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.
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
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.
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.
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.
It's a retrospective cohort study of 9,537 men treated for testosterone deficiency through a UK men's health provider between 2019 and 2024, published in the World Journal of Men's Health in April 2026. Authors Clift, Johnson, Huang, and Morgentaler tracked lab markers, symptoms, and quality of life over a mean follow-up of 8.47 months. It is one of the largest real-world TRT safety datasets ever published.
What did the study find about hematocrit?
Roughly 1 in 4 men (24.15%) crossed the 0.54 L/L hematocrit threshold within 12 months — the level at which most clinicians pause therapy, reduce dose, or order a phlebotomy. Mean hematocrit rose by 0.03 L/L across the cohort. Baseline testosterone did not predict who would spike. Everyone on TRT needs hematocrit monitored, not just high-risk subgroups.
How much did libido improve on TRT?
Libido scores rose 1.26 points on a 5-point Likert scale, moving from 1.94 at baseline to 3.20 at 12 months. That is the largest improvement of any quality-of-life domain measured. It's also practical evidence for why the FDA is now considering a formal indication for low libido in idiopathic hypogonadism.
Was the study funded by a TRT company?
The data came from a UK men's health provider's own clinical records, and senior author Abraham Morgentaler is one of the most prominent TRT advocates in the field. That matters for interpretation. The effect sizes are consistent with other literature, but real-world cohorts cannot match the rigor of a randomized controlled trial like TRAVERSE.
What treatments did men in the study receive?
Most were on subcutaneous testosterone injections (89.2%). Three quarters (75.2%) were also prescribed hCG, which is typical of fertility-conscious and private-pay TRT protocols. Smaller groups received topical testosterone (3.8%), clomiphene (7.1%), or tadalafil (13.7%). This reflects modern combination therapy, not testosterone-only protocols.
Does this change how I should approach TRT?
Three takeaways. One: expect symptom improvement — libido, energy, and mood all improved meaningfully by month 12. Two: hematocrit monitoring at baseline, 3 months, 6 months, and 12 months is non-negotiable because you cannot predict who will spike. Three: ask your clinic whether they include hCG. Combination protocols are the real-world standard now, not testosterone alone.
