Beverly M. K. Biller

The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushings syndrome. PARTICIPANTS The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. CONSENSUS PROCESS Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Societys CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments. CONCLUSIONS After excluding exogenous glucocorticoid use, we recommend testing for Cushings syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma. We recommend initial use of one test with high diagnostic accuracy (urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-h dexamethasone suppression test). We recommend that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test. Patients with concordant abnormal results should undergo testing for the cause of Cushings syndrome. Patients with concordant normal results should not undergo further evaluation. We recommend additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease

BACKGROUND Cushings disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushings disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushings disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS The significant decrease in cortisol levels in patients with Cushings disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).

Osteopenia in Men with a History of Delayed Puberty

BACKGROUND AND METHODS The effect of delayed puberty on peak bone mineral density in men is unknown. To determine whether such a delay reduces normal peak bone density and leads to osteopenia during adulthood, we measured radial bone mineral density by single-photon absorptiometry and spinal bone mineral density by dual-energy x-ray absorptiometry in 23 men who had a history of constitutionally delayed puberty and 21 men who underwent normal puberty. Their mean ages were 26 and 24 years, respectively. The groups were matched for other factors known to affect bone mass. RESULTS The mean (+/- SD) radial bone mineral density was significantly lower in the men with a history of delayed puberty than in the normal men (0.73 +/- 0.07 vs. 0.80 +/- 0.05 g per square centimeter; P less than 0.0002). Spinal bone mineral density was also significantly lower in the men with delayed puberty than in the normal men (1.03 +/- 0.10 vs. 1.13 +/- 0.11 g per square centimeter; P less than 0.003). Radial bone density was at least 1 SD below the mean value for the normal men in 15 of the 23 men with a history of delayed puberty, and spinal bone density was similarly decreased in 10 of the 23. CONCLUSIONS Adult men with a history of constitutionally delayed puberty have decreased radial and spinal bone mineral density. These findings suggest that the timing of puberty is an important determinant of peak bone density in men. Because the peak bone mineral density achieved during young adulthood is a major determinant of bone density in later life, men in whom puberty was delayed may be at increased risk for osteoporotic fractures when they are older.

Clinically nonfunctioning pituitary tumors are monoclonal in origin

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

CONTEXT There is currently no medical therapy for Cushings disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. OBJECTIVE Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushings disease. DESIGN We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. PATIENTS Thirty-nine patients with either de novo Cushings disease who were candidates for pituitary surgery or with persistent or recurrent Cushings disease after surgery without having received prior pituitary irradiation. INTERVENTION Patients self-administered sc pasireotide 600 microg twice daily for 15 d. MAIN OUTCOME MEASURE Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. RESULTS Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. CONCLUSIONS Pasireotide produced a decrease in UFC levels in 76% of patients with Cushings disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.

Effects of Growth Hormone Administration on Inflammatory and Other Cardiovascular Risk Markers in Men with Growth Hormone Deficiency: A Randomized, Controlled Clinical Trial

Several studies have shown that cardiovascular mortality is increased among growth hormonedeficient adults (1-3). Increased arterial intimamedia thickness and a higher prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in adults with child- or adult-onset growth hormone deficiency (4-7). The growth hormone deficiency syndrome is associated with a cluster of cardiovascular risk factors (8), including central adiposity (9-11), increased visceral fat (12), insulin resistance (13), and dyslipoproteinemia (3, 14). Growth hormone replacement affects many of these variables, but mechanisms implicated in growth hormone action on the process of atherosclerosis are unknown. In addition, it is not clear whether growth hormone replacement affects the incidence of cardiovascular events. Long-term growth hormone replacement therapy decreases total body fat (12, 15-19), including visceral fat (17). Decreases in central fat assessed by waist-to-hip ratio have been reported in some studies (12, 15, 17, 19) but not in others (16, 20, 21). Administration of growth hormone causes short-term insulin resistance (12), but long-term therapy may restore insulin sensitivity (22). Growth hormone treatment increases lipoprotein(a) levels, but its effects on other lipoproteins remain controversial. Some studies have reported decreases in low-density lipoprotein (LDL) cholesterol levels, with or without increases in high-density lipoprotein (HDL) cholesterol levels (15, 23, 24), whereas others have not (5, 25, 26). Key factors probably involved in these discrepant findings include heterogeneity of age at onset of growth hormone deficiency (childhood versus adulthood), sex, and methodologic issues, such as dose and duration of treatment. In addition, most studies were short-term or uncontrolled. Inflammation plays a central role in the pathophysiology of atherosclerosis (27). Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall, and markers along the inflammatory cascade have been reported to predict cardiovascular risk (28). High-sensitivity testing for C-reactive protein is one of the best validated markers (29-33). Other distal indicators of inflammation, such as serum amyloid polypeptide A and interleukin-6, likewise predict coronary risk (34). Growth hormone is known to have important immunomodulatory effects (35-37). We therefore hypothesized that the effects of growth hormone on the process of atherosclerosis might be mediated through the cytokine inflammatory pathway. In a randomized, 18-month, placebo-controlled study, we investigated the effect of long-term growth hormone replacement therapy on interleukin-6, C-reactive protein, serum amyloid polypeptide A, and other classic cardiovascular risk factors in men with adult-onset growth hormone deficiency. Methods Patients Forty men (mean age, 49 years [range, 24 to 64 years]) were recruited from the Massachusetts General Hospital, Boston, Massachusetts, and surrounding communities. Methods and other results from this study have been reported elsewhere [16, 38]. Patients were identified through hospital records and referrals. All patients met the following criteria: 1) normal growth and development; 2) benign sellar neoplasm, pituitary apoplexy, or idiopathic hypopituitarism diagnosed after age 18 years, and 3) peak growth hormone level less than 5 g/L after two pharmacologic stimuli. Patients were excluded if they had a history of cancer, acromegaly, or diabetes or if they had not been stable and receiving appropriate replacement for other hormonal deficiencies for at least 6 months. All patients who met the criteria and were willing to participate entered the study. The study was approved by the subcommittee on human studies at Massachusetts General Hospital, and all patients gave written informed consent. Protocol After baseline evaluation, patients were randomly assigned to receive either daily injections with recombinant human growth hormone (Nutropin, Genentech, Inc., South San Francisco, California) or placebo for 18 months. The computerized randomization, performed by Genentech, stratified patients by age. Patients were hospitalized at baseline and every 6 months for anthropometric, nutritional, and fat distribution evaluations. Fasting blood samples were drawn for measurement of insulin-like growth factor I (IGF-I), glucose, insulin, lipids, and hemoglobin A1c values. Levels of IGF-I, glucose, insulin, and lipids were also determined at 1 and 3 months; hemoglobin A1c values were measured at 3 months. Serum and plasma aliquots were collected and frozen at 20 C. Levels of C-reactive protein, serum amyloid polypeptide A, interleukin-6, and lipoprotein(a) were measured in serum that was obtained at the baseline, 6-month, and 18-month visits and had been stored without previous thawing. The initial growth hormone dosage was 10 g/kg of body weight per day, and patients self-administered the growth hormone subcutaneously at night. The dose was subsequently titrated to maintain IGF-I levels within the sex- and age-adjusted normal range. Anthropometry, Nutritional Assessment, and Fat Distribution Height, weight, and waist and hip circumferences were measured, and percentage of ideal body weight, waist-to-hip ratio, and body mass index were calculated for each patient. Nutritional intake was evaluated every 6 months by using food records. Nutrient calculations were performed by using Nutrition Data System software, developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota. Dual-energy x-ray absorptiometry (Hologic QDR-2000, Waltham, Massachusetts) was performed to determine fat distribution. According to the manufacturer, the coefficient of variation for body fat is 1.5%. The body fat percentage was calculated by dividing the weight of fat by total body weight. Percentage of truncal fat and extremity fat were determined similarly. The ratio of truncal fat to total fat and the ratio of truncal fat to extremity fat were calculated as described elsewhere (39). Biochemical Analysis Serum IGF-I levels were measured by radioimmunoassay after acid-alcohol extraction (Nichols Institute, San Juan Capistrano, California). Lipoprotein(a), serum amyloid polypeptide A, and C-reactive protein levels were simultaneously measured on the Behring BNII analyzer (Dade Behring, Newark, Delaware) by using ultrasensitive and latex-enhanced immunotechniques. The interassay coefficients of variation were less than 6%, 7%, and 5.6% respectively, over a wide range of concentrations. Interleukin-6 levels were measured by using ultrasensitive enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota) with an interassay coefficient of variation of 5.8%. Other assays were performed at Massachusetts General Hospital, as described elsewhere (40). Statistical Analysis We prospectively chose to divide the analysis into two phases: short-term (months 1 and 3) and long-term (months 6, 12, and 18). The short-term effect represents the mean of the month 1 and month 3 changes from baseline, and the long-term effect represents the mean of the month 6, month 12 (when available), and month 18 changes from baseline. The primary analysis used repeated-measures analysis of covariance (SAS PROC MIXED, SAS Institute, Inc., Cary, North Carolina), controlling for baseline value and month, to estimate the mean change from baseline within and between groups. The analysis we used is equivalent to a random-effects model with a fixed group effect and a random patient effect; this analysis correctly accounts for ignorable missing data. Results from the primary analysis are reported, unless otherwise noted, as the least-squares mean change from baseline (SE) within the growth hormone group compared with that within the placebo group, as estimated from the model. The P value for the comparison between groups is also given. All P values are two sided, and values less than 0.05 were considered statistically significant. In a secondary analysis, we used a random-slopes model with a fixed baseline effect, fixed treatment effect, fixed treatment-by-month interaction, and a random-intercept and a random-month effect for each patient to test for a time-by-treatment interaction over months 6 through 18. The time-by-treatment interaction, which represents the difference in slopes between the two groups, was considered statistically significant if the P value was less than 0.1. Pearson product moment correlation coefficients were computed to estimate 1) the correlation between mean IGF-I levels at months 1 and 3 and long-term changes in the outcome variables and 2) changes in IGF-I levels and changes in outcome variables; P values less than 0.05 were considered statistically significant. We used SAS software, version 8 (SAS Institute, Inc.), for all data analyses. Role of Study Sponsor Genentech provided growth hormone, statistical support for the random assignment of patients, and partial grant support. The company had no involvement in the design of the study, collection and analysis of the data, writing of the paper, or the decision to submit the manuscript for publication. Results Table 1 shows clinical characteristics of the pituitary disorder in the study patients. Clinical and biochemical characteristics of the patients at baseline are shown in Tables 2 and 3, respectively. Patients assigned to receive growth hormone or placebo did not differ with regard to any variable studied except central fat (estimated as ratios of truncal fat to total fat and truncal fat to extremity fat), which was slightly higher in the growth hormone group. One patient assigned to the growth hormone group had a history of coronary artery disease. Medications used, including statins, nonsteroidal anti-inflammatory drugs, and steroids, did not differ between the two groups. Table 1. Characteristics of Pituitary Disorders Table 2.

Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome.

CONTEXT Cushings syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations. OBJECTIVE Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS. DESIGN AND SETTING We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers. PARTICIPANTS Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT). INTERVENTION Mifepristone was administered at doses of 300-1200 mg daily. MAIN OUTCOME MEASURES We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT. RESULTS In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P < 0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women. CONCLUSIONS Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

OBJECTIVE The objective is to formulate clinical practice guidelines for treating Cushings syndrome. PARTICIPANTS Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. EVIDENCE The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS Treatment of Cushings syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushings syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.

Long-Term Mortality after Transsphenoidal Surgery for Cushing Disease

Survival of patients treated for Cushing disease with current management techniques between 1978 and 1996 was better than the poor survival historically associated with this disorder.