A Comprehensive Monograph on Testosterone (DB00624): From Molecular Structure to Clinical and Regulatory Realities

Executive Summary

Testosterone, the principal endogenous androgenic steroid hormone, is fundamental to the development, maturation, and physiological maintenance of male reproductive tissues and secondary sexual characteristics. In its capacity as a pharmaceutical agent (DrugBank ID: DB00624), testosterone serves as a cornerstone therapy for male hypogonadism, a clinical syndrome characterized by deficient hormone production. Its mechanism of action is centered on its function as an agonist of the nuclear androgen receptor (AR). This interaction occurs either directly or, more potently, through its primary active metabolite, 5α-dihydrotestosterone (DHT), which is synthesized in target tissues. Activation of the AR initiates a cascade of gene transcription events that orchestrate the hormone's broad physiological effects.[1]

The primary and most rigorously defined therapeutic indication for testosterone is as replacement therapy for male hypogonadism. This encompasses both primary hypogonadism, which originates from testicular failure, and secondary (or hypogonadotropic) hypogonadism, which results from dysfunction of the hypothalamic-pituitary axis.[1] Regulatory bodies, including the U.S. Food and Drug Administration (FDA), mandate that a diagnosis be unequivocally confirmed through at least two separate, low serum testosterone measurements taken in the morning, in conjunction with clinical symptoms, before initiating therapy.[5]

The native testosterone molecule exhibits very poor oral bioavailability due to extensive first-pass hepatic metabolism, a pharmacokinetic limitation that has driven decades of pharmaceutical innovation.[7] Consequently, a diverse array of formulations has been developed to achieve therapeutic concentrations. These include long-acting intramuscular injectable esters (e.g., cypionate, enanthate, undecanoate), which form a depot for slow release; various topical systems (gels, patches, solutions) that provide continuous transdermal absorption; and more recent alternative delivery systems such as oral undecanoate capsules that utilize lymphatic absorption, long-lasting subcutaneous pellets, and mucoadhesive buccal tablets. Each formulation possesses a unique pharmacokinetic profile, presenting distinct advantages and disadvantages regarding dosing frequency, serum level stability, and potential for adverse effects like secondary exposure.[8]

The safety and regulatory landscape of testosterone therapy is complex and has undergone significant evolution. A pivotal development occurred in 2023-2025 when the FDA, based on conclusive evidence from the large-scale Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, removed the long-standing Boxed Warning regarding major adverse cardiovascular events.[12] This action was accompanied by the institution of a new, class-wide warning regarding the risk of increased blood pressure, shifting the primary focus of cardiovascular risk management for these products.[13]

In the United States, testosterone is classified as a Schedule III controlled substance under the Controlled Substances Act. This classification reflects its established medical utility alongside a recognized potential for abuse and dependence, particularly within athletic and bodybuilding communities where it is used for its anabolic properties at supraphysiologic doses.[15] This regulatory status imposes specific restrictions on prescribing, dispensing, and patient access, which has become a significant point of discussion and advocacy, particularly concerning its role in gender-affirming hormone therapy.[18]

Chemical Profile and Physicochemical Properties

A comprehensive understanding of testosterone begins with its fundamental chemical identity, structure, and physical properties, which dictate its biological behavior and the pharmaceutical strategies required for its effective delivery.

Nomenclature and Identification

Testosterone is known by a variety of names and is cataloged across numerous chemical and pharmacological databases under specific identifiers. The multiplicity of synonyms reflects its long history of scientific study and clinical use since its isolation in 1935.[8]

• Primary Common Name: Testosterone.[1]
• Systematic (IUPAC) Names: The formal chemical name is (17β)-17-Hydroxyandrost-4-en-3-one. A more detailed systematic name describing its complex stereochemistry is (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one.[20]
• Key Identifiers: The unique identifiers for testosterone are crucial for unambiguous reference in research, regulatory filings, and clinical practice.
• CAS (Chemical Abstracts Service) Number: 58-22-0.[1] This is the most common and specific identifier for the base compound. Different esterified forms have their own unique CAS numbers (e.g., testosterone cypionate: 58-20-8).[8]
• DrugBank ID: DB00624.[1]
• PubChem Compound ID (CID): 6013.[26]
• Molecular Formula: C19H28O2.[15]
• Molecular Weight: Approximately 288.42 g/mol.[2]
• InChIKey (IUPAC International Chemical Identifier Key): MUMGGOZAMZWBJJ-DYKIIFRCSA-N.[8]
• SMILES (Simplified Molecular Input Line Entry System): CC12CCC3C(C1CCC2O)CCC4=CC(=O)CCC34C.[21]

Molecular Structure

Testosterone is a member of the androstanoid class of steroid hormones, which are biologically synthesized from cholesterol.[22] Its structure is characterized by a distinctive polycyclic framework that is the foundation of its biological activity.

The core structure is a tetracyclic system composed of four fused hydrocarbon rings, known as the androstane nucleus. This framework consists of three six-membered cyclohexane rings (labeled A, B, and C) and one five-membered cyclopentane ring (labeled D).[22] The overall structure is relatively planar, which facilitates its interaction with the ligand-binding domain of the androgen receptor.

Two key functional groups are appended to this steroid nucleus, and their specific placement and orientation are critical for androgenic activity:

1. A ketone group (C=O) is located at the third carbon position (C-3) of the A-ring.
2. A hydroxyl group (−OH) is located at the 17th carbon position (C-17) of the D-ring. The stereochemistry of this hydroxyl group is crucial; it must be in the beta (β) orientation (projecting "up" from the plane of the ring system) for optimal biological activity. Its stereoisomer, epitestosterone (17α-hydroxy), is largely inactive.[21]

There is also a double bond between carbons 4 and 5 in the A-ring.21

Physical and Chemical Properties

The physicochemical properties of testosterone directly influence its absorption, distribution, and the design of its pharmaceutical formulations.

• Appearance: Under standard conditions, testosterone is a white or slightly cream-white crystalline powder that is odorless and stable in air.[15]
• Melting Point: The melting point of crystalline testosterone is approximately 155 °C (311 °F).[7]
• Solubility: Testosterone is highly lipophilic (fat-soluble) and hydrophobic (water-insoluble). It is classified as practically insoluble in water.[15] This property allows it to readily cross cell membranes to reach its intracellular receptor but also presents a major challenge for formulation. It is freely soluble in several organic solvents, including alcohol, chloroform (at 100 mg/mL), and dioxane, and is also soluble in vegetable oils.[15] This solubility in oils is exploited in the formulation of intramuscular injectable depot preparations.[15]

The following table provides a consolidated reference for the key chemical identifiers and properties of testosterone.

Property/Identifier	Value	Source(s)
DrugBank ID	DB00624	1
CAS Number	58-22-0	1
Systematic (IUPAC) Name	(17β)-17-Hydroxyandrost-4-en-3-one	20
Molecular Formula	C19​H28​O2​	15
Molecular Weight	288.42 g/mol	21
Physical Appearance	White or creamy white crystalline powder	15
Melting Point	~155 °C	7
Water Solubility	Insoluble	15
Organic Solvent Solubility	Freely soluble in alcohol, chloroform, dioxane; soluble in vegetable oils	15
InChIKey	MUMGGOZAMZWBJJ-DYKIIFRCSA-N	8
SMILES	CC12CCC3C(C1CCC2O)CCC4=CC(=O)CCC34C	21

Pharmacology and Mechanism of Action

The pharmacological effects of testosterone are extensive, influencing a wide range of tissues and physiological processes. These effects are governed by its specific interactions with cellular receptors and its subsequent metabolism into other biologically active steroids. The challenges posed by its pharmacokinetic profile have been the primary impetus for the development of the diverse range of therapeutic formulations available today.

Pharmacodynamics

The biological effects of testosterone are mediated through its function as a ligand for the androgen receptor, a member of the nuclear receptor superfamily. The overall physiological response to testosterone administration is a composite of the actions of testosterone itself and its two principal active metabolites: 5α-dihydrotestosterone (DHT) and estradiol.[1]

The Prohormone Nature of Testosterone

A critical aspect of testosterone's pharmacodynamics is its role as a prohormone. While it is a potent androgen in its own right, its full spectrum of biological activity is only realized through its conversion in various target tissues. This dual-action and triple-ligand system explains the wide range of physiological and potential adverse effects seen with testosterone therapy.

1. Direct Action of Testosterone: Free, unbound testosterone diffuses across the cell membrane into the cytoplasm of target tissue cells. There, it binds directly to the androgen receptor (AR). This binding event induces a conformational change in the AR, causing it to dissociate from heat shock proteins. The activated ligand-receptor complex then translocates into the cell nucleus.[2] Within the nucleus, the complex dimerizes and binds to specific DNA sequences known as Hormone Response Elements (HREs) located in the promoter regions of target genes. This binding modulates the rate of gene transcription, either up- or down-regulating protein synthesis and thereby producing the androgenic effects.[1] This direct action is particularly important in muscle tissue.
2. Conversion to 5α-Dihydrotestosterone (DHT): In many androgen-dependent tissues, including the prostate, skin, hair follicles, and external genitalia, testosterone functions primarily as a prohormone for the more potent androgen, DHT. The cytoplasmic enzyme 5α-reductase irreversibly converts testosterone to DHT.[2] DHT binds to the same androgen receptor as testosterone but does so with approximately five times greater affinity and dissociates more slowly, resulting in a significantly amplified androgenic signal.[2] Many of the classic masculinizing effects, such as the growth and development of the prostate and seminal vesicles, the growth of facial and body hair, and sebum production leading to acne, are predominantly mediated by DHT.[1]
3. Conversion to Estradiol: Testosterone also serves as the direct precursor to the primary estrogen, estradiol. This conversion is catalyzed by the enzyme aromatase, which is found in high concentrations in adipose (fat) tissue, bone, and the brain.[1] The estradiol produced from this conversion is essential for many effects previously attributed solely to testosterone, including the maintenance of bone mineral density, the negative feedback regulation of gonadotropin (LH and FSH) secretion at the pituitary and hypothalamus, and aspects of libido and cognitive function. This pathway is also responsible for certain adverse effects of high-dose testosterone therapy, most notably gynecomastia (breast tissue development in males), which arises from the increased conversion of excess testosterone to estradiol.[2]

This complex interplay means that the clinical effects of testosterone replacement therapy are a result of actions on both the androgen and estrogen receptor systems. This understanding is fundamental to interpreting its efficacy and side effect profile and has led to clinical strategies that sometimes involve co-administration of drugs that block these conversion pathways, such as 5α-reductase inhibitors or aromatase inhibitors.[8]

Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The entire history of testosterone formulation development can be understood as a direct response to the molecule's inherent pharmacokinetic weaknesses: extremely poor oral bioavailability and a very short native half-life. Each class of product represents a different strategy to overcome these challenges.

Absorption

The route of administration dictates the absorption profile of testosterone.

• Oral: When native testosterone is taken orally, it is well-absorbed from the gastrointestinal tract but is subject to extensive and rapid degradation during its first pass through the liver. This "first-pass metabolism" results in very low bioavailability, rendering simple oral administration of the crystalline hormone clinically ineffective.[7] To overcome this, oral formulations like Jatenzo® and Tlando® use testosterone undecanoate, an esterified prodrug formulated in an oil-based mixture. This formulation promotes absorption through the intestinal lymphatic system, bypassing the portal circulation and the liver, thereby allowing therapeutic levels to be reached.[4]
• Intramuscular (IM) Injection: This was the first successful method to bypass hepatic metabolism. Long-chain esters of testosterone (e.g., cypionate, enanthate) are dissolved in an oil vehicle (like cottonseed oil) and injected deep into a muscle.[15] The oil forms a depot from which the esterified testosterone is slowly leached into the circulation. Plasma esterases then cleave the ester side chain, releasing free, active testosterone over a prolonged period.[3] This method provides a long duration of action but is characterized by supraphysiological peak levels shortly after injection, followed by a decline to subtherapeutic trough levels before the next dose, which can lead to fluctuations in mood, energy, and libido.[3] For instance, a 200 mg injection of testosterone cypionate can cause serum levels to spike to 400% of baseline within 24 hours, remaining elevated for 3-5 days before declining.[3]
• Transdermal (Topical): Gels (e.g., AndroGel®), patches (e.g., Androderm®), and solutions (e.g., Axiron®) were developed to provide more stable, continuous absorption over a 24-hour period, better mimicking the natural diurnal rhythm of testosterone secretion.[11] The hormone is absorbed through the skin into the systemic circulation. This approach avoids the peaks and troughs of injections and the first-pass effect of oral administration. However, its primary and most significant drawback is the risk of secondary exposure, where the gel can be transferred to women or children through skin-to-skin contact, leading to unintended virilization.[1]

Distribution

Once in the systemic circulation, testosterone is highly protein-bound. Approximately 98% of circulating testosterone is bound to one of two plasma proteins: sex hormone-binding globulin (SHBG), which binds with high affinity (accounting for 40-60% of binding), and albumin, which binds with lower affinity (accounting for 40-50% of binding).[2] Only the small fraction (about 2%) that remains unbound, or "free," is considered biologically active and available to diffuse into target tissues to exert its effects.[3] Conditions that alter SHBG levels (e.g., liver disease, thyroid disorders, obesity) can significantly impact the amount of free, active testosterone.

Metabolism

Testosterone is metabolized primarily in the liver, but also in its target tissues. As described in the pharmacodynamics section, the two most important metabolic pathways involve conversion to its major active metabolites:

1. 5α-reduction to DHT in the skin, prostate, and liver.[3]
2. Aromatization to estradiol in adipose tissue and the brain.[1]

Testosterone and its metabolites are further inactivated, primarily in the liver, by conversion to 17-keto steroids, such as androsterone and etiocholanolone. These inactive metabolites are then conjugated with glucuronic or sulfuric acid to increase their water solubility for excretion.[1]

Excretion

The water-soluble conjugates of testosterone metabolites are eliminated from the body primarily via the kidneys. About 90% of an administered dose is excreted in the urine. A smaller amount, approximately 6%, is excreted in the feces, mostly in unconjugated form.[3] The elimination half-life of native, unmodified testosterone in the plasma is very short, estimated to be between 10 and 100 minutes.[1] In contrast, the effective half-life of esterified injectable forms is much longer, dictated by the slow release from the IM depot; for example, the half-life of testosterone cypionate is approximately 8 days.[3]

The following table provides a comparative summary of the pharmacokinetic profiles of major testosterone formulations, highlighting the clinical trade-offs between different delivery systems.

Formulation Type	Brand Example(s)	Typical Dosing Frequency	Approx. Time to Peak (Tmax)	Apparent Half-Life	Key Advantage	Key Disadvantage
IM Cypionate/Enanthate	Depo-Testosterone	Every 2-4 weeks	4-5 days	~8 days	Infrequent dosing, low cost	Supraphysiologic peaks and subtherapeutic troughs; mood/libido fluctuations
IM Undecanoate	Aveed	Every 10 weeks (after loading)	~7 days	Long (weeks)	Very infrequent dosing	Risk of POME; requires in-office administration and observation
Transdermal Gel	AndroGel, Fortesta	Once daily	2-24 hours (product dependent)	~24 hours (continuous absorption)	Stable serum levels, mimics circadian rhythm	High risk of secondary transference to others; daily application required
Oral Undecanoate	Jatenzo, Tlando	Twice daily	4-5 hours	~9 hours	Non-invasive, no transference risk	Requires dosing with food; twice-daily adherence needed
Subdermal Pellet	Testopel	Every 3-6 months	~1 month	~2.5 months	Very infrequent dosing, no transference risk	Requires minor surgical procedure for insertion/removal; risk of pellet extrusion
Buccal Tablet	Striant	Twice daily	10-12 hours	~24 hours (continuous absorption)	No transference risk, quick reversal upon removal	Twice-daily adherence needed; potential for gum irritation

Clinical Applications, Efficacy, and Therapeutic Context

The clinical use of testosterone has evolved significantly since its introduction, expanding from a niche treatment for severe hormonal deficiencies to a widely prescribed medication. This expansion has been accompanied by considerable controversy and regulatory scrutiny, particularly regarding its use in aging men. A clear distinction must be made between its rigorously defined, FDA-approved indications and other off-label or investigational uses.

FDA-Approved Indications

The U.S. Food and Drug Administration has approved testosterone replacement therapy (TRT) for specific, well-defined medical conditions characterized by a pathological deficiency of the hormone.

Male Hypogonadism

The sole primary indication for testosterone therapy is for the treatment of male hypogonadism.[1] The FDA requires that the diagnosis be established unequivocally before treatment is initiated. This involves demonstrating both the presence of clinical signs and symptoms of testosterone deficiency and the confirmation of low serum testosterone levels on at least two separate occasions, with blood samples drawn in the morning when levels are typically at their peak.[5] Normal testosterone levels in adult men generally range from 300 to 1,000 ng/dL.[6]

Hypogonadism is categorized into two main types, both of which are approved indications for TRT:

1. Primary Hypogonadism (Hypergonadotropic Hypogonadism): This condition arises from a failure of the testes to produce testosterone. The pituitary gland attempts to compensate by increasing its output of gonadotropins, leading to elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Causes can be congenital, such as Klinefelter's syndrome or vanishing testis syndrome, or acquired, resulting from conditions like bilateral torsion, orchitis, orchiectomy (surgical removal of the testes), or testicular damage from chemotherapy, radiation, alcohol, or heavy metals.[5]
2. Hypogonadotropic Hypogonadism (Secondary Hypogonadism): This condition results from a failure of the hypothalamic-pituitary axis to produce sufficient gonadotropins (LH and FSH) to stimulate the testes. Consequently, both testosterone and gonadotropin levels are low or inappropriately normal. Causes may be congenital, such as idiopathic gonadotropin or Luteinizing Hormone-Releasing Hormone (LHRH) deficiency, or acquired due to pituitary-hypothalamic injury from tumors, trauma, or radiation.[5]

The Controversy of "Low T" and the FDA's Limitation of Use

A significant point of contention in modern endocrinology is the treatment of "age-related hypogonadism," often marketed to the public as "Low T." This refers to the gradual decline in testosterone levels that occurs naturally in men with age. Aggressive direct-to-consumer advertising campaigns, particularly by manufacturers like AbbVie for its product AndroGel, have been accused of "disease mongering"—creating a widespread perception that common symptoms of aging, such as decreased energy, reduced muscle mass, and lower libido, constitute a treatable medical condition.[39] These campaigns successfully created a multi-billion dollar market by medicalizing the aging process.[40]

In response to this trend and a lack of evidence for benefit versus risk in this population, the FDA has taken a firm and consistent stance. The agency explicitly states that testosterone products are not approved for the treatment of low testosterone levels due to aging alone.[8] All prescription testosterone labels are required to include a "Limitation of Use" statement clarifying that the safety and efficacy of testosterone have not been established in men with age-related hypogonadism.[13] This regulatory position highlights a fundamental disconnect between the commercially driven market for "Low T" treatments and the evidence-based, approved indications for the drug.

Other Established and Investigational Uses

Beyond male hypogonadism, testosterone has several other niche or emerging applications.

• Metastatic Breast Cancer: Testosterone enanthate is approved for the palliative treatment of inoperable, metastatic (androgen-responsive) mammary cancer in women who are between one and five years postmenopausal.[1]
• Gender-Affirming Hormone Therapy: Testosterone is the standard of care for masculinizing hormone therapy in transgender men. It is used to induce the development of male secondary sexual characteristics, such as facial hair growth, voice deepening, and changes in muscle and fat distribution, as well as cessation of menses.[8] However, its classification as a Schedule III controlled substance creates significant access barriers for this medically necessary care, a point of contention for medical and advocacy groups.[18]
• Delayed Puberty in Males: In cases of pathologically delayed puberty, a short course of testosterone can be used to initiate pubertal development.[9] This treatment requires careful clinical supervision, including periodic radiographic monitoring of bone age of the wrist and hand (typically every 6 months). This is crucial because androgens can accelerate bone maturation and lead to premature closure of the epiphyseal growth plates, which could compromise the patient's final adult height.[5]
• Menopausal Symptoms: Testosterone is sometimes used off-label, often through compounding pharmacies, to treat symptoms in postmenopausal women, particularly low libido (hypoactive sexual desire disorder) and vasomotor symptoms.[1]
• Investigational Uses: Research has explored the potential benefits of testosterone in other areas. Studies have suggested improvements in depressive symptoms, particularly in men with confirmed hypogonadism, and increased exercise capacity and muscle strength in men with chronic heart failure.[8] It has also been investigated as a potential component of a male contraceptive regimen, as high doses suppress spermatogenesis.[8]

Review of Pivotal Clinical Trials

The clinical understanding of testosterone's safety, particularly concerning cardiovascular health, has been profoundly shaped by recent, large-scale clinical trials.

The TRAVERSE Trial

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was a landmark, FDA-mandated, multicenter, randomized, double-blind, placebo-controlled noninferiority trial. It was designed specifically to address the long-standing question of whether testosterone therapy increases the risk of major adverse cardiovascular events (MACE).[12]

• Study Population: The trial enrolled over 5,200 men between the ages of 45 and 80 years who had symptomatic hypogonadism (pre-screening testosterone level <300 ng/dL) and pre-existing cardiovascular disease or a high risk of developing it.[13] This population was intentionally selected as being most vulnerable to potential cardiovascular harm.
• Primary Endpoint: The primary safety endpoint was the first occurrence of an event in the MACE composite, which included cardiovascular death, nonfatal myocardial infarction (heart attack), or nonfatal stroke.[36] The trial was designed to determine if testosterone was non-inferior to placebo, meaning it was not significantly worse.
• Key Findings:
• Non-Inferiority for MACE: The TRAVERSE trial successfully met its primary endpoint. A primary cardiovascular event occurred in 7.0% of patients in the testosterone group compared to 7.3% in the placebo group (Hazard Ratio, 0.96; 95% Confidence Interval [CI], 0.78 to 1.17). Since the upper bound of the confidence interval (1.17) was well below the pre-specified noninferiority margin of 1.5, the trial concluded that testosterone therapy did not result in a higher risk of MACE compared to placebo in this high-risk population.[13]
• Secondary Safety Signals: While reassuring on the primary endpoint, the trial did reveal a statistically significant higher incidence of several other adverse events in the testosterone group. These included atrial fibrillation, acute kidney injury, and pulmonary embolism (0.9% in the testosterone group vs. 0.5% in the placebo group).[13]
• Regulatory Impact: The results of the TRAVERSE trial were pivotal. They provided the robust evidence the FDA needed to re-evaluate its previous warnings. Based on these findings, the agency removed the Boxed Warning related to cardiovascular risk from all testosterone product labels in 2023-2025, a major shift in the risk-benefit communication for the drug class.[12]

Other Relevant Trials

Numerous other clinical trials have been conducted to evaluate the efficacy and safety of specific testosterone formulations. For example, trials have directly compared oral testosterone undecanoate (LPCN 1021, which became Jatenzo®) to topical gel formulations, focusing on safety and efficacy in hypogonadal men.[43] Other studies have investigated the effects of testosterone on specific physiological parameters, such as endothelial function and microcirculation in type 2 diabetic patients with hypogonadism.[44] These trials contribute to the body of evidence guiding the selection of appropriate formulations and identifying patient populations who may derive particular benefit or be at higher risk.

Marketed Formulations, Dosage, and Administration

The pharmaceutical market offers a wide variety of testosterone formulations, each designed to overcome the pharmacokinetic challenges of the native hormone and provide a viable option for long-term replacement therapy. The choice of formulation is a critical clinical decision based on patient preference, lifestyle, cost, adherence potential, and the specific pharmacokinetic profile of the product.

Injectable Esters (Intramuscular)

Intramuscular (IM) injections are a long-standing and cost-effective method of testosterone administration. They work by creating a depot of esterified testosterone in an oil vehicle within the muscle, from which the hormone is slowly released.

• Testosterone Cypionate and Testosterone Enanthate: These are the most commonly prescribed injectable forms in the United States.[9] They are chemically very similar and are often used interchangeably.
• Brand Names: Depo-Testosterone (cypionate), Delatestryl (enanthate).[9]
• Dosage: The typical dosage range is 50 mg to 400 mg administered via deep gluteal IM injection every two to four weeks.[5] Dosing must be individualized based on patient response and serum trough levels.
• Administration: Given as a deep intramuscular injection.[5]
• Clinical Considerations: While effective and inexpensive, this dosing schedule is known to produce undesirable pharmacokinetics, with initial supraphysiological peaks that can cause mood swings or irritability, followed by subtherapeutic troughs toward the end of the dosing interval that can lead to a recurrence of hypogonadal symptoms.[3] More frequent injections of smaller doses (e.g., 50-100 mg weekly) can mitigate these fluctuations.[10]
• Testosterone Undecanoate: This is a very long-acting ester formulation.
• Brand Name: Aveed®.[9]
• Dosage: The regimen is 750 mg (3 mL) IM, followed by a second 750 mg dose 4 weeks later, and then 750 mg every 10 weeks thereafter.[9]
• Administration: Due to the risk of a serious adverse reaction called Pulmonary Oil Microembolism (POME)—a reaction that can cause coughing, shortness of breath, and chest pain—Aveed® must be administered in a healthcare setting. Patients must be observed for 30 minutes following each injection.[11]

Topical Preparations (Transdermal)

Topical formulations are designed to deliver a consistent daily dose of testosterone through the skin, providing more stable serum levels than traditional IM injections.

• Gels: These are the most popular topical formulations.
• Brand Names: AndroGel®, Testim®, Fortesta®, Vogelxo®.[1]
• Dosage: Applied once daily, typically in the morning. The starting dose varies by product (e.g., AndroGel® 1.62% starts at 40.5 mg, Fortesta® at 40 mg). Doses can be adjusted based on follow-up serum testosterone levels.[10] Many products use a metered-dose pump for easy dose titration.
• Administration: Applied to clean, dry, intact skin. The application site is product-specific: shoulders and upper arms for AndroGel® 1.62% and Vogelxo™; shoulders, upper arms, or abdomen for AndroGel® 1%; and front or inner thighs for Fortesta®.[33] The gel must be allowed to dry before covering with clothing.
• Clinical Considerations: The primary concern is the high risk of secondary exposure to women and children via skin-to-skin contact. Strict precautions are required, including washing hands immediately after application and keeping the application site covered.[1]
• Solution:
• Brand Name: Axiron®.[1]
• Dosage: The initial dose is 60 mg (30 mg applied to each underarm) once daily.[33]
• Administration: Applied to the underarms using a special no-touch applicator designed to minimize the risk of hand contamination and transference.[11]
• Patches:
• Brand Name: Androderm®.[47]
• Dosage: A patch delivering 2 mg or 4 mg of testosterone is applied once daily at night.[38]
• Administration: Applied to the skin on the back, abdomen, upper arm, or thigh. The application site must be rotated, with at least 7 days before reusing a site.[11]
• Clinical Considerations: A significant number of users experience skin irritation, blistering, or pruritus at the application site.[11] As of recent reports, Allergan (AbbVie) has discontinued Androderm®, and was the sole supplier of testosterone patches, leaving this formulation type unavailable.[50]

Alternative Delivery Systems

Newer formulations have sought to provide the benefits of stable levels without the drawbacks of injections or topical transference.

• Oral Capsules (Testosterone Undecanoate):
• Brand Names: Jatenzo®, Tlando®.[4]
• Dosage: Taken twice daily (morning and evening) with food to ensure proper absorption. The starting dose for Jatenzo® is 237 mg twice daily, and for Tlando® is 225 mg twice daily. The dose is adjusted based on serum testosterone concentrations.[4]
• Administration: Swallowed whole with food.
• Subcutaneous Pellets:
• Brand Name: Testopel®.[9]
• Dosage: Two to six 75 mg pellets (totaling 150-450 mg) are implanted subcutaneously. The dose provides therapeutic testosterone levels for 3 to 6 months.[9]
• Administration: Implanted under the skin (e.g., in the hip or buttock area) during a minor in-office surgical procedure performed under local anesthesia.
• Buccal System:
• Brand Name: Striant®.[1]
• Dosage: One 30 mg mucoadhesive tablet is applied twice daily, approximately 12 hours apart.[10]
• Administration: The tablet is placed on the gum above an incisor tooth, where it adheres and slowly releases testosterone for absorption through the oral mucosa.

The following table provides a comprehensive overview of major testosterone formulations, their manufacturers, and key clinical characteristics.

Route	Brand Name(s)	Manufacturer(s)	Formulation	Typical Starting Dose & Frequency	Key Administration Instructions
Intramuscular	Depo-Testosterone	Pfizer	Testosterone Cypionate Injection	50-200 mg every 2-4 weeks	Deep gluteal IM injection 5
Intramuscular	Aveed	Endo Pharmaceuticals	Testosterone Undecanoate Injection	750 mg at week 0, week 4, then every 10 weeks	IM injection; must be administered in a healthcare setting with 30-min observation for POME 11
Transdermal	AndroGel	AbbVie Inc.	Testosterone Gel 1% & 1.62%	40.5 mg (1.62%) or 50 mg (1%) once daily	Apply to clean, dry skin of shoulders/upper arms. Wash hands after use. Cover site with clothing 33
Subcutaneous	Xyosted	Antares Pharma Inc.	Testosterone Enanthate Auto-Injector	75 mg once weekly	Subcutaneous injection into the abdomen using a pre-filled auto-injector 10
Oral	Jatenzo	Tolmar, Inc. (acquired from Clarus)	Testosterone Undecanoate Capsule	237 mg twice daily	Take with food to ensure absorption 4
Oral	Tlando	Antares Pharma Inc.	Testosterone Undecanoate Capsule	225 mg twice daily	Take with food to ensure absorption 4
Subcutaneous	Testopel	Endo Pharmaceuticals	Testosterone Pellets	150-450 mg every 3-6 months	Pellets are implanted subcutaneously in a minor surgical procedure 9
Buccal	Striant	Endo Pharmaceuticals	Mucoadhesive Buccal Tablet	30 mg twice daily	Apply to gum region above an incisor tooth; alternate sides with each application 11

Safety Profile, Risk Management, and Contraindications

The therapeutic use of testosterone is associated with a well-defined profile of potential adverse events, risks, and contraindications. Many of these risks are not idiosyncratic toxicities but rather predictable, dose-dependent exaggerations of the hormone's natural physiological effects. Effective risk management, therefore, relies heavily on appropriate patient selection, careful dose titration, and diligent monitoring.

The Nature of Testosterone's Adverse Effects

A defining feature of testosterone's safety profile is that its primary risks are direct extensions of its known biological functions. This contrasts with many drugs that have off-target or unexpected toxicities.

• Androgenic Effects: Testosterone's role in stimulating sebaceous glands leads to acne and oily skin.[8] Its action on hair follicles can worsen male-pattern baldness.
• Prostate Effects: Its function in promoting prostate growth can lead to the worsening of symptoms in men with benign prostatic hyperplasia (BPH) and raises a theoretical concern about stimulating the growth of subclinical prostate cancer.[5]
• Erythropoietic Effects: Its role in stimulating red blood cell production (erythropoiesis) can, at therapeutic doses, lead to polycythemia (an abnormally high hematocrit), which increases blood viscosity and the risk of thromboembolic events.[4]
• Metabolic Effects from Aromatization: Its conversion to estradiol is responsible for the potential side effect of gynecomastia (breast tissue development).[2]
• Fluid and Electrolyte Effects: Testosterone can cause sodium and water retention (edema), particularly in patients with underlying cardiac, renal, or hepatic disease.[4] This may be related to effects on the mineralocorticoid receptor.[3]

This direct link between mechanism and adverse effect underscores that safety management is not about avoiding an unpredictable reaction, but about maintaining the hormone's physiological effects within a safe therapeutic window through careful monitoring.

Adverse Events

Adverse events associated with testosterone therapy range from common and manageable to rare but serious.

• Common Adverse Events:
• Application Site Reactions: For topical products, skin redness, irritation, itching, and rashes are common.[11] For injectables, pain, swelling, and inflammation at the injection site can occur.[11]
• Dermatologic: Acne and oily skin are frequently reported.[8]
• Endocrine/Reproductive: Gynecomastia and breast pain can occur.[4] Changes in libido are also possible.
• Neurologic: Headaches are a common side effect.[4]
• Psychiatric: Mood swings, irritability, and nervousness may be experienced, particularly with the fluctuating levels of injectable formulations.[45]
• Serious Adverse Events:
• Cardiovascular:
• Increased Blood Pressure: This is a class-wide risk, confirmed by post-market studies, leading to a new warning on all testosterone product labels. Uncontrolled hypertension increases the risk of MACE.[4]
• Venous Thromboembolism (VTE): There is an established risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), potentially linked to testosterone-induced polycythemia.[4]
• Major Adverse Cardiovascular Events (MACE): While the TRAVERSE trial was reassuring regarding MACE in a supervised setting, the potential for heart attack and stroke remains a key concern, especially in the context of increased blood pressure or pre-existing risk factors.[2]
• Hematologic: Polycythemia (increase in hematocrit) is a well-known risk that requires routine monitoring. If hematocrit rises excessively, dose reduction or temporary cessation of therapy may be necessary.[4]
• Urologic: Worsening of BPH symptoms (e.g., urinary urgency, weak stream). There is also a potential risk of stimulating the growth of an occult prostate cancer. Routine monitoring with PSA and digital rectal exams is standard practice.[4]
• Hepatic: While rare with modern formulations at therapeutic doses, long-term use of high doses of older, oral alkylated androgens was associated with serious liver toxicity, including peliosis hepatis and hepatocellular carcinoma. Caution is still advised.[3]
• Psychiatric: In cases of abuse and supraphysiologic dosing, serious psychiatric events including major depression, mania, aggression, and suicidal ideation have been reported.[4]
• Endocrine: High doses of exogenous testosterone suppress the hypothalamic-pituitary-gonadal axis, leading to suppression of spermatogenesis and testicular atrophy, which can result in infertility.[9] In pediatric patients, it can cause premature closure of bony epiphyses, compromising final adult height.[5]
• Respiratory: Testosterone therapy may cause or worsen sleep apnea, particularly in patients with risk factors like obesity or chronic lung disease.[5]

Warnings, Precautions, and Contraindications

Regulatory agencies have mandated specific warnings and have defined populations in whom testosterone use is contraindicated.

• Key Warnings and Precautions:
• Blood Pressure Increase: A prominent, class-wide warning. Blood pressure should be monitored at baseline and periodically during therapy, and hypertension should be managed appropriately.[4]
• Secondary Exposure (Topical Products): A Boxed Warning exists for some topical products regarding the risk of virilization in children and women who are secondarily exposed. Patients must be counseled extensively on prevention measures: wash hands with soap and water after application, allow the gel to dry completely, and cover the application site with clothing.[1]
• Abuse and Dependence: As a Schedule III controlled substance, testosterone carries a risk of abuse and dependence. Prescribers should be alert to this possibility.[9]
• Contraindications: Testosterone therapy is absolutely contraindicated in the following populations:
• Men with carcinoma of the breast or with known or suspected carcinoma of the prostate.[5]
• Women who are pregnant, may become pregnant, or are breastfeeding. Testosterone is teratogenic and can cause virilization of a female fetus.[4]
• Individuals with a known hypersensitivity to testosterone or any components of the specific formulation.[5]

Drug and Disease Interactions

Testosterone can interact with other medications and can exacerbate certain underlying medical conditions.

• Disease Interactions: Caution is required in patients with:
• Heart, Kidney, or Liver Disease: Increased risk of edema and fluid retention.[4]
• Benign Prostatic Hyperplasia (BPH): Risk of worsening urinary symptoms.[5]
• Sleep Apnea: Risk of exacerbation.[5]
• Hyperlipidemia: Testosterone can alter serum lipid profiles.[4]
• Drug Interactions: The following table summarizes clinically significant drug interactions.

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation
Oral Anticoagulants (e.g., Warfarin)	Testosterone may decrease the synthesis of vitamin K-dependent clotting factors and increase the anticoagulant effect.	Increased risk of bleeding.	Monitor INR or prothrombin time more frequently, especially upon initiation, dose adjustment, or discontinuation of testosterone. Adjust anticoagulant dose as needed. 9
Insulin & Oral Antidiabetic Agents	Androgens may improve glucose tolerance and decrease blood glucose levels.	Increased risk of hypoglycemia.	Patients with diabetes may require a reduction in their antidiabetic medication dosage. Monitor blood glucose levels closely. 3
Corticosteroids (e.g., Prednisone)	Concomitant use may enhance the fluid-retaining properties of both agents.	Increased risk of edema and fluid retention.	Use with caution, particularly in patients with pre-existing cardiac, renal, or hepatic disease. Monitor for signs of fluid overload. 5
Propranolol	May alter the clearance of propranolol.	Potential for altered therapeutic effect of propranolol.	Monitor clinical response to propranolol. 45

Regulatory and Commercial Landscape

The trajectory of testosterone as a therapeutic agent has been heavily influenced by a dynamic interplay between pharmaceutical marketing, evolving scientific evidence, public health concerns, and regulatory actions. This has created a complex legal and commercial environment, particularly over the last two decades.

Regulatory History and FDA Labeling Evolution

The FDA's oversight of testosterone products provides a compelling case study in post-market pharmacovigilance and responsive labeling changes.

• Early History & Rise in Use: Testosterone was first isolated in 1935 and received approval for medical use in 1939.[8] For decades, its use was confined to classical hypogonadism. However, between 2001 and 2011, prescription rates in the United States tripled, driven by the marketing of "Low T" as a common condition in aging men.[8]
• Emerging Safety Concerns (2014-2015): This surge in use coincided with the publication of observational studies and an increase in adverse event reports suggesting a possible link between TRT and an increased risk of heart attack, stroke, and death.[13] In response, the FDA took several key actions:
• January 2014: Issued a Drug Safety Communication to announce it was investigating this cardiovascular risk.[42]
• March 2015: Concluded that a possible increased cardiovascular risk exists and required manufacturers to add this information to product labeling. Crucially, the FDA mandated a Boxed Warning—its strongest warning—to highlight this risk and required manufacturers to conduct a large, definitive clinical trial to clarify the issue. This mandated trial would become the TRAVERSE study.[13]
• Abuse and Dependence Warning (2016): The FDA approved class-wide labeling changes to add a new warning about the potential for abuse and dependence, and the serious cardiovascular and psychiatric risks associated with supraphysiologic dosing.[17]
• Blood Pressure Risk Identified (2018-2023): Post-market requirement studies, known as Ambulatory Blood Pressure Monitoring (ABPM) studies, were conducted for all testosterone products. These studies consistently confirmed that testosterone use leads to small but statistically significant increases in blood pressure, raising a class-wide safety concern.[13]
• The Post-TRAVERSE Era (2023-2025): The submission and review of the TRAVERSE trial results in 2023 triggered the most significant labeling update in a decade. The FDA's actions reflected a recalibration of risk based on this new, high-quality evidence:

1. Removal of the Boxed Warning: Based on the TRAVERSE trial's finding of non-inferiority for MACE, the FDA removed the Boxed Warning related to an increased risk of adverse cardiovascular outcomes from all testosterone products.[12]
2. Addition of a New Warning: Based on the consistent findings from the ABPM studies, a new, class-wide warning for increases in blood pressure was added to all product labels.[12]
3. Retention of Limitation of Use: The FDA retained the language specifying that testosterone is not approved for the treatment of age-related hypogonadism, reinforcing its stance on the appropriate patient population.[14]

This regulatory arc—from a signal of harm leading to a strong warning, which in turn forces a definitive study, the results of which then lead to a more refined and evidence-based warning—exemplifies the reactive and evolving nature of the U.S. pharmacovigilance system.

The following table summarizes this key regulatory timeline.

Year(s)	FDA Action / Communication	Key Content and Rationale
2014	Drug Safety Communication	Announced investigation into risk of stroke, heart attack, and death based on observational studies and adverse event reports. 42
2015	Labeling Change Mandate	Required addition of a Boxed Warning for possible increased cardiovascular risk. Mandated a large post-market cardiovascular outcomes trial (TRAVERSE). 13
2016	New Warning Added	Added a new warning to all labels regarding the risks associated with abuse and dependence of testosterone and other anabolic steroids. 17
2018-2023	Post-Market Studies	Required and reviewed Ambulatory Blood Pressure Monitoring (ABPM) studies, which confirmed a class-wide effect of increasing blood pressure. 13
2023-2025	Major Labeling Update (Post-TRAVERSE)	Removed the cardiovascular risk Boxed Warning. Added a new class-wide warning for increases in blood pressure. Retained the Limitation of Use for age-related hypogonadism. 12

Controlled Substance Status

The legal status of testosterone significantly impacts its prescribing and accessibility.

• Classification: In 1990, the Anabolic Steroids Control Act placed testosterone and other anabolic androgenic steroids (AAS) into Schedule III of the Controlled Substances Act (CSA).[17] This classification denotes that the drug has an accepted medical use but also possesses a moderate to low potential for physical dependence or a high potential for psychological dependence and abuse.[57]
• Prescribing and Dispensing Implications: This status imposes several restrictions. Prescriptions for Schedule III substances cannot be refilled more than five times and are not valid more than six months after the date they are written. States and private insurers may impose further limitations, such as 30-day supply limits or restrictions on mail-order delivery.[18]
• Policy and Advocacy: The Schedule III status has become a point of significant debate. Advocates for the transgender community argue that it creates unnecessary and discriminatory barriers to medically necessary gender-affirming care. They point out that these restrictions can limit access through telemedicine, reduce the number of providers willing to prescribe due to DEA licensing requirements, and subject patients to surveillance through Prescription Drug Monitoring Programs (PDMPs). There have been calls from lawmakers and advocacy groups to the DEA and other federal agencies to consider rescheduling testosterone to a less restrictive schedule (like Schedule V) or descheduling it entirely, noting that estrogen, the primary feminizing hormone, is not a controlled substance.[18]

Market and Litigation

The testosterone market is a highly competitive and litigious space.

• Major Manufacturers: The market is dominated by several large pharmaceutical companies, including AbbVie and its predecessor Abbott (AndroGel), Pfizer (Depo-Testosterone), Tolmar (Jatenzo), and Antares Pharma (Xyosted).[40] The market has seen significant corporate activity, including acquisitions (Tolmar acquiring Jatenzo from the struggling Clarus Therapeutics) and product discontinuations (Allergan/Actavis ceasing production of the Androderm patch).[50]
• Market Dynamics: The commercial history is marked by aggressive direct-to-consumer advertising, which created the "Low T" market, and extensive patent litigation between brand-name manufacturers and generic competitors seeking to enter the market.[41]
• Product Liability Litigation: In the wake of the FDA's 2014-2015 warnings, manufacturers, most notably AbbVie, faced thousands of product liability lawsuits. Plaintiffs alleged that the companies deceptively marketed their drugs for an unapproved indication (age-related "Low T") while failing to adequately warn of the serious cardiovascular risks, which allegedly led to heart attacks, strokes, and other injuries in users.[39] Many of these cases have been resolved through large-scale settlements.[62]

Synthesis and Expert Recommendations

The clinical management of testosterone deficiency requires a nuanced understanding of the available formulations, a rigorous approach to patient selection and monitoring, and an appreciation for the evolving safety and regulatory landscape. The optimal therapeutic strategy is not one-size-fits-all but must be tailored to the individual patient's clinical needs, lifestyle, and preferences.

Comparative Analysis and Formulation Selection

The choice of a testosterone formulation is a central decision in TRT, driven by the trade-offs inherent in each delivery system's pharmacokinetic profile.

• Injectables vs. Topicals: This represents the classic clinical choice. Long-acting intramuscular injections (cypionate, enanthate) offer the convenience of infrequent dosing (every 2-4 weeks) and are highly cost-effective. However, they are associated with significant fluctuations in serum levels, creating supraphysiologic peaks and subtherapeutic troughs that can lead to instability in mood, libido, and energy. In contrast, daily topical preparations (gels, solutions) provide much more stable, near-physiologic serum concentrations that mimic the body's natural circadian rhythm. This stability comes at the cost of requiring daily application and, most importantly, carrying a significant risk of accidental transference to partners or children, which requires meticulous preventive measures.
• The "Third Way" Formulations: A growing category of alternative formulations aims to provide the benefits of both systems without their primary drawbacks.
• Subcutaneous Pellets (Testopel®): Offer the "set it and forget it" convenience of very infrequent dosing (every 3-6 months) with stable hormone levels and no transference risk. The main drawbacks are the need for a minor surgical procedure for implantation and removal, and the risk of local site complications like infection or pellet extrusion.
• Oral Capsules (Jatenzo®, Tlando®): Provide a non-invasive route that completely avoids transference risk. However, they require strict twice-daily adherence and must be taken with fatty meals to ensure proper lymphatic absorption, which may be a challenge for some patients.
• Buccal System (Striant®): Also avoids transference risk and offers stable absorption. The primary limitations are the need for twice-daily application and the potential for gum irritation, pain, or taste disturbance.
• Long-Acting Injectable (Aveed®): Offers the longest dosing interval (10 weeks), but the requirement for in-office administration and a 30-minute observation period for POME risk makes it less convenient than other options.

Ultimately, the selection of a formulation should be a shared decision between the clinician and an informed patient, weighing factors such as the patient's aversion to needles, ability to adhere to a daily regimen, household situation (presence of women or children), insurance coverage and cost, and desire for stable versus fluctuating hormone levels.

Clinical Practice Guidelines

Based on the comprehensive data, the following guidelines are recommended for the safe and effective use of testosterone replacement therapy:

1. Rigorous Patient Selection:

• Restrict therapy to patients with a confirmed diagnosis of classical male hypogonadism, supported by both consistent clinical symptoms and at least two documented low morning serum testosterone levels.[5]
• Adhere strictly to the FDA's Limitation of Use. Avoid initiating therapy for symptoms of aging in the absence of a confirmed pathological diagnosis of hypogonadism.[14]
• Thoroughly screen for all contraindications, including known or suspected prostate or breast cancer and pregnancy in a partner.[5]

2. Comprehensive Baseline Assessment: Before initiating therapy, conduct a full baseline evaluation that includes:

• A detailed medical history and physical examination, including a digital rectal exam (DRE) in appropriate age groups.
• Baseline laboratory tests: total testosterone (morning sample), prostate-specific antigen (PSA), complete blood count (for hematocrit), and a lipid panel.[5]
• A baseline blood pressure measurement is now a critical component of the initial assessment due to the new class-wide warning.[12]

3. Diligent Therapeutic Monitoring:

• Hormone Levels: Monitor serum testosterone levels 3 to 6 months after initiation and then annually to ensure they are within the normal therapeutic range (typically 300-1,000 ng/dL).[38] The timing of the blood draw is critical and depends on the formulation: measure trough levels just prior to the next injection for IM esters; measure 2-8 hours after application for some gels; or follow product-specific guidelines.[11]
• Safety Labs: Monitor hematocrit at baseline, at 3-6 months, and then annually. If the hematocrit exceeds 54%, therapy should be stopped or the dose reduced until it returns to a safe level.[12] Monitor PSA and conduct a DRE at 3-6 months and then as per standard prostate cancer screening guidelines.[5]
• Blood Pressure: Monitor blood pressure regularly throughout treatment. Initiate or adjust antihypertensive therapy as needed if blood pressure increases.[4]

4. Patient Counseling and Risk Mitigation:

• Discuss all potential risks and benefits with the patient, including the risks of VTE, polycythemia, and worsening BPH.
• For patients using topical formulations, provide exhaustive and repeated counseling on the critical importance of preventing secondary exposure. This includes washing hands thoroughly, covering the application site, and washing the site before anticipated skin-to-skin contact.[34]
• Periodically re-evaluate the ongoing need for therapy and assess for adverse effects at each visit.

Future Directions

Despite recent advances, several questions regarding testosterone therapy remain, and future research and policy will likely focus on the following areas:

• Unresolved Clinical Questions: The long-term effects of TRT on the incidence (not just progression) of prostate cancer require further study. While the TRAVERSE trial was reassuring for MACE, the clinical significance of the observed increased risks of atrial fibrillation and pulmonary embolism needs to be better understood and may influence patient selection in the future.
• Therapy in Underserved Populations: More robust, long-term data are needed on the safety and efficacy of testosterone in specific populations, including its use in gender-affirming care for transgender individuals and for indications like hypoactive sexual desire disorder in women.
• Formulation Innovation: The search for the "ideal" testosterone formulation continues. Future developments will likely focus on novel long-acting delivery systems that provide even more stable and physiologic hormone profiles with enhanced convenience and safety, such as new oral formulations that are less dependent on food for absorption or improved injectable technologies.
• Regulatory Policy: The ongoing debate surrounding the Schedule III status of testosterone is a significant policy issue.[18] As the use of testosterone for gender-affirming care becomes more prevalent, the pressure on regulatory bodies to reconsider the scheduling and remove potential barriers to this medically necessary treatment will likely intensify.

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