Most TRT safety data comes from two places: randomized controlled trials on a few thousand men, and VA database studies with messy confounders. In April 2026, a new paper in the World Journal of Men's Health added a third angle — a clean, real-world cohort of 9,537 men treated through a single UK men's health provider.
The headline: TRT works, and the biggest safety signal is still hematocrit.
Key Takeaways
- 9,537 men tracked over a mean 8.47 months on modern TRT protocols
- Libido improved 1.26 points on a 5-point scale — the largest gain of any symptom measured
- 24.15% of men crossed the 0.54 L/L hematocrit threshold within 12 months
- Baseline testosterone did not predict who would spike hematocrit
- 75% of men were also on hCG, reflecting today's combination-therapy standard
- The study supports the FDA's current push to expand TRT indications for low libido
What the Study Actually Measured
This was a retrospective cohort study led by Ashley Kieran Clift and Abraham Morgentaler, using de-identified clinical records from a UK men's health provider between 2019 and 2024. The cohort is younger than most TRT trial populations — median age 42, interquartile range 36 to 49.
Cohort Snapshot
| Parameter |
Detail |
| Total patients |
9,537 men |
| Median age |
42 years (IQR 36-49) |
| Follow-up |
Mean 8.47 months |
| Subcutaneous testosterone |
89.20% (n=8,517) |
| Topical testosterone |
3.84% (n=366) |
| hCG co-prescribed |
75.23% (n=7,079) |
| Clomiphene co-prescribed |
7.08% (n=675) |
| Tadalafil co-prescribed |
13.72% (n=1,308) |
| Journal |
World Journal of Men's Health |
| Publication date |
April 2026 |
The protocol mix here is the first thing worth flagging. Nine out of ten men were on subcutaneous injections rather than intramuscular or topicals. Three quarters were also on hCG. That is the modern private-pay TRT template — not the old once-every-two-weeks intramuscular cypionate monotherapy that most insurance-based practices still run. If you are considering TRT, this cohort reflects what online clinics actually prescribe.
If you want a deeper look at injection route trade-offs, the subcutaneous vs. intramuscular TRT guide breaks down absorption, peaks, and side-effect profiles. For the fertility angle driving hCG use, see HCG for fertility on TRT.
The Hematocrit Signal Is the Story
Hematocrit — the percentage of blood volume made of red blood cells — is the single most common reason men get pulled off TRT. Testosterone stimulates erythropoietin and bone marrow, and if your blood gets too thick, you have a higher risk of clots, strokes, and cardiovascular events.
What the Study Found
- Mean hematocrit rise: 0.03 L/L at 12 months (from baseline to endpoint)
- Proportion crossing 0.54 L/L (the clinical threshold for concern): 24.15% by 12 months
- Baseline testosterone level did not predict who would spike
That last point matters. You might expect men with severely low testosterone to get the biggest hematocrit jump when they start therapy — but the data did not show that. Clinically, this means you cannot look at someone's starting labs and predict whether they will run into polycythemia.
What 0.54 L/L Means in Plain English
A hematocrit of 0.54 L/L is equivalent to 54% — meaning more than half of your blood volume is red cells. Most labs flag anything above 52% in men. At 54% and above, clinicians typically intervene with one or more of:
- Dose reduction (usually 10-20%)
- Splitting the weekly dose into smaller, more frequent injections
- Switching from intramuscular to subcutaneous administration
- Therapeutic phlebotomy (blood donation that lowers red cell mass)
- Checking ferritin — iron depletion from repeated phlebotomy is a real risk
The TRT polycythemia and hematocrit guide walks through each of these tactics and when to pick which one.
Monitoring Cadence That Actually Catches It
Given that 1 in 4 men will spike, and baseline labs do not predict who, you need a monitoring schedule that catches elevation before it becomes dangerous. A defensible protocol:
| Time Point |
Labs to Draw |
| Baseline (pre-TRT) |
CBC, total and free testosterone, estradiol, PSA, lipid panel, CMP |
| 6-8 weeks |
Total and free testosterone, CBC, estradiol |
| 3 months |
Total and free testosterone, CBC, estradiol, PSA |
| 6 months |
CBC, estradiol, PSA |
| 12 months |
Full repeat of baseline panel |
| Annually |
Full repeat of baseline panel |
Any clinic that is not pulling CBC at these intervals is cutting corners. If you want a checklist for interviewing providers, use the questions to ask a TRT clinic guide.
The Libido Finding Is a Big Deal
Libido improved 1.26 points on a 5-point scale — more than any other symptom measured. Men went from 1.94 ("low desire") at baseline to 3.20 ("moderate desire") at 12 months.
This is not just a lifestyle benefit. It is regulatory evidence.
On April 16, 2026, the FDA formally invited TRT manufacturers to pursue a new indication for low libido in men with idiopathic hypogonadism. The agency asked sponsors to contact them by April 30, 2026 to discuss sNDA requirements. Studies like this one are exactly the type of real-world effectiveness data the FDA has signaled it will weigh in that process. For the full regulatory context, see FDA opens TRT pathway for low libido.
Every Quality-of-Life Domain Improved
| Domain |
Baseline |
12 Months |
| Libido |
1.94 |
3.20 |
| Energy |
Significant improvement (p<0.001) |
Reached ≥3 |
| Strength |
Significant improvement |
Reached ≥3 |
| Erection quality |
Significant improvement |
Reached ≥3 |
| Work performance |
Significant improvement |
Reached ≥3 |
| Happiness |
Significant improvement |
Reached ≥3 |
| Life enjoyment |
Significant improvement |
Reached ≥3 |
| Sports ability |
Significant improvement |
Reached ≥3 |
Every single quality-of-life domain improved to statistical significance, and every one reached an average rating of 3 ("moderate") or higher by month 12. This mirrors what the TRT results at 6 months and TRT results at 1 year data have shown in smaller cohorts.
What This Study Cannot Tell You
Real-world cohorts are not randomized trials. A few limitations matter when you read the headline numbers.
No placebo group. Any man who pays for TRT and shows up for follow-up labs expects to feel better. Placebo effect on symptom scores is real, and this design cannot separate pharmacology from expectation.
Selection bias. Men who enrolled with a private men's health provider in the UK are not representative of the general hypogonadal population. They are younger, more affluent, more motivated, and more likely to adhere to protocols.
Short follow-up. Mean 8.47 months. Cardiovascular events, prostate cancer, and long-term bone effects all require multi-year surveillance. For those outcomes, the TRAVERSE trial and its extension studies remain the strongest evidence.
No cardiovascular event data. The paper focused on lab markers and symptoms. It did not report MACE outcomes, strokes, or mortality. For that, look to TRAVERSE.
Combination therapy complicates attribution. With 75% of men on hCG and 14% on tadalafil, you cannot cleanly assign libido and erection improvements to testosterone alone. That's the real world — but it also means the isolated effect of testosterone is smaller than the headline numbers suggest.
How to Use This Data When Choosing a Clinic
Three practical questions to ask any TRT provider in light of this evidence.
1. Do You Offer Subcutaneous Injections?
The study cohort was 89% subcutaneous. Subcutaneous injections hurt less, absorb more steadily, and show lower hematocrit spikes than weekly intramuscular dosing. If a clinic only offers intramuscular cypionate every two weeks, that is a dated protocol.
2. Do You Co-Prescribe hCG?
Three quarters of men in this cohort were on hCG. That is the modern standard for men who want to preserve fertility, maintain testicular volume, or support downstream hormone production. Insurance-based practices often refuse hCG because it is not FDA-approved for this use. Cash-pay and online clinics routinely prescribe it. See TRT with insurance vs. without for how the two models differ.
3. How Often Do You Pull CBC?
The 24% hematocrit spike rate is the single most actionable safety number in this paper. A clinic that pulls labs only at baseline and annually will miss elevations until you are already polycythemic. You want at minimum: baseline, 6-8 weeks, 3 months, 6 months, 12 months, then annually. If a clinic's standard protocol does less than that, raise it directly or go elsewhere.
Our independent ratings of the top providers on these three dimensions live at Best online TRT clinics 2026.
Bottom Line
The 2026 Clift-Morgentaler cohort adds the largest real-world TRT dataset to date. The efficacy signal is strong — especially on libido, which is likely to drive the FDA's upcoming indication expansion. The safety signal is focused: hematocrit monitoring is the single most important thing a clinic can do to keep you safe on testosterone.
If you are considering TRT, use this data to ask better questions. If you are already on TRT, use it to audit your monitoring schedule.
References
- Clift AK, Johnson H, Huang DR, Morgentaler A. Real-World Outcomes and Safety of Testosterone Therapy: A Longitudinal, Retrospective Cohort Study of Over 9,000 Men. World Journal of Men's Health. 2026. DOI: 10.5534/wjmh.250245.
- U.S. Food and Drug Administration. FDA Takes Step Forward on Testosterone Therapy for Men. Press announcement, April 16, 2026.
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy (TRAVERSE). N Engl J Med. 2023;389:107-117.
- Ohlander SJ, Varghese B, Pastuszak AW. Erythrocytosis Following Testosterone Therapy. Sex Med Rev. 2018;6(1):77-85.
- Jones SD, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJG. Erythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male. Sex Med Rev. 2015;3(2):101-112.
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