Pharmacokinetics of testosterone

The pharmacology of testosterone, an androgen and anabolic steroid (AAS) medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

Testosterone

Clinical data
Routes of administration	Oral, buccal, sublingual, intranasal, transdermal (gel, cream, patch, solution), vaginal (cream, gel, suppository), rectal (suppository), intramuscular or subcutaneous injection (oil solution, aqueous suspension), subcutaneous implant (pellet)
Drug class	Androgen, anabolic steroid
Pharmacokinetic data
Bioavailability	Oral: very low (due to extensive first pass metabolism)
Protein binding	97.0–99.5% (to SHBG and albumin)[1]
Metabolism	Liver (mainly reduction and conjugation)
Elimination half-life	2–4 hours
Excretion	Urine (90%), feces (6%)

Testosterone is a naturally occurring and bioidentical AAS, or an agonist of the androgen receptor, the biological target of androgens like endogenous testosterone and dihydrotestosterone (DHT).

Testosterone is used by both men and women and can be taken by a variety of different routes of administration.[2]

Routes of administration

See also: Testosterone (medication) § Available forms

Testosterone can be taken by a variety of different routes of administration.[2][3] These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches, solutions), vaginal (creams, gels, suppositories), rectal (suppositories), by intramuscular or subcutaneous injection (in oil solutions or aqueous suspensions), and as a subcutaneous implant.[2][3] The pharmacokinetics of testosterone, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration.[2] Likewise, the potency of testosterone, and its local effects in certain tissues, for instance the liver, differ by route of administration as well.[2] In particular, the oral route is subject to a high first-pass effect, which results in high levels of testosterone in the liver and consequent hepatic androgenic effects, as well as low potency due to first-pass metabolism in the intestines and liver into metabolites like dihydrotestosterone and androgen conjugates.[2] Conversely, this is not the case for non-oral routes, which bypass the first pass.[2]

Different testosterone routes and dosages can achieve widely varying circulating testosterone levels.[2] For purposes of comparison with normal physiological circumstances, circulating levels of total testosterone in men range from about 250 to 1,100 ng/dL (mean 630 ng/dL) and in women range from about 2 to 50 ng/dL (mean 32 ng/dL).[4][5][6][7] Testosterone levels decline with age in men.[8] In women with polycystic ovary syndrome (PCOS), a condition of androgen excess, testosterone levels are typically around 50 to 80 ng/dL, with a range of about 30 to 140 ng/dL.[9][10][7] Total testosterone levels are about 20-fold and free testosterone levels about 40-fold higher in men than in women on average.[11] Similarly, testosterone production is approximately 30 times higher in men than in women.[12]

Available forms of testosterone

Route	Ingredient	Form	Dose	Frequency	Major brand names
Oral	Testosterone undecanoate	Capsule	40 mg	2–4x per day	Andriol, Andriol Testocaps, Jatenzo
Sublingual	Testosterone	Tablet	10 mg	1–4x per day	Testoral
Buccal	Testosterone	Tablet	30 mg	2x per day	Striant
Intranasal	Testosterone	Nasal gel	5.5 mg per spray (120 sprays per bottle)	3x per day	Natesto
Transdermal	Testosterone	Non-scrotal patch	2.5, 4, 5, or 6 mg T per day	1x every 1–2 days	Androderm, AndroPatch, TestoPatch
		Non-scrotal patch	150 or 300 μg T per day	1x every 3–4 days	Intrinsa
		Scrotal patch	4 or 6 mg T per day	1x per day	Testoderm
		Topical gel (1–2.5%)	25, 50, 75, 100, or 125 mg T per application	1x per day	AndroGel, Testim, TestoGel
		Axillary solution (2%)	30 mg T per application	1x per day	Axiron
Rectal	Testosterone	Suppository	40 mg	2–3x per day	Rektandron, Testosteron
Injection (IM or SC)	Testosterone^a	Aqueous suspension	25, 50, or 100 mg/mL	1x every 2–3 days	Andronaq, Sterotate, Virosterone
	Testosterone propionate^a	Oil solution	5, 10, 25, 50, or 100 mg/mL	1x every 2–3 days	Testoviron
	Testosterone isobutyrate^a	Aqueous suspension	25 mg/mL	1x every 1–2 weeks	Agovirin-Depot, Perandren M
	Testosterone enanthate	Oil solution	50, 100, 180, 200, or 250 mg/mL	1x every 1–4 weeks	Delatestryl
	Testosterone cypionate	Oil solution	50, 100, 200, or 250 mg/mL	1x every 1–4 weeks	Depo-Testosterone
	Mixed testosterone esters	Oil solution	100 or 250 mg/mL	1x every 2–4 weeks	Sustanon 100, Sustanon 250
	Testosterone undecanoate	Oil solution	750 or 1000 mg per injection	1x every 10–14 weeks	Aveed, Nebido, Reandron
Implant	Testosterone	Pellet	50, 75, 100, or 200 mg	1x every 3–6 months	TestoImplant, Testopel
Abbreviations: T = Testosterone. Footnotes: ^a = Discontinued or mostly discontinued. Notes: (1): This table does not include dosage information, which cannot necessarily be extrapolated from the provided information. (2): This table mostly 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.

Androgen replacement therapy formulations and dosages used in men

Route	Medication	Major brand names	Form	Dosage
Oral	Testosterone^a	–	Tablet	400–800 mg/day (in divided doses)
	Testosterone undecanoate	Andriol, Jatenzo	Capsule	40–80 mg/2–4x day (with meals)
	Methyltestosterone^b	Android, Metandren, Testred	Tablet	10–50 mg/day
	Fluoxymesterone^b	Halotestin, Ora-Testryl, Ultandren	Tablet	5–20 mg/day
	Metandienone^b	Dianabol	Tablet	5–15 mg/day
	Mesterolone^b	Proviron	Tablet	25–150 mg/day
Buccal	Testosterone	Striant	Tablet	30 mg 2x/day
	Methyltestosterone^b	Metandren, Oreton Methyl	Tablet	5–25 mg/day
Sublingual	Testosterone^b	Testoral	Tablet	5–10 mg 1–4x/day
	Methyltestosterone^b	Metandren, Oreton Methyl	Tablet	10–30 mg/day
Intranasal	Testosterone	Natesto	Nasal spray	11 mg 3x/day
Transdermal	Testosterone	AndroGel, Testim, TestoGel	Gel	25–125 mg/day
		Androderm, AndroPatch, TestoPatch	Non-scrotal patch	2.5–15 mg/day
		Testoderm	Scrotal patch	4–6 mg/day
		Axiron	Axillary solution	30–120 mg/day
	Androstanolone (DHT)	Andractim	Gel	100–250 mg/day
Rectal	Testosterone	Rektandron, Testosteron^b	Suppository	40 mg 2–3x/day
Injection (IM or SC)	Testosterone	Andronaq, Sterotate, Virosterone	Aqueous suspension	10–50 mg 2–3x/week
	Testosterone propionate^b	Testoviron	Oil solution	10–50 mg 2–3x/week
	Testosterone enanthate	Delatestryl	Oil solution	50–250 mg 1x/1–4 weeks
		Xyosted	Auto-injector	50–100 mg 1x/week
	Testosterone cypionate	Depo-Testosterone	Oil solution	50–250 mg 1x/1–4 weeks
	Testosterone isobutyrate	Agovirin Depot	Aqueous suspension	50–100 mg 1x/1–2 weeks
	Testosterone phenylacetate^b	Perandren, Androject	Oil solution	50–200 mg 1x/3–5 weeks
	Mixed testosterone esters	Sustanon 100, Sustanon 250	Oil solution	50–250 mg 1x/2–4 weeks
	Testosterone undecanoate	Aveed, Nebido	Oil solution	750–1,000 mg 1x/10–14 weeks
	Testosterone buciclate^a	–	Aqueous suspension	600–1,000 mg 1x/12–20 weeks
Implant	Testosterone	Testopel	Pellet	150–1,200 mg/3–6 months
Notes: Men produce about 3 to 11 mg testosterone per day (mean 7 mg/day in young men). Footnotes: ^a = Never marketed. ^b = No longer used and/or no longer marketed. Sources: See template.

Androgen replacement therapy formulations and dosages used in women

Route	Medication	Major brand names	Form	Dosage
Oral	Testosterone undecanoate	Andriol, Jatenzo	Capsule	40–80 mg 1x/1–2 days
	Methyltestosterone	Metandren, Estratest	Tablet	0.5–10 mg/day
	Fluoxymesterone	Halotestin	Tablet	1–2.5 mg 1x/1–2 days
	Normethandrone^a	Ginecoside	Tablet	5 mg/day
	Tibolone	Livial	Tablet	1.25–2.5 mg/day
	Prasterone (DHEA)^b	–	Tablet	10–100 mg/day
Sublingual	Methyltestosterone	Metandren	Tablet	0.25 mg/day
Transdermal	Testosterone	Intrinsa	Patch	150–300 μg/day
		AndroGel	Gel, cream	1–10 mg/day
Vaginal	Prasterone (DHEA)	Intrarosa	Insert	6.5 mg/day
Injection	Testosterone propionate^a	Testoviron	Oil solution	25 mg 1x/1–2 weeks
	Testosterone enanthate	Delatestryl, Primodian Depot	Oil solution	25–100 mg 1x/4–6 weeks
	Testosterone cypionate	Depo-Testosterone, Depo-Testadiol	Oil solution	25–100 mg 1x/4–6 weeks
	Testosterone isobutyrate^a	Femandren M, Folivirin	Aqueous suspension	25–50 mg 1x/4–6 weeks
	Mixed testosterone esters	Climacteron^a	Oil solution	150 mg 1x/4–8 weeks
		Omnadren, Sustanon	Oil solution	50–100 mg 1x/4–6 weeks
	Nandrolone decanoate	Deca-Durabolin	Oil solution	25–50 mg 1x/6–12 weeks
	Prasterone enanthate^a	Gynodian Depot	Oil solution	200 mg 1x/4–6 weeks
Implant	Testosterone	Testopel	Pellet	50–100 mg 1x/3–6 months
Notes: Premenopausal women produce about 230 ± 70 μg testosterone per day (6.4 ± 2.0 mg testosterone per 4 weeks), with a range of 130 to 330 μg per day (3.6–9.2 mg per 4 weeks). Footnotes: ^a = Mostly discontinued or unavailable. ^b = Over-the-counter. Sources: See template.

Testosterone levels in males and females

Total testosterone
Stage	Age range	Male		Female
		Values	SI units	Values	SI units
Infant	Premature (26–28 weeks)	59–125 ng/dL	2.047–4.337 nmol/L	5–16 ng/dL	0.173–0.555 nmol/L
	Premature (31–35 weeks)	37–198 ng/dL	1.284–6.871 nmol/L	5–22 ng/dL	0.173–0.763 nmol/L
	Newborn	75–400 ng/dL	2.602–13.877 nmol/L	20–64 ng/dL	0.694–2.220 nmol/L
Child	1–6 years	ND	ND	ND	ND
	7–9 years	0–8 ng/dL	0–0.277 nmol/L	1–12 ng/dL	0.035–0.416 nmol/L
	Just before puberty	3–10 ng/dL*	0.104–0.347 nmol/L*	<10 ng/dL*	<0.347 nmol/L*
Puberty	10–11 years	1–48 ng/dL	0.035–1.666 nmol/L	2–35 ng/dL	0.069–1.214 nmol/L
	12–13 years	5–619 ng/dL	0.173–21.480 nmol/L	5–53 ng/dL	0.173–1.839 nmol/L
	14–15 years	100–320 ng/dL	3.47–11.10 nmol/L	8–41 ng/dL	0.278–1.423 nmol/L
	16–17 years	200–970 ng/dL*	6.94–33.66 nmol/L*	8–53 ng/dL	0.278–1.839 nmol/L
Adult	≥18 years	350–1080 ng/dL*	12.15–37.48 nmol/L*	–	–
	20–39 years	400–1080 ng/dL	13.88–37.48 nmol/L	–	–
	40–59 years	350–890 ng/dL	12.15–30.88 nmol/L	–	–
	≥60 years	350–720 ng/dL	12.15–24.98 nmol/L	–	–
	Premenopausal	–	–	10–54 ng/dL	0.347–1.873 nmol/L
	Postmenopausal	–	–	7–40 ng/dL	0.243–1.388 nmol/L
Bioavailable testosterone
Stage	Age range	Male		Female
		Values	SI units	Values	SI units
Child	1–6 years	0.2–1.3 ng/dL	0.007–0.045 nmol/L	0.2–1.3 ng/dL	0.007–0.045 nmol/L
	7–9 years	0.2–2.3 ng/dL	0.007–0.079 nmol/L	0.2–4.2 ng/dL	0.007–0.146 nmol/L
Puberty	10–11 years	0.2–14.8 ng/dL	0.007–0.513 nmol/L	0.4–19.3 ng/dL	0.014–0.670 nmol/L
	12–13 years	0.3–232.8 ng/dL	0.010–8.082 nmol/L	1.1–15.6 ng/dL	0.038–0.541 nmol/L
	14–15 years	7.9–274.5 ng/dL	0.274–9.525 nmol/L	2.5–18.8 ng/dL	0.087–0.652 nmol/L
	16–17 years	24.1–416.5 ng/dL	0.836–14.452 nmol/L	2.7–23.8 ng/dL	0.094–0.826 nmol/L
Adult	≥18 years	ND	ND	–	–
	Premenopausal	–	–	1.9–22.8 ng/dL	0.066–0.791 nmol/L
	Postmenopausal	–	–	1.6–19.1 ng/dL	0.055–0.662 nmol/L
Free testosterone
Stage	Age range	Male		Female
		Values	SI units	Values	SI units
Child	1–6 years	0.1–0.6 pg/mL	0.3–2.1 pmol/L	0.1–0.6 pg/mL	0.3–2.1 pmol/L
	7–9 years	0.1–0.8 pg/mL	0.3–2.8 pmol/L	0.1–1.6 pg/mL	0.3–5.6 pmol/L
Puberty	10–11 years	0.1–5.2 pg/mL	0.3–18.0 pmol/L	0.1–2.9 pg/mL	0.3–10.1 pmol/L
	12–13 years	0.4–79.6 pg/mL	1.4–276.2 pmol/L	0.6–5.6 pg/mL	2.1–19.4 pmol/L
	14–15 years	2.7–112.3 pg/mL	9.4–389.7 pmol/L	1.0–6.2 pg/mL	3.5–21.5 pmol/L
	16–17 years	31.5–159 pg/mL	109.3–551.7 pmol/L	1.0–8.3 pg/mL	3.5–28.8 pmol/L
Adult	≥18 years	44–244 pg/mL	153–847 pmol/L	–	–
	Premenopausal	–	–	0.8–9.2 pg/mL	2.8–31.9 pmol/L
	Postmenopausal	–	–	0.6–6.7 pg/mL	2.1–23.2 pmol/L
Sources: See template.

Oral administration

Oral testosterone

Testosterone is well-absorbed but extensively metabolized with oral administration due to the first pass through the intestines and liver.[2][13][14][3] It is rapidly and completely inactivated in men at doses of less than 200 mg.[2][13] In large doses, such as 200 mg however, significant increases in circulating testosterone levels become apparent.[2][13] In addition, while a 60 mg dose has no effect on testosterone levels in men, this dose does measurably increase testosterone levels in prepubertal boys and women.[13] The oral bioavailability of testosterone in young women after a single 25 mg dose was found to be 3.6 ± 2.5%.[15] High levels of testosterone are also achieved with a 60 mg dose of oral testosterone in men with liver cirrhosis.[2] These findings are attributed to induction of liver enzymes by testosterone and consequent activation of its own metabolism.[2][13] Substitution dosages of oral testosterone in men are in the range of 400 to 800 mg/day.[13][14] Such doses exceed the amount of testosterone produced by the body, which is approximately 7 mg/day, by approximately 100-fold.[2][13][14] The elimination half-life of oral testosterone is rapid at about 5 to 7 hours.[14][16] As a result, it requires administration several times per day in divided doses.[14] Due to its limitations, such as the high doses required and necessity of multiple daily doses, oral testosterone is not used clinically in its unmodified form.[14][3]

Oral testosterone has been studied in combination with a 5α-reductase inhibitor to reduce its first-pass metabolism and improve its bioavailability.[2][17]

Oral testosterone undecanoate

Instead of in its free unesterified form, testosterone is used by oral administration in the form of testosterone undecanoate.[2] Due to the unique chemical properties afforded by its long fatty acid ester chain, this testosterone ester is partially absorbed from the gastrointestinal tract into the lymphatic system, thereby bypassing a portion of first-pass metabolism in the liver and producing measurable increases in testosterone levels at much lower doses than free testosterone.[2][3] Of oral testosterone undecanoate that reaches circulation, 90 to 100% is transported lymphatically.[18] However, its duration remains short, with an elimination half-life of 1.6 hours and a mean residence time of 3.7 hours.[19][20][21] Oral testosterone undecanoate is provided as 40 mg oil-filled capsules and requires administration 2 to 4 times per day (i.e., 80 to 160 mg/day) for substitution in men.[2][19][3] It must be taken with food containing at least a moderate or "normal" amount of fat in order to achieve adequate absorption.[2][22][23][24] In addition, there is very high interindividual variability in levels of testosterone with oral testosterone undecanoate.[25] The bioavailability of oral testosterone undecanoate taken with food is 3 to 7%.[18][26] Inappropriately high levels of testosterone have been observed with 10 to 40 mg/day oral testosterone undecanoate in women.[27][28] The oral bioavailability of testosterone undecanoate in young women after a single 40 mg dose was found to be 6.8 ± 3.3%.[15]

A novel self-emulsifying formulation of oral testosterone undecanoate in 300-mg capsules for use once per day is under development.[25]

First-pass effect and differences

Oral testosterone and oral testosterone undecanoate are not hepatotoxic, unlike orally administered 17α-alkylated anabolic steroids such as methyltestosterone and fluoxymesterone but similarly to parenteral routes and forms of bioidentical testosterone like injections.[29][2][25]

Buccal administration

Testosterone can be used by buccal administration (e.g., brand name Striant).[2]

Sublingual administration

Testosterone can be used by sublingual administration.[2][30][31] A 10 mg sublingual tablet with the brand name Testoral was previously marketed for use one to four times per day in men.[32]

Inhalational administration

Testosterone has been studied by inhalation.[33]

Intranasal administration

Testosterone can be used by intranasal administration (e.g., brand name Natesto).[2]

Transdermal administration

See also: Testosterone (patch)

Testosterone is available for transdermal administration in the form of gels, creams, scrotal and non-scrotal patches, and axillary solutions.[2]

Transdermal testosterone gel has a bioavailability of about 8 to 14% when administered to recommended skin sites including the abdomen, arms, shoulders, and thighs.[34][35] Scrotal skin is the thinnest skin of the body[36] and has enhanced absorption characteristics relative to other skin areas.[37][38][39][40] Application of testosterone gels and creams to the scrotum has been studied and achieves much higher levels of testosterone than conventional skin sites.[41][42][43][44] Scrotal application of testosterone requires approximately 5-fold lower doses relative to non-scrotal application.[45][36]

The development of transdermal preparations of testosterone (and of progesterone)[46] has been more difficult than the case of estradiol.[36] This is because testosterone levels in men are about 100 to 1,000 times higher than estradiol levels in women (300 to 1,000 ng/dL vs. 50 to 150 pg/mL, respectively).[36] Non-scrotal testosterone patches were assessed and were found to be ineffective in raising testosterone levels in men.[36] As a result, scrotal testosterone patches were initially marketed.[36] Subsequently, however, non-scrotal testosterone patches with special permeation enhancers that could successfully increase testosterone levels were developed and marketed.[36] However, non-scrotal testosterone patches nonetheless require a large skin area for application (up to 60 cm²) and must be replaced daily.[36]

Supraphysiological levels of dihydrotestosterone (DHT) occur with scrotal application of testosterone, whereas this does not occur with non-scrotal transdermal application.[36] This is due to the high expression of 5α-reductase in scrotal skin.[36] Estradiol levels are similar with scrotal versus non-scrotal application of transdermal testosterone.[36]

Low-dose transdermal testosterone patches in women have been found to result in testosterone levels of 64 ng/dL with 150 μg/day and 102 ng/dL with 300 μg/day.[27] When testosterone is used transdermally in women, hair growth at the application sites can be a problem.[47]

Vaginal administration

In women, testosterone can be used by vaginal administration of creams, suppositories, and vaginal rings available from compounding pharmacies.[48][49][50][51][52][53]

Rectal administration

Testosterone levels with single-dose rectal administration of a 40 mg testosterone suppository in hypogonadal men.[13]

Testosterone was marketed as a suppository for rectal administration by Ferring Pharmaceuticals from the early 1960s under brand names such as Rektandron and Testosteron.[29][54][55] Rectal administration of testosterone avoids the first-pass effect with oral administration similarly to other non-oral routes.[2] A single 40 mg dose of rectal testosterone has been found to result in maximal testosterone levels of almost 1,200 ng/dL within 30 minutes.[13] Subsequently, testosterone levels steadily decline, reaching levels of about 700 ng/dL after 4 hours and levels of about 400 ng/dL after 8 hours.[13] Other studies have also assessed the use of rectal testosterone, with similar findings.[2][56][57][58] Rectal use of testosterone requires administration two or three times per day to maintain adequate testosterone levels.[13][2] The route is poorly accepted, owing to its inconvenience.[2] Rectal testosterone has been used in transmasculine hormone therapy.[59]

Intramuscular injection

See also: Androgen ester

Testosterone levels over 16 weeks with intramuscular injection of different testosterone esters in hypogonadal men.[19]

Testosterone can be administered by intramuscular injection either as an aqueous suspension of testosterone or as an oil solution or aqueous suspension of testosterone esters such as testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate, and testosterone isobutyrate.[2][21][3] An even longer-acting testosterone ester that was developed but ultimately never marketed is testosterone buciclate.[3] These preparations are prodrugs of progesterone that have a long-lasting depot effect when injected into muscle or fat, ranging from days to months in duration.[2]

The bioavailability of drugs that are administered intramuscularly is generally almost 95%.[60]

As oil solutions by intramuscular injection, the elimination half-lives of testosterone esters 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.[8][19] The pharmacokinetics of testosterone cypionate are said to be the same as those of testosterone enanthate, with "extremely comparable" patterns of testosterone release.[21][19] Due to their varying and different elimination half-lives, the different intramuscular testosterone esters are administered with differing frequencies.[61] 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.[61] Due to its relatively short duration, testosterone propionate is now relatively little used and testosterone undecanoate is the preferred testosterone ester for intramuscular use.[8][19] Testosterone undecanoate and testosterone buciclate can be injected intramuscularly as infrequently as four times per year.[8][19]

High doses of testosterone esters by intramuscular injection have been studied in healthy young men.[62] Levels of testosterone with intramuscular injections of testosterone cypionate were about 700 ng/dL for 100 mg/week, 1100 ng/dL for 250 mg/week, and 2000 ng/dL for 500 mg/week.[62][63] In another study, testosterone levels with 600 mg/week testosterone enanthate by intramuscular injection were 2,800–3,200 ng/dL.[62][64]

Intramuscular injection of testosterone propionate as an oil solution, aqueous suspension, and emulsion has been compared.[65]

Intramuscular injection of testosterone-containing biodegradeable microspheres has been studied.[2]

Structural properties of major testosterone esters

Androgen	Structure	Ester				Relative mol. weight	Relative T content^b	Duration^c
		Position	Moiety	Type	Length^a			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 buciclate^d		C17β	Bucyclic acid^e	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.

Pharmacokinetics of testosterone esters

Testosterone ester	Form	Route	Tmax	t1/2	MRT
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	10 days	4.5 days	8.5 days
Testosterone undecanoate	Tea seed oil solution	Intramuscular injection	13.0 days	20.9 days	34.9 days
Testosterone undecanoate	Castor oil solution	Intramuscular injection	11.4 days	33.9 days	36.0 days
Testosterone buciclate^a	Aqueous suspension	Intramuscular injection	25.8 days	29.5 days	60.0 days
Notes: Testosterone cypionate has similar pharmacokinetics to TE. Footnotes: ^a = Never marketed. Sources: See template.

Parenteral durations of androgens/anabolic steroids

Medication	Form	Major brand names	Duration
Testosterone	Aqueous suspension	Andronaq, Sterotate, Virosterone	2–3 days
Testosterone propionate	Oil solution	Androteston, Perandren, Testoviron	3–4 days
Testosterone phenylpropionate	Oil solution	Testolent	8 days
Testosterone isobutyrate	Aqueous suspension	Agovirin Depot, Perandren M	14 days
Mixed testosterone esters^a	Oil solution	Triolandren	10–20 days
Mixed testosterone esters^b	Oil solution	Testosid Depot	14–20 days
Testosterone enanthate	Oil solution	Delatestryl	14–28 days
Testosterone cypionate	Oil solution	Depovirin	14–28 days
Mixed testosterone esters^c	Oil solution	Sustanon 250	28 days
Testosterone undecanoate	Oil solution	Aveed, Nebido	100 days
Testosterone buciclate^d	Aqueous suspension	20 Aet-1, CDB-1781^e	90–120 days
Nandrolone phenylpropionate	Oil solution	Durabolin	10 days
Nandrolone decanoate	Oil solution	Deca Durabolin	21–28 days
Methandriol	Aqueous suspension	Notandron, Protandren	8 days
Methandriol bisenanthoyl acetate	Oil solution	Notandron Depot	16 days
Metenolone acetate	Oil solution	Primobolan	3 days
Metenolone enanthate	Oil solution	Primobolan Depot	14 days
Note: All are via i.m. injection. 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.

Subcutaneous injection

See also: Androgen ester

Testosterone esters like testosterone enanthate and testosterone cypionate can be given by subcutaneous injection instead of intramuscular injection. Studies have shown that subcutaneous injection of testosterone and closely related esters in oil like testosterone cypionate, testosterone enantate, and nandrolone decanoate is effective and has similar pharmacokinetics to intramuscular injection.[66][67][68][69][70][71][72]

Subcutaneous implant

Testosterone can be administered in the form of a subcutaneous pellet implant.[2]

The bioavailability of testosterone when administered as a subcutaneous pellet implant is virtually 100%.[73] Levels of testosterone vary considerably between individuals, but are fairly constant within individuals.[27] The absorption half-life of subdermal testosterone implants is 2.5 months.[8] The replacement interval is once every four to six months.[27][74] A single 50 mg testosterone pellet implanted every 4 to 6 months has been found to result in testosterone levels of 70 to 90 ng/dL in women.[27]

Intravenous injection

Testosterone esters like testosterone enanthate are hydrolyzed into testosterone so rapidly in the blood that testosterone and testosterone enanthate have nearly identical pharmacokinetics when administered via intravenous injection.[2]

General

Absorption

The oral bioavailability of testosterone is very low.[8][75] The bioavailability of oral testosterone undecanoate is 3 to 7%.[18][26] Topical testosterone gels have a bioavailability of about 8 to 14% when administered to recommended skin sites including the abdomen, arms, shoulders, and thighs.[34][35] The bioavailability of testosterone by subcutaneous implant is virtually 100%.[73] The bioavailability of drugs that are administered intramuscularly is generally almost 95%.[60]

Distribution

In the circulation, 97.0 to 99.5% of testosterone is bound to plasma proteins, with 0.5 to 3.0% unbound.[1] It is tightly bound to SHBG and weakly to albumin.[1] Of circulating testosterone, 30 to 44% is bound to SHBG while 54 to 68% is bound to albumin.[1] Testosterone that is unbound is referred to as free testosterone and testosterone that is bound to albumin is referred to as bioavailable testosterone.[1] 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 a certin extent.[1] When referenced collectively (i.e., free, bioavailable, and SHBG-bound), circulating testosterone is referred to as total testosterone.[1]

Metabolism

See also: Testosterone § Metabolism

Testosterone metabolism in humans This diagram illustrates the metabolic pathways involved in the metabolism of testosterone in humans. In addition to the transformations shown in the diagram, conjugation via sulfation and glucuronidation occurs with testosterone and metabolites that have one or more available hydroxyl (–OH) groups.

Testosterone is metabolized primarily in the liver mainly (90%) by reduction via 5α- and 5β-reductase and conjugation via glucuronidation and sulfation.[1][76][77] The major urinary metabolites of testosterone are androsterone glucuronide and etiocholanolone glucuronide.[1][76][77][78]

The elimination half-life of testosterone varies depending on the route of administration and formulation and on whether or not it is esterified.[8] The elimination half-life of testosterone in the blood or by intravenous injection is only about 10 minutes.[8][19] Conversely, testosterone and testosterone esters in oil solution or crystalline aqueous suspension administered by intramuscular or subcutaneous injection have much longer half-lives, in the range of days to months, due to slow release from the injection site.[8][19]

Elimination

Testosterone and its metabolites are eliminated in urine.[79] It is excreted mainly as androsterone glucuronide and etiocholanolone glucuronide.[78] It is also excreted to a small extent as other conjugates such as testosterone glucuronide (1%), testosterone sulfate (0.03%), and androstanediol glucuronides.[78][80] Only a very small amount of testosterone (less than 0.01%) is found unchanged in the urine.[79][80]

See also

• Pharmacodynamics of estradiol
• Pharmacokinetics of estradiol
• Pharmacodynamics of progesterone
• Pharmacokinetics of progesterone

References

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Further reading

• Behre, Hermann M.; Nieschlag, Eberhard; Nieschlag, Eberhard; Behre, Hermann M.; Nieschlag, Susan (26 July 2012). "Testosterone preparations for clinical use in males". In Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (eds.). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 309–335. doi:10.1017/CBO9781139003353.016. ISBN 978-1-107-01290-5.
• Byrne, M.M.; Nieschlag, E. (2017). "Androgens: Pharmacological Use and Abuse". doi:10.1016/B978-0-12-809324-5.03356-3. Cite journal requires |journal= (help)