Testosterone Replacement Therapy: The Emperor's New Clothes

Abstract

The mean age of the world population has steadily increased in the last decades, as a result of increased life expectancy and reduced birth rate. Global aging has led to a greater worldwide cost for healthcare: hormonal alterations contribute to the pathogenesis of several conditions and might cause a significant reduction in the perceived sense of well-being. Menopause is archetypal of hormonal alterations occurring during aging: in males, sex hormones do not decrease abruptly, yet testosterone levels decrease steadily and continuously during aging, ultimately resulting in late-onset hypogonadism. Treatment of this condition might mitigate most symptoms; however, testosterone replacement therapy (TRT) should be prescribed only in selected patients and it should not be considered as an antiaging treatment. In recent years, different authors have questioned health risks associated with testosterone treatment; while position statements from many scientific societies seem to be reassuring, the Food and Drug Administration has issued a warning in regard to the possible side effects of this therapy. We aim to review recent controversies and discoveries in regard to TRT.

Introduction

During the last decade, life expectancy has increased, even dramatically in some countries, as a result of the improvements in sanitation, housing, and education¹: an ever-increasing amount of age-related conditions, including cardiovascular (CV) and metabolic diseases,² has led to a similar ever-increasing cost for public health. Addressing these illnesses, or preventing them if feasible, has become one of the most important targets of modern medicine also as a tool for reducing healthcare costs of multimorbidities. Since the end of the 19th century, hormonal replacement has often been in the spotlight as a possible rejuvenation treatment³; while production of many hormones undergoes physiologic changes in the elderly, there is consistent evidence proving that testosterone (T) supplementation might improve some symptoms of aging.

Decline in serum T levels starts as soon as 30 years of age^4
–6 and progresses at a steady rate throughout the rest of one's life: early reports on this topic have measured the yearly decrease in T concentrations between 0.4% and 2%,^7,8 and many recent studies confirm similar trends.^9

–12 This form of testosterone deficiency (TD) is commonly described as late-onset hypogonadism (LOH): not all men experience TD during old age, and signs and symptoms may often vary among those who do.¹³ The annual incidence of hypogonadism is 20% in men in their 60s and 30% in men in their 70s, quoting Seftel.¹⁴ In the European Male Aging Study, the overall prevalence of symptomatic LOH (estimated from at least three sexual symptoms and biochemical evaluation) was 2.1%, ranging from 0.1% for men 40–49 years of age to 5.1% for those 70–79 years.¹⁵

TD is often the results of testicular dysfunction and reduced responsivity from the hypothalamic–pituitary–testicular axis: men who undergo clinical conditions, which might impair either or both (i.e., obesity, orchiectomy, diabetes, testicular radiotherapy, etc.), are usually more prone to develop TD at an earlier stage.¹³

Existing guidelines from several international societies^16

–21 suggest that TD is a “clinical and biochemical syndrome characterized by a deficiency of testosterone or testosterone action, and relevant symptoms and signs” that “may affect the function of multiple organ systems and result in significant detriment in the quality of life, including alterations in sexual function.” There is no agreement in regard to the threshold values for total T,²² although it is generally accepted that a subject with T >12 nmol/L (roughly 350 ng/mL) requires no treatment, whereas one with T <8 nmol/L (roughly 230 ng/mL) might do.

Diagnosis of TD requires careful physical investigation and measurement of serum T from a blood sample to be collected in the morning, as recommended by most international societies. If T is below 12 nmol/L in the first sample, confirmation of the aforementioned result should be obtained by repeating measurement of serum total and free T (either measured by equilibrium dialysis or calculated using the Vermeulen formula, based on sex hormone-binding globulin and albumin), together with luteinizing hormone and prolactin to identify specific forms of TD; bioavailable T, a more robust estimate of the level of bioactive testosterone, can be measured using free online calculators like the one at www.issam.ch/freetesto.htm

However, as reported by Huhtaniemi,²³ the recommendations are often ignored, and correct investigation and follow-up occur only in a small percentage of patients undergoing testosterone replacement therapy (TRT). As said, TD is experienced differently by each patient, and signs and symptoms are often vague and easily mistaken for normal features of aging: reduced sexual desire, loss of muscle strength,²⁴ depressed mood, and erectile dysfunction,²⁵ commonly identified as characteristics of old age, are features of TD, which may be improved by adequate treatment.²⁶

Negative consequences on cognition,²⁷ body mass,²⁸ and sexual function²⁹ have been observed in men undergoing androgen deprivation therapy.

Positive effects of TRT on sexual function,³⁰ glycometabolic profile,³¹ and body composition³² have been clearly described by several meta-analysis studies; injected T seems able to induce more evident improvements in muscle strength³³ and bone mineral density³⁴ compared to transdermal preparations. Recently, disclosed results from the Testosterone Trials³⁵ have shown that treating symptomatic men aged 65 years or older for 1 year to restore T concentration to the mid-normal range for men aged 19–40 years improved sexual function and mood without significant benefits to vitality. Although there was no statistics observed in regard to the rate of CV events between the control and placebo groups, a directional trend for a 33% reduction in CV events with TRT was observed.

Indications and contraindications for TRT—and its implication in rejuvenation medicine—have been widely discussed by Lang et al.³⁶ in 2012: we aim to review recent discoveries and controversies in the field of testosterone supplementation.

Prostate Cancer, Lower Urinary Tract Symptoms, and TRT

Lower urinary tract symptoms (LUTS) are among the most common clinical complaints in adult men, from 8% to 31% during middle age to 27%–44% of men in their 70s,³⁷ and include storage (irritative) symptoms, voiding (obstructive) symptoms, and postmicturition symptoms.³⁸ LUTS influence quality of life, as they can impair daily activities, sleep, and sexual function: prevention and treatment have been among the most extensively studied topics in urologic research in the last decades, and the role of both endogenous and exogenous testosterone on prostate and LUTS has been investigated thoroughly. Prostate growth is affected by androgens, and it is a widely known fact that antiandrogens are used for treatment of prostate cancer; however, as clearly observed by St. Sauver et al.,³⁹ lower T is associated with faster worsening of prostate symptoms. Likewise, benign prostatic hyperplasia (BPH) most frequently occurs in the elderly, who reportedly have lower T levels. LUTS are a multifactorial condition, and therefore, clinicians should not oversimplify the role of T in the pathogenesis of prostate disease⁴⁰; existing guidelines⁴¹ provide no information concerning the effects of TRT on the evolution of LUTS, and yet there seems to be much to be said concerning in this regard.

Hypogonadism can be considered a “feature” of metabolic syndrome,⁴² which in turn can be considered one of the factors involved in the pathogenesis of some prostate symptoms, including BPH.^37,43 Immune response and dysregulation are involved in BPH on multiple stages; even though there is ample room for debate with regard to the precise causes of inflammation, there is convincing evidence that hypogonadism results in a pro-inflammatory state, in which fibroblasts, reactive oxygen species, and vascular growth factor all contribute to the enlargement of the prostate.⁴⁴ As proven by many authors^37,45,46 in different studies, TRT might help in preventing some of the conditions ultimately resulting in BPH, thus providing relief from LUTS. Furthermore, not only BPH and LUTS seem to be improved by undergoing TRT⁴⁷ but also withdrawal from the treatment seems to be associated with worsening of the symptoms.⁴⁸

From a pathophysiological point of view, the issue of TRT in patients with LUTS or prostate cancer is confounding: recent evidence suggests that TRT is not harmful for both conditions, and yet androgens stimulate prostate tissue growth. The key to solve this riddle lies in the androgen receptor: quoting Morgentaler and Traish,⁴⁹ there seems to be a limit to the ability of androgens to stimulate prostate growth—in particular, prostate cancer growth is insensitive to T variations above a certain threshold. The “Saturation model,” as hypothesized by Morgentaler and Traish,⁴⁹ would explain why prostate cancer occurs in the elderly instead of at the age of maximum T concentration—although by no means this should be interpreted as a permit to uncontrolled administration of TRT;⁵⁰ it is, however, likely that TRT might prevent LUTS progression.^44,51 Despite the bulk of evidence from clinical trial showing that TRT does not increase urinary symptoms, it is important to remember that this has been observed in the context of clinical trials: concern still remains that TRT might increase urinary symptoms over a longer period.

An extensive meta-analysis by Cui et al.⁵² from 22 randomized control trials (RCT) investigated the safety of TRT in 2351 patients in regard to prostate cancer: the odds ratio (OR) for several formulations of TRT and different endpoints failed to reach statistical significance, proving that treatment is not associated to a greater risk of prostatic neoplasia. Caution is advised, however, as none of the analyzed studies provided follow-up for more than 36 months. Data from this research agree with previous results from the analysis of 3886 men with prostate cancer and 6438 controls among 18 prospective studies,⁵³ which showed no effect of endogenous sex hormones, including T, on the risk of developing the disease. Calof et al.⁵⁴ in a previous meta-analysis also suggested that no statistically significant difference was observed in the incidence of prostate cancer between subjects undergoing TRT and controls; furthermore, the increase in prostate-specific antigen (PSA) levels, which is often triggered by TRT, leads to more frequent biopsies, thus increasing the rate of prostate cancer discovery without actually increasing the incidence of the disease.

Treatment with T in patients with a diagnosis of prostate cancer is somewhat controversial: recommendations suggest against treating these men, but in recent studies, no increase in the rate of recurrence following prostatectomy⁵⁵ and brachytherapy⁵⁶ was observed among patients undergoing TRT. However, a significant increase in PSA levels—a sign of biochemical progression–occurred in treated patients, thus making a definite conclusion in this regard hard to reach.^55,57

TRT and CV Issues

During the last decade, the number of published articles recognizing positive effects of TRT has steadily increased: evidence that lower T levels are associated with increased risk of atherosclerosis^58,59 and that TRT has beneficial effects on several CV outcomes^60
–62 has emerged, opening the path for further research. However, TRT has become astonishingly controversial^63

–66: three studies^67
–69 and one meta-analysis⁷⁰ published between 2010 and 2014 stand out among the plethora of studies involving TRT, as the authors described increased risk of CV events among patients undergoing androgen supplementation. However, these four articles have been highly criticized for the number of critical methodological shortcomings,^16,65,66,71 and many international societies have asked for withdrawal of some of the cited articles based on their unreliability. The requests from researchers worldwide were not able to prevent the enormous media coverage of these four articles; as a result, lawsuits for hypothesized side effects of TRT have increased, physicians are less prone to prescribe TRT, and therefore, symptoms of TD remain largely unnoticed and untreated.

The first study, a RCT published by Basaria et al. in 2010,⁶⁹ investigated the effects of TRT on muscular and functional responses in men aged ≥65 years with total T between 100 and 350 ng/mL or free T <50 pg/mL who were randomly assigned to placebo gel or T gel. The study was interrupted before its intended conclusion as the rate of CV events in the treatment group greatly exceeded the control group; however, previous CV health of the recruited subjects was not adequately taken into consideration and evaluation of CV events was not among the study outcomes. Furthermore, a supraphysiological dose of T was administered to the patients (100 mg/day of T gel, later titrated to 50–150 mg/day), and the authors reported minor events of little clinical significance—premature ventricular contractions, pedal edema, and palpitations—among reasons for suspending the study. The authors themselves concluded that “the lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone⁶⁹”; however, the study resulted in public outcry and has been frequently cited as evidence for the negative CV consequences of TRT.

In 2013, Xu et al. published a systematic review and meta-analysis⁷⁰ of 27 RCT reporting CV events following TRT, including the aforementioned study by Basaria et al.⁶⁹ The meta-analysis of the data showed significant effects of TRT on CV events, with a minor number of events reported in trials funded by pharmaceutical industry: these statements, as predictable, worsened the climate of “antiandrogenism,” which had just begun. However, it should be pointed out that the study by Xu et al. ignored trials, in which no CV events were reported, thus increasing the weight of the remaining studies; furthermore, Basaria's study was the only outlier among the referenced articles with a significant OR in regard to CV events,⁷² and in consideration of its reported shortcomings, many authors have doubted its reliability.⁷³ It is worth mentioning that more recent meta-analysis studies by Borst et al.⁷⁴ and by Corona et al.⁷⁵ have found no causal role between TRT and CV events, proving that a definite conclusion in regard to the safety of TRT is still missing.

The third article, a retrospective study by Vigen et al. published in 2013,⁶⁸ aimed at investigating all-cause mortality, myocardial infarction (MI), and ischemic stroke in men with T <300 ng/dL who underwent coronary angiography in the Veterans Affairs system between 2005 and 2011. The authors used a complex statistical model, including over 50 variables, which resulted in a significantly increased number of CV events in patients who had received a T prescription compared to controls, and excluded from their research over 1130 men who had suffered major CV events (stroke and MI) before receiving a prescription.^76,77 Raw data seemed to prove that the risk for untreated subjects was in fact twice as high as treated men. The article has been corrected twice after its publication, casting doubt on reliability of the submitted data⁷³: results from Vigen's study would have been reversed by proper statistical evaluation^76,77 and many international scientific societies have, therefore, requested retraction of the article.

The fourth and last article, by Finkle et al.,⁶⁷ was a retrospective analysis of insurance claim data in 55,593 men with information only in regard to diagnosis codes, procedure codes, and prescription data. Rate of MI was increased within 30 days after filling a TRT prescription compared with the previous 12 months: however, the lack of a control group, the missing information in regard to confounding factors (obesity, diabetes, smoking habit…) and, most importantly, the absence of a precise diagnosis of hypogonadism^66,78,79 and of pre- and posttreatment T levels⁸⁰ all contribute to the unreliability of this research.

Based on these studies and their resulting public outcry, in 2015, the FDA issued a warning for TRT, suggesting that it should be prescribed only in cases of confirmed low T levels and only in “men with disorders of the testicles, pituitary gland, or brain that cause hypogonadism,” to avoid “attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging.” However, as stated by the American Association of Clinical Endocrinologists and the American College of Endocrinology in their conjoined position statement,⁷⁸ the suggestion that TRT should be considered only in a limited percentage of hypogonadal men, furthermore, with no clear indications in regard to “aging,” is unsatisfactory to say the least.

Lower levels of T are a marker of poor general health⁸¹: hypogonadal men are reportedly^81
–83 more prone to CV events, and yet there seems to be no definite evidence on the effects of TRT in this regard. Even though most studies report benefits from it, TRT should not be recommended as a therapy for heart disease,^84,85 and it is worth remembering that patients undergoing TRT should be closely monitored for known adverse effects, including increase in hematocrit—a risk factor for CV events on its own—and sleep apneas.

Conclusions

Is testosterone a friend or a foe? For the last 65 years, clinicians worldwide have suggested against using TRT in fear of the possible effects on prostate enlargement, and yet new evidence has pointed in another direction, suggesting that T might be beneficial for treatment of LUTS and BPH. However, even if new hypotheses start to line up, there is still much to understand with regard to the role of TRT in different conditions, including prostate cancer. Sadly, the costs of a large RCT aimed to assess the real effect and safety of TRT on LUTS in hypogonadal men remain prohibitive^37,86; meta-analysis studies focusing on this topic might solve the pending issues.

CV health in hypogonadal men is under close scrutiny; while most studies have shown an association between TRT and improvement in several parameters of CV health, including endothelial dysfunction, atherosclerosis, and metabolic syndrome, there is still room for debate. The recently issued FDA warning hangs like the sword of Damocles over the head of any endocrinologist: once again, until any doubt is ruled out by specific meta-analysis studies, prescription of TRT requires careful individual evaluation of coexisting comorbidities.

In the words of Morgentaler,⁶⁶ testosterone is neither a scourge nor a panacea, but only good medicine—and as such, it would be silly both to refuse to acknowledge its usefulness on the basis of unjustified fears and to prescribe it to every aging man in hope to provide an “elixir of youth.” Hypogonadal men might find some improvement in the symptoms of old age,^87,88 but there is no evidence to date neither that the benefits of unnecessary TRT outweigh the risks in eugonadal men nor that its safety in hypogonadal men should be doubted based on actual evidence.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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