Danazol Treatment for Telomere Diseases
Open accessAbstract
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. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).
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Danazol treatment in aplastic anaemia patients with critically short telomeres improves their condition by increasing telomerase expression and lengthening telomeres, supporting a causative role of telomere length.
“The use of the androgen receptor agonist danazol in patients with aplastic anaemia with critically short telomeres improved their condition by increasing telomerase expression and lengthening telomeres. This provides support for a causative role of telomere length in this disease83.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [83]
The Abstract Results and Discussion (page not provided) report telomere elongation and hematologic improvement during danazol treatment. But the study enrolled patients with a range of telomere diseases, not only aplastic anaemia, and the Discussion says telomerase activity could not be reliably measured. It does not establish that increased telomerase expression caused the improvement or that telomere length was the causal factor. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDanazol, a synthetic testosterone, has been used clinically for many years in aplastic anaemia with some efficacy.
“androgen therapy, based on the clinical use of danazol, a synthetic testosterone, has been part of clinical practice for many years in the treatment of aplastic anaemia with some efficacy83”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [83]
The Discussion says androgens have been used for marrow failure syndromes since the 1960s, and the References include studies of androgen treatment for aplastic anemia. The Methods identify danazol as a synthetic sex hormone with androgenic properties, and the Results report hematologic responses in patients with telomere diseases. The paper does not establish that danazol itself has been used for many years to treat aplastic anemia or that its efficacy was demonstrated in that population. (LLM, conf=0.84)
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“The hormones have a substantial effect on adult male and female TL, and the impact of hormonal therapy was a subject of numerous studies [121, 122].”
BackgroundPulmonary phenotypes associated with genetic variation in telomere-related genes
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Danazol Treatment for Telomere Diseases
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The Spectrum of Hepatic Involvement in Patients With Telomere Disease
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“Telomere gene sequencing was performed as described.(14) Subjects were considered if they had a confirmed genetic mutation in a telomere gene and/ or clinical features of telomere disease and short telomeres.”
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Self-citationLung transplantation in idiopathic pulmonary fibrosis
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“We believe, however, that it would be premature to consider the clinical use of potential telomere lengthening therapies such as danazol or lithium outside of research trials [36, 37].”
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Pathogenic TERT promoter variants in telomere diseases
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“Twenty-one patients and three relatives from the cohort were enrolled in a clinical trial for treatment with danazol for two years (Supplementary Table S3) (ref.(16)).”
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Telomeres as Therapeutic Targets in Heart Disease
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Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita
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Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease
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The Telomeric Complex and Metabolic Disease
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The Importance of Telomere Shortening for Atherosclerosis and Mortality
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“In humans, the administration of the synthetic androgen Danazol to patients with telomeropathies resulted in LTL elongation and improvement of hematologic parameters [42].”
BackgroundDietz, A. C., Mehta, P. A., Vlachos, A., Savage, S. A., Bresters, D., Tolar, J., Boulad, F., Dalle, J., Bonfim, C., de la Fuente, J., et al. (2017) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2017.01.075 · Cited by 45 · see citing works
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MethodPharmacotherapy for idiopathic pulmonary fibrosis: current landscape and future potential
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Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases
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Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives
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Telomeres in Interstitial Lung Disease
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Genome-Protecting Compounds as Potential Geroprotectors
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“Particularly, in mice with aplastic anemia and danazol administration [742] and in patients with telomeropathies [743], testosterone therapy led to elongation of leukocyte telomeres and improved health parameters.”
Backgroundp53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita
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Ovarian rescue in women with premature ovarian insufficiency: facts and fiction
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Safety and efficacy of pirfenidone in patients carrying telomerase complex mutation
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Hereditary Predisposition to Hematopoietic Neoplasms
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BackgroundTelomere Abnormalities in the Pathobiology of Idiopathic Pulmonary Fibrosis
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“Danazol has been tested in patients with a TRG mutation and hematological abnormalities, but the data concerning the lung in that study are very limited [8].”
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- Authors
- Townsley, D. M., Dumitriu, B., Liu, D., Biancotto, A., Weinstein, B., Chen, C., Hardy, N., Mihalek, A. D., Lingala, S., Kim, Y. J., Yao, J., Jones, E., Gochuico, B. R., Heller, T., Wu, C. O., Calado, R. T., Scheinberg, P., & Young, N. S.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-05-19
- Volume
- 374
- Issue
- 20
- Pages
- 1922-1931
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4968696
- OpenAlex
- W2394724717
- Cited by
- 415
- References
- 40
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 36 · 2023: 46 · 2022: 32 · 2021: 45 · 2020: 46 · 2019: 41 · 2018: 49 · 2017: 46 · 2016: 19
- FWCI
- 41.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health (Z99 HL999999)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- danazol, telomere shortening, telomere length, telomerase, sex hormones, androgens, bone marrow failure syndromes, telomere maintenance, telomere elongation, hematologic response, liver cirrhosis, pulmonary fibrosis, drug safety, elevated liver enzymes, muscle cramps, treatment discontinuation
- MeSH terms
- Administration, Oral, Adolescent, Adult, Aged, Bone Marrow Diseases, Danazol, Estrogen Antagonists, Female, Hair Color, Humans, Liver Cirrhosis, Male, Middle Aged, Mutation, Prospective Studies, Pulmonary Fibrosis, Up-Regulation, Telomere, Telomerase, Young Adult
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