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 impor...

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Acromegaly: An Endocrine Society Clinical Practice Guideline

Objective: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). Participants: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. Process: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. Conclusions: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develo...

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Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)

Medical progress: Acromegaly.

Association between premature mortality and hypopituitarism

The p16INK4a/CDKN2A tumor suppressor and its relatives

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly

Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing's disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.

Mortality in Patients with Pituitary Disease

OBJECTIVE
Pituitary radiotherapy (RT) is often used as adjuvant treatment in the post-operative period for patients with clinically non-functioning pituitary tumours (NFTs). There is a distinct lack of objective data, however, describing the efficacy of RT in preventing the regrowth of these tumours. We have therefore determined whether the recurrence rate for NFTs is significantly lower in patients treated with post-operative RT compared with that observed in patients not treated with RT.

PATIENTS AND METHODS
A retrospective case notes review was performed on 126 patients with NFTs treated at two institutions in the UK. One hospital routinely administered RT within 12 months of initial pituitary surgery whereas the other used post-operative RT only rarely. The main outcome measure was regrowth of pituitary tumours following surgery in patients who did or did not receive post-operative RT.

RESULTS
There was no significant difference between patients who received RT versus those who did not in terms of age, sex, initial tumour size or mode of operation. The actuarial progression-free survival was 93% at both 10 years and at 15 years for the RT treated group, and was 68% and 33%, respectively, for the non-RT-treated group. Using Cox's model for proportional hazard analysis, we found the only prognostic factor for NFT regrowth was the administration of pituitary RT (P < 0.00005).

CONCLUSIONS
Radiotherapy administered within 12 months of initial pituitary surgery for non-functioning pituitary tumours significantly reduces the risk of tumour regrowth. It remains to be determined whether sequential MRI scanning can help delineate those patients who should receive radiotherapy following pituitary surgery for non-functioning pituitary tumours.

Radiotherapy for non-functioning pituitary tumours

Context: A number of retrospective studies report that patients with acromegaly have increased morbidity and premature mortality, with standardized mortality ratios (SMR) of 1.3–3. Many patients with acromegaly develop hypopituitarism as a result of the pituitary adenoma itself or therapies such as surgery and radiotherapy. Pituitary radiotherapy and hypopituitarism have also been associated with an increased SMR. Methods: Using the West Midlands Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9–21 yr). Results: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7–2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9–3.2); P < 0.0005; and gonadotropin deficiency SMR, ...

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A. S. Bates

Papers

Association between premature mortality and hypopituitarism

Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly

Mortality in Patients with Pituitary Disease

Radiotherapy for non-functioning pituitary tumours

ACTH Deficiency, Higher Doses of Hydrocortisone Replacement, and Radiotherapy Are Independent Predictors of Mortality in Patients with Acromegaly