We present a case where a patient with intermediate-risk MDS and hypogonadism experienced a sustained increase in hgb levels of over 2 g/dL using testosterone and ESAs. The role of testosterone in enhancing erythropoiesis is widely recognized in laboratory and clinical settings, and TRT has well documented use in treating anemia for a variety of conditions such as aplastic anemia, end-stage renal disease, and hypogonadism (Pencina et al. 2023; Nassani et al. 2023; Ballal et al. 1991). While the mechanisms of its erythropoietic effect are still not fully understood, several hypotheses have been proposed, including stimulating EPO production, lowering hepcidin levels, prolonging RBC survival, and even directly influencing hematopoietic stem cells via IGF-1 induction (Moriyama et al. 1975; Guo et al. 2013; Beran et al. 1982). There is also clinical evidence to suggest that testosterone and ESAs are synergistic and should be used in combination for optimal effect (Ballal et al. 1991). Notably, our patient’s anemia continued to improve despite having low follow-up levels of EPO upon discontinuation of aranesp.

The literature on testosterone in treating MDS-related anemia is scarce, with only two prospective studies and a single case report available (Table 1). Riccardi et al. (1987) in 1987 treated 101 patients with refractory cytopenia, 64 of whom had MDS, with high-dose testosterone enanthate (TE) (7–10 mg weekly IM). In the MDS cohort, 44% responded to TE, 94% of which had increase in hgb and/or reduction in transfusion requirement. Median duration of response was 13 months and responsive patients had improved survival versus non-responders. No pre-treatment testosterone levels were recorded.

Mei et al. (2023) observed a 65% response rate within 43 low-risk MDS patients who received a combination of EPO (10,000 IU/day), all-trans retinoic acid (25 mg/m2/day), and testosterone undecanoate (80 mg twice daily). Responders had an increase in hgb (greater than 1.5 mg/dL increase from baseline) and were transfusion independent. No significant difference in response was found between those with initial EPO ≤ 500 mU/mL versus > 500 mU/mL. Interestingly, better efficacy was noted in patients with SF3B1 compared to those with ASXL1 mutations. The most common adverse events reported were dry skin and fatigue. This study also did not report testosterone levels.

Finally, a case study by Iijima et al. (2011) detailed a 70-year-old man with low-risk MDS and hypogonadism who received TE and showed a sustained response in both his anemia and thrombocytopenia despite having previously failed the derivative synthetic testosterone methenolone in the past.

The limited studies reviewed vary in level of evidence and type of TRT used but overall suggest that TRT shows promise as a potential therapy for MDS-related cytopenia. Riccardi et al. and Mei et al. interestingly did not assess pre-treatment testosterone levels, and yet still reported substantial response rates in their cohorts. The above findings also hint at a potential association between genetic markers and efficacy of TRT, in addition to the possibility that TRT remains a viable alternative even in situations where anabolic-adrenergic steroids have not worked.

Ferrucci et al. (2006) reported that male patients with lower TT had significantly reduced hgb, higher prevalence of anemia, and increased risk of developing anemia compared to subjects with normal TT. In anemic hypogonadal patients who received TRT, the TRAVERSE randomized control trial demonstrated a significant response in anemia and energy levels lasting up to 4 years (Pencina et al. 2023). The Hypogonadism in Males (HIM) study identified prevalence of hypogonadism in men aged ≥ 45 to be 38.7%, based on TT < 300 ng/dL (Mulligan et al. 2006). And while direct studies on hypogonadism incidence in MDS are lacking, studies in other malignancies report increased prevalence of hypogonadism when compared to healthy male cohorts. For example, a cross-sectional study by Fleishman et al. reported a 46% prevalence in leukemia and lymphoma, while a prospective study in multiple myeloma found a prevalence of hypogonadism of 74% (Fleishman et al. 2010; John et al. 2019).

The long-term safety of TRT, particularly regarding its links to prostate cancer and cardiovascular disease, is not well established. While there is evidence for the role of androgens in prostate cancer pathogenesis and TRT has been shown to increase PSA levels in some men, clinical studies have not demonstrated a significant increase in prostate cancer incidence or mortality in TRT-treated hypogonadal patients (Fernández-Balsells et al. 2010; Grech et al. 2014). Similarly, TRT has also not been conclusively linked to increased risk of myocardial infarction, stroke, venous thromboembolism, or overall mortality (Shores et al. 2021). However, it is also important to recognize that in the older MDS population, where median age of diagnosis is 72 years old and median survival is 5.3 years for low-risk cases (Tefferi et al. 2009), any theoretical mortality risk from prostate cancer or cardiovascular events is likely lower and possibly outweighed by the potential quality of life benefits of TRT.