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Understanding the long-term risks and benefits of testosterone replacement


Academic year: 2021

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Nathan Hale, DO Samuel Deem, DO




also called

andropause and androgen

deficiency of the aging male,

is a clinical condition in which

low levels of serum testosterone are

found in association with specific signs

and symptoms. During the aging process,

serum testosterone concentration declines

approximately 1.6% per year after the age of



Although hypogonadism is a relatively common

condition in the aging population, it is one of the most

difficult to recognize and treat. This is because the condition

closely resembles the physiologic aging process.

Understanding the

long-term risks and

benefits of testosterone



symptoms or promotes acute urinary retention, BPH represents a relative contraindication, which is no longer applicable after successful treatment of LUT obstruction. Monitoring for worsening signs and symptoms of BPH is an important part of TRT.

Sleep apnea

TRT has been considered to have a negative effect on obstructive sleep apnea (OSA). It is believed to potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases. Though no clear link has been established, men receiving TRT should be informed about the potential risk of OSA when starting testosterone. In addition, physicians should counsel patients already diagnosed with sleep apnea that symptoms may worsen with testosterone replacement. However, in a recent randomized, placebo-controlled trial, testosterone undecanoate was administered intramuscularly (IM) in men with obesity and OSA, and overnight polysomnography was monitored at 0, 7, and 18 weeks. Testosterone treatment resulted in mild worsening of the sleep apnea at 7 weeks, but then resolved by 18 weeks. At 18 weeks, there were no significant differences in ventilator markers between the 2 groups,3 suggesting

that there may exist a time-dependent relationship between testosterone replacement and sleep apnea. Further research is necessary to explore the safety of TRT in the setting of sleep apnea. Currently, uncontrolled sleep apnea is a relative contraindication to TRT.

Congestive heart failure

Low levels of testosterone have been associated with increased mortality and morbidity in men with CHF. Despite this observation, severe CHF is currently a relative contraindication of TRT. This recommendation is based largely on animal studies, which have suggested that TRT may induce hypertrophy, fibrosis, and apoptosis in cardiomyocytes. However, there is a growing body of literature to support the use of testosterone in and increase the risk of male breast

cancer. Future prospective research will be necessary to determine whether such an association exists between TRT and male breast cancer. Most experts agree that TRT should be avoided in men with a history of breast cancer.

Benign prostatic hyperplasia

The role of androgen in the development of benign prostatic hyperplasia (BPH) is well documented. Testosterone supplements increase prostate volume, with a mild increase in prostate-specific antigen levels in older men. Although a meta-analysis showed that the total number of prostate events combined was significantly greater in testosterone-treated than in placebo-treated men, the majority of events

are due to prostate biopsy.2 At the

same time, many studies have failed to show significant exacerbation of voiding symptoms attributable to BPH during testosterone supplementation. Complications such as urinary retention have not occurred at higher rates than in controls receiving placebo nor has there been any difference in urine flow rates, post-voiding residual urine volumes, and prostate voiding symptoms with patients receiving treatment in these studies. This is explained by the poor correlation between prostate volume and urinary symptoms. Although there are no compelling data to suggest that TRT in men with BPH exacerbates lower urinary tract (LUT) Male hypogonadism typically

presents as fatigue, weakness, decreased libido and energy, erectile dysfunction, reduced muscle and bone mass, and increased central obesity. These signs and symptoms make it difficult to understand the extent to which the clinical features are due to aging, testosterone deficiency, or both. Detection and treatment are important because testosterone replacement therapy (TRT) can result in clinical benefits. Successful management of TRT requires an understanding of the risks and benefits of treatment (Table 1).

Treatment risks

The risks of TRT are largely determined by the patient’s age, life circumstances, and other comorbidities. The treating clinician must understand the risks involved, including a risk of prostate cancer, benign prostatic hypertrophy, worsening symptoms of sleep apnea and congestive heart failure (CHF), liver toxicity, polycythemia, and infertility.

Prostate cancer

It is well established that prostate cancer is an androgen-sensitive disease. Therefore, untreated prostate cancer is often considered an absolute contraindication to TRT. However, current evidence suggests that TRT does not increase the risk of prostate cancer over the general population. It appears that testosterone does not directly cause prostate cancer, but it has been shown to accelerate the growth of prostate cancer, if present. There is some evidence that testosterone replacement can be offered in men with previously treated prostate cancer; however, this decision should be made on a very individualized basis. The risks and benefits must be clearly understood by the patient and informed consent obtained before testosterone replacement.

Breast cancer

Very little data exist linking testosterone replacement with breast cancer. It is believed that high levels of testosterone may lead to increased aromatization to an active derivative of estrogen, which may then stimulate breast tissue receptors

Although the

condition is

relatively common

among aging men,

its similarity to the

physiological aging

process makes it

hard to recognize

and treat.


exception of testosterone undecanoate, are discouraged. These unfavorable hepatic effects do not appear to be associated with transdermal or IM injections. However, current standards recommend periodic liver function testing when receiving TRT.


There is a correlation between high testosterone levels and high hemoglobin, most likely because testosterone

stimulates erythropoiesis. Erythrocytosis can develop during TRT, especially in older men. Hypogonadism causes a decline in hemoglobin that can be restored with TRT. But, the elevation in hemoglobin above a certain level may increase morbidity, particularly in the elderly. The elevated hemoglobin concentration levels lead to an increase in blood viscosity, which could

exacerbate vascular disease in the coronary, cerebrovascular, or peripheral vascular circulation. This is especially true in patients with other diseases that cause secondary polycythemia, such as chronic obstructive pulmonary disease. Testosterone injections are more likely to cause polycythemia than topical preparations. Approximately 5% of transdermal users developed polycythemia, and the majority of changes took place over the first 3 months of treatment.5 It has been

demonstrated that testosterone dosage correlates with the incidence of erythrocytosis. Periodic hematological assessment is indicated before treatment, then at 3 to 6 months and 12 months in the first year of treatment, and then annually thereafter. If hematocrit becomes elevated, therapy should be discontinued until hematocrit decreases to an acceptable level. The clinician can consider restarting the therapy, but this may require a dose adjustment, a change in formulation or delivery method, and/or periodic phlebotomy to keep hematocrit below 52% to 55%.


All forms of exogenous testosterone replacement have a suppressive effect on the hypothalamic-pituitary-gonadal axis through feedback inhibition of pituitary follicle-stimulating hormone. This suppression results in decreased endogenous production of testosterone and spermatogenesis. This negative impact is usually transient and disappears some months after discontinuation of TRT. However, testosterone replacement is associated with a decreased likelihood of achieving conception.6 Hypogonadal

patients considering TRT should be informed about infertility risks, and if fertility is desired, alternative treatments with gonadotrophins or antiestrogens may be useful.

Treatment benefits

As the prevalence of hypogonadism continues to rise, understanding the benefits of TRT is increasingly important. The treating clinician must analyze the risk-to-benefit ratio on an the face of mild-to-moderate CHF

in the setting of hypogonadal men. Randomized, placebo-controlled trials have shown improvement of exercise capacity, functional capacity, and ventilator efficiency as well as improved peripheral muscle function. However, despite these improvements, all studies failed to detect any significant changes in central hemodynamics or left ventricular function.4

Liver dysfunction

Benign and malignant hepatic tumors, intrahepatic cholestasis, hepatotoxicity, and liver failure have been reported with TRT. Prolonged use of high doses of orally active 17-α-alkyl androgens (methyltestosterone) has been associated with serious hepatic adverse effects. For this reason, the oral forms of testosterone, with the


replacement.2 However, the effect of

TRT on glycemic control of men with DM is still uncertain. Testosterone plays a role in lipid metabolism as well. TRT decreases low-density lipoprotein (LDL) and total cholesterol. However, HDL has also been shown to decrease, which may temper any cardiovascular benefit in lowering LDL. TRT appears to have no significant effect on triglyceride (TG) levels. The decrease in cholesterol is believed to be related to the decrease in the visceral abdominal fat under the influence of androgens, which inhibit lipoprotein lipase activity and increase lipolysis with improvement of insulin sensitivity and mobilization of TGs.2 Although TRT appears to

be a new strategy for the treatment of MetS, concerns about its effect on adipocytokines, such as adiponectin, have prevented widespread usage for the management of MetS. Currently, TRT is viewed as an adjuvant therapy in MetS in the hypogonadal male.

Sexual function

Hypogonadism may be responsible for sexual dysfunction. When low testosterone levels are found, many aging men experience symptoms of low libido, changes in erectile function, and sexual satisfaction. It is thought that low serum testosterone level is rarely the major cause of erectile dysfunction in the aging male, although it may play a subsidiary role in many cases of erectile dysfunction. TRT has been shown to be the most beneficial to sexual function in men with a testosterone level below 346 ng/dL.11 A meta-analysis

of testosterone replacement effects on sexual dysfunction has shown that the largest improvement occurs in the individual’s libido, whereas only groups.9 However, many of these studies

were small in nature. TRT has never been shown to prevent the occurrence of fractures.9 Further investigation will

be necessary to confirm the long-term benefits of testosterone therapy for improving bone strength, preventing osteoporosis, and associated fractures.

Metabolic syndrome

Metabolic syndrome (MetS) is characterized by central obesity, insulin resistance, dyslipidemia, and hypertension. Low testosterone is associated with each of these MetS characteristics. The relationship of testosterone to these conditions is complex. An inverse relationship exists between serum testosterone levels and degree of obesity in men, particularly visceral obesity. TRT has been shown to decrease body fat mass and waist circumference, a marker for central adiposity (Table 2). Several epidemiology studies have shown a close association between low serum testosterone levels and type 2 diabetes mellitus (DM) in men.10 There

is a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance, and an improvement in insulin sensitivity was noted after individual basis. In order to do this, the

clinician must understand the potential benefits of TRT. Current research suggests that TRT has beneficial effects on muscle mass, bone mineral density (BMD), lipid metabolism, sexual function, mood, and cognitive function.

Muscle mass

Declining testosterone levels have been associated with decreased strength and muscle mass in aging men. The New Mexico Aging Process Study revealed correlations between testosterone levels and muscle strength.7 Several

studies found TRT to be beneficial in improving muscle strength in the face of hypogonadism. However, many of these studies failed to show significant changes in functional ability. Meta-analyses of randomized trials in both middle-aged and older men with hypogonadism have shown that TRT is associated with increased lean muscle mass, decreased fat deposition, and increased strength when compared to placebo. Some studies have failed to show these benefits. The long-term benefits of testosterone on functional improvements require further investigation.

Bone mineral density

The pivotal role of testosterone in bone mass acquisition, bone turnover, and fracture risk is well documented. Thus, it is reasonable to consider that hypogonadism contributes to bone loss. There is a strong association between low bone density, bone loss, osteoporosis, and low testosterone in aging males.8 A

meta-analysis of 14 randomized, placebo-controlled trials revealed an increase in BMD in the testosterone replacement

Table 2. Positive impact of TRT on characteristics of metabolic syndrome

Decreases Increases

Body fat mass Insulin sensitivity2

Waist circumference

Low-density lipoproteins (LDLs) Total cholesterol

Table 1. Potential risks and benefits associated with TRT

Risks Benefits

Prostate cancer Increased muscle mass7

Breast cancer Increased bone mineral density (BMD)9

Worsening of benign prostatic hyperplasia Improved lipid metabolism Worsening of sleep apnea Improved sexual function11

Worsening of congestive heart failure (CHF) Improved mood13

Liver dysfunction Improved cognitive function Infertility


9. Hoppe E, Bouvard B, Royer M, et al. Is androgen therapy indicated in men with osteoporosis? Joint Bone Spine. 2013;80:459-465.

10. Tsujimura A. The relationship between testosterone deficiency and men’s health. World J Mens Health. 2013;31(2):126-135. 11. Isidori AM, Giannetta E, Gianfrilli D, et

al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol. 2005;63(4):381-394. 12. Bolona ER, Uraga MV, Haddad RM, et

al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):20-28. 13. Zarrouf FA, Artz S, Griffith J, Sirbu C,

Kommor M. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract. 2009;15(4):289-305. 14. Orengo CA, Fullerton L, and Kunik ME.

Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriatr Psychiatry Neurol. 2005;18(1):20-24. 15. Thilers PP, MacDonald SWS, Herlitz A. The

association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-old-men and woyear-old-men. Psychoneuroendocrinology. 2006;31(5):565-576.

Men with significant erythrocytosis, severe untreated sleep apnea, prostate cancer, or high risk of cardiovascular event should avoid TRT. In many scenarios, the benefits of TRT on muscle mass, strength, BMD, sexual function, mood, and overall well-being may outweigh the risks, but careful consideration must be taken with each patient. Response to testosterone replacement should be assessed, and if there is no improvement of symptoms, TRT should be

discontinued and further investigation into other causes conducted.

Many questions regarding the treatment of hypogonadism remain to be answered. The long-term benefits and risks of testosterone replacement will become clearer as the effects of testosterone replacement on all health-related outcomes are studied over an extended period of time. HW


1. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660-1665.

2. Bassil N, Alkaade S, Morley J. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5:427-448. 3. Killick R, Wang D, Hoyos CM, et al. The

effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomized, placebo-controlled trial. J Sleep Res. 2013;22:331-336.

4. Volterrani M, Rosano G, Iellamo F. Testosterone and heart failure. Endocrine. 2012;42:272-277. 5. Snyder PJ, Peachey H, Hannoush P, Berlin

JA, Loh L, Lenrow DA. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:2647-2653. 6. Lui PY, Baker HW, Jayadev V, Zacharin M,

Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotrophin treatment of gonadotrophin-deficient infertile men: predictors of fertility outcomes. J Clin Endocrinol. 2009;94:801-808. 7. Morley JE, Kaiser FE, Perry HM, et al.

Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46(4):410-413.

8. Liu H, Paige NM, Goldzweig CL, et al. Screening for osteoporosis in the men: a systematic review for an American College of Physicians guideline. Ann Intern Med. 2008;148(9):685-701. small, nonsignificant, and inconsistent

improvements in erectile function and sexual satisfaction were observed.12


Depression is more commonly found in the aging hypogonadal man. TRT has been associated with improved mood and overall sense of well-being. A meta-analysis showed some beneficial effects of TRT on depression scores.13

However, this has not been consistently shown across all trials. The usage of testosterone replacement as an antidepressant for the general population is not recommended. Concomitant usage of testosterone replacement and serotonin reuptake inhibitors has been shown to be beneficial in hypogonadal men.14 Additional studies will be

required to assess the role of TRT in the depressed hypogonadal male.

Cognitive function

As men age, many changes occur in their cognitive abilities. Declining cognitive ability occurs due to a number of comorbidities, such as vascular disease and neurological pathology. Hypogonadism appears to be one of the causes. Lower levels of testosterone appear to have an effect on abilities, such as spatial abilities, verbal abilities, and cognitive function.15 Many of the studies

that have shown a benefit to cognitive function with testosterone replacement have been smaller in sample size and short in duration. This makes the long-term effects difficult to predict. Studies of longer duration and larger sample sizes are needed to confirm the benefits of TRT on cognitive performance.

Final notes

The incidence of male hypogonadism is rapidly increasing, and more treatment options are available than ever before. These rapid changes have increased awareness of the condition, and revealed the complex nuances of the management, of hypogonadism. Before initiating treatment, the risks and benefits of testosterone therapy must be clearly discussed with the patient while assessing for other comorbidities in which TRT may be dangerous.

About the Authors

Samuel Deem, DO, is a graduate of the West Virginia School of Osteopathic Medicine in Lewisburg, West Virginia. Dr Deem completed his surgical residency at Pinnacle Health in Harrisburg, Pennsylvania, followed by urology residency at Charleston Area Medical Center in Charleston, West Virginia. He then completed a urologic oncology fellowship at the Medical University of South Carolina before starting practice at Charleston Area Medical Center in 2011. He focuses his practice on genitourinary oncology and general treatment of men’s urologic health. He can be reached at Samuel.Deem@camc.org.

Nathan Hale, DO, graduated with his bachelor’s degree in biochemistry from the Brigham Young University Hawaii and his master’s degree in human nutrition from Columbia University. He graduated from the Arizona College of Osteopathic Medicine in 2010 and is currently a fourth-year resident in urologic surgery at Charleston Area Medical Center. His current research interest is the effects of metabolic syndrome on various urologic conditions. Dr Hale can be reached at natehalesletters@gmail.com.


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