Androgen Replacement

[Michael Scally MD]

Morgentaler A. Controversies and Advances with Testosterone Therapy: A 40-Year Perspective. Urology. https://www.sciencedirect.com/science/article/pii/S0090429515011061

Testosterone therapy (TTh) has become highly controversial.

Yet there are important health consequences of testosterone deficiency, and meaningful benefits with treatment.

There is level 1 evidence that TTh improves sexual function and desire, body composition, and bone density.

Concerns regarding cardiovascular risk were based on two deeply flawed retrospective studies, and are contradicted by dozens of studies showing CV benefits of TTh or higher endogenous testosterone, including placebo-controlled studies in men with known heart disease (angina, heart failure).

Prostate cancer should no longer be considered a risk of TTh.

Testosterone is neither scourge nor panacea- it is just good medicine.

 

[Michael Scally MD]

[Yes] Testosterone is Protective Against Cardiac Disease
[For Full-Text Email mike.scally@asih.net (Include Title)]

FOR decades the main concern associated with testosterone therapy (TTh) has been the potential associated risk of prostate cancer.

However, in the last several years the paradigm has shifted and potential associated cardiovascular (CV) risks have now taken center stage.

These cardiovascular concerns were spawned by an initial study in 2010 and 3 subsequent studies in 2013 and 2014.

Despite the significant limitations associated with these 4 reports, the FDA (U.S. Food and Drug Administration) issued a warning in 2015 about the potential increased risk of CV events with the use of all testosterone products.

This warning led to a significant increase in litigation, television advertisements by trial lawyers and increased fear among patients on TTh.

What is ironic is that there are more compelling data to support that TTh may not only be safe, but actually protective of cardiac health.

Khera M. Testosterone is Protective Against Cardiac Disease. J Urol. https://www.sciencedirect.com/science/article/pii/S0022534716001245


[No] Testosterone is Protective Against Cardiac Disease
[For Full-Text Email mike.scally@asih.net (Include Title)]

In short, evidence to determine short and longterm cardiovascular risk or benefit with TR does not currently exist.

Published prospective trials were neither powered nor designed to examine cardiac risk end points.

Whether some subpopulations of hypogonadal men have higher CV risk (? elderly and frail) or lower CV risk (? high cardiac risk) with TR remains to be determined.

Results of a T intervention trial specifically designed to assess cardiac risk (not benefit) are expected soon.

Kohler TS. Testosterone is Protective Against Cardiac Disease. J Urol. https://www.sciencedirect.com/science/article/pii/S0022534716001257

 

[Dr JIM]

I thought this WAS and IS a major part of the problem!

 

[Michael Scally MD]

Al-Khazaali A, Arora R, Muttar S. Controversial Effects of Exogenous Testosterone on Cardiovascular Diseases. Am J Ther. Controversial Effects of Exogenous Testosterone on Cardiovas... : American Journal of Therapeutics

The use of testosterone (T) among men aged 40 years or older was increased more than 3 times from 0.81% in 2001 to 2.91% in 2011. Until recently, the majority of the studies did not show any increased cardiovascular (CV) risk by using T in male patients with hypogonadism. What is more, some studies had observed a protective effect of using T against CV diseases. However, in 2010, a randomized clinical trial (RCT) was intended to study the advantage of T gel in older men with limitations in mobility; the study was stopped due to unexpected high prevalence of CV adverse outcome. These findings were confirmed by 2 other studies published in November of 2013 and January of 2014. Consequently, the Food and Drug Administration (FDA) had announced in January 2014 that it will reassess the safety of those treatments. Meanwhile, the agency had not reached to a definitive conclusion that FDA-approved testosterone therapy raises the risk of stroke, heart attack, or death. A report released in the broadcast of the NBC Nightly News in September of this year that the FDA says "there's little evidence that T boosting drugs taken by millions of American men are actually effective." NBC notes that the agency also pointed out that it was not convinced that they carry serious risk either. "The condition has been marketed as low 'T', and the medications are offered to help with low sex drive and fatigue among some men," notes NBC. The European Medicines Agency EMA's Pharmacovigilance Risk Assessment Committee has also responded to the concern of potential CV adverse outcomes associated with the use of T, and they have concluded in their October meeting of this year that the use of T in men who do not produce enough T raises the risk of heart diseases. In our review, we highlighted the association between exogenous T and major adverse CV outcomes. Additionally, we focused on the interplay between exogenous T and some endocrine abnormalities such as diabetes mellitus type 2, metabolic syndrome, dyslipidemia, and obesity.

 

[Michael Scally MD]

How To Define Hypogonadism? Results From A Population Of Men Consulting For Sexual Dysfunction
https://www1.essm-congress.org/guest/AbstractView?ABSID=9911 (Abstract View)

Objective - The thresholds for testosterone (T) and the symptoms required for defining late onset hypogonadism (LOH) are under debate.

The aims of the study are:
i) to verify the association between total and calculated free T (cfT) and sexual symptoms and
ii) to identify thresholds for total and calculated free T to discriminate symptomatic from asymptomatic men.

Methods - A consecutive series of 4,890 men attending the Outpatient Clinic for sexual dysfunction was retrospectively studied. Biochemical parameters were collected. The relationships between symptoms and total or calculated free T were evaluated as LOESS curves.

Results - Severe impairment in morning erections, low libido and ED were reported by 14.6%, 2.7% and 60.2%, respectively. Simultaneous presence of severe ED and impaired morning erections or low desire were reported by 12.7% and 1.9%, respectively. Severely reduced desire and morning erections were complained of by 1.0%. The simultaneous presence of the three severe sexual symptoms was reported by 0.8%.

Receiver Operating Curve (ROC) analysis showed that the highest accuracy for total T and cfT in detecting subjects with two symptoms was observed for reduced morning erections and desire (area under the ROC curve [AUC]=0.670±0.04 and 0.747±0.04, for total T and cfT respectively, both p<0.0001). The addition of the third symptom, ED, further improved the accuracy (AUC=0.681±0.05 and 0.784±0.04, for total T and cfT respectively, both p<0.0001).

The assessment of the Youden index showed that the best thresholds for detecting men with androgen deficiency-related symptoms are 10.4 nmol/L for total T and ranges 225-260 pmol/L for cfT.

Conclusion - The simultaneous presence of reduced morning erections and desire is the cluster of symptoms that, along with total T<10.4 nmol/L or cfT<225 pmol/L, defines LOH in a specific, evidence-based manner.

 

[Dr JIM]

One important variable is missing in this study; a reversal of symptoms in response to therapy.

 

[Michael Scally MD]

Editorial Comment – Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism

This comprehensive review reaffirms and refutes several important issues outlined in the 2010 endocrine guidelines, which deal with male hypogonadism and testosterone replacement therapy (TRT).

Reevaluation of the 2010 endocrine guidelines shows that severe lower urinary tract symptoms and obstructive sleep apnea may not be contraindications to TRT.

Furthermore, reevaluation of the 2010 guidelines confirms that TRT is contraindicated in men with prostate cancer and that TRT does not cause cardiovascular disease.

This latter point seems to refute the Food and Drug Administration position regarding a relationship between TRT and cardiovascular safety.

These data may continue to help guide the clinician who treats the male patient with hypogonadism.

Seftel AD. Re: Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. J Urol 2016;195(2):441. Re: Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis

 

[Michael Scally MD]

Editorial Comment - Screening and Monitoring in Men Prescribed Testosterone Therapy

These and similar data provided the impetus for the Food and Drug Administration (FDA) to reexamine the field of testosterone replacement therapy (TRT).

These data suggested that many patients did not receive a proper evaluation before or after TRT. Thus, the FDA convened an advisory committee meeting in September 2014 to discuss TRT.

The committee concluded that the available evidence supported an indication for TRT only in men with classic hypogonadism, and that drug labels should describe the efficacy and safety of testosterone products.

Subsequently there has been a change to the TRT product label, which includes the addition of cardiovascular safety issues and the indication to use TRT in men with classic hypogonadism.

As demonstrated by several current publications, the FDA changes to the product label have come under scrutiny.

Seftel AD. Re: Screening and Monitoring in Men Prescribed Testosterone Therapy in the U.S., 2001-2010. J Urol 2016;195(2):440-3. https://www.sciencedirect.com/science/article/pii/S0022534715051253

 

[Michael Scally MD]

Editorial Comment – Association of Testosterone and Cardiovascular Risk

The American Association of Clinical Endocrinologists and the American College of Endocrinology jointly undertook a review of the literature on testosterone replacement therapy.

They concluded that there is no compelling evidence that testosterone therapy either increases or decreases cardiovascular risk.

This is another study that seems to refute the Food and Drug Administration position.

Seftel AD. Re: American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of Testosterone and Cardiovascular Risk. J Urol 2016;195(2):442. Re: American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of Testosterone and Cardiovascular Risk

 

[Michael Scally MD]

Lowenstein L, Shechter A, Porst H, Tripodi F, Reisman Y. Physicians' attitudes towards androgen replacement therapy for male and female sexual dysfunction. Int J Impot Res. http://www.nature.com/ijir/journal/vaop/ncurrent/full/ijir20162a.html

Androgen deficiency syndrome is a commonly diagnosed condition. The aim of this study was to investigate common clinical practices of specialists in the field of sexual medicine regarding androgen replacement treatment for men and women.

Attendees of the 16th Annual Congress of the European Society of Sexual Medicine held in January 2014 in Istanbul, Turkey, were asked to participate in a survey during the congress days. A 24-item self-report, closed-question questionnaire was distributed.

Three sections were accessed:
sociodemographic data,
professional background and
personal practice patterns regarding androgen substitution in men and women.

A total of 133 physicians (mean age 47 years; range 25-79) completed the survey.

Responses were inconsistent regarding the lab tests used for primary evaluation of male androgen deficiency. The majority of participants (62%) recommended testosterone replacement therapy for symptomatic men with testosterone levels <8 nmol l-1 (231 ng dl-1). Similarly, most physicians (88%) recognized a correlation between libido and testosterone levels in women. Only 42% and 53% reported they would prescribe testosterone to women with low libido, premenopausal and postmenopausal, respectively.

This survey showed discrepancies among physicians regarding testosterone replacement therapy for men and women.

 

[Michael Scally MD]

Zhao JV, Lam TH, Jiang C, et al. A Mendelian randomization study of testosterone and cognition in men. Sci Rep 2016;6:21306. A Mendelian randomization study of testosterone and cognition in men : Scientific Reports

Testosterone replacement for older men is increasingly common, with some observations suggesting a protective effect on cognitive function. We examined the association of endogenous testosterone with cognitive function among older men in a Mendelian randomization study using a separate-sample instrumental variable (SSIV) analysis estimator to minimize confounding and reverse causality.

A genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). The association of genetically predicted testosterone with delayed 10-word recall score and Mini-Mental State Examination (MMSE) score was assessed at baseline and follow-up using generalized estimating equation among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study.

Predicted testosterone was not associated with delayed 10-word recall score (-0.02 per nmol/L testosterone, 95% confidence interval (CI) -0.06-0.02) or MMSE score (0.06, 95% CI -0.002-0.12). These estimates were similar after additional adjustment for age, education, smoking, use of alcohol, body mass index and the Framingham score.

Our findings do not corroborate observed protective effects of testosterone on cognitive function among older men.

 

[Michael Scally MD]

Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon caused by accumulating disease-burden?

AIM: To summarize the available evidence supporting the link between late onset hypogonadism (LOH) and associated common clinical illnesses, focusing on metabolic diseases. The possible benefits or risks related to testosterone replacement therapy (TRT) in these conditions will also be analyzed.

METHODS: An extensive Medline search was performed.

RESULTS: LOH is closely associated with a worse metabolic profile and a higher cardiovascular risk. The relationship between hypogonadism obesity and insulin resistance is complex and bidirectional. Emerging evidence suggests a positive role of TRT in improving body composition and metabolic outcomes in subjects with LOH.

CONCLUSION: Despite the aforementioned data, it is not completely known whether reduced testosterone levels in elderly males might play a direct pathogenetic role in these conditions or whether low T and associated morbidities are concomitant conditions, both associated with the aging process. Further and longer studies are advisable to confirm the preliminary results.

Corona G, Maseroli E, Rastrelli G, et al. Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon caused by accumulating disease-burden? Focusing on metabolic diseases. Minerva Endocrinol. Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon caused by accumulating disease-burden? Focusing on metabolic diseases - Minerva Endocrinol 2016 Feb 17 - Minerva Medica - Journals

 

[Michael Scally MD]

Mascarenhas A, Khan S, Sayal R, Knowles S, Gomes T, Moore JE. Factors that may be influencing the rise in prescription testosterone replacement therapy in adult men: a qualitative study. Aging Male. An Error Occurred Setting Your User Cookie

OBJECTIVE: To explore and describe the factors that may be influencing the rise of prescribing and use of testosterone replacement therapy (TRT) in adult men.

DESIGN: A rapid qualitative research design using semi-structured interviews with providers and patients.

SETTING: Ontario, Canada.

PARTICIPANTS: Nine men who have used TRT (referred to as "patients"), and six primary care clinicians and seven specialists (collectively referred to as "providers") who prescribed or administered TRT.

METHOD: Patients' and providers' perspectives were investigated through semi-structured interviews. A purposive sampling approach was used to recruit all participants. We conducted qualitative analysis using the framework approach for applied health research.

MAIN FINDINGS: Participants perceived the following factors to have influenced TRT prescriptions and use in adult men: provider factors (diagnostic ambiguity of age-related hypogonadism and beliefs about appropriateness of TRT) and patient factors (access to information on TRT and drug seeking behavior). They perceived that these factors have perpetuated a rise in prescription in the absence of clear clinical guidelines and unclear research evidence on the safety and efficacy of TRT.

CONCLUSION: The findings of this study highlight that much work still needs to be done to improve diagnostic accuracy and encourage appropriate TRT prescription in adult men. In addition, both patients and providers need more information about the risks and long-term effects of TRT in men.

 

[Michael Scally MD]

Albert SG, Morley JE. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a Systematic Review. Clin Endocrinol (Oxf). Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a Systematic Review - Albert - 2016 - Clinical Endocrinology - Wiley Online Library

BACKGROUND: Although male hypogonadism is associated with increased cardiovascular events (CVE), recent concerns are that testosterone supplementation may increase CVE. The purpose was to determine associations with age, initiation or mode of therapy to explain these discrepancies.

DATA SYNTHESIS: Meta-analyses were supplemented through SCOPUS and Pub Med with search terms "testosterone", "random", and "trial". CVE, defined before data extraction, were: death, myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, coronary bypass, syncope, arrhythmia, hospital admission for congestive heart failure, or cerebrovascular event.

RESULTS: There were 45 trials with 5328 subjects evaluated, with a mean age of 63.3 (SD +/-7.9) years, followed for mean study duration of 10.6 (+/- 8.6) months. Overall, testosterone supplementation was not associated with increased CVE risk ratio, (rr) =1.10 (95% CI 0.86; 1.41, p=0.45).

However there was an increase event rate during the first 12 months, rr=1.79 (1.13;2.83, p=0.012), predominantly in those >/=65 years, rr= 2.90(1.35;6.21, p=0.006). Within studies with lipid data, CVE were associated with fall in HDL, p=0.002.

Intramuscular testosterone appeared neutral for CVE, rr=0.96(0.462;1.98,p=0.91) compared with oral testosterone(rr=2.28(95%CI 2.28;8.59, p=0.22) and transdermal testosterone, rr=2.80 (1.38;5.68,p=0.004). Intramuscular testosterone had the least effect of lowering HDL and non-HDL cholesterol (both p<0.001).

CONCLUSIONS: Testosterone supplementation may be associated with increased CVE in those >/=65 years especially during the first year. Biological actions may differ depending upon mode of testosterone administration with intramuscular testosterone having less cardiovascular risk.

 

[Michael Scally MD]

Testosterone Therapy in Men with Testosterone Deficiency: Are the Benefits and Cardiovascular Risks Real or Imagined?

In the adult male testosterone (T) deficiency (TD) is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects.

A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure and improvements in sexual function. T therapy is associated with amelioration of diabetes and reduced mortality.

However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials and meta-analyses, all revealed no increase in CV risks in men receiving T therapy.

In this review, the benefits of T therapy in men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health.

Traish AM. Testosterone Therapy in Men with Testosterone Deficiency: Are the Benefits and Cardiovascular Risks Real or Imagined? Am J Physiol Regul Integr Comp Physiol. http://ajpregu.physiology.org/content/early/2016/07/22/ajpregu.00174.2016 (Testosterone Therapy in Men with Testosterone Deficiency: Are the Benefits and Cardiovascular Risks Real or Imagined? | Regulatory, Integrative and Comparative Physiology)

 

[Michael Scally MD]

[Researchers say there are no benefits of testosterone treatments for men Researchers say there are no benefits of testosterone treatments for men]

Huo S, Scialli AR, McGarvey S, et al. Treatment of Men for “Low Testosterone”: A Systematic Review. PLoS ONE 2016;11(9):e0162480. Treatment of Men for “Low Testosterone”: A Systematic Review

Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition.

We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables.

Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo.

Testosterone is ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido.

Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function.

Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood.

The prescription of testosterone supplementation for low-T for cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized clinical trials.

 

[Dr JIM]

There's A LOT of truth to the authors conclusions esp when a studies design does not exclude
emotional disorders as an indication for "TRT".

 

[Michael Scally MD]

[No] Cardiovascular Risks of Exogenous Testosterone Use

Purpose - We sought to evaluate whether exogenous testosterone therapy is associated with increased risk of serious cardiovascular events as compared to other treatments or placebo.

Methods - Study selection included randomized controlled trials (RCTs) and observational studies which enrolled men aged 18 years or older receiving exogenous testosterone for three or more days were included. The primary outcomes were death due to all causes, myocardial infarction and stroke. Secondary outcomes were other hard clinical outcomes such as heart failure, arrhythmia and cardiac procedures.

Peto Odds ratio was used to pool data from RCTs. Risk of bias was assessed using Cochrane Collaboration tool and Newcastle and Ottawa scale respectively. The strength of evidence was evaluated using the Grades of Recommendation, Assessment, Development and Evaluation Working Group approach.

Results - A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared to placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (OR 0.87, 95% CI 0.39-1.93, 16 RCTs), stroke (OR 2.17, CI 0.63-7.54, 9 RCTs) or mortality (OR 0.88, CI 0.55-1.41, 20 RCTs). Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision and inconsistency

Conclusions - We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone.

Alexander GC, Iyer G, Lucas E, Lin D, Singh S. Cardiovascular risks of exogenous testosterone use among men: A systematic review and meta-analysis. The American Journal of Medicine. http://www.amjmed.com/article/S0002-9343(16)31024-5/abstract

 

[Michael Scally MD]

Maggi M, Wu FCW, Jones TH, et al. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME). International Journal of Clinical Practice 2016;70(10):843-52. Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME) - Maggi - 2016 - International Journal of Clinical Practice - Wiley Online Library

Aims: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG).

Methods: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2–3 years. Independent adjudication was performed on all mortalities and CV outcomes.

Results: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time.

A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related.

The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events.

Conclusions: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry.

 

[Michael Scally MD]

Cassimatis DC, Crim MT, Wenger NK. Low Testosterone in Men with Cardiovascular Disease or Risk Factors: To Treat or Not To Treat? Curr Treat Options Cardio Med. 2016;18:75. Low Testosterone in Men with Cardiovascular Disease or Risk Factors: To Treat or Not To Treat?

Current evidence supports the use of testosterone replacement in men with the clinical-biochemical syndrome of hypogonadism, defined as low testosterone serum levels and symptoms such as fatigue, exercise intolerance, erectile dysfunction, low libido, or depression.

Although the evidence consistently shows that hypogonadism is associated with elevated cardiovascular risk, evidence is mixed regarding whether testosterone (T) replacement provides cardiovascular (CV) benefit or harm.

For a man with symptomatic hypogonadism in the setting of CV disease, clinical heart failure, and/or traditional CV risk factors (hypertension, diabetes, and hyperlipidemia), a balanced approach would be to counsel him that overall, the evidence should not dissuade him from utilizing T replacement for non-cardiac symptom relief but that more data are needed before a definitive recommendation can be made about T replacement for CV benefit.

THE PREPONDERANCE OF AVAILABLE EVIDENCE, REVIEWED IN THIS ARTICLE, SUGGESTS THAT T REPLACEMENT, AT APPROPRIATE DOSES AND WITH MONITORED RESPONSE, IS LIKELY TO BE SAFE FOR MEN WITH CV DISEASE OR CV RISK FACTORS AND MAY EVEN REDUCE MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE).

The 2015 American Association of Clinical Endocrinologists and American College of Endocrinology position statement supports this stance and calls for improved prospective data.

There is a clear need for a large, prospective randomized trial evaluating the impact of T replacement on MACE, for men both with and without CV disease or CV risk factors.

Clinicians should be aware that all men who elect to take T replacement therapy require regular follow-up with the prescribing physician to include both clinical assessment and surveillance laboratory assessment of total T level, complete blood count, and prostate specific antigen.