ReviewsErythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male
Introduction
Hypogonadism, or testosterone deficiency (TD), is more common as men age. Recent studies have estimated nearly 5 million new cases of hypogonadism in men between the ages of 49 and 60 years over the last decade [1]. With a concurrent rise in direct marketing by pharmaceutical companies, testosterone replacement therapy (TRT) in the aging male has increased dramatically. Multiple terms have been used to classify age‐related hypogonadism, including andropause, male climacteric syndrome, late‐onset hypogonadism, and androgen deficiency of the aging male. The American Urological Association (AUA) defines hypogonadism as “biochemically low testosterone levels in the setting of a cluster of clinical symptoms, which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood” [2]. Additionally, men afflicted by hypogonadism may experience reduced muscle mass, physical strength, and bone mineral density, as well as anemia and increased body fat [3]. Many men diagnosed with TD do benefit from TRT. However, TRT has come under close scrutiny of late, as there is conflicting evidence regarding the effect of TRT on the cardiovascular system. Some recent studies implicate TRT in increasing cardiovascular events [4], whereas others document TRT as having a protective effect 5, 6. In a policy statement issued in February 2014, the AUA recognized the controversy surrounding TRT, and endorsed its use in the treatment of men suffering with hypogonadism “after a full discussion of potential adverse effects.” The AUA went on to state that definitive studies have not been performed, and, consequently, the effects of TRT on cardiovascular disease are not fully elucidated [2].
It is recognized that androgens have an erythrogenic effect on the hematologic system [7]. Elevations in hemoglobin (Hb) and hematocrit (Hct) levels are frequently described consequences of TRT [8] and recent meta‐analyses have confirmed that blood profile changes are the most common adverse drug events seen with this therapy 9, 10. It has been proposed that long‐term elevation of Hb and Hct may increase the risk of venothromboembolism (VTE), but this hypothesis is not universally agreed upon [11]. The use of exogenous testosterone as treatment for hypogonadism in the aging male is expected to increase as more and more diagnostic testing is conducted. In light of this, patient safety and avoidance of inimical side effects should be a priority for all treatments. Here, we provide an analysis of the proposed mechanisms that may explain the hematological response observed with TRT, a review of the effects this response may have on VTE risk, and recommendations for considering TRT in patients with risk for veno‐thrombotic events.
Section snippets
Hypogonadism
The Endocrine Society's clinical practice guidelines define hypogonadism as a “clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic‐pituitary‐testicular axis” [3]. The hypothalamic–pituitary–testicular axis is a dynamic physiological system involved with the homeostatic maintenance of testicular activity (Figure 1). Disruption
TRT for Hypogonadism
Men have turned to TRT as a treatment (for hypogonadism) because of its benefits to the aging process. TRT improves insulin resistance, increases bone and muscle mass, and decreases subcutaneous fat 27, 28. One recent study showed that TRT helps reverse obesity and the metabolic syndrome, lowers low‐density lipoprotein (LDL), triglycerides, blood glucose, HbA1c, and blood pressure, as well as increases high‐density lipoprotein (HDL) and improves erectile function [29]. Another study showed that
Erythrocytosis and Polycythemia as Adverse Drug Events During TRT
Contemporary controversy surrounding TRT centers on the risk for potential venous thromboembolism (VTE). The Food and Drug Administration (FDA) recently mandated that testosterone manufacturers include a warning label stating that testosterone may increase risk of VTE (FDA report 6/19/2014). It has been proposed that the risk for VTE was due to the secondary blood profile changes; however, reports of VTE not associated with erythrocytosis or polycythemia have questioned this notion. As the
The Effect of Route of Administration on Changes in Hb and Hct
Of the multiple methods of TRT administration, it is understood that injectable formulations cause the greatest increases in serum T levels from baseline [35]. This form of therapy is also associated with the greatest treatment‐induced increase in Hb and Hct (Table 1). When injectable options are used, rapid, supraphysiological peaks quickly followed by subphysiological troughs may occur. This pattern is thought to explain why injectable preparations cause the greatest increases in vascular
Risk for VTE with Increased Hct
Whether TRT‐induced increases in Hct lead to an increased risk for veno‐thrombotic events remains uncertain. Although it is known that enhanced blood viscosity poses a threat for ischemic sequela, the relationship between Hct and the risk for developing VTE remains controversial 11, 73. The direct relationship between TRT‐induced elevations in Hct and subsequent risk for VTE has not been investigated through randomized controlled trials (RCTs). The literature on this topic consists primarily of
Clinical Recommendations
The safety and efficacy of TRT in the aging man has been well established. Current TRT regimens include (adapted from Bhasin et al. [3]):
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75–100 mg of testosterone enanthate or cypionate administered IM weekly, or 150–200 mg of administered every 2 weeks.
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One or two 5‐mg nongenital, testosterone patches applied nightly over the skin of the back, thigh, or upper arm, away from pressure areas.
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5–10 g of a 1% testosterone gel applied daily over a covered area of nongenital skin.
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30 mg of a bioadhesive
Areas for Future Research
With many questions regarding hematological parameters and TRT remaining unanswered, larger, multicenter prospective trials are warranted to better assess the risks of increased Hb and Hct as side effects of TRT. Furthermore, a complete understanding of the androgenic stimulation of erythropoiesis from a basic science perspective would allow for the development of therapies with fewer adverse effects. One alternative option to TRT that currently exists is the use of anti‐estrogens (i.e., ER
Conclusion
TRT for treatment of hypogonadism in the aging male continues to gain in popularity. A number of formulations have been developed to provide advantageous pharmacologic properties while providing multiple options for delivery. The most frequent adverse drug event seen with TRT is the abnormal increase in Hb and Hct. Proposed mechanisms to explain this phenomenon include increases in EPO production and set point, enhanced iron bioavailability and turnover, and augmented hematopoietic stem cell
Addendum
On September 17, 2014, an FDA Advisory Committee meeting was held to assess two issues related to TRT:
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Identification of the appropriate patient population for whom testosterone therapy replacement should be indicated.
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Potential risk of major adverse cardiovascular events associated with testosterone therapy.
Following the extensive discourse of this meeting, the expert panel voted heavily in favor of the decision for the FDA to impose stricter limitations on the testosterone drug industry.
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The author(s) report no conflicts of interest.