Karen K Miller

Publications of Karen K Miller

• Growth Hormone Replacement has a Greater Effect on Quality of Life in Growth Hormone-Deficient Women with a History of Acromegaly.

  Authors: Elena Valassi, Danielle J Brick, Jessica C Johnson, Beverly M K Biller, Anne Klibanski, Karen K Miller

  Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 02/2012;

  Objective: To compare the response in quality of life (QoL) to GH replacement in GH-deficient women with a history of acromegaly to that of women with GHD of other etiologies.Methods: Fifty-fiveObjective: To compare the response in quality of life (QoL) to GH replacement in GH-deficient women with a history of acromegaly to that of women with GHD of other etiologies.Methods: Fifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other etiologies of GHD. We compared two, six-month, randomized, placebo-controlled studies of GH therapy in women with hypopituitarism conducted using the same design - one in women with a history of acromegaly and one without. QoL was assessed with the following questionnaires: Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA); Symptom Questionnaire; Short-Form Health Survey (SF-36).Results: The two groups had comparable mean pretreatment age, BMI and QoL scores, and comparable mean GH dose at 6 months (0.61±0.30 vs. 0.67±0.27 mcg/d). After 6 months of GH replacement, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 subscales (Role Limitations due to Physical Health, Energy/Fatigue, Emotional Well-Being, Social Functioning), and the Somatic Symptom subscale of the Symptom Questionnaire, than women with GHD of other etiologies. Poorer pre-treatment QoL was associated with a greater improvement in QoL after GH administration.Conclusions: In this study, GH replacement therapy improved QoL in women with GHD and a previous history of acromegaly but not in women with GHD due to other hypothalamic / pituitary disorders. Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly.

• Effects of transdermal testosterone on natriuretic peptide levels in women: a randomized placebo-controlled pilot study.

  Authors: Eleanor Lin, Elizabeth McCabe, Christopher Newton-Cheh, Kenneth Bloch, Emmanuel Buys, Thomas Wang, Karen K Miller

  Fertility and sterility. 12/2011; 97(2):489-93.

  To investigate whether testosterone administration alters natriuretic peptide levels in women. Three-month, double-blind, randomized, placebo-controlled study. Clinical research center. Fifty-oneTo investigate whether testosterone administration alters natriuretic peptide levels in women. Three-month, double-blind, randomized, placebo-controlled study. Clinical research center. Fifty-one women with hypoandrogenemia due to hypopituitarism. Transdermal testosterone (300 μg daily) or placebo patch. N-Terminal pro-B-type natriuretic peptide (NT-proBNP) levels. NT-proBNP levels decreased in the transdermal testosterone group compared with placebo over three months. The difference between groups remained significant after controlling for baseline age, systolic blood pressure, body mass index, and homeostasis model assessment of insulin resistance. Change in NT-proBNP over 3 months was inversely associated with change in free testosterone levels. Testosterone administration to women results in decreased natriuretic peptide levels, suggesting that testosterone may be an inverse regulator of the natriuretic peptide system. CLINICAL TRIALS REGISTRATION NUMBER: NCT00027430.

• Estradiol levels predict bone mineral density in male collegiate athletes: a pilot study.

  Authors: Kathryn E Ackerman, Gary S Skrinar, Eva Medvedova, Madhusmita Misra, Karen K Miller

  Clinical endocrinology. 09/2011; 76(3):339-45.

  Objective  Strenuous training commonly results in amenorrhoea, which contributes to bone loss in some female collegiate athletes. However, the impact of athletic training on endocrine function andObjective  Strenuous training commonly results in amenorrhoea, which contributes to bone loss in some female collegiate athletes. However, the impact of athletic training on endocrine function and bone mineral density (BMD) in male collegiate athletes is less well understood. The objective of the study was to investigate the specific endocrine determinants of BMD in male collegiate runners and wrestlers, including the potential impact of gonadal steroid levels. Design  Cross-sectional study. Patients  Twenty-six division I collegiate male athletes (wrestlers, runners and golfers). Measurements  Main outcome measures included (i) BMD endpoints measured by dual energy x-ray absorptiometry (DXA); (ii) endocrine end-points: total and free oestradiol, total and free testosterone; (iii) body composition end-points: lean and fat mass, measured by DXA; and (iv) exercise end-points: maximal oxygen uptake (VO(2) max), number of miles run weekly and grip strength. Results  Free and total oestradiol levels were important positive determinants of BMD. In contrast, total and free testosterone levels were not significant predictors of BMD at any skeletal site (except for free testosterone at the radius). In addition, lean body mass, % ideal body weight, total body weight, body mass index (BMI) and hours per week of resistance training were positive predictors of BMD. VO(2) max was a negative predictor of BMD. Mean BMD was higher at all skeletal sites in the wrestlers compared with the runners and a comparison group (golfers). Conclusions  Our data suggest that oestradiol levels, BMI, and resistance training are more important determinants of BMD in male collegiate athletes than testosterone.

• Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass.

  Authors: Elizabeth A Lawson, Daniel A Donoho, Justine I Blum, Erinne M Meenaghan, Madhusmita Misra, David B Herzog, Patrick M Sluss, Karen K Miller, Anne Klibanski

  The Journal of clinical psychiatry. 08/2011; 72(11):1546-51.

  Anorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data showAnorexia nervosa is characterized by self-induced starvation and associated with severe bone and fat loss. Oxytocin is a peptide hormone involved in appetite and energy homeostasis. Recent data show that oxytocin has an anabolic effect on bone and stimulates osteoblast function. There is limited information about oxytocin levels or their relationship to decreased bone mineral density in anorexia nervosa. Our objective was to investigate the relationship between oxytocin levels, bone mineral density, and body composition in women with anorexia nervosa. We studied 36 women, mean ± SEM age 27.6 ± 1.3 years: 17 with DSM-IV anorexia nervosa and 19 healthy controls in a cross-sectional study. Oxytocin levels were determined from pooled serum samples obtained every 20 minutes from 8 pm to 8 am during an inpatient overnight visit. Fasting leptin levels were measured. Bone mineral density at the anterior-posterior and lateral spine and hip and body composition were assessed by dual energy x-ray absorptiometry. The study was conducted from September 2004 to June 2008. Subjects with anorexia nervosa versus healthy controls had lower mean ± SEM oxytocin levels (14.3 ± 1.5 vs 31.8 ± 5.1 pg/mL, P = .003), leptin levels (2.7 ± 0.5 vs 11.4 ± 1.1 ng/mL, P < .0001), bone mineral density (anterior-posterior spine: 0.83 ± 0.02 vs 1.04 ± 0.03; lateral spine: 0.63 ± 0.02 vs 0.81 ± 0.02; total hip: 0.79 ± 0.03 vs 0.97 ± 0.03 g/cm², P < .0001), and fat mass (8.8 ± 0.6 vs 19.7 ± 0.9 kg, P < .0001). Oxytocin levels were associated with bone mineral density at the anterior-posterior (r = 0.40, P = .02) and lateral (r = 0.36, P = .04) spine, fat mass (r = 0.42, P = .01), and leptin levels (r = 0.55, P = .001). Overnight secretion of oxytocin in women with anorexia nervosa is decreased compared with healthy women. Low oxytocin levels are associated with decreased bone mineral density and body fat and may contribute to anorexia nervosa-induced bone loss.

• Influence of sex and hormone status on circulating natriuretic peptides.

  Authors: Carolyn S P Lam, Susan Cheng, Karen Choong, Martin G Larson, Joanne M Murabito, Christopher Newton-Cheh, Shalender Bhasin, Elizabeth L McCabe, Karen K Miller, Margaret M Redfield, Ramachandran S Vasan, Andrea D Coviello, Thomas J Wang

  Journal of the American College of Cardiology. 08/2011; 58(6):618-26.

  The aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults. Women have higher circulating natriuretic peptide concentrationsThe aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults. Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion. We measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone-binding globulin plasma levels in 4,056 men and women (mean age 40 ± 9 years) from the Framingham Heart Study Third-Generation cohort. Sex/hormone status was grouped as: 1) men; 2) post-menopausal women not receiving hormone replacement therapy; 3) pre-menopausal women not receiving hormonal contraceptives; 4) post-menopausal women receiving hormone replacement therapy; and 5) pre-menopausal women receiving hormonal contraceptives. Circulating NT-proBNP levels were associated with sex/hormone status (overall p < 0.0001). Men had lower NT-proBNP levels than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP levels than women who were not receiving hormone therapy (all p < 0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, free testosterone (FT) levels decreased and sex hormone-binding globulin levels increased in tandem with increasing NT-proBNP levels. In sex-specific analyses, NT-proBNP levels decreased across increasing quartiles of FT in men (p for trend <0.01) and women (p for trend <0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations. These findings suggest that lower levels of circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.

• Relation of visceral adiposity to circulating natriuretic peptides in ambulatory individuals.

  Authors: Susan Cheng, Caroline S Fox, Martin G Larson, Joseph M Massaro, Elizabeth L McCabe, Abigail May Khan, Daniel Levy, Udo Hoffmann, Christopher J O'Donnell, Karen K Miller, Christopher Newton-Cheh, Andrea D Coviello, Shalender Bhasin, Ramachandran S Vasan, Thomas J Wang

  The American journal of cardiology. 08/2011; 108(7):979-84.

  Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals mayNatriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relation of plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) to regional adiposity in 1,873 community-based individuals (46% women, mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multidetector computed tomography. In gender-specific multivariable analyses adjusting for age and blood pressure, log NT-pro-BNP was inversely associated with VAT in men (beta -0.11 per standard deviation increment, p <0.001) and women (beta -0.19, p <0.001). Log NT-pro-BNP was inversely associated with SAT in women only (beta -0.14, p <0.001). In models containing VAT and SAT, only VAT was significantly associated with log NT-pro-BNP (men, beta -0.137, p <0.001; women, beta -0.184, p <0.001). VAT remained associated with log NT-pro-BNP even after adjustment for body mass index and waist circumference (beta -0.119, p <0.001) and in analyses restricted to nonobese patients (beta -0.165, p <0.001). Adjustment for insulin resistance attenuated the associations of NT-pro-BNP with VAT and SAT. In conclusion, this study demonstrates that circulating NT-pro-BNP is related to variations in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide "deficiency" observed in obesity.

• Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat.

  Authors: Elizabeth A Lawson, Karen K Miller, Justine I Blum, Erinne Meenaghan, Madhusmita Misra, Kamryn T Eddy, David B Herzog, Anne Klibanski

  Clinical endocrinology. 07/2011; 76(4):520-5.

  Objective  Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negativelyObjective  Leptin is anorexigenic, and levels are markedly decreased in women with low body weight and high in women with obesity. Ghrelin opposes leptin effects on appetite and is negatively associated with body mass index. These appetite-regulating hormones may have opposing effects on mood and stress pathways. Women with anorexia nervosa (AN), hypothalamic amenorrhoea (HA) and obesity are at increased risk of depression and anxiety. It is unknown whether dysregulation of leptin or ghrelin contributes to the development of depression and/or anxiety in these disorders. We investigated the relationship between leptin and ghrelin levels and symptoms of depression, anxiety and perceived stress in women across the weight spectrum. Design  Cross-sectional. Patients  64 women: 15 with AN, 12 normal-weight with HA, 17 overweight or obese (OB) and 20 normal-weight in good health (HC). Measurements  Fasting serum leptin and plasma ghrelin levels were measured. Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) and the Perceived Stress Scale were administered. Results  Leptin levels were inversely associated with HAM-D, HAM-A and Perceived Stress scores. The negative relationships between leptin and severity of symptoms of both depression and anxiety remained significant after controlling for body fat or weight. There was no relationship between ghrelin and symptoms of depression or anxiety. Although ghrelin levels were positively associated with the degree of perceived stress, this relationship was not significant after controlling for body fat or weight. Conclusions  Leptin may mediate depressive symptoms across the weight spectrum. Further investigation of the role of leptin in modulating mood will be important.

• Effects of oral contraceptives on natriuretic peptide levels in women with hypothalamic amenorrhea: a pilot study.

  Authors: Eleanor Lin, Steven Grinspoon, Thomas Wang, Karen K Miller

  Fertility and sterility. 06/2011; 95(8):2605-7.

  Natriuretic peptides, which are important regulators of salt handling and blood pressure, are 60%-75% higher in healthy young women than in men, consistent with a gender dimorphism. In thisNatriuretic peptides, which are important regulators of salt handling and blood pressure, are 60%-75% higher in healthy young women than in men, consistent with a gender dimorphism. In this randomized, placebo-controlled study in women with functional hypothalamic amenorrhea, we show that administration of oral contraceptives (OC) increases natriuretic peptide levels and that end-of-study free T levels are inversely associated with amino-terminal pro-B-type natriuretic peptide levels, consistent with the hypothesis that natriuretic peptide levels may be mediated by differences in gonadal steroid concentrations-estrogens (E) or androgens.

• Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.

  Authors: Madhusmita Misra, Debra Katzman, Karen K Miller, Nara Mendes, Deirdre Snelgrove, Melissa Russell, Mark A Goldstein, Seda Ebrahimi, Laura Clauss, Thomas Weigel, Diane Mickley, David A Schoenfeld, David B Herzog, Anne Klibanski

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 06/2011; 26(10):2430-8.

  Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional andAnorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including hypogonadism and low estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high estrogen doses given as an oral contraceptive do not improve BMD. The impact of physiologic estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] ≥15 years, n = 96) were randomized to 100 µg of 17β-estradiol (with cyclic progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low-dose oral ethinyl-estradiol (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, 11.25 µg from 12 to 18 months) to mimic pubertal estrogen increases or placebo for 18 months. All BMD measures assessed by dual-energy X-ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to estrogen (AN E + ) did not differ from those randomized to placebo (AN E-) for age, maturity, height, BMI, amenorrhea duration, and BMD parameters. Spine and hip BMD Z-scores increased over time in the AN E+ compared with the AN E- group, even after controlling for baseline age and weight. It is concluded that physiologic estradiol replacement increases spine and hip BMD in girls with AN.

• Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study.

  Authors: Karen K Miller, Erinne Meenaghan, Elizabeth A Lawson, Madhusmita Misra, Suzanne Gleysteen, David Schoenfeld, David Herzog, Anne Klibanski

  The Journal of clinical endocrinology and metabolism. 04/2011; 96(7):2081-8.

  Anorexia nervosa is complicated by severe bone loss and clinical fractures. Mechanisms underlying bone loss in adults with anorexia nervosa include increased bone resorption and decreased formation.Anorexia nervosa is complicated by severe bone loss and clinical fractures. Mechanisms underlying bone loss in adults with anorexia nervosa include increased bone resorption and decreased formation. Estrogen administration has not been shown to prevent bone loss in this population, and to date, there are no approved, effective therapies for this comorbidity. To determine whether antiresorptive therapy with a bisphosphonate alone or in combination with low-dose transdermal testosterone replacement would increase bone mineral density (BMD) in women with anorexia nervosa. We conducted a12-month, randomized, placebo-controlled study at a clinical research center. Participants included 77 ambulatory women with anorexia nervosa. Subjects were randomized to risedronate 35 mg weekly, low-dose transdermal testosterone replacement therapy, combination therapy or double placebo. BMD at the spine (primary endpoint), hip, and radius and body composition were measured by dual-energy x-ray absorptiometry. Risedronate increased posteroanterior spine BMD 3%, lateral spine BMD 4%, and hip BMD 2% in women with anorexia nervosa compared with placebo in a 12-month clinical trial. Testosterone administration did not improve BMD but increased lean body mass. There were few side effects associated with either therapy. Risedronate administration for 1 yr increased spinal BMD, the primary site of bone loss in women with anorexia nervosa. Low-dose testosterone did not change BMD but increased lean body mass.

• Appetite-regulating hormones cortisol and peptide YY are associated with disordered eating psychopathology, independent of body mass index.

  Authors: Elizabeth A Lawson, Kamryn T Eddy, Daniel Donoho, Madhusmita Misra, Karen K Miller, Erinne Meenaghan, Janet Lydecker, David Herzog, Anne Klibanski

  European journal of endocrinology / European Federation of Endocrine Societies. 02/2011; 164(2):253-61.

  Disordered eating occurs in women at both weight extremes of anorexia nervosa (AN) and obesity. Cortisol, peptide YY (PYY), leptin, and ghrelin are hormones involved in appetite and feeding behaviorDisordered eating occurs in women at both weight extremes of anorexia nervosa (AN) and obesity. Cortisol, peptide YY (PYY), leptin, and ghrelin are hormones involved in appetite and feeding behavior that vary with weight and body fat. Abnormal levels of these hormones have been reported in women with AN, functional hypothalamic amenorrhea (HA), and obesity. The relationship between appetite-regulating hormones and disordered eating psychopathology is unknown. We therefore studied the relationship between orexigenic and anorexigenic hormones and disordered eating psychopathology in women across a range of weights. A cross-sectional study of 65 women, 18-45 years: 16 with AN, 12 normal-weight with HA, 17 overweight or obese, and 20 normal-weight in good health. Two validated measures of disordered eating psychopathology, the Eating Disorders Examination-Questionnaire (EDE-Q) and Eating Disorders Inventory-2 (EDI-2), were administered. Fasting PYY, leptin, and ghrelin levels were measured; cortisol levels were pooled from serum samples obtained every 20 min from 2000 to 0800 h. Cortisol and PYY levels were positively associated with disordered eating psychopathology including restraint, eating concerns, and body image disturbance, independent of body mass index (BMI). Although leptin levels were negatively associated with disordered eating psychopathology, these relationships were not significant after controlling for BMI. Ghrelin levels were generally not associated with EDE-Q or EDI-2 scores. Higher levels of cortisol and PYY are associated with disordered eating psychopathology independent of BMI in women across the weight spectrum, suggesting that abnormalities in appetite regulation may be associated with specific eating disorder pathologies.

• Modular MR-compatible lower leg exercise device for whole-body scanners.

  Authors: Reza Hosseini Ghomi, Miriam A Bredella, Bijoy J Thomas, Karen K Miller, Martin Torriani

  Skeletal radiology. 01/2011; 40(10):1349-54.

  To develop a modular MR-compatible lower leg exercise device for muscle testing using a clinical 3 T MR scanner. An exercise device to provide isotonic resistance to plantar- or dorsiflexion wasTo develop a modular MR-compatible lower leg exercise device for muscle testing using a clinical 3 T MR scanner. An exercise device to provide isotonic resistance to plantar- or dorsiflexion was constructed from nonferrous materials and designed for easy setup and use in a clinical environment. Validation tests were performed during dynamic MR acquisitions. For this purpose, the device was tested on the posterior lower leg musculature of five subjects during 3 min of exercise at 30% of maximum voluntary plantarflexion during 31-phosphorus MR spectroscopy ((31)P-MRS). Measures of muscle phosphocreatine (PCr), inorganic phosphate (Pi), and pH were obtained before, during, and after the exercise protocol. At the end of exercise regimen, muscle PCr showed a 28% decrease from resting levels (to 21.8 ± 3.9 from 30.4 ± 3.0 mM) and the average PCr recovery rate was 35.3 ± 8.3 s. Muscle Pi concentrations increased 123% (to 14.6 ± 4.7 from 6.5 ± 3.3 mM) and pH decreased 1.5% (to 7.06 ± 0.14 from 7.17 ± 0.07) from resting levels. The described MR-compatible lower leg exercise was an effective tool for data acquisition during dynamic MR acquisitions of the calf muscles. The modular design allows for adaptation to other whole-body MR scanners and incorporation of custom-built mechanical or electronic interfaces and can be used for any MR protocol requiring dynamic evaluation of calf muscles.

• Adiponectin is inversely associated with intramyocellular and intrahepatic lipids in obese premenopausal women.

  Authors: Miriam A Bredella, Martin Torriani, Reza H Ghomi, Bijoy J Thomas, Danielle J Brick, Anu V Gerweck, Lindsey M Harrington, Karen K Miller

  Obesity (Silver Spring, Md.). 12/2010; 19(5):911-6.

  Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content inAdiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy ((1)H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m(2)) who underwent (1)H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMA(IR)), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMA(IR). Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.

• Determinants of bone mineral density in obese premenopausal women.

  Authors: Miriam A Bredella, Martin Torriani, Reza Hosseini Ghomi, Bijoy J Thomas, Danielle J Brick, Anu V Gerweck, Lindsey M Harrington, Anne Breggia, Clifford J Rosen, Karen K Miller

  Bone. 12/2010; 48(4):748-54.

  Despite being a risk factor for cardiovascular disease and diabetes mellitus, obesity has been thought to protect against osteoporosis. However, recent studies have demonstrated a differential impactDespite being a risk factor for cardiovascular disease and diabetes mellitus, obesity has been thought to protect against osteoporosis. However, recent studies have demonstrated a differential impact of specific fat compartments on bone mineral density (BMD) with visceral adipose tissue (VAT) having potential detrimental effects on BMD. Visceral obesity is also associated with dysregulation of the GH/IGF-1 axis, an important regulator of bone homeostasis. The purpose of our study was to evaluate the differential effects of abdominal fat depots and muscle, vitamin D, and hormonal determinants, including insulin-like growth factor-1 (IGF-1), testosterone, and estradiol, on trabecular BMD of the lumbar spine. We studied 68 healthy obese premenopausal women (mean BMI, 36.7±4.2 kg/m(2)). Quantitative computed tomography (QCT) was used to assess body composition and lumbar trabecular BMD. There was an inverse association between BMD and VAT, independent of age and BMI (p=0.003). IGF-1 correlated positively with BMD and negatively with VAT and, in stepwise multivariate regression modeling, was the strongest predictor of BMD and procollagen type 1 amino-terminal propeptide (P1NP). Thigh muscle cross sectional area (CSA) and thigh muscle density were also associated with BMD (p<0.05), but 25-hydroxyvitamin D [25(OH)D], testosterone, free testosterone, and estradiol levels were not. 25(OH)D was associated inversely with BMI, total, and subcutaneous abdominal adipose tissue (p<0.05). These findings support the hypothesis that VAT exerts detrimental effects, whereas muscle mass exerts positive effects on BMD in premenopausal obese women. Moreover, our findings suggest that IGF-1 may be a mediator of the deleterious effects of VAT on bone health through effects on bone formation.

• Comparison of DXA and CT in the assessment of body composition in premenopausal women with obesity and anorexia nervosa.

  Authors: Miriam A Bredella, Reza Hosseini Ghomi, Bijoy J Thomas, Martin Torriani, Danielle J Brick, Anu V Gerweck, Madhusmita Misra, Anne Klibanski, Karen K Miller

  Obesity (Silver Spring, Md.). 11/2010; 18(11):2227-33.

  Accurate methods for assessing body composition in subjects with obesity and anorexia nervosa (AN) are important for determination of metabolic and cardiovascular risk factors and to monitorAccurate methods for assessing body composition in subjects with obesity and anorexia nervosa (AN) are important for determination of metabolic and cardiovascular risk factors and to monitor therapeutic interventions. The purpose of our study was to assess the accuracy of dual-energy X-ray absorptiometry (DXA) for measuring abdominal and thigh fat, and thigh muscle mass in premenopausal women with obesity, AN, and normal weight compared to computed tomography (CT). In addition, we wanted to assess the impact of hydration on DXA-derived measures of body composition by using bioelectrical impedance analysis (BIA). We studied a total of 91 premenopausal women (34 obese, 39 with AN, and 18 lean controls). Our results demonstrate strong correlations between DXA- and CT-derived body composition measurements in AN, obese, and lean controls (r = 0.77-0.95, P < 0.0001). After controlling for total body water (TBW), the correlation coefficients were comparable. DXA trunk fat correlated with CT visceral fat (r = 0.51-0.70, P < 0.0001). DXA underestimated trunk and thigh fat and overestimated thigh muscle mass and this error increased with increasing weight. Our study showed that DXA is a useful method for assessing body composition in premenopausal women within the phenotypic spectrum ranging from obesity to AN. However, it is important to recognize that DXA may not accurately assess body composition in markedly obese women. The level of hydration does not significantly affect most DXA body composition measurements, with the exceptions of thigh fat.

• Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study.

  Authors: Pouneh K Fazeli, Elizabeth A Lawson, Rajani Prabhakaran, Karen K Miller, Daniel A Donoho, David R Clemmons, David B Herzog, Madhusmita Misra, Anne Klibanski

  The Journal of clinical endocrinology and metabolism. 11/2010; 95(11):4889-97.

  Anorexia nervosa (AN), a state of chronic nutritional deprivation, is characterized by GH resistance with elevated GH levels and decreased levels of IGF-I. The effects of supraphysiologicalAnorexia nervosa (AN), a state of chronic nutritional deprivation, is characterized by GH resistance with elevated GH levels and decreased levels of IGF-I. The effects of supraphysiological recombinant human GH (rhGH) on GH resistance in AN are not currently known. The aim was to investigate whether supraphysiological rhGH increases IGF-I levels in AN. We conducted a randomized, placebo-controlled study in a Clinical Research Center. We studied 21 women with AN, 10 (mean age, 28 ± 2.1 yr) treated with rhGH and 11 (mean age, 29.2 ± 2.6 yr) treated with placebo. rhGH (mean maximum daily dose, 1.4 ± 0.12 mg/d) or placebo was administered to patients for 12 wk. IGF-I, N-terminal propeptide of type 1 procollagen, type I collagen C-telopeptide, glucose, and insulin levels were measured at wk 0, 1, 2, 3, 4, 8, and 12; C-terminal propeptide of type 1 procollagen, leptin, and free fatty acid levels were measured at wk 0 and 12. Body composition, including total fat and lean mass, was measured by dual-energy x-ray absorptiometry at wk 0 and 12. IGF-I levels did not differ between the groups at baseline or after treatment (median after 12 wk-rhGH, 124 ng/ml, interquartile range, 94.5, 170.3; vs. placebo, 85.5 ng/ml, interquartile range, 62, 139; P = 0.3). Similarly, changes in glucose, insulin, free fatty acids, and bone markers did not differ between the groups. Total fat mass and percentage fat mass (rhGH, -2.5 ± 0.6%, vs. placebo, 2.2 ± 1.1%; P = 0.004) decreased significantly in the rhGH group compared to placebo despite comparable weight. Supraphysiological rhGH administration decreases fat mass in AN without increasing IGF-I levels, supporting the role of GH as a mediator of lipolysis independent of IGF-I.

• Growth hormone status predicts left ventricular mass in patients after cure of acromegaly.

  Authors: Tamara L Wexler, Ronen Durst, David McCarty, Michael H Picard, Lindsay Gunnell, Zehra Omer, Pouneh Fazeli, Karen K Miller, Anne Klibanski

  Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 10/2010; 20(5):333-7.

  Growth hormone excess and growth hormone deficiency (GHD) are both associated with increased cardiovascular morbidity. A specific acromegaly-related cardiomyopathy has been described, characterizedGrowth 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. 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. 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. Mean age and BMI, 44.6 ± 2.3 years (SEM) and 30.7 ± 1.3 kg/m², 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. 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.

• Women with anorexia nervosa: finite element and trabecular structure analysis by using flat-panel volume CT.

  Authors: Conor J Walsh, Catherine M Phan, Madhusmita Misra, Miriam A Bredella, Karen K Miller, Pouneh K Fazeli, Harun H Bayraktar, Anne Klibanski, Rajiv Gupta

  Radiology. 10/2010; 257(1):167-74.

  To use finite element modeling based on flat-panel volume computed tomography (CT) and bone mineral density (BMD) provided by dual-energy x-ray absorptiometry (DXA) to compare bone failure load,To use finite element modeling based on flat-panel volume computed tomography (CT) and bone mineral density (BMD) provided by dual-energy x-ray absorptiometry (DXA) to compare bone failure load, stiffness, and trabecular structure in women with anorexia nervosa (AN) and age-matched normal-weight control subjects. The study was approved by the institutional review board and complied with HIPAA guidelines. Informed consent was obtained. Fourteen women, eight with AN (mean age, 26.6 years) and six control subjects (mean age, 26.3 years), underwent flat-panel volume CT of the distal radius to determine apparent trabecular bone volume fraction (BV/TV), apparent trabecular number (TbN), apparent trabecular thickness (TbTh), and apparent trabecular separation (TbSp). Bone strength and stiffness were calculated from uniaxial compression tests by using finite element models created from flat-panel volume CT. DXA was used to determine BMD of the radius, lumbar spine, and hip. Means ± standard deviations of all variables were calculated for both groups and compared (Student t test). Univariate regression analysis and stepwise regression modeling were performed. Patients with AN had lower values for stiffness (284.77 kN/mm ± 76.14 vs 389.97 kN/mm ± 84.90, P = .04), failure load (4.98 kN ± 1.23 vs 7.01 kN ± 1.52, P = .02), BV/TV (0.32% ± 0.09 vs 0.44% ± 0.02, P = .007), and TbN (1.15 mm(-3) ± 0.20 vs 1.43 mm(-3) ± 0.13, P = .008) and higher values for TbSp (0.62 mm ± 0.20 vs 0.40 mm ± 0.04, P = .02) compared with normal-weight control subjects. TbTh was lower in women with AN (P = .1). BMD measurements were significantly lower for the AN group. BMD measurements and trabecular parameters (except TbTh) correlated with stiffness and failure load (r = 0.58 to 0.83). Failure load and stiffness are abnormal in women with AN compared with those in normal-weight control subjects and correlate with BMD and trabecular parameters.

• Comparison of 3.0 T proton magnetic resonance spectroscopy short and long echo-time measures of intramyocellular lipids in obese and normal-weight women.

  Authors: Miriam A Bredella, Reza Hosseini Ghomi, Bijoy J Thomas, Karen K Miller, Martin Torriani

  Journal of magnetic resonance imaging : JMRI. 08/2010; 32(2):388-93.

  To compare correlations of intramyocellular lipids (IMCL) measured by short and long echo-time proton magnetic resonance spectroscopy (1H-MRS) with indices of body composition and insulin resistanceTo compare correlations of intramyocellular lipids (IMCL) measured by short and long echo-time proton magnetic resonance spectroscopy (1H-MRS) with indices of body composition and insulin resistance in obese and normal-weight women. We quantified IMCL of tibialis anterior (TA) and soleus (SOL) muscles in 52 premenopausal women (37 obese and 15 normal weight) using single-voxel 1H-MRS PRESS at 3.0 T with short (30 msec) and long (144 msec) echo times. Statistical analyses were performed to determine correlations of IMCL with body composition as determined by computed tomography (CT) and insulin resistance indices and to compare correlation coefficients from short and long echo-time data. Signal-to-noise ratio (SNR), linewidth, and coefficients of variation (CV) of short and long echo-time spectra were calculated. Short and long echo-time IMCL from TA and SOL significantly correlated with body mass index (BMI) and abdominal fat depots (r = 0.32 to 0.70, P = <0.05), liver density (r = -0.39 to -0.50, P < 0.05), and glucose area under the curve as a measure of insulin resistance (r = 0.47 to 0.49, P < 0.05). There was no significant difference between correlation coefficients of short and long echo-time spectra (P > 0.5). Short echo-time IMCL in both muscles showed significantly higher SNR (P < 0.0001) and lower CVs when compared to long echo-time acquisitions. Linewidth measures were not significantly different between groups. IMCL quantification using short and long echo-time 1H-MRS at 3.0 T is useful to detect differences in muscle lipid content in obese and normal-weight subjects. In addition, IMCL correlates with body composition and markers of insulin resistance in this population with no significant difference in correlations between short and long echo-times. Short echo-time IMCL quantification of TA and SOL muscles at 3.0 T was superior to long echo-time due to better SNR and better reproducibility.

• Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women.

  Authors: Miriam A Bredella, Martin Torriani, Reza Hosseini Ghomi, Bijoy J Thomas, Danielle J Brick, Anu V Gerweck, Clifford J Rosen, Anne Klibanski, Karen K Miller

  Obesity (Silver Spring, Md.). 05/2010; 19(1):49-53.

  Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiationRecent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF-1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18-41 kg/m², mean 30 ± 7 kg/m²) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H-MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF-1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF-1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF-1 as an important regulator of the fat and bone lineage.