Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function in Aging Men.

CONTEXT: Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations. OBJECTIVE: To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men. DESIGN, PARTICIPANTS, AND INTERVENTION: 177 men aged 60 to 80 were randomly assigned to receive goserelin acetate plus either 0 (placebo), 1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks or placebos for both medications (controls). PRIMARY OUTCOMES: Changes in serum C-telopeptide (CTX), total body fat by dual energy X-ray absorptiometry, and self-reported sexual desire. RESULTS: Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0 to 99, 100 to 199, 200 to 299, or 300 to 499 ng/dL, whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0 to 99 or 100 to 199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were <100 ng/dL. CONCLUSION: Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.

Left ventricular hypertrophy is a possible biomarker for early mortality after type B aortic dissection.

OBJECTIVE: Data regarding the cardiac abnormalities associated with Stanford type B aortic dissection (TBAD) and whether these abnormalities are related to outcomes are limited. We describe the prevalence of cardiac abnormalities in patients with TBAD as detected by echocardiography. METHODS: This retrospective review included patients with TBAD presenting between 1990 and 2016. Echocardiograms performed within 6 weeks of acute TBAD were reviewed. Cardiac function, valve abnormalities, and stigmata of hypertensive heart disease including left ventricular hypertrophy (LVH) were ascertained. Characteristics of patients who did and did not receive echocardiograms were compared. Outcomes of patients with and without evidence of LVH on echocardiography were also compared. RESULTS: Of 239 patients with TBAD, 90 had echocardiograms performed within 6 weeks of acute TBAD (74% male; mean age, 57.8 ± 13.2 years). Echocardiograms were obtained at a median of 2 days (range, 0-41 days) from acute TBAD. Patients who had echocardiograms were more likely to present with malperfusion (28% vs 14%; P < .01) and had a trend toward increased operative repair during the subacute phase (17.4% vs 9.5%; P = .07) compared with patients who did not receive an echocardiogram. A majority of patients (57%) had at least mild LVH, including 39% of patients without a prior diagnosis of hypertension. Fibrocalcific changes associated with hypertension, including aortic sclerosis and mitral annular calcification, were noted in 40% and 11% of the patients, respectively. Among patients with LVH, there was a trend toward higher all-cause mortality (35% vs 23%; P = .21) and a younger age at death (58 ± 14 years vs 66 ± 13 years; P = .19) despite a similar age at TBAD onset. In a multivariable analysis controlling for age, sex, and admission estimated glomerular filtration rate, LVH independently predicted all-cause mortality (hazard ratio, 2.38; 95% confidence interval, 1.02-5.56; P = .04). CONCLUSIONS: LVH and other findings of hypertensive heart disease are common in patients with TBAD. LVH predicted all-cause mortality after TBAD in this small group of patients. Further exploration of the relationship between the chronic effects of hypertension and using LVH as an objective biomarker to risk stratify patients with TBAD and long-term outcomes after TBAD is warranted.

Effects of Testosterone and Estradiol Deficiency on Vasomotor Symptoms in Hypogonadal Men.

CONTEXT: The hormonal basis of vasomotor symptoms (VMS) in hypogonadal men is incompletely understood. OBJECTIVE: To determine the contributions of testosterone and estradiol deficiency to VMS in hypogonadal men. DESIGN: Two randomized trials were conducted sequentially between September 2004 and April 2011. Controls were recruited separately. SETTING: A single-site academic medical center. PARTICIPANTS: Healthy men ages 20-50, with normal serum testosterone levels. INTERVENTION: Cohort 1 (n = 198, 81% completion) received goserelin acetate every 4 weeks to suppress gonadal steroids and were randomized to placebo or 1.25, 2.5, 5, or 10 g of testosterone gel daily for 16 weeks. Cohort 2 (n = 202, 78% completion) received the same regimen as cohort 1 plus anastrozole to block aromatization of testosterone. Controls (n = 37, 89% completion) received placebos for goserelin acetate and testosterone. MAIN OUTCOME MEASURES: Incidence of visits with VMS. This was a preplanned secondary analysis. RESULTS: VMS were reported at 26% of visits in cohort 1, and 35% of visits in cohort 2 (P = .02), demonstrating an effect of estradiol deficiency. When adjacent estradiol level groups in cohort 1 were compared, the largest difference in VMS incidence was observed between the 5-9.9 and 10-14.9 pg/mL groups (38% vs 16%, P < .001). In cohort 2, the 10-g testosterone group differed significantly from placebo (16% vs 43%, P = .048) after adjustment for small differences in estradiol levels, indicating that high testosterone levels may suppress VMS. CONCLUSIONS: Estradiol deficiency is the key mediator of VMS in hypogonadal men. At high levels, testosterone may have a suppressive effect.

Gonadal steroid-dependent effects on bone turnover and bone mineral density in men.

BACKGROUND: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS: One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS: As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS: Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00114114. FUNDING: AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Statin Use and Aneurysm Risk in Patients With Bicuspid Aortic Valve Disease.

BACKGROUND: No medical therapy has been proven to prevent the progression of aortic dilatation in bicuspid aortic valve (BAV) disease, and prophylactic aortic surgery remains the mainstay of treatment. HYPOTHESIS: Among patients with BAV disease who are referred for surgery, preoperative statin use is associated with decreased odds of ascending aortic dilatation. METHODS: We reviewed all BAV patients who underwent aortic valve and/or aortic surgery at our center between April 2004 and December 2013. Aortic diameter (AD), defined as the maximum ascending aortic dimension, was determined by magnetic resonance imaging, computed tomography, or echocardiography. Patients were divided into 2 groups: maximal AD <4.5 cm or ≥4.5 cm. The association between preoperative statin use and aortic dilatation was assessed using multivariable logistic regression modeling. RESULTS: Of 680 consecutive patients, 405 (60%) had AD <4.5 cm (mean age, 60 ± 14 years; 45% on statins), whereas 275 (40%) had AD ≥4.5 cm (mean age, 54 ± 13 years; 35% on statins) at the time of surgery. After adjusting for age, body surface area, sex, hypertension, aortic stenosis, severity of aortic regurgitation, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and ß-blockers, patients with AD ≥4.5 cm had 0.66× lower odds (95% confidence interval: 0.45-0.96) of being on preoperative statins compared with those with AD <4.5 cm (P = 0.029). CONCLUSIONS: In a retrospective study of BAV patients referred for surgery, preoperative statin use was associated with lower odds of clinically significant ascending aortic dilatation.

Differences in skeletal microarchitecture and strength in African-American and white women.

African-American women have a lower risk of fracture than white women, and this difference is only partially explained by differences in dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro-finite element analysis (µFEA) in African-American (n = 100) and white (n = 173) women participating in the Study of Women's Health Across the Nation (SWAN). African-American women had larger and denser bones than whites, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p < 0.05 for all). African-Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African-Americans at both skeletal sites (p < 0.05 for all), and lower cortical porosity in African-Americans at the tibia (p < 0.05). African-American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African-American and white women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African-Americans and probably explain, at least in part, the lower fracture risk of African-American women.

Cortical microstructure and estimated bone strength in young amenorrheic athletes, eumenorrheic athletes and non-athletes.

CONTEXT: Lower bone density in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and non-athletes may increase fracture risk during a critical time of bone accrual. Finite element analysis (FEA) is a unique tool to estimate bone strength in vivo, and the contribution of cortical microstructure to bone strength in young athletes is not well understood. OBJECTIVE: We hypothesized that FEA-estimated stiffness and failure load are impaired in AA at the distal radius and tibia compared to EA and non-athletes despite weight-bearing exercise. DESIGN AND SETTING: Cross-sectional study; Clinical Research Center SUBJECTS: 34 female endurance athletes involved in weight-bearing sports (17 AA, 17 EA) and 16 non-athletes (14-21 years) of comparable age, maturity and BMI OUTCOME MEASURES: We used HR-pQCT images to assess cortical microarchitecture and FEA to estimate bone stiffness and failure load. RESULTS: Cortical perimeter, porosity and trabecular area at the weight-bearing tibia were greater in both groups of athletes than non-athletes, whereas the ratio (%) of cortical to total area was lowest in AA. Despite greater cortical porosity in EA, estimated tibial stiffness and failure load was higher than in non-athletes. However, this advantage was lost in AA. At the non-weight-bearing radius, failure load and stiffness were lower in AA than non-athletes. After controlling for lean mass and menarchal age, athletic status accounted for 5-9% of the variability in stiffness and failure load, menarchal age for 8-23%, and lean mass for 12-37%. CONCLUSION: AA have lower FEA-estimated bone strength at the distal radius than non-athletes, and lose the advantage of weight-bearing exercise seen in EA at the distal tibia.

Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls.

CONTEXT: Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes. OBJECTIVE: We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight-bearing exercise. DESIGN AND SETTING: We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital. SUBJECTS AND OUTCOME MEASURES: We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15-21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. RESULTS: Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18-24% of the variability in tibial trabecular number and separation. CONCLUSION: In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA.