Elevated Dihydrotestosterone is Associated with Testosterone Induced Erythrocytosis

Abstract

INTRODUCTION Erythrocytosis is the most common dose-limiting adverse effect of testosterone therapy (TTh), but the mechanisms of T-mediated erythropoiesis remain unclear. In this study, we examine risk factors for erythrocytosis associated with TTh. METHODS Retrospective review of 179 hypogonadal men on TTh in a single andrology clinic was performed. Demographic data, TTh formulation and duration of treatment, and 5α reductase inhibitor (5ARI) use were assessed. Serum dihydrotestosterone (DHT), total T (TT), free T (FT), follicle stimulating hormone (FSH), luteinizing hormone (LH), Hematocrit (Hct), and lipid levels were extracted and changes during treatment determined. Spearman’s rank correlation was used to identify relationships between change in Hct (ΔHct) and study variables. RESULTS Of 179 patients, 49 (27%) developed a ≥10% ΔHct and 36 (20.1%) developed erythrocytosis (Hct ≥50%) at a median follow-up of 7 months. Topical gels were used by 41.3% of patients, injectable T by 52.5%, and subcutaneous pellets by 6.1%. More men who developed ΔHct ≥10% used injectable T than men with ΔHct <10% (65% vs. 48%, p=0.035), and were less likely to be on 5ARI (2% vs. 15%, p=0.017). Men with ΔHct ≥10% had higher post-treatment DHT levels (605.0 vs. 436.0 ng/dL, p=0.017) and lower LH and FSH levels than men with ΔHct <10%. Spearman’s rank correlations yielded relationships between ΔHct and post-treatment DHT (ρ=0.258, p=0.001) and TT (ρ=0.171, p=0.023). CONCLUSION DHT may play a role in TTh-related erythrocytosis, and monitoring of DHT levels during TTh should be considered. In men who develop erythrocytosis, 5ARIs may be therapeutic.

Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen

“…Erythrocytosis also occurred significantly earlier in men on injectable T formulations when compared with the other two formulations. While the mechanism of T‐induced erythrocytosis is unclear, erythrocytosis is associated with supraphysiologic T and E levels [1,2,12,27], as well as hepcidin, dihydrotesosterone and erythropoietin levels, and androgen receptor CAG repeat length [9,36–38]. It should be noted that mean T levels in men treated with injectable T were higher than those treated with gels or pellets, which may contribute to the increased likelihood of erythroctyosis in this group.…”

“…Erythrocytosis is the most frequent dose‐limiting adverse effect of TTh; an increase in blood viscosity can exacerbate preexisting vascular disease [9]. For this study, we defined erythrocytosis as Hct ≥ 50%, which is the cutoff value we use in clinical practice for T dose adjustment or recommendation of therapeutic phlebotomy.…”

“…In addition to ameliorating hypogonadal symptoms [1,3], T therapy (TTh) can lead to increased muscle mass and bone density [4][5][6], and reversal of the metabolic syndrome [2,7]. However, TTh is associated with potential adverse effects including elevated serum estrogen levels, gynecomastia, local reactions, alterations in serum lipids, erythrocytosis, testicular atrophy, male infertility, and cardiovascular effects [1,2,[8][9][10][11].…”

Erythrocytosis Following Testosterone Therapy

“…Other studies have correlated dihydrotestosterone (DHT) with increased hematocrit, independent of testosterone and free T levels, implicating DHT in testosterone-induced erythrocytosis [59–61]. Several randomized control trials have attempted to further elucidate a relationship between DHT and testosterone-induced erythrocytosis by examining whether patients on 5α-reductase inhibitors and TTh were less likely to develop erythrocytosis [62]. While one study showed a 4.7% increase in Hct, another showed no difference in post-treatment Hct [63–65].…”

Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk

“…74 Recent findings also suggest a possible role for serum dihydrotestosterone, a potent metabolite of T, in the development T-induced erythrocytosis. 75 An increased Hct has long been known to be associated with increased blood viscosity, 76e78 and it is this hyperviscosity that is one hypothesis to denote an increased risk for thromboembolic events and ischemic sequela. 1,79e81 Rates of T-induced erythrocytosis seem dependent upon both T dose and T serum level, with higher T doses and levels associated with greater rates of erythrocytosis.…”