Testosterone Therapy and Cardiovascular Risk

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madman

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


Abstract

Background


Treatment of “adult-onset hypogonadism” (AOH) with exogenous testosterone therapy (TTh) to raise serum testosterone (T) levels may influence cardiovascular (CV) risk factors in patients with AOH, whereas low endogenous T levels are associated with an increased CV risk and mortality.

Aim

To critically evaluate studies reporting increased CV risk associated with TTh and to provide an overview of the risks and benefits of restoring T levels through exogenous TTh.

Methods

A review of publications focusing on the association between TTh and increased CV risk was conducted, and the study methodologies and conclusions of each were critically evaluated. Further, recent clinical and epidemiological studies associating AOH or TTh with a change in CV risk, and pertinent hematologic and vascular effects noted in animal studies and in vitro, as well as in clinical practice were also reviewed.

Outcomes

A review of the literature shows that untreated testosterone deficiency and/or low T is associated with an increase in CV risk and adverse outcomes, with numerous studies and meta-analyses to support a positive association between exogenous TTh and an improvement in CV risk factors in men with AOH.

Results

Numerous studies in the literature demonstrate the positive benefits of using TTh; however, since 2013, some publications have suggested a link to increased CV risk associated with TTh. A number of these studies.

Clinical Implications

A careful assessment of the patient's current health status and CV risk factors should be weighed against the benefits and possible risks resulting from TTh, and consideration should be given to deferring treatment pending resolution or stabilization of CV disease or risk factors.

Strengths & Limitations

In this review, we provide an in-depth analysis of studies reporting increased CV risk with TTh. Many of the studies were not well-designed, randomized, double-blind, prospective clinical trials but rather post hoc analyses of cohort data. These studies may reflect bias in how treatment and nontreatment decisions are made or reflect conclusions based on widely cited methodological flaws.

Conclusions

Appropriate patient selection supported by low pre-treatment T levels and monitoring T levels during treatment with the goal of achieving and maintaining physiologic levels all contributes to the safe and effective use of TTh in men with AOH.



Introduction

In 2015, an expert panel assembled by the Sexual Medicine Society of North America (SMSNA) convened to discuss how to diagnose and treat men with “adult-onset hypogonadism” (AOH), a clinical and biochemical syndrome that is a clinically distinct testosterone deficiency (TD) and may be accompanied by signs and symptoms commonly associated with both testicular and hypothalamic-pituitary dysfunction (Table 1).1 This syndrome has elements of both primary and secondary hypogonadism, with many men presenting with an inadequate pituitary response to low testosterone (T) levels.1 Although testosterone (T) levels decline as men age, AOH is not exclusively characterized by an “age-related” TD; rather, it can occur in men who may have common comorbidities associated with aging.2,3 Established risk factors for the development of AOH include cardiovascular disease (CVD), obesity, type 2 diabetes, chronic obstructive pulmonary disease, HIV infection, obstructive sleep apnea and/or sleep disorders, chronic opioid use, and corticosteroid use.1,4

Treatment of AOH often involves lifestyle modifications such as weight loss and improved diet, exercise, and sleep, together with exogenous T therapy (TTh). TTh is used for the treatment of TD, with the goal of restoring T concentrations to within the physiological range (∼300–1,100 ng/dL), often alleviating TD-related signs and symptoms.5,6 Guidelines from various societies for the diagnosis and treatment of TD are listed in Appendix 1.6, 7, 8, 9, 10 Today, many Food and Drug Administration (FDA)-approved TTh are available to restore serum T levels within the normal physiological range, each formulation associated with a unique efficacy and adverse event (AE) profile. In addition, there are differences in dose, pharmacokinetics, and method of administration (Table 2).11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Benefits of TTh include improvements in sexual function,29, 30, 31 increased muscle mass and decreased fat mass32,33; effects on physical performance30,34 and energy levels are more varied.31,35 However, based on potential TTh misuse, the FDA limited the indications for TTh to classical primary and secondary hypogonadism, and not for AOH.36,37 Specifically, the FDA concluded that the available evidence does not support an indication for TTh for “age-related hypogonadism,” placing those physicians who treat men with AOH in the predicament of prescribing T off-label.

Although TTh has been in clinical use for nearly a century, prior to 2013, few publications supported an increased CV risk in patients treated with TTh; in fact, most showed beneficial CV effects of TTh and that low T levels were generally associated with an increased risk of atherosclerosis, CV risk factors, and mortality.38,39 Since 2013, published studies have contradicted this body of literature, contributing to ongoing debates in the medical community regarding the effects of TTh on cardiovascular health.40, 41, 42, 43

As the literature is replete with studies demonstrating beneficial impacts of TTh on CV and overall health, we limited our review to the literature supportive of negative effects of TTh on CVD and summarize the available data on the putative mechanisms underlying increased CV risk. We also address the impact of both the current FDA perspective and various professional society guidelines on the use of TTh for the treatment of AOH in clinical practice.




No Association Found Between TTh and an Increase in CV Risk

Putative Mechanisms Underlying CV Risk


T-Induced Erythrocytosis
Erythrocytosis, generally defined as a hemoglobin (Hb) level higher than 18.5 g/dL or hematocrit (Hct) ≥52%, is the most common dose-limiting adverse effect of TTh.69,70 TTh is frequently associated with elevations in both Hb and Hct.51,54,71,72 The mechanism by which T induces erythrocytosis is believed to involve erythropoietin stimulation73 and suppression of hepcidin.74 Recent findings also suggest a possible role for serum dihydrotestosterone, a potent metabolite of T, in the development of T-induced erythrocytosis.75 An increased Hct has long been known to be associated with increased blood viscosity,76, 77, 78 and it is this hyperviscosity that is one hypothesis to denote an increased risk for thromboembolic events and ischemic sequela.1,79, 80, 81

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.82, 83, 84 In addition, certain T formulations seem to be more likely to induce erythrocytosis than others.82,84, 85, 86 A measurement of Hct >50% is significantly (P < .0001) more common with T injections (66.7%) than with T gels (12.8%) or pellets (35.1%).87,88 However, it may be the dose or the pharmacokinetic (PK) profile of the formulation, rather than the actual route of administration, that has a greater influence on erythrocytosis72,84: use of short-acting injectable T preparations is more commonly associated with serum T fluctuations and supraphysiologic T levels.86,88,89 In contrast, longer-acting preparations (eg, extended-release intramuscular (IM) injections, subcutaneous injections, T implants) that do not cause prolonged supraphysiologic levels to tend to be associated with a lower incidence of erythrocytosis.82,90, 91, 92 Specifically, extended-release injections of testosterone undecanoate (TU) are associated with a rate of erythrocytosis of approximately 7%.93

In terms of CV risks associated with T-induced erythrocytosis, prospective, randomized, controlled trials have failed to detect a direct relationship between T-induced erythrocytosis and subsequent risk for CV events (including stroke and deep vein thrombosis).94, 95, 96, 97, 98 However, as proposed by Kloner et al, a large, prospective, randomized, placebo-controlled, double-blinded, long-term study with a clearly defined objective of evaluating the effect of TTh on MACE in men with verified symptomatic hypogonadism of at least 1 year is needed to assess the effect of TTh on CV safety.99 The currently ongoing TRAVERSE study (ClinicalTrials.gov Identifier: NCT03518034), is a blinded, placebo-controlled study that began recruiting patients in 2018 with a target enrollment of 6,000 patients and aims to investigate the effect of topical TTh on MACE in symptomatic men with TD.61 The results of this study are forthcoming. The current Endocrine Society Clinical Practice and American Urology Association guidelines state that Hct values > 54% warrant discontinuation of TTh or therapeutic phlebotomy and consideration of dose reduction.6,100 In addition, if Hct levels become markedly elevated, phlebotomy should be considered for expedited normalization of levels.


Estradiol
E2 has a variety of physiological functions in men, including effects on the brain, cartilage, and bone, as well as on CV health.101, 102, 103 Abnormal increases in E2 can lead to mood swings, breast tissue changes, and fluid retention. Most (∼80%) of the circulating E2 in men is derived from aromatization of circulating T.104,105 In men with TD, E2 concentrations are also low, and during TTh, E2 tends to increase when serum T increases, largely maintaining the T: E2 ratio.106 However, imbalances in this ratio in either direction (ie, higher or lower T: E2 ratios) could be harmful, potentially promoting the development of heart disease and increasing the risk of cerebrovascular disease.107,108 One study has reported in older, obese men receiving IM T injections, a higher rate of whole-body T aromatization, possibly due to the higher fat mass in older men.106 However, another study showing no correlation between age and body mass index with E2 levels or has not confirmed this87 so at the current time, it is unclear whether fat mass plays a role in influencing T: E2 ratios and whether increasing aromatization of T to E2 has any role of increasing CV risk.


Human Platelet Thromboxane A2
Although the mechanism is not well understood, in vitro studies suggest that one potentially prothrombotic influence of T is the upregulation of platelet TXA2 receptors. The function of human TXA2 is to assist in platelet aggregation and vascular smooth muscle contraction,109,110 and increased platelet aggregation potentially promote atherogenesis/thrombosis.111 During numerous thrombotic CV events, including unstable angina, the synthesis of TXA2 is increased.112 However, there is no direct evidence for an association between TXA2 receptor density and CV risk in humans,111,113 nor is there evidence that a T-induced TXA2 increase induces increased CV risk.


Blood Pressure
Animal studies have shown that T and its metabolites play a significant role in BP control and deficiency may contribute to the pathogenesis of hypertension.114 The antihypertensive effects of androgens may be mediated by blocking L-type voltage-gated calcium channels and, to a lesser extent, by blocking multiple signaling pathways operating during α-adrenoreceptor-induced vasoconstriction.115 These findings demonstrate that hypotestosteronemia may be a risk factor for hypertension.114 Plasma concentrations of natriuretic peptides (NPs) are elevated in heart failure, and these peptides are considered to play a compensatory role for heart failure due to their diuretic, natriuretic, and vasodilating actions.116 Higher levels of N-terminal pro-B-type NP (NT-proBNP) have been reported in hypertensive patients, and a strong association between circulating cardiac NPs and CV risk has been reported in a systematic review and meta-analysis of 40 prospective studies.117,118 Recently, a study reported the negative effect of T on the cardiac NP system. Healthy men (n = 202) aged 20 to 50 years were treated with goserelin acetate to suppress endogenous T and estradiol production and anastrozole to prevent the aromatization of T to estradiol and were then randomly assigned to 5 different doses of topical T gel. The authors report that suppressing T production in men increased circulating NP levels, which decreased following 12 weeks of T gel treatment, but also offer that higher T levels may only partly explain why men have lower NP levels compared with women.119 However, in a randomized, double-blind, placebo-controlled trial of hypogonadal men with heart failure, treatment with 5 mg transdermal T patch did not result in any significant change in serum BNP levels.120 The exact mechanism for T-induced BP reduction has not been completely elucidated.


Insufficient Repletion of Serum T Levels
One hypothesis for the association between TTh and CV risk that is sometimes seen in clinical studies is that when physiological T levels are not achieved using TTh, either because of T underdosing or overdosing, CV risks may increase. Since we know that low endogenous T levels are associated with increased CV risk, it is reasonable that TTh with less-than-adequate efficacy or poor compliance that fails to raise serum T levels to >300 ng/dL would be associated with, but not necessarily causative of, an increased CV risk relative to a population with serum T levels in the physiological range.121, 122, 123, 124, 125, 126 Recently, a large (N = 10,041 men) database study examined the association of circulating T levels with a panel of 10 high-sensitivity CV risk biomarkers (including cardiac troponin I, endothelin-1, interleukin-6, tumor necrosis factor-α, interleukin-17A, NT-proBNP, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, Hb A1c, and leptin).127 An inverse relationship between plasma T levels and CV risk was observed for 9 of the 10 CV markers (Figure 1127).

Conversely, the effects of supraphysiologic serum T levels (>1,100 ng/dL) on CV risk have been less studied, since it is not a goal of TTh to raise T levels above the upper limit of the normal physiological range. In general, lower circulating T levels predict higher CVD-related mortality. However, it is possible that a U-shaped association exists between circulating androgens and CV events or mortality outcomes, where serum T at very low or very high levels may be associated with an increase in CV risk.128 In the TOM trial, men with the highest quartile T levels (512-1957 ng/dL) had an increased risk for unconfirmed CV events (HR: 2.4; P = .05) compared with all other subjects in the study.42 Similarly, an analysis of 495 men taken from the larger French Three-City prospective cohort study found a J-shaped association between plasma T and ischemic arterial disease in men 65 years and older.129 The HR associated with the lowest and the highest T quintiles relative to the second quintile were 2.23 and 3.61, respectively (P < .01). Additional analysis for coronary heart disease showed similar results (HR: 3.11 and 4.75). This J-shaped association was also observed between bioavailable T and ischemic arterial disease risk.129 These studies are observational and do not prove causality; randomized controlled trials are needed to fully clarify the effects of T on CV risk in men.

There are known differences in serum T levels because of the use of different types of T formulations. Specifically, compared with patches and gels, IM injections of T dosed on an infrequent basis are associated with serum T peaks and troughs that cause supraphysiologic levels soon after the injections and before the T levels drop back down into the physiological range.47,86,130,131 In contrast, a weekly subcutaneous, auto-injectable T formulation received FDA approval in 2018 and is able to achieve a more stable PK profile resulting in less fluctuation in serum T levels.132,133



Discussion

Perspectives on the Current Status of the Literature on CV Risk With Respect to TD and TTh






Conclusions


In summary, upon a critical examination of the literature purported to support an increase in CV risk with TTh, we did not find definitive evidence to support that TTh increases CV risk. To date, there have not been large, long-term, placebo-controlled studies examining the risk or safety of TTh on CV outcomes. However, there is overwhelming evidence spanning multiple decades from numerous researchers whose studies show an improvement of CV risk factors in response to TTh in men with AOH. When prescribing TTh, it is important to consider appropriate patient selection and patients' CV risk factors, obtain pretreatment T levels, select a formulation that allows for patient compliance, and monitor for potential TTh-related AEs. T levels of men receiving TTh must be monitored to ensure physiological T levels are achieved and maintained to benefit patients’ overall health as well as CV outcomes and per major guidelines, to ameliorate TD signs and symptoms.

So how can we reconcile these differing perspectives on patient management? What are the key considerations for T prescribers? Clearly, the benefits from TTh afforded to men with idiopathic and/or AOH are an important consideration. However, given the restrictions of the new FDA indications, a large majority of such men are being treated with TTh off-label.156 Further research aimed at clarifying the relationship between TTh and CV risks should be aggressively pursued and is currently being examined in the TRAVERSE study. In the meantime, it is important to (i) appreciate the limitations of the evidence that forms the basis for the FDA warnings and (ii) follow guidelines regarding prescreening and monitoring of T levels before and during TTh. In addition, there are differences in the various T formulations with respect to PK and AEs; therefore, it is important to select a formulation that is most appropriate for the patient. Importantly, AEs, including those related to CVD, may be exacerbated by underdosing or fluctuating levels of T.
 

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madman

Super Moderator
Table 1. Clinical signs, symptoms, and conditions consistent with adult-onset hypogonadism and low testosterone levels
Screenshot (3219).png
 

madman

Super Moderator
Figure 1. Relationship between low testosterone levels and increased cardiovascular risk.127 Panel A shows the cardiovascular risk-adjusted for age and BMI. Panel B show the cardiovascular risk-adjusted for age, BMI, HbA1c, high-sensitivity C-reactive protein, and high-density lipoprotein. *Testosterone levels <250 ng/dL associated increased likelihood of elevated levels. BMI ¼ body mass index. Figure reprinted with permission from Pastuszak AW, et al J Sex Med 2017;14:1,095-1,103
Screenshot (3225).png
 

madman

Super Moderator
Table 3. Studies showing relationship between low endogenous testosterone and increased cardiovascular risk and mortality
Screenshot (3226).png

Screenshot (3227).png
 
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