Elsevier

Sexual Medicine Reviews

Volume 3, Issue 2, April 2015, Pages 101-112
Sexual Medicine Reviews

Reviews
Erythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male

https://doi.org/10.1002/smrj.43Get rights and content

Abstract

Introduction

Testosterone replacement therapy (TRT) is a common treatment for hypogonadism in aging males. Men with low to low‐normal levels of testosterone have documented benefit from hormone replacement. Recent meta‐analyses have revealed that increases in hemoglobin (Hb) and hematocrit (Hct) are the variants most commonly encountered. Clinically, this response is described as erythrocytosis or polycythemia secondary to TRT. However, the recent Food and Drug Administration warning regarding the risk for venothromboembolism (VTE) has made the increases in Hb and Hct of more pertinent concern. The risks associated with androgen replacement need further examination.

Aim

To review the available literature on erythrocytosis and polycythemia secondary to TRT. To discuss potential etiologies for this response, the role it plays in risk for VTE, and recommendations for considering treatment in at‐risk populations.

Methods

A literature review was performed through PubMed regarding TRT and erythrocytosis and polycythemia.

Main Outcome Measures

To assess the mechanisms of TRT‐induced erythrocytosis and polycythemia with regard to basic science, pharmacologic preparation, and route of delivery. To review Hct and risk for thrombotic events. To offer clinical suggestions for therapy in patients at risk for veno‐thrombotic events.

Results

Men undergoing TRT have a 315% greater risk for developing erythrocytosis (defined as Hct > 0.52) when compared with control. Mechanisms involving iron bioavailability, erythropoietin production, and bone marrow stimulation have been postulated to explain the erythrogenic effect of TRT. The association between TRT‐induced erythrocytosis and subsequent risk for VTE remains inconclusive.

Conclusions

All TRT formulations cause increases in Hb and Hct, but injectables tend to produce the greatest effect. The evidence regarding the risk for VTE with increased Hct is inconclusive. For patients with risk factors for veno‐thrombotic events, formulations that provide the smallest effect on blood parameters hypothetically provide the safest option. Further trials are needed to fully evaluate the hematological side effects associated with TRT. Jones SD Jr, Dukovac T, Sangkum P, Yafi FA, and Hellstrom WJG. Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male. Sex Med Rev 2015;3:101–112.

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]):

  • 75–100 mg of testosterone enanthate or cypionate administered IM weekly, or 150–200 mg of administered every 2 weeks.

  • One or two 5‐mg nongenital, testosterone patches applied nightly over the skin of the back, thigh, or upper arm, away from pressure areas.

  • 5–10 g of a 1% testosterone gel applied daily over a covered area of nongenital skin.

  • 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:

  • Identification of the appropriate patient population for whom testosterone therapy replacement should be indicated.

  • 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.

References (93)

  • A.B. Araujo et al.

    Prevalence and incidence of androgen deficiency in middle‐aged and older men: Estimates from the Massachusetts Male Aging Study

    J Clin Endocrinol Metab

    (2004)
  • American Urological Association. AUA position statement on testosterone therapy. AUA website. 2014. Available at:...
  • S. Bhasin et al.

    Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline

    J Clin Endocrinol Metab

    (2010)
  • W.D. Finkle et al.

    Increased risk of non‐fatal myocardial infarction following testosterone therapy prescription in men

    PLoS ONE

    (2014)
  • V. Muraleedharan et al.

    Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes

    Eur J Endocrinol

    (2013)
  • C. Zhao et al.

    Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits

    Can Urol Assoc J

    (2013)
  • N.T. Shahidi

    Androgens and erythropoiesis

    N Engl J Med

    (1973)
  • J.S. Tenover

    Effects of testosterone supplementation in the aging male

    J Clin Endocrinol Metab

    (1992)
  • O.M. Calof et al.

    Adverse events associated with testosterone replacement in middle‐aged and older men: A meta‐analysis of randomized, placebo‐controlled trials

    J Gerontol A Biol Sci Med Sci

    (2005)
  • M.M. Fernández‐Balsells et al.

    Clinical review 1: Adverse effects of testosterone therapy in adult men: A systematic review and meta‐analysis

    J Clin Endocrinol Metab

    (2010)
  • A.J. Schreijer et al.

    High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander?

    Haematologica

    (2010)
  • A.M. Isidori et al.

    Male hypogonadism

    Pituitary

    (2008)
  • G.S. Conway

    Clinical manifestations of genetic defects affecting gonadotrophins and their receptors

    Clin Endocrinol (Oxf)

    (1996)
  • S. Basaria

    Male hypogonadism

    Lancet

    (2014)
  • A.M. Matsumoto

    Fundamental aspects of hypogonadism in the aging male

    Rev Urol

    (2003)
  • J.E. Morley et al.

    Longitudinal changes in testosterone, luteinizing hormone, and follicle‐stimulating hormone in healthy older men

    Metabolism

    (1997)
  • S.M. Harman et al.

    Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging

    J Clin Endocrinol Metab

    (2001)
  • G. Sartorius et al.

    Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self‐reporting very good health: The healthy man study

    Clin Endocrinol (Oxf)

    (2012)
  • T.G. Travison et al.

    The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men

    J Clin Endocrinol Metab

    (2007)
  • T. Mulligan et al.

    Prevalence of hypogonadism in males aged at least 45 years: The HIM study

    Int J Clin Pract

    (2006)
  • C. Wang et al.

    Investigation, treatment and monitoring of late‐onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations

    Eur J Endocrinol

    (2008)
  • M.J. Diver et al.

    Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle‐aged men compared with those in young men

    Clin Endocrinol (Oxf)

    (2003)
  • A.M. Matsumoto

    Andropause: Clinical implications of the decline in serum testosterone levels with aging in men

    J Gerontol A Biol Sci Med Sci

    (2002)
  • M. Blute et al.

    Erectile dysfunction and testosterone deficiency

    Front Horm Res

    (2009)
  • F.C. Wu et al.

    Identification of late‐onset hypogonadism in middle‐aged and elderly men

    N Engl J Med

    (2010)
  • E. Barrett‐Connor et al.

    Bioavailable testosterone and depressed mood in older men: The Rancho Bernardo Study

    J Clin Endocrinol Metab

    (1999)
  • D. Kapoor et al.

    Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes

    Eur J Endocrinol

    (2006)
  • L. Katznelson et al.

    Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism

    J Clin Endocrinol Metab

    (1996)
  • D.J. Yassin et al.

    Long‐term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health‐related quality of life

    J Sex Med

    (2014)
  • L. Nikolaenko et al.

    Testosterone replacement ameliorates nonalcoholic fatty liver disease in castrated male rats

    Endocrinology

    (2014)
  • K. Okada et al.

    Comprehensive evaluation of androgen replacement therapy in aging Japanese men with late‐onset hypogonadism

    Aging Male

    (2014)
  • J.R. Kovac et al.

    Patient satisfaction with testosterone replacement therapies: The reasons behind the choices

    J Sex Med

    (2014)
  • J.B. Layton et al.

    Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011

    J Clin Endocrinol Metab

    (2014)
  • J. Baillargeon et al.

    Trends in androgen prescribing in the United States, 2001 to 2011

    JAMA Intern Med

    (2013)
  • J.J. An et al.

    PS3‐36: Testosterone replacement therapy patterns for aging males in a managed care setting

    Clin Med Res

    (2013)
  • S. Basaria et al.

    New modalities of transdermal testosterone replacement

    Treat Endocrinol

    (2003)
  • K.M. Lakshman et al.

    Safety and efficacy of testosterone gel in the treatment of male hypogonadism

    Clin Interv Aging

    (2009)
  • H.M. Conaglen et al.

    Retrospective investigation of testosterone undecanoate depot for the long‐term treatment of male hypogonadism in clinical practice

    J Sex Med

    (2014)
  • F. Jockenhövel et al.

    Effects of various modes of androgen substitution therapy on erythropoiesis

    Eur J Med Res

    (1997)
  • G.A. Wittert et al.

    Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low‐normal gonadal status

    J Gerontol A Biol Sci Med Sci

    (2003)
  • M. Maggio et al.

    Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men

    Andrology

    (2013)
  • J.D. Dean et al.

    Long‐term effects of Testim® 1% testosterone gel in hypogonadal men

    Rev Urol

    (2005)
  • R.K. Cavender et al.

    Subcutaneous testosterone pellet implant (Testopel®) therapy for men with testosterone deficiency syndrome: A single‐site retrospective safety analysis

    J Sex Med

    (2009)
  • C. Wang et al.

    New testosterone buccal system (Striant) delivers physiological testosterone levels: Pharmacokinetics study in hypogonadal men

    J Clin Endocrinol Metab

    (2004)
  • N. Bassil et al.

    The benefits and risks of testosterone replacement therapy: A review

    Ther Clin Risk Manag

    (2009)
  • D. Francomano et al.

    Effects of 5‐year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome

    Urology

    (2014)
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      Citation Excerpt :

      Polycythemia presents a potential additional concern for men on TTh. A recent literature review demonstrated that men on TTh have a 315% greater chance of developing erythrocytosis and polycythemia than controls.37 Increases in hemoglobin and hematocrit were observed with every type of testosterone formulation (intramuscular injection, oral, transdermal patch, topical gel, subcutaneous pellets, buccal), although the effect was most significant with intramuscular injections.

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    The author(s) report no conflicts of interest.

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