Tibolone

Source: Wikipedia, the free encyclopedia.
Tibolone
Clinical data
Trade namesLivial, Tibella, Tibofem, others
Other namesTIB; 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.comProfessional Drug Facts
Pregnancy
category
  • AU: D
Progestin; Estrogen; Androgen; Anabolic steroid
ATC code
Legal status
Legal status
conjugates[7]
Elimination half-life45 hours[8]
ExcretionKidney: 40%[5]
Feces: 60%[5]
Identifiers
  • (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
JSmol)
  • 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=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 checkY
  • Key:WZDGZWOAQTVYBX-XOINTXKNSA-N checkY
  (verify)

Tibolone, sold under the brand name Livial among others, is a

postmenopausal osteoporosis and endometriosis.[1][9][10][11] The medication is available alone and is not formulated or used in combination with other medications.[12] It is taken by mouth.[1]

synthetic steroid with weak estrogenic, progestogenic, and androgenic activity, and hence is an agonist of the estrogen, progesterone, and androgen receptors.[13][1][8][6] It is a prodrug of several metabolites.[1][13][14] The estrogenic effects of tibolone may show tissue 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]

Medical uses

Tibolone is used in the treatment of

female sexual dysfunction.[24]

Tibolone reduces

vaginal dryness, dyspareunia), and has positive effects on mood and sexual function.[25][22][26] The medication may have greater benefits on libido than standard menopausal hormone therapy, which may be related to its androgenic effects.[22][26] It is associated with low rates of vaginal bleeding and breast pain.[25]

A 2015

network meta-analysis of randomized controlled trials found that tibolone was associated with a significantly decreased risk of breast cancer (RRTooltip relative risk = 0.317).[27] 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.[27] However, paradoxically, other research has found evidence supporting an increased risk of breast cancer with tibolone.[28][29]

Available forms

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

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.[31]

Tibolone can infrequently produce androgenic side effects such as acne and increased facial hair growth.[8] Such side effects have been found to occur in 3 to 6% of treated women.[8]

A 2016

cardiovascular events (ORTooltip Odds ratio = 1.38), and an increased risk of endometrial 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 of endometrial cancer in most studies.[33]

Pharmacology

Pharmacodynamics

Δ4-Tibolone, one of the active metabolites of tibolone.

Tibolone possesses a complex

antimineralocorticoid activity.[1][35] The ovulation-inhibiting dosage of tibolone is 2.5 mg/day.[1]

Estrogenic activity

Tibolone and its two major

affinity of estradiol for the ERTooltip 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 show

receptor modulation that vary in different target tissues.[34][15] 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.[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 major sex hormone classes.[35] 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.[32]

It was reported in 2002 that tibolone or its metabolite δ4-tibolone is

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 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.[41][48][49] 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.[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]

Progestogenic activity

Tibolone and

δ4-tibolone act as agonists of the progesterone receptor (PR).[1][49][54] 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.[1][49] In spite of its high affinity for the PR however, δ4-tibolone possesses only weak progestogenic activity, about 13% of that of norethisterone.[1][49] 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.[1][49]

Androgenic activity

Tibolone, mainly via δ4-tibolone, has androgenic activity.

affinity of metribolone for the androgen 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 of testosterone.[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 reduced

HDL cholesterol levels, 20% reduction in triglyceride levels, and 50% reduction in SHBG levels) observed with tibolone.[49][1] They are also responsible for the androgenic side effects of tibolone such as acne and increased hair growth in some women.[8]

Other activities

Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as antagonists of the

antimineralocorticoid activity.[1][35]

Pharmacokinetics

Tibolone metabolism.[7]

The mean

SULT2A1.[35]
elimination half-life of tibolone is 45 hours.[8] It is excreted in urine 40% and feces 60%.[5][8]

Chemistry

See also:
List of androgens/anabolic steroids, and 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

19-nortestosterone.[9][1] 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.[1][57][58][17] Tibolone is the 7α-methyl derivative of the progestin noretynodrel (17α-ethynyl-δ5(10)-19-nortestosterone).[1] 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).[9]

History

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

Society and culture

Generic names

Tibolone is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.[9][10] It is also known by its developmental code name ORG-OD-14.[8]

Brand names

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

Availability

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]

Legal status

Tibolone is a Schedule IV controlled substance in Canada under the 1996 Controlled Drugs and Substances Act.[2][61] It is classified as an anabolic steroid under this act, due to its relatively high activity as an AR agonist, and is the only norethisterone (17α-ethynyl-19-nortestosterone) derivative that is classified as such.[2][61] Tibolone is banned by WADATooltip 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]

References

  1. ^
    S2CID 24616324
    .
  2. ^ a b c "Controlled Drugs and Substances Act (S.C. 1996, c. 19)". Justice Laws Website. 2016-11-30.
  3. ^ "Summary Basis of Decision (SBD) for Tibella". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ^ "Livial 2.5mg tablets - Summary of Product Characteristics (SmPC)". (emc). 29 September 2020. Retrieved 8 November 2020.
  5. ^ a b c d e f g h "Tibolone 2.5 mg Tablets" (PDF). Public Assessment Report. United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). Archived from the original (PDF) on 2018-04-25. Retrieved 2018-03-17.
  6. ^
    S2CID 18346113
    .
  7. ^
    S2CID 20064812
    .
  8. ^
    PMID 9881330
    .
  9. ^
    ISBN 978-0-412-46630-4
    .
  10. ^
    ISBN 978-94-011-4439-1
    .
  11. ^ a b "Tibolone". AdisInsight.
  12. ^ a b c d e "Tibolone International". Drugs.com.
  13. ^
    ISBN 978-3-319-59318-0
    .
  14. ^
    ISBN 978-3-319-52210-4
    .
  15. ^
    ISBN 978-0-203-02496-6
    .
  16. ^
    ISBN 978-0-7637-5329-0
    .
  17. ^
    ISBN 978-1-4511-4847-3
    .
  18. ^
    S2CID 19872216
    .
  19. ^
    ISBN 978-0-19-803620-3
    .
  20. PMID 19160262
    .
  21. S2CID 31195615
    .
  22. ^
    PMID 18488873
    .
  23. PMID 19317264
    .
  24. PMID 19731119
    .
  25. ^
    PMID 15883105
    .
  26. ^
    S2CID 11724490
    .
  27. ^
    PMID 26582062
    .
  28. PMID 17068276
    .
  29. PMID 17638619
    .
  30. ^
    ISBN 978-93-5090-833-4
    .
  31. ^ "Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects, New Report Says". U.S. Department of Health & Human Services - Agency for Healthcare Research and Quality. September 2009. Retrieved 2 June 2014.
  32. ^
    PMID 27733017
    .
  33. PMID 27451318
    .
  34. ^
    ISBN 978-1-4614-6837-0
    .
  35. ^
    S2CID 9924409
    .
  36. S2CID 19797254
    .
  37. S2CID 34806156
    .
  38. S2CID 29486350
    .
  39. S2CID 29109808
    .
  40. ^
    S2CID 36623115
    .
  41. ^
    S2CID 20759583
    .
  42. ^
    S2CID 26948113
    .
  43. ^
    S2CID 37940652
    .
  44. S2CID 9631629
    .
  45. S2CID 1728585
    .
  46. ISBN 978-92-832-1291-1
    .
  47. PMID 26780736
    .
  48. ^
    PMID 17496790
    .
  49. ^ a b c d e f g h i j k l m Kuhl H (2011). "Pharmacology of progestogens" (PDF). Journal für Reproduktionsmedizin und Endokrinologie. 8 (Special Issue 1): 157–176.
  50. S2CID 54252942
    .
  51. PMID 9494772
    .
  52. S2CID 3813229
    .
  53. PMID 23930207
    .
  54. ^
    S2CID 5906796
    .
  55. S2CID 92612
    .
  56. PMID 17662596
    .
  57. ISBN 978-0-203-90924-9
    .
  58. ISBN 978-1-59454-134-6
    .
  59. S2CID 5555829
    .
  60. ISBN 978-1-84214-263-9
    .
  61. ^ a b "Controlled Drugs and Substances Act SCHEDULE IV (Sections 2, 4 to 7.1, 10, 29, 55 and 60)". Justice Laws Website. 2020-10-29. Retrieved 8 November 2020.
  62. ^ "2022 Prohibited List: SUBSTANCES AND METHODS PROHIBITED AT ALL TIMES" (PDF). World Anti-Doping Agency. WADA. Retrieved 21 February 2022.

Further reading