Testosterone Replacement--Should You Start?

Questions about testosterone replacement are incredibly common these days. A lot of men find it difficult to navigate the current hormone replacement landscape, not knowing who to believe. The Lone Tree, Highlands Ranch, and Greenwood Village areas of Colorado have seen a significant increase in "TRT clinics" popping up. Many of these local "TRT clinics" are incentivized to rush men through the decision to start testosterone. Unfortunately for some clinics, more prescriptions means more money. Here at South Denver Concierge in Lone Tree, Colorado, Dr. Kenji Kaye, MD, believes the decision to start testosterone should be a comprehensive, unpressured discussion focused on evidence-based medicine—not a one-size-fits-all approach.

Why Testosterone Drops

There are many hypotheses regarding why modern testosterone levels are significantly lower than historical levels. Even when corrected for age, men's testosterone levels today are around 50-80% lower compared to 50 years ago. There is strong evidence that our world of microplastics, phthalates, BPAs, and PFAs are to blame.

How Should We Test For Testosterone?

Testing for testosterone is not as easy as taking a random blood sample (and saliva should rarely, if ever, be utilized). We must take into account the time of day, sleep habits, stress levels, and also type of test ordered before we interpret and diagnose low testosterone. Many "TRT clinics" opt for quick and cheap finger prick or saliva testing which may be inaccurate if not tested utilizing liquid chromatography–tandem mass spectrometry (LC-MS/MS). For clinical practice, venous blood analyzed by LC-MS/MS remains the gold standard, with capillary blood LC-MS/MS as a validated alternative.

Free testosterone should also be tested. Free testosterone represents the biologically active fraction. The most accurate method is equilibrium dialysis, but this is technically demanding and not widely available. Calculated free testosterone, using total testosterone, SHBG, and albumin, is a reasonable alternative if the calculation uses validated equations and the input assays are accurate.

Sleep and time of day testing can drastically change results as well. If you had one or two poor nights of sleep or are under stress this can sometimes give a falsely LOW number when your true average testosterone levels may be clinically normal. Additionally, the gold standard for testing is between the hours of 8 a.m.-10 a.m. (for those of us with regular sleep cycle). Testosterone levels are measured between 8 a.m. and 10 a.m. because serum testosterone exhibits a diurnal rhythm, with peak concentrations in the early morning hours. This timing maximizes diagnostic accuracy by capturing the highest daily value, reducing the risk of false low results and misdiagnosis of hypogonadism. The Endocrine Society guideline specifically recommends morning, fasting samples for testosterone measurement, as levels decline by 20–25% by late afternoon in younger men and, although the diurnal variation is blunted with age, morning sampling remains important even in older men.

Low Testosterone Sometimes Requires Further Testing

Clinically low testosterone in a man less than 40 years old should be investigated further. It is not always as simple as having "Low T". A proper evaluation might require an MRI of the pituitary gland. Pituitary Adenomas are relatively rare but one of the presenting symptoms can be hypogonadism as many adenomas can secrete another hormone called prolactin. We have detected many younger patients that were diagnosed with "low T" by an outside clinic and offered testosterone replacement. When in reality they had an undiagnosed pituitary adenoma that needed to be addressed.

Another condition that should be examined for in certain situations is the presence of a condition called hemochromatosis which is an iron overload condition that may only manifest initially as hypogonadism.

Obstructive Sleep Apnea (OSA) is also another common cause of male hypogonadism. Patients should be screened for possible OSA as a cause of their low testosterone. We have had many patients who had undiagnosed OSA that when properly treated their low testosterone returned to normal.

Real Risks and Downsides to TRT

"TRT Clinics" often minimized risks and the downsides to starting testosterone in order to get as many men on testosterone as possible. However, we always discuss with our patients potential side effects and downsides to being on testosterone.

For example, once a man starts on replacement their body often significantly reduces its own natural production as the body is now receiving exogenous hormones (from outside the body). This suppresses the natural hypothalamic-pituitary-testicular axis by a negative feedback mechanism. This can lead to noticeable testicular shrinkage and a physiologic dependence on testosterone replacement that can be difficult to reverse.

Other risks include impacting fertility for men who are planning on having a family. Because TRT reduces the bodies natural production of testosterone, the reduction in intratesticular testosterone results in significant changes to sperm quality and concentration.

The recent TRAVERSE trial, which was a large multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, looked at major adverse cardiovascular events in testosterone replacement. The overall conclusion was that testosterone replacement was noninferior to placebo when considering major adverse cardiovascular events (MACE). This means that testosterone was not WORSE than placebo in terms of causing a MACE. This was great news as it answered a longstanding question about the cardiovascular safety of testosterone replacement. However the study did demonstrate a statistically significant increase in nonfatal arrhythmias like atrial fibrillation.

Men need to be aware of the real risks of TRT and take these into account before embarking down the TRT pathway. Many testosterone clinics in the Lone Tree, Highlands Ranch, and Greenwood Village areas of Colorado are incentivized to get as many people on testosterone as possible without fully reviewing these risks with their patients. South Denver Concierge is committed to providing thoughtful, evidence-based and honest testosterone evaluation and treatment for our patients.

We also need to consider the fact that patients on TRT will need to plan to inject themselves ideally at least twice a week. This will also require our patients to plan accordingly with travel. While not insurmountable our patients need to consider these factors.

Sometimes TRT is Not the First Step

Optimize lifestyle first: 7–9 hours sleep, resistance training 3x/week, 10–20% body fat, stress control. Then get baseline labs (total/free T, PSA, hematocrit, etc.). Evaluate for other medical conditions including pituitary adenoma, hemochromatosis or even obstructive sleep apnea.

The Bottom Line

For confirmed primary hypogonadism in men testosterone replacement can be life changing. However careful examination for underlying causes in certain cases should be considered before embarking on testosterone replacement. South Denver Concierge is not like other "TRT clinics". We do not benefit financially from the sale or prescribing of testosterone. Your in-depth evaluation with a board-certified internal medicine physician will give you an unbiased, evidence-based assessment of your testosterone levels.

References:

Cardiovascular Safety of Testosterone-Replacement Therapy

Authors: A. Michael Lincoff, M.D., Shalender Bhasin, M.B., B.S., Panagiotis Flevaris, M.D., Ph.D., Lisa M. Mitchell, R.N., B.S.N., Shehzad Basaria, M.D., William E. Boden, M.D., Glenn R. Cunningham, M.D., +18 , for the TRAVERSE Study Investigators*Author Info & Affiliations

Published June 16, 2023

N Engl J Med 2023;389:107-117 VOL. 389 NO. 2

Naelitz BD, Momtazi-Mar L, Vallabhaneni S, Cannarella R, Vij SC, Parekh NV, Bole R, Lundy SD. Testosterone replacement therapy and spermatogenesis in reproductive age men. Nat Rev Urol. 2025 Oct;22(10):703-719. doi: 10.1038/s41585-025-01032-8. Epub 2025 May 9. PMID: 40346275.

Tritos NA, Miller KK. Diagnosis and Management of Pituitary Adenomas: A Review. JAMA. 2023;329(16):1386–1398. doi:10.1001/jama.2023.5444