Androgen Treatment Leads to Elongated Telomeres in Small Trial

Tara Haelle

May 20, 2016

The sex hormone danazol increased telomere length in patients with telomere diseases, according to a phase 1–2 study published in the May 19 issue of the New England Journal of Medicine.

"Not only was telomere loss prevented by treatment with danazol in our patients, but a mean increase of 386 bp telomeric repeats had occurred by study completion, with improvement usually observed early during the course of hormone therapy," write Danielle M. Townsley, MD, from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, and colleagues. "Hematologic improvement in all blood counts accompanied telomere elongation."

In an accompanying editorial, Peter Landor, MD, PhD, from the University of Groningen in the Netherlands, writes that the "exciting findings...provide food for thought about the role of telomeres and telomerase in hematopoietic stem cells."

Telomere diseases such as dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and liver cirrhosis result from inadequate or absent telomere maintenance and repair from mutations in the genes responsible for those functions. That failure can also contribute to bone marrow failure and an increased risk for cancer. Previous study of a mouse model with telomere dysfunction, however, had shown hematologic improvement and a lengthening of telomeres after male hormone treatment.

"Androgens have been a therapeutic option for marrow failure syndromes since the 1960s, without a clear mechanism for their action," the authors write. "In retrospect, some patients with a response probably had telomere deficits."

The 27 patients enrolled from August 2011 through May 2014 each had pulmonary fibrosis or a low blood, platelet, or neutrophil count, as well as age-adjusted telomere length at or below the first percentile and/or identified mutations in telomere maintenance and repair genes. All the patients took 400 mg danazol orally twice daily over the course of 24 months or until the study stopped.

Just more than half the patients were female (56%), and they ranged in age from 17 to 66 years. One patient had a mutation in RTEL1, three had DKC1 mutations, seven had TERC mutations, and 10 had TERT mutations. The researchers could not identify pathogenic mutations in the remaining six patients, but they met the criteria for telomere lengths below the first percentile.

All 12 patients who reach 24 months of treatment met the primary endpoint of at least a 20% reduction in telomere attrition, leading the researchers to halt the study early because the unexpectedly high efficacy rate provided enough data to reject the null hypothesis. All but one of those patients (92%) actually gained telomere length (average, 386 bp; 95% confidence interval [CI], 178 - 593 bp), vs baseline, at 24 months.

Ten of those patients (83%) also showed a hematologic response, the secondary endpoint.

Because the other 15 patients did not complete 24 months of treatment, the intention-to-treat analysis resulted in 44% efficacy (95% CI, 26 - 64). However, among 21 patients reaching 6 months in the study, 16 experienced a mean increase of 175 bp (95% CI, 79 - 271) in telomere length. Similarly, 16 of 18 patients available for evaluation at 12 months had a mean increase of 360 bp (95% CI, 209 - 512) in telomere length.

Meanwhile, 19 of the 24 patients available for evaluation at 3 months (79%) showed a hematologic response. A hematologic response was also seen in 17 of the 21 patients reaching 6 months and in 14 of the 18 patients reaching 12 months.

Among the 13 patients who were transfusion-dependent at baseline, only one patient still needed regular transfusions after the danazol treatment. A mean increase in hemoglobin, absolute reticulocyte counts, neutrophil counts, and platelet counts also occurred in those patients with initial deficiencies.

Adverse effects included elevated liver enzyme levels in 41% of the patients, and muscle cramps occurred in 33%. Both are known adverse effects of danazol and occurred at grade 2 or less in those patients. In addition, 26% of patients had edema and 26% had lipid abnormalities. Three patients withdrew from the study after a grade 3 or 4 adverse event, and two discontinued treatment as a result of low-grade adverse effects.

Aside from absence of a control group, the study's limitations included the heterogeneity in the genetic basis for telomere biologic deficiencies and the natural fluctuation of telomere attrition that can occur with measurements over time.

"The role of telomerase in hematopoietic stem cells has been puzzling ever since the first reports of the loss of telomeric DNA with age in both human leukocytes and purified hematopoietic stem cells," writes Dr Lansdorp before discussing the various hypotheses regarding the function of telomerase. He notes that studies of patients with dyskeratosis congenita have shown that "a moderate reduction in telomerase levels...can give rise to a clinically diverse spectrum of 'telomere maintenance' disorders," therefore suggesting that hematopoietic stem cells are essential for preventing exhaustion of stem cells.

"The findings of Townsley et al. support the idea that an elevation in telomerase levels through treatment with androgens results in modest leukocyte telomere elongation (instead of the expected shortening) in patients with disorders characterized by very short telomeres, as well as the idea that such telomere elongation is associated with improvements in blood counts," writes Dr Lansdorp. "[W]hen these data are combined with those from previous studies cited in the article, they leave little doubt that significant and clinically relevant telomere elongation can be achieved through treatment with androgens in these patients."

Additional research can help establish dosage and duration of treatment, he writes.

The research was funded by the National Heart, Lung, and Blood Institute, National Human Genome Research Institute, and National Institute of Diabetes and Digestive and Kidney Diseases. The authors and editorialist have disclosed no relevant financial relationships. Dr. Lansdorp reports other support from Repeat Diagnostics Inc.

N Engl J Med. 2016;374:1922-1931, 1978-1980. Article full text, Editorial full text

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