Testosterone Treatments: Beyond Replacement

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

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.


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.10 In both the exogenous testosterone and aromatase inhibitor groups, testosterone levels were significantly increased.11 Other studies support the finding of increased testosterone in men with aromatase inhibition.12 However, in this study at least, estradiol increased in the testosterone group and decreased in the aromatase inhibitor group.11 This may be of particular interest because the role of estradiol as a male hormone has been drawing increasing interest.12

For men with suboptimal testosterone, addressing lifestyle considerations and nutritional interventions first is not only safe, but may lead to the desired results.

Dosing and Optimum Levels

If supplementation is required, the dose of testosterone needed to create specific effects in the body varies widely.13 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

Reference 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.14 Data was collected from men who participated in the National Health and Nutrition Examination Surveys (NHANES).14

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

NHANES III – phase I (1988-1991) data:14

  • 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:14

  • 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.14

Therapy Risks & Side Effects

Testosterone therapy can cause a range of side effects,6,15 such as:

  • Reduced fertility
  • Fluid retention
  • Obstructive sleep apnea

There may be other risks, including cardiovascular and respiratory risks,16 although data is not yet conclusive,17 and those risks may be due to flaws in study design.18 At least one study suggests testosterone may actually be cardioprotective.19 In addition, the as-yet-inconclusive role of testosterone in prostate cancer continues to garner controversy and attention.20,21

A 2020 review conducted for the American College of Physicians reported on the analysis of 38 randomized controlled trials, finding that:22

  • 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 someone’s overall physiology. From a Functional Medicine perspective, low testosterone levels may be a biomarker for the presence of an underlying co-morbidity. Low testosterone levels have been associated with co-morbidities such as hypertension and type 2 diabetes.23 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. IFM’s Toolkit contains numerous patient education materials that can help in working with men and women with hormonal imbalances.


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