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Testosterone (T) is a medication and naturally occurring steroid hormone.[3] It is used to treat male hypogonadism and certain types of breast cancer.[3] It may also be used to increase athletic ability in the form of doping.[3] It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful.[4] Testosterone can be used as a gel or patch that is applied to the skin, injection into a muscle, tablet that is placed in the cheek, or tablet that is taken by mouth.[3]

Testosterone
Testosteron.svg
Testosterone molecule ball.png
Clinical data
Pronunciation/tɛˈstɒstərn/ teh-STOS-tə-rohn[1]
Trade namesAndroGel, Testim, TestoGel, others
SynonymsAndrost-4-en-17β-ol-3-one
AHFS/Drugs.comMonograph
MedlinePlusa614041
License data
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration
Transdermal (gel, cream, solution, patch), by mouth (as testosterone undecanoate), in the cheek, intranasal (gel), intramuscular injection (as esters), subcutaneous pellets
Drug classAndrogen, anabolic steroid
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: very low (due to extensive first pass metabolism)
Protein binding97.0–99.5% (to SHBG and albumin)[2]
MetabolismLiver (mainly reduction and conjugation)
Elimination half-life2–4 hours[citation needed]
ExcretionUrine (90%), feces (6%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H28O2
Molar mass288.431 g/mol g·mol−1
3D model (JSmol)
Specific rotation+110.2°
Melting point155 °C (311 °F)
  (verify)

Common side effects of testosterone include acne, swelling, and breast enlargement in men.[3] Serious side effects may include liver toxicity, heart disease, and behavioral changes.[3] Women and children who are exposed may develop masculinization.[3] It is recommended that individuals with prostate cancer not use the medication.[3] It can cause harm to the baby if used during pregnancy or breastfeeding.[3] Testosterone is in the androgen family of medications.[3]

Testosterone was first isolated in 1935 and approved for medical use in 1939.[5][6] Rates of use have increased three times in the United States between 2001 and 2011.[7] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[8] It is available as a generic medication.[3] The price depends on the dose and form of the product.[9] In 2016 it was the 146th most prescribed medication in the United States with more than 4 million prescriptions.[10]

Contents

Medical usesEdit

The primary use of testosterone is the treatment of males with too little or no natural testosterone production, also termed hypogonadism or hypoandrogenism (androgen deficiency).[11] This treatment is referred to as hormone replacement therapy (HRT), or alternatively, and more specifically, as testosterone replacement therapy (TRT) or androgen replacement therapy (ART). It is used to maintain serum testosterone levels in the normal male range. Decline of testosterone production with age has led to interest in testosterone supplementation.[12]

DeficiencyEdit

Testosterone deficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally low testosterone production. It may occur because of testicular dysfunction (primary hypogonadism) or hypothalamic–pituitary dysfunction (secondary hypogonadism) and may be congenital or acquired.[13][medical citation needed]

Low levels due to agingEdit

Testosterone levels may decline gradually with age.[14][15] The United States Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone supplement have been established for low testosterone levels due to aging.[4] The FDA has required that labels on testosterone include warnings about increased risk of heart attacks and stroke.[4]

Transgender menEdit

To take advantage of its virilizing effects, testosterone is administered to transgender men as part of masculinizing hormone therapy,[16] titrated to clinical effect with a "target level" of the average male's testosterone level.[17]

Medications and dosages used in masculinizing hormone therapy for transgender men

Medication Brand names Type Route Dosage
Testosterone undecanoate Andriol, Jatenzo Androgen Oral 40–80 mg/2–3x day (with meals)
Testosterone Striant Androgen Buccal 30 mg 2x/day
Natesto Nasal spray 11 mg 3x/day
AndroGel, others Transdermal gel 25–100 mg/day
Androderm, others Transdermal patch 2.5–10 mg/day
Axiron Axillary solution 30–120 mg/day
Testopel Subcutaneous implant 150–600 mg/3–6 months
Testosterone enanthate Delatestryl, others Androgen Injection (IM or SC) 50–100 mg/week or 100–250 mg/2–4 weeks
Testosterone cypionate Depo-Testosterone, others Androgen Injection (IM or SC) 50–100 mg/week or 100–250 mg/2–4 weeks
Testosterone isobutyrate Agovirin Depot Androgen Injection (IM or SC) 50–100 mg/week
Mixed testosterone estersa Sustanon 250, others Androgen Injection (IM or SC) 250 mg/2–3 weeks or 500 mg/3–6 weeks
Testosterone undecanoate Aveed, Nebido, others Androgen Injection (IM or SC) 750–1,000 mg/10–14 weeks
GnRH analogue Various GnRH modulator Parenteral (various) Variable
Elagolix Orilissa GnRH antagonist Oral 150 mg/day or 200 mg/twice a day
Medroxyprogesterone acetateb Provera, others Progestin Oral 5–10 mg/day
Depo-Provera, others Injection (IM) 150 mg/3 months
Depo-SubQ Provera 104 Injection (SC) 104 mg/3 months
Lynestrenolb Orgametril, others Progestin Oral 5–10 mg/day
Finasteridec Propecia, Proscar 5α-Reductase inhibitor Oral 1 mg/day
Dutasteridec Avodart 5α-Reductase inhibitor Oral 0.5 mg/day
Footnotes: a = Specifically 12% testosterone propionate, 24% testosterone phenylpropionate, 24% testosterone isocaproate, and 40% testosterone decanoate. b = For suppression of menses only. c = For prevention/treatment of scalp hair loss only. Sources: See template.

WomenEdit

Testosterone therapy is effective in the short-term for the treatment of hypoactive sexual desire disorder (HSDD) in women.[18] However, its long-term safety is unclear.[18] Because of a lack data to support its efficacy and safety, the Endocrine Society recommends against the routine use of testosterone in women to treat low androgen levels due to hypopituitarism, adrenal insufficiency, surgical removal of the ovaries, high-dose corticosteroid therapy, or other causes.[18] Similarly, because of a lack of data to support its efficacy and safety, the Endocrine Society recommends against the general use of testosterone in women to treat infertility; sexual dysfunction due to causes other than HSDD; to improve cognitive, cardiovascular, metabolic, and/or bone health; or to improve general well-being.[18]

A 2014 systematic review and meta-analysis of 35 studies consisting of over 5,000 postmenopausal women with normal adrenal gland function found that testosterone therapy was associated with significant improvement in a variety of domains of sexual function.[19] Such domains included frequency of sexual activity, orgasm, arousal, and sexual satisfaction among others.[19] Women who were menopausal due to ovariectomy showed significantly greater improvement in sexual function with testosterone relative to those who had normal menopause.[19] In addition to beneficial effects on sexual function, testosterone was associated with changes in blood lipids including decreased levels of total cholesterol, triglycerides, and high-density lipoprotein and increased levels of low-density lipoprotein.[19] However, such changes were small in magnitude, and their long-term influence on cardiovascular outcomes is unclear.[19] The changes were more pronounced with oral testosterone undecanoate compared to parenteral (e.g., transdermal) testosterone.[19] Testosterone showed no significant effect on depressed mood or anxiety, anthropomorphic measures like body weight or body mass index, or bone mineral density.[19] Conversely, it was associated with a significant incidence of androgenic side effects including acne and hirsutism, and other androgenic side effects like weight gain, pattern hair loss, and voice deepening were also reported in some trials but were excluded from the meta-analysis due to insufficient data.[19] The overall quality of the evidence was rated as low and was considered to be inconclusive in certain areas, for instance long-term safety.[19]

A subsequent 2017 systematic review and meta-analysis of over 3,000 postmenopausal women similarly found that transdermal testosterone therapy was effective in improving multiple domains of sexual function in the short-term treatment of HSDD.[20] Androgenic adverse effects such as acne and hirsutism were significantly greater in incidence, while no significant differences in "increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study" were seen relative to the controls.[20]

Although sufficient doses of testosterone are effective in improving sexual function in postmenopausal women, there is little support for the notion that testosterone is a critical hormone for sexual desire and function in women under normal physiological circumstances.[21][22] Low doses of testosterone resulting in physiological levels of testosterone (< 50 ng/dL) have not been found to significantly increase sexual desire or function in women in most studies.[21] Similarly, there appears to be little to no relationship between total or free testosterone levels within the normal physiological range and sex drive in premenopausal women.[22][21] Only high doses of testosterone resulting in supraphysiological levels of testosterone (> 50 ng/dL) significantly increase sexual desire in women, with levels of testosterone of 80 to 150 ng/dL described as "slightly" increasing sex drive.[21][22] In accordance, men experience sexual dysfunction at testosterone levels of below 300 ng/dL, with men that have levels of testosterone of approximately 200 ng/dL often experiencing such problems.[22] The high doses of testosterone that are required to increase sex drive in women may have a significant risk of masculinization with long-term therapy, and may be inappropriate.[22][21] In 2003, the FDA rejected Intrinsa, a 300 µg/day testosterone patch for the treatment of sexual dysfunction in postmenopausal women, due to limited efficacy (about one additional sexually satisfying event per month), concerns about safety and potential adverse effects with long-term therapy, and concerns about inappropriate off-label use.[21][22] It appears that in women, rather than testosterone, estradiol may be the most important hormone involved in sexual desire, although data on the clinical use of estradiol to increase sexual desire in women is limited.[21][23][24]

There are no testosterone products approved for use in women in the United States and many other countries.[25] There are approved testosterone products for women in Australia and some European countries.[25] Testosterone pellet implants are approved for use in postmenopausal women in the United Kingdom.[26][27] Testosterone products for men can be used off-label in women in the United States.[25] Alternatively, testosterone products for women are available from compounding pharmacies in the United States, although such products are unregulated and manufacturing quality is not ensured.[28]

Androgen replacement therapy formulations and dosages used in women

Route Medication Form(s) Major brand name(s) Dosage
Oral Testosterone undecanoatea Capsule Andriol, Jatenzo 40–80 mg 1x/1–2 days
Methyltestosteroneb Tablet Metandren; Estratest 0.5–10 mg/day
Normethandronea,b Tablet Ginecoside 5 mg/day
Tibolonea Tablet Livial 1.25–2.5 mg/day
Prasterone (DHEA)c Tablet N/A 25–100 mg/day
Sublingual Testosteroned Tablet N/A 0.25–0.5 mg/day
Methyltestosterone Tablet Metandren 0.25 mg/day
Transdermal Testosteronea Patch Intrinsa 150–300 μg/day
Testosterone Cream; Gel AndroGel 5–10 mg/day
Vaginal Testosteroned Cream; Gel N/A ? mg 1x/1–3 days
Testosteroned Suppository N/A 1 mg 1x/2 days
Prasterone (DHEA) Insert Intrarosa 6.5 mg/day
Intramuscular Testosterone enanthateb Oil Delatestryl; Primodian Depot 25–100 mg 1x/4–6 weeks
Testosterone cypionateb Oil Depo-Testost.; Depo-Testadiol 25–100 mg 1x/4–6 weeks
Testosterone isobutyratea,b Water Femandren M, Folivirin 25–50 mg 1x/4–6 weeks
Testosterone EBHb,e Oil Climacteron 150 mg 1x/4–8 weeks
Nandrolone decanoate Oil Deca-Durabolin 25–50 mg 1x/6–12 weeks
Prasterone enanthatea,b Oil Gynodian Depot 200 mg 1x/4–6 weeks
Subcutaneous Testosterone Implant Testopel 50–100 mg 1x/3–6 months
Footnotes: a = Not available or no longer available in the United States. b = Alone and/or in combination with an estrogen. c = Over-the-counter. d = Compounded only. e = Discontinued. Sources: See template.

Androgen/anabolic steroid dosages for breast cancer

Route/form Androgen Dosage
Oral Methyltestosterone 30–200 mg/day
Fluoxymesterone 10–40 mg 3x/day
Calusterone 40 mg 4x/day
Normethandrone 40 mg/day
IM injection Testosterone propionate 50–100 mg 3x/week
Testosterone enanthate 200–400 mg 1x/2–4 weeks
Testosterone cypionate 200–400 mg 1x/2–4 weeks
Methandriol (aq. susp.) 100 mg 3x/week
Androstanolone (aq. susp.) 300 mg 3x/week
Drostanolone propionate 100 mg 3x/week
Nandrolone decanoate 50–100 mg 1x/1–3 weeks
Nandrolone phenylpropionate 50–100 mg/week
Notes: Dosages are not necessarily equivalent. Sources: See template.

Available formsEdit

Testosterone has been marketed for use by oral, buccal, intranasal, transdermal (patches), topical (gels), intramuscular (injection), and subcutaneous (implant administration.[29][30][31] It is provided unmodified and as a testosterone ester such as testosterone cypionate, testosterone enanthate, testosterone propionate, or testosterone undecanoate, which act as prodrugs of testosterone.[29][30][31] The most common route of administration for testosterone is by intramuscular injection.[29] However, it has been reported that AndroGel, a transdermal gel formulation of testosterone, has become the most popular form of testosterone in androgen replacement therapy for hypogonadism in the United States.[30]

Available forms of testosterone

Route Ingredient Form Dose Frequency Major brand names
Oral Testosterone undecanoate Capsules 40 mg Two to four times per day Andriol, Andriol Testocaps
Buccal Testosterone Tablets 30 mg Two times per day Striant
Intranasal Testosterone Gel 5.5 mg per spray (120 sprays per bottle) Three times per day Natesto
Transdermal Testosterone Non-scrotal patches 2.5, 4, 5, or 6 mg T per 24 hours Once every 1–2 days Androderm, AndroPatch, TestoPatch
Non-scrotal patches 150 or 300 μg T per 24 hours Once every 3–4 days Intrinsa
Scrotal patches 4 or 6 mg T per 24 hours Once per day Testoderm
Topical gel (1–2.5%) 25, 50, 75, 100, or 125 mg T per application Once per day AndroGel, Testim, TestoGel
Axillary solution (2%) 30 mg T per application Once per day Axiron
Intramuscular
injection
Testosteronea Ampoules/vials 25, 50, or 100 mg/mL Once every 2–3 days Andronaq, Sterotate, Virosterone
Testosterone cypionate Ampoules/vials 50, 100, 200, or 250 mg/mL Once every 1–4 weeks Depo-Testosterone
Testosterone enanthate Ampoules/vials 50, 100, 180, 200, or 250 mg/mL Once every 1–4 weeks Delatestryl
Testosterone propionatea Ampoules/vials 5, 10, 25, 50, or 100 mg/mL Once every 2–3 days Testoviron
Testosterone undecanoate Ampoules 750 or 1000 mg per injection Once every 10–14 weeks Aveed, Nebido, Reandron
Subcutaneous Testosterone Implants 50, 75, 100, or 200 mg Once every 3–6 months TestoImplant, Testopel
Abbreviations: T = Testosterone. Footnotes: a = Mostly discontinued. Notes: (1): This table does not include dosage information, which cannot necessarily be extrapolated from the provided information. (2): This table does not include combination products. (3): Some of these formulations have been marketed previously but may no longer be available (e.g., transdermal testosterone scrotal patches, intramuscular testosterone suspension, intramuscular testosterone propionate). (4): The availability of pharmaceutical testosterone products differs by country (see Testosterone (medication) § Availability). Sources: See template.

Non-medical useEdit

AthleticsEdit

Testosterone is used as a form of doping among athletes in order to improve performance.[32] Testosterone is classified as an anabolic agent and is on the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods.[32] Hormone supplements cause the endocrine system to adjust its production and lower the natural production of the hormone, so when supplements are discontinued, natural hormone production is lower than it was originally.[citation needed]

Anabolic–androgenic steroids (AAS), including testosterone and its esters, have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles' protein synthesis. As a result, muscle fibers become larger and repair faster than the average person's.[citation needed]

After a series of scandals and publicity in the 1980s (such as Ben Johnson's improved performance at the 1988 Summer Olympics), prohibitions of AAS use were renewed or strengthened by many sports organizations. Testosterone and other AAS were designated a "controlled substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act.[33] Their use is seen as an issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such use from sports regulators. Steroid use once again came into the spotlight recently as a result of Canadian professional wrestler Chris Benoit's double murder-suicide in 2007; however, there is no evidence implicating steroid use as a factor in the incident.[citation needed]

Some female athletes may have naturally higher levels of testosterone than others, and may be asked to consent to sex verification and either surgery or drugs to decrease testosterone levels.[34] This has proven contentious, with the Court of Arbitration for Sport suspending the IAAF policy due to insufficient evidence of a link between high androgen levels and improved athletic performance.[35][36]

Detection of abuseEdit

A number of methods for detecting testosterone use by athletes have been employed, most based on a urine test. These include the testosterone/epitestosterone ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the carbon-13/carbon-12 ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individual's own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair.[37][38][39][40]

ContraindicationsEdit

Absolute contraindications of testosterone include prostate cancer, elevated hematocrit (>54%), uncontrolled congestive heart failure, various other cardiovascular diseases, and uncontrolled obstructive sleep apnea.[41] Breast cancer is said by some sources to be an absolute contraindication of testosterone therapy,[41] but androgens including testosterone have also actually been used to treat breast cancer.[42] Relative contraindications of testosterone include elevated prostate-specific antigen (PSA) in men with a high risk of prostate cancer due to ethnicity or family history, severe lower urinary tract symptoms, and elevated hematocrit (>50%).[41]

Side effectsEdit

Adverse effects may also include minor side effects such as oily skin, acne, and seborrhea, as well as loss of scalp hair, which may be prevented or reduced with 5α-reductase inhibitors.[43] In women, testosterone can produce hirsutism (excessive facial/body hair growth), deepening of the voice, and other signs of virilization. Exogenous testosterone may cause suppression of spermatogenesis in men, leading to, in some cases, reversible infertility.[44] Gynecomastia and breast tenderness may occur with high dosages of testosterone due to peripheral conversion of testosterone by aromatase into excessive amounts of the estrogen estradiol.[45] Testosterone treatment, particularly in high dosages, can also be associated with mood changes, increased aggression, increased sex drive, spontaneous erections, and nocturnal emissions.[46][47][48][49]

Other side effects include increased hematocrit, which can require venipuncture in order to treat, and exacerbation of sleep apnea.[50]

The FDA stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging.[4] The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.[4] They have also required the label include concerns about abuse and dependence.[51]

Long-term adverse effectsEdit

Cardiovascular diseaseEdit

Adverse effects of testosterone supplementation may include increased cardiovascular events (including strokes and heart attacks) and deaths based on three peer-reviewed studies involving men taking testosterone replacement.[52] In addition, an increase of 30% in deaths and heart attacks in older men has been reported.[53] Due to an increased incidence of adverse cardiovascular events compared to a placebo group, a Testosterone in Older Men with Mobility Limitations (TOM) trial (a National Institute of Aging randomized trial) was halted early by the Data Safety and Monitoring Committee.[54] On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking FDA-approved testosterone-replacement led the FDA to announce that it would be investigating the issue.[55] Later, in September 2014, the FDA announced, as a result of the "potential for adverse cardiovascular outcomes", a review of the appropriateness and safety of Testosterone Replacement Therapy (TRT).[56][57][58] The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.[59]

Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease;[60][61] more recent studies, however, do raise concerns.[62] A 2013 study, published in the Journal of the American Medical Association, reported "the use of testosterone therapy was significantly associated with increased risk of adverse outcomes." The study began after a previous, randomized, clinical trial of testosterone therapy in men was stopped prematurely "due to adverse cardiovascular events raising concerns about testosterone therapy safety."[53]

Prostate cancerEdit

Testosterone in the presence of a slow-growing prostate cancer is assumed to increase its growth rate. However, the association between testosterone supplementation and the development of prostate cancer is unproven.[63] Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation.[64]

It may accelerate pre-existing prostate cancer growth in individuals who have undergone androgen deprivation.[50] It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.[14]

Ethnic groups have different rates of prostate cancer.[65] Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences.[65] This apparent paradox can be resolved by noting that prostate cancer is very common. In autopsies, 80% of 80-year-old men have prostate cancer.[66]

Pregnancy and breastfeedingEdit

Testosterone is contraindicated in pregnancy and not recommended during breastfeeding.[67] Androgens like testosterone are teratogens and are known to cause fetal harm, such as producing virilization and ambiguous genitalia.

InteractionsEdit

5α-Reductase inhibitorsEdit

5α-Reductase inhibitors like finasteride and dutasteride can slightly increase circulating levels of testosterone by inhibiting its metabolism.[68] However, these drugs do this via prevention of the conversion of testosterone into its more potent metabolite dihydrotestosterone (DHT), and this results in dramatically reduced circulating levels of DHT (which circulates at much lower relative concentrations).[68][69] In addition, local levels of DHT in so-called androgenic (5α-reductase-expressing) tissues are also markedly reduced,[68][69] and this can have a strong impact on certain effects of testosterone.[31][70] For instance, growth of body and facial hair and penile growth induced by testosterone may be inhibited by 5α-reductase inhibitors, and this could be considered undesirable in the context of, for instance, puberty induction.[70][71] On the other hand, 5α-reductase inhibitors may prevent or reduce adverse androgenic side effects of testosterone like scalp hair loss, oily skin, acne, and seborrhea.[31] In addition to the prevention of testosterone conversion into DHT, 5α-reductase inhibitors also prevent the formation of neurosteroids like 3α-androstanediol from testosterone, and this may have neuropsychiatric consequences in some men.[72]

Aromatase inhibitorsEdit

Aromatase inhibitors like anastrozole prevent the conversion of testosterone into estradiol by aromatase.[31] As only a very small fraction of testosterone is converted into estradiol, this does not affect testosterone levels, but it can prevent estrogenic side effects like gynecomastia that can occur when testosterone is administered at relatively high dosages.[31] However, estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone.[73] Testosterone therapy is sometimes combined with an aromatase inhibitor for men with secondary hypogonadism who wish to conceive children with their partners.[74]

Cytochrome P450 inhibitorsEdit

Inhibitors and inducers of cytochrome P450 enzymes like CYP3A4 have been associated with little or no effect on circulating testosterone levels.[citation needed]

Antiandrogens and estrogensEdit

Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone.[75][76] Estrogens can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of sex hormone-binding globulin (SHBG), a carrier protein that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens.[76][77]

PharmacologyEdit

PharmacodynamicsEdit

Relative androgenic to anabolic
activity in animals

Medication Ratio
Testosterone 1:1
Testosterone cypionate 1:1
Testosterone enanthate 1:1
Methyltestosterone 1:1
Fluoxymesterone 1:2
Oxymetholone 1:3
Oxandrolone 1:3–1:13
Nandrolone decanoate 1:2.5–1:4
Sources: See template.

Testosterone is a high affinity ligand for and agonist of the nuclear androgen receptor (AR). In addition, testosterone binds to and activates membrane androgen receptors (mARs) such as GPRC6A and ZIP9. Testosterone is also potentiated via transformation by 5α-reductase into the more potent androgen DHT in so-called androgenic tissues such as the prostate gland, seminal vesicles, skin, and hair follicles. In contrast to the case of testosterone, such potentiation occurs to a reduced extent or not at all with most synthetic AAS (as well as with DHT), and this is primarily responsible for the dissociation of anabolic and androgenic effects with these agents.[78] In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the estrogen estradiol via aromatase.[79] This occurs in many tissues, especially adipose tissue, the liver, and the brain, but primarily in adipose tissue.[79] Testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol, a neurosteroid and potent positive allosteric modulator of the GABAA receptor, and 3β-androstanediol, a potent and preferential agonist of the ERβ.[80] These metabolites, along with estradiol, may be involved in a number of the effects of testosterone in the brain, including its antidepressant, anxiolytic, stress-relieving, rewarding, and pro-sexual effects.[80]

Effects in the body and brainEdit

The ARs are expressed widely throughout the body, including in the penis, testicles, epididymides, prostate gland, seminal vesicles, fat, skin, bone, bone marrow, muscle, larynx, heart, liver, kidneys, pituitary gland, hypothalamus, and elsewhere throughout the brain.[81][82] Through activation of the ARs (as well as the mARs), testosterone has many effects, including the following:[81][29][additional citation(s) needed]

PharmacokineticsEdit

 
Testosterone levels over 16 weeks with intramuscular injection of different testosterone esters in hypogonadal men.[81]

Testosterone is not active orally except in extremely high dosages due to poor absorption and extensive first-pass metabolism.[76] In addition, steroidal androgens including testosterone are hepatotoxic and there is a potential for liver injury with high dosages of oral testosterone due to the production of supraphysiological local concentrations of drug in the liver.[83] Instead of oral ingestion, testosterone is administered parenterally in the form of topical gels and creams, transdermal patches, buccal tablets, and subdermal implants.[76][84] In addition, it is administered via depot intramuscular injection in the form of long-acting ester prodrugs such as testosterone cypionate, testosterone enanthate, and testosterone propionate, as well as the particularly long-lasting testosterone undecanoate.[76] Testosterone buciclate is an even longer-acting testosterone ester that has been developed, but has yet to be approved for medical use.[76]

Although testosterone itself is not used orally, testosterone undecanoate is approved and used orally.[76] Due to the unique chemical properties afforded by its very long ester chain, testosterone undecanoate partially bypasses first-pass liver metabolism via absorption from the gastrointestinal tract directly into the lymphatic system and then into circulation.[76] Of oral testosterone undecanoate that reaches circulation, 90 to 100% is transported lymphatically.[85] This ester is not hepatotoxic at the dosages used.[76] However, oral testosterone undecanoate has variable pharmacokinetics and must be taken two to four times a day with food.[76] In addition to testosterone undecanoate, the combination of testosterone with a 5α-reductase inhibitor like dutasteride can render testosterone orally active when it is given in the form of oil-filled capsules.[86] This is via reduction of the first-pass hepatic metabolism of testosterone.[86]

Pharmacokinetics of testosterone esters

Testosterone ester Form Route of administration Elimination half-life Mean residence time
Testosterone undecanoate Oil-filled capsules Oral 1.6 hours 3.7 hours
Testosterone propionate Oil solution Intramuscular injection 0.8 days 1.5 days
Testosterone enanthate Castor oil solution Intramuscular injection 4.5 days 8.5 days
Testosterone undecanoate Tea seed oil solution Intramuscular injection 20.9 days 34.9 days
Testosterone undecanoate Castor oil solution Intramuscular injection 33.9 days 36.0 days
Testosterone buciclatea Aqueous suspension Intramuscular injection 29.5 days 60.0 days
Notes: Testosterone cypionate has very similar pharmacokinetics to TE. Footnotes: a = Never marketed. Sources: See template.

Parenteral durations of androgens/anabolic steroids

Compound Brand name(s) Type Duration
Testosterone (aq. susp.) Andronaq, Sterotate, Virosterone Androgen 2–3 days
Testosterone propionate Androteston, Perandren, Testoviron Androgen 3–4 days
Testosterone phenylpropionate Testolent Androgen 8 days
Testosterone isobutyrate (aq. susp.) Agovirin Depot, Perandren M Androgen 14 days
Mixed testosterone estersa Triolandren Androgen 10–20 days
Mixed testosterone estersb Testosid Depot Androgen 14–20 days
Testosterone enanthate Delatestryl Androgen 14–20 days
Testosterone cypionate Depovirin Androgen 14–20 days
Mixed testosterone estersc Sustanon 250 Androgen 28 days
Testosterone undecanoate Aveed, Nebido Androgen 100 days
Testosterone buciclate (aq. susp.)d 20 Aet-1, CDB-1781e Androgen 90–120 days
Nandrolone phenylpropionate Durabolin Anabolic 10 days
Nandrolone decanoate Deca Durabolin Anabolic 21 days
Methandriol (aq. susp.) Notandron, Protandren Androgen 8 days
Methandriol bisenanthoyl acetate Notandron Depot Androgen 16 days
Metenolone acetate Primobolan Anabolic 3 days
Metenolone enanthate Primobolan Depot Anabolic 14 days
Note: All are via i.m. injection of oil solution unless noted otherwise. Footnotes: a = TP, TV, and TUe. b = TP and TKL. c = TP, TPP, TiCa, and TD. d = Studied, but never marketed. e = Developmental code names. Sources: See template.

AbsorptionEdit

The oral bioavailability of testosterone is very low and virtually negligible.[29][87] The bioavailability of oral testosterone undecanoate is 3 to 7%.[85][88] Topical testosterone gels have a bioavailability of about 8 to 14% when administered to recommended skin sites including the abdomen, arms, shoulders, and thighs.[89][90] The bioavailability of testosterone via implant is virtually 100%,[91] while the bioavailability of drugs that are administered intramuscularly is generally almost 95%.[92]

DistributionEdit

In circulation, 97.0 to 99.5% of testosterone is bound to plasma proteins, with 0.5 to 3.0% unbound.[2] It is tightly bound to SHBG and weakly to albumin.[2] Of circulating testosterone, 30 to 44% is bound to SHBG while 54 to 68% is bound to albumin.[2] Testosterone that is unbound is referred to as free testosterone and testosterone that is bound to albumin is referred to as bioavailable testosterone.[2] Unlike testosterone that is bound to SHBG, bioavailable testosterone is bound to plasma proteins weakly enough such that, similarly to free testosterone, it may be biologically active, at least to some extent.[2] When referenced collectively (i.e., free, bioavailable, and SHBG-bound), circulating testosterone is referred to as total testosterone.[2]

MetabolismEdit

 
 
Testosterone metabolism in humans. Conjugation (sulfation and glucuronidation) occurs both with testosterone and with all of the other steroids that have one or more available hydroxyl (-OH) groups in this diagram.

Testosterone is metabolized primarily in the liver mainly (90%) by reduction via 5α- and 5β-reductase and conjugation via glucuronidation and sulfation.[2][75][93] The major urinary metabolites of testosterone are androsterone glucuronide and etiocholanolone glucuronide.[2][75][93][94]

The elimination half-life of testosterone varies depending on the route of administration and formulation and on whether or not it is esterified.[29] Oral testosterone undecanoate (in oil capsules) has a terminal half-life of 1.6 hours.[81] Because of its very short terminal half-life, oral testosterone undecanoate is taken two to four times per day.[81] In contrast to oral testosterone, other forms of testosterone including topical gels and solutions, transdermal patches, and buccal tablets have an extended-release effect and can be administered less frequently, at intervals, depending on the route/formulation, of once a day, twice a day, or once every other day.[29][81]

Whereas the terminal half-life of unesterified testosterone administered via intramuscular injection is very short at only around 10 minutes, the terminal half-lives of intramuscular testosterone esters are far longer.[29][81] Administered in the form of oil solutions, the terminal half-lives are 0.8 days for testosterone propionate, 4.5 days for testosterone enanthate, 20.9 days (in tea seed oil) and 33.9 days (in caster oil) for testosterone undecanoate, and 29.5 days for testosterone buciclate.[29][81] Although exact values are not available for intramuscular testosterone cypionate, its pharmacokinetics are said to be the same as those of testosterone enanthate, with "extremely comparable" patterns of testosterone release.[31][81] Due to their varying and different terminal half-lives, the different intramuscular testosterone esters are administered with differing frequencies.[95] Testosterone propionate is injected two to three times per week, testosterone enanthate and testosterone cypionate are injected once every two to four weeks, and testosterone undecanoate and testosterone buciclate are injected once every 10 to 14 weeks.[95] Due to its relatively short duration, testosterone propionate is now relatively little used and testosterone undecanoate is the preferred testosterone ester for intramuscular use.[29][81] Testosterone undecanoate and testosterone buciclate can be injected intramuscularly as little as four times per year.[29][81]

The absorption half-life of subdermal testosterone implants is 2.5 months.[29] The replacement interval is once every four to five months.[96]

EliminationEdit

Testosterone and its metabolites are eliminated in the urine.[97] It is excreted mainly as androsterone glucuronide and etiocholanolone glucuronide.[94] It is also excreted to a small extent as other conjugates such as testosterone glucuronide (1%), testosterone sulfate (0.03%), and androstanediol glucuronides.[94][98] Only a very small amount of testosterone (less than 0.01%) is found unchanged in the urine.[97][98]

ChemistryEdit

Testosterone is a naturally occurring androstane steroid and is also known by the chemical name androst-4-en-17β-ol-3-one.[99] It has a double bond between the C4 and C5 positions (making it an androstene), a ketone group at the C3 position, and a hydroxyl (alcohol) group at the C17β position.[99]

DerivativesEdit

Testosterone esters are substituted at the C17β position with a lipophilic fatty acid ester moiety of varying chain length.[100] Major testosterone esters include testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone undecanoate.[76][99][101] A C17β ether prodrug of testosterone, cloxotestosterone acetate, has also been marketed, although it is little known and is used very rarely or no longer.[99] Another C17β ether prodrug of testosterone, silandrone, also exists but was never marketed, and is notable in that it is orally active.[99] In addition to ester and ether prodrugs, androgen prohormones or precursors of testosterone, such as dehydroepiandrosterone (DHEA), androstenediol, and androstenedione, exist as well, and convert into testosterone to variable extents upon oral ingestion.[102] Unlike testosterone ester and ether prodrugs however, these prohormones are only weakly androgenic/anabolic.[102]

All synthetic AAS are derivatives of testosterone.[102] Prominent examples include nandrolone (19-nortestosterone), metandienone (17α-methyl-δ1-testosterone), and stanozolol (a 17α-alkylated derivative of DHT). Unlike testosterone, AAS that are 17α-alkylated, like metandienone and stanozolol, are orally active. This is due to steric hindrance of C17β-position metabolism during the first-pass through the liver. In contrast, most AAS that are not 17α-alkylated, like nandrolone, are not active orally, and must instead be administered via intramuscular injection. This is almost always in ester form; for instance, in the case of nandrolone, as nandrolone decanoate or nandrolone phenylpropionate.

Structural properties of major testosterone esters

Androgen Structure Ester Relative
mol. weight
Relative
T contentb
Durationc
Position Moiety Type Lengtha Rank Group
Testosterone
 
1.00 1.00 11 Short
Testosterone propionate
 
C17β Propanoic acid Straight-chain fatty acid 3 1.19 0.84 10 Short
Testosterone isobutyrate
 
C17β Isobutyric acid Aromatic fatty acid – (~3) 1.24 0.80 9 Moderate
Testosterone cypionate
 
C17β Cyclopentylpropanoic acid Aromatic fatty acid – (~6) 1.43 0.70 8 Moderate
Testosterone phenylpropionate
 
C17β Phenylpropanoic acid Aromatic fatty acid – (~6) 1.46 0.69 7 Moderate
Testosterone isocaproate
 
C17β Isohexanoic acid Branched-chain fatty acid – (~5) 1.34 0.75 6 Moderate
Testosterone caproate
 
C17β Hexanoic acid Straight-chain fatty acid 6 1.35 0.75 5 Moderate
Testosterone enanthate
 
C17β Heptanoic acid Straight-chain fatty acid 7 1.39 0.72 4 Moderate
Testosterone decanoate
 
C17β Decanoic acid Straight-chain fatty acid 10 1.53 0.65 3 Long
Testosterone undecanoate
 
C17β Undecanoic acid Straight-chain fatty acid 11 1.58 0.63 2 Long
Testosterone buciclated
 
C17β Bucyclic acide Aromatic carboxylic acid – (~9) 1.58 0.63 1 Long
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative testosterone content by weight (i.e., relative androgenic/anabolic potency). c = Duration by intramuscular or subcutaneous injection in oil solution (except TiB and TB, which are in aqueous suspension). d = Never marketed. e = Bucyclic acid = trans-4-Butylcyclohexane-1-carboxylic acid. Sources: See individual articles.

HistoryEdit

Testosterone was first isolated and synthesized in 1935.[103] Shortly thereafter, in 1937, testosterone first became commercially available as a pharmaceutical drug in the form of pellets and then in ester form for intramuscular injection as the relatively short-acting testosterone propionate.[31][29][104] Methyltestosterone, one of the first synthetic AAS and orally active androgens, was introduced in 1935, but was associated with hepatotoxicity and eventually became largely medically obsolete.[104] In the mid-1950s, the longer-acting testosterone esters testosterone enanthate and testosterone cypionate were introduced.[104] They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century.[104] In the 1970s, testosterone undecanoate was introduced for oral use in Europe,[104] although intramuscular testosterone undecanoate had already been in use in China for several years.[105] Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later (in the early to mid 2000s and 2014, respectively).[2][106]

Society and cultureEdit

UsageEdit

In the US in the 2000s, companies and figures in the popular media have heavily marketed notions of "andropause" as something parallel to menopause; these notions have been rejected by the medical community.[107][108] Additionally, advertising from drug companies selling testosterone and human growth hormone, as well as dietary supplement companies selling all kinds of "boosters" for aging men, have emphasized the "need" of middle-aged or ageing men for testosterone.[109] There is a medical condition called late-onset hypogonadism; according to Thomas Perls and David J. Handelsman, writing in a 2015 editorial in the Journal of the American Geriatrics Society, it appears that this condition is overdiagnosed and overtreated.[109] Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales."[109]

Generic namesEdit

Testosterone is the generic name of testosterone in English and Italian and the INN, USAN, USP, BAN, and DCIT of the drug, while testostérone is its French name and the DCF.[99][110][111] It is also referred to in Latin as testosteronum, in Spanish and Portuguese as testosterona, and in German, Dutch, and Russian and other Slavic languages as testosteron.[110][111] The Cyrillic script of testosterone is тестостерон.[112]

Brand namesEdit

 
A vial of Depo-Testosterone (testosterone cypionate in oil) for intramuscular injection.

Testosterone is marketed under a large number of brand names throughout the world.[110] Major brand names of testosterone and/or its esters include Andriol, Androderm, AndroGel, Axiron, Delatestryl, Depo-Testosterone, Intrinsa, Nebido, Omnadren, Primoteston, Sustanon, Testim, TestoGel, TestoPatch, Testoviron, and Tostran.[76][78][110]

AvailabilityEdit

United StatesEdit

As of November 2016, unmodified (non-esterified) testosterone is available in the United States in the following formulations:[113]

  • Topical gels: AndroGel, Fortesta, Testim, Testosterone (generic)
  • Topical solutions: Axiron, Testosterone (generic)
  • Transdermal patches: Androderm, Testoderm (discontinued), Testoderm TTS (discontinued), Testosterone (generic)
  • Intranasal gels: Natesto
  • Buccal tablets: Striant
  • Pellet implants: Testopel

And the following ester prodrugs of testosterone are available in the United States in oil solutions for intramuscular injection:[113]

Unmodified testosterone was also formerly available for intramuscular injection but was discontinued.[113]

Testosterone cypionate and testosterone enanthate were formerly available in combination with estradiol cypionate and estradiol valerate, respectively, under the brand names Depo-Testadiol and Ditate-DS, respectively, as oil solutions for intramuscular injection, but these formulations have been discontinued.[113]

Unlike in Europe, Canada, and much of the rest of the world, oral testosterone undecanoate is not available in the United States.[113][114][115]

CanadaEdit

As of November 2016, testosterone is available in Canada in the form of topical gels (AndroGel, Testim), topical solutions (Axiron), transdermal patches (Androderm), and intranasal gels (Natesto).[116] Testosterone cypionate (Depo-Testosterone, Testosterone Cypionate (generic)), testosterone enanthate (Delatestryl, PMS-Testosterone Enanthate), and testosterone propionate (Testosterone Propionate (generic)) are available as oil solutions for intramuscular injection and testosterone undecanoate (Andriol, PMS-Testosterone, Taro-Testosterone) is available in the form of oral capsules.[116] Testosterone buccal tablets and pellet implants do not appear to be available in Canada.[116]

Other countriesEdit

Testosterone and/or its esters are widely available in countries throughout the world in a variety of formulations.[110]

Legal statusEdit

Testosterone and its esters, along with other AAS, are prescription-only controlled substances in many countries throughout the world. In the United States, they are Schedule III drugs under the Controlled Substances Act, in Canada, they are Schedule IV drugs under the Controlled Drugs and Substances Act, and in the United Kingdom, they are Class C drugs under the Misuse of Drugs Act.[117][118]

LitigationEdit

As of 2014, a number of lawsuits are underway against manufacturers of testosterone, alleging a significantly increased rate of stroke and heart attack in elderly men who use testosterone supplementation.[119]

Doping in sportsEdit

There are many known cases of doping in sports with testosterone and its esters by professional athletes.

ResearchEdit

DepressionEdit

Testosterone has been used to treat depression in men who are of middle age with low testosterone. However, a 2014 review showed no benefit on the mood of the men with normal levels of testosterone or on the mood of the older men with low testosterone.[120] Conversely, a 2009 review found that testosterone had an antidepressant effect in men with depression, especially those with hypogonadism, HIV/AIDS, and in the elderly.[121]

Heart failureEdit

Testosterone replacement can significantly improve exercise capacity, muscle strength and reduce QT intervals in men with chronic heart failure (CHF). Over the 3 to 6-month course of the studies reviewed, testosterone therapy appeared safe and generally effective, and (ruling out prostate cancer) the authors found no justification to absolutely restrict its use in men with CHF.[122] A similar 2012 review also found increased exercise capacity and reasoned the benefits generlizable to women.[123] However, both reviews advocate larger, longer term, randomized controlled trials.[122][123]

Male contraceptionEdit

Testosterone, as esters such as testosterone undecanoate or testosterone buciclate, has been studied and promoted as a male contraceptive analogous to estrogen-based contraceptives in women. Otherwise considered an adverse effect of testosterone, reduced spermatogenesis can be further suppressed with the addition of a progestin such as norethisterone enanthate or levonorgestrel butanoate, improving the contraceptive effect.[124][125]

AnorgasmiaEdit

Testosterone is under development in a low-dose intranasal formulation for the treatment of anorgasmia in women.[126]

Scalp hair lossEdit

A study found that of 76 pre- and postmenopausal women with hair thinning, 63% experienced hair regrowth when treated with subcutaneous testosterone implants that resulted in average testosterone levels of over 300 ng/dL for 12 months.[127] No woman reported hair loss or thinning during testosterone treatment.[127]

MiscellaneousEdit

Testosterone therapy may improve the management of type 2 diabetes.[128] Low testosterone has been associated with the development of Alzheimer's disease.[129][130]

Topical androgens like testosterone have been used and studied in the treatment of cellulite in women.[131]

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