The March 2014 issue of EndoScan addressed some of the then-current controversies regarding testosterone (T) supplementation, and reviewed relevant publications. In the interim 2 years, media reports have continued to abound regarding the putative benefits and risks of T supplementation. Some uncertainty may stem from the unclear normal range in older men, and an ongoing debate regarding whether testosterone decline with age is pathologic or simply physiologic. New research has shed light on a few of the issues, while other questions remain unanswered. There is no clear consensus on the impact of testosterone replacement on cardiovascular health, nor, given some of the results we review here, even the role of testosterone replacement in restoring libido and erectile function.
In this EndoScan, we review baseline and existing long-term results of the anticipated Testosterone Trials (TTrials) and Testosterone's Effects on Atherosclerosis Progression in Aging Men (TEAAM) trial, other recent research on the impact of T use on sexual function and cardiovascular risk, and options for treatment of hypogonadal men desiring fertility. An overview of the hypothalamic-pituitary-gonadal axis, and why testosterone use itself is not appropriate if fertility is actively sought, is included at the bottom of this page.
The U.S. Food and Drug Administration (FDA) issued a statement in March 2015 advocating that testosterone treatment be limited to particular etiologies of hypogonadism, and noting a potential cardiovascular risk.1 In part in response to this, the American Association of Clinical Endocrinologists (AACE) published a position statement advocating consideration of testosterone treatment in symptomatic men with low testosterone regardless of etiology, and stating that there is insufficient data to establish cardiovascular risk.2 There is an ongoing one-year randomized clinical TTrial focusing on cardiovascular markers in older men with hypogonadism; the TTrials are a multicenter randomized clinical effort to investigate effects of T replacement in men >65 years old.
The Testosterone in Older Men with Mobility Limitations (TOM) trial by Basaria and colleagues noted a higher rate of cardiovascular adverse events in men on testosterone group (23 subjects on testosterone gel vs 5 subjects on placebo, out of 209 men ≥65 years of age with baseline T 100-350 ng/dL; average age 74 years), leading to early termination of the study in 2010.4 The reports of adverse cardiac events in two retrospective observational studies (Vigen et al, 2013; Finkle et al, 2013) spurred by early termination of the TOM trial are profiled in our 2014 EndoScan.
We review here a more recent study by Basaria and colleagues, which found no significant relationship between testosterone use and markers of subclinical atherosclerotic progress. In their randomized, double-blind, placebo-controlled TEAAM trial, Basaria and colleagues studied the effect of testosterone use in 308 men >60 years old (mean age, 67.6 years) over a 3 year period. Using carotid artery intima-media thickness or coronary artery calcium as markers, they found no significant association between testosterone and progression of subclinical atherosclerosis. In contrast to previous studies,3-5 they also found no difference in measures of sexual function and health-related quality of life. This may relate to the trial size, or the inclusion of men with baseline testosterone levels within the lower normal range (ie, not hypogonadal). They also reported a lack of change in ejaculatory function. This parallels results reported by Paduch and colleagues in their phase 2 randomized placebo-controlled trial of testosterone replacement in hypogonadal younger men.
A different cardiovascular question was investigated by Layton and colleagues. They examined whether the preparation of testosterone used (gel, patch, or injection) is related to increased cardiovascular risk, in a retrospective observational study of claims and medical records. They found that all preparations of testosterone (injection, patch, or gel) were associated with some increase in the cardiovascular events studied, with the greatest relative risk in men using an injected preparation of testosterone.
Neither database study had baseline testosterone level information to establish that participants had hypogonadism. The effects of testosterone replacement in hypogonadism may differ from those of testosterone use in men without definitive hypogonadism. The results must be interpreted within this context: the Layton study results suggest the relative risk of different preparations, but should not be used to infer the risk of T therapy overall.
A Medicare–based observational study by Baillargeon and colleagues' reported that there was no increase in myocardial infarction in men >66 years of age with ≥1 intramuscular testosterone injection(s) during the study period of January 1997-December 2005, compared to a matched non-user cohort. This study has a number of limitations, including the absence of data regarding use of other medications (including other forms of testosterone), and, notably, the lack of information regarding baseline testosterone levels or presence of hypogonadism.6
The completed cardiovascular health TTrial may further elucidate the impact of testosterone replacement in older men with definitive hypogonadism.
We review baseline data from the Sexual Function, Vitality, and Physical Function TTrials, in which Cunningham and colleagues report a relationship between baseline testosterone levels and sexual desire, sexual activity, and erectile function, but not physical function or vitality. They did not find a relationship between baseline estradiol levels and sexual function measurements. These results seem at odds with the work of Finklestein and colleagues , but this discrepancy may be due to differences in study design and cohort: Cunningham and colleagues report on baseline data on men 65 years and older, Finkelstein and colleagues studied the effects of different T and E2 (estradiol) levels in men ages 20-50 years, and it may well be that threshold hormone levels at which symptoms occur differ by age.
The one-year results of the Sexual Function, Vitality, and Physical Function TTrials (Snyder et al), reported that testosterone replacement was associated with improvements in sexual desire and activity, erectile function, and to a lesser degree in mood, but not in vitality (no lessening of fatigue) or walking distance. While no increase in cardiovascular events was noted, the study was not powered to address risks. There is a TTrial focusing on cardiovascular health in older men which is ongoing. The results of testosterone replacement across the full complement of large multisite TTrials are eagerly anticipated—not only on sexual function, vitality, and physical function, but also on cognitive function, anemia, bone, and cardiovascular health.
We also report the results of Paduch and colleagues, who studied the effect of testosterone replacement on ejaculatory dysfunction in hypogonadal men, and reported no effect. It is interesting to surmise that this may relate to the effect of testosterone on gonadotropins.
Wiehle and colleagues, spurred by reports that testosterone was being prescribed to men for hypogonadism regardless of the men's desire for fertility, conducted a phase 2b study of enclomiphene citrate (EC) vs T in 124 men with baseline T <250 ng/dL. Use of EC led to increased T levels as effectively as topical T, and did not result in the same decrease in gonadotropins or sperm concentration. They did not, however, find an increase in sperm concentration vs placebo over the 3 month study period. Of note, the etiology of hypogonadism was not specified; there is theoretical, and some clinical, evidence that clomiphene citrate is not effective in patients with pituitary disease. Exogenous testosterone should not be used in men actively seeking fertility, as it suppresses endogenous production of lutenizing hormone and follicle-stimulating hormone, thus hampering spermatogenesis (See Figure 1).
As always, the specific cohort is important in determining the generalizability of the results. In addition, the establishment of hypogonadism is a distinguishing factor in studies. Hypogonadism should be diagnosed based on the presence of clinical symptoms and measurements of low morning testosterone; some groups recommend its use only in certain defined etiologies. There is no clear consensus on the exact time of morning measurement, nor whether total or free or bioavailable T should be used. There is consensus that testosterone should be replaced only in the presence of measured hypogonadism; in 2014, Layton and colleagues described the apparent use of testosterone in many men without proper testing.
We use the term testosterone replacement to refer to the use of T in men with unequivocally low T levels: at least two separate early morning testosterone levels below the reference range. Four studies reviewed here (Cunningham et al;Snyder et al; Paduch et al; Wiehle et al) included only men with definitive hypogonadism, specifying two morning measurements below typical normal range (though, of note, the time of testosterone measurement was not always as closely controlled as many groups recommend.) The study by Basaria and colleagues included men with low and low-normal testosterone, using 400 ng/mL as the upper limit for inclusion, and the database-based study by Layton and colleagues included no information on whether testosterone was measured or hypogonadism established.
A note on the hypothalamic-pituitary-gonadal axis
In a healthy male in hormonal equilibrium, both testosterone and sperm are made in the testes (Figure 1). LH is secreted from the pituitary and stimulates testicular production of testosterone. FSH is secreted from the pituitary and stimulates spermatogenesis (for which testosterone is also necessary). When sufficient testosterone is produced, the testosterone serves as a negative feedback signal to inhibit further pituitary LH and FSH secretion. If exogenous testosterone is given, it will suppress both LH and FSH production. Thus, exogenous testosterone can treat testosterone deficiency but inhibits fertility.
1. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. March 3, 2015. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm.
2. Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the association of testosterone and cardiovascular risk. Endocr Pract. 2015;21(9):1066-1073.
3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
4. Foresta C, Caretta N, Rossato M, et al. Role of androgens in erectile function. J Urol. 2004;171(6 Pt 1):2358-2362.
5. Mikhail N. Does testosterone have a role in erectile function? Am J Med. 2006;119(5):373-382.
6. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother. 2014;48(9):1138-1144.