Danielle J. Brick

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

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 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.

Determinants of bone mineral density in obese premenopausal women

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 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

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 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.

Peak Growth Hormone-Releasing Hormone-Arginine-Stimulated Growth Hormone Is Inversely Associated with Intramyocellular and Intrahepatic Lipid Content in Premenopausal Women with Obesity

CONTEXT Visceral adiposity is a strong determinant of GH secretion, and low endogenous GH secretion is associated with increased insulin resistance, a key component of the metabolic syndrome. Increased fat accumulation in skeletal muscle and liver may play an etiological role in the development of insulin resistance and other complications of the metabolic syndrome. Little is known about the role of decreased endogenous GH secretion in the pathogenesis of insulin resistance in obesity. OBJECTIVE To investigate the relationship between intramyocellular lipids (IMCL), intrahepatic lipids, and peak-stimulated GH in premenopausal women with obesity. DESIGN AND SETTING We conducted a cross-sectional study at a clinical translational research center. PATIENTS Patients included 21 premenopausal women with obesity (mean body mass index, 34.0 +/- 4.5 kg/m(2)) and 17 normal-weight controls (mean body mass index, 21.9 +/- 2.0 kg/m(2)) of comparable mean age. MAIN OUTCOMES MEASURES IMCL and intrahepatic lipids were measured with proton magnetic resonance spectroscopy ((1)H-MRS). Body composition was measured with magnetic resonance imaging. Peak GH was measured after stimulation with GHRH-arginine. RESULTS Obese subjects had higher IMCL, intrahepatic lipids, abdominal and thigh fat, and thigh muscle mass compared with normal-weight controls. There were strong inverse associations between peak GH and both IMCL and intrahepatic lipids independent of age and visceral adiposity. There were positive associations between IMCL and intrahepatic lipids with measures of insulin resistance and serum triglycerides. CONCLUSION In premenopausal women with obesity, peak GH is inversely associated with IMCL and intrahepatic lipids independent of age and visceral adiposity. This suggests that low GH may contribute to insulin resistance in obesity through effects on muscle and intrahepatic lipids.

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.

Low-dose transdermal testosterone augmentation therapy improves depression severity in women.

BACKGROUND Inadequate response to antidepressant monotherapy in women with major depressive disorder is common. Testosterone administration has been shown to be an effective augmentation therapy in depressed hypogonadal men with selective serotonin reuptake inhibitor-resistant depression. However, the effects of low-dose testosterone as augmentation therapy in women with treatment-resistant depression have not been studied. METHODS Low-dose transdermal testosterone (300 mcg/day, Intrinsa, Procter and Gamble Pharmaceuticals) was administered to nine women with treatment-resistant depression in an 8 week open-label pilot protocol. RESULTS There was a statistically significant improvement in mean Montgomery-Asberg Depression Rating Scale (MADRS) scores at 2 weeks, sustained through the 8 week period. Two-thirds of subjects achieved a response to the treatment (decrease in MADRS score of 250%) and 33% achieved remission (final MADRS score <10) after 8 weeks of therapy. Mean levels of fatigue, as measured by the MADRS lassitude item, significantly decreased at all time points with a mean 38% decrease from baseline to 8 weeks. CONCLUSION These preliminary pilot data suggest that low-dose transdermal testosterone may be an effective augmentation therapy in women with treatment-resistant depression. Further studies are warranted. CNS Spectr. 2009;14(12):688-694

Determinants of IGF1 and GH across the weight spectrum: from anorexia nervosa to obesity

CONTEXT Chronic starvation is characterized by GH resistance, and obesity is characterized by decreased GH secretion. In both extremes, IGF1 levels may be low and androgen levels may be abnormal. OBJECTIVE To investigate the determinants of IGF1 and GH across the weight spectrum in women. DESIGN Cross-sectional study. SETTING Clinical research center. STUDY PARTICIPANTS In total, 32 women had participated in the study: 11 women with anorexia nervosa (AN), 11 normal-weight women, and 10 obese women of comparable mean age. INTERVENTION None. MAIN OUTCOME MEASURES Pooled hourly overnight serum samples assayed for IGF1, GH, estradiol (E(2)), testosterone, SHBG, insulin, free fatty acids, and trunk fat. RESULTS Free testosterone was higher in obese women and lower in women with AN than in normal-weight women, and was the only independent (and positive) predictor of IGF1 levels, accounting for 14% of the variability (P=0.032) in the group as a whole. This relationship was stronger when obese women were excluded, with free testosterone accounting for 36% of the variability (P=0.003). Trunk fat accounted for 49% of the variability (P<0.0001) of GH, with an additional 7% of the variability attributable to E(2) (P=0.042) in the group as a whole, but was not a significant determinant of GH secretion when obese women were excluded. CONCLUSIONS Free testosterone is a significant determinant of IGF1 levels in women across the body weight spectrum. In contrast, GH secretion is differentially regulated at the extremes of the weight spectrum.

Metabolic and Endocrine correlates of cognitive function in healthy young women

Obesity has been associated with cognitive decline in longitudinal studies of older individuals. We hypothesized that the cognitive sequelae of obesity may be detectable in the reproductive years. In addition, we explored the hypothesis that these associations may be mediated by the hormonal milieu.

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

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 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 (1H‐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/m2) who underwent 1H‐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 (HOMAIR), 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 HOMAIR. 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.

Effect of growth hormone replacement therapy on the quality of life in women with growth hormone deficiency who have a history of acromegaly versus other disorders.

OBJECTIVE To compare the response in quality of life (QoL) to growth hormone (GH) replacement in women with GH deficiency (GHD) and a history of acromegaly with that in women with GHD of other causes. METHODS Fifty-five women with GHD were studied: 17 with prior acromegaly and 38 with other causes of GHD. We compared two 6-month, randomized, placebo-controlled studies of GH therapy in women with hypopituitarism conducted with use of the same design-one in women with a history of acromegaly and one in women with no prior acromegaly. QoL was assessed with the following questionnaires: the QoL-Assessment of Growth Hormone Deficiency in Adults (AGHDA), the Symptom Questionnaire, and the 36-Item Short-Form Health Survey (SF-36). RESULTS The 2 groups had comparable mean pretreatment age, body mass index, and QoL scores and comparable mean GH dose at 6 months (0.61 ± 0.30 versus 0.67 ± 0.27 mg daily). After 6 months of GH replacement therapy, women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score, four SF-36 sub-scales (Role Limitations due to Physical Health, Energy or Fatigue, Emotional Well-Being, and Social Functioning), and the Somatic Symptoms subscale of the Symptom Questionnaire than did women with GHD of other causes. Poorer pretreatment QoL was associated with a greater improvement in QoL after administration of GH. CONCLUSION In this study, GH replacement therapy improved QoL in women with GHD and a history of acromegaly but not in women with GHD due to other hypothalamic and 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.