Testosterone Therapy in Males with Testosterone Deficiency (TD): Debunking the Myths

Testosterone Therapy in Males with Testosterone Deficiency (TD): Debunking the Myths

Since my last writing, I have continued my studies on female hormones and hormone replacement therapy and I have dug deep into the male literature on testosterone (T) and testosterone therapy (TTh). Similar to my quest to learn everything about female hormones and hormone therapy, the same holds true for testosterone and TTh in males.

In this writing, I am going to share some of what I have learned about T and TTh and provide you with the evidence to support your clinical decision making. This brief review will focus on debunking the myths associated with TTh. I chose this topic because, similar to menopausal hormone therapy (MHT) in females, there are misconceptions regarding TTh in testosterone deficient males (TD-M) that overshadow the evidence.

TD is associated with comorbidities that go beyond sexual symptoms. These include: metabolic syndrome, obesity, diabetes, hypertension, dyslipidemia, etc. Studies have documented increased mortality, greater atherosclerosis and coronary artery disease incidence, and increased low-trauma fracture rates.[i]^{,[ii],[iii],[iv]}

The evidence has consistently documented that TTh improves body composition, sexual function, bone mineral density, and metabolic parameters. In males with TD, TTh is not recommended to improve cognitive performance, even though low total testosterone (TT) levels are associated with cognitive decline. However, replacing TTh has not convincingly demonstrated cognitive improvement.[v]^{,[vi],[vii],[viii],[ix],[x],[xi],[xii],[xiii],[xiv],[xv],[xvi],[xvii],[xviii],[xix],[xx],[xxi]}

Despite TTh’s benefits, 2 concerns are often raised that may limit testosterone’s use in males who otherwise meet diagnostic criteria for TTh. These myths—TTh increases prostate cancer (PC) and increases cardiovascular disease (CVD)—will be addressed below. Let’s dig in to the data!

Truth: TTh does not cause PC

Since Huggins and Hodges reported in 1941 that castration led to metastatic PC regression and TTh administered to men with PC activates PC growth, the belief for decades had been that TTh causes PC. The evidence indicates that T has a limited ability to stimulate prostate growth with maximum androgen stimulation achieved at low TT concentrations. The saturation point, namely the TT concentration at which androgen binding to the androgen receptor is maximal, is approximately 250ng/dL.^{1-3,[xxii],[xxiii],[xxiv],[xxv],[xxvi]}

The saturation model explains the paradoxical observation that prostate tissue is exquisitely sensitive to changes in serum TT at low concentrations, but becomes indifferent to changes at higher TT concentrations. A threshold effect occurs, in which increasing TT concentrations reach a limit (the saturation point) beyond which there is no further ability to induce androgen-driven changes in prostate tissue growth. See diagram below.^1-3,22-26

²⁵

The saturation model shifted the paradigm away from the Huggins and Hodges’ androgen hypothesis. Despite this, Huggins and Hodges’ findings continue to raise concerns that TTh increases PC risk in males without a PC diagnosis.

This myth has been quashed by the extensive literature concluding that TTh does not increase PC risk.^{1-3,22-26,[xxvii],[xxviii]} In 2004, Rhoden and Morgentaler²⁶ published a comprehensive literature review and did not find compelling evidence that higher endogenous TT levels or TTh was associated with increased PC risk.²⁶

In 2008, Roddam^[xxix] published a frequently-cited collaborative analysis of pooled worldwide data from 18 longitudinal studies. Roddam found no association between PC risk and serum TT or dihydrotestosterone (DHT) concentrations. Males with higher TT levels were found to be at no greater PC risk than males with lower androgen levels. In other words, there is no significant relationship between serum androgens and PC risk.²⁹

In 2012, Muller^[xxx] published data from the REDUCE trial’s placebo arm. REDUCE was a randomized, double-blind, placebo-controlled, parallel-group study. Muller’s often-cited study documented that PC risk is unrelated to serum androgen concentrations. High TT levels do not predispose to PC and low TT levels are not protective.^30,[xxxi]

The importance of Muller’s publication cannot be overemphasized. It lays to rest a false belief that has misinformed medical practice for decades. The truth is: T and TTh do not increase PC risk.

Since Muller’s publication, a large database has accumulated corroborating REDUCE’s placebo results. See appendix A, a table summarizing the often-cited key studies.

Briefly, Loeb[xxxii] and Baillargeon[xxxiii] concluded that TD-M who were treated with TTh and developed PC had more favorable and less aggressive disease. In addition, all the cited studies (Cui,²⁸ Loeb,³² Baillargeon,³³ and Schenk[xxxiv]) found that males with TD, treated with TTh, were at no greater PC risk than untreated males. Confirming these studies, Wallis^[xxxv] found that over a cumulative 5 years, long-term testosterone exposure was associated with a decreased PC risk.³⁵

What about estradiol’s role in PC development? This is beyond the scope of this writing. Estrogens and the prostate have a complicated relationship. Prostatic estrogens are produced by androgen aromatization, either in-situ or peripherally. The prostate has both estrogen receptor alpha (ER-a) and estrogen receptor beta (ER-β). ER-β is the most prevalent estrogen receptor in the human prostate. The prostatic ratio of testosterone to estradiol and abnormal androgen aromatization to estrogens are 2 theories thought to be important for PC development and progression.[xxxvi]^{,[xxxvii],[xxxviii],[xxxix],[xl],[xli]}

Finally, in males on TTh who have an unexpected increase in PSA, don’t stop the TTh; just refer to a urologist.

Truth: There is no convincing evidence that TTh increases CV risk, non-fatal MI, or death

There are no long-term, large, randomized, double-blind, placebo-controlled trials evaluating TTh and cardiovascular outcomes. There is an ongoing large RCT (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy in ResponSE in Hypogonadal Men [TRAVERSE]), which will address TTh and CVD.[xlii] What is promising is that the study has not been stopped early, suggesting the results are encouraging.

Despite no RCTs, a wealth of evidence has accumulated over the past 2 decades concluding: low serum TT levels are associated with increased atherosclerosis risk, CV risk factors, and mortality, and that TTh has beneficial effects on CV risk factors and risk biomarkers. The evidence supports TTh’s CV safety and that TTh may decrease CV events and mortality.[xliii]^,[xliv]

This all changed when 4 studies provided talking points for those who believed that TTh was unnecessary and TD didn’t really exist. Two studies were retrospective analysis (Vigen⁴⁶ and Finkle⁴⁷), 1 was a meta-analysis (Xu⁴⁸), and there was 1 RCT T gel study (Basaria⁴⁵). In 2014, these 4 studies led the FDA to mandate a label change to T products warning against possible MI and stroke. Men’s health experts all over the world have questioned these studies’ validity, accuracy, and credibility. See appendix B, a table summarizing these often-cited flawed studies.

Basaria ^[xlv] published the TOM trial, which was not designed to address adverse CV events. Most of the reported “CV events” were of questionable clinical significance. There were 4 major CV events, all of which occurred in the T-group. Further analysis found that these events occurred in males with higher TT levels (> 1000ng/dL) when prescribed higher than approved T gel doses.⁴⁵

Vigen[xlvi] and Finkle[xlvii] were both retrospective analysis with methodological flaws. Vigen⁴⁶ misrepresented its primary results and included 10% females in an all-male study. Vigen reported higher T-treated male events vs untreated males, when the absolute event rate was only 10.1% in the T-treated group vs. 21.2% in the untreated group.⁴⁶

The Finkle⁴⁷ study had serious data concerns. They compared pre-treatment MI rates with post-prescription MI rates, which measure different things. Further, T-related CV events were low and actually were lower than the expected rates in the general population.⁴⁷

Xu’s^[xlviii] metanalysis involving 27 studies found more CV events in T-treated males vs placebo-treated males. Two studies made up 35% of the cases. One was the TOM trial discussed above. The other was the 1986 Copenhagen study, where oral micronized T was given to males with cirrhosis. When these 2 studies are removed, the adverse CV event rates were similar in the T-treated and placebo groups, with a slightly lower rate in the T-group.⁴⁸

Since the FDA advisory committee meeting in 2014, numerous studies have been published addressing CV risk and TTh. See appendix C, a table summarizing some often-cited studies documenting TTh’s safety and decreased event rates.

TEAAM^[xlix] and the T-Trials^5,[l] assessed surrogate markers, CaC and/or CIMT. These RCT’s documented no increase in either CIMT or CaC. However, these are surrogate markers. What about hard CV outcomes? A number of observational studies documented decreased CV events.

Sharma,[li] Anderson,[lii] Wallis,[liii] and Cheetham[liv] all documented that TTh was associated with decreased MACE rates. Sharma⁵¹ published a retrospective analysis concluding that MI and mortality were significantly decreased in males with TD, treated with TTh and whose serum TT levels normalized (> 500-800ng/dL), when compared to males who either received TTh but had persistently low TT levels or who received no TTh.⁵¹

Anderson⁵² confirmed Sharma’s results. Anderson⁵² reported that in males who achieved normal TT levels, the 3-year MACE and death rates were significantly lower when compared to males with low TT levels (< 212ng/dL). MACE rates were similar for males with higher TT levels and normal TT levels. However, in males with high TT levels (> 742ng/dL) there was a trend towards increased stroke risk. The authors recommended a conservative approach to TTh.⁵²

Wallis⁵³ published a population-based, matched-cohort study assessing the association between cumulative TTh exposure and mortality, CV events, and PC. Wallis documented that the longer the TTh, the greater the mortality risk reduction.⁵³

Cheetham⁵⁴ found that TTh was associated with decreased MACE after a median follow-up of 3.4 years. The hazard ratio for adverse CV events was one-third lower in the T-treated group when compared to the non-treated group.⁵⁴

Conclusion

TTh in males with TD is safe and does not increase PC. There is a TT saturation point (TT ~ 250ng/dL) where there is no further ability to induce androgen-driven changes in prostate tissue growth. Estradiol’s role in PC is complicated. The literature suggests that the prostatic ratio of testosterone to estradiol and aberrant androgen aromatization to estrogens are 2 theories thought to be important for PC development and progression.

The evidence suggesting that TTh increases CV risk is weak and flawed. The International Expert Consensus Conference on Testosterone Deficiency and its Treatment,² along with its 2019 update,[lv] and the American Association of Clinical Endocrinologists[lvi] all conclude: the evidence does not indicate increased CV risk with TTh.

Notwithstanding all the evidence I presented, before prescribing TTh, I would recommend CV risk stratification. In addition, all males being prescribed TTh should be counseled regarding the black-box warning that is on all T prescriptions. I hope I have provided sound evidence to support TTh’s safe use in males and to not hold back necessary T prescriptions because of 4 flawed studies that received a lot of press.