Tibolone

Clinical data
Trade names	Livial, Tibella, Tibofem, others
Other names	TIB; ORG-OD-14; 7α-Methylnoretynodrel; 7α-Methyl-17α-ethynyl-19-nor-δ5(10)-testosterone; 17α-Ethynyl-7α-methylestr-5(10)-en-17β-ol-3-one; 7α-Methyl-19-nor-17α-pregn-5(10)-en-20-yn-17-ol-3-one
AHFS/Drugs.com	Professional Drug Facts
Pregnancy category	AU: D
Routes of administration	By mouth[1]
Drug class	Progestogen;Progestin;Estrogen;Androgen;Anabolic steroid
ATC code	G03CX01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule IV[2][3] UK: POM (Prescription only)[4]
Pharmacokinetic data
Bioavailability	92%[5]
Protein binding	96.3% (toalbumin; low affinity forSHBGTooltip sex hormone-binding globulin)[5]
Metabolism	Liver,intestines (hydroxyl-ation,isomerization,conjugation)[1][8]
Metabolites	•Δ4-Tibolone[6] •3α-Hydroxytibolone[6] •3β-Hydroxytibolone[6] •Sulfateconjugates[7]
Eliminationhalf-life	45 hours[8]
Excretion	Kidney: 40%[5] Feces: 60%[5]
Identifiers
IUPAC name (7R,8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-7,13-dimethyl-1,2,4,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
CAS Number	5630-53-5 Y
PubChemCID	444008
DrugBank	DB09070 Y
ChemSpider	392038 Y
UNII	FF9X0205V2
KEGG	D01639 Y
ChEBI	CHEBI:32223 Y
ChEMBL	ChEMBL2103774 Y
CompTox Dashboard(EPA)	DTXSID5023667
ECHA InfoCard	100.024.609
Chemical and physical data
Formula	C21H28O2
Molar mass	312.453 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C4CCC\1=C(\C[C@H]([C@@H]2[C@@H]/1CC[C@]3([C@H]2CC[C@]3(C#C)O)C)C)C4
InChI InChI=1S/C21H28O2/c1-4-21(23)10-8-18-19-13(2)11-14-12-15(22)5-6-16(14)17(19)7-9-20(18,21)3/h1,13,17-19,23H,5-12H2,2-3H3/t13-,17-,18+,19-,20+,21+/m1/s1 Y Key:WZDGZWOAQTVYBX-XOINTXKNSA-N Y
(verify)

Tibolone, sold under the brand nameLivial among others, is amedication which is used inmenopausal hormone therapy and in the treatment ofpostmenopausal osteoporosis andendometriosis.^{[1][9][10][11]} The medication is available alone and is not formulated or used in combination with other medications.^[12] It is takenby mouth.^[1]

Side effects of tibolone includeacne andincreased hair growth among others.^[8] Tibolone is asyntheticsteroid with weakestrogenic,progestogenic, andandrogenic activity, and hence is anagonist of theestrogen,progesterone, andandrogen receptors.^{[13][1][8][6]} It is aprodrug of severalmetabolites.^[1][13][14] The estrogenic effects of tibolone may showtissue selectivity in their distribution.^{[13][15][14][16]}

Tibolone was developed in the 1960s and was introduced for medical use in 1988.^[17][18] It is marketed widely throughout the world.^[12][19] The medication is not available in the United States.^[12][19]

Tibolone is used in the treatment ofmenopausalsymptoms likehot flashes andvaginal atrophy,postmenopausal osteoporosis, andendometriosis.^[1][20][11] It has similar or greatereffectiveness compared to older menopausal hormone therapy medications, but shares a similarside effect profile.^[21][22][23] It has also been investigated as a possible treatment forfemale sexual dysfunction.^[24]

Tibolone reduceshot flashes, preventsbone loss, improvesvaginal atrophy andurogenital symptoms (e.g.,vaginal dryness,dyspareunia), and has positive effects onmood andsexual function.^[25][22][26] The medication may have greater benefits onlibido than standard menopausal hormone therapy, which may be related to itsandrogenic effects.^[22][26] It is associated with low rates ofvaginal bleeding andbreast pain.^[25]

A 2015network meta-analysis ofrandomized controlled trials found that tibolone was associated with a significantly decreased risk ofbreast cancer (RRTooltip relative risk = 0.317).^[27] The decrease in risk was greater than that observed with most of thearomatase inhibitors andselective estrogen receptor modulators that were included in the analysis.^[27] However, paradoxically, other research has found evidence supporting an increased risk of breast cancer with tibolone.^[28][29]

Tibolone is available in the form of 2.5 mgoraltablets.^[30] It is typically used once daily at a dosage of 1.25 or 2.5 mg.^[30]

A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests thattamoxifen,raloxifene, and tibolone used to reduce the risk ofbreast cancer significantly reduce the occurrence of invasive breast cancer in midlife and older women, but also increase the risk ofadverse effects.^[31]

Tibolone can infrequently produceandrogenic side effects such asacne andincreased facial hair growth.^[8] Such side effects have been found to occur in 3 to 6% of treated women.^[8]

A 2016Cochrane review has been published on the short-term and long-term effects of tibolone, includingadverse effects.^[32] Possible adverse effects of tibolone include unscheduledvaginal bleeding (ORTooltip Odds ratio = 2.79; incidence 13–26% more than placebo), an increased risk ofbreast cancer in women with a history of breast cancer (ORTooltip Odds ratio = 1.5) although apparently not without a history of breast cancer (ORTooltip Odds ratio = 0.52), an increased risk ofcerebrovascular events (strokes) (ORTooltip Odds ratio = 1.74) andcardiovascular events (ORTooltip Odds ratio = 1.38), and an increased risk ofendometrial cancer (ORTooltip Odds ratio = 2.04).^[32] However, most of these figures are based on very low-quality evidence.^[32]

Tibolone has been associated with increased risk ofendometrial cancer in most studies.^[33]

Tibolone possesses a complexpharmacology and has weakestrogenic,progestogenic, andandrogenic activity.^[8][1][6] Tibolone,3α-hydroxytibolone, and3β-hydroxytibolone act asagonists of theestrogen receptors.^[1][6] Tibolone and its metaboliteδ⁴-tibolone act asagonists of theprogesterone andandrogen receptors,^[34] while 3α-hydroxytibolone and 3β-hydroxytibolone, conversely, act asantagonists of these receptors.^[6] Relative to other progestins, tibolone, including its metabolites, has been described as possessing moderate functionalantiestrogenic activity (that is, progestogenic activity), moderate estrogenic activity, high androgenic activity, and no clinically significantglucocorticoid,antiglucocorticoid,mineralocorticoid, orantimineralocorticoid activity.^[1][35] Theovulation-inhibiting dosage of tibolone is 2.5 mg/day.^[1]

Tibolone and its two majoractive metabolites,3α-hydroxytibolone and3β-hydroxytibolone, act aspotent, fully activatingagonists of theestrogen receptor (ER), with a high preference for theERα.^[6][34][15] These estrogenic metabolites of tibolone have much weaker activity as estrogens thanestradiol (e.g., have 3–29% of theaffinity of estradiol for theERTooltip estrogen receptor), but occur at relatively high concentrations that are sufficient for full and marked estrogenic responses to occur.^[1][15][36]

The estrogenic effects of tibolone showtissue selectivity in their distribution, with desirable effects inbone, thebrain, and thevagina, and lack of undesirable action in theuterus,breast, andliver.^[15][13][14] The observations of tissue selectivity with tibolone have been theorized to be the result ofmetabolism, enzyme modulation (e.g., ofestrogen sulfatase andestrogen sulfotransferase), andreceptor modulation that vary in different target tissues.^[34][15] This selectivity differsmechanistically from that ofselective estrogen receptor modulators (SERMs) such astamoxifen, which produce their tissue selectivity via means of modulation of the ER.^[34][15] As such, to distinguish it from SERMs, tibolone has been variously described as a "selective tissue estrogenic activity regulator" (STEAR),^[15] "selective estrogen enzyme modulator" (SEEM),^[16] or "tissue-specific receptor and intracrine mediator" (TRIM).^[35] More encompassingly, tibolone has also been described as a "selective progestogen, estrogen, and androgen regulator" (SPEAR), which is meant to reflect the fact that it is tissue-selective and that it regulates effects not only of estrogens but of all three of the majorsex hormone classes.^[35] Although indications of tissue selectivity with tibolone have been observed, the medication has paradoxically nonetheless been associated with increased risk ofendometrial cancer andbreast cancer in clinical studies.^[32]

It was reported in 2002 that tibolone or its metabolite δ⁴-tibolone istransformed byaromatase into the potent estrogen 7α-methylethinylestradiol in women, analogously to the transformation ofnorethisterone intoethinylestradiol.^[37] Controversy and disagreement followed when other researchers contested the findings however.^{[38][39][40][41][42][43]} By 2008, these researchers had asserted that tibolone is not aromatized in women and that the previous findings of 7α-methylethinylestradiol detection were merely a methodological artifact.^[40][42][43] In accordance, a 2009 study found that anaromatase inhibitor had no effect on the estrogenic potencies of tibolone or its metabolitesin vitro, unlike the case oftestosterone.^[6] In addition, another 2009 study found that the estrogenic effects of tibolone onadiposity in rats do not requirearomatization (as indicated by the use of aromataseknockout mice), further in support that 3α-hydroxytibolone and 3β-hydroxytibolone are indeed responsible for such effects.^[44] These findings are also in accordance with the fact that tibolone decreasessex hormone-binding globulin (SHBG) levels by 50% in women and does not increase the risk ofvenous thromboembolism (VTE) (RRTooltip Rate ratio = 0.92), which would not be expected if the medication formed a potent, liver metabolism-resistant estrogen similar to ethinylestradiol in important quantities.^[1][45] (For comparison,combined oral contraceptives containing ethinylestradiol, due mostly or completely to the estrogen component, have been found to increase SHBG levels by 200 to 400% and to increase the risk of VTE by about 4-fold (ORTooltip odds ratio = 4.03).)^[46][47]

In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α-methylethinylestradiol in small quantities.^[48][49] They have claimed that 19-nortestosterone derivatives like tibolone, due to lacking a C19methyl group, indeed are not substrates of the classical aromatase enzyme, but instead are still transformed into the corresponding estrogens by othercytochrome P450monooxygenases.^[41][48][49] In accordance, the closely structurally related AAStrestolone (7α-methyl-19-nortestosterone or 17α-desethynyl-δ⁴-tibolone) has been found to be transformed into 7α-methylestradiol by humanplacentalmicrosomesin vitro.^[43][50] Also in accordance, considerably disproportionate formation of ethinylestradiol occurs when norethisterone is taken orally (and hence undergoes first-pass metabolism in the liver) relative to parenterally,^[51][52] despite the absence of aromatase in the adult human liver.^[49][53]

Tibolone andδ⁴-tibolone act as agonists of theprogesterone receptor (PR).^[1][49][54] Tibolone has low affinity of 6% of that ofpromegestone for the PR, while δ⁴-tibolone has high affinity of 90% of that of promegestone for the PR.^[1][49] In spite of its high affinity for the PR however, δ⁴-tibolone possesses only weakprogestogenic activity, about 13% of that ofnorethisterone.^[1][49] The weak progestogenic activity of tibolone may not be sufficient to fully counteract estrogenic activity of tibolone in theuterus and may be responsible for the increased risk ofendometrial cancer that has been observed with tibolone in women in large cohort studies.^[1][49]

Tibolone, mainly via δ⁴-tibolone, has androgenic activity.^[49][1] Whereas tibolone itself has only about 6% of theaffinity ofmetribolone for theandrogen receptor, δ⁴-tibolone has relatively high affinity of about 35% of the affinity of metribolone for this receptor.^[49][1] At typical clinical dosages in women, the androgenic effects of tibolone are weak.^[49][1] However, relative to other 19-nortestosterone progestins, the androgenic activity of tibolone is high, with a potency comparable to that oftestosterone.^[49][1] Indeed, the androgenic effects of tibolone have been ranked as stronger than those of all other commonly used 19-nortestosterone progestins (e.g.,norethisterone,levonorgestrel, others).^[49][1]

The androgenic effects of tibolone have been postulated to be involved in the reducedbreastcellproliferation, reducedbreast cancer risk, improvement insexual function, less unfavorable changes inhemostatic parameters relative to estrogen–progestogen combinations, and changes inliver protein synthesis (e.g., 30% reductions inHDL cholesterol levels, 20% reduction intriglyceride levels, and 50% reduction in SHBG levels) observed with tibolone.^[49][1] They are also responsible for the androgenic side effects of tibolone such asacne andincreased hair growth in some women.^[8]

Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as antagonists of theglucocorticoid andmineralocorticoid receptors, with preference for the mineralocorticoid receptor.^[6] However, their affinities for these receptors are low, and tibolone has been described as possessing no clinically significantglucocorticoid,antiglucocorticoid,mineralocorticoid, orantimineralocorticoid activity.^[1][35]

The meanoralbioavailability of tibolone is 92%.^[5] Itsplasma protein binding is 96.3%.^[5] It is bound toalbumin, and both tibolone and its metabolites have lowaffinity for SHBG.^[5][1] Tibolone ismetabolized in theliver andintestines.^[1][8] It is aprodrug and is rapidly transformed into severalmetabolites, includingδ⁴-tibolone,3α-hydroxytibolone, and3β-hydroxytibolone, as well assulfateconjugates of these metabolites.^[1][54][7] 3α-Hydroxytibolone is formed by3α-hydroxysteroid dehydrogenase, 3β-hydroxytibolone is formed by3β-hydroxysteroid dehydrogenase, δ⁴-tibolone is formed byΔ^5-4-isomerase, and the sulfate conjugates of tibolone and its metabolites are formed bysulfotransferases, mainlySULT2A1.^[35][55] The sulfate conjugates can be transformed back into free steroids bysteroid sulfatase.^[56] Following a single oral dose of 2.5 mg tibolone, peak serum levels of tibolone were 1.6 ng/mL, of δ⁴-tibolone were 0.8 ng/mL, of 3α-hydroxytibolone were 16.7 ng/mL, and of 3β-hydroxytibolone were 3.7 ng/mL after 1 to 2 hours.^[1] Theelimination half-life of tibolone is 45 hours.^[8] It isexcreted inurine 40% andfeces 60%.^[5][8]

Tibolone, also known as 7α-methylnoretynodrel, as well as 7α-methyl-17α-ethynyl-19-nor-δ⁵⁽¹⁰⁾-testosterone or as 7α-methyl-17α-ethynylestr-5(10)-en-17β-ol-3-one, is asyntheticestranesteroid and aderivative oftestosterone and19-nortestosterone.^[9][1] It is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of the estrane subgroup of the 19-nortestosterone family of progestins.^{[1][57][58][17]} Tibolone is the 7α-methyl derivative of the progestinnoretynodrel (17α-ethynyl-δ⁵⁽¹⁰⁾-19-nortestosterone).^[1] Other steroids related to tibolone include the progestinnorgesterone (17α-vinyl-δ⁵⁽¹⁰⁾-19-nortestosterone) and theanabolic steroidstrestolone (7α-methyl-19-nortestosterone) andmibolerone (7α,17α-dimethyl-19-nortestosterone).^[9]

Tibolone was developed in the 1960s.^[17] It was first introduced in theNetherlands in 1988, and was subsequently introduced in theUnited Kingdom in 1991.^[18][59]

Tibolone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andJANTooltip Japanese Accepted Name.^[9][10] It is also known by its developmental code nameORG-OD-14.^[8]

Tibolone is marketed under the brand names Livial, Tibofem, and Ladybon among others.^[9][10][12]

Tibolone is used widely in the European Union, Asia, Australasia, and elsewhere in the world, but is not available in the United States.^[12][19][60]

Tibolone is aSchedule IVcontrolled substance in Canada under the 1996Controlled Drugs and Substances Act.^[2][61] It is classified as ananabolic steroid under this act, due to its relatively high activity as anAR agonist, and is the only norethisterone (17α-ethynyl-19-nortestosterone) derivative that is classified as such.[2]^[61] Tibolone is banned byWADATooltip World Anti-Doping Agency as an anabolic steroid category S1 largely due to its conversion to the delta-4 tibolone metabolite, which is a potent androgen.^[62]

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