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PubMed2002

Optimizing somatostatin analog therapy in acromegaly: long-acting formulations.

Somatostatin peptide analogs have revolutionized the medical treatment of patients with acromegaly. More recent deep intramuscular depot preparations have further improved control, with consistent suppression of growth hormone secretion and optimal lowering of insulin-like growth factor-1. Effective control of growth hormone should, with long-term use, reduce morbidity and mortality from acromegaly and has been shown to result in partial involution of the pituitary adenoma in the majority of treated patients. The currently available depot formulations allow for an injection frequency of 14 days (lanreotide LA 30mg) to 28 days (octreotide LAR 20mg) according to the manufacturers' recommendations. In clinical practice, dose titration by evaluating a growth hormone day profile prior to the next injection can extend the interval between injection (to 6 or even 8 weeks in certain individuals). This is especially true for octreotide LAR, which also has increased flexibility regarding dosage with a 10 and 30mg preparation. The annual 'drug cost' is broadly similar between the two formulations though the additional expenditure on nurse time and clinic visits incurred by an increased injection frequency is a significant consideration. Decreased injection frequency improves acceptability for the patient without a loss in treatment efficacy. A subjective return of typical acromegalic symptoms, such as sweating and headache, also seem to be useful in predicting the timing of the next injection. Other formulations and doses of lanreotide are currently being evaluated, but more interestingly, newer analogs with greater efficacy at the type 5 somatostatin receptor subtype, and pan-receptor analogs, are being developed. These peptides, in conjunction with the likely availability of a growth hormone receptor blocking agent (pegvisomant), will further expand the medical therapy options for patients with acromegaly.

Acromegaly↗
PubMed2003

Clinical use of pegvisomant for the treatment of acromegaly.

Understanding the mechanisms by which growth hormone (GH) interacts with its receptor has led to the design of compounds that function as GH receptor antagonists. One such compound has been conjugated to polyethylene glycol (PEG) to produce a drug, pegvisomant, which has been extensively investigated as a treatment for acromegaly. It was recently approved for clinical use in the US and will shortly be available on prescription in Europe. Studies have shown that the drug is able to normalize circulating levels of insulin-like growth factor-1 (IGF-1), the principal mediator of GH action, in 97% of patients with active acromegaly, as well as improve the symptoms and signs associated with GH excess. Serum IGF-1 levels have been used as the chief marker of efficacy of treatment with pegvisomant. The drug is able to achieve biochemical control in patients wholly or partially resistant to somatostatin analogs. Preliminary data suggests that pegvisomant may be a particularly suitable choice of medical therapy for patients with acromegaly and coexistent diabetes mellitus.

Acromegaly↗
PubMed2004

Lanreotide Autogel for acromegaly: a new addition to the treatment armamentarium.

Since their introduction into clinical practice, somatostatin analogs have been the pharmacological therapy of choice for the treatment of acromegaly. The first preparations of somatostatin analogs available for clinical use were administered subcutaneously two or three times daily, which was not optimal with respect to patient compliance. The introduction of long-acting formulations of somatostatin analogs has overcome this inconvenience. Lanreotide Autogel, a new viscous, supersaturated, aqueous solution of lanreotide, is available in a prefilled syringe and administered by deep subcutaneous injection every 28 days. Lanreotide Autogel has different pharmacokinetic properties from the earlier lanreotide slow-release (SR) formulation, which may account for its better tolerability. Furthermore, lanreotide Autogel is at least as efficacious as the other somatostatin analogs in lowering growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in the majority and in restoring safe GH and age-normalized IGF-1 levels in about 50-60% of patients with acromegaly. In conclusion, lanreotide Autogel is a valuable new addition to the acromegaly treatment armamentarium. Patients receiving intramuscular lanreotide SR injections every 7-14 days can be switched to an appropriate dose of deep subcutaneous lanreotide Autogel every 28 days, without any impact on safety or loss of efficacy.

Acromegaly↗
PubMed1996

Acromegaly associated with Chiari-I malformation and polycystic ovary syndrome.

We report a 19-year-old female case of acromegaly associated with Chiari-I malformation and polycystic ovary syndrome. She also had syringomyelia and thoracic scoliosis. Although the association of acromegaly and Chiari-I malformation was by chance, exaggerated secretion of growth hormone may have aggravated the scoliosis. The incidence of polycystic ovary in acromegalic patients remains to be elucidated. However, elevation of plasma insulin and insulin-like growth factor, that is usually observed in patients with acromegaly, could stimulate androgen production in the ovaries. The patient was successfully treated with transsphenoidal adenomectomy for pituitary tumor and correction surgery for thoracic scoliosis.

Acromegaly↗
PubMed1990

The diagnosis of acromegaly: value of inferior petrosal sinus sampling.

The early diagnosis of acromegaly may be difficult when serum levels of growth hormone are minimally elevated and imaging of the pituitary gland fails to show an adenoma. However, transsphenoidal surgery has the greatest chance of cure at this stage. We therefore investigated the value of sampling petrosal sinuses for measurement of growth hormone in this group of patients. Simultaneous bilateral sampling of the inferior petrosal sinuses to measure serum concentrations of growth hormone was performed in five patients suspected of having acromegaly but with nondiagnostic CT scans (n = 5) and MR images (n = 3) of the pituitary gland. Levels of growth hormone from the petrosal sinuses were five to 36 times greater than levels in the peripheral veins in all five patients, and three of four showed a marked response to growth hormone-releasing hormone. During transsphenoidal surgery, growth hormone-producing microadenomas were resected completely in four patients. In the fifth patient, a left-sided microadenoma had invaded the cavernous sinus and could not be resected completely. Lateralization of the adenomas within the pituitary gland on the basis of differences in levels of growth hormone between the two petrosal sinuses was not completely reliable. Elevated levels of growth hormone in selective samples from the inferior petrosal sinuses can help support an early diagnosis of acromegaly when peripheral growth hormone levels and imaging are not diagnostic.

Acromegaly↗
PubMed1987

Arterial hypertension in acromegaly: altered dopaminergic control of aldosterone secretion.

In order to elucidate the role of the dopaminergic system in the control of aldosterone secretion in acromegaly with arterial hypertension 10 patients and 10 healthy volunteers were studied. Plasma aldosterone and prolactin were determined by radioimmunological methods after dopaminergic receptor blockade with metoclopramide and sulpiride. Plasma aldosterone was also determined after adrenal stimulation with synthetic corticotrophin (Synacthen). In patients with acromegaly and hypertension, the aldosterone secretion in response to metoclopramide was completely inhibited whereas induced with corticotrophin was lower than in controls. Also prolactin secretion in response to metoclopramide or sulpiride was markedly lower as compared with that in controls. Sulpiride did not stimulate aldosterone secretion either in patients or in healthy controls. The results indicate that the dopaminergic control of aldosterone secretion in acromegaly with arterial hypertension is altered.

Acromegaly↗
PubMed1989

High blood pressure and hyperinsulinaemia in acromegaly and in obesity.

As previously shown, in essential hypertension postprandial plasma insulin concentrations are elevated. In order to determine a relationship of high blood pressure and plasma insulin levels in acromegaly and in obesity 59 subjects with normal glucose tolerance were studied. They were divided into three groups: (I) patients with acromegaly: 7 normotensives and 8 hypertensives, (II) 12 obese normotensives and 12 obese hypertensives and (III) 10 non-obese hypertensives, and 10 healthy subjects. Blood glucose and plasma insulin concentrations were measured in a fasting state and after an oral glucose load of 75 g. The fasting insulin concentrations in all the acromegalics and in all the obese patients were higher than those in healthy subjects. The insulin response to the glucose load was significantly enhanced in all the three groups of hypertensive patients compared with those of matched normotensive controls. The results indicate that insulin may play a role in the regulation of blood pressure in essential hypertension, and in such hyperinsulinaemic disorders as acromegaly and obesity.

Acromegaly↗
PubMed2004

Pharmacological approach to the treatment of acromegaly.

The treatment of patients with persistently active acromegaly has been facilitated over the past decade by the advent of highly specific and selective pharmacological agents. Somatostatin analogs, derived from the native inhibitory hormone somatostatin, are available in extended-duration preparations and are effective in reducing serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) as well as in improving the adverse clinical effects of acromegaly. Cabergoline, an agonist with a specificity for the dopamine D-2 receptor, has been shown to suppress IGF-I levels and induce tumor shrinkage in 35 and 50% of patients, respectively. The GH receptor antagonists compete with naturally occurring GH for binding with the GH receptor. As such, pegvisomant normalizes circulating IGF-I levels in 80 to 90% of patients with acromegaly. This last line of therapy should be considered for use in patients in whom surgery and medical therapy with somatostatin and/or dopamine agonists are either ineffective or poorly tolerated.

Acromegaly↗
PubMed1979

Acromegaly with normal growth-hormone levels and pituitary histology. Case report.

In rare cases, acromegalic patients have normal basal concentrations of growth hormone, and their acromegaly results from abnormal growth-hormone secretory patterns. A patient is reported with the clinical features of acromegaly, who had elevated somatomedin levels and an enlarged sella turcica, but whose serum growth-hormone levels on continuous monitoring were in the normal range, with levels of 2.8 to 8.9 ng/ml. Dynamic studies of growth hormone revealed normal responses to hypo- and hyperglycemia, but abnormal responses to L-dopa and thyroid-releasing hormone. At surgery, neither a pituitary adenoma nor eosinophilic hyperplasia was present. It is likely that this patient's acromegaly resulted from the presence of chronically high normal levels of growth hormone.

Acromegaly↗
PubMed1996

Surgical outcome after repeated transsphenoidal surgery in acromegaly.

Transsphenoidal selective adenomectomy is the most efficient primary treatment for acromegaly. However, management of persistent or recurrent disease remains controversial. The objective of the present study was to evaluate the early and long-term efficacy and safety of a second transsphenoidal surgery performed in those cases. The results of a retrospective study of 16 patients undergoing reoperation by the senior author (J.H.) between 1970 and 1991 are reported. Reoperation was performed for persistent or progressive acromegaly in 11 patients, visual impairment in four, and disease recurrence in one. Normalization of growth hormone (GH) was defined as a basal GH level of less than 5 micrograms/L and suppression to less than 2 micrograms/L during the oral glucose tolerance test. Long-term follow-up data were available in 15 patients. The second transsphenoidal surgery induced a greater than 50% decrease of GH level in 11 patients. Three (19%) of 16 patients were cured according to the authors' criteria and remained so after 2, 7, and 20 years. Two more patients had a postoperative basal GH level of less than 5 micrograms/L but incomplete suppression during the oral glucose tolerance test. Thus, a total of five patients (31%) achieved a basal GH of less than 5 micrograms/L. One other patient who had no initial improvement after the second transphenoidal surgery had spontaneous normalization of his GH level after 13 years. The following complications of the second surgery occurred in three patients: one subarachnoid hemorrhage, two new visual field defects, one cranial nerve palsy, and one meningitis. Moreover, 10 patients (62.5%) developed one or more new pituitary hormone deficiencies. In conclusion, reoperation for persistent or recurrent acromegaly has low success and high complication rates. According to the authors' experience, this procedure should be reserved for patients unresponsive to other forms of therapy or with progressive visual impairment despite medical therapy.

Acromegaly↗
PubMedDate not supplied

Diagnosis of acromegaly in a patient with type 1 diabetes mellitus.

OBJECTIVE: To describe a case of acromegaly in a young patient with poorly controlled diabetes mellitus and suggest guidelines to distinguish acromegaly and high growth hormone (GH) levels previously reported in poorly controlled type 1 diabetes. METHODS: We present a detailed case report, including clinical findings and serial laboratory results in a patient with type 1 diabetes and a GH-secreting pituitary tumor. RESULTS: A 28-year-old woman with type 1 diabetes underwent assessment for secondary amenorrhea and worsening glycemic control. A low estradiol level and an inappropriately low level of follicle-stimulating hormone prompted magnetic resonance imaging of the head, which demonstrated a pituitary adenoma. Subsequent endocrine investigation revealed a high insulin-like growth factor I (IGF-I) level (849 mg/L; normal range, 122 to 400). The concentration of insulin-like growth factor-binding protein-3 (IGFBP-3) was also elevated (5.5 mg/L; normal range, 2.0 to 4.2). GH levels measured during episodes of spontaneous hyperglycemia (>180 mg/dL) were in the range of 3 to 5 ng/mL and failed to suppress to below 2 ng/mL after a bromocriptine suppression test. The patient underwent transsphenoidal resection of a pituitary tumor, which stained positively for GH by immunohistochemistry. Postoperatively, glycemic control improved, with decreased fluctuations of hypoglycemia and hyperglycemia, despite a decrease in insulin requirements. CONCLUSION: This report highlights the difficulty in interpreting GH and IGF-I levels in patients with type 1 diabetes. In addition, a detailed review of the literature suggests that IGFBP-3 measurements may be helpful in confirming the diagnosis of concurrent acromegaly and distinguishing it from high GH levels attributable to poor control of diabetes.

Acromegaly↗
PubMedDate not supplied

Feline acromegaly: a review of the syndrome.

Acromegaly is characterized by chronic excessive growth hormone (GH) secretion by the pituitary gland. Feline acromegaly is most commonly caused by a functional pituitary tumor. Definitive diagnosis can be difficult because of the gradual disease onset, subtle clinical signs, unavailability of relevant laboratory tests, and client financial investment. The most significant clinical finding of acromegaly is the presence of insulin-resistant diabetes mellitus. Diagnosis is currently based upon brain imaging and measurement of serum GH and/or insulin-like growth factor-1 concentrations. Definitive treatment in cats is not well described, but radiation therapy appears promising.

Acromegaly↗
PubMed1984

Acromegaly and colon cancer.

The occurrence of colon cancer in 1 patient with acromegaly prompted a study of an additional 12 patients with acromegaly. In addition to the index case, 1 patient was retrospectively discovered to have colon cancer, and 1 was found to have colonic adenocarcinoma in the course of the study. One patient had a presumptive sigmoid polyp shown by barium enema but refused further studies. Eight patients received colonoscopy. Two patients had adenomatous polyps and 1 had two hyperplastic polyps. This study supports previously published data on the occurrence of colon polyps in patients with acromegaly and suggests that the incidence of colon cancer is much higher than that expected by chance.

Acromegaly↗
PubMed1989

Spinal and peripheral bone mineral densities in acromegaly: the effects of excess growth hormone and hypogonadism.

STUDY OBJECTIVE: To measure spinal and peripheral bone mineral densities in patients with acromegaly. DESIGN: Retrospective study. SETTING: Tertiary care center. SUBJECTS: Twenty-four patients with acromegaly and 24 case controls. Seventeen patients (12 eugonadal and 5 hypogonadal) had "active" disease as indicated by elevated plasma concentrations of growth hormone or somatomedin C or both at the time of the study. Seven patients (all hypogonadal) had inactive disease by these criteria. MEASUREMENTS AND MAIN RESULTS: Bone mineral was measured by single photon absorptiometry of the forearm and dual photon absorptiometry of the spine. The forearm bone mineral content of patients with active disease, regardless of gonadal status, was significantly higher than that of normal subjects (P less than 0.001) or of patients with inactive disease (P less than 0.001). The disease "activity" (17.2 +/- 3.7; CI, 9.5 to 24.9) and the sex of the patient (female, -16.6 +/- 3.4; CI, -23.7 to -9.5) were the only independent predictors of forearm measurements. Vertebral bone densities were lower in acromegalic patients than in normal subjects (P less than 0.001). Vertebral values were correlated with the gonadal status of the patients (hypogonadism, -0.126 +/- 0.056; CI, -0.244 to -0.009) and with serum calcium concentrations (0.592 +/- 0.274; CI, 0.032 to 1.153) but not with acromegalic activity. In 13 patients, forearm bone was measured before and after treatment (mean duration of follow-up, 3.4 years). Patients with persistently elevated, plasma somatomedin C concentrations at the end of the study period showed a mean annual increase of 1.5% in forearm measurements during the period of observation, whereas patients with normal concentrations showed a mean annual decrease of 1.0% (P less than 0.01 for the difference between the groups). The percent change in forearm bone mineral content per year (y) was highly correlated with residual somatomedin C activity (x): y = 2.023x - 2.75; r = 0.665. CONCLUSIONS: Forearm and vertebral bone mineral measurements change in opposite directions in acromegaly. The high forearm values are attributable to the growth-promoting action of growth hormone and somatomedin C, whereas low vertebral values are associated with hypogonadism.

Acromegaly↗
PubMed1990

Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety.

STUDY OBJECTIVE: To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. DESIGN: Nonrandomized, controlled trial. SETTING: Tertiary care center at a medical research institute. PATIENTS: Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). INTERVENTIONS: Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. MEASUREMENTS AND MAIN RESULTS: Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. CONCLUSION: Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.

Acromegaly↗
PubMed1990

Cardiovascular effects of the somatostatin analog octreotide in acromegaly.

OBJECTIVE: To determine the cardiovascular effects of the somatostatin analog octreotide in patients with acromegaly. DESIGN: Prospective nonrandomized study. SETTING: Referral-based endocrinology clinic. PATIENTS: Seven patients with active acromegaly, three of whom had refractory congestive heart failure. The other four patients were free of symptoms associated with heart failure. INTERVENTIONS: All patients were treated with octreotide, 100 to 500 micrograms subcutaneously three times daily. The three patients with heart failure continued to receive cardiovascular therapy (angiotensin converting enzyme inhibitors, digitalis, diuretics). MEASUREMENTS AND MAIN RESULTS: During octreotide therapy, patients showed a rapid decrease in growth hormone and insulin-like growth factor 1 (IGF-1): Mean levels (+/- SD) fell from 28.1 +/- 32.7 micrograms/L to 5.2 +/- 8.3 micrograms/L and 740 +/- 126 micrograms/L to 372 +/- 64 micrograms/L, respectively (P less than 0.025). Plasma volume returned to normal and heart rate decreased significantly. In the four patients without heart failure, right-heart catheterization done before and after 3 months of octreotide therapy showed an 18.3% +/- 11% reduction in stroke volume and a return to normal of the cardiac index. The three patients with congestive heart failure, evaluated before and after 40 days and up to 2 years of therapy, showed a dramatic clinical improvement that was associated with an increase in stroke volume (by 24% to 51%). In these patients, the cardiac index remained in the normal range, filling pressures were markedly decreased, and pulmonary wedge pressure returned to normal. This improvement was sustained for up to 3 years in the two patients with heart failure who were receiving long-term treatment. CONCLUSION: The rapid and sustained cardiac improvement seen in our patients shows that octreotide therapy for patients with acromegaly may be highly beneficial, even in those patients with advanced cardiac failure.

Acromegaly↗
PubMed1994

Effect of octreotide, a somatostatin analog, on sleep apnea in patients with acromegaly.

OBJECTIVE: To determine the effects of octreotide, a somatostatin analog, on the severity of sleep apnea and on growth hormone levels in patients with acromegaly. DESIGN: Open-label, prospective study. SETTING: Tertiary referral hospital. PATIENTS: 19 patients with active acromegaly. INTERVENTION: Octreotide in a 6-month, stepwise incremental dosage. MEASUREMENTS: Sleep studies and indices of hormonal activity (levels of insulin-like growth factor 1 [IGF-1] and growth hormone). RESULTS: A 50% decrease occurred in the respiratory disturbance index (baseline compared with 6 months, 39 events/h compared with 19 events/h; P = 0.0002), and a 40% decrease occurred in total apnea time (27.6% of total sleep time compared with 15.1%; P = 0.001). Indices of oxygen desaturation, sleep quality, and subjective sleepiness improved after 6 months of octreotide. A parallel decrease was noted in mean levels of growth hormone (40.0 micrograms/L compared with 9.1 micrograms/L; P = 0.003) and IGF-1 (107 nmol/L compared with 47 nmol/L; P = 0.0001). However, no correlation was noted between the decrease in the total amount of sleep time spent in apnea and the decrease in growth hormone levels (rho = -0.35; P > 0.2). The residual respiratory disturbance index after 6 months of treatment was similar in patients who improved, regardless of whether or not biochemical remission (IGF-1 < 35 nmol/L) occurred. CONCLUSIONS: Improvement in indices of sleep apnea severity occurs in association with octreotide treatment in patients with sleep apnea and acromegaly. However, sleep apnea may either persist despite normalization of growth hormone levels or may improve markedly even if there is only partial biochemical remission.

Acromegaly↗
PubMed1981

Acromegaly: reassessment of the long-term therapeutic effectiveness of transsphenoidal pituitary surgery.

Of 11 patients with active acromegaly treated with transsphenoidal selective pituitary adenomectomy, four failed to show evidence of clinical improvement. An additional four patients showed clinical and biochemical improvement after the surgical procedure but, with more prolonged follow-up, showed a recurrence of acromegaly. Only three patients had prolonged clinical and biochemical evidence of improvement; they had glucose suppressed growth hormone concentrations of 1.0, 2.7, and 2.8 ng/mL 22, 40, and 24 months, respectively, after the surgical procedure. Two of these three patients, however, showed an increase in growth hormone concentration after thyrotropin-releasing hormone injection, a finding that suggests the possibility of eventual relapse. Our data also clearly indicated a need for more rigorous criteria for biochemical cure of acromegaly than those used previously. Study of 20 healthy volunteers showed that growth hormone concentration should normally be suppressible to less than 2.0 ng/mL after 100 g oral glucose.

Acromegaly↗