Skin Is the Only Route That Bypasses the Liver and Allows Daily Dosing

There are three ways to give testosterone, and only one of them avoids the liver and allows daily administration.

Oral. Testosterone given by mouth is inactivated in the liver, which is why parenteral routes or modifications of the molecule were required from the beginning.[1] The modified oral androgens that survive first-pass metabolism cause hepatotoxicity.[2]

Injection. Bypasses the liver. Doses at intervals of days to months, and all the clinically used injectable esters were characterised as having unfavourable pharmacokinetics against the goal of constant physiological levels.[3]

Skin. Bypasses the liver and permits daily dosing.

That is the case for the transdermal route, stated without embellishment.

Why skin is nonetheless hard

The barrier is the point of skin. Its job is to keep things out, and testosterone does not cross it readily.

Transdermal delivery is therefore a permeation problem before it is anything else,[4] governed by the concentration gradient, the surface area, and the resistance of the skin at that site. Early patches solved it by choosing the most permeable site available; later products solved it with formulation chemistry. The permeation science itself — why testosterone crosses skin when most drugs cannot — is in how testosterone crosses skin.

The history of that engineering — scrotal patch to non-scrotal patch to gel — is The T Files S4.

What skin does not solve

Transfer. A treated skin surface can move drug to another person, which is why testosterone gels carry an FDA boxed warning covering virilization in secondarily exposed children.[6] This applies to every topical testosterone as a class — see gel transfer risk.

Variability. Absorption depends on site, area and skin, which makes dose reproducibility an engineering requirement rather than a given.[4]

Every route trades one problem for another. That is the honest framing of the whole subject, set out in the pharmacokinetic Goldilocks problem.

Frequently asked questions

Is transdermal better than injection? The Endocrine Society guideline does not rank routes. It asks clinicians to weigh pharmacokinetics, patient preference, formulation-specific adverse effects, treatment burden and cost together.[7]

Why can't I take a testosterone tablet? It is inactivated in the liver.[1]

Does skin delivery avoid the peak-and-trough problem? Daily administration narrows the interval, which is a pharmacokinetic argument rather than a demonstrated outcome benefit — set out honestly in daily vs weekly dosing.

Next in this series

The transfer problem is the defining constraint of topical testosterone, and it is worth understanding properly.

Continue with the problem with gels.

References

7 sources

1. 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
2. Jockenhövel F. Testosterone supplementation: what and how to give. Aging Male. 2003;6(3):200–206. PMID 14628500
3. 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
4. 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
5. Amory JK, Blithe DL, Sitruk-Ware R, et al. Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone). Contraception. 2023;124:110064. doi:10.1016/j.contraception.2023.110064 · PMID 37210024
6. 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
7. 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