History of Testosterone Therapy Injections: How TRT Began and Why It Evolved

Written by Keen Meds  ·  Reviewed by Licensed Clinical Providers  ·  March 1, 2026

Key Insight: Testosterone propionate, the first widely used injectable testosterone, became clinically available in the late 1930s. Testosterone cypionate — still one of the most prescribed forms today — was introduced in the 1950s.

When a man today receives a testosterone prescription, he has access to options that did not exist a decade ago: gels, patches, nasal sprays, oral capsules, and transdermal sprays. But for the first fifty years of testosterone replacement therapy, physicians had one primary tool: an injection.

The clinical history of injectable testosterone spans roughly eight decades, from the late 1930s through the present. Understanding that history helps explain why the specific formulations in use today were developed, what problems they were designed to solve, and why a significant portion of patients and clinicians eventually started looking for alternatives. The core problem, known as peaks and troughs, has been present since the first clinical uses of injectable testosterone and remained largely unsolved until non-injection delivery methods arrived.

The First Injectable Forms: Testosterone Propionate (1937-1940s)

Within two years of testosterone's chemical synthesis in 1935, pharmaceutical chemists had developed the first injectable formulation: testosterone propionate. By esterifying testosterone at its 17-beta hydroxyl group with propionic acid, chemists created a compound that was more stable in oil-based solutions and could be administered intramuscularly.

Testosterone propionate became clinically available in the late 1930s and was used throughout the 1940s for the treatment of hypogonadism, delayed puberty, and certain cases of anemia. It was also studied, with mixed results, for use in menopausal women and for various wasting conditions.

The pharmacological limitation of testosterone propionate was its short half-life. Once injected, the ester was cleaved by esterases in the bloodstream, releasing free testosterone. That free testosterone was metabolized and cleared relatively quickly, with testosterone levels returning toward baseline within 48 to 72 hours. This meant that patients needed injections every two to three days to maintain therapeutic levels.

The short-acting nature of testosterone propionate also meant that the peaks-and-troughs problem was acute. Testosterone levels spiked sharply in the 24 to 48 hours after injection, sometimes into supraphysiological ranges, then declined steeply toward hypogonadal levels before the next injection. Patients often experienced this as a predictable cycle of feeling well in the days immediately after injection and feeling notably worse in the days before the next one.

The Long-Acting Esters: Enanthate and Cypionate (1950s-1960s)

The development of longer-acting testosterone esters in the 1950s addressed the injection frequency problem, though not the peaks-and-troughs problem itself. By attaching longer-chain fatty acids to the testosterone molecule, chemists created esters that dissolved and released testosterone more slowly from an oil depot at the injection site.

Testosterone enanthate, esterified with heptanoic acid, was introduced in the early 1950s. Testosterone cypionate, esterified with cyclopentylpropionic acid, became commercially available in the mid-1950s under the brand name Depo-Testosterone and is still among the most commonly prescribed testosterone formulations in the United States today.

Both enanthate and cypionate have half-lives of approximately 4 to 7 days in clinical practice, allowing injection intervals of 1 to 2 weeks for most patients. This represented a major practical improvement over propionate. A patient could receive an injection every 7 to 14 days rather than every 2 to 3 days, making outpatient testosterone therapy genuinely feasible.

The trade-off was the same as with propionate, just stretched over a longer time window. Testosterone levels still peaked sharply in the first 2 to 4 days after injection, often reaching supraphysiological concentrations. They then declined steadily over the following week, frequently falling into the low-normal or subtherapeutic range by injection day.

Clinical Uses in the Mid-Twentieth Century

Beyond hypogonadism, injectable testosterone was explored for a range of conditions during the mid-twentieth century. Physicians used it for aplastic anemia and other forms of anemia, for which it showed genuine benefit in stimulating erythropoiesis. It was administered for cachexia and wasting associated with chronic illness. It was studied as a contraceptive when given at high doses to suppress sperm production, though no commercially viable male contraceptive was developed from this work.

By the 1960s and 1970s, injectable testosterone was also being used illicitly by athletes and bodybuilders seeking performance enhancement. This use, which operated entirely outside medical supervision and typically involved doses far exceeding what any clinical indication would require, contributed to the social and regulatory complexity that surrounded testosterone throughout the latter half of the twentieth century.

Why Injections Remained Dominant for Decades

Despite the known limitations of the peaks-and-troughs pharmacokinetic profile, injectable testosterone remained the most commonly prescribed formulation for hypogonadism for approximately five decades. Several factors explain this persistence.

First, injections worked. They reliably raised testosterone levels. Patients with symptomatic hypogonadism reported improvement. Second, there were no alternatives until the 1970s. No viable non-injection testosterone delivery method existed for clinical use. Oral testosterone formulations existed, but oral alkylated testosterone carried significant liver toxicity risks. Third, injectables were inexpensive. The manufacturing cost of testosterone cypionate or enanthate in oil was very low, making them accessible in healthcare systems where cost was a primary consideration.

The Peaks-and-Troughs Problem as a Driver of Innovation

The pharmacokinetic limitations of injectable testosterone were well characterized in the medical literature by the 1970s and 1980s. Studies using testosterone assays measured the sharp post-injection peaks and the pre-injection troughs, and correlations with patient-reported mood, energy, and sexual function were documented.

This pharmacokinetic problem became the explicit driver of the next phase of testosterone delivery innovation. Clinicians and researchers asked a straightforward question: could testosterone be delivered in a way that produced stable, physiological blood levels throughout the day rather than a sharply oscillating pattern tied to injection timing?

That question led directly to the development of testosterone patches in the 1970s and 1980s, testosterone gels in the 1990s and early 2000s, and eventually a range of transdermal delivery technologies.

Understanding Your Testosterone Today

The clinical history of injectable testosterone is, in large part, the history of a problem in search of a better solution. Stable, physiological testosterone delivery was the goal from the beginning. The options available to patients today reflect decades of formulation chemistry aimed at achieving precisely that.

Keen Meds connects you with licensed clinical providers for a telehealth evaluation and lab review. If your testosterone is clinically low, you may qualify for a prescription for Testosterone Spray Rx -- a needle-free transdermal testosterone program.