Current therapy and drug pipeline for the treatment of patients with acromegaly

Introduction  Acromegaly is a multisystem disease resulting from chronic exposure to supraphysiological levels of growth hormone (GH), and is associated with significant morbidity and excess mortality. The etiology is almost exclusively an underlying pituitary adenoma. Current therapeutic interventions include surgery, radiotherapy, and medical therapy. Results  Despite surgery, around 50% of patients fail to achieve the biochemical targets shown to correlate with normalization of mortality rates. Radiotherapy is efficacious in controlling tumor growth and GH secretion; still, achievement of biochemical targets may take up to a decade and a number of safety issues have been raised with this treatment modality. Medical therapy, therefore, has an important role as adjuvant therapy in patients who fail to achieve control with surgery, or while awaiting the effects of radiotherapy to be realized. Furthermore, medical therapy is increasingly being used as primary therapy. Current medical therapies include dopaminergic agonists, somatostatin analogs, and GH receptor (GHR) antagonists. Dopaminergic agonists achieve biochemical targets in up to 30% of patients, and somatostatin analogs in around 60%. The currently available GHR antagonist pegvisomant effectively controls insulin-like growth factor-I levels in over 90% of patients; however, it has no effect on the tumor itself and has considerable financial implications. Research into optimizing the somatostatin and dopaminergic systems has led to promising advances in agonist development. Moieties with selectivity for various combinations of somatostatin receptor subtype receptors have been examined, along with molecules that additionally show high affinity for the dopaminergic D2 receptor. Of the molecules studied in vitro, only pasireotide (SOM230) and BIM-23A760 are currently undergoing further development. Other innovations to improve convenience of currently available drugs are also being investigated. Conclusion  Significant advances in under standing of the somatostatin and dopaminergic system have aided drug development. This may lead to new clinically available therapies enabling control of acromegaly in a larger proportion of patients, and at an earlier stage in their disease management.     

The treatment of acromegaly with special reference to trans-sphenoidal hypophysectomy.

Experience in the management of 100 cases of acromegaly is described. Three quarters of these had been referred directly to the endocrine clinic at the Middlesex Hospital. The remainder were referred from the Royal Post-graduate Hospital because they were thought unsuitable for yttrium implantation. The patients were studied by clinical assessment of severity, by measurement of basal growth hormone levels on three separate mornings, and by a review of possible complications. Particular attention was paid to diabetes, hypertension, cardiomegaly, respiratory, vascular and skeletal changes as well as visual field defect. Aggressive treatment was recommended in 77 patients. It was not recommended in the remainder on account of age, intercurrent illness or the apparent mildness of the condition. Fifty-nine patients were treated by trans-sphenoidal hypophysectomy. In 46 of the 59 patients the mean basal growth hormone level has been reduced to 5 ng/ml or less. In 39 this followed operation, in five operation and subsequent X-ray therapy and in two operation and the continuing effect of previously implanted yttrium. Of these 46 patients in whom the growth hormone level has been reduced to normal, 26 do not show any deficiency of anterior pituitary trophic hormones, 13 have gonadotrophin defect (in eight of these it was present before the operation) and seven require full replacement therapy. One patient died at home six weeks after the operation from a pulmonary embolus. There was one case of CSF rhinorrhoea which stopped spontaneously and three of acute frontal sinusitis. Trans-sphenoidal hypophysectomy is shown to be an effective means of treating acromegaly. If the basal level of growth hormone is not reduced to normal by six weeks after operation, it is recommended that a course of X-ray therapy should be given. This does not apply if irradiation has been used before operation.     

肢端肥大症患者心脏损害的超声表现

目的 通过超声心动图检查，观察肢端肥大症患者心脏结构和功能的改变，以及出现高血压并发症后对心脏的影响。方法 研究对象为56例确诊为肢端肥大症的患者，其中17例合并高血压，定为亚组病例。对照组34例。两组均行超声心动图检查，测定心脏结构及功能并对结果进行分析。结果 （1）患病组心肌重量（LVM）及心肌重量指数（LVMi）较对照组明显增加，LVMi达到左室肥厚（LVH）的比例为46．7％，高血压亚组增高更为明显；（2）反映心脏收缩功能的参数射血分数（EF）两组比较，差异无显著性；（3）反映心脏舒张功能的参数左室等容舒张时间（IRT）和二尖瓣减速时间（MDT），患病组较对照组明显延长，说明心肌松弛性受损。结论 肢端肥大症患者超声心动图表现为明显的心肌肥厚和心肌重量的增加，伴发高血压的患者心肌肥厚有加重的趋势。心脏功能的改变以舒张功能损害为主，反映心肌松弛性减低；而收缩功能则可在较长时间内维持在正常范围。     

Management and treatment of patients with fractured ribs

Rib fractures are a common injury to the chest. The mainstay of treatment is adequate analgesia coupled with meticulous respiratory care in order to prevent complications. Treatment can be as an outpatient, but patients with more severe fractures may be admitted to hospital for oxygen therapy, ventilation, aggressive analgesic techniques and physiotherapy. Significant morbidity and mortality rates have been reported with rib fractures. To avoid complications, accurate diagnosis, adequate analgesia and effective physiotherapy are essential.     

2例McCune-Albright综合征合并生长激素腺瘤患者的围手术期护理

总结了2例McCune-Albright综合征合并生长激素腺瘤患者行经蝶垂体腺瘤切除术的护理方法.患者均行神经导航辅助下经蝶窦入路垂体腺瘤切除术.术前重视患者的心理变化.为手术做好动态MRI等相关检查及治疗.术后严密观察患者有无继发性蝶鞍区出血、脑脊液漏、水电解质紊乱、垂体功能低下等并发症.患者手术顺利,术后恢复良好.患者术后生长激素水平均有明显下降,这内分泌学治愈.     

Abnormal growth hormone responses to L-dopa and thyrotropin-releasing hormone in patients with acromegaly.

Changes in growth hormone (gh) release in response to L-dopa, TRH, arginine and LH-RH were studied in 15 patients with acromegaly to investigate the mechanism of so-called 'paradoxical decrease' of GH secretion often observed in acromegalics after the administration of L-dopa. Among 15 patients, 11 showed GH increase with TRH, 8 with arginine, and 4 with LH-RH. On the other hand, six out of these 15 patients showed a distinct paradoxical GH decrease after L-dopa administration. Two cases showed an increase in GH on L-dopa as seen in normal subjects. The responses of GH release, either an increase or a decrease, was proved fairly constant when several patients had been examined repeatedly. Changes of GH induced by L-dopa were compared wwith those by TRH, arginine, and LH-RH. There were no correlation between the changes by L-dopa and those by TRH, arginine, and LH-RH when compared simply. But a significant negative correlation (r=-0.861) was found between percent changes by L-dopa and logarithm of increase ratio (peak value of GH after the stimulation/basal value) induced by TRH. More close correlation (r=-0.881) was obtained when the percent changes by L-dopa was (formula: see text). This result would imply that paradoxical GH decrease by L-dopa in acromegalic patients is more remarkable when their GH secretion is more responsive to TRH and less responsive to arginine. When this correlation is considered in connection with the reported effects of L-dopa on GH and thyroid stimulating hormne (TSH) in man, the following hypothesis might be proposed: L-dopa has two opposing actions on the hypothalamo-pituitary system; 1) inhibition of TRH release or suppression of GH release from TRH sensitive GH producing cells, and 2) arginine-like facilitation of GH release presumably via stimulation of GH-RF. The paradoxical GH decrease in acromegalics on L-dopa is explained by the dominance of the former action.     

Lanreotide for the treatment of acromegaly

Lanreotide is an eight-amino acid peptide, which is an analog of the native somatostatin peptide, physiological inhibitor of growth hormone (GH). The drug shows high binding affinity for somatostatin receptors, SSTR2 and SSTR5, which is the primary mechanism considered to be responsible for decreasing GH secretion and GH cell proliferation in acromegaly. Two different formulations of lanreotide are currently available: lanreotide slow release, which requires intramuscular injection every 7–14 days, and lanreotide autogel, which requires deep subcutaneous injection every 4–8 weeks. Several studies have been published to date on the use of lanreotide in acromegaly. Antisecretory efficacy has been reported in 35%–70% of cases; this huge variability is probably explained by different indications (eg, primary or adjunctive postsurgical treatment), or the fact that some studies were based on patients known to be responders to somatostatin analogs. As a primary treatment, antisecretory efficacy was very similar, confirming the possibility of lanreotide as an option in cases of unsuccessful surgery, contraindication, or surgery refusal. Lanreotide also has antitumoral effects as it induces a decrease in tumor volume of 〉25% in 30%–70% of patients. This could be beneficial before transsphenoidal surgery, as a pretreatment, to decrease tumor volume and ease surgery; however, to date, advantages in terms of final remission or uncured status remain a matter of debate. Side effects are rare; the most frequent being gastrointestinal discomfort and increased risk of gallstone formation, and glucose metabolism modifications. Comparison with the other somatostatin analog, octreotide, tends to show identical levels of efficacy between both drugs. Lanreotide thus seems to be an effective treatment in acromegaly. To date, however, lanreotide is still considered as only suspending GH secretion, thus requiring prolonged and costly treatment.     

Management of patients with atrial fibrillation: diagnosis and treatment

This article focuses on the diagnosis and management of atrial fibrillation (AF). It looks briefly at normal electrical conduction in the heart and how this differs during AF. The article also describes methods for diagnosis and the range of treatments available to patients.     

Quantitative ultrasound at the hand phalanges in patients with acromegaly

The aim of this study was assessment of skeletal status using quantitative ultrasound (QUS) at hand phalanges in patients with acromegaly. A group of 38 patients with acromegaly (27 women and 11 men) with a mean age of 57.21 +/- 9.85 years was compared with a control group of 44 men and 108 women matched for gender, age and body size. Amplitude-dependent speed of sound (Ad-SoS) at hand phalanges had lower values in patients with acromegaly than in controls, both in the entire group and in men and women, respectively. The positive correlation between Ad-SoS and height and the negative one between Ad-SoS and age was found in the entire group of patients with acromegaly. No correlations between Ad-SoS and time from diagnosis or duration of the symptoms were found. Age affected Ad-SoS significantly less in the entire patient group than in controls. Similarly, in women, age and body mass affected Ad-SoS less than in controls. A stepwise multiple regression analysis carried out in the patient group identified age as the only factor significantly influencing negatively the Ad-SoS value (regression equation: Ad-SoS (m/s) = 2124 m/s - 3.26 x age (years) [r2= 0.26, standard error of estimate = 55.1, p < 0.01]). In conclusion, our data demonstrate that, in patients with acromegaly, skeletal status assessed by QUS was affected. This could reflect the worsening of the mechanical properties of bones studied and the increased risk of fractures in other sites of the skeleton. The changes observed were not related to acromegaly-associated hypogonadism. Further studies to assess the role of QUS in acromegaly are necessary and fracture prevalence and risk ought to be established.     

Effectiveness of lysenyl-forte treatment in acromegaly and hyperprolactinemia syndrome

Lysenyl-forte, a derivative of polysynthetic ergot alkaloids, producing a dopaminergic and antiserotoninergic action was employed to treat acromegaly and prolactin hypersecretion in 11 and 71 patients, respectively. Clinical effect was established basing on a complex of clinical, x-ray, neuro-ophthalmologic and hormonal evidence. Acromegaly treatment proved efficient: 7 patients (63%) showed partial relief of clinical signs, reduced STH blood level. Out of 48 patients with prolactinemia a response was registered in 34 (71%): a more than 50% decrease in prolactin concentration, normal levels of the hormone in 35% of the patients. A menstrual cycle recovered, galactorrhea diminished, 2 women got pregnant. A positive effect was noticed in management of 13 sterile men with prolactin hypersecretion, in 6 patients with idiopathic prolactin hypersecretion, in 4 women with primary hypothyrosis and galactorrhea. Compared to parlodel, lysenyl was not superior in the frequency of side effects, though was inferior in clinical effectiveness. The drug is recommended for wide-scale use.     

Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly.

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.     

Plasma growth hormone responses to sulpiride in patients with acromegaly

The role of endogenous dopamine (DA) on plasma GH secretion was studied in 12 patients with active acromegaly. After intramuscular administration of 100 mg sulpiride, 3 out of 12 patients showed distinct increases in their plasma GH (cases 1-3: sulpiride-responders). The GH increases far exceeded the ranges of physiological fluctuation in two cases studied (case 1 & 3). After domperidone administration, case 3 showed a quite similar GH increase as after sulpiride. Plasma GH responses to TRH and sulpiride were still observed in case 2 even after the basal GH levels were normalized by the transsphenoidal hypophysectomy. The three sulpiride-responders showed so-called paradoxical GH decreases following the administration of L-dopa (500 mg, p.o.) or DA (5 micrograms/kg/min over 90 min, i.v.). However, the basal plasma PRL levels and the responses to sulpiride in these 3 cases were not homogeneous. These results indicate that endogenous DA has a tonic inhibitory effect on GH secretion in some cases of acromegaly, and that tumorous somatotrophs rather than elevated GH levels are the critical factor for such inhibition. Further, the sensitivities of somatotrophs and lactotrophs to DA appeared to be heterogeneous in acromegalic patients.     

An audit of outcome of treatment in acromegaly

In order to determine whether acromegaly is still associatedwith increased mortality, a hospital case note review of allpatients with acromegaly followed up in Stoke-on-Trent since1967 was carried out Of 79 subjects identified, 51 are aliveand being monitored and 28 have died. Mortality was comparedto the general population by life table analysis. Secretionof growth hormone was assessed and compared in dead and alivepatients. The effect of diabetes, hypertension, and growth hormonesecretion on long-term outcome was assessed. Acromegaly is stillassociated with increased mortality, with an overall ratio ofobserved to expected deaths equal to 2.68 (95% C.I. 1.8–3.9;p<0.001), but the survival of 31 (39%) patients whose growthhormone level had been reduced to below 5 mU/l was equal tothat of the general population (O/E = 1.42; 95% C.I. 0.46–3.31:p<0.05). The dead patients had had significantly higher growthhormone levels than those still alive, but mortality did notappear to be influenced by diabetes or hypertension. The causeof death was vascular in 57% of cases. Growth hormone hypersecretionis still associated with excess mortality in acromegaly. Thepresent study suggests that the therapeutic objective shouldbe to lower average daytime growth hormone levels to less than5 mU/l. There is need for a large study to compare differentmodes of treatment in terms of their effect on growth hormonesecretion and on long-term outcome.