Abstract
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients’ individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.
Highlights
Telomeres are important DNA repeat sequences located at the end of the eukaryotic chromosomes
To evaluate the effect of the androgen derivatives (ADs) on healthy cells, 100,000 Peripheral Blood Mononuclear Cells (PBMC)/mL derived from the healthy donor were cultured with three increasing concentrations of each ADs, namely danazol (DN), oxymetholone (OX) and nandrolone (ND) up to 9 days, based on previous publications [21,27,28] in order to compare their effect on cell proliferation
Based on data obtained first from individual case reports [20] as well as eventually from prospective clinical trials [18], patients with Dyskeratosis congenita (DKC) have increasingly been treated with ADs for the last years
Summary
Telomeres are important DNA repeat sequences located at the end of the eukaryotic chromosomes. For DKC patients, recent studies showed promising results with improvement of peripheral blood counts and, at least in some patients, elongation of prematurely shortened telomeres [18,19,20] These studies showed that treatment with AD was mediated by up-regulation of TERT via the stimulation of the intracellular estrogen receptor and, as a consequence, enhancement of the enzymatic activity of telomerase [18,21]. And in line with these studies [18,19,20], we could show that long-term treatment with danazol and oxymetholone improved blood counts and elongated telomere length in patients with DKC and mutations in TERT and TERC genes [22]. We tested the differential activity of the three most frequently used ADs, namely danazol, oxymetholone and nandrolone in four patients with DKC in vitro
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
