insights

Testosterone Treatments: Beyond Replacement

smiling man doing pushup at the gym
Read Time: 5 Minutes

The market for testosterone replacement treatments has grown in recent years and remains strong. A 2017 JAMA study documented a huge increase in direct-to-consumer advertising for testosterone supplementation, which has also been associated with increased prescribing trends.1 In 2013, testosterone supplementation brought in $2 billion in sales for pharmaceutical companies.2 Although trends suggest that that rapid growth in prescriptions has slowed,3 many men visit the doctor specifically seeking a testosterone prescription. Yet 80-85% of men supplementing testosterone discontinue treatment after a year.4

In healthy men under 50 years of age, serum testosterone ranges from 300-1,000 ng/dl, and levels start to drop after the age of 50.5 The American Urological Association (AUA) guidelines state that testosterone therapy can be considered if serum levels of testosterone are under 300 ng/dl and clinical symptoms are present.6

Despite this, up to 25% of men receiving testosterone therapy did not have their levels tested prior to the prescription.6

(Video Time: 2 Minutes) IFM educator Mark Holthouse MD, IFMCP, discusses testosterone deficiency and how this topic is addressed during IFM's Hormone Advanced Practice Module, from etiologies to diagnosis and treatment.

Lifestyle Interventions

Suboptimal testosterone levels are often amenable to lifestyle interventions. For instance, high-intensity interval training increases free testosterone in older, sedentary men,7 as well as masters athletes.8 Reducing alcohol intake also increases free testosterone.9

One intervention to consider prior to exogenous testosterone is nutritional: natural aromatase inhibitors. A range of foods and vitamins naturally inhibit aromatase, which decreases the conversion of testosterone into estradiol, resulting in increased testosterone levels. A 2021 systematic review found that two herbal extracts, fenugreek seed extracts and ashwagandha root and root/leaf extracts, may have positive effects on testosterone concentrations in men.10

Hormone International
In one large trial, aromatase inhibitors and testosterone supplementation resulted in similar outcomes to placebo for many cardiovascular measures, but aromatase inhibitors significantly reduced abdominal fat, an effect not seen in the testosterone group.11 In both the exogenous testosterone and aromatase inhibitor groups, testosterone levels were significantly increased.12 Other studies support the finding of increased testosterone in men with aromatase inhibition.13 However, in this study at least, estradiol increased in the testosterone group and decreased in the aromatase inhibitor group.12 This may be of particular interest because the role of estradiol as a male hormone has been drawing increasing interest.13For men with suboptimal testosterone, addressing lifestyle considerations and nutritional interventions first is not only safe but may lead to the desired results. There are several foods, herbs, and supplements that can be used to inhibit or slow aromatase activity. For men who have suboptimal testosterone, lowering aromatase activity may help support and optimize healthy testosterone levels. IFM has created a handout called “Aromatase Inhibitors” for clinician and patient use in the IFM Toolkit, which includes a list of foods, herbs, and nutrients that inhibit aromatase. To access this educational resource, log in to the IFM website and select “My Toolkit,” then search for “Aromatase Inhibitors.”

Dosing and Optimum Levels

If supplementation is required, the dose of testosterone needed to create specific effects in the body varies widely.14 Ongoing monitoring is needed to ensure supplementation is reaching the desired range of free testosterone,6 yet reporting suggests that nearly half of patients’ blood levels are not monitored after testosterone therapy.6

Optimal ranges for testosterone levels have not been well established.6 A study published in July 2019 suggested optimal circulating testosterone target levels for healthy aging men through the analysis of survey data and previously measured serum total testosterone concentrations.15 Data was collected from men who participated in the National Health and Nutrition Examination Surveys (NHANES).15

Comparison data between a healthier target population of never-smoking, lean men of 20 years of age or more without specific comorbidities and a general population of all men who took the surveys showed the following:

NHANES III – phase I (1988-1991) data:15

  • Median testosterone level was 4-9% higher in the target population than all men.
  • Median total testosterone by age in years (20 to 39; 40 to 59; 60 or more):
    • Target population: 624 ng/dl; 537 ng/dl; 461 ng/dl
    • All men: 599 ng/dl; 486 ng/dl; 435 ng/dl

Continuous NHANES (1999-2004) data:15

  • Median testosterone level was 13-24% higher in the target population than all men.
  • Median total testosterone by age in years (20 to 39; 40 to 59; 60 or more):
    • Target population: 626 ng/dl; 586 ng/dl; 422 ng/dl
    • All men: 542 ng/dl; 445 ng/dl; 392 ng/dl

The study aimed to use its findings to both better inform clinical guidelines used to address testosterone deficiency and to help establish target total serum testosterone levels for men in nondrug intervention trials.15

Therapy Risks & Side Effects

Testosterone therapy can cause a range of side effects,6,16 such as:

  • Reduced fertility
  • Fluid retention
  • Obstructive sleep apnea

There may be other risks, including cardiovascular and respiratory risks,17 although data is not yet conclusive,18 and those risks may be due to flaws in study design.18 At least one study suggests testosterone may be cardioprotective.20 In addition, the as-yet-inconclusive role of testosterone in prostate cancer continues to garner controversy and attention.21,22

A 2020 review conducted for the American College of Physicians reported on the analysis of 38 randomized controlled trials, finding that:23

  • Testosterone therapy improved sexual function and quality of life for older men who had low testosterone levels and who did not have a medical condition known to cause hypogonadism; however, the improvements were small, with low to moderate-sized effects reported.
  • Testosterone therapy had little to no effect on other symptoms such as physical functioning, depressive symptoms, energy and vitality, and cognition.
  • The trials often excluded men who were at high risk of cardiovascular events or prostate cancer; therefore, no relationship could be established between those conditions and testosterone therapy.
  • According to the review, “Harms evidence reported in trials was judged to be insufficient, or of low certainty for most harm outcomes.”
  • The long-term efficacy and safety of testosterone therapy is unknown among the noted population.

As with other hormonal imbalances, low testosterone may indicate a change in a patient’s overall physiology. From a functional medicine perspective, low testosterone levels may be a marker for the presence of an underlying physiological imbalance, and low levels have been associated with comorbidities such as hypertension and type 2 diabetes.24 The functional medicine model assesses an individual patient’s genetic, biochemical, and lifestyle factors to help create a personalized treatment plan for their testosterone deficiency diagnosis. To learn more about optimizing testosterone function, consider attending IFM’s Hormone Advanced Practice Module (APM):

LEARN MORE ABOUT RE-ESTABLISHING HORMONAL BALANCE >

Related Articles

Restoring Thyroid Hormone Balance

Nutrition and Impacts on Hormone Signaling 

Sex Hormones & the Female Brain: A Focus on Mood Disorders

References

  1. Layton JB, Kim Y, Alexander GC, Emery SL. Association between direct-to-consumer advertising and testosterone testing and initiation in the United States, 2009-2013. 2017;317(11):1159-1166. doi:10.1001/jama.2016.21041
  2. Bhasin S. A perspective on the evolving landscape in male reproductive medicine. J Clin Endocrinol Metab. 2016;101(3):827-836. doi:1210/jc.2015-3843
  3. Baillargeon J, Kuo YF, Westra JR, Urban RJ, Goodwin JS. Testosterone prescribing in the United States, 2002-2016. 2018;320(2):200-202. doi:10.1001/jama.2018.7999
  4. Bandari J, Ayyash OM, Emery SL, Wessel CB, Davies BJ. Marketing and testosterone treatment in the USA: a systematic review. Eur Urol Focus. 2017;3(4-5):395-402. doi:1016/j.euf.2017.10.016
  5. Seftel AD. Male hypogonadism. Part I: epidemiology of hypogonadism. Int J Impot Res. 2006;18(2):115-120. doi:1038/sj.ijir.3901397
  6. American Urological Association. Evaluation and management of testosterone deficiency. Published 2018. Accessed May 18, 2022. https://www.auanet.org/guidelines/testosterone-deficiency-guideline
  7. Hayes LD, Herbert P, Sculthorpe NF, Grace FM. Exercise training improves free testosterone in lifelong sedentary aging men. Endocr Connect. 2017;6(5):306-310. doi:1530/EC-17-0082
  8. Herbert P, Hayes LD, Sculthorpe NF, Grace FM. HIIT produces increases in muscle power and free testosterone in male masters athletes. Endocr Connect. 2017;6(7):430-436. doi:1530/EC-17-0159
  9. Sandher RK, Aning J. Diagnosing and managing androgen deficiency in men. 2017;261(1803):19-22.
  10.  Smith SJ, Lopresti AL, Teo SYM, Fairchild TJ. Examining the effects of herbs on testosterone concentrations in men: a systematic review. Adv Nutr. 2021;12(3):744-765. doi:1093/advances/nmaa134
  11.  Dias JP, Shardell MD, Carlson OD, et al. Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters. Andrology. 2017;5(1):31-40. doi:1111/andr.12284
  12.  Dias JP, Melvin D, Simonsick EM, et al. Effects of aromatase inhibition vs. testosterone in older men with low testosterone: randomized-controlled trial. Andrology. 2016;4(1):33-40. doi:1111/andr.12126
  13.  Russell N, Grossmann M. Mechanisms in endocrinology: estradiol as a male hormone. Eur J Endocrinol. 2019;181(1):R23-R43. doi:1530/EJE-18-1000
  14.  Finkelstein JS, Lee H, Burnett-Bowie SM, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011-1022. doi:1056/NEJMoa1206168
  15.  Platz EA, Barber JR, Chadid S, et al. Nationally representative estimates of serum testosterone concentration in never-smoking, lean men without aging-associated comorbidities. J Endocr Soc. 2019;3(10):1759-1770. doi:1210/js.2019-00151
  16.  Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi:1210/jc.2018-00229
  17.  Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122. doi:1056/NEJMoa1000485
  18.  Mohler ER 3rd, Ellenberg SS, Lewis CE, et al. The effect of testosterone on cardiovascular biomarkers in the testosterone trials. J Clin Endocrinol Metab. 2018;103(2):681-688. doi:1210/jc.2017-02243
  19.  Hackett GI. Testosterone replacement therapy and mortality in older men. Drug Saf. 2016;39(2):117-130. doi:1007/s40264-015-0348-y
  20.  Cheetham TC, An J, Jacobsen SJ, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med.2017;177(4):491-499. doi:1001/jamainternmed.2016.9546
  21.  Klap J, Schmid M, Loughlin KR. The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy. J Urol. 2015;193(2):403-413. doi:1016/j.juro.2014.07.123
  22.  Claps M, Petrelli F, Caffo O, et al. Testosterone levels and prostate cancer prognosis: systematic review and meta-analysis. Clin Genitourin Cancer. 2018;16(3):165-175.e2. doi:1016/j.clgc.2018.01.005
  23.  Diem SJ, Greer NL, MacDonald R, et al. Efficacy and safety of testosterone treatment in men: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020;172(2):105-118. doi:7326/M19-0830
  24.  Anaissie J, DeLay KJ, Wang W, Hatzichristodoulou G, Hellstrom WJ. Testosterone deficiency in adults and corresponding treatment patterns across the globe. Tranl Androl Urol. 2017;6(2):183-191. doi:21037/tau.2016.11.16

 

Related Insights