Testosterone (medication)

This article is about the medication. For the natural hormone, see Testosterone.
Testosterone (medication)
Clinical data
Pronunciation tess-toss-ter-own[1]
Trade names Androgel, Testim, Testogel, others
AHFS/Drugs.com Monograph
MedlinePlus a614041
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
ATC code G03BA03 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral: very low (due to extensive first pass metabolism)
Protein binding 97.0–99.5% (to SHBG and albumin)[2]
Metabolism Liver (mainly reduction and conjugation)
Biological half-life 2–4 hours
Excretion Urine (90%), feces (6%)
Identifiers
Synonyms Androst-4-en-17β-ol-3-one
CAS Number 58-22-0 YesY
57-85-2 (propionate)
315-37-7 (enanthate)
58-20-8 (cypionate)
5949-44-0 (undecanoate)
PubChem (CID) 6013
IUPHAR/BPS 2858
DrugBank DB00624 YesY
ChemSpider 5791 YesY
UNII 3XMK78S47O YesY
KEGG D00075 YesY
ChEBI CHEBI:17347 YesY
ChEMBL CHEMBL386630 YesY
Chemical and physical data
Formula C19H28O2
Molar mass 288.42 g/mol
3D model (Jmol) Interactive image
Specific rotation +110.2°
Melting point 155 °C (311 °F)
SEC combustion −11080 kJ/mol
  (verify)

Testosterone is a medication and naturally occurring steroid hormone.[3] It is used to treat male hypogonadism and certain types of breast cancer. 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]

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

Testosterone was first isolated in 1935.[5] Rates of use have increased three times in the United States between 2001 and 2011.[6] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[7] It is available as a generic medication.[3] The price depends on the form of testosterone used.[8]

Medical uses

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

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).[9] 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.[10]

Deficiency

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.[11]

Low levels due to aging

Testosterone levels may decline gradually with age.[12][13] 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 men

To take advantage of its virilizing effects, testosterone is administered to transgender men as part of their hormone therapy,[14] with a "target level" of the average male's testosterone level.

Women

Low sexual desire

Testosterone supplementation is effective in the short term for hypoactive sexual desire disorder.[15] However, its long term safety is unclear.[15]

Low testosterone levels

Treating low androgen levels with testosterone is not generally recommended in women when it is due to hypopituitarism, adrenal insufficiency, or following surgical removal of the ovaries.[15] It is also not usually recommended for improving cognition, the risk of heart disease, bone strength or for generalized well being.[15]

Non-medical use

Athletics

Testosterone is used as a form of doping among athletes in order to improve performance.[16] Testosterone is classified as an anabolic agent and is on the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods.[16] Several application methods for testosterone, including intramuscular injections, transdermal gels and patches, and implantable pellets. 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.

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.

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.[17] 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.

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.[18] 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.[19][20]

Detection of abuse

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.[21][22][23][24]

Contraindications

Absolute contraindications of testosterone include prostate cancer, elevated hematocrit (>54%), uncontrolled congestive heart failure, various other cardiovascular diseases, and uncontrolled obstructive sleep apnea.[25] Breast cancer is said by some sources to be an absolute contraindication of testosterone therapy,[25] but androgens including testosterone have also actually been used to treat breast cancer.[26] 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%).[25]

Interactions

5α-Reductase inhibitors

5α-Reductase inhibitors like finasteride and dutasteride slightly increase circulating levels of testosterone by inhibiting its metabolism. However, these drugs do this via prevention of the conversion of testosterone into its more potent metabolite dihydrotestosterone (DHT), and this results in strongly reduced circulating levels of DHT (which circulates at much lower relative concentrations). In addition, local levels of DHT in so-called androgenic (5α-reductase-expressing) tissues are also markedly reduced, and this can have a marked impact on certain effects of testosterone. For instance, growth of body and facial hair and penis enlargement induced by testosterone may be inhibited by 5α-reductase inhibitors, and this may be considered undesirable in the context of, for instance, puberty induction. 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. In addition to the prevention of testosterone conversion into DHT, 5α-reductase inhibitors also prevent the formation of neurosteroids like 3α-androstanediol from testosterone.

Aromatase inhibitors

Aromatase inhibitors like anastrozole prevent the conversion of testosterone into estradiol by aromatase. 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 that can occur when testosterone is administered at relatively high dosages.

Cytochrome P450 inhibitors

Inhibitors of cytochrome P450 enzymes like the CYP3A4 inhibitor ketoconazole have been associated with only very small effects on circulating testosterone levels.

Antiandrogens and estrogens

Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. 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.

Adverse effects

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.[27] 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.[28] 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.[29] Testosterone treatment, particularly in high dosages, can also be associated with mood changes, increased aggression, increased sex drive, spontaneous erections, and nocturnal emissions.[30][31][32][33]

Other side effects include increased hematocrit, which can require venipuncture in order to treat, and exacerbation of sleep apnea.[34]

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.[35]

Long-term adverse effects

Cardiovascular disease

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.[36] In addition, an increase of 30% in deaths and heart attacks in older men has been reported.[37] 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.[38] 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.[39] 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).[40][41][42] The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.[43]

Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease;[44][45] more recent studies, however, do raise concerns.[46] 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."[37]

Prostate cancer

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.[47] Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation.[48]

It may accelerate pre-existing prostate cancer growth in individuals who have undergone androgen deprivation.[34] 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.[12]

Ethnic groups have different rates of prostate cancer.[49] Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences.[49] 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.[50]

Pregnancy and breastfeeding

Testosterone is contraindicated in pregnancy and not recommended during breastfeeding.[51] Androgens like testosterone are teratogens and are known to cause fetal harm, such as producing virilization and ambiguous genitalia.

Pharmacology

Dihydrotestosterone

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. 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.[52] In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the estrogen estradiol via aromatase.[53] This occurs in many tissues, especially adipose tissue, the liver, and the brain, but primarily in adipose tissue.[53] 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.[54] Research suggests that these metabolites, along with estradiol, are involved in a number of the effects of testosterone in the brain, including its antidepressant, anxiolytic, stress-relieving, rewarding, and pro-sexual effects.[54]

Pharmacokinetics

Routes of administration

Testosterone is not active orally except in extremely high dosages due to poor absorption and extensive first-pass metabolism.[55] 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.[56] Instead of oral ingestion, testosterone is administered parenterally in the form of topical gels and creams, transdermal patches, buccal tablets, and subdermal implants.[55][57] 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.[55] Testosterone buciclate is an even longer-acting testosterone ester that has been developed, but has yet to be approved for medical use.[55]

Although testosterone itself is not used orally, testosterone undecanoate is approved and used orally.[55] 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.[55] Of oral testosterone undecanoate that reaches circulation, 90 to 100% is transported lymphatically.[58] This ester is not hepatotoxic at the dosages used.[55] However, oral testosterone undecanoate has variable pharmacokinetics and must be taken two to four times a day with food.[55] 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.[59] This is via reduction of the first-pass hepatic metabolism of testosterone.[59]

Absorption

The oral bioavailability of testosterone is very low and virtually negligible.[60][61] The bioavailability of oral testosterone undecanoate is 3 to 7%.[62][58] Topical testosterone gels have a bioavailability of 10% when administered to recommended skins sites including the abdomen, arms, shoulders, and thighs.[63] The bioavailability of testosterone via implant is virtually 100%,[64] while the bioavailability of drugs that are administered intramuscularly is generally almost 95%.[65]

Distribution

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]

Metabolism

Testosterone is metabolized primarily in the liver mainly (90%) by reduction via 5α- and 5β-reductase and conjugation via glucuronidation and sulfation.[2][66][67] The main urinary metabolites of testosterone are androsterone glucuronide and etiocholanolone glucuronide.[2][66][67][68]

Terminal half-life and duration

Pharmacokinetics of testosterone esters[69][70]
Preparation Route MRT t½
Testosterone undecanoate p.o. 3.7 hours 1.6 hours
Testosterone propionate i.m. 1.5 days 0.8 days
Testosterone enanthate
(in castor oil) 		i.m. 8.5 days 4.5 days
Testosterone undecanoate
(in tea seed oil) 		i.m. 34.9 days 20.9 days
Testosterone undecanoate
(in castor oil) 		i.m. 36.0 days 33.9 days
Testosterone buciclate
(aqueous suspension) 		i.m. 60.0 days 29.5 days

The terminal half-life of testosterone varies depending on the route of administration and formulation and on whether or not it is esterified.[60] Oral testosterone undecanoate (in oil capsules) has a terminal half-life of 1.6 hours.[69] Because of its very short terminal half-life, oral testosterone undecanoate is taken two to four times per day.[69] 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.[60][69]

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.[60][69] 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.[60][69] 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.[69][71] Due to their varying and different terminal half-lives, the different intramuscular testosterone esters are administered with differing frequencies.[72] 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.[72] Due to its relatively short duration, testosterone propionate is now relatively little used and testosterone undecanoate is the preferred testosterone ester for intramuscular use.[60][69] Testosterone undecanoate can be injected intramuscularly as little as four times per year.[60][69]

The absorption half-life of subdermal testosterone implants is 2.5 months.[60] The replacement interval is once every four to five months.[73]

Elimination

Testosterone and its metabolites are eliminated in the urine.[74] It is excreted mainly as androsterone glucuronide and etiocholanolone glucuronide.[68] It is also excreted to a small extent as other conjugates such as testosterone glucuronide and androstanediol glucuronides.[68] Only a very small amount of testosterone is found unchanged in the urine.[74]

Chemistry

Testosterone is an androstane (C19) steroid and is also known by the chemical name androst-4-en-17β-ol-3-one.[75] 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.[75]

Derivatives

Testosterone esters are substituted at the C17β position with a lipophilic fatty acid ester moiety of varying chain length.[76] Major testosterone esters include testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone undecanoate.[55][75][77] 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.[75] Another C17β ether prodrug of testosterone, silandrone, also exists but was never marketed, and is notable in that it is orally active.[75] 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.[78] Unlike testosterone ester and ether prodrugs however, these prohormones are only weakly androgenic/anabolic.[78]

All synthetic AAS are derivatives of testosterone.[78] 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.

History

Testosterone was first isolated and synthesized in 1935.[79] 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.[80][60][71] Methyltestosterone, the first AAS and orally active androgen, was introduced in 1935, but was associated with hepatotoxicity and eventually became largely medically obsolete.[80] In the mid-1950s, the longer-acting testosterone esters testosterone enanthate and testosterone cypionate were introduced.[80] They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century.[80] In the 1970s, testosterone undecanoate was introduced for oral use in Europe,[80] although intramuscular testosterone undecanoate had already been in use in China for several years.[81] Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later (in the early to mid 2000s and 2014, respectively).[82][2]

Society and culture

Generic name

Testosterone (pronounced tess-toss-ter-own)[1] 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.[83][84][75] 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.[83][84] The Cyrillic script of testosterone is тестостерон.[85]

Brand names

Testosterone is marketed under a large number of brand names throughout the world.[83] 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.[83][55][52]

Availability

United States

As of November 2016, unmodified (non-esterified) testosterone is available in the United States in the following formulations:[86]

And the following ester prodrugs of testosterone are available in the United States in oil solutions for intramuscular injection:[86]

Unmodified testosterone was also formerly available for intramuscular injection but was discontinued.[86]

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.[86]

Unlike in Europe, Canada, and much of the rest of the world, oral testosterone undecanoate is not available in the United States.[86][87][33]

Canada

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).[88] 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.[88] Testosterone buccal tablets and pellet implants do not appear to be available in Canada.[88]

Other countries

Testosterone and/or its esters are widely available in countries throughout the world in a variety of formulations.[83]

Legal status

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.

Litigation

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.[89]

Research

Depression

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.[90]

Heart failure

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.[91] A similar 2012 review also found increased exercise capacity and reasoned the benefits generlizable to women.[92] However, both reviews advocate larger, longer term, randomized controlled trials.[91][92]

Male contraception

Testosterone 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, improving the contraceptive effect.[93][94]

Miscellaneous

Testosterone therapy may improve the management of type 2 diabetes.[95] Low testosterone has been associated with the development of Alzheimer's disease.[96][97]

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