Ninety Years of Trying to Hit a Number That Doesn't Move

The goal has a name: mid-normal. The Endocrine Society suggests aiming at testosterone concentrations in the mid-normal range during treatment with any of the approved formulations, weighing patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden and cost.[1]

Not the top of the range. The middle. And after ninety years of engineering, the historical verdict on how well the field can hit it is modest: over 85 years, preparations have been slowly improved so that physiological serum levels can now be achieved.[2]

Why "too much" is a real edge, not a hedge

The dose-response evidence draws the upper boundary precisely. Across weekly doses producing mean nadir concentrations of 253, 306, 542, 1,345 and 2,370 ng/dL:[3]

• Fat-free mass, strength, muscle volume, hemoglobin and IGF-I rose with concentration
• Fat mass and HDL cholesterol fell with concentration
• Sexual function, mood, visual-spatial cognition and PSA did not change significantly at any dose

So the things that scale with going higher include two risk markers, and exclude most of what men want. Erythrocytosis is already the most common side effect of testosterone therapy, with published guidance to decrease or discontinue above a hematocrit of 54%.[4]

That is the ceiling, and it is drawn by measurement rather than caution.

Why "too little" is also real

Under-treatment is a genuine failure mode, not the safe default. The point of therapy is to correct a confirmed deficiency, and a dose that never reaches the target has the risks of treatment without the benefit.

The guideline's diagnostic standard makes the floor meaningful too: diagnosis requires symptoms and unequivocally, consistently low concentrations, confirmed on a repeated fasting morning measurement.[1] Both ends of the range matter.

What each route trades

Ninety years of delivery engineering, and every option is a position on the same trade-off:

Oral. Inactivated in the liver; the 17-alpha-alkylated versions that survive first-pass cause hepatotoxicity.[5]

Injectable esters. Bypass the liver, extend the interval — and all the clinically used esters were characterised as having unfavourable pharmacokinetics against the goal of constant physiological levels.[6] Longer esters add the oil-depot reaction, POME.

Patches. Daily and hepatically bypassing; occlusion and permeation enhancers brought skin reactions, and gels displaced them for patient acceptability and their non-occlusive nature.[7]

Gels and sprays. Daily, non-occlusive, well accepted — and they put drug on a skin surface that can transfer to other people, with an FDA boxed warning attached.[8]

There is no option without a cost. That is why the guideline lists five considerations instead of naming a winner.[1]

What this means practically

Mid-normal is the destination. A result in the middle of the range is the treatment working, not an under-dose to be corrected.

Timing changes the reading. With interval dosing, when the sample is drawn determines what it says. Ask your clinician when to draw relative to your last dose — see the 3-month panel.

Hematocrit is the parameter that pushes back. It is monitored precisely because it rises with concentration.[3][4]

Frequently asked questions

Why not aim for the top of the normal range? Because hemoglobin rises and HDL falls with concentration, while mood, sexual function and cognition did not improve at any dose in the dose-response study.[3] The guideline's target is mid-normal.[1]

Has any route actually solved this? Physiological serum levels can now be achieved — after 85 years of slow improvement.[2] "Solved" overstates it; "achievable" is accurate.

Which formulation is best? The guideline does not say, and neither will this page. It names five factors to weigh together.[1]

Where the story goes next

The delivery question does not end with gels. The seasons covering the cardiovascular scare, metabolism, women, contraception and modern practice are in progress.

In the meantime: what higher doses buy you and daily vs weekly dosing.

References

8 sources

1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744. doi:10.1210/jc.2018-00229 · PMID 29562364
2. Nieschlag E, Nieschlag S. ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use. Eur J Endocrinol. 2019;180(6):R201–R212. doi:10.1530/EJE-19-0071 · PMID 30959485
3. Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172–E1181. doi:10.1152/ajpendo.2001.281.6.E1172 · PMID 11701431
4. Agrawal P, Singh SM, Kohn T. Management of Erythrocytosis in Men Receiving Testosterone Therapy: Clinical Consultation Guide. Eur Urol Focus. 2023;9(1):20–21. doi:10.1016/j.euf.2022.10.008 · PMID 36335038
5. Jockenhövel F. Testosterone supplementation: what and how to give. Aging Male. 2003;6(3):200–206. PMID 14628500
6. Partsch CJ, Weinbauer GF, Fang R, et al. Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol. 1995;132(4):514–519. doi:10.1530/eje.0.1320514 · PMID 7711892
7. Hadgraft J, Lane ME. Transdermal delivery of testosterone. Eur J Pharm Biopharm. 2015;92:42–48. doi:10.1016/j.ejpb.2015.02.015 · PMID 25709060
8. U.S. Food and Drug Administration. AndroGel (testosterone gel) 1% — prescribing information, including BOXED WARNING: secondary exposure to testosterone. Reference ID 021015s044. 2019. accessdata.fda.gov