Bijoy J. Thomas

Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men

BACKGROUND Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations. METHODS We provided 198 healthy men 20 to 50 years of age with goserelin acetate (to suppress endogenous testosterone and estradiol) and randomly assigned them to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole (to suppress the conversion of testosterone to estradiol). Changes in the percentage of body fat and in lean mass were the primary outcomes. Subcutaneous- and intraabdominal-fat areas, thigh-muscle area and strength, and sexual function were also assessed. RESULTS The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced. CONCLUSIONS The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; estrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. Our findings support changes in the approach to evaluation and management of hypogonadism in men. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00114114.).

Increased Bone Marrow Fat in Anorexia Nervosa

CONTEXT Although women with anorexia nervosa (AN) have severe depletion of body fat, a paradoxical increase in bone marrow fat has been described. Recent data suggest that marrow fat measured by 1H-magnetic resonance spectroscopy (MRS) in combination with bone mineral density (BMD) may be more valuable than either parameter alone in detecting bone weakness. OBJECTIVE The objective of the study was to investigate the effect of AN on accumulation of marrow fat in spine and femur using 1H-MRS and the relationship between marrow fat, BMD, and body composition in subjects with AN and normal-weight controls. DESIGN This was a cross-sectional study. SETTING The study was conducted at a referral center. PATIENTS Patients included 10 women with AN (29.8 +/- 7.6 yr) and 10 normal-weight age-matched women (29.2 +/- 5.2 yr). INTERVENTIONS There were no interventions. MAIN OUTCOMES MEASURE Marrow fat content of the fourth lumbar vertebra and femur measured by 1H-MRS. BMD of spine and hip measured by dual-energy x-ray absorptiometry. RESULTS Subjects with AN had higher marrow fat at the fourth lumbar vertebra and femur compared with controls (P = 0.004-0.01). There was an inverse correlation between marrow fat of L4 and femur and BMD of the spine and hip (r = -0.56 to -0.71, P = 0.01-0.0002) and body mass index and sc adipose tissue of the thigh (r = -0.49 to -0.71, P = 0.03-0.0007). There was an inverse correlation between femur marrow fat and sc and total abdominal adipose tissue (r = -0.53 to -0.67, P = 0.003-0.03). CONCLUSION Women with AN have greater lumbar and femoral marrow fat than controls, and marrow fat correlates inversely with BMD. This paradoxical increase in marrow fat at a time when sc and visceral fat are markedly reduced raises important questions about functional consequences of this process.

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.

Ischiofemoral impingement syndrome: an entity with hip pain and abnormalities of the quadratus femoris muscle.

OBJECTIVE The purpose of this study was to describe the MRI findings of an entity in which patients present with hip pain, abnormal MR signal intensity of the quadratus femoris muscle, and narrowing of the ischiofemoral space. MATERIALS AND METHODS We reviewed MR images of 12 hips in nine patients with hip pain and abnormal MR signal intensity of the quadratus femoris muscle. Using axial MR images, two musculoskeletal radiologists measured the ischiofemoral and quadratus femoris spaces. We also examined changes to muscles and tendons for the presence of edema and tears. Data were compared with 11 hips in 10 control subjects. Statistical analyses determined interobserver variability and differences between groups. RESULTS Subjects with an abnormal quadratus femoris muscle were all women 30-71 years old (mean age, 53 years) and had significantly narrower ischiofemoral spaces when compared with control subjects (13 +/- 5 vs 23 +/- 8 mm, respectively; p = 0.002). The quadratus femoris space was significantly narrower in affected subjects (7 +/- 3 vs 12 +/- 4 mm; p = 0.002). Abnormalities of the quadratus femoris muscle included edema (100%), partial tear (33%), and fatty infiltration (8%). The hamstring tendons of affected subjects showed evidence of edema (50%) and partial tears (25%). CONCLUSION Ischiofemoral impingement may represent a cause of hip pain and should be considered in cases with MR signal abnormality of quadratus femoris muscle.

Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT

Major alterations in body composition, such as with obesity and weight loss, have complex effects on the measurement of bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA). The effects of altered body fat on quantitative computed tomography (QCT) measurements are unknown. We scanned a spine phantom by DXA and QCT before and after surrounding with sequential fat layers (up to 12 kg). In addition, we measured lumbar spine and proximal femur BMD by DXA and trabecular spine BMD by QCT in 13 adult volunteers before and after a simulated 7.5 kg increase in body fat. With the spine phantom, DXA BMD increased linearly with sequential fat layering at the normal (p < 0.01) and osteopenic (p < 0.01) levels, but QCT BMD did not change significantly. In humans, fat layering significantly reduced DXA spine BMD values (mean ± SD: −2.2 ± 3.7%, p = 0.05) and increased the variability of measurements. In contrast, fat layering increased QCT spine BMD in humans (mean ± SD: 1.5 ± 2.5%, p = 0.05). Fat layering did not change mean DXA BMD of the femoral neck or total hip in humans significantly, but measurements became less precise. Associations between baseline and fat‐simulation scans were stronger for QCT of the spine (r2 = 0.97) than for DXA of the spine (r2 = 0.87), total hip (r2 = 0.80), or femoral neck (r2 = 0.75). Bland‐Altman plots revealed that fat‐associated errors were greater for DXA spine and hip BMD than for QCT trabecular spine BMD. Fat layering introduces error and decreases the reproducibility of DXA spine and hip BMD measurements in human volunteers. Although overlying fat also affects QCT BMD measurements, the error is smaller and more uniform than with DXA BMD. Caution must be used when interpreting BMD changes in humans whose body composition is changing.

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.

Determinants of Bone Microarchitecture and Mechanical Properties in Obese Men

CONTEXT Recent studies have suggested that obesity in men is associated with increased fracture risk. Obesity in men is also associated with dysregulation of the GH/IGF-I and gonadal steroid axes, important regulators of bone homeostasis. OBJECTIVE The aim of the study was to investigate body composition and endocrine determinants of bone microarchitecture and mechanical properties in obese men. DESIGN AND SETTING We conducted a cross-sectional study at a clinical research center. PARTICIPANTS Thirty-five obese men (mean age, 33.8 ± 6.4 yr; mean body mass index, 36.5 ± 5.8 kg/m(2)) participated in the study. OUTCOME MEASURES Distal radius microarchitecture and mechanical properties were measured by three-dimensional high-resolution peripheral quantitative computed tomography and microfinite element analysis; body composition by computed tomography; bone marrow fat by proton magnetic resonance spectroscopy; total and free estradiol and testosterone; IGF-I; peak glucagon-stimulated GH; 25-hydroxyvitamin D. RESULTS Men with high visceral adipose tissue (VAT) had impaired mechanical properties compared to men with low VAT (P < 0.05), despite comparable body mass index. VAT was inversely associated and thigh muscle was positively associated with mechanical properties (P < 0.05). Bone marrow fat was inversely associated with cortical parameters (P ≤ 0.02). Free estradiol was positively associated with total density (P = 0.05). Free testosterone was positively associated with trabecular thickness and inversely with trabecular number (P ≤ 0.05). Peak stimulated GH was positively associated with trabecular thickness, as was IGF-I with cortical area (P ≤ 0.04). CONCLUSION VAT and bone marrow fat are negative predictors and muscle mass is a positive predictor of microarchitecture and mechanical properties in obese men. Testosterone, estradiol, and GH are positive determinants of trabecular microarchitecture, and IGF-I is a positive determinant of cortical microarchitecture. This supports the notion that VAT is detrimental to bone and that decreased GH and testosterone, characteristic of male obesity, may exert deleterious effects on microarchitecture, whereas higher estradiol may be protective.

Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa.

Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN‐R). We also studied the relationship between preadipocyte factor (Pref)‐1—a member of the EGF‐like family of proteins and regulator of adipocyte and osteoblast differentiation—and fat depots and BMD in AN‐R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean ± SEM]) and 15 normal‐weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by 1H‐magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref‐1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN‐R compared with AN (p = 0.03) and was comparable to levels in HC. Pref‐1 levels were also significantly lower in AN‐R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref‐1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = −0.71; p = 0.004). Therefore, we have shown that MAT and Pref‐1 levels decrease with recovery from AN. Our data suggest that Pref‐1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency.

Relationship between sleep apnea, fat distribution, and insulin resistance in obese children.

BACKGROUND Obstructive sleep apnea (OSA) is associated with obesity, inflammation, and insulin resistance. The role of fat distribution in OSA pathogenesis has not been established in children. The objective of the study is to examine the relationship between fat distribution, OSA, and insulin resistance in an unselected population of obese children. METHODS All obese (BMI > 95th percentile) children (ages 5-18 y) seen at a pediatric obesity clinic were invited to participate. Subjects underwent polysomnography, and were tested for dyslipidemia, inflammation, and insulin resistance measured by the homeostasis model assessment (HOMA). In a subset of subjects, magnetic resonance (MRI) imaging was used to determine the abdominal visceral and subcutaneous adipose tissue areas and magnetic resonance spectroscopy (MRS) spectroscopy was used to intramyocellular lipids in leg muscles. MEASUREMENTS AND MAIN RESULTS 31 obese subjects enrolled and completed polysomnography and serum testing, and 19 subjects underwent MRI/MRS. The mean age was 12.6 ± 3.0 y and the mean body mass index (BMI) was 39.5 ± 11.2 kg/m(2). Forty-eight percent had OSA (mean apnea hypopnea index [AHI] 6.26 ± 6.77 events/h) Subjects with OSA had significantly increased BMI, log HOMA, triglycerides, and leptin compared to those without OSA. In regression analysis, only BMI z-score was associated with log HOMA. In the subset of patients with imaging data, visceral fat area was strongly predictive of AHI (p = 0.003, r(2) = 0.556). BMI z-score, gender, and age were not predictive. CONCLUSIONS Visceral fat distribution is independently predictive of OSA severity in obese children.