Danazol Treatment for Telomere Diseases

Discussion in 'Men's Health Forum' started by Michael Scally MD, May 18, 2016.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine


    Townsley DM, Dumitriu B, Liu D, et al. Danazol Treatment for Telomere Diseases. New England Journal of Medicine 2016;374(20):1922-31. http://www.nejm.org/doi/full/10.1056/NEJMoa1515319


    BACKGROUND - Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.

    METHODS - In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months.

    The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months.

    The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.

    RESULTS - After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point.

    Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]).

    Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months.

    Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively.

    CONCLUSIONS - In our study, treatment with danazol led to telomere elongation in patients with telomere diseases.


     
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  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Associations Between Circulating Sex Steroid Hormones and Leukocyte Telomere Length

    Preliminary evidence suggests that sex steroid hormones, such as danazol (a synthetic sex steroid hormone), may be involved in enhancing telomerase activity. Elucidating underlying mechanisms of telomerase activity may further therapeutic options for individuals with telomeropathies and potentially avert certain age‐related conditions.

    Therefore, we conducted a cross‐sectional study to investigate the relationship between circulating sex steroid hormones and SHBG with leukocyte telomere length among 499 males in NHANES (1999–2002 surveys). Sample‐weighted linear regression analyses were conducted to assess age‐adjusted and multivariable‐adjusted estimates of associations. Estimates were rescaled to represent telomere length change in base pairs per half the value of the interquartile range of the independent variable.

    Estradiol and free estradiol were significantly inversely associated with leukocyte telomere length (βcontinuous per § IQR = −61, p = 0.04; free estradiol βcontinuous per § IQR = −67, p = 0.03). testosterone, free testosterone, androstanediol glucuronide, and SHBG were not associated with leukocyte telomere length.

    The inverse association seen in this study indicates that a danazol‐induced hypoestrogenic state could partly underlie the previously observed association between danazol therapy and increased leukocyte telomere length.

    Coburn SB, Graubard BI, Trabert B, McGlynn KA, Cook MB. Associations between circulating sex steroid hormones and leukocyte telomere length in men in the National Health and Nutrition Examination Survey. Andrology 2018. https://doi.org/10.1111/andr.12494