentalomas rarely increase in size, follow-up with CT or MRI is recommended after one, two and five years. Macro-incidentalomas (> or = 10 mm in diameter) should initially be investigated with respect to possible visual field defects and any evidence of pituitary insufficiency, particularly hypogonadism. In some instances, macro-incidentalomas increase in size and require monitoring with MRI or CT at closer intervals, i.e., after six months, and then after one and two years, and every other year thereafter.

The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender.

The aim of the present trial was to study the individual responsiveness to GH treatment in terms of body composition and to search for possible predictors of the response in GH-deficient adults. Sixty-eight patients (44 men and 24 women) with a mean age of 44.3 (1.2) yr and verified GH deficiency participated in a 2-phase treatment trial with an initial randomized, double blind, placebo-controlled, 6-month period, followed by an open treatment period, thereby ensuring all patients 12 months of GH treatment. Recombinant human GH was administered sc daily at bedtime, with a target dose of 12 micrograms/kg x day. GHBP was measured by ligand-mediated immunofunctional assay, and serum insulin-like growth factor I (IGF-I) was determined by RIA after acid-ethanol extraction, using a truncated IGF-I analog as the radioligand. Lean body mass (LBM) and body fat (BF) were determined by dual energy x-ray absorptiometry, and total body water (TBW) was determined by bioelectrical impedance. During the placebo control period, serum IGF-I,LBM, and TBW increased (P < 0.001), whereas BF decreased (P < 0.001) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo. After 12 months of GH treatment, the individual changes in BF ranged from -12.5 to 4.3 kg and from -4.5 to 10.1 kg in LBM. Age (P < 0.05) and baseline GHBP level (P < 0.01) were inversely correlated with the increase in LBM. The GH-induced increment in IGF-I and TBW was greater in men than in women (P < 0.01), whereas the decreases in BF were similar in men and women. This trial demonstrates the variability in responsiveness to GH administration in GH-deficient adults. The best response to GH was obtained in younger patients with low GHBP levels. Furthermore, men responded better than women.

Bilateral isolated adrenal coccidioidomycosis.

A case of bilateral isolated adrenal coccidioidomycosis in a previously healthy and immunocompetent 43-year-old Caucasian male is presented. He had never travelled to a coccidioidomycosis endemic area. Subclinical adrenal dysfunction was found with elevated plasma ACTH and mineralocorticosteroid and androgen pathway abnormalities. The implement of the fungal infection on adrenal function, and the diagnosis and management of adrenal coccidioidomycosis are discussed.

Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy.

To evaluate the consequences of growth hormone (GH) deficiency on bone mineral density and to evaluate the effects of GH substitution therapy, 68 adults (25 females and 43 males) aged 22-61 (mean 44.2 +/- 1.2) years with GH deficiency (GHD) were studied. Fifty-eight patients had panhypopituitarism, three had isolated GHD and in seven patients at least one additional pituitary function was affected. Twenty-one patients had childhood onset GHD. The patients were randomized to receive either GH in daily injections (0.125 IU.kg-1. week-1 for the first 4 weeks and subsequently 0.25 IU.kg-1. week-1) or placebo for 6 months. The trial continued as an open study with GH treatment for 6 to 12 months, with data presented as compiled data of 12 months of GH treatment in 64 patients. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry and bone turnover was assessed by serum markers of bone metabolism (osteocalcin, procollagen I peptide, cross-linked telopeptide of type I collagen and alkaline phosphatase activity), In women with adult onset GHD (N = 19) and in men with childhood onset GHD (N = 15), total body, spine and hip BMD was significantly reduced at baseline compared to Swedish age- and sex-matched control material. In men with adult onset of GHD (N = 28), BMD did not differ from male controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased blood pressure response to infused noradrenaline in normotensive as compared to hypertensive patients with primary hypothyroidism.

OBJECTIVE AND PATIENTS: To further explore the difference in plasma noradrenaline in normotensive and hypertensive hypothyroid patients we have investigated the pressor response to exogenous noradrenaline in 11 normotensive and five hypertensive patients with primary hypothyroidism before and after thyroxine replacement. Seven healthy subjects served as controls. DESIGN: The patients were studied under metabolic ward conditions and received a Na+ and K+ defined diet for 4 days. The controls received the same diet on an ambulatory basis for 3 days and were admitted to the ward in the evening on the third day. In the morning of day 4 a graded noradrenaline infusion was given. When the increase in systolic blood pressure in two consecutive registrations was at least 20 mmHg as compared to basal values the noradrenaline infusion was stopped. The dose required to increase systolic blood pressure by 20 mmHg (I20) was determined. RESULTS: During hypothyroidism the I20 was 120 ng/kg BW/min in normotensive patients and 39 in hypertensive patients as compared to 62 in controls. The I20 was higher in normotensives as compared to hypertensives (P = 0.041). The I20 was not different in hypertensives as compared to controls. When the patients had become euthyroid I20 decreased to 51 ng/kg BW/min (P = 0.04) in the normotensives, but remained unchanged in the hypertensives. There was no difference in I20 between normotensive and hypertensive patients in the euthyroid state, or when compared to controls. CONCLUSION: The pressor response to noradrenaline was decreased in normotensive hypothyroid as compared to hypertensive hypothyroid patients, indicating a decreased peripheral sensitivity to noradrenaline in normotensive hypothyroid patients. Following thyroxine replacement the decreased response became normal.

Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state.

The use of venous plasma noradrenaline levels as a marker of general sympathetic tone has been questioned as changes in local sympathetic activity may influence the venous levels. To compare arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism, arterial and venous blood were sampled during strictly standardized conditions during hypothyroid and euthyroid states. The patients were hospitalized for 5 days at a metabolic ward on a standardized sodium and potassium intake. On the fourth day catheters were positioned in the axillary artery and vein. Blood samples were drawn simultaneously for noradrenaline and adrenaline determinations during resting conditions. The arterial and venous plasma noradrenaline levels did not differ significantly, neither during hypothyroidism nor during euthyroidism. The arteriovenous difference in plasma adrenaline was similar during hypothyroidism compared to euthyroidism, indicating similar peripheral extraction rate of catecholamines during hypothyroidism as compared to euthyroidism. During hypothyroidism venous and arterial noradrenaline were significantly higher as compared to euthyroidism. In conclusion, there is no difference between arterial and venous noradrenaline levels either in the hypothyroid or the euthyroid state, and the peripheral extraction rate of plasma noradrenaline seems to be similar in hypothyroidism and euthyroidism. The local contribution of noradrenaline from the arm, reflecting local sympathetic nervous activity, is limited during resting conditions. In hypothyroid patients plasma noradrenaline levels are increased as compared to the euthyroid state, indicating increased general sympathetic activity in hypothyroidism.

Plasma neuropeptide Y (NPY) and galanin before and during exercise in type 1 diabetic patients with autonomic dysfunction.

Plasma neuropeptide Y (NPY), plasma galanin and plasma catecholamines were determined before and during an ergometer exercise test in 11 type 1 diabetic patients (age 19-36 years, mean 30; duration of diabetes 2-18 years, mean 9) with autonomic dysfunction and in 13 age-matched healthy controls (age 24-36 years, mean 29). Before exercise, plasma NPY (100 +/- 6 pmol/l vs 144 +/- 7 pmol/l; P less than 0.001) and plasma galanin (54 +/- 3 pmol/l vs 77 +/- 5 pmol/l; P less than 0.005) were significantly lower in patients than in controls. During exercise, plasma NPY, plasma adrenaline, and plasma noradrenaline increased in patients and controls while galanin only increased in patients. Since there was a direct correlation between plasma NPY before exercise and the increment (delta 80%) in noradrenaline during exercise (r = 0.54; P less than 0.01), it is suggested that plasma NPY determined in the basal situation may be a useful marker of sympathetic nerve failure in diabetic patients.

Early postoperative basal serum GH level and the GH response to TRH in relation to the long-term outcome of surgical treatment for acromegaly: a report on 39 patients.

During a 10-year period 39 patients with acromegaly, aged 23-73 years, underwent selective adenomectomy via a trans-sphenoidal or transfrontal (one case) approach. Six to 12 months after the operation, the serum level of growth hormone (GH) was reduced to less than 5 micrograms l-1 in 28 patients (74%) in at least two of three random samples and/or suppressed to less than 3 micrograms l-1 during an oral glucose load, thus fulfilling the commonly used criteria for a successful operation. In 10 patients these criteria for adequate GH reduction were not fulfilled, but their median S-GH level was reduced from 38 to 11 micrograms l-1 (P less than 0.01) after the operation. Surgery was successful in 11 of 13 (85%) patients with a microadenoma (less than 10 mm in diameter), in 10 of 14 (71%) patients with an adenoma of diameter greater than 10 mm but still enclosed in the sella, and in seven of 11 (64%) patients with locally invasive tumours. Impaired pituitary function was observed in 23% of the patients after surgery, independent of tumour size. In one patient the postoperative period was complicated by a lethal intracranial infection. During follow-up for 1-10 years, four patients relapsed, after 1, 1.5, 6 and 9 years, respectively. Patients for whom surgery appeared to have been ineffective at the evaluation 6-12 months postoperatively, or who later relapsed were identified by early (within 7 d) postoperative serum GH with a sensitivity of 90%. The accuracy for identification of a satisfactory outcome of surgery was 85%, and the predictive value was 90%. The corresponding values for the GH response to TRH measured 6-12 months postoperatively were 47, 40 and 54%, respectively. It is concluded that the basal level of serum GH measured 1-7 d postoperatively has higher sensitivity and specificity than the GH response to TRH 6-12 months postoperatively for evaluation of the effect of surgery on GH overproduction, and that it has a higher predictive power with regard to the long-term outcome of surgery for acromegaly.

The activity of the renin-angiotensin-aldosterone system before and during submaximal bicycle exercise in relation to circulatory catecholamines in patients with type 1 (insulin-dependent) diabetes mellitus.

To evaluate the renin-angiotensin-aldosterone system in relation to circulatory catecholamines, we determined renin activity, angiotensin II, aldosterone, adrenaline, and noradrenaline in plasma before and during a submaximal bicycle exercise test in 23 Type 1 (insulin-dependent) diabetic patients (aged 19-57 years, mean 37; duration of diabetes 2-32 years, mean 16), 17 with signs of cardiac autonomic neuropathy, and in 18 healthy non-diabetic subjects (aged 24-41 years, mean 29). At rest, Type 1 diabetic patients showed significantly lower aldosterone values than control subjects (0.14 +/- 0.02 nmol/l and 0.22 +/- 0.02 nmol/l; p less than 0.01) while renin activity (1.0 +/- 0.1 nmol.l-1.h-1 and 0.9 +/- 0.1 nmol.l-1.h-1) and angiotensin II (14 +/- 1 nmol/l and 18 +/- 2 nmol/l) did not differ significantly between patients and control subjects. During exercise, increments (increase from the resting value to the value at 80% of maximal working capacity) in renin (1.5 +/- 0.4 nmol.l-1.h-1 and 3.7 +/- 0.5 nmol.l-1.h-1; p less than 0.001), angiotensin II (28 +/- 8 nmol/l and 60 +/- 8 nmol/l; p less than 0.001), aldosterone (0.16 +/- 0.04 nmol/l and 0.25 +/- 0.05 nmol/l; p less than 0.05), adrenaline (1.96 +/- 0.49 nmol/l and 2.92 +/- 0.51 nmol/l; p less than 0.05), and noradrenaline (12.01 +/- 1.25 nmol/l and 18.74 +/- 1.45 nmol/l; p less than 0.01) were significantly lower in the patients than in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Normal visual fields as assessed by computerized static threshold perimetry in patients with untreated primary hypothyroidism.

In this prospective study, 25 consecutive patients with untreated primary hypothyroidism were tested with a highly sensitive perimetric technique, since a high prevalence of visual field defects has been described in this condition. All patients had clinical hypothyroidism, a serum TSH value greater than 20 mU/l (reference range 0.4-4.0) and decreased/low normal serum total T4 concentration. Visual fields were tested with fully automated threshold-measuring computerized perimetry of the central 30 degrees field. Interpretation of fields included computer-assisted analysis provided by a perimetric statistical programme package. In 23 patients, conventional inspection and computer-assisted analysis showed no visual field defects. Two patients were excluded from the latter analysis: one patient who did not respond adequately at computerized perimetry and in whom manual field tests were entirely normal: one patient who had low sensitivity values in the uppermost parts of both visual fields owing to markedly swollen upper eye lids. In conclusion, although pituitary hyperplasia has been well documented in primary hypothyroidism, the present prospective study clearly indicates that visual field defects are not a common finding in patients with this disease.

Impaired responses of plasma catecholamines to exercise in diabetic patients with abnormal heart rate reactions to tilt.

The plasma catecholamine response to a standardized bicycle exercise test was evaluated in 24 insulin-dependent diabetic (IDDM) patients in whom the heart rate reactions to deep breathing (E/I ratio) and to tilt, the immediate acceleration and the transient deceleration (acceleration and brake indices), had been assessed as tests of autonomic neuropathy. Patients with an abnormal acceleration index (n = 8) showed, compared with non-diabetic (n = 18) controls who had participated in previous studies, an impaired increment in noradrenaline during exercise (80% of maximal working capacity) (MWC) (12.38 +/- 1.46 nmol l-1 vs. 18.74 +/- 1.45 nmol l-1; P less than 0.01) and adrenaline (50% of MWC: 0.25 +/- 0.04 nmol l-1 vs. 0.54 +/- 0.08 nmol l-1; P less than 0.05). Similarly, patients with an isolated abnormal brake index (n = 6), i.e. with a normal acceleration index and a normal E/I ratio, showed compared with controls an impaired increment in noradrenaline (9.53 +/- 1.66 nmol l-1 vs. 18.74 +/- 1.45 nmol l-1; P less than 0.01) and adrenaline (1.41 +/- 0.22 nmol l-1 vs. 2.92 +/- 0.51 nmol l-1; P less than 0.05) during 80% of MWC. IDDM patients with abnormal heart rate reactions to tilt, an abnormal acceleration index or an abnormal brake index show impaired catecholamine responses to exercise, which can be demonstrated also in patients without signs of parasympathetic neuropathy.

The effect of naloxone on blood pressure, heart rate, plasma catecholamines, renin activity and aldosterone following exercise in healthy males.

There is evidence that endogenous opioids are involved in blood pressure regulation. In the present study the effect of naloxone on the cardiovascular, sympathoadrenomedullary and renin-aldosterone response to physical exercise was investigated in 8 healthy males. Each subject performed a submaximal work test twice, i.e. with and without naloxone. The test consisted of ergometer bicycling for 10 minutes on 50% of the maximal working capacity (MWC), immediately followed by 10 min on 80% of MWC. Ten minutes before exercise the subjects received in a single blind randomized order a bolus dose of naloxone (100 micrograms/kg) or a corresponding volume of the preservatives of the naloxone preparation (control) followed by a slow infusion of naloxone (50 micrograms/kg/h) or preservatives, respectively. Naloxone was without effect on the exercise-induced changes in systolic blood pressure, heart rate, plasma noradrenaline, renin activity and aldosterone, but the adrenaline response increased markedly. The present results indicate that opioid receptors are involved in the plasma adrenaline response to submaximal exercise, but not in the regulation of systolic blood pressure, heart rate, plasma noradrenaline, renin activity and plasma aldosterone.