Laurence Katznelson

OBJECTIVE: The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Acquired hypogonadism is being increasingly recognized in adult men. However, the effects of long term testosterone replacement on bone density and body composition are largely unknown. We investigated 36 adult men with acquired hypogonadism (age, 22-69 yr; median, 58 yr), including 29 men with central hypogonadism and 7 men with primary hypogonadism, and 44 age-matched eugonadal controls. Baseline evaluation included body composition analysis by bioimpedance, determination of site-specific adipose area by dual energy quantitative computed tomography scan (QCT) of the lumbar spine, and measurements of spinal bone mineral density (BMD) using dual energy x-ray absortiometry, spinal trabecular BMD with QCT, and radial BMD with single photon absorptiometry. Percent body fat was significantly greater in the hypogonadal men compared to eugonadal men (mean +/- SEM, 26.4 +/- 1.1% vs. 19.2 +/- 0.8%; P < 0.01). The mean trabecular BMD determined by QCT for the hypogonadal men was 115 +/- 6 mg K2HPO4/cc. Spinal BMD was significantly lower than that in eugonadal controls (1.006 +/- 0.024 vs. 1.109 +/- 0.028 g/cm2; P = 0.02, respectively). Radial BMD was similar in both groups. Testosterone enanthate therapy was initiated in 29 hypogonadal men at a dose of 100 mg/week, and the subjects were evaluated at 6-month intervals for 18 months. During testosterone therapy, the percent body fat decreased 14 +/- 4% (P < 0.001). There was a 13 +/- 4% decrease in subcutaneous fat (P < 0.01) and a 7 +/- 2% increase in lean muscle mass (P = 0.01) during testosterone therapy. Spinal BMD and trabecular BMD increased by 5 +/- 1% (P < 0.001) and 14 +/- 3% (P < 0.001), respectively. Radial BMD did not change. Serum bone-specific alkaline phosphatase and urinary deoxypyridinoline excretion, markers of bone formation and resorption, respectively, decreased significantly over the 18 months (P = 0.003 and P = 0.04, respectively). We conclude that testosterone therapy given to adult men with acquired hypogonadism decreases sc fat and increases lean muscle mass. In addition, testosterone therapy reduces bone remodeling and increases trabecular bone density. The beneficial effects of androgen administration on body composition and bone density may provide additional indications for testosterone therapy in hypogonadal men.

To analyze the long term outcome after multimodality therapy for acromegaly, a retrospective review was performed on 162 patients who underwent transsphenoidal surgery at Massachusetts General Hospital between 1978 and 1996. The surgical cure rate for microadenomas was 91%, that for macroadenomas was 48%, and it was 57% overall. The surgical cure rate was significantly dependent on tumor size, but was not dependent on age or sex. An improvement in the surgical cure rate was noted over the course of the review, from 45% before 1987 to 73% since 1991. Long term follow-up was obtained in 99% of U.S. residents (149 of 151), with a mean follow-up period of 7.8 yr. Adjuvant radiation and/or pharmacological therapy was given to 61 patients. Of the entire group, 83% (124 of 149) were in biochemical remission as determined by normalization of serum insulin-like growth factor I levels or by GH suppression after oral glucose tolerance testing at last contact or at death. The recurrence rate was 6% at 10 yr and 10% at 15 yr after surgery in those patients who initially met the criteria for surgical cure. The 10-yr survival rate was 88%, and there were 12 deaths at postoperative intervals of 2-12 yr, with the most common cause of death being cardiovascular disease. A Cox proportional hazards model showed that patient-years with persistent disease carried a 3.5-fold [95% confidence interval (CI), 1.0-12; P = 0.02] relative mortality risk compared to those patient-years in remission. A Poisson person-years regression analysis showed no significant difference in survival between those 86 patients cured at operation and an age- and sex-matched sample from the U.S. population [standardized mortality ratio (SMR), 0.84; 95% CI, 0.3-2.2; P = 0.35]. A similar analysis on the entire group of 149 patients showed no significant difference in survival from that in a control sample (SMR, 1.16; 95% CI, 0.66-2.0; P = 0.3). Mortality risk for patient-years with persistent active disease after unsuccessful treatment vs. that in the U.S. population sample remained increased (SMR, 1.8; 95% CI, 0.9-3.6; P = .05). This analysis suggests that the decreased survival previously reported to be associated with acromegaly can be normalized by successful surgical and adjunctive therapy.