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.

Bioadhesives are biopolymers with potential applications in wound healing, drug delivery, and tissue engineering. Pectin, a plant-based heteropolysaccharide, has recently demonstrated potential as a mucoadhesive in the gut. Since mucoadhesion is a process likely involving the interpenetration of the pectin polymer with mucin chains, we hypothesized that pectin may also be effective at targeting the glycocalyx of the visceral mesothelium. To explore the potential role of pectin as a mesothelial bioadhesive, we studied the interaction of various pectin formulations with the mesothelium of the lung, liver, bowel, and heart. Tensile strength, peel strength, and shear resistance of the bioadhesive-mesothelial interaction were measured by load/displacement measurements. In both high-methoxyl pectins (HMP) and low-methoxyl pectins, bioadhesion was greatest with an equal weight % formulation with carboxymethylcellulose (CMC). The tensile strength of the high-methoxyl pectin was consistently greater than low-methoxyl or amidated low-methoxyl formulations (p < 0.05). Consistent with a mechanism of polymer-glycocalyx interpenetration, the HMP adhesion to tissue mesothelium was reversed with hydration and limited by enzyme treatment (hyaluronidase, pronase, and neuraminidase). Peel and shear forces applied to the lung/pectin adhesion resulted in a near-interface structural failure and the efficient isolation of intact en face pleural mesothelium. These data indicate that HMP, in an equal weight % mixture with CMC, is a promising mesothelial bioadhesive for use in experimental and therapeutic applications.

Pleural injury and associated air leaks are a major influence on patient morbidity and healthcare costs after lung surgery. Pectin, a plant-derived heteropolysaccharide, has recently demonstrated potential as an adhesive binding to the glycocalyx of visceral mesothelium. Since bioadhesion is a process likely involving the interpenetration of the pectin-based polymer with the glycocalyx, we predicted that the pectin-based polymer may also be an effective sealant for pleural injury. To explore the potential role of an equal (weight%) mixture of high-methoxyl pectin and carboxymethylcellulose as a pleural sealant, we compared the yield strength of the pectin-based polymer to commonly available surgical products. The pectin-based polymer demonstrated significantly greater adhesion to the lung pleura than the comparison products (p < 0.001). In a 25 g needle-induced lung injury model, pleural injury resulted in an air leak and a loss of airway pressures. After application of the pectin-based polymer, there was a restoration of airway pressure and no measurable air leak. Despite the application of large sheets (50 mm) of the pectin-based polymer, multifrequency lung impedance studies demonstrated no significant increase in tissue damping (G) or hysteresivity (η)(p > 0.05). In 7-day survival experiments, the application of the pectin-based polymer after pleural injury was associated with no observable toxicity, 100% survival (N = 5), and restored lung function. We conclude that this pectin-based polymer is a strong and nontoxic bioadhesive with the potential for clinical application in the treatment of pleural injuries.