Testosterone gel vs injection: what changes depending on the route of administration

When someone compares testosterone gel with the injectable form, the underlying question is nearly always the same: which one gets into the bloodstream better, and which one works harder? It is a fair question, but the answer is less intuitive than it looks. Before talking about any specific hormone, it helps to understand a concept that runs through the whole of pharmacology: bioavailability, meaning the fraction of a dose that genuinely reaches the circulation and can act. And this is where the route of administration changes everything. Here we explain what is known, with the data, without promising anything that has not been demonstrated.

The short answer

• Bioavailability describes the fraction of a dose that reaches the systemic circulation, and it can vary significantly depending on the route of administration (EUPATI Open Classroom).
• The intravenous route has 100% bioavailability by definition: it is the reference standard against which other routes are compared, not a measure of it being clinically more potent (EUPATI Open Classroom).
• Drugs that pass through the gastrointestinal tract can undergo intestinal and hepatic metabolism (first-pass effect) before reaching the bloodstream, which reduces their bioavailability (EUPATI Open Classroom).
• The idea that intravenous always beats oral has been dismantled in trials: in OVIVA, oral treatment was non-inferior to IV in bone and joint infection (Li HK et al., NEJM 2019).

What bioavailability is and why the route matters

Bioavailability, abbreviated as F in pharmacology, is the fraction of a drug dose that reaches the systemic circulation intact and remains available to produce its effect. Not all of the dose you administer ends up circulating in the blood: some of it can be lost along the way, and how much is lost depends largely on where the drug enters. That is the underlying reason why gel and injection are not simply interchangeable.

The reference standard is the intravenous route. By definition, the bioavailability of an intravenous dose is 100%, because the drug enters the bloodstream directly with no barriers in between. That 100% serves as the absolute benchmark against which all other routes are compared: absolute oral bioavailability, for example, is calculated by comparing the area under the blood concentration curve after an oral dose with that of the same drug given intravenously, adjusting for dose if they differ. One nuance is worth underlining, because it is often misread: the fact that the intravenous route has an F of 100% does not mean it is more potent or clinically better. It is simply the definition of the starting point.

The first-pass effect: why oral loses out along the way

The big difference between routes lies in what is known as the first-pass effect. Drugs given into the gastrointestinal tract can be metabolised in the intestine and the liver before reaching the general circulation, and that metabolism can reduce bioavailability significantly. In other words: you take a dose, but only part of it survives the journey to the bloodstream. That is why many molecules are formulated for routes that bypass that step, such as the transdermal route of a gel, or injection.

Fentanyl offers a well-measured example: in one pharmacokinetic study, dose-adjusted absolute bioavailability was 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product (PMC8648480, 2021). The speed changes too: time to peak concentration was shortest by the intravenous route (0.06 h), followed by intranasal (0.21 h) and, more slowly, oral transmucosal (1.20 h). It is a different drug and cannot be extrapolated to hormones, but it illustrates the principle well: the route determines how much gets there and at what rate.

There are even extreme cases where the route is everything. Prostaglandins are inactivated in the lungs, so their bioavailability can be practically zero even after an intravenous injection. The lesson for the reader is clear: there is no universally superior route; it depends on the molecule, on where it is metabolised and on what you are trying to achieve.

The myth that injections are always more effective

There is a widely held belief, among patients too, that whatever goes in via a vein or an injection works better than something swallowed or applied to the skin. It is an idea with more tradition than evidence behind it: historically it rested on a specialist opinion published in 1970 and was then perpetuated in guidelines, protocols and textbooks, despite the scant evidence supporting it. When it was finally put to the test in proper trials, the result surprised a lot of people.

The OVIVA trial, multicentre, randomised and designed for non-inferiority, compared oral with intravenous antibiotics in bone and joint infection. Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and in 67 of 509 (13.2%) in the oral group, with an intention-to-treat risk difference of −1.4 percentage points (90% CI −4.9 to 2.2): oral was not inferior. The intravenous group also had a longer hospital stay (14 versus 11 days), more early discontinuations of treatment (18.9% versus 12.8%) and more catheter-related complications (9.4% versus 1.0%). In fact, of 2,077 patients screened, only 80 were excluded because no appropriate oral antibiotic was available.

The POET trial pointed in the same direction in stabilised left-sided endocarditis: switching to an oral antibiotic in the community, after at least 10 days of intravenous therapy and provided the patient could take the medication, was non-inferior to continued IV. The composite outcome occurred in 12.1% of those treated intravenously and in 9.0% of those treated orally (OR 0.72; 95% CI 0.37 to 1.36). At long-term follow-up (median 3.5 years), the primary outcome appeared in 38.2% of the IV group versus 26.4% of the oral group (HR 0.64; 95% CI 0.45 to 0.91).

These trials involve antibiotics, not hormones, and they serve to dismantle the general myth, not to transfer figures across to testosterone. But an honest caveat is in order: none of this means the oral route works always and for everyone. Switching from one route to another requires strict conditions of clinical stability, good absorption and an appropriate context. Indeed, POET makes clear that its results do not apply to right-sided endocarditis or to infections outside the list studied.

When and how a change of route is considered

In hospital settings there are structured criteria for deciding when to move from intravenous to oral, precisely so that the decision does not rest on intuition. The IVOS criteria are organised into five sections: timing of the intravenous antimicrobial review, clinical signs and symptoms, markers of infection, availability of the enteral route, and exclusions by type of infection (systematic review, PubMed 37419640, 2023).

Other frameworks are even more specific. Using a modified Delphi procedure, six criteria for switching from intravenous to oral were developed, operationalised into 16 measurable conditions, all of which must be met in hospitalised adults after 48–72 hours of intravenous therapy (Akhloufi H et al., J Antimicrob Chemother 2017). Along the same lines, the UK START SMART–FOCUS guidance recommends reviewing the diagnosis and the continued need for antibiotics at 48–72 hours and documenting a clear action plan. The common thread is that the route is chosen on the basis of criteria, not habit.

Frequently asked questions

Is injectable testosterone stronger than the gel?

Not necessarily: the idea that injections are always more effective is a myth without solid backing. What changes between routes is the bioavailability and the speed at which the drug reaches the bloodstream, not any automatic superiority. The right route depends on the molecule, on the aim of treatment and on an individual assessment of each person.

What is the bioavailability of a medicine?

It is the fraction of a dose that reaches the systemic circulation and remains available to act (EUPATI Open Classroom). It varies according to the route of administration: by definition, the intravenous route is 100% and serves as the reference for comparing the rest. With routes that pass through the digestive tract, part of the dose is lost to the first-pass effect.

Why does less of what you swallow reach the bloodstream?

Because drugs given into the gastrointestinal tract can be metabolised in the intestine and the liver before reaching the general circulation, which is known as the first-pass effect (EUPATI Open Classroom). That step can reduce bioavailability significantly. This is why some formulations opt for routes that avoid it, such as transdermal or injectable.

Can you switch from the injectable route to the oral one at any time?

No: changing route requires strict conditions of clinical stability, adequate absorption and an appropriate context. In hospital settings there are structured criteria, such as IVOS or frameworks that require several conditions to be met after 48–72 hours of intravenous therapy. The decision is always taken by a professional assessing each case.

In summary

What to take away is straightforward: the route of administration changes how much drug reaches the bloodstream and how fast, but there is no universally superior route, and the idea that injections always win is based more on habit than on evidence. The right choice depends on the molecule, on the goal and, above all, on an individual assessment. For men's hormonal health, there is one route that is genuinely appropriate in Spain today: medical treatment with prior assessment, a prescription where appropriate from a doctor registered in Spain, and ongoing follow-up. At AiON you can check whether you are eligible and take the first step with an initial assessment.