Anabolic steroids may increase life expectancy because they delay aging. On the other hand they may increase the risk of cancer in a much more fundamental way than endocrinologists suspect. These apparently contradictory conclusions can be drawn from a human study that American doctors published in the New England Journal of Medicine.
Yep, we’re writing about telomeres again. Telomeres are located at the ends of the chromosomes in the DNA. Every time your cells divide, your telomeres get a little bit smaller. And once the telomeres have disappeared your cells can’t divide any more. The faster the length of telomeres decreases, the faster you age.
Some people’s telomeres become shorter at a faster rate because of a hereditary genetic defect. One symptom of this defect is anaemia. The cells in the bone marrow are unable to manufacture enough blood cells because the cells age too quickly. Some doctors prescribe anabolic steroids such as danazol [structural formula shown above] to combat this type of anaemia. But exactly how danazol normalises the production of blood cells is not known.
The researchers wondered whether danazol perhaps has an effect on the length of the telomeres. This reasoning was based on the results of a 2009 in-vitro study in which androgens activated the enzyme telomerase in human cells. [Blood. 2009 Sep 10; 114(11):2236-43.]
The researchers used two dozen patients for their experiment. All of them had telomeres that decreased in length faster than normal as a result of a genetic defect, and were therefore unable to produce enough blood cells.
The test subjects were given two doses a day of 400 hundred mg danazol. So they took a total of 800 mg danazol daily.
In the two years that the subjects were given danazol, the length of their telomeres increased, according to the figure below. A year after the administration had stopped the effect had largely disappeared.
The figure below shows the rate at which telomere length decreases in normal individuals [Normal], and the rate at which the length decreases in people where that goes quicker [Telomeropathy]. The effect of danazol on telomere length is also shown in the same figure.
“Our results may have broader relevance for the frequent use of androgens for blood diseases in the developing world and for testosterone replacement in aging men in developed countries”, the researchers wrote. “Longevity has been linked to telomere attrition rates in mammals.” [Cell Rep. 2012 Oct 25;2(4):732-7.]
That sounds promising, but the researchers add that there may be advantages and disadvantages. “Telomere attrition and dysfunction have been implicated in the development of cancer in both mice [Nature. 2000 Aug 10;406(6796):641-5.] and humans.” [JAMA. 2010 Sep 22;304(12):1358-64.] [JAMA. 2010 Jul 7;304(1):69-75.] [Blood. 2015 Jan 22;125(4):706-9.]
“The advantages and risks associated with the modification of telomere loss will need to be assessed in attempts to alter physiologic aging in humans.”
“Evolution to myelodysplastic syndrome or acute myeloid leukemia has been infrequent in historical studies of androgen treatment for bone marrow failure. [Am J Med 1981; 71: 543-51.] The mitigation of telomere erosion by sex hormones may abrogate early molecular steps in chromosome instability and oncogenesis and warrants investigation in clinical trials.”
Danazol Treatment for Telomere Diseases
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.
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.
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.
In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)