RATIONALE Pulmonary fibrosis is an interstitial lung disease (ILD) feature with no curative (other than lung transplantation) or preventative treatments. Recent evidence supports a causal role of short telomeres, and our pre-print findings suggest a potentially protective interaction between optimised sex hormone concentration (testosterone and oestrogen) in men and women and telomere maintenance pathways1. Sex hormone bioavailability is regulated by sex hormone binding globulin (SHBG) in both sexes. Supra-physiological dosing of testosterone in men causes erythrocytosis, so monitoring of haemoglobin concentration and haematocrit is required. STARSHIP set out to assess whether future therapeutic trials of sex hormone supplementation in ILD could be safe and warranted without causing supra-physiological dosing. METHODS Venepuncture was performed on 102 outpatients (age 49-89y, male n=80 [78%]) with fibrotic ILD a ta single regional centre in the UK. Age and sex-matched control samples were obtained from the Exeter 10,000 (EXTEND) biobank. Blood leukocyte telomere length (LTL; measured using high-throughput single telomere length analysis) and sex hormone/SHBG concentrations were determined in all samples. Patients consented for access to their clinical data (including routine pulmonary function). In-depth interviews were carried out by telephone with 93 self-selecting patients, using structured interviews with questions informed by clinical practice, the research team ,and patient partners. RESULTS Almost all male ILD patients (n=77/79) had haemoglobin concentrations and haematocrit below the upper reference limit. Compared to age-matched controls (AMCs) mean LTL was shorter for patients (4.57kb [95%CI: 4.46-4.69] vs 4.78kb [95%CI:4.67-4.89], p<0.006). Mean bioavailable testosterone was lower in male patients (4.95nmol/L[95%CI: 4.50-5.41] vs 6.40nmol/L [95%CI: 5.82-6.98] in AMC; p<0.0001, n=80). Oestrogen concentrations were low for both female patients and controls in keeping with their post-menopausal age, with higher SHBG concentrations for patients (mean 73.7nmol/L [95%CI: 58.6-88.9] vs 52.9nmol/L [95%CI: 42.0-63.8] in AMC; p=0.022). Mean free androgen index (FAI) was below the reference range for female patients (mean 0.51 [95%CI: 0.35-0.67] vs 1.23 [95%CI: 0.77-1.69] in AMC; p= 0.0036, N=22). Both DLCO% predicted (p=0.0005) and FVC% predicted(p=0.005) correlated with bioavailable testosterone concentration in male patients (age-adjusted analysis). FVC% predicted associated with FAI in females (p=0.013) but no association was seen between FAI and DLCO% predicted. CONCLUSIONS Interventional trials of sex hormone supplementation without causing supra-physiological dosing warrant further exploration in patients with ILD
