Male Hypogonadism: History of Treatment Over Decades

The 19th Century: Organotherapy and the First Androgen Experiments

Before synthetic hormones existed, physicians hypothesized that testicular secretions controlled male vitality. Charles-Édouard Brown-Séquard, a French-American physiologist, reported in 1889 that he had injected himself with extracts from dog and guinea pig testes and experienced improved energy and cognitive function. His claim, published in The Lancet, launched what became known as organotherapy. The results were almost certainly placebo-driven, but the conceptual leap mattered: a circulating testicular substance governed male physiology [1].

Why Brown-Séquard's Work Still Matters Clinically

Brown-Séquard's paper prompted dozens of European researchers to pursue testicular extracts commercially. By the early 1900s, crude orchic preparations were sold as rejuvenating tonics, none of them standardized, none proven by today's standards. That commercial chaos eventually forced regulators to demand chemical isolation of the active compound, setting the stage for the 1930s breakthrough.

The Eugen Steinach Era: Vasectomy as Rejuvenation

Between 1910 and 1930, Austrian physiologist Eugen Steinach promoted vasectomy as a "rejuvenation" operation, theorizing it would concentrate internal testicular secretions. Yeats, Freud, and several heads of state reportedly underwent the procedure. No controlled evidence supported it [2]. The Steinach craze illustrates how desperately clinicians and patients sought a solution to androgen deficiency before biochemistry could provide one.

The 1930s: Testosterone Isolated and Synthesized

The modern era of hypogonadism treatment begins in 1935. Adolf Butenandt at the University of Göttingen and Leopold Ruzicka in Zurich independently synthesized testosterone from cholesterol, and both shared the 1939 Nobel Prize in Chemistry [3]. Within two years, pharmaceutical manufacturers produced testosterone propionate, the first injectable ester with a short half-life requiring injections every 1 to 3 days.

First Clinical Trials in Hypogonadal Men

Carl Moore and colleagues at the University of Chicago demonstrated in 1937 that intramuscular testosterone propionate restored secondary sexual characteristics in castrated men. These early case series established proof of concept that exogenous androgen could substitute for absent testicular production, the principle underlying every TRT formulation approved since [4].

Testosterone Propionate: Effective but Inconvenient

Testosterone propionate was FDA-approved in 1937 and remained a clinical mainstay through the 1940s. Its short ester chain meant peak-and-trough pharmacokinetics that patients found burdensome. A man required injections two or three times per week to maintain stable serum levels. The obvious clinical need for a longer-acting compound drove the next formulation advance.

The 1950s, 1960s: Longer Esters and Oral Androgens

By the early 1950s, chemists had produced testosterone enanthate and testosterone cypionate, both with half-lives of roughly 4 to 5 days, allowing weekly or biweekly injections. Testosterone cypionate received FDA approval in 1951 and testosterone enanthate in 1953. Both became standard of care for primary hypogonadism in the United States and remain widely prescribed today [5].

Methyltestosterone: The Oral Option and Its Problems

Oral testosterone was appealing to patients who avoided injections. Methyltestosterone, a 17-alpha-alkylated androgen, was available from the 1940s onward. It survived first-pass hepatic metabolism, unlike native testosterone, but its hepatotoxicity risk, including peliosis hepatis and cholestatic jaundice, led most endocrinologists to abandon it by the 1980s [6]. The lesson shaped regulatory expectations for every subsequent oral formulation: hepatic safety biomarkers became a mandatory component of approval packages.

Subcutaneous Pellet Implants: An Overlooked Early Technology

Testosterone pellet implants were actually described as early as 1940 by Drs. Deansley and Parkes in the United Kingdom. Pellets containing 75 to 200 mg of crystalline testosterone were inserted subcutaneously every 3 to 6 months. The approach saw limited U.S. Uptake for decades because injectable esters were cheaper and better understood, but the pellet concept never disappeared entirely [7].

The 1970s, 1980s: The Hypothalamic-Pituitary Axis Takes Center Stage

A critical shift in clinical thinking occurred once researchers mapped the hypothalamic-pituitary-gonadal (HPG) axis in detail. The distinction between primary hypogonadism (testicular failure, elevated LH and FSH) and secondary hypogonadism (hypothalamic or pituitary failure, low or inappropriately normal LH and FSH) became clinically actionable [8].

Clomiphene Citrate and the Off-Label Era

Clomiphene citrate, a selective estrogen receptor modulator (SERM) approved by the FDA in 1967 for female anovulation, was studied off-label in men with secondary hypogonadism beginning in the 1970s. By blocking estrogen receptors at the hypothalamus, clomiphene disinhibits GnRH pulsatility, raising LH, FSH, and endogenous testosterone. Small studies from the 1970s and 1980s showed increases in serum testosterone of 100 to 200 ng/dL in men with functional secondary hypogonadism [9]. Clomiphene remains off-label for this indication in the U.S. To this day but is listed as an option in Endocrine Society guidance.

Human Chorionic Gonadotropin (hCG) Enters Practice

HCG, which mimics LH at the Leydig cell, was introduced as a treatment for secondary hypogonadism and cryptorchidism in the 1970s. Because hCG stimulates intratesticular testosterone production and preserves spermatogenesis, it became the preferred option for hypogonadal men who wished to maintain fertility, a clinical niche that exogenous testosterone therapy directly suppresses [10].

GnRH Pulse Therapy for Kallmann Syndrome

Kallmann syndrome, the congenital form of hypogonadotropic hypogonadism often accompanied by anosmia, requires pulsatile GnRH to restore the HPG axis. Portable subcutaneous GnRH pumps, delivering 75 to 150 ng/kg every 90 minutes, were studied in the late 1970s and early 1980s and shown to induce spermatogenesis in men with Kallmann syndrome who would otherwise remain infertile [11]. This technology remains the most physiologically precise available for that specific subtype.

The 1990s: Transdermal Testosterone Arrives

The 1990s produced the first non-injectable, non-oral mainstream alternatives. Scrotal testosterone patches (Testoderm) received FDA approval in 1993. The scrotal skin, with its thin stratum corneum and high 5-alpha-reductase activity, delivered adequate systemic testosterone but produced dihydrotestosterone (DHT) levels substantially above the normal range, raising concerns about prostate effects [12].

Non-Scrotal Patches and the Rise of Patient Choice

Androderm, a non-scrotal transdermal patch, received FDA approval in 1995. It could be applied to the back, abdomen, thigh, or upper arm and produced more physiologic DHT levels than scrotal patches. Skin irritation at the patch site affected up to 36% of users in clinical trials, limiting long-term adherence [13]. Still, the patch era marked the first time patients could self-administer testosterone without a syringe.

Testosterone Cypionate Remains Dominant

Despite new transdermal options, intramuscular testosterone cypionate remained the most prescribed TRT formulation throughout the 1990s, largely because of cost. A vial of generic testosterone cypionate cost a fraction of branded patches. That economic reality has persisted: as of 2023, injectable testosterone cypionate and enanthate still account for the majority of TRT prescriptions written in the United States [14].

The 2000s: Gels, Buccal Systems, and a Prescribing Surge

AndroGel 1% (testosterone gel) received FDA approval in February 2000 and changed prescribing behavior rapidly. The gel offered once-daily application, stable serum levels, easy dose titration by adjusting packet size, and no skin irritation comparable to patches. Within five years of launch, AndroGel was one of the top-selling branded drugs in the United States [15].

The Transfer Risk Problem

Gel formulations introduced a new safety concern: secondary exposure. A 2009 FDA black-box warning addressed the risk of testosterone transfer to women and children through skin-to-skin contact, following case reports of virilization in young children whose fathers used gel formulations [16]. Prescribers were instructed to counsel patients to wash application sites before contact and to cover the area with clothing.

Buccal Testosterone

Striant, a testosterone buccal system delivering 30 mg twice daily via a mucoadhesive tablet applied to the upper gum, received FDA approval in 2003. Absorption bypassed first-pass hepatic metabolism. Gum irritation and altered taste affected a meaningful minority of users, and the formulation never achieved significant market share, but it expanded the mechanistic range of available options [17].

Prescribing Trends and Controversy

Testosterone prescriptions in the United States tripled between 2001 and 2011, from approximately 1.3 million to 3.8 million annual prescriptions [18]. That surge drew scrutiny. Critics argued that many prescriptions were issued to men with age-related decline rather than classical hypogonadism, a population for whom strong trial evidence was, at the time, absent. The debate shaped the design of the Testosterone Trials (TTrials), a landmark NIH-funded study launched in 2010.

The 2010s: Long-Acting Injectables, Pellets Resurge, and the TTrials

The 2010s brought the most extensive controlled-trial evidence in the history of TRT, new long-acting formulations, and updated society guidelines that tightened diagnostic criteria.

Testosterone Undecanoate (Aveed): Once Every 10 Weeks

Aveed, an injectable testosterone undecanoate in castor oil, received FDA approval in March 2014. Its dosing schedule (750 mg at week 0, week 4, then every 10 weeks) dramatically reduced injection burden for patients on long-term therapy [19]. The approval carried a Risk Evaluation and Mitigation Strategy (REMS) requiring administration in a clinical setting because of a serious risk of pulmonary oil microembolism following injection.

The Testosterone Trials: What Controlled Evidence Actually Showed

The TTrials, published in the New England Journal of Medicine in 2016, enrolled 790 men aged 65 or older with serum testosterone below 275 ng/dL and at least one hypogonadal symptom. Testosterone gel (targeting a level of 500 ng/dL) versus placebo was tested across seven coordinated trials. Sexual function improved significantly (P<0.001), and walking distance and some measures of vitality improved modestly. Bone density increased. However, a higher rate of noncalcified coronary artery plaque was observed in the testosterone group, raising cardiovascular questions that subsequent studies have continued to probe [20].

The Endocrine Society 2018 Guideline

The Endocrine Society issued its updated Clinical Practice Guideline on testosterone therapy in men with hypogonadism in 2018. The guideline recommends testosterone therapy for men with classic hypogonadism (two morning serum testosterone measurements below 300 ng/dL plus symptoms), advises against treatment in men seeking fertility without concurrent gonadotropin or pulsatile GnRH therapy, and recommends against routine treatment of age-related testosterone decline in the absence of confirmed low levels [21].

As stated directly in that guideline: "We recommend against starting testosterone therapy in patients who are actively trying to father children, who have uncontrolled heart failure, have had a myocardial infarction or stroke in the past 6 months, or have thrombophilia."

Pellets Resurge as a Mainstream Option

Subcutaneous testosterone pellets, implanted in the buttock or flank under local anesthesia every 3 to 6 months, saw a commercial resurgence in the United States after about 2008, driven partly by direct-to-consumer marketing and partly by patient preference for the "set and forget" dosing schedule. Each pellet contains 75 to 200 mg of crystalline testosterone fused into a cylinder roughly 3 mm in diameter. A typical male implant uses 6 to 12 pellets per session. Extrusion rates of 5 to 10% per session have been reported in observational data [22].

The 2020s: TLANDO, JATENZO, Nasal Gel, and Cardiovascular Clarity

The current decade has produced three developments that distinguish it from all prior eras: FDA approval of the first non-hepatotoxic oral testosterone formulations, a large randomized cardiovascular safety trial, and the emergence of peptide-based secretagogues as adjunctive options.

Oral Testosterone Without Hepatotoxicity: JATENZO and TLANDO

Jatenzo (testosterone undecanoate oral capsule) received FDA approval in March 2019. Unlike 17-alpha-alkylated predecessors, testosterone undecanoate is absorbed via the intestinal lymphatic system, bypassing portal hepatic circulation and avoiding hepatotoxicity [23]. Dosing starts at 237 mg twice daily with a meal containing at least 19 grams of fat. A clinical trial (N=166) showed 87% of men achieved average testosterone levels within the normal range (300 to 1,000 ng/dL) at 12 weeks [24].

TLANDO (testosterone undecanoate 225 mg oral capsule) received FDA approval in March 2022, offering a fixed twice-daily dose without fat-intake requirements for efficacy, simplifying counseling [25].

Natesto: Intranasal Testosterone

Natesto, a 4.5% testosterone nasal gel delivering 11 mg per actuation (dosed three times daily), received FDA approval in 2014. Its short pharmacokinetic profile, with peak serum levels at 30 to 60 minutes and return to baseline within 4 to 6 hours, produced less suppression of LH and FSH than longer-acting formulations. A 2019 study (N=60) found that 88% of Natesto users maintained sperm concentrations above 15 million/mL at 6 months, compared with rates near zero for men on standard injectable TRT [26]. That profile makes it an option for hypogonadal men who have not completed family planning.

The TRAVERSE Trial: Cardiovascular Safety Confirmed

The TRAVERSE trial, published in the New England Journal of Medicine in June 2023, enrolled 5,204 men aged 45 to 80 with hypogonadism and pre-existing or high risk of cardiovascular disease. Testosterone gel versus placebo was compared over a mean follow-up of 22 months. The trial found non-inferiority of testosterone for the primary MACE endpoint (cardiovascular death, noncardiac infarction, and stroke): incidence was 7.0% in the testosterone group versus 7.3% in placebo [27]. The trial showed a higher rate of atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone arm, findings that continue to inform prescribing in high-risk populations.

As the TRAVERSE authors stated: "Testosterone-replacement therapy was non-inferior to placebo with respect to the incidence of major adverse cardiac events."

Enclomiphene and Kisspeptin: The Axis-Stimulating Frontier

Enclomiphene citrate, the trans-isomer of clomiphene with less of the estrogenic agonist activity, is in late-stage clinical development for secondary hypogonadism. Phase II trials showed mean testosterone increases of approximately 170 ng/dL above baseline at 12 weeks [28]. Kisspeptin-10 and kisspeptin-54, neuropeptides that drive GnRH pulsatility upstream of the hypothalamus, are in Phase I and II trials for functional hypogonadotropic hypogonadism, particularly in men with obesity-related androgen suppression [29].

A Decade-by-Decade Summary of Formulation Milestones

| Era | Key Development | Primary Limitation Addressed Next | |---|---|---| | 1889 | Organotherapy (Brown-Séquard) | No active compound isolated | | 1935 | Testosterone synthesized | Short-acting, injection-only | | 1951 to 1953 | Enanthate and cypionate esters | Biweekly injections still required | | 1960s | Methyltestosterone (oral) | Hepatotoxicity led to abandonment | | 1993 to 1995 | Transdermal patches | Skin irritation, DHT elevation | | 2000 | Testosterone gel (AndroGel) | Transfer risk to partners and children | | 2003 | Buccal system (Striant) | Poor tolerability, taste disturbance | | 2014 | Aveed (long-acting injectable) | REMS: clinic-only administration | | 2014 | Natesto (intranasal) | Three-times-daily dosing burden | | 2019 | Jatenzo (oral undecanoate) | Fat-meal requirement for absorption | | 2022 | TLANDO (oral undecanoate) | Newest oral; long-term data still accumulating |

Diagnostic Criteria: How the Threshold Has Shifted

Diagnosing hypogonadism has been as contested as treating it. Early practice relied on symptom scores alone. The introduction of reliable radioimmunoassay for serum testosterone in the 1970s gave clinicians a laboratory anchor, but the threshold below which treatment is warranted has moved repeatedly.

From Symptom Scores to Biochemical Cutoffs

The Androgen Deficiency in Aging Males (ADAM) questionnaire, developed by Morley et al. And validated in a cohort of 316 men, became widely used in primary care after its publication in 2000 [30]. Its sensitivity was approximately 88%, but specificity was only 60%, meaning a large proportion of men who screened positive did not have biochemically confirmed hypogonadism.

The Current 300 ng/dL Threshold and Its Critics

The Endocrine Society 2018 guideline sets 300 ng/dL total testosterone (measured on two morning samples by a reliable assay) as the biochemical threshold for diagnosis. The American Urological Association uses the same cutoff. The AACE/ACE 2016 position statement uses 200 ng/dL for unequivocal deficiency and 200 to 400 ng/dL as a zone requiring symptom confirmation [31]. These differing thresholds partially explain why hypogonadism prevalence estimates vary so widely across epidemiological studies.

The Role of Regulatory Milestones in Shaping Clinical Practice

FDA actions have shaped TRT practice as much as clinical trial data. The 2010 FDA safety communication questioning the cardiovascular safety of testosterone briefly suppressed prescribing before TRAVERSE data provided reassurance. The 2015 label change requiring all testosterone products to carry a warning about possible increased cardiovascular risk affected prescribing patterns measurably [32].

The FDA's 2021 removal of the broader "age-related hypogonadism" indication from approved labeling, restricting approved indications to classical hypogonadism caused by identified pathology (Klinefelter syndrome, orchidectomy, pituitary disease, and similar conditions), clarified that off-label use in age-related decline carries regulatory weight [33].

Current Standard of Care: Where Evidence Points in 2025

The Endocrine Society 2023 update affirms intramuscular testosterone cypionate or enanthate as first-line options for most patients because of cost-effectiveness, a long safety record spanning more than 70 years of postmarketing data, and flexible dosing [21]. Transdermal gels remain appropriate when patients cannot self-inject or prefer daily application. Oral undecanoate formulations are gaining adoption, particularly among men who find gels inconvenient and injections aversive.

Men with secondary hypogonadism who want to preserve fertility should receive hCG monotherapy or hCG combined with FSH, not standard TRT, per both the Endocrine Society and the American Urological Association guidelines.

For symptomatic men with borderline testosterone levels (300 to 400 ng/dL), a shared decision-making approach guided by symptom burden, metabolic risk, and patient preference is appropriate; no guideline currently mandates treatment in that range.