ABSTRACT
Recognising the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of adrenocorticotropic hormone, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intra-cutaneous pancreatic islet cell transplantation, using a fully biodegradable temporising matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture and intracutaneous injection into a skin site pre-prepared using a biodegradable temporising matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored and the transplant site was examined at end-point. Outcome measures included cellular histochemistry, systemic hormone production and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site, and an ability to self-organise into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by identification of accessory adrenals and regenerative cortical tissue within the adrenal bed post-mortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step towards clinical translation. These results demonstrate potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.
ABSTRACT
OBJECTIVE: Obstructive sleep apnea (OSA) is generally considered to lower serum testosterone concentration in men, although data supporting this as a direct effect are limited. The aim of this study was to determine the relationship between the presence and severity of OSA and testosterone in a community-based cohort of men aged over 40 years. DESIGN AND METHODS: Anthropometry, polysomnography and biomedical information were collected from enrolled, consenting men from the prospective, longitudinal MAILES study cohort. Fasting morning blood samples (n = 1869) were drawn between 2010 and 2012 for measurement of testosterone using liquid chromatography mass spectrometry. Home polysomnography was completed in 861 men between 2010 and 2012. The final analysis sample consisted of 623 men aged 41-86 years. The effect of OSA on testosterone were analyzed using linear regression models controlling for potential confounders (age, BMI and sex hormone binding globulin (SHBG)). RESULTS: The mean (s.d.) cohort characteristics were: age 59.0 (10.2) years, testosterone 16.8 (5.3) nmol/L, SHBG 32.9 (13.1) nmol/L, BMI 28.6 (4.2) kg/m2 and apnoea hypopnoea index (AHI) 14.9 (13.7). OSA was present in 51.5%. There was an inverse relationship between AHI and testosterone (P = 0.01), which was lost after covariate adjustment. CONCLUSIONS: These data suggest that obesity, rather than OSA per se, determine testosterone concentration. This accords with the graded effect of weight loss, but limited effect of continuous positive airway pressure to increase testosterone, and highlights the importance of managing obesity in men with low testosterone concentration, particularly in the context of OSA.
