Tibolone

Last updated
Tibolone
Tibolone.svg
Tibolone molecule ball.png
Clinical data
Trade names Livial, 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.com International Drug Names
Pregnancy
category
  • ADEC Category D
Routes of
administration
By mouth [1]
Drug class Progestogen; Progestin; Estrogen; Androgen; Anabolic steroid
ATC code
Legal status
Legal status
  • CA:Schedule IV [2]
Pharmacokinetic data
Bioavailability 92% [3]
Protein binding 96.3% (to albumin; low affinity for SHBG) [3]
Metabolism Liver, intestines (hydroxyl-ation, isomerization, conjugation) [1] [4]
Metabolites Δ4-Tibolone [5]
3α-Hydroxytibolone [5]
3β-Hydroxytibolone [5]
Sulfate conjugates [6]
Elimination half-life 45 hours [4]
Excretion Urine: 40% [3]
Feces: 60% [3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.024.609 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H28O2
Molar mass 312.453 g·mol−1
3D model (JSmol)
   (verify)

Tibolone, sold under the brand names Livial, Tinox and Tibofem among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. [1] [7] [8] [9] The medication is available alone and is not formulated or used in combination with other medications. [10] It is taken by mouth. [1]

Contents

Side effects of tibolone include acne and increased hair growth among others. [4] Tibolone is a synthetic steroid with weak estrogenic, progestogenic, and androgenic activity, and hence is an agonist of the estrogen, progesterone, and androgen receptors. [11] [1] [4] [5] It is a prodrug of several metabolites. [1] [11] [12] The estrogenic effects of tibolone may show tissue selectivity in their distribution. [11] [13] [12] [14]

Tibolone was developed in the 1960s and was introduced for medical use in 1988. [15] [16] It is marketed widely throughout the world, for instance in Europe. [10] [17] The medication is notably not available in the United States or Canada. [10] [17] It is a controlled substance in Canada, with the classification of an anabolic steroid. [2]

Medical uses

Tibolone is used in the treatment of menopausal symptoms like hot flashes and vaginal atrophy, postmenopausal osteoporosis, and endometriosis. [1] [18] [9] It has similar or greater effectiveness compared to older menopausal hormone therapy medications, but shares a similar side effect profile. [19] [20] [21] It has also been investigated as a possible treatment for female sexual dysfunction. [22]

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. [23] [20] [24] The medication may have greater benefits on libido than standard menopausal hormone therapy, which may be related to its androgenic effects. [20] [24] It is associated with low rates of vaginal bleeding and breast pain. [23]

A 2015 network meta-analysis of randomized controlled trials found that tibolone was associated with a significantly decreased risk of breast cancer (RR = 0.317). [25] 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. [25] However, paradoxically, other research has found evidence supporting an increased risk of breast cancer with tibolone. [26] [27]

Available forms

Tibolone is available in the form of 2.5 mg oral tablets. [28] It is typically used once daily at a dosage of 1.25 or 2.5 mg. [28]

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. [29]

Tibolone can infrequently produce androgenic side effects such as acne and increased facial hair growth. [4] Such side effects have been found to occur in 3 to 6% of treated women. [4]

A 2016 Cochrane review has been published on the short-term and long-term effects of tibolone, including adverse effects. [30] Possible adverse effects of tibolone include unscheduled vaginal bleeding (OR = 2.79; incidence 13–26% more than placebo), an increased risk of breast cancer in women with a history of breast cancer (OR = 1.5) although apparently not without a history of breast cancer (OR = 0.52), an increased risk of cerebrovascular events (strokes) (OR = 1.74) and cardiovascular events (OR = 1.38), and an increased risk of endometrial cancer (OR = 2.04). [30] However, most of these figures are based on very low-quality evidence. [30]

Tibolone has been associated with increased risk of endometrial cancer in most studies. [31]

Pharmacology

Pharmacodynamics

D -Tibolone, one of the active metabolites of tibolone. D4-Tibolone.svg
Δ -Tibolone, one of the active metabolites of tibolone.

Tibolone possesses a complex pharmacology and has weak estrogenic, progestogenic, and androgenic activity. [4] [1] [5] Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as agonists of the estrogen receptors. [1] [5] Tibolone and its metabolite δ4-tibolone act as agonists of the progesterone and androgen receptors, [32] while 3α-hydroxytibolone and 3β-hydroxytibolone, conversely, act as antagonists of these receptors. [5] 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. [1] [33] The ovulation-inhibiting dosage of tibolone is 2.5 mg/day. [1]

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. [5] [32] [13] 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 ER), but occur at relatively high concentrations that are sufficient for full and marked estrogenic responses to occur. [1] [13] [34]

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. [13] [11] [12] 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. [32] [13] 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. [32] [13] As such, to distinguish it from SERMs, tibolone has been variously described as a "selective tissue estrogenic activity regulator" (STEAR), [13] "selective estrogen enzyme modulator" (SEEM), [14] or "tissue-specific receptor and intracrine mediator" (TRIM). [33] 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. [33] 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. [30]

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. [35] Controversy and disagreement followed when other researchers contested the findings however. [36] [37] [38] [39] [40] [41] 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. [38] [40] [41] 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. [5] 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. [42] 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) (RR = 0.92), which would not be expected if the medication formed a potent, liver metabolism-resistant estrogen similar to ethinylestradiol in important quantities. [1] [43] (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 (OR = 4.03).) [44] [45]

In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α-methylethinylestradiol in small quantities. [46] [47] 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. [39] [46] [47] 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 . [41] [48] 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, [49] [50] despite the absence of aromatase in the adult human liver. [47] [51]

Progestogenic activity

Tibolone and δ4-tibolone act as agonists of the progesterone receptor (PR). [1] [47] [52] 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] [47] In spite of its high affinity for the PR however, δ4-tibolone possesses only weak progestogenic activity, about 13% of that of norethisterone. [1] [47] 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] [47]

Androgenic activity

Tibolone, mainly via δ4-tibolone, has androgenic activity. [47] [1] 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. [47] [1] At typical clinical dosages in women, the androgenic effects of tibolone are weak. [47] [1] However, relative to other 19-nortestosterone progestins, the androgenic activity of tibolone is high, with a potency comparable to that of testosterone. [47] [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). [47] [1]

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. [47] [1] They are also responsible for the androgenic side effects of tibolone such as acne and increased hair growth in some women. [4]

Other activities

Tibolone, 3α-hydroxytibolone, and 3β-hydroxytibolone act as antagonists of the glucocorticoid and mineralocorticoid receptors, with preference for the mineralocorticoid receptor. [5] However, their affinities for these receptors are low, and tibolone has been described as possessing no clinically significant glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity. [1] [33]

Pharmacokinetics

Tibolone metabolism. Tibolone metabolism.png
Tibolone metabolism.

The mean oral bioavailability of tibolone is 92%. [3] Its plasma protein binding is 96.3%. [3] It is bound to albumin, and both tibolone and its metabolites have low affinity for SHBG. [3] [1] Tibolone is metabolized in the liver and intestines. [1] [4] 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. [1] [52] [6] 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. [33] [53] The sulfate conjugates can be transformed back into free steroids by steroid sulfatase. [54] 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] The elimination half-life of tibolone is 45 hours. [4] It is excreted in urine 40% and feces 60%. [3] [4]

Chemistry

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. [7] [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] [55] [56] [15] 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). [7]

History

Tibolone was developed in the 1960s. [15] It was first introduced in the Netherlands in 1988, and was subsequently introduced in the United Kingdom in 1991. [16] [57]

Society and culture

Generic names

Tibolone is the generic name of the drug and its INN, USAN, BAN, DCF, and JAN. [7] [8] It is also known by its developmental code name ORG-OD-14. [4]

Brand names

Tibolone is marketed under the brand names Livial, Tibofem, and Ladybon among others. [7] [8] [10]

Availability

Tibolone and is used widely in Europe, Asia, Australasia, and elsewhere in the world, but is notably not available in the United States or Canada. [10] [17] [58]

Tibolone is a Schedule IV controlled substance in Canada under the 1996 Controlled Drugs and Substances Act. [2] 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]

Related Research Articles

Progestogen (medication) Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

Methyltestosterone chemical compound

Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low doses as a component of menopausal hormone therapy for menopausal symptoms like hot flashes, osteoporosis, and low sexual desire in women, and to treat breast cancer in women. It is taken by mouth or held in the cheek or under the tongue.

Desogestrel chemical compound

Desogestrel, sold under the brand names Cerazette and Mircette among many others, is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

Norethisterone acetate chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is taken by mouth.

Norgestimate chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

Norethisterone chemical compound

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

Dydrogesterone chemical compound

Dydrogesterone, sold under the brand name Duphaston and Femoston, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, and as a component of menopausal hormone therapy. It is taken by mouth.

Ethisterone chemical compound

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

Dienogest chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT) or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss. They are in large part related to the diminished levels of sex hormones that occur during menopause.

Normethandrone chemical compound

Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women. It is taken by mouth.

Noretynodrel chemical compound

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

Trimegestone chemical compound

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

Nomegestrol acetate chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

Δ<sup>4</sup>-Tibolone chemical compound

Δ4-Tibolone, also known as 7α-methylnorethisterone or as 7α-methyl-17α-ethynyl-19-nortestosterone, is a synthetic androgen and progestin which was never marketed. The compound is a major active metabolite of tibolone, which itself is a prodrug of δ4-tibolone along with 3α-hydroxytibolone and 3β-hydroxytibolone. Tibolone and δ4-tibolone are thought to be responsible for the androgenic and progestogenic activity of tibolone, while 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for its estrogenic activity.

5α-Dihydronorethisterone chemical compound

5α-Dihydronorethisterone is a major active metabolite of norethisterone (norethindrone). Norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.

17α-Allyl-19-nortestosterone chemical compound

17α-Allyl-19-nortestosterone, also known as 3-ketoallylestrenol or as 17α-allylestr-4-en-17β-ol-3-one, is a progestin which was never marketed. It is a combined derivative of the anabolic–androgenic steroid and progestogen nandrolone (19-nortestosterone) and the antiandrogen allyltestosterone (17α-allyltestosterone). The drug is a major active metabolite of allylestrenol, which is thought to be a prodrug of 17α-allyl-19-nortestosterone.

3α-Hydroxytibolone chemical compound

3α-Hydroxytibolone is a synthetic steroidal estrogen which was never marketed. Along with 3β-hydroxytibolone and δ4-tibolone, it is a major active metabolite of tibolone, and 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for the estrogenic activity of tibolone.

3β-Hydroxytibolone chemical compound

3β-Hydroxytibolone is a synthetic steroidal estrogen which was never marketed. Along with 3α-hydroxytibolone and δ4-tibolone, it is a major active metabolite of tibolone, and 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for the estrogenic activity of tibolone.

Estetrol (medication)

Estetrol (E4), tentative brand names Donesta (alone) and Estelle/PeriNesta, is an estrogen medication and naturally occurring steroid hormone which is under development for use as a birth control pill in combination with a progestin, in menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss, and for the treatment of breast cancer, prostate cancer, osteoarthritis, and migraine. It is taken by mouth.

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Further reading