Both routes exist for the same reason: oral testosterone is inactivated in the liver, so parenteral administration or molecular modification is required.[1] Everything that differentiates them is a consequence of how each solved that.
The two answers
Injection. An ester in oil, deposited in muscle, releasing over days to months. Bypasses the liver, extends the interval. Every clinically used injectable ester was characterised as having unfavourable pharmacokinetics measured against the goal of constant physiological levels,[2] and long-acting oil depots carry their own reaction — pulmonary oil microembolism, reviewed across 7,978 patients and found rare, with almost all cases resolving spontaneously within 60 minutes.[3]
Transdermal. Absorbed through skin, bypassing the liver, administered daily. Gels dominate the transdermal market for patient acceptability and their non-occlusive nature,[4] and they carry the transfer problem — an FDA boxed warning on secondary exposure, with virilization reported in exposed children.[5]
What can and cannot be compared
Can be compared: pharmacokinetics. Interval dosing produces a documented trough; the dose-response study reports nadir concentrations from 253 to 2,370 ng/dL across five weekly doses.[10] Daily administration narrows the interval by definition.
Can be compared: formulation-specific adverse effects. POME belongs to oil depots.[3] Transfer belongs to topicals.[5] They are different risks, not different amounts of one risk.
Has been compared, once, head to head. A 24-week randomised trial put 66 hypogonadal men on either a nightly transdermal system or 200 mg testosterone enanthate IM every two weeks.[6] The injection arm produced supraphysiological levels of testosterone, bioavailable testosterone and estradiol for several days after each injection; the transdermal arm stayed within normal physiological ranges.
The differences that emerged were objective, not symptomatic:
| Transdermal | IM enanthate | |
|---|---|---|
| Morning levels within normal range | 77–100% | 19–84% |
| Abnormal hematocrit elevations | 15.4% | 43.8% |
| LH suppressed to subnormal | 0% | 31% |
| Sexual function and mood | maintained | maintained |
Both treatments maintained sexual function and mood at prior levels.[6] So the smoother profile showed up in blood counts and gonadotropins — not in how men reported feeling.
Still cannot be compared: interval alone. That trial varied route, product and dosing interval together, so it cannot attribute the difference to any one of them. And two other injectable regimens demonstrably do not swing: weekly subcutaneous cypionate held levels stable across the interval in a small study of 11 patients,[7] and long-acting undecanoate produced serum levels not exceeding the upper limit of normal, with a castor-oil half-life of 33.9 ± 4.9 days.[11] The swing belongs to a particular ester-route-interval combination, not to injections as a category.
The five factors, applied
Pharmacokinetics. Interval dosing has a documented trough;[10] daily narrows it. A mechanism, not a demonstrated outcome benefit.
Patient preference. Needles versus a daily application. Not trivial — adherence to topical therapy in routine care is low, and adherent men do better.[9]
Formulation-specific adverse effects. POME for oil depots;[3] transfer for topicals.[5] Household composition is genuine clinical input here.
Treatment burden. Frequent-but-small versus rare-but-an-event.
Cost. Varies.
What does not differ
Monitoring, the mid-normal target, and the diagnostic requirement are identical across routes.[8] Delivery changes how the hormone arrives, not who should receive it or how they are watched.
Frequently asked questions
Which is better? The guideline ranks none, naming five factors instead.[8] The one randomised head-to-head found objective advantages for the daily transdermal profile — fewer hematocrit elevations, less gonadotropin suppression — with no difference in reported mood or sexual function.[6]
Is transdermal more "physiological"? Daily dosing narrows the interval — a pharmacokinetic property. Calling it more physiological in outcome terms goes beyond what has been tested.
Is POME a reason to avoid injections? It is one input. The review found it rare, with almost all cases resolving spontaneously within an hour.[3]
Is transfer a reason to avoid topicals? It is a reason to follow the precautions and to tell your prescriber who you live with.[5]
Next in this series
One more: what a transdermal spray is, in the context of everything above.
Continue with transdermal spray TRT.
References
11 sources
- 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
- 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
- Adam JA, Pastuszak AW, Christensen MB, et al. Occurrence of pulmonary oil microembolism (POME) with intramuscular testosterone undecanoate injection: literature review. Int J Impot Res. 2023;35(5):439–446. doi:10.1038/s41443-022-00585-1 · PMID 35610506
- 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
- 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
- Dobs AS, Meikle AW, Arver S, et al. Pharmacokinetics, Efficacy, and Safety of a Permeation-Enhanced Testosterone Transdermal System in Comparison with Bi-Weekly Injections of Testosterone Enanthate for the Treatment of Hypogonadal Men. J Clin Endocrinol Metab. 1999;84(10):3469–3478. doi:10.1210/jcem.84.10.6078 · PMID 10522982
- McFarland J, Craig W, Clarke NJ, et al. Serum Testosterone Concentrations Remain Stable Between Injections in Patients Receiving Subcutaneous Testosterone. J Endocr Soc. 2017;1(8):1095–1103. doi:10.1210/js.2017-00148 · PMID 29264562
- 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
- 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
- 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
- Behre HM, Abshagen K, Oettel M, et al. Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol. 1999;140(5):414–419. doi:10.1530/eje.0.1400414 · PMID 10229906