AcroVoice: eliciting the patients' perspective on acromegaly disease activity.

PURPOSE: To determine how patients define acromegaly disease activity and treatment success and to quantify from the patients' perspective the relative importance of each disease parameter included in the ACRODAT®. METHODS: One hundred acromegaly patients on medical therapy (mean age = 47.1 years; SD = 11.96) completed an online preference study evaluating hypothetical patient profiles described in terms of insulin-like growth factor-I (IGF-I) levels, tumor size, comorbid conditions, signs/symptoms, and quality of life (QoL). Participants first completed a single-profile task experiment by rating 20 single patient profiles as exhibiting stable, mild, or significant disease activity based on treatment success. Next, participants completed a double-profile discrete choice experiment (DCE) by selecting the patient that was doing "better" from 15 profile pairs. Results were analyzed using logistic and conditional logistic models. RESULTS: When choosing between stable vs. mild or significant disease activity, signs/symptoms, tumor size, and IGF-I levels were weighted equally; IGF-I and signs and symptoms were valued equally when selecting mild vs. significant disease activity. The DCE showed that, statistically, all disease parameters, except comorbid conditions, predicted health status equally. Tumor size and IGF-I levels each accounted for 23% of the decision-making process; QoL, signs/symptoms, and comorbid conditions accounted for 21%, 19%, and 14%, respectively. CONCLUSION: All five ACRODAT® parameters had some influence on disease activity from the patients' perspective. To account for patients' preferences and optimize treatment and outcomes, a holistic disease management approach should be employed.

Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women's Medical University.

OBJECTIVE: The purpose of this study was to survey the clinical characteristics, complications, and therapeutic outcome in patients with acromegaly. PATIENTS AND METHODS: The clinical features of 65 patients with acromegaly (31 males, 34 females; mean age: 50+/-2 yr.) who were admitted to Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. RESULTS: The retrospective analysis revealed that the diagnosis of acromegaly was preceded by approximately 8.1+/-1.1 years of signs and symptoms of the disease. Forty-six of the 65 patients (71%) had macroadenomas, 16 (25%) had microadenomas, and the remaining three had empty sella. The rate of biochemical cure or remission was 81% for microadenoma (13/16), 64% for macroadenoma without extrasellar extension (9/14), and 13% for macroadenoma with cavernous sinus extension (2/15). Eighteen (28%) patients had impaired glucose tolerance (IGT) and 32 (49%) had diabetes mellitus (DM). After treatment for acromegaly, glucose metabolism was analyzed again in 38 patients, and it improved in 26 patients with IGT or DM. Twenty-five of 65 patients (38%) had hypertension. Of 26 patients who underwent barium enema or colonoscopy, 10 had colonic polyps and 4 had colon cancer. CONCLUSION: This study suggests that long-term excessive growth hormone (GH) secretion causes many complications. Therefore, awareness of the early symptoms and signs of acromegaly and long-term careful management of complications, along with therapy to reduce serum GH/insulin-like growth factor (IGF)-I levels, are important for patients with acromegaly.

Intracellular calcium ion responses to somatostatin in cells from human somatotroph adenomas.

OBJECTIVE: Various GH secretory responses to long-acting somatostatin (SRIH) analogues have been observed during the treatment of acromegalic patients. The effects of SRIH on intracellular Ca2+ homeostasis in human somatotroph adenoma cells has not been examined in detail, and the underlying mechanisms therefore remain to be determined. Using isolated cells from human somatotroph adenomas, we have investigated the SRIH-induced intracellular Ca2+ responses at a single-cell level with computerized real time intracellular calcium ion (Ca2+i) imaging. PATIENTS: Adenoma specimens were obtained from 4 male and 11 female acromagalic patients (mean age 56, range 26-72 years) undergoing transsphenoidal hypophysectomy. METHODS: The identity of the biopsy material obtained was confirmed by Immunocytochemistry for hGH and in situ hybridization histochemistry using a 35S end-labelled hGH oligodeoxynucleotide probe and probes complementary to proopiomelanocortin and prolactin. Genomic DNA coding for somatostatin receptor (SSTR2) from each adenoma was PCR amplified and sequenced. Cells cultured from these adenoma were subject to computerized real time intracellular Ca2+i imaging at a single cell level. RESULTS: In cells from 11 of the 15 adenomas, SRIH produced a reversible, dose-independent reduction in [Ca2+]i from the mean of 167 +/- 11 to 43 +/- 3 nM within 51 +/- 1.8 s, and blocked the growth hormone releasing hormone (GRH)-induced increase in [Ca2+]i as expected. In the same adenomas, withdrawal of SRIH after a 30 second exposure produced a small but significant increase in resting [Ca2+]i. Pretreatment with pertussis toxin abolished the SRIH-Induced inhibition of [Ca2+]i and prevented the SRIH-induced inhibition of the effect of GRH on [Ca2+]i. One of the remaining 4 adenomas was completely unresponsive to SRIH despite responding vigorously to other ligands and Immunostaining strongly for GH. Surprisingly, cells from 3 adenomas showed a paradoxical increase in [Ca2+]i in response to SRIH in some or, in one case, all of the cells examined. In all adenomas the sequence of SSTR2 corresponded to wild-type. CONCLUSIONS: In the majority of cells derived from human somatotrophic adenomas, SRIH caused a reduction in baseline [Ca2+]i and inhibition of GRH-induced [Ca2+]i increase, as observed in somatotrophs of other species. In addition, SRIH was found either to induce a paradoxical increase in [Ca2+]i or to have no effect on [Ca2+]i in a small proportion of somatotroph adenomas examined. This finding corroborates the clinical observation that the response to SRIH analogues varies markedly between somatotroph adenoma patients. There was no evidence of SSTR2 mutations in any of the adenomas examined.

Peripheral glucose metabolism in healthy subjects and in endocrine diseases.

1. Seventeen healthy male subjects were studied after an overnight fast (12-14 h) and for 3 h after ingestion of 75 g glucose to investigate peripheral glucose metabolism (uptake, oxidative and nonoxidative metabolism) using the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. In normal subjects, during the 3-h study period, 30.3 +/- 2.1 g (40.4% of the ingested load) of glucose were processed by skeletal muscle in the body as a whole and 8.1 +/- 0.6 g were completely oxidized while 22.2 +/- 2.3 g were utilized through the nonoxidative pathway in muscle tissue. 2. After ingesting 75 g of glucose, normal women showed greater glucose uptake per unit of muscle mass and a predominant tendency toward utilizing glucose by a nonoxidative pathway than did normal men. The higher glucose uptake of the female group and an insulin response not significantly different from that of the male group suggest that muscle insulin sensitivity is greater in normal women. 3. The study of the effects of 50 and 100 g glucose loads on the peripheral glucose metabolism of normal men revealed a dose-dependent metabolic response in muscle tissue to these oral glucose challenges with respect to forearm muscle glucose uptake and nonoxidative glucose metabolism. The oxidative responses of the muscle tissue were not directly proportional to the oral glucose loads. 4. The administration of carbohydrate, usually glucose, leads to a decrease in the serum level of inorganic phosphorus (Pi), attributed to Pi flow from the extracellular to the intracellular compartment as part of the increased glucose metabolism induced by insulin. However, our data indicate that muscle tissue is not the site responsible for the fall in serum Pi after glucose ingestion. 5. Spontaneous human hyperthyroidism increases glucose uptake by the forearm muscles in the postabsorptive state and during an oral glucose challenge, with increased fluxes of glucose through the oxidative and nonoxidative pathways. 6. The insulin resistance occurring in the presence of chronic growth hormone (GH) excess is accompanied by impaired muscle glucose uptake and nonoxidative glucose metabolism. These probably are early derangements because they are also observed in acromegalic patients with normal glucose tolerance. 7. A clear-cut dissociation between peripheral glucose and potassium transport was observed in the forearm muscle of acromegalic patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The pulsatile GH secretion in acromegaly: hypothalamic or pituitary origin?

OBJECTIVE: We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone-releasing hormone (GHRH) and somatostatin and its effects on IGF-I plasma levels in acromegaly. DESIGN: In six acromegalic patients not cured by previous treatment we compared the 24-hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 micrograms octreotide every 8 hours and with continuous s.c. infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 micrograms GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4-week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross-over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions. MEASUREMENTS: Serum GH and plasma IGF-I concentrations were analysed by serial array averaging. IGF-I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied. RESULTS: With both treatments, the initially elevated basal 24-hour mean serum GH concentrations (58.0 +/- 9.7 mU/l mean +/- SEM) decreased significantly (bolus: 11.5 +/- 4.9 mU/l, P < 0.001 vs basal; continuous infusion: 7.6 +/- 1.9 mU/l, P < 0.001 vs basal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P < 0.05). IGF-I plasma concentrations were lowered significantly (P < 0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P < 0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase. CONCLUSION: Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary-derived mechanism for GH pulse generation in acromegaly.

Metabolic factors for urolithiasis in acromegalic patients.

1. Acromegaly is associated with metabolic disturbances of calcium and phosphorus which can also contribute to renal lithogenesis. 2. In order to characterize these disturbances more precisely, an oral calcium load test was performed on 14 active acromegalic patients. Serum and urinary levels of calcium, phosphorus, uric acid, creatinine and urinary cyclic AMP were determined. 3. Of the 14 patients, 5 (36%) presented hypercalciuria, 5 (36%) presented intestinal calcium hyperabsorption, and 6 (43%) had uric acid hyperexcretion. Two patients (14%) presented nephrolithiasis. 4. The medical records of 32 additional acromegalic patients with or without active disease were reviewed for a history of previous stones, which was observed in three cases (9.5%). 5. The present data suggest that nephrolithiasis occurs more frequently among acromegalic patients because of the underlying metabolic disturbances of calcium presented by this population.

Metabolic factors for urolithiasis in acromegalic patients

Acromegaly is associated with metabolic disturbances of calcium and phosphorus which can also contribute to renal lithogenesis. In order to characterize these disturbances more precisely, an oral calcium load test was performed on 14 active acromegalic patients. Serum and urinary levels of calcium, phosphorus, uric acid, creatinine and urinary cyclic AMP were determined. Of the 14 patients, 5 (36%) presented hypercalciuria, 5 (36%) presented intestinal calciumhyperabsorption and 6 (43%) had uric acid hyperexcretion. Two patients (14%) presented nephrolithiasis. The medical records of 32 additional acromegalic patients with or without active disease were reviewed for a history of previous stones, which was observed in three cases (9.5%). The present data suggest that nephrolithiasis occurs more frequently among acromegalic patients because of the underlying metabolic disturbances of calcium presented by this population

Placental and pituitary growth hormone secretion during pregnancy in acromegalic women.

It is now well established that during the second half of normal pregnancy, the human placenta secretes its specific GH variant (placental GH) in increasing amounts up to delivery. During the same period, pituitary GH secretion is progressively suppressed. The present study was aimed at clarifying the physiology of GH secretion in pregnant acromegalic women. Two young women remained acromegalic despite transphenoidal removal of their pituitary adenoma. Increased basal levels of GH and insulin-like growth factor-I (IGF-I) as well as paradoxical GH release after TRH injection were noted. Both women became pregnant and delivered term babies without any complication. In both patients, pituitary GH remained elevated during the entire pregnancy, contrary to the situation in normal women. Paradoxical GH release after TRH treatment was also present, whereas no response was observed in five normal control subjects. GH pulsatility studies revealed a highly pulsatile secretory pattern of pituitary GH, in contrast to that in normal woman, whose placental GH is secreted tonically. Tissue placental GH concentrations were within the range of levels in normal placentas. An increase in serum IGF-I in late pregnancy was also similar to that observed in normal pregnancy. These findings confirm that increased IGF-I levels are not pituitary GH dependent in late pregnancy. They add new evidence that adenomatous somatotrophs lack an IGF-I-dependent feedback regulation present in normal somatotrophs.

Urolithiasis in acromegaly.

Hypercalcemia, hypercalciuria, and hyperphosphatemia are common findings in acromegaly, yet there are only a few reports on the occurrence of urinary stones in these patients. We reviewed the files of 64 patients with acromegaly. A total of 8 patients had evidence of renal calculi: 4 patients underwent nephrolithotomy, 3 had stones which were seen on intravenous pyelography, and 1 patient voided a stone. Moreover, 2 other patients suffered from recurrent typical episodes of renal colic. In view of the high incidence of urolithiasis in our series we believe that more attention should be paid to detection of urinary stones in acromegalics to avoid further complications and suffering.

Zinc, copper, manganese, and selenium metabolism in patients with human growth hormone deficiency or acromegaly.

This study was designed to evaluate trace metal metabolism in patients with known abnormalities of human growth hormone (hGH). The mean concentration of zinc in plasma and urine decreased in patients with hGH deficiency after hGH injection, whereas, after adenomectomy, in patients with acromegaly, zinc increased in plasma, remained the same in erythrocytes, and decreased in urine. There was a negative correlation between plasma zinc and serum hGH levels and a positive correlation between urinary zinc excretion and serum hGH levels in acromegaly. In hGH deficiency, the copper content remained unchanged in plasma and erythrocytes and rose in urine after treatment; however, in acromegaly, the copper content increased in plasma and remained unchanged in erythrocytes and urine after surgery. The mean concentration of erythrocyte manganese did not change significantly after treatment in patients with hGH deficiency or acromegaly, but the pre-hGH treatment level of erythrocyte manganese in hGH deficiency was lower than in the controls. Plasma selenium concentrations were decreased in hGH deficiency and increased in acromegaly patients after therapy. These results suggest that hGH affects the metabolism of zinc, copper, manganese, and selenium.

Changes in calcium homeostasis in acromegaly treated by pituitary adenomectomy.

Patients with acromegaly have alterations in mineral metabolism. To determine the effect of correction of excess GH secretion on calcium metabolism, we studied 12 acromegalic patients before and 3-4 weeks after pituitary adenomectomy. Treatment of acromegaly resulted in significant decreases in both serum calcium [from 9.3 +/- 0.2 to 8.7 +/- 0.1 mg/dl (mean +/- SEM); P less than 0.01] and urinary calcium excretion (from 200 +/- 24 to 88 +/- 12 mg/24 h; P less than 0.0002). Serum phosphate also decreased significantly (P less than 0.01) from 4.8 +/- 0.2 to 4.3 +/- 0.2 mg/dl. Both serum immunoreactive PTH and calcitonin levels were normal initially and did not change after surgery. The mean serum 25-hydroxyvitamin D (25OHD) level was significantly (P less than 0.01) lower and the 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was significantly (P less than 0.0001) higher in acromegaly compared with measurements in 25 normal subjects. After surgery, the serum 25OHD level did not change; however, the serum 1,25-(OH)2D concentration fell significantly (P less than 0.0001) from 60 +/- 4 to 43 +/- 2 pg/ml. A positive correlation was found between the decrements in urinary calcium excretion and the serum 1,25-(OH)2D level when the comparison was made between the decrements as percentages of pretreatment values (r = 0.64; P less than 0.05). The accumulated data suggest that the hypercalciuria in acromegaly might be due to intestinal calcium hyperabsorption, which could be attributed to the elevated circulating 1,25-(OH)2D level. Excessive GH secretion might stimulate the production of 1,25-(OH)2D and might also directly stimulate calcium absorption.

Changes in bone metabolism during treatment of acromegaly.

Bone metabolism was studied in 17 acromegalic patients, who responded to either medical treatment with bromocriptine (12 patients), or to transsphenoidal surgery (5 patients). Parameters of bone turnover decreased, e.g. serum acid phosphatase (9.2 +/- 0.7 vs 8.1 +/- 0.6 U/l, P less than 0.05) and the ratio of hydroxyproline/creatinine (33.6 +/- 4.4 vs 18.3 +/- 2.0, P less than 0.01) in the urine. No changes were observed in parathyroid function or concentrations of calcitonin. Serum 1,25-dihydroxycholecalciferol decreased (32.6 +/- 3.6 vs 20.6 +/- 1.8 ng/l, P less than 0.01) and 24,25-dihydroxycholecalciferol increased (4.3 +/- 0.6 vs 6.7 +/- 1.0 micrograms/l, P less than 0.05). No correlation between the percentual changes in serum growth hormone levels and 1,25-dihydroxycholecalciferol was found, suggesting an indirect effect of growth hormone on the renal 25-hydroxycholecalciferol-1-alpha-hydroxylase. The possible mechanisms involved are discussed, including the effects of growth hormone and somatomedin on bone.

Iliac crest bone mass and remodelling in acromegaly.

Iliac crest bone biopsies from 18 patients with active acromegaly, of whom 11 had received tetracycline double-labelling, were evaluated by quantitative histomorphometry and compared with age- and sex-matched normal controls. A significant increase (P less than 0.01) was found in both cortical (175%) and trabecular (130%) bone mass. In trabecular bone, resorption surfaces and active (tetracycline-labelled) and total formation surfaces were increased (P less than 0.05 and P less than 0.01, respectively) causing an enhanced bone turn-over at tissue level (P less than 0.01). The increased trabecular bone mass indicates a positive net balance per remodelling cycle and, therefore, larger than normal bone remodelling units, which in part may explain the increased bone turn-over at tissue level. The activity of the osteoblasts active in mineralization (the appositional rate) was increased (P less than 0.01) and positively related to the fasting serum growth hormone levels (Rs = 0.69, P less than 0.05). The average activity of active and inactive osteoblasts (bone formation rate at basic metabolic unit (BMU) level) was insignificantly increased. The proportion of active (tetracycline labelled) to nonactive formation surfaces was normal. The bone changes were unrelated to serum levels and urinary excretions of calcium and phosphorus or to renal excretion of total and non-dialyzable hydroxyproline or cAMP.

Mechanisms of inactivation of hypothalamic regulatory hormones.

The mechanisms of enzymic inactivation of thyrotropin-releasing hormone, luteinizing hormone-releasing hormone and somatostatin, the three fully-characterized hypothalamic regulatory hormones, and the possible physiological significance of the peptidases in neuroendocrine control has been reviewed. Application of the criteria of enzyme location (at the sites of biosynthesis, release, action, elimination and excretion), appropriate biochemical characteristics of the enzymes and changes in enzyme activity in physiological circumstances all suggest that the peptidases can contribute to the mechanisms controlling the hypothalamic hormones' release and actions. Besides their physiological function, the enzymes may also be directly involved in certain pathological conditions. There is evidence to indicate that the enzymes degrading the regulatory hormones may participate in the process of hormone activation as well as inactivation. A continuing investigation of the peptidases may lead to a better understanding of the established endocrine and other putative functions of these hypothalamic polypeptide hormones.

[The action of somatotropic hormone on bone and on phospho-calcic metabolism]. / Action de l'hormone somatotrope sur l'os et le métabolisme phospho-calcique

The author reviews present knowledge concerning the action of somatotropic hormone on the kidney, the intestine, and on developmental changes in bone. He reviews, in particular, the controversial question of acromegalic osteoporosis and in this connexion considers the possibility of associated hyperparathyroidism.

Recently discovered hypothalamic-pituitary hormones.

In recent years a variety of peptide hormones have been isolated from the mammalian hypothalamus and pituitary. Several hypothalamic hormones, including thyroliberin (thyrotropin-releasing factory), luliberin (luteinizing hormone-releasing factor), and somatostatin (somatotropin release-inhibiting factor), have been characterized and synthesized. The subsequent development of radioimmunoassays for these hormones has made possible the study of their physiology. The measurement of prolactin in serum and the release of pituitary hormones after the administration of the hypothalamic hormones has proved to be useful in clinical diagnosis. The use of hypothalamic hormones in treating various clinical disorders and the isolation and characterization of new releasing and inhibiting hormones in the hypothalamus are actively being investigated.