Tibolone

{{Short description|Chemical compound}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 470610138 | image = Tibolone.svg | image_class = skin-invert-image | width = 225 | alt = | image2 = Tibolone molecule ball.png | image_class2 = bg-transparent | width2 = 235 | alt2 =

| tradename = Livial, Tibella, Tibofem, others | Drugs.com = {{drugs.com|ppa|tibolone}} | pregnancy_AU = D | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = By mouth<ref name="pmid16112947" /> | class = Progestogen; Progestin; Estrogen; Androgen; Anabolic steroid | ATC_prefix = G03 | ATC_suffix = CX01

| legal_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Schedule IV | legal_CA_comment = <ref name="CDSA1996" /><ref>{{cite web | title=Summary Basis of Decision (SBD) for Tibella | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00456&lang=en | access-date=29 May 2022}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref>{{cite web | title=Livial 2.5mg tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=29 September 2020 | url=https://www.medicines.org.uk/emc/product/1597 | access-date=8 November 2020}}</ref> | legal_US =  | legal_US_comment = | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status =

| bioavailability = 92%<ref name="MHRA-PAR" /> | protein_bound = 96.3% (to albumin; low affinity for {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="MHRA-PAR" /> | metabolism = Liver, intestines (hydroxyl-ation, isomerization, conjugation)<ref name="pmid16112947" /><ref name="pmid9881330" /> | metabolites = • Δ4-Tibolone<ref name="pmid19464167" /> • 3α-Hydroxytibolone<ref name="pmid19464167" /> • 3β-Hydroxytibolone<ref name="pmid19464167" /> • Sulfate conjugates<ref name="pmid15145448" /> | elimination_half-life = 45 hours<ref name="pmid9881330">{{cite journal | vauthors = Albertazzi P, Di Micco R, Zanardi E | title = Tibolone: a review | journal = Maturitas | volume = 30 | issue = 3 | pages = 295–305 | date = November 1998 | pmid = 9881330 | doi = 10.1016/S0378-5122(98)00059-0 }}</ref> | excretion = Kidney: 40%<ref name="MHRA-PAR" /> Feces: 60%<ref name="MHRA-PAR" />

| CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 5630-53-5 | PubChem = 444008 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB09070 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 392038 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = FF9X0205V2 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D01639 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 32223 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 2103774 | synonyms = 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

| IUPAC_name = (7''R'',8''R'',9''S'',13''S'',14''S'',17''R'')-17-ethynyl-17-hydroxy-7,13-dimethyl-1,2,4,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-3-one | C=21 | H=28 | O=2 | 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 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = WZDGZWOAQTVYBX-XOINTXKNSA-N }}

'''Tibolone''', sold under the brand name '''Livial''' among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="GanellinTriggle1996">{{cite book | vauthors = Ganellin CR, Triggle DJ | title = Dictionary of Pharmacological Agents|url=https://books.google.com/books?id=A0THacd46ZsC&pg=PA1974|date=21 November 1996|publisher=CRC Press|isbn=978-0-412-46630-4|pages=1974–}}</ref><ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title = Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA275|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=275–}}</ref><ref name="AdisInsight">{{cite web | url = https://adisinsight.springer.com/drugs/800008188 | title = Tibolone | work = AdisInsight }}</ref> The medication is available alone and is not formulated or used in combination with other medications.<ref name="Drugs.com" /> It is taken by mouth.<ref name="pmid16112947" />

Side effects of tibolone include acne and increased hair growth among others.<ref name="pmid9881330" /> Tibolone is a synthetic steroid with weak estrogenic, progestogenic, and androgenic activity, and hence is an agonist of the estrogen, progesterone, and androgen receptors.<ref name="Cano2017">{{cite book | vauthors = Cano A | title = Menopause: A Comprehensive Approach|url=https://books.google.com/books?id=leM8DwAAQBAJ&pg=PA103|date=2 November 2017|publisher=Springer|isbn=978-3-319-59318-0|pages=103–}}</ref><ref name="pmid16112947" /><ref name="pmid9881330" /><ref name="pmid19464167" /> It is a prodrug of several metabolites.<ref name="pmid16112947" /><ref name="Cano2017" /><ref name="FalconeHurd2017">{{cite book | vauthors = Falcone T, Hurd WW | title = Clinical Reproductive Medicine and Surgery: A Practical Guide|url=https://books.google.com/books?id=pzgoDwAAQBAJ&pg=PA182|date=14 June 2017|publisher=Springer|isbn=978-3-319-52210-4|pages=182–}}</ref> The estrogenic effects of tibolone may show tissue selectivity in their distribution.<ref name="Cano2017" /><ref name="SchneiderNaftolin2004" /><ref name="FalconeHurd2017" /><ref name="KingBrucker2010" />

Tibolone was developed in the 1960s and was introduced for medical use in 1988.<ref name="FritzSperoff2012" /><ref name="de VriesBromley2005" /> It is marketed widely throughout the world.<ref name="Drugs.com" /><ref name="CouncilMedicine2003" /> The medication is not available in the United States.<ref name="Drugs.com" /><ref name="CouncilMedicine2003" />

==Medical uses== Tibolone is used in the treatment of menopausal symptoms like hot flashes and vaginal atrophy, postmenopausal osteoporosis, and endometriosis.<ref name="pmid16112947" /><ref name="pmid19160262">{{cite journal | vauthors = Al Kadri H, Hassan S, Al-Fozan HM, Hajeer A | title = Hormone therapy for endometriosis and surgical menopause | journal = The Cochrane Database of Systematic Reviews | issue = 1 | article-number = CD005997 | date = January 2009 | pmid = 19160262 | doi = 10.1002/14651858.CD005997.pub2 | veditors = Al Kadri H }}</ref><ref name="AdisInsight" /> It has similar or greater effectiveness compared to older menopausal hormone therapy medications, but shares a similar side effect profile.<ref name="pmid18377345">{{cite journal | vauthors = Lazovic G, Radivojevic U, Marinkovic J | title = Tibolone: the way to beat many a postmenopausal ailments | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 6 | pages = 1039–1047 | date = April 2008 | pmid = 18377345 | doi = 10.1517/14656566.9.6.1039 | s2cid = 31195615 }}</ref><ref name="pmid18488873" /><ref name="pmid19317264">{{cite journal | vauthors = Vavilis D, Zafrakas M, Goulis DG, Pantazis K, Agorastos T, Bontis JN | title = Hormone therapy for postmenopausal breast cancer survivors: a survey among obstetrician-gynaecologists | journal = European Journal of Gynaecological Oncology | volume = 30 | issue = 1 | pages = 82–84 | year = 2009 | pmid = 19317264 }}</ref> It has also been investigated as a possible treatment for female sexual dysfunction.<ref name="pmid19731119">{{cite journal | vauthors = Ziaei S, Moghasemi M, Faghihzadeh S | title = Comparative effects of conventional hormone replacement therapy and tibolone on climacteric symptoms and sexual dysfunction in postmenopausal women | journal = Climacteric | volume = 13 | issue = 2 | pages = 147–156 | date = April 2010 | pmid = 19731119 | doi = 10.1080/13697130903009195 }}</ref>

Tibolone reduces hot flashes, prevents bone loss, improves vaginal atrophy and urogenital symptoms (e.g., vaginal dryness, dyspareunia), and has positive effects on mood and sexual function.<ref name="pmid15883105">{{cite journal | vauthors = Kenemans P, Speroff L | title = Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group | journal = Maturitas | volume = 51 | issue = 1 | pages = 21–28 | date = May 2005 | pmid = 15883105 | doi = 10.1016/j.maturitas.2005.02.011 }}</ref><ref name="pmid18488873">{{cite journal | vauthors = Garefalakis M, Hickey M | title = Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence | journal = Clinical Interventions in Aging | volume = 3 | issue = 1 | pages = 1–8 | date = 2008 | pmid = 18488873 | pmc = 2544356 | doi = 10.2147/CIA.S1043 | doi-access = free }}</ref><ref name="pmid11973439">{{cite journal | vauthors = Davis SR | title = The effects of tibolone on mood and libido | journal = Menopause | volume = 9 | issue = 3 | pages = 162–170 | date = 2002 | pmid = 11973439 | doi = 10.1097/00042192-200205000-00004 | s2cid = 11724490 }}</ref> The medication may have greater benefits on libido than standard menopausal hormone therapy, which may be related to its androgenic effects.<ref name="pmid18488873" /><ref name="pmid11973439" /> It is associated with low rates of vaginal bleeding and breast pain.<ref name="pmid15883105" />

A 2015 network meta-analysis of randomized controlled trials found that tibolone was associated with a significantly decreased risk of breast cancer ({{abbrlink|RR|relative risk}} = 0.317).<ref name="pmid26582062">{{cite journal | vauthors = Mocellin S, Pilati P, Briarava M, Nitti D | title = Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials | journal = Journal of the National Cancer Institute | volume = 108 | issue = 2 | date = February 2016 | pmid = 26582062 | doi = 10.1093/jnci/djv318 | doi-access = free }}</ref> The decrease in risk was greater than that observed with most of the aromatase inhibitors and selective estrogen receptor modulators that were included in the analysis.<ref name="pmid26582062" /> However, paradoxically, other research has found evidence supporting an increased risk of breast cancer with tibolone.<ref name="pmid17068276">{{cite journal | vauthors = Erel CT, Senturk LM, Kaleli S | title = Tibolone and breast cancer | journal = Postgraduate Medical Journal | volume = 82 | issue = 972 | pages = 658–662 | date = October 2006 | pmid = 17068276 | pmc = 2653908 | doi = 10.1136/pgmj.2005.037184 }}</ref><ref name="pmid17638619">{{cite journal | vauthors = Wang PH, Cheng MH, Chao HT, Chao KC | title = Effects of tibolone on the breast of postmenopausal women | journal = Taiwanese Journal of Obstetrics & Gynecology | volume = 46 | issue = 2 | pages = 121–126 | date = June 2007 | pmid = 17638619 | doi = 10.1016/S1028-4559(07)60005-9 | doi-access = free }}</ref>

===Available forms=== Tibolone is available in the form of 2.5 mg oral tablets.<ref name="Meeta2013">{{cite book|author=Meeta|title=Postmenopausal Osteoporosis: Basic and Clinical Concepts|url=https://books.google.com/books?id=72cbBQAAQBAJ&pg=PA117|date=15 December 2013|publisher=Jaypee Brothers Publishers|isbn=978-93-5090-833-4|pages=117–}}</ref> It is typically used once daily at a dosage of 1.25 or 2.5 mg.<ref name="Meeta2013" />

==Side effects== A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to reduce the risk of breast cancer significantly reduce the occurrence of invasive breast cancer in midlife and older women, but also increase the risk of adverse effects.<ref name="AHRQ2009">{{cite web| url=http://archive.ahrq.gov/news/newsroom/press-releases/2009/brcanmed.html| title=Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects, New Report Says| publisher=U.S. Department of Health & Human Services - Agency for Healthcare Research and Quality| date=September 2009|access-date=2 June 2014}}</ref>

Tibolone can infrequently produce androgenic side effects such as acne and increased facial hair growth.<ref name="pmid9881330" /> Such side effects have been found to occur in 3 to 6% of treated women.<ref name="pmid9881330" />

A 2016 Cochrane review has been published on the short-term and long-term effects of tibolone, including adverse effects.<ref name=":0">{{cite journal | vauthors = Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V, Marata AM, Magrini N, D'Amico R, Bassi C, Maestri E | display-authors = 6 | title = Short-term and long-term effects of tibolone in postmenopausal women | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | article-number = CD008536 | date = October 2016 | pmid = 27733017 | pmc = 6458045 | doi = 10.1002/14651858.CD008536.pub3 }}</ref> Possible adverse effects of tibolone include unscheduled vaginal bleeding ({{abbrlink|OR|Odds ratio}} = 2.79; incidence 13–26% more than placebo), an increased risk of breast cancer in women with a history of breast cancer ({{abbrlink|OR|Odds ratio}} = 1.5) although apparently not without a history of breast cancer ({{abbrlink|OR|Odds ratio}} = 0.52), an increased risk of cerebrovascular events (strokes) ({{abbrlink|OR|Odds ratio}} = 1.74) and cardiovascular events ({{abbrlink|OR|Odds ratio}} = 1.38), and an increased risk of endometrial cancer ({{abbrlink|OR|Odds ratio}} = 2.04).<ref name=":0" /> However, most of these figures are based on very low-quality evidence.<ref name=":0" />

Tibolone has been associated with increased risk of endometrial cancer in most studies.<ref name="pmid27451318">{{cite journal | vauthors = Sjögren LL, Mørch LS, Løkkegaard E | title = Hormone replacement therapy and the risk of endometrial cancer: A systematic review | journal = Maturitas | volume = 91 | pages = 25–35 | date = September 2016 | pmid = 27451318 | doi = 10.1016/j.maturitas.2016.05.013 }}</ref>

==Pharmacology==

Tibolone possesses a complex pharmacology and has weak estrogenic, progestogenic, and androgenic activity.<ref name="pmid9881330" /><ref name="pmid16112947" /><ref name="pmid19464167">{{cite journal | vauthors = Escande A, Servant N, Rabenoelina F, Auzou G, Kloosterboer H, Cavaillès V, Balaguer P, Maudelonde T | display-authors = 6 | title = Regulation of activities of steroid hormone receptors by tibolone and its primary metabolites | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 116 | issue = 1–2 | pages = 8–14 | date = August 2009 | pmid = 19464167 | doi = 10.1016/j.jsbmb.2009.03.008 | s2cid = 18346113 | url = https://www.hal.inserm.fr/inserm-00396319/file/Maudelonde_Table_1.pdf }}</ref> Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as agonists of the estrogen receptors.<ref name="pmid16112947" /><ref name="pmid19464167" /> Tibolone and its metabolite δ4-tibolone act as agonists of the progesterone and androgen receptors,<ref name="FalconeHurd2013" /> while 3α-hydroxytibolone and 3β-hydroxytibolone, conversely, act as antagonists of these receptors.<ref name="pmid19464167" /> Relative to other progestins, tibolone, including its metabolites, has been described as possessing moderate functional antiestrogenic activity (that is, progestogenic activity), moderate estrogenic activity, high androgenic activity, and no clinically significant glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity.<ref name="pmid16112947" /><ref name="pmid12419081" /> The ovulation-inhibiting dosage of tibolone is 2.5 mg/day.<ref name="pmid16112947" />

====Estrogenic activity==== Tibolone and its two major active metabolites, 3α-hydroxytibolone and 3β-hydroxytibolone, act as potent, fully activating agonists of the estrogen receptor (ER), with a high preference for the ERα.<ref name="pmid19464167" /><ref name="FalconeHurd2013">{{cite book| vauthors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery: A Practical Guide|url=https://books.google.com/books?id=TAYnR1b8jRkC&pg=PA152|date=22 May 2013|publisher=Springer Science & Business Media|isbn=978-1-4614-6837-0|pages=152–}}</ref><ref name="SchneiderNaftolin2004">{{cite book | vauthors = Schneider HP, Naftolin F | name-list-style = vanc | title = Climacteric Medicine - Where Do We Go?: Proceedings of the 4th Workshop of the International Menopause Society|url=https://books.google.com/books?id=jaOebeNbAkUC&pg=PA126|date=22 September 2004|publisher=CRC Press|isbn=978-0-203-02496-6|pages=126–}}</ref> These estrogenic metabolites of tibolone have much weaker activity as estrogens than estradiol (e.g., have 3–29% of the affinity of estradiol for the {{abbrlink|ER|estrogen receptor}}), but occur at relatively high concentrations that are sufficient for full and marked estrogenic responses to occur.<ref name="pmid16112947" /><ref name="SchneiderNaftolin2004" /><ref name="pmid11162927">{{cite journal | vauthors = Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ | title = Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 74 | issue = 4 | pages = 213–222 | date = November 2000 | pmid = 11162927 | doi = 10.1016/s0960-0760(00)00125-4 | s2cid = 19797254 }}</ref>

The estrogenic effects of tibolone show tissue selectivity in their distribution, with desirable effects in bone, the brain, and the vagina, and lack of undesirable action in the uterus, breast, and liver.<ref name="SchneiderNaftolin2004" /><ref name="Cano2017" /><ref name="FalconeHurd2017" /> The observations of tissue selectivity with tibolone have been theorized to be the result of metabolism, enzyme modulation (e.g., of estrogen sulfatase and estrogen sulfotransferase), and receptor modulation that vary in different target tissues.<ref name="FalconeHurd2013" /><ref name="SchneiderNaftolin2004" /> This selectivity differs mechanistically from that of selective estrogen receptor modulators (SERMs) such as tamoxifen, which produce their tissue selectivity via means of modulation of the ER.<ref name="FalconeHurd2013" /><ref name="SchneiderNaftolin2004" /> As such, to distinguish it from SERMs, tibolone has been variously described as a "selective tissue estrogenic activity regulator" (STEAR),<ref name="SchneiderNaftolin2004" /> "selective estrogen enzyme modulator" (SEEM),<ref name="KingBrucker2010">{{cite book | vauthors = King T, Brucker MC | title = Pharmacology for Women's Health|url=https://books.google.com/books?id=u1wq63x4VsYC&pg=PA371|date=25 October 2010|publisher=Jones & Bartlett Learning|isbn=978-0-7637-5329-0|pages=371–}}</ref> or "tissue-specific receptor and intracrine mediator" (TRIM).<ref name="pmid12419081" /> 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 major sex hormone classes.<ref name="pmid12419081" /> Although indications of tissue selectivity with tibolone have been observed, the medication has paradoxically nonetheless been associated with increased risk of endometrial cancer and breast cancer in clinical studies.<ref name=":0" />

It was reported in 2002 that tibolone or its metabolite δ4-tibolone is transformed by aromatase into the potent estrogen 7α-methylethinylestradiol in women, analogously to the transformation of norethisterone into ethinylestradiol.<ref name="pmid12082366">{{cite journal | vauthors = Wiegratz I, Sänger N, Kuhl H | title = Formation of 7 alpha-methyl-ethinyl estradiol during treatment with tibolone | journal = Menopause | volume = 9 | issue = 4 | pages = 293–295 | year = 2002 | pmid = 12082366 | doi = 10.1097/00042192-200207000-00011 | s2cid = 34806156 }}</ref> Controversy and disagreement followed when other researchers contested the findings however.<ref name="pmid12628686">{{cite journal | vauthors = de Gooyer ME, Oppers-Tiemissen HM, Leysen D, Verheul HA, Kloosterboer HJ | title = Tibolone is not converted by human aromatase to 7alpha-methyl-17alpha-ethynylestradiol (7alpha-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS | journal = Steroids | volume = 68 | issue = 3 | pages = 235–243 | date = March 2003 | pmid = 12628686 | doi = 10.1016/S0039-128X(02)00184-8 | s2cid = 29486350 }}</ref><ref name="pmid16712888">{{cite journal | vauthors = Raobaikady B, Parsons MF, Reed MJ, Purohit A | title = Lack of aromatisation of the 3-keto-4-ene metabolite of tibolone to an estrogenic derivative | journal = Steroids | volume = 71 | issue = 7 | pages = 639–646 | date = July 2006 | pmid = 16712888 | doi = 10.1016/j.steroids.2006.03.006 | s2cid = 29109808 }}</ref><ref name="pmid17006378">{{cite journal | vauthors = Zacharia LC, Jackson EK, Kloosterboer HJ, Imthurn B, Dubey RK | title = Conversion of tibolone to 7alpha-methyl-ethinyl estradiol using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry: interpretation and clinical implications | journal = Menopause | volume = 13 | issue = 6 | pages = 926–934 | year = 2006 | pmid = 17006378 | doi = 10.1097/01.gme.0000227331.49081.d7 | s2cid = 36623115 }}</ref><ref name="pmid17653961">{{cite journal | vauthors = Kuhl H, Wiegratz I | title = Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications? | journal = Climacteric | volume = 10 | issue = 4 | pages = 344–353 | date = August 2007 | pmid = 17653961 | doi = 10.1080/13697130701380434 | s2cid = 20759583 }}</ref><ref name="pmid17237734">{{cite journal | vauthors = Dröge MJ, Oostebring F, Oosting E, Verheul HA, Kloosterboer HJ | title = 7alpha-Methyl-ethinyl estradiol is not a metabolite of tibolone but a chemical stress artifact | journal = Menopause | volume = 14 | issue = 3 Pt 1 | pages = 474–480 | year = 2007 | pmid = 17237734 | doi = 10.1097/01.gme.0000247015.63877.d4 | s2cid = 26948113 }}</ref><ref name="pmid18365860">{{cite journal | vauthors = Kloosterboer HJ | title = Tibolone is not aromatized in postmenopausal women | journal = Climacteric | volume = 11 | issue = 2 | pages = 175; author reply 175-175; author reply 176 | date = April 2008 | pmid = 18365860 | doi = 10.1080/13697130701752087 | s2cid = 37940652 }}</ref> 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.<ref name="pmid17006378" /><ref name="pmid17237734" /><ref name="pmid18365860" /> In accordance, a 2009 study found that an aromatase inhibitor had no effect on the estrogenic potencies of tibolone or its metabolites ''in vitro'', unlike the case of testosterone.<ref name="pmid19464167" /> In addition, another 2009 study found that the estrogenic effects of tibolone on adiposity in rats do not require aromatization (as indicated by the use of aromatase knockout mice), further in support that 3α-hydroxytibolone and 3β-hydroxytibolone are indeed responsible for such effects.<ref name="pmid19182696">{{cite journal | vauthors = Van Sinderen ML, Boon WC, Ederveen AG, Kloosterboer HJ, Simpson ER, Jones ME | title = The estrogenic component of tibolone reduces adiposity in female aromatase knockout mice | journal = Menopause | volume = 16 | issue = 3 | pages = 582–588 | year = 2009 | pmid = 19182696 | doi = 10.1097/gme.0b013e31818fb20b | s2cid = 9631629 }}</ref> These findings are also in accordance with the fact that tibolone decreases sex hormone-binding globulin (SHBG) levels by 50% in women and does not increase the risk of venous thromboembolism (VTE) ({{abbrlink|RR|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.<ref name="pmid16112947" /><ref name="pmid20230416">{{cite journal | vauthors = Renoux C, Dell'Aniello S, Suissa S | title = Hormone replacement therapy and the risk of venous thromboembolism: a population-based study | journal = Journal of Thrombosis and Haemostasis | volume = 8 | issue = 5 | pages = 979–986 | date = May 2010 | pmid = 20230416 | doi = 10.1111/j.1538-7836.2010.03839.x | s2cid = 1728585 | doi-access = free }}</ref> (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 ({{abbrlink|OR|odds ratio}} = 4.03).)<ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA157|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=157–}}</ref><ref name="pmid26780736">{{cite journal | vauthors = Heit JA, Spencer FA, White RH | title = The epidemiology of venous thromboembolism | journal = Journal of Thrombosis and Thrombolysis | volume = 41 | issue = 1 | pages = 3–14 | date = January 2016 | pmid = 26780736 | pmc = 4715842 | doi = 10.1007/s11239-015-1311-6 }}</ref>

In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α-methylethinylestradiol in small quantities.<ref name="pmid17496790">{{cite journal | vauthors = Kuhl H, Wiegratz I | title = In vivo conversion of TIB to MEE not an artifact generated by heat | journal = Menopause | volume = 14 | issue = 2 | pages = 331–4; author reply 334–5 | date = 2007 | pmid = 17496790 | doi = 10.1097/01.gme.0000264447.18842.da }}</ref><ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of progestogens | journal = Journal für Reproduktionsmedizin und Endokrinologie | volume = 8 | issue = Special Issue 1 | pages = 157–176 | year = 2011 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref> They have claimed that 19-nortestosterone derivatives like tibolone, due to lacking a C19 methyl group, indeed are not substrates of the classical aromatase enzyme, but instead are still transformed into the corresponding estrogens by other cytochrome P450 monooxygenases.<ref name="pmid17653961" /><ref name="pmid17496790" /><ref name="Kuhl2011" /> In accordance, the closely structurally related AAS trestolone (7α-methyl-19-nortestosterone or 17α-desethynyl-δ4-tibolone) has been found to be transformed into 7α-methylestradiol by human placental microsomes ''in vitro''.<ref name="pmid18365860" /><ref name="pmid8142308">{{cite journal | vauthors = LaMorte A, Kumar N, Bardin CW, Sundaram K | title = Aromatization of 7 alpha-methyl-19-nortestosterone by human placental microsomes in vitro | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 48 | issue = 2–3 | pages = 297–304 | date = February 1994 | pmid = 8142308 | doi = 10.1016/0960-0760(94)90160-0 | s2cid = 54252942 }}</ref> 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,<ref name="pmid9494772">{{cite journal | vauthors = Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K | title = In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women | journal = Contraception | volume = 56 | issue = 6 | pages = 379–385 | date = December 1997 | pmid = 9494772 | doi = 10.1016/S0010-7824(97)00174-1 }}</ref><ref name="pmid29522253">{{cite journal | vauthors = Friedrich C, Berse M, Klein S, Rohde B, Höchel J | title = In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate | journal = Journal of Clinical Pharmacology | volume = 58 | issue = 6 | pages = 781–789 | date = June 2018 | pmid = 29522253 | doi = 10.1002/jcph.1079 | s2cid = 3813229 }}</ref> despite the absence of aromatase in the adult human liver.<ref name="Kuhl2011" /><ref name="pmid23930207">{{cite journal | vauthors = Hata S, Miki Y, Saito R, Ishida K, Watanabe M, Sasano H | title = Aromatase in human liver and its diseases | journal = Cancer Medicine | volume = 2 | issue = 3 | pages = 305–315 | date = June 2013 | pmid = 23930207 | pmc = 3699842 | doi = 10.1002/cam4.85 }}</ref>

====Progestogenic activity==== Tibolone and δ4-tibolone act as agonists of the progesterone receptor (PR).<ref name="pmid16112947" /><ref name="Kuhl2011" /><ref name="pmid11996321">{{cite journal | vauthors = Verhoeven CH, Vos RM, Delbressine LP | title = The in vivo metabolism of tibolone in animal species | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 27 | issue = 1 | pages = 1–10 | year = 2002 | pmid = 11996321 | doi = 10.1007/BF03190399 | s2cid = 5906796 }}</ref> Tibolone has low affinity of 6% of that of promegestone for the PR, while δ4-tibolone has high affinity of 90% of that of promegestone for the PR.<ref name="pmid16112947" /><ref name="Kuhl2011" /> In spite of its high affinity for the PR however, δ4-tibolone possesses only weak progestogenic activity, about 13% of that of norethisterone.<ref name="pmid16112947" /><ref name="Kuhl2011" /> The weak progestogenic activity of tibolone may not be sufficient to fully counteract estrogenic activity of tibolone in the uterus and may be responsible for the increased risk of endometrial cancer that has been observed with tibolone in women in large cohort studies.<ref name="pmid16112947" /><ref name="Kuhl2011" />

====Androgenic activity==== Tibolone, mainly via δ4-tibolone, has androgenic activity.<ref name="Kuhl2011" /><ref name="pmid16112947" /> Whereas tibolone itself has only about 6% of the affinity of metribolone for the androgen receptor, δ4-tibolone has relatively high affinity of about 35% of the affinity of metribolone for this receptor.<ref name="Kuhl2011" /><ref name="pmid16112947" /> At typical clinical dosages in women, the androgenic effects of tibolone are weak.<ref name="Kuhl2011" /><ref name="pmid16112947" /> However, relative to other 19-nortestosterone progestins, the androgenic activity of tibolone is high, with a potency comparable to that of testosterone.<ref name="Kuhl2011" /><ref name="pmid16112947" /> 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).<ref name="Kuhl2011" /><ref name="pmid16112947" />

The androgenic effects of tibolone have been postulated to be involved in the reduced breast cell proliferation, reduced breast cancer risk, improvement in sexual function, less unfavorable changes in hemostatic parameters relative to estrogen–progestogen combinations, and changes in liver protein synthesis (e.g., 30% reductions in HDL cholesterol levels, 20% reduction in triglyceride levels, and 50% reduction in SHBG levels) observed with tibolone.<ref name="Kuhl2011" /><ref name="pmid16112947" /> They are also responsible for the androgenic side effects of tibolone such as acne and increased hair growth in some women.<ref name="pmid9881330" />

====Other activities==== Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as antagonists of the glucocorticoid and mineralocorticoid receptors, with preference for the mineralocorticoid receptor.<ref name="pmid19464167" /> However, their affinities for these receptors are low, and tibolone has been described as possessing no clinically significant glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity.<ref name="pmid16112947" /><ref name="pmid12419081" />

===Pharmacokinetics=== class=skin-invert-image|thumb|right|350px|Tibolone metabolism.<ref name="pmid15145448" />

The mean oral bioavailability of tibolone is 92%.<ref name="MHRA-PAR">{{cite web | url = http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con2023754.pdf | title = Tibolone 2.5 mg Tablets | work = Public Assessment Report | publisher = United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) | access-date = 2018-03-17 | archive-date = 2018-04-25 | archive-url = https://web.archive.org/web/20180425200325/http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con2023754.pdf }}</ref> Its plasma protein binding is 96.3%.<ref name="MHRA-PAR" /> It is bound to albumin, and both tibolone and its metabolites have low affinity for SHBG.<ref name="MHRA-PAR" /><ref name="pmid16112947" /> Tibolone is metabolized in the liver and intestines.<ref name="pmid16112947" /><ref name="pmid9881330" /> It is a prodrug and is rapidly transformed into several metabolites, including δ4-tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone, as well as sulfate conjugates of these metabolites.<ref name="pmid16112947" /><ref name="pmid11996321" /><ref name="pmid15145448">{{cite journal | vauthors = Falany JL, Macrina N, Falany CN | title = Sulfation of tibolone and tibolone metabolites by expressed human cytosolic sulfotransferases | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 88 | issue = 4–5 | pages = 383–391 | date = April 2004 | pmid = 15145448 | doi = 10.1016/j.jsbmb.2004.01.005 | s2cid = 20064812 }}</ref> 3α-Hydroxytibolone is formed by 3α-hydroxysteroid dehydrogenase, 3β-hydroxytibolone is formed by 3β-hydroxysteroid dehydrogenase, δ4-tibolone is formed by Δ5-4-isomerase, and the sulfate conjugates of tibolone and its metabolites are formed by sulfotransferases, mainly SULT2A1.<ref name="pmid12419081">{{cite journal | vauthors = Purdie DW | title = What is tibolone--and is it a SPEAR? | journal = Climacteric | volume = 5 | issue = 3 | pages = 236–239 | date = September 2002 | pmid = 12419081 | doi = 10.1080/cmt.5.3.236.239 | s2cid = 9924409 }}</ref> <ref name="pmid16360722">{{cite journal | vauthors = Wang M, Ebmeier CC, Olin JR, Anderson RJ | title = Sulfation of tibolone metabolites by human postmenopausal liver and small intestinal sulfotransferases (SULTs) | journal = Steroids | volume = 71 | issue = 5 | pages = 343–351 | date = May 2006 | pmid = 16360722 | doi = 10.1016/j.steroids.2005.11.003 | s2cid = 92612 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1083&context=veterans | url-access = subscription }}</ref> The sulfate conjugates can be transformed back into free steroids by steroid sulfatase.<ref name="pmid17662596">{{cite journal | vauthors = Falany JL, Falany CN | title = Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 107 | issue = 3–5 | pages = 202–210 | date = 2007 | pmid = 17662596 | pmc = 2697607 | doi = 10.1016/j.jsbmb.2007.03.046 }}</ref> 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.<ref name="pmid16112947" /> The elimination half-life of tibolone is 45 hours.<ref name="pmid9881330" /> It is excreted in urine 40% and feces 60%.<ref name="MHRA-PAR" /><ref name="pmid9881330" />

==Chemistry== {{See also|List of progestogens|List of androgens/anabolic steroids|List of estrogens}}

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 a synthetic estrane steroid and a derivative of testosterone and 19-nortestosterone.<ref name="GanellinTriggle1996" /><ref name="pmid16112947" /> It is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the estrane subgroup of the 19-nortestosterone family of progestins.<ref name="pmid16112947" /><ref name="Pasqualini2002">{{cite book | vauthors = Pasqualini JR | title = Breast Cancer: Prognosis, Treatment, and Prevention | url = https://books.google.com/books?id=l4XLBQAAQBAJ&pg=PA222|date=17 July 2002|publisher=CRC Press|isbn=978-0-203-90924-9|pages=222–}}</ref><ref name="Yao2005">{{cite book | vauthors = Yao AP | title = Trends in Breast Cancer Research | url = https://books.google.com/books?id=vXvljojPp-UC&pg=PA58 | year=2005|publisher=Nova Publishers|isbn=978-1-59454-134-6|pages=58–}}</ref><ref name="FritzSperoff2012">{{cite book | vauthors = Fritz MA, Speroff L | title = Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA769|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=769–}}</ref> Tibolone is the 7α-methyl derivative of the progestin noretynodrel (17α-ethynyl-δ5(10)-19-nortestosterone).<ref name="pmid16112947" /> Other steroids related to tibolone include the progestin norgesterone (17α-vinyl-δ5(10)-19-nortestosterone) and the anabolic steroids trestolone (7α-methyl-19-nortestosterone) and mibolerone (7α,17α-dimethyl-19-nortestosterone).<ref name="GanellinTriggle1996" /> ===Synthesis=== The original book method involved a Birch reduction of Almestrone.<ref>{{cite journal | vauthors=((Wieland, P.)), ((Anner, G.)) | journal=Helvetica Chimica Acta | title=Synthese von 7α‐Methyl‐3‐oxo‐Δ 4,9,11 ‐19‐norandrostatrienen. Über Steroide, 211. Mitteilung | volume=50 | issue=6 | pages=1453–1461 | date= January 1967 | url=https://onlinelibrary.wiley.com/doi/10.1002/hlca.19670500602 | doi=10.1002/hlca.19670500602| url-access=subscription }}</ref><ref>{{cite book | vauthors=((Lednicer, D.)) | date= 2011 | title=Steroid chemistry at a glance | publisher=Wiley | series=Chemistry at a glance | edition=1. publ | isbn=9780470660843}}</ref><ref>NL6406797 idem Jongh Hendrik Paul De, Nicolaas Pieter Van Vliet, US3340279 (1967 to Organon).</ref>

The Chinese have offered their own improvements:<ref>Zeng Chunling, et al. CN117887795 (2024 to Hunan Keyixin Biomedical Co., Ltd.).</ref><ref>孙晓明, et al. CN114409717 (2023 to Hunan Keyixin Biomedical Co ltd).</ref> The new scheme appears to run on Mentabolan precursor. class=skin-invert-image|center|500px (6,7-dehydro-androstenedione) 4,6-Estradiene-3,17-dione [13209-45-5] ('''1''') is reacted with Grignard reagent to give Mentabolan [17000-78-1] ('''2'''). This is a conjugate addition and requires the addition of a catalytic amount of a cuprous salt (c.f. Gilman reagent). Ketalization with ethyleneglycol gives [141664-12-2] ('''3'''). Note that ketalization with methanol was also a possibility (this is easier to deketalize and therefore can lead to fewer by-products). Deketalization gives PC57096972 ('''4'''). Care must be taken so there is no alkene migration. Ethynylation with Ethynyltrimethylsilane [1066-54-2] ('''5''') gives ('''6'''). Deprotection of the trimethylsilyl group with oxalic acid completes the synthesis of tibolone ('''7''').

A chemical synthesis starting from trestolone was said to be an improvement upon existing methods:<ref>Jacek Martynow, et al. WO2004031204 (to Instytut Farmaceutiyczny).</ref> Background art:<ref>Liu, A., Carlson, K. E., Katzenellenbogen, J. A. (May 1992). "Synthesis of high-affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography". Journal of Medicinal Chemistry. 35 (11): 2113–2129. doi:10.1021/jm00089a024.</ref> class=skin-invert-image|center|500px The ketalization of Trestolone (7a-methylnandrolone) [3764-87-2] ('''1''') was made to occur with good selectivity for 3,3-ethylenedioxy-17b-hydroxy-7a-methyl-5(10)-estrene, PC15661073 ('''2'''). Oxidation with PCC at low temperature gave 3,3-ethylenedioxy-7a-methyl-5(10)-estren-17-one [141664-12-2] ('''3'''). Ethynylation afforded Tibolone 3-Ethylene Ketal [677299-58-0] ('''4'''). Careful deprotection occurred without migration of the olefin to yield tibolone ('''5''') and not Isotibolone.

This method is thought to be one of the predominant modern industrial routes:<ref>Alan K. Greenwood, Derek McHattie, Parveen Bhatarah, WO2004078774 (to Resolution Chemicals Limited).</ref> Precursor:<ref>Zeng Chunling, et al. CN118290508 (2024 to Hunan Xinhexin Biological Medicine Co ltd).</ref> class=skin-invert-image|center|500px Aromatization of Trestolone Acetate (U-15,614) [6157-87-5] ('''1''') with copper(II)bromide is followed by methylation of the 3-hydroxy group to give 3-Methoxy-7alpha-methylestra-1,3,5(10)-trien-17beta-ol [15506-01-1] ('''2'''). Birch reduction of this gives 3-Methoxy-7alpha-methyl-estra-2,5(10)-dien-17beta-ol [15506-02-2] ('''3'''). Oxidation of the alcohol gives 3-Methoxy-7alpha-methyl-estra-2,5(10)-dien-17-one [5210-25-3] ('''4'''). Ethynylation of this gives 2-Dehydro-3-methoxy Tibolone [15506-05-5] ('''5'''). Hydrolysis of the enol-ether completed the synthesis of tibolone ('''6''').

Others (thought to be obsolete):<ref>{{cite journal | vauthors=((Van Vliet, N. P.)), ((Broess, A. I. A.)), ((Peters, J. A. M.)), ((Van Den Broek, A. J.)), ((Leemhuis, J. A. J.)), ((Zeelen, F. J.)) | journal=Recueil des Travaux Chimiques des Pays-Bas | title=An alternative synthesis of 17β‐hydroxy‐7α‐methyl‐19‐nor‐17α‐pregn‐5(10)‐en‐20‐yn‐3‐one (Org OD 14) | volume=105 | issue=4 | pages=111–115 | date= January 1986 | url=https://onlinelibrary.wiley.com/doi/10.1002/recl.19861050403 | doi=10.1002/recl.19861050403| url-access=subscription }}</ref>

==History== Tibolone was developed in the 1960s.<ref name="FritzSperoff2012" /> It was first introduced in the Netherlands in 1988, and was subsequently introduced in the United Kingdom in 1991.<ref name="de VriesBromley2005">{{cite journal | vauthors = de Vries CS, Bromley SE, Thomas H, Farmer RD | title = Tibolone and endometrial cancer: a cohort and nested case-control study in the UK | journal = Drug Safety | volume = 28 | issue = 3 | pages = 241–249 | year = 2005 | pmid = 15733028 | doi = 10.2165/00002018-200528030-00005 | s2cid = 19872216 }}</ref><ref name="BerningCoelingh Bennink2009">{{cite journal | vauthors = Berning B, Bennink HJ, Fauser BC | title = Tibolone and its effects on bone: a review | journal = Climacteric | volume = 4 | issue = 2 | pages = 120–136 | date = June 2001 | pmid = 11428176 | doi = 10.1080/cmt.4.2.120.136 | s2cid = 5555829 }}</ref>

==Society and culture==

===Generic names=== ''Tibolone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="GanellinTriggle1996" /><ref name="MortonHall2012" /> It is also known by its developmental code name ''ORG-OD-14''.<ref name="pmid9881330" />

===Brand names=== Tibolone is marketed under the brand names Livial, Tibofem, and Ladybon among others.<ref name="GanellinTriggle1996" /><ref name="MortonHall2012" /><ref name="Drugs.com">{{cite web | url = https://www.drugs.com/international/tibolone.html | title = Tibolone International | work = Drugs.com }}</ref>

===Availability=== Tibolone is used widely in the European Union, Asia, Australasia, and elsewhere in the world, but is not available in the United States.<ref name="Drugs.com" /><ref name="CouncilMedicine2003">{{cite book | vauthors = Segal SJ, Mastroianni L | title=Hormone Use in Menopause and Male Andropause: A Choice for Women and Men: A Choice for Women and Men|url=https://archive.org/details/hormoneuseinmeno0000sega| url-access = registration |date=4 October 2003|publisher=Oxford University Press, USA|isbn=978-0-19-803620-3|pages=[https://archive.org/details/hormoneuseinmeno0000sega/page/73 73]–}}</ref><ref name="GoldsteinMeston2005">{{cite book | vauthors = Goldstein I, Meston CM, Davis S, Traish A | author-link2 = Cindy M. Meston |title=Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment|url=https://books.google.com/books?id=3J7TnwpbZQwC&pg=PA556|date=17 November 2005|publisher=CRC Press|isbn=978-1-84214-263-9|pages=556–}}</ref>

===Legal status=== Tibolone is a Schedule IV controlled substance in Canada under the 1996 Controlled Drugs and Substances Act.<ref name="CDSA1996">{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/|title=Controlled Drugs and Substances Act (S.C. 1996, c. 19)|date=2016-11-30|website=Justice Laws Website}}</ref><ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act SCHEDULE IV (Sections 2, 4 to 7.1, 10, 29, 55 and 60) | website=Justice Laws Website | date=2020-10-29 | url=https://laws-lois.justice.gc.ca/eng/acts/C-38.8/section-sched95660.html | access-date=8 November 2020}}</ref> It is classified as an anabolic steroid under this act, due to its relatively high activity as an {{abbr|AR|androgen receptor}} agonist, and is the only norethisterone (17α-ethynyl-19-nortestosterone) derivative that is classified as such.<ref name="CDSA1996" /><ref name="CDSA" /> Tibolone is banned by {{abbrlink|WADA|World Anti-Doping Agency}} as an anabolic steroid category S1 largely due to its conversion to the Isotibolone metabolite, which is a potent androgen.<ref>{{cite web |title=2022 Prohibited List: SUBSTANCES AND METHODS PROHIBITED AT ALL TIMES |url=https://www.wada-ama.org/sites/default/files/2022-01/2022list_draft_explanatory_list_en_0.pdf |website=World Anti-Doping Agency |publisher=WADA |access-date=21 February 2022}}</ref>

== References == {{Reflist}}

== Further reading == {{refbegin|30em}} * {{cite journal | vauthors = | title = Tibolone (Livial)--a new steroid for the menopause | journal = Drug and Therapeutics Bulletin | volume = 29 | issue = 20 | pages = 77–78 | date = September 1991 | pmid = 1935591 }} * {{cite journal | vauthors = Ross LA, Alder EM | title = Tibolone and climacteric symptoms | journal = Maturitas | volume = 21 | issue = 2 | pages = 127–136 | date = February 1995 | pmid = 7752950 | doi = 10.1016/0378-5122(94)00888-E }} * {{cite journal | vauthors = Rymer JM | title = The effects of tibolone | journal = Gynecological Endocrinology | volume = 12 | issue = 3 | pages = 213–220 | date = June 1998 | pmid = 9675570 | doi = 10.3109/09513599809015548 }} * {{cite journal | vauthors = Ginsburg J, Prelevic GM | title = Tibolone and the serum lipid/lipoprotein profile: does this have a role in cardiovascular protection in postmenopausal women? | journal = Menopause | volume = 6 | issue = 2 | pages = 87–89 | date = 1999 | pmid = 10374212 | doi = 10.1097/00042192-199906020-00002 }} * {{cite journal | vauthors = Gompel A, Jacob D, de Chambine S, Mimoun M, Decroix Y, Rostene W, Poitout P | title = [Action of SERM and SAS (tibolone) on breast tissue] | language = fr | journal = Contraception, Fertilité, Sexualité | volume = 27 | issue = 5 | pages = 368–375 | date = May 1999 | pmid = 10401183 }} * {{cite journal | vauthors = Maudelonde T, Brouillet JP, Pujol P | title = [Anti-estrogens, selective estrogen receptor modulators (SERM), tibolone: modes of action] | language = fr | journal = Contraception, Fertilité, Sexualité | volume = 27 | issue = 9 | pages = 620–624 | date = September 1999 | pmid = 10540506 }} * {{cite journal | vauthors = von Holst T | title = [Alternatives to hormone replacement therapy: raloxifene and tibolone] | language = de | journal = Zeitschrift für Ärztliche Fortbildung und Qualitätssicherung | volume = 94 | issue = 3 | pages = 205–209 | date = April 2000 | pmid = 10802895 }} * {{cite journal | vauthors = Palacios S | title = Tibolone: what does tissue specific activity mean? | journal = Maturitas | volume = 37 | issue = 3 | pages = 159–165 | date = January 2001 | pmid = 11173177 | doi = 10.1016/S0378-5122(00)00184-5 }} * {{cite journal | vauthors = Kloosterboer HJ | title = Tibolone: a steroid with a tissue-specific mode of action | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 76 | issue = 1–5 | pages = 231–238 | date = 2001 | pmid = 11384882 | doi = 10.1016/S0960-0760(01)00044-9 | s2cid = 8139376 }} * {{cite journal | vauthors = | title = Tibolone: new type of hormone replacement | journal = Harvard Women's Health Watch | volume = 9 | issue = 5 | page = 5 | date = December 2001 | pmid = 11751099 }} * {{cite journal | vauthors = Modelska K, Cummings S | title = Tibolone for postmenopausal women: systematic review of randomized trials | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 1 | pages = 16–23 | date = January 2002 | pmid = 11788614 | doi = 10.1210/jcem.87.1.8141 | doi-access = free }} * {{cite journal | vauthors = Gorai I | title = [Drugs in development for the treatment of osteoporosis: Tibolone] | language = ja | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 60 | issue = Suppl 3 | pages = 552–571 | date = March 2002 | pmid = 11979954 }} * {{cite journal | vauthors = Jamin C, Poncelet C, Madelenat P | title = [Tibolone] | language = fr | journal = Presse Médicale | volume = 31 | issue = 28 | pages = 1314–1322 | date = September 2002 | pmid = 12355994 }} * {{cite journal | vauthors = Reginster JY | title = [Postmenopausal hormonal treatment: conventional hormone replacement therapy or tibolone? Effects on bone] | language = fr | journal = Journal de Gynécologie, Obstétrique et Biologie de la Reproduction | volume = 31 | issue = 6 | pages = 541–549 | date = October 2002 | pmid = 12407324 }} * {{cite journal | vauthors = Kloosterboer HJ, Ederveen AG | title = Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 83 | issue = 1–5 | pages = 157–165 | date = December 2002 | pmid = 12650712 | doi = 10.1016/S0960-0760(03)00055-4 | s2cid = 25443489 }} * {{cite journal | vauthors = de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ | title = Receptor profiling and endocrine interactions of tibolone | journal = Steroids | volume = 68 | issue = 1 | pages = 21–30 | date = January 2003 | pmid = 12475720 | doi = 10.1016/S0039-128X(02)00112-5 | s2cid = 40426061 }} * {{cite journal | vauthors = Swegle JM, Kelly MW | title = Tibolone: a unique version of hormone replacement therapy | journal = The Annals of Pharmacotherapy | volume = 38 | issue = 5 | pages = 874–881 | date = May 2004 | pmid = 15026563 | doi = 10.1345/aph.1D462 | s2cid = 20473128 }} * {{cite journal | vauthors = Gorai I | title = [Tibolone] | language = ja | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 62 | issue = Suppl 2 | pages = 555–559 | date = February 2004 | pmid = 15035189 }} * {{cite journal | vauthors = Devogelaer JP | title = A review of the effects of tibolone on the skeleton | journal = Expert Opinion on Pharmacotherapy | volume = 5 | issue = 4 | pages = 941–949 | date = April 2004 | pmid = 15102576 | doi = 10.1517/14656566.5.4.941 | s2cid = 25827970 }} * {{cite journal | vauthors = Reed MJ, Kloosterboer HJ | title = Tibolone: a selective tissue estrogenic activity regulator (STEAR) | journal = Maturitas | volume = 48 | issue = Suppl 1 | pages = S4–S6 | date = August 2004 | pmid = 15337241 | doi = 10.1016/j.maturitas.2004.02.013 }} * {{cite journal | vauthors = Kloosterboer HJ | title = Tissue-selectivity: the mechanism of action of tibolone | journal = Maturitas | volume = 48 | issue = Suppl 1 | pages = S30–S40 | date = August 2004 | pmid = 15337246 | doi = 10.1016/j.maturitas.2004.02.012 }} * {{cite journal | vauthors = Kloosterboer HJ | title = Tissue-selective effects of tibolone on the breast | journal = Maturitas | volume = 49 | issue = 1 | pages = S5–S15 | date = September 2004 | pmid = 15351102 | doi = 10.1016/j.maturitas.2004.06.022 }} * {{cite journal | vauthors = von Schoultz B | title = The effects of tibolone and oestrogen-based HT on breast cell proliferation and mammographic density | journal = Maturitas | volume = 49 | issue = 1 | pages = S16–S21 | date = September 2004 | pmid = 15351103 | doi = 10.1016/j.maturitas.2004.06.011 }} * {{cite journal | vauthors = Liu JH | title = Therapeutic effects of progestins, androgens, and tibolone for menopausal symptoms | journal = The American Journal of Medicine | volume = 118 | issue = 12 | pages = 88–92 | date = December 2005 | pmid = 16414332 | doi = 10.1016/j.amjmed.2005.09.040 }} * {{cite journal | vauthors = Verheul HA, Kloosterboer HJ | title = Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 102 | issue = 1–5 | pages = 195–204 | date = December 2006 | pmid = 17113982 | doi = 10.1016/j.jsbmb.2006.09.037 | s2cid = 33499701 }} * {{cite journal | vauthors = Ettinger B | title = Tibolone for prevention and treatment of postmenopausal osteoporosis | journal = Maturitas | volume = 57 | issue = 1 | pages = 35–38 | date = May 2007 | pmid = 17350774 | doi = 10.1016/j.maturitas.2007.02.008 }} * {{cite journal | vauthors = Notelovitz M | title = Postmenopausal tibolone therapy: biologic principles and applied clinical practice | journal = MedGenMed | volume = 9 | issue = 1 | page = 2 | date = January 2007 | pmid = 17435612 | pmc = 1924982 }} * {{cite journal | vauthors = Jacobsen DE, Samson MM, Kezic S, Verhaar HJ | title = Postmenopausal HRT and tibolone in relation to muscle strength and body composition | journal = Maturitas | volume = 58 | issue = 1 | pages = 7–18 | date = September 2007 | pmid = 17576043 | doi = 10.1016/j.maturitas.2007.04.012 }} * {{cite journal | vauthors = Campisi R, Marengo FD | title = Cardiovascular effects of tibolone: a selective tissue estrogenic activity regulator | journal = Cardiovascular Drug Reviews | volume = 25 | issue = 2 | pages = 132–145 | date = 2007 | pmid = 17614936 | doi = 10.1111/j.1527-3466.2007.00007.x | doi-access = free }} * {{cite journal | vauthors = Carranza Lira S | title = [Relation between hormonal therapy and tibolone with SERMs in postmenopausal women's myomes growth] | language = es | journal = Ginecologia y Obstetricia de Mexico | volume = 76 | issue = 10 | pages = 610–614 | date = October 2008 | pmid = 19062511 }} * {{cite journal | vauthors = Huang KE, Baber R | title = Updated clinical recommendations for the use of tibolone in Asian women | journal = Climacteric | volume = 13 | issue = 4 | pages = 317–327 | date = August 2010 | pmid = 20443720 | pmc = 2942871 | doi = 10.3109/13697131003681458 }} * {{cite journal | vauthors = Biglia N, Maffei S, Lello S, Nappi RE | title = Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials | journal = Gynecological Endocrinology | volume = 26 | issue = 11 | pages = 804–814 | date = November 2010 | pmid = 20586550 | doi = 10.3109/09513590.2010.495437 | s2cid = 7203038 }} * {{cite journal | vauthors = Kotani K, Sahebkar A, Serban C, Andrica F, Toth PP, Jones SR, Kostner K, Blaha MJ, Martin S, Rysz J, Glasser S, Ray KK, Watts GF, Mikhailidis DP, Banach M | display-authors = 6 | title = Tibolone decreases Lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients | journal = Atherosclerosis | volume = 242 | issue = 1 | pages = 87–96 | date = September 2015 | pmid = 26186655 | doi = 10.1016/j.atherosclerosis.2015.06.056 | url = https://research-repository.uwa.edu.au/en/publications/6e9e0c05-f025-44b7-bab1-a9d49916878d }} * {{cite journal | vauthors = Pinto-Almazán R, Segura-Uribe JJ, Farfán-García ED, Guerra-Araiza C | title = Effects of Tibolone on the Central Nervous System: Clinical and Experimental Approaches | journal = BioMed Research International | volume = 2017 | article-number = 8630764 | date = 2017 | pmid = 28191467 | pmc = 5278195 | doi = 10.1155/2017/8630764 | doi-access = free }} * {{cite journal | vauthors = Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF, Lambrinoudaki I, Theodorou M, Goulis DG | display-authors = 6 | title = The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis | journal = Maturitas | volume = 99 | pages = 27–36 | date = May 2017 | pmid = 28364865 | doi = 10.1016/j.maturitas.2017.02.009 | hdl-access = free | hdl = 10044/1/48763 }} * {{cite journal | vauthors = Løkkegaard EC, Mørch LS | title = Tibolone and risk of gynecological hormone sensitive cancer | journal = International Journal of Cancer | volume = 142 | issue = 12 | pages = 2435–2440 | date = June 2018 | pmid = 29349823 | doi = 10.1002/ijc.31267 | doi-access = free }} {{refend}}

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