Faculty Bibliography

CONTEXT: Growth hormone excess and growth hormone deficiency (GHD) are both associated with increased cardiovascular morbidity. A specific acromegaly-related cardiomyopathy has been described, characterized in part by increased left ventricular mass (LVM). Growth hormone deficiency is associated with reduced LVM. Following cure of acromegaly with surgery or radiation therapy, GHD may develop; however, its effects on cardiac morphology and function in this population are not established. OBJECTIVE: We hypothesized that the development of GHD in patients with prior acromegaly would be associated with cardiac morphologic and functional changes that differ from those in patients who are GH sufficient following cure of acromegaly. DESIGN: A cross-sectional study was conducted in a Clinical Research Center. Study participants consisted of three groups of subjects (n=34): I. Cured acromegaly with GHD (n=15), II. Cured acromegaly with GH sufficiency (n=8), and III. Active acromegaly (n=11). Main outcome measures included cardiac morphology and function, using echocardiography parameters. RESULTS: Mean age and BMI, 44.6 +/- 2.3 years (SEM) and 30.7 +/- 1.3 kg/m(2), respectively, were not different among the three groups. Mean peak GH values were: I. 2.8 +/- 0.4 ng/ml; II. 30.1 +/- 9.1 ng/ml (p=0.0002.) In group I, left ventricular mass, indexed to body surface area (LVMi), was within the normal range in all patients; moreover, left ventricular (LV) geometry was normal. At least 50% of patients in groups II and III had elevated LVMi, and in 50% of patients, LV geometry was abnormal, indicating pathologic hypertrophy. Ejection fraction was similar between all three groups. There were no significant differences in diastolic function. CONCLUSIONS: Patients who develop GHD following cure of acromegaly do not demonstrate elevated LV mass, in contrast to patients with a history of acromegaly but normal GH levels or to patients with active acromegaly. This suggests that GH status after treatment of acromegaly correlates with LV mass, and that, in GH sufficient patients, reversal of remodeling may be slower than previously thought. These data suggest that it will be important to determine whether GH replacement alters left ventricular morphology over time.

CONTEXT: The effects of GH replacement therapy in patients who develop GH deficiency (GHD) after cure of acromegaly have not been established in a placebo-controlled study. OBJECTIVE: The objective of the study was to determine whether GH replacement improves body composition, cardiovascular risk markers and quality of life in patients with GHD and prior acromegaly. DESIGN: This was a 6-month, randomized, placebo-controlled study. SETTING: The study was conducted at a clinical translational science center. STUDY PARTICIPANTS: Participants included 30 subjects with prior acromegaly and current GHD. INTERVENTION: INTERVENTIONs included GH or placebo. MAIN OUTCOME MEASURES: Body composition (dual-energy x-ray absorptiometry and cross-sectional computed tomography at L4), cardiovascular risk markers (high-sensitivity C-reactive protein (hsCRP), total, high-density lipoprotein and low-density lipoprotein cholesterol, fibrinogen, and carotid intimal-medial thickness), and quality of life were measured. RESULTS: The mean GH dose at 6 months was 0.58 +/- 0.26 mg/d. Total fat mass, visceral adipose tissue (-15.3 +/- 18.6 vs. 1.3 +/- 12.5%, P = 0.01), and total abdominal fat decreased, and fat-free mass increased, in the GH vs. placebo group. Mean hsCRP levels decreased, but there was no GH effect on other cardiovascular risk markers. There was no change in glycosylated hemoglobin or homeostasis model assessment insulin resistance index. Quality of life improved with GH. Side effects were minimal. CONCLUSIONS: This is the first randomized, placebo-controlled study of the effects of GH replacement therapy on body composition and cardiovascular end points in patients who have developed GH deficiency after treatment for acromegaly, a disease complicated by metabolic and body composition alterations and increased cardiovascular risk. GH replacement decreased visceral adipose tissue, increased fat-free mass, decreased hsCRP, and improved quality of life in patients with GHD after cure of acromegaly, with minimal side effects and without an increase in insulin resistance.

CONTEXT: Anorexia nervosa (AN) and functional hypothalamic amenorrhea (HA) are associated with low bone density, anxiety, and depression. Women with AN and HA have elevated cortisol levels. Significant hypercortisolemia, as in Cushing's disease, causes bone loss. It is unknown whether anxiety and depression and/or cortisol dysregulation contribute to low bone density in AN or HA. OBJECTIVE: Our objective was to investigate whether hypercortisolemia is associated with bone loss and mood disturbance in women with HA and AN. DESIGN AND SETTING: We conducted a cross-sectional study in a clinical research center. PARTICIPANTS: We studied 52 women [21 healthy controls (HC), 13 normal-weight women with functional HA, and 18 amenorrheic women with AN]. OUTCOME MEASURES: Serum samples were measured every 20 min for 12 h overnight and pooled for average cortisol levels. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at anteroposterior and lateral spine and hip. Hamilton Rating Scales for Anxiety (HAM-A) and Depression (HAM-D) were administered. RESULTS: BMD was lower in AN and HA than HC at all sites and lower in AN than HA at the spine. On the HAM-D and HAM-A, AN scored higher than HA, and HA scored higher than HC. Cortisol levels were highest in AN, intermediate in HA, and lowest in HC. HAM-A and HAM-D scores were associated with decreased BMD. Cortisol levels were positively associated with HAM-A and HAM-D scores and negatively associated with BMD. CONCLUSIONS: Hypercortisolemia is a potential mediator of bone loss and mood disturbance in these disorders.

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.

OBJECTIVE: To report the case of a man who presented with profoundly elevated parathyroid hormone levels in the setting of hypercalcemia, a palpable neck mass, renal disease, and metabolic bone disease. METHODS: We describe the clinical, imaging, and laboratory findings of the patient, including results from genetic testing of the CDC73 gene (HRPT2), and review the relevant literature. RESULTS: A 28-year-old man with a history of childhood abdominal neuroblastoma treated with chemotherapy and field radiation therapy presented with a 2-week history of persistent left scapular pain and swelling. He had a freely mobile, 1-cm, homogeneous, nontender, firm nodule in the right anterior neck. Parathyroid hormone concentration at hospital admission was 1127 pg/mL. Single-photon emission computed tomography after intravenous administration of technetium Tc 99m-labeled sestamibi revealed an intense focus of abnormal radiotracer uptake on early and delayed images in the right anterior inferior neck. Computed tomography imaging of the chest and neck revealed a 1.9-cm, smooth, calcified nodule posterior to the right lobe of the thyroid gland and diffusely osteopenic bones with trabecular resorption and numerous scattered lucent regions consistent with brown tumors. On bilateral neck exploration, a right inferior parathyroid mass and the left superior parathyroid gland were excised. The remaining 2 parathyroid glands were identified intraoperatively and appeared normal. Genetic testing of the CDC73 gene did not detect germline mutations. CONCLUSIONS: This case highlights the overlap between the clinical findings seen in primary hyperparathyroidism and parathyroid carcinoma. Enhanced understanding of the genetic and molecular bases of primary hyperparathyroidism and parathyroid carcinoma should aid in the diagnosis of these diseases and the care of affected patients.

OBJECTIVE: Anorexia nervosa is associated with a high prevalence of psychiatric comorbidities, including anxiety and depression, and with endocrine dysfunction, including relative androgen deficiency compared with healthy young women. Because androgens are known to affect mood and behavior, we hypothesized that low endogenous androgen production in anorexia nervosa would predict anxiety and depression severity. METHOD: Serum androgen levels and severity of depression (Hamilton Rating Scale for Depression) and anxiety (Hamilton Rating Scale for Anxiety) were measured in 43 community-dwelling women with DSM-IV-defined anorexia nervosa from May 2004 to July 2006. RESULTS: Strong inverse associations were observed between both total and free testosterone and anxiety and depression severity, independent of weight. Free testosterone was also inversely associated with 4 eating-disordered thinking and behavior subscales of the Eating Disorder Inventory 2 (EDI-2). Mean free testosterone blood levels were lower in women with clinically significant anxiety and in women with clinically significant depression, compared with those without. In stepwise regression models, free testosterone was an important predictor of anxiety and depression severity. EDI-2 ineffectiveness, perfectionism, interpersonal distress, and social insecurity scores were also inversely associated with androgen levels, independent of weight. CONCLUSIONS: Our data suggest that low androgen levels may contribute to anxiety, depression, and eating-disordered thinking and behavior in women with anorexia nervosa and form the basis for future studies to investigate the effectiveness of androgen replacement therapy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00089843.

CONTEXT: Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population. OBJECTIVE: Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women. DESIGN AND SETTING: We conducted a cross-sectional study at a general clinical research center. STUDY PARTICIPANTS: A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls. MAIN OUTCOME MEASURES: Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed. RESULTS: Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass. CONCLUSIONS: Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether oral contraceptive use, mediated by reductions in endogenous androgen levels, is deleterious to skeletal health in such women.

Sensory axons extend from the chick olfactory epithelium to the telencephalon well before the maturation of their target, the olfactory bulb. During a waiting period of several days, olfactory axons arrive and accumulate outside the CNS while the bulb differentiates beneath them. Semephorin-3A is expressed in the tel-encephalon during this period and has been proposed to prevent their entry into the CNS. We show that the misexpression of a dominant-negative neuropilin-1 that blocks SEMA-3A-mediated signaling in olfactory sensory axons induces many of them to enter the tel-encephalon prematurely and to overshoot the olfactory bulb. These results suggest that chemorepellents can prevent the premature innervation of immature targets.

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot-Marie-Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology.