How Testosterone Crosses Skin, and Why That Route Exists at All

Male hypogonadism has been treated with exogenous testosterone since the 1930s. Transdermal patches arrived in the 1980s, with gels and solutions following in subsequent decades.[1] The reason the skin route was worth developing is narrow and specific: it is the only way to deliver testosterone daily, at physiological-ish concentrations, without a needle and without the liver destroying it first.

The barrier

Skin's outermost layer, the stratum corneum, is a barrier built to stop things crossing. Most drugs cannot get through it in useful quantities. The ones that can share a rough profile — small enough, and lipophilic enough to partition into the lipid matrix between the corneocytes, while still able to leave that matrix and enter the aqueous tissue below.

Testosterone happens to fit. That is a fact about the molecule, not an achievement of any formulation, and it is why transdermal testosterone products exist at all while transdermal versions of most drugs do not.

The permeation characteristics of testosterone, the pharmacokinetics that follow application, and the formulations currently on the market are reviewed together by Hadgraft and Lane.[1]

Why the route was worth having

Testosterone given orally is largely inactivated by the liver before reaching the circulation. Every delivery method is an answer to that, and each answer has a cost — the full set is in ninety years of delivery methods.

The skin's specific advantage is not that it absorbs better than a depot injection. It is that it can be dosed every day. A depot delivers a bolus that decays over an interval; a daily topical dose restarts each morning. That difference in shape, rather than any difference in potency, is the argument for the route — set out in why skin is the best delivery route.

What the formulation actually controls

Since the molecule's permeability is fixed, a formulation can only influence three things: how much drug is presented to the skin, over what area, and in what vehicle.

That is why gels took the market for reasons that were not pharmacokinetic. Gels dominate transdermal testosterone replacement, in the review's own words, "presumably because of their greater patient acceptability and non-occlusive nature compared with patches."[1] Comfort, not absorption.

It is also why the formulation-specific hazard of gels is a surface problem rather than an absorption problem: specific incidences of secondary transfer of gels to children, with consequent unwanted effects such as precocious puberty, have been reported.[1] Drug on the outside of the skin can move to another person before it is absorbed. See the transfer warning.

What a metered spray measured

A metered pump spray is a liquid formulation applied to skin to deliver drug systemically. In an open-label, randomised, placebo-controlled three-period study, twelve healthy men received 50 mg of a transdermal spray preparation, its placebo, and 50 mg of a commercially available 1% topical testosterone gel.[2]

Mean AUC(0,12 h) was 61.8 ng·mL⁻¹·h for the spray versus 57.7 for the gel and 50.7 for placebo. Mean Cmax(0,12 h) was 6.6 ng·mL⁻¹ for the spray and 6.5 for the gel, against 5.7 for placebo. The 90% confidence intervals on the ratios fell within the 80–125% bioequivalence limits (Cmax 89.2–112.3%, AUC 93.5–120.5%).[2]

The paper's conclusion is that the spray delivered testosterone systemically and that concentrations over 12 hours were bioequivalent to an existing topical gel.[2]

One number in that set deserves attention, and it is the placebo. Placebo AUC was 50.7 against the spray's 61.8 — the untreated baseline accounts for most of the measured signal, because these were healthy men making their own testosterone. That is not a flaw in the study; it is a property of measuring an endogenous hormone. It is also why the question of correcting for endogenous testosterone matters so much in later work on the same platform, and why the honest account of what these papers do and do not establish is set out separately in what three published papers support — and four things they don't.

What absorption science cannot tell you

Three limits worth stating.

1. Bioequivalence over 12 hours in healthy volunteers is not a clinical outcome. It says a formulation delivers comparably to another formulation, in men who did not need treatment.
2. Skin varies. Site, thickness, hydration, temperature, and what happens to the area afterwards all affect delivery. This is why application instructions are specific rather than decorative.
3. The regulatory picture moves independently of the pharmacology. Hadgraft and Lane noted a regulatory review of all testosterone replacement therapies underway at the time of writing, with possible implications for prescribing.[1] That review became the class-wide labeling actions covered in the controversy years.

Bottom line

Testosterone crosses skin because its size and solubility suit the barrier — a property of the molecule, not of any product. The route earns its place because it allows daily dosing without a needle and without first-pass inactivation.

What a formulation controls is dose, area and vehicle, which is why the differences between topical products show up mainly in acceptability and in transfer risk rather than in how much hormone gets across.

References

2 sources

1. 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
2. Chik Z, Johnston A, Tucker AT, et al. Pharmacokinetics of a new testosterone transdermal delivery system, TDS®-testosterone in healthy males. Br J Clin Pharmacol. 2006;61(3):275–279. doi:10.1111/j.1365-2125.2005.02542.x · PMID 16487220