Tibolone was developed in the 1960s and was introduced for medical use in 1988.[17][18] It is marketed widely throughout the world.[12][19] The medication is not available in the United States.[12][19]
Tibolone is available in the form of 2.5 mg
oraltablets.[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]
A 2016
Cochrane review has been published on the short-term and long-term effects of tibolone, including
adverse effects.[32] Possible adverse effects of tibolone include unscheduled
vaginal bleeding (
ORTooltip Odds ratio = 2.79; incidence 13–26% more than placebo), an increased risk of
breast cancer in women with a history of breast cancer (
ORTooltip Odds ratio = 1.5) although apparently not without a history of breast cancer (
ORTooltip Odds ratio = 0.52), an increased risk of
cerebrovascular events (strokes) (
ORTooltip Odds ratio = 1.74) and
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]
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.[15][13][14] 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.[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
transformed by
aromatase into the potent estrogen 7α-methylethinylestradiol in women, analogously to the transformation of
norethisterone into
ethinylestradiol.[37] Controversy and disagreement followed when other researchers contested the findings however.[38][39][40][41][42][43] By 2008, these researchers had asserted that tibolone is not aromatized in women and that the previous findings of 7α-methylethinylestradiol detection were merely a methodological artifact.[40][42][43] In accordance, a 2009 study found that an
aromatase inhibitor had no effect on the estrogenic potencies of tibolone or its metabolites in vitro, unlike the case of
testosterone.[6] 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.[44] 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) (
RRTooltip Rate ratio = 0.92), which would not be expected if the medication formed a potent, liver metabolism-resistant estrogen similar to ethinylestradiol in important quantities.[1][45] (For comparison,
combined oral contraceptives containing ethinylestradiol, due mostly or completely to the estrogen component, have been found to increase SHBG levels by 200 to 400% and to increase the risk of VTE by about 4-fold (
ORTooltip odds ratio = 4.03).)[46][47]
In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α-methylethinylestradiol in small quantities.[48][49] They have claimed that 19-nortestosterone derivatives like tibolone, due to lacking a C19
methyl group, indeed are not substrates of the classical aromatase enzyme, but instead are still transformed into the corresponding estrogens by other
cytochrome P450monooxygenases.[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
placentalmicrosomesin 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.[49][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.[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
breastcellproliferation, 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.[49][1] They are also responsible for the androgenic side effects of tibolone such as
acne and
increased hair growth in some women.[8]
Tibolone, also known as 7α-methylnoretynodrel, as well as 7α-methyl-17α-ethynyl-19-nor-δ5(10)-testosterone or as 7α-methyl-17α-ethynylestr-5(10)-en-17β-ol-3-one, is a
syntheticestranesteroid and a
derivative of
testosterone and
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 steroidstrestolone (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
generic name of the drug and its
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 IVcontrolled 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]
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