Ninety Years of Delivery Methods, and the One Constraint Behind All of Them

Testosterone was synthesised in 1935. Within months the field ran into the constraint that has shaped every product since: given orally, testosterone is inactivated in the liver, so parenteral forms of administration or modifications of the molecule had to be found.[1]

Ninety years later, the list of delivery methods is long. Every entry on it is an answer to that sentence.

The first two answers, both from the 1930s

Pellets. Testosterone was compressed into pellets and implanted under the skin, bypassing the gut entirely.[2]

Molecular modification. Alternatively, change the molecule so it survives the liver. 17α-methyltestosterone did exactly that and was used for years. It is now obsolete because of liver toxicity.[2]

Those two moves — go around the liver, or change the drug so the liver cannot destroy it — define the whole field. Everything after is refinement.

Injections: 1950s onward

Attaching an ester and suspending it in oil creates a depot that releases slowly from muscle. By the 1950s longer-acting injectable testosterone enanthate had become the preferred therapeutic modality, and in the 1970s orally effective testosterone undecanoate was added to the range of preparations.[2]

The full progression — propionate to enanthate to undecanoate, and the subcutaneous alternative — is covered in the history of testosterone injections.

What injections cannot escape is the shape of a depot: a peak after the dose, a trough before the next one.

The skin: patches, then gels

Skin is the other route that bypasses first-pass metabolism, and unlike a depot it can be dosed daily. Early transdermal patches arrived in the 1980s, with gel and solution preparations following in subsequent decades.[3]

Each step traded one problem for another.

• The first patch went on the scrotum and required preparation most men were unwilling to do — see the first scrotal patch.
• Non-scrotal patches solved the placement problem and introduced a skin-reaction problem — the patch that moved off the scrotum.
• Gels took the market. The pharmaceutical-science literature attributes this to "greater patient acceptability and non-occlusive nature compared with patches"[3] — that is, comfort and convenience, not superior pharmacokinetics.

Gels carry a formulation-specific hazard the patches did not: testosterone can transfer from treated skin to another person on contact, which is the subject of the FDA's boxed warning on those products and of the warning that isn't about the man taking it.

Where a metered spray sits

A metered transdermal spray is the same route as a gel — through skin, bypassing the liver, dosed daily — engineered for a smaller, faster-drying application. Pharmacokinetics for a transdermal spray system in healthy males have been published,[4] and what those papers do and do not support is set out plainly in what three published papers support.

The claim worth making about the route is modest and defensible: skin is the only route that bypasses the liver and allows daily dosing without a needle. Anything stronger needs its own evidence.

The pattern

Read as a list, the methods look like progress. Read against the constraint, they look like a series of trades:

Method	Solves	Costs
Pellets	Oral inactivation, long interval	Minor procedure to implant; fixed once placed
Oral 17α-methyl	Oral inactivation	Liver toxicity — obsolete[2]
Injections	Oral inactivation	Peak-and-trough curve; needles
Patches	Daily dosing, no needle	Skin reactions; placement
Gels	Comfort, acceptability	Transfer risk to others
Metered spray	Daily dosing, small application area	Evidence base narrower than gels'

Nobody has removed the constraint. They have distributed its consequences differently.

Why this matters when choosing

The Endocrine Society guideline lists five things to weigh when selecting a formulation: pharmacokinetics, patient preference, formulation-specific adverse effects, treatment burden and cost.[5]

Notice that "which one is best" is not on that list, because it is not a well-formed question. A man who will not inject reliably is not well served by the formulation with the best curve, and adherence to topical therapy is itself measurable and imperfect.[6]

Bottom line

Ninety years of testosterone delivery is one problem and a series of trades against it. The liver still inactivates oral testosterone. Depots still have peaks and troughs. Skin still permits daily dosing without a needle, and gels still transfer.

Choosing a delivery method is choosing which of those trade-offs you would rather live with — which is why pellets versus a spray is a more useful comparison than any ranking.

References

6 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. Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16(2):161–168. doi:10.4103/1008-682X.122358 · PMID 24435052
3. 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
4. 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
5. 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
6. Grabner M, Hepp Z, Raval A, et al. Topical Testosterone Therapy Adherence and Outcomes Among Men With Primary or Secondary Hypogonadism. J Sex Med. 2018;15(2):148–158. doi:10.1016/j.jsxm.2017.11.225 · PMID 29425664