By ZRT Laboratory
An FDA-approved testosterone gel was shown to significantly increase risk for adverse cardiovascular, respiratory and dermatological events in men aged 65 or older who had impaired mobility and increased health risks. This is according to a study published in the prestigious New England Journal of Medicine (NEJM) that casts a shadow on the common use of testosterone therapy in older men for boosting energy and vitality [1].
These unexpected negative results fly in the face of decades of good research on testosterone therapy in older men showing it to be beneficial to the cardiovascular system, and to improve sexual function, mood, energy level, and muscle and bone mass and strength. What went wrong? Why were the results so different from hundreds of other publications painting testosterone as the elixir of youth and vitality?
The NEJM Study: What the Numbers Show
In the NEJM study, testosterone-treated men had mean venous serum testosterone levels of 574 ± 403 ng/dL, compared with 292 ± 160 ng/dL in the placebo group. The Endocrine Society Clinical Practice Guidelines suggest that testosterone should be dosed to achieve serum levels about mid-range for a healthy young male. The 50–150 mg topical testosterone gel put the treated men well within the expected mid-physiological range seen in healthy young men (approximately 500–1000 ng/dL). So based on conventional serum testing, one would conclude that overdosing was not responsible for the adverse reactions. Or was it?
The Problem with Venous Serum Testing for Topical Testosterone
The 10% Absorption Assumption
It is assumed that when testosterone is delivered as a topical gel, only 10% is absorbed and utilised by the body. This is based on measuring the total amount of testosterone detectable in venous serum over 12–24 hours after application. With this conventional wisdom of 10% absorption, topical testosterone gel has been FDA-approved at a pharmacological dose approximately 10 times higher (50–100 mg) than the amount a healthy young male’s testes will manufacture in a day (approximately 5–10 mg).
Venous Serum Does Not Reflect Tissue Exposure
It is also assumed that serum testosterone measurements from a venous blood draw actually reflect how much testosterone is entering tissues throughout the body. What evidence do we have that the pharmacological dose used in the NEJM study was actually delivering a physiological dose of testosterone into the tissues of these older men? The correct answer is none.
However, there are other means to look more closely at tissue exposure to testosterone — by measuring the level in the fluid of tissues bathed by capillary beds, as opposed to blood flowing away from tissues (venous blood). Saliva and capillary blood (finger-prick) provide the next-best alternative, as they are easily accessible body fluids more representative of the direct interaction of capillary beds with tissues.
What ZRT’s Database Reveals
Over the past decade, ZRT Laboratory has measured steroid hormone levels (estradiol, progesterone, testosterone, DHEAS, cortisol) in saliva and capillary blood from men and women using a wide range of hormone doses and delivery systems — topical creams and alcoholic gels, oral, intramuscular injections, subcutaneous pellets, sublingual drops and troches. Data from well over a million people has been recorded.
Topical Delivery Creates a 10–20x Discrepancy
When steroid hormones are produced endogenously and released into the bloodstream, levels in venous blood serum are quantitatively equivalent to whole capillary blood drawn from the finger. In contrast, when testosterone is applied topically as a cream, gel or spray, levels in capillary blood are remarkably higher — by 10–20 fold — than venous blood levels. Salivary hormones are often greater than 100% of venous serum levels, which ordinarily are only 2–3%.
This remarkable increase is NOT seen when hormones are delivered orally, or as intramuscular injections or subcutaneous pellet implants. With these delivery systems, capillary blood and venous serum levels are approximately the same.
The Real Tissue Exposure in the NEJM Study
With reference to the use of topical testosterone gels at the 50–150 mg dosage, ZRT finds mean capillary blood levels of testosterone to be approximately 5,000 ng/dL — approximately 10 times higher than the venipuncture serum levels reported in the NEJM study (574 ± 403 ng/dL). Furthermore, men using higher pharmacological topical testosterone gel have capillary blood levels of estradiol that usually exceed 100 pg/ml — very high for males. While physiological levels of estrogens are beneficial to the male cardiovascular system, higher levels can be harmful. Estrogens were not monitored in the NEJM study, so it is not possible to know if levels were higher than the physiological range. It is very possible that some of the cardiovascular events observed were precipitated by excess estrogens derived from excess testosterone.
If you are using topical testosterone therapy and want to accurately assess your tissue-level hormone exposure, our Comprehensive Male Saliva Hormone Profile (LCMS) measures testosterone, estradiol, DHEA, cortisol and other key hormones in saliva using highly accurate LCMS analysis — the most clinically relevant method for monitoring topical hormone therapy.
The Dose Makes the Poison
The Swiss alchemist Paracelsus noted some 500 years ago: “All things are poison and nothing is without poison. Only the dose permits something not to be poisonous.” Hormones are no different. A physiological level of testosterone is unquestionably life-enhancing in men of all ages who suffer from testosterone deficiency. However, at a high enough dose, testosterone — like all hormones — has the potential to transition from an elixir to a dangerous drug.
For men wanting a comprehensive hormonal baseline before starting or adjusting testosterone therapy, our LCMS 9-Hormone Saliva Test Panel for Male provides an expanded picture including testosterone, estradiol, progesterone, DHEA, cortisol and additional androgens — all measured via the gold-standard LCMS method.
For men who prefer a blood-based assessment alongside hormone testing, our Advanced Male Wellness Test combines hormone analysis with a specialist doctor report — providing a thorough picture of male hormonal and metabolic health from a simple at-home finger-prick collection.
Hormone Lab UK is the official UK test provider of ZRT Laboratory.
Originally ZRT Laboratory. Reproduced with permission. Last reviewed: May 2026.