Andrea L. Utz

Acromegaly: An Endocrine Society Clinical Practice Guideline

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.

Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study.

CONTEXT Data regarding gender-specific efficacy of GH on critical endpoints are lacking. There are no randomized, placebo-controlled studies of physiological GH therapy solely in women. OBJECTIVE Our objective was to determine the effects of physiological GH replacement on cardiovascular risk markers and body composition in women with GH deficiency (GHD). DESIGN This was a 6-month, randomized, placebo-controlled, double-blind study. SETTING The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS 43 women with GHD due to hypopituitarism were included in the study. INTERVENTION Study participants were randomized to receive GH (goal mid-normal serum IGF-1) or placebo. MAIN OUTCOME MEASURES Cardiovascular risk markers, including high-sensitivity C-reactive protein, tissue plasminogen activator, and body composition, including visceral adipose tissue by cross-sectional computed tomography, were measured. RESULTS Mean daily GH dose was 0.67 mg. The mean IGF-1 sd score increased from -2.5 +/- 0.3 to -1.4 +/- 0.9 (GH) (P < 0.0001 vs. placebo). High-sensitivity C-reactive protein decreased by 38.2 +/- 9.6% (GH) vs.18.2 +/- 6.0% (placebo) (P = 0.03). Tissue plasminogen activator and total cholesterol decreased, and high-density lipoprotein increased. Homeostasis model assessment-insulin resistance and other markers were unchanged. Body fat decreased [-5.1 +/- 2.0 (GH) vs. 1.9 +/- 1.0% (placebo); P = 0.002] as did visceral adipose tissue [-9.0 +/- 5.9 (GH) vs. 4.3 +/- 2.7% (placebo); P = 0.03]. Change in IGF-1 level was inversely associated with percent change in visceral adipose tissue (r = -0.61; P = 0.002), total body fat (r = -0.69; P < 0.0001), and high-sensitivity C-reactive protein (r = -0.51; P = 0.003). CONCLUSIONS Low-dose GH replacement in women with GHD decreased total and visceral adipose tissue and improved cardiovascular markers, with a relatively modest increase in IGF-1 levels and without worsening insulin resistance.

Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa

INTRODUCTION Anorexia nervosa (AN) is a psychiatric illness that results in significant bone loss. Studies examining the neuroendocrine dysregulation that occurs in AN may increase understanding of endocrine systems that regulate bone mass. Peptide YY (PYY) is an anorexigenic peptide derived primarily from the intestine, with actions mediated via activation of Y receptors. We have previously shown that PYY levels are elevated in adolescents with AN. Y2 receptor knockout mice have increased bone mineral density (BMD) and thus PYY may play a role in regulating bone mass. We hypothesized that PYY levels would be inversely associated with BMD in women with AN. METHODS This was a cross-sectional study performed in a General Clinical Research Center of 12 adult women with AN, (mean+/-SEM) mean age 30.9+/-1.8 years, BMI 17.1+/-0.4 kg/m2, and % ideal body weight 77.5+/-1.7%. PYY concentrations were measured hourly from 20:00 h to 08:00 h. BMD was measured using dual X-ray absorptiometry (DXA). RESULTS In women with AN, mean overnight PYY levels strongly inversely correlated with BMD at the PA spine (r=-0.77, p=0.003), lateral spine (r=-0.82, p=0.002), total hip (r=-0.75, p=0.005), femoral neck (r=-0.72, p=0.009), total radius (r=-0.72, p=0.009) and 1/3 distal radius (r=-0.81, p=0.002). Body mass index was inversely correlated with PYY level (r=-0.64, p=0.03). Multivariate stepwise regression analysis was performed to determine the contribution of age, duration of AN, BMI, fat-free mass, and PYY to BMD. For PA and lateral spine, PYY was the primary determinant of BMD, accounting for 59% and 67% of the variability, respectively. Fat-free mass and duration of anorexia nervosa were the primary determinants of BMD at other skeletal sites. CONCLUSIONS In women with anorexia nervosa, an elevated PYY level is strongly associated with diminished BMD, particularly at the spine. Therefore further investigation of the hypothesis that PYY may contribute to the prevalent bone pathology in this disorder is merited.

Growth hormone deficiency is associated with decreased quality of life in patients with prior acromegaly.

CONTEXT Both GH deficiency (GHD) and GH excess are associated with a decreased quality of life. However, it is unknown whether patients with GHD after treatment for acromegaly have a poorer quality of life than those with normal GH levels after cure of acromegaly. OBJECTIVE The aim of the study was to determine whether patients with GHD and prior acromegaly have a poorer quality of life than those with GH sufficiency after cure of acromegaly. DESIGN AND SETTING We conducted a cross-sectional study in a General Clinical Research Center. STUDY PARTICIPANTS Forty-five patients with prior acromegaly participated: 26 with GHD and 19 with GH sufficiency. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES We evaluated quality of life, as measured by 1) the Quality of Life Adult Growth Hormone Deficiency Assessment (QoL-AGHDA); 2) the Short-Form Health Survey (SF-36); and 3) the Symptom Questionnaire. RESULTS Mean scores on all subscales of all questionnaires, except for the anger/hostility and anxiety subscales of the Symptom Questionnaire, showed significantly impaired quality of life in the GH-deficient group compared with the GH-sufficient group. Peak GH levels after GHRH-arginine stimulation levels were inversely associated with QoL-AGHDA scale scores (R = -0.53; P = 0.0005) and the Symptom Questionnaire Depression subscale scores (R = -0.35; P = 0.031) and positively associated with most SF-36 subscale scores. CONCLUSIONS Our data are the first to demonstrate a reduced quality of life in patients who develop GHD after cure of acromegaly compared to those who are GH sufficient. Further studies are warranted to determine whether GH replacement would improve quality of life for patients with GHD after cure from acromegaly.

Growth Hormone Deficiency by Growth Hormone Releasing Hormone-Arginine Testing Criteria Predicts Increased Cardiovascular Risk Markers in Normal Young Overweight and Obese Women

CONTEXT Little is known about the relationship between GH and cardiovascular risk markers in women without organic hypothalamic/pituitary disease. OBJECTIVE The objective of the study was to determine whether healthy young overweight and obese women, who would be classified as having GH deficiency (GHD) based on standard criteria used in hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml), have increased cardiovascular risk markers. DESIGN This was a cross-sectional study. SETTING The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS Forty-five women of reproductive age, mean age 33.1 +/- 1.2 yr and mean body mass index (BMI) 30.9 +/- 1.0 kg/m(2). INTERVENTION There was no intervention. MAIN OUTCOME MEASURES Measures included carotid intima-medial thickness, high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, E-selectin, soluble intercellular adhesion molecule-1, TNF-alpha receptor I, TNF-alpha receptor II, fasting insulin levels, and oral glucose tolerance testing. RESULTS Twenty-six percent of overweight or obese subjects and none with BMI less than 25 kg/m(2) met criteria for GHD. Subjects who met GHD criteria had a mean BMI of 37.0 +/- 1.7 kg/m(2) (range 28.6-43.6 kg/m(2)), and their mean waist circumference (110.1 +/- 3.5 cm) was higher than in overweight/obese women with GH sufficiency (P = 0.007). Mean carotid intima-media thickness, hsCRP, soluble intercellular adhesion molecule-1, TNF-alpha receptor I, and TNF-alpha receptor II levels were higher, and HDL lower, in women meeting GHD criteria than in GH sufficiency. Differences in HDL, hsCRP, and TNF-alpha receptor II remained after controlling for age plus BMI, waist circumference, or trunk fat. There were no differences in measures of insulin resistance. CONCLUSIONS There may be a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight.

Gender effects on cardiac valvular function in hyperprolactinaemic patients receiving cabergoline: a retrospective study

Background  Ergot‐derived dopamine agonists are associated with increased risk of valvular dysfunction in Parkinson’s disease. The risk of valvular disease associated with lower doses of cabergoline used to treat prolactinomas remains controversial.

Bioactive Insulin-Like Growth Factor-I in Obesity

CONTEXT In obesity, total IGF-I is not reduced to the degree predicted by low GH levels, and free IGF-I levels are normal to high. Total and free IGF-I may not reflect IGF-I biological activity because immunoassays cannot account for the modifying effects of IGF binding proteins on interactions between IGF-I and its receptor. OBJECTIVE The aim of the study was to investigate the biological activity of IGF-I in obesity. DESIGN AND SETTING We conducted a cross-sectional study at a General Clinical Research Center. STUDY PARTICIPANTS Thirty-four healthy women (11 lean, 12 overweight, and 11 obese) of comparable age (overall mean, 30.7 +/- 1.3 yr) participated in the study. INTERVENTION There were no interventions. MAIN OUTCOME MEASURES We measured bioactive IGF-I (as measured by a kinase receptor activation assay), IGFBP-1, and GH using 6-h pools of serum collected every 10 min for 24 h, and fasting IGF-I and IGFBP-3. RESULTS Mean 24-h GH (R = -0.76; P < 0.0001), total IGF-I (R = -0.36; P = 0.040), and IGFBP-1 (R = -0.41; P = 0.017) levels were inversely associated with BMI, whereas bioactive IGF-I and IGFBP-3 levels were not. Mean bioactive IGF-I was similar in the groups [2.72 +/- 0.22 (lean), 3.10 +/- 0.32 (overweight), and 2.43 +/- 0.23 [corrected] (obese) microg/liter; overall P = 0.22]. Percentage bioactive IGF-I [(bioactive/total IGF-I) x 100] was higher in obese subjects than both lean and overweight subjects (P = 0.039). CONCLUSIONS Despite low GH secretion in obesity and decreasing IGFBP-1 with increasing BMI, 24-h mean bioactive IGF-I levels are not reduced in obese women and do not correlate with BMI or IGFBP-1 levels. This argues against elevated bioactive IGF-I as the etiology of reduced GH secretion through a feedback mechanism in obesity.

The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome

Adrenocorticotropin hormone (ACTH)-dependent Cushings syndrome is most often due to a pituitary corticotroph adenoma, with ectopic ACTH-secreting tumors representing approximately 15% of cases. Biochemical and radiological techniques have been established to help distinguish between these two entities, and thus aid in the localization of the neoplastic lesion for surgical resection. The test that offers the highest sensitivity and specificity is bilateral inferior petrosal sinus sampling (BIPSS). BIPSS is an interventional radiology procedure in which ACTH levels obtained from venous drainage very near the pituitary gland are compared to peripheral blood levels before and after corticotropin hormone (CRH) stimulation. A gradient between these two locations indicates pituitary Cushings, whereas the absence of a gradient suggests ectopic Cushings. Accurate BIPSS results require hypercortisolemia to suppress normal corticotroph ACTH production and hypercortisolemia at the time of the BIPSS to assure excessive ACTH secretion. In some cases, intrapituitary gradients from side-to-side can be helpful to localize small corticotroph adenomas within the sella. BIPSS has rare complications and is considered safe when performed at centers with experience in this specialized technique.

Androgens May Mediate a Relative Preservation of IGF-I Levels in Overweight and Obese Women Despite Reduced Growth Hormone Secretion

CONTEXT Obesity is characterized by reduced GH secretion, but data regarding IGF-I levels and their determinants are conflicting. OBJECTIVES The objectives were to determine whether IGF-I levels are reduced and to investigate determinants of GH and IGF-I in healthy overweight and obese women. DESIGN A cross-sectional study was performed. SETTING The study was conducted at a General Clinical Research Center. STUDY PARTICIPANTS Thirty-four healthy women without pituitary/hypothalamic disease participated, including 11 lean [body mass index (BMI) <25 kg/m(2)], 12 overweight (BMI > or =25 kg/m(2) and <30 kg/m(2)), and 11 obese (BMI > or =30 kg/m(2)) women of comparable age (overall mean age, 30.7 +/- 7.8 yr). INTERVENTION There was no intervention. MAIN OUTCOME MEASURES The main outcome measures were frequent sampling (every 10 min for 24 h) for GH, peak GH after GHRH-arginine stimulation, IGF-I, IGF binding protein-3, estrone, estradiol, testosterone, free testosterone, SHBG, homeostasis model assessment of insulin resistance, and abdominal fat. RESULTS Mean 24-h GH and peak stimulated GH were lower in overweight than lean women and lowest in obese women. Mean IGF-I levels trended lower in obese, but not overweight, compared with lean women. Free testosterone was positively associated with IGF-I (R = 0.36, P = 0.04) but not with GH measures. Visceral fat was the only determinant of mean 24-h GH (R(2) = 0.66, P < 0.0001) and of peak stimulated GH (R(2) = 0.63, P < 0.0001), and mean 24-h GH accounted for 39% of the variability of IGF-I (P = 0.0002), with an additional 28% (P < 0.0001) attributable to free testosterone levels. CONCLUSIONS Despite a linear decrease in GH secretion and peak stimulated GH levels with increasing BMI in healthy overweight and obese women, IGF-I levels were not commensurately reduced. Androgens may contribute to this relative preservation of IGF-I secretion in overweight and obese women despite reduced GH secretion.

Anthropometry, CT, and DXA as predictors of GH deficiency in premenopausal women: ROC curve analysis

Visceral adiposity is a strong determinant of growth hormone (GH) secretion, and states of GH deficiency are associated with increased visceral adiposity and decreased lean body mass. The purpose of our study was to determine the sensitivity and specificity of different methods of assessing body composition [anthropometry, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT)] to predict GH deficiency in premenopausal women and threshold values for each technique to predict GH deficiency, using receiver operator characteristic (ROC) curve analysis. We studied a group of 45 healthy lean, overweight, and obese premenopausal women who underwent anthropometric measurements (body mass index, waist and hip circumferences, skin fold thickness), DXA, CT, and a GH-releasing hormone-arginine stimulation test. ROC curve analysis was used to determine cutoff values for each method to identify GH deficiency. Visceral adiposity measured by CT showed the highest sensitivity and specificity for identifying subjects with GH deficiency with a cutoff of >9,962 mm(2) [area under the curve (AUC), 0.95; sensitivity, 100%; specificity, 77.8%; P = 0.0001]. Largest waist circumference showed high sensitivity and specificity with a cutoff of >101.7 cm (AUC, 0.89; sensitivity, 88.9%; specificity, 75%; P = 0.0001). When the ROC curves of visceral fat measured by CT and largest waist circumference were compared, the difference between the two methods was not statistically significant (P = 0.36). Our study showed that the largest waist circumference predicts the presence of GH deficiency in healthy premenopausal women with high sensitivity and specificity and nearly as well as CT measurement of visceral adiposity. It can be used to identify women in whom GH deficiency is likely and therefore in whom formal GH stimulation testing might be indicated.