Male Hypogonadism: History of Treatment Over Decades

Male hypogonadism, a condition in which the testes produce insufficient testosterone (primary hypogonadism) or the pituitary-hypothalamic signal driving testosterone production fails (secondary hypogonadism), has been treated with some form of testicular hormone therapy for over 130 years. Testosterone replacement therapy (TRT) is the modern umbrella term for exogenous testosterone dosing, distinct from axis-stimulating therapies such as human chorionic gonadotropin (hCG), clomiphene citrate, or pulsatile gonadotropin-releasing hormone (GnRH), which raise a man's own testosterone rather than replacing it.

The useful question about this history is not "when was testosterone discovered" but "which problem did each new formulation actually solve, and what new problem did it create." Every major advance in TRT, from 1930s injectable esters to 2020s oral capsules, traded one limitation for another: convenience for injection burden, absorption for hepatotoxicity, daily application for transfer risk to household contacts. That pattern is the most clinically useful lens for a patient or clinician choosing among today's options, because it explains why no single formulation is universally "best" and why guideline bodies still weigh trade-offs individually.

Direct answer

Testosterone was chemically synthesized in 1935 and the first injectable ester (testosterone propionate) reached clinical use around 1937, following decades of unproven organotherapy dating to Charles-Édouard Brown-Séquard's 1889 self-experiments. Since then, treatment has moved through longer-acting injectable esters (1950s), oral androgens later abandoned for liver toxicity, transdermal patches and gels (1990s-2000s), long-acting injectables and pellets (2010s), and non-hepatotoxic oral capsules (2019-2022). The evidence anchor for current cardiovascular safety is the large randomized TRAVERSE trial, published in the New England Journal of Medicine in 2023, which is the type of controlled comparison earlier decades of TRT never had. Several specific figures in older secondary sources describing this history (exact trial sizes, extrusion rates, questionnaire sensitivity numbers) could not be verified against primary literature for this draft and are flagged below rather than stated as fact.

The 19th century: organotherapy, before anyone understood the hormone

Before testosterone was identified, physicians theorized that a substance secreted by the testes governed male vitality. In 1889, French-American physiologist Charles-Édouard Brown-Séquard reported that injecting himself with extracts of dog and guinea pig testes improved his energy and cognitive function. His report is widely cited in endocrinology histories as the origin point of "organotherapy," but the effect he described is generally regarded by historians of medicine as most consistent with a placebo response rather than a pharmacologic one, since crude tissue extract would not deliver a meaningful dose of an active steroid.

That claim nonetheless launched a commercial wave of unstandardized testicular extract "tonics" sold across Europe and the United States into the early 1900s. Between roughly 1910 and 1930, Austrian physiologist Eugen Steinach separately promoted vasectomy as a rejuvenation procedure, theorizing it would concentrate internal testicular secretions; this too lacked controlled supporting evidence. Both episodes are worth noting for a reason beyond curiosity: they illustrate why regulators eventually required chemical isolation and standardized dosing before a hormone product could be marketed, a requirement that shaped every formulation that followed.

The 1930s: testosterone isolated and synthesized

Testosterone was independently synthesized from cholesterol by Adolf Butenandt in Germany and Leopold Ruzicka in Switzerland in 1935; both later shared the 1939 Nobel Prize in Chemistry for work on sex hormones. Within a few years, testosterone propionate became available as the first chemically defined injectable androgen. Early case series in castrated or hypogonadal men reported that intramuscular testosterone propionate restored secondary sexual characteristics, establishing the basic principle behind every TRT formulation since: exogenous androgen can substitute for absent testicular production.

Testosterone propionate's short ester chain gave it a short half-life, requiring injections roughly every one to three days to hold stable levels. That inconvenience is the reason the field almost immediately began looking for longer-acting esters.

The 1950s-1960s: longer esters and the oral androgen dead end

Testosterone cypionate and testosterone enanthate, both with half-lives of roughly four to five days, entered clinical use in the early-to-mid 1950s and allowed weekly or biweekly dosing instead of near-daily injections. These two esters became the standard of care for primary hypogonadism in the United States and remain among the most widely prescribed injectable formulations today.

Oral testosterone was attractive to patients who wanted to avoid injections, and methyltestosterone (a 17-alpha-alkylated androgen) was used from the 1940s onward because alkylation lets the molecule survive first-pass liver metabolism. That same alkylation, however, is associated with hepatotoxicity, including peliosis hepatis and cholestatic jaundice, and most endocrinologists had abandoned methyltestosterone by the 1980s. This history is the direct reason hepatic safety data became a required part of every later oral androgen's approval package, including the very different oral formulations approved decades later.

Subcutaneous testosterone pellet implants also existed in this general era, but the specific early dosing regimens, adoption patterns, and reasons for their limited mid-century U.S. uptake are not well characterized in the sources reviewed for this article and should not be stated as settled fact.

The 1970s-1980s: mapping the hormonal axis and treating around fertility

As researchers mapped the hypothalamic-pituitary-gonadal (HPG) axis, the clinical distinction between primary hypogonadism (testicular failure, with elevated LH and FSH) and secondary hypogonadism (hypothalamic or pituitary failure, with low or inappropriately normal LH and FSH) became actionable, because it determines whether replacing testosterone directly or stimulating the axis is the appropriate strategy.

Three axis-based therapies emerged in this period:

• Clomiphene citrate, an estrogen receptor antagonist at the hypothalamus, was FDA-approved for female anovulation in 1967 and was studied off-label in men with secondary hypogonadism starting in the 1970s. It disinhibits GnRH pulsatility, raising LH, FSH, and endogenous testosterone. It remains an off-label option today and is discussed in current Endocrine Society guidance, though it has never carried an FDA-approved indication for male hypogonadism.
• Human chorionic gonadotropin (hCG), which mimics LH at the Leydig cell, entered practice for secondary hypogonadism and cryptorchidism in the 1970s. Because it stimulates intratesticular testosterone production without suppressing spermatogenesis the way exogenous testosterone does, it became the preferred option for hypogonadal men who want to preserve fertility.
• Pulsatile GnRH therapy, delivered by a portable subcutaneous pump, was studied for Kallmann syndrome (a congenital form of hypogonadotropic hypogonadism, often with anosmia) in the late 1970s and early 1980s and can induce spermatogenesis in men who would otherwise remain infertile. It remains the most physiologically precise option for that specific subtype, though it is used far less often today than hCG-based regimens because of the equipment and monitoring burden.

The 1990s: the first non-injectable mainstream options

Scrotal testosterone patches (Testoderm) were FDA-approved in 1993. Because scrotal skin is thin and rich in 5-alpha-reductase, absorption through it produced dihydrotestosterone (DHT) levels well above the normal physiologic ratio, raising theoretical concerns about prostate exposure that limited enthusiasm for the scrotal route.

Androderm, a non-scrotal patch applied to the back, abdomen, thigh, or upper arm, was approved in 1995 and produced more physiologic DHT levels, but skin irritation at the application site was common enough in trials to limit long-term adherence for some patients. Even so, injectable testosterone cypionate remained the most-prescribed formulation through the 1990s, largely on cost grounds, and injectable esters still account for a substantial share of U.S. TRT prescriptions today.

The 2000s: gels, a prescribing surge, and a new safety signal

AndroGel 1% (testosterone gel) received FDA approval in February 2000 and changed prescribing behavior quickly: once-daily application, more stable serum levels than injections, and easier dose titration than patches made it popular with both patients and prescribers.

Gel formulations introduced a distinct safety problem that injectables and patches did not have to the same degree: secondary exposure. The FDA added a boxed warning addressing the risk of testosterone transfer to women and children through skin-to-skin contact after case reports of virilization in children whose fathers used gel products. Prescribers are instructed to counsel patients to wash application sites and cover them before close contact with others. Striant, a twice-daily buccal tablet approved in 2003, offered another non-injectable route but never gained significant market share because of gum irritation and taste disturbance in a meaningful minority of users.

U.S. testosterone prescribing rose substantially during this decade. The precise multiple and annual prescription counts cited in some secondary sources for 2001-2011 could not be verified against a primary source for this draft and should be treated as approximate pending confirmation. What is well documented is that the rise drew regulatory and clinical scrutiny, because a meaningful share of prescriptions were reportedly written for men with age-related testosterone decline rather than classical, pathology-driven hypogonadism, a population for which controlled trial evidence was largely absent at the time. That scrutiny is the direct backdrop for the NIH-funded Testosterone Trials (TTrials), which launched around 2010.

The 2010s: long-acting injectables, pellet resurgence, and the first large controlled trials

Aveed (testosterone undecanoate injection)

Aveed, an injectable testosterone undecanoate formulation in castor oil, received FDA approval in 2014. Its extended dosing interval (an initial two doses four weeks apart, then roughly every ten weeks) substantially reduced injection frequency for long-term users. Because of a rare but serious risk of pulmonary oil microembolism at the time of injection, Aveed carries a Risk Evaluation and Mitigation Strategy (REMS) that requires administration in a healthcare setting with a post-injection observation period.

The Testosterone Trials (TTrials)

The TTrials, a set of coordinated NIH-funded studies published in the New England Journal of Medicine around 2016, enrolled older men with confirmed low testosterone and at least one hypogonadal symptom and compared testosterone gel against placebo. Reported findings generally described improved sexual function and modest improvements in some measures of vitality and bone density, alongside a signal for increased noncalcified coronary artery plaque in the testosterone group. That cardiovascular signal is what motivated the larger, dedicated safety trial run in the following decade (TRAVERSE, discussed below). Readers should treat exact percentage or sample-size figures for the TTrials as needing verification against the original NEJM publication rather than any secondary summary, including this one.

Endocrine Society guideline update

The Endocrine Society issued an updated Clinical Practice Guideline on testosterone therapy in men with hypogonadism around 2018. In general terms, the guideline supports testosterone therapy for men with confirmed classical hypogonadism, advises against testosterone therapy (in favor of gonadotropin or pulsatile GnRH approaches) for men actively trying to conceive, and recommends against routine treatment of age-related testosterone decline absent confirmed low levels and symptoms. A verbatim quotation of the guideline's specific cardiovascular contraindication language appeared in the prior draft of this article without a checkable source; because it cannot be verified here, it has been removed rather than repeated, and any specific contraindication list should be confirmed against the current published guideline before being presented to a reader as a direct quotation.

Pellet resurgence

Subcutaneous testosterone pellets, implanted under local anesthesia and releasing hormone over roughly three to six months, saw renewed commercial interest in the United States after around 2008. Reported pellet counts per session, per-pellet dosing, and extrusion rates vary across sources; the specific figures in this draft's predecessor were not traceable to a checkable primary source and should be verified before publication rather than presented as an established rate.

The 2020s: non-hepatotoxic oral testosterone and a definitive cardiovascular trial

Choosing a formulation class today: a decision framework built from the historical failure modes

Every era in this history solved a delivery or safety problem and introduced a new one. The table below is meant to help a reader (with their clinician) reason about which historical trade-off actually applies to their situation, rather than defaulting to whichever formulation is most heavily marketed.

Use this table as a basis for discussing testosterone therapy options with your doctor, rather than as a replacement for personalized assessment of your hypogonadism and treatment plan.

Oral testosterone without the older hepatotoxicity problem

Jatenzo (testosterone undecanoate oral capsule) received FDA approval in 2019, and TLANDO (a different oral testosterone undecanoate capsule) followed in 2022. Both differ mechanistically from 1960s-era methyltestosterone: testosterone undecanoate is absorbed through the intestinal lymphatic system, largely bypassing first-pass portal circulation, which is why these formulations do not carry the hepatotoxicity signal associated with 17-alpha-alkylated oral androgens. Jatenzo's labeling requires dosing with a meal containing a meaningful amount of fat for reliable absorption; TLANDO was designed to reduce that dietary dependency. Specific efficacy percentages and trial sizes reported for these approvals in earlier secondary summaries should be confirmed against FDA labeling or the sponsor's published trial data before being cited as precise figures.

Natesto: intranasal testosterone and fertility preservation

Natesto, an intranasal testosterone gel dosed multiple times daily, received FDA approval in 2014. Its pharmacokinetic profile, a rapid peak followed by a fast return to baseline, produces less suppression of LH and FSH than longer-acting formulations, which is the mechanistic rationale for describing it as a fertility-preserving option in hypogonadal men who have not completed family planning. Specific sperm-concentration outcome percentages attributed to this effect in earlier drafts require verification against the primary trial publication before being presented as established.

The TRAVERSE trial: the cardiovascular question finally tested directly

The TRAVERSE trial, a large randomized cardiovascular safety trial in men with hypogonadism and pre-existing or elevated cardiovascular risk, was published in the New England Journal of Medicine in 2023 and found that testosterone gel was non-inferior to placebo on the primary composite cardiac endpoint, while also showing higher rates of atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone group. This trial is the strongest available evidence anchor for cardiovascular safety counseling in men with cardiovascular risk factors, and it should be weighed ahead of the earlier, smaller TTrials signal when the two appear to conflict, because TRAVERSE was purpose-built and powered for cardiac outcomes. A related discussion of testosterone therapy and cardiovascular event risk in hypogonadal patients is available in the peer-reviewed literature (Testosterone therapy in hypogonadal patients and the associated risks of cardiovascular events), and readers or clinicians who want the primary numeric findings from TRAVERSE itself should confirm them against the original NEJM publication rather than any secondary summary, including this one.

Axis-stimulating research: enclomiphene and kisspeptin

Enclomiphene citrate, an isomer of clomiphene with different estrogenic activity, has been studied in men with secondary hypogonadism, and kisspeptin-based peptides that act upstream of GnRH neurons are in early-phase clinical research, particularly for functional hypogonadotropic hypogonadism associated with obesity. Neither is FDA-approved for male hypogonadism as of this writing (2025), and specific efficacy figures from phase II research should be treated as preliminary trial evidence, not established clinical practice, until confirmed in later-phase trials and regulatory review.

Diagnostic thresholds have shifted as much as the treatments

Diagnosis has been almost as contested as treatment. Before reliable testosterone immunoassays existed in the 1970s, diagnosis relied on symptom impressions alone. Even after biochemical testing became routine, the threshold for treatment has never been fully uniform across guideline bodies: the Endocrine Society and the American Urological Association generally use 300 ng/dL total testosterone (on two morning samples) as the diagnostic threshold, while other professional statements have used lower or tiered cutoffs. This disagreement is a genuine, unresolved feature of the field, not an error to be corrected by picking one number, and it is a major reason epidemiological estimates of hypogonadism prevalence vary so widely across studies.

What regulatory action changed, separate from clinical trial data

FDA labeling changes have shaped prescribing independently of trial results. A 2015 label update required testosterone products to carry cardiovascular risk warning language, and a subsequent narrowing of approved indications restricted labeled use to classical hypogonadism from identified causes (for example Klinefelter syndrome, orchiectomy, or pituitary disease) rather than broader age-related decline. Off-label prescribing for age-related low testosterone continues in practice, but it sits outside the FDA-approved indication, and that distinction matters when a patient is weighing insurance coverage or risk-benefit counseling with a prescriber. Coverage and label details are dated to the point of writing and should be reconfirmed at prescribing time.

Evidence boundary: what is established, what is plausible, what is not settled

Established: Testosterone was synthesized in 1935; injectable esters (propionate, then cypionate and enanthate) were the mainstay through most of the 20th century; methyltestosterone was abandoned for hepatotoxicity; transdermal gels and patches introduced transfer-risk and irritation trade-offs respectively; TRAVERSE (NEJM, 2023) found testosterone gel non-inferior to placebo for major cardiac events in men with elevated cardiovascular risk while showing higher rates of atrial fibrillation, pulmonary embolism, and acute kidney injury; exogenous testosterone suppresses spermatogenesis and hCG or pulsatile GnRH are the standard alternatives for men preserving fertility.

Plausible but not fully verified here: Specific trial sample sizes, efficacy percentages, and adverse event rates attributed in earlier secondary summaries to the TTrials, Jatenzo and TLANDO approval trials, Natesto fertility outcomes, and pellet extrusion rates. These claims are directionally consistent with what is known about each formulation class but should be checked against the primary publication or FDA label before being restated as precise figures in patient-facing material.

Not established: A single universal biochemical threshold for diagnosing hypogonadism across all guideline bodies; the long-term (multi-decade) cardiovascular and prostate safety profile of oral testosterone undecanoate capsules, which have a much shorter postmarketing history than injectable esters; and efficacy or safety of enclomiphene or kisspeptin-based therapies outside early-phase trials.

This article does not provide individualized diagnosis or dosing guidance. A man with symptoms of low testosterone should be evaluated with confirmed morning laboratory testing and a clinical history, and anyone with chest pain, signs of a blood clot, or other acute symptoms while on testosterone therapy should seek urgent medical care rather than waiting for a routine follow-up.

Note for editorial review: numerous specific figures in the prior version of this article (trial sample sizes, efficacy percentages, extrusion rates, questionnaire sensitivity/specificity, direct quotations attributed to guideline documents and the TRAVERSE authors) could not be traced to a verifiable primary source during this revision and have been either removed, generalized, or explicitly flagged for verification. Before publication, historical approval-year claims and any restated numeric findings should be checked against FDA drug approval records, the original NEJM publications for the TTrials and TRAVERSE, and the current Endocrine Society guideline text.