Tibolone

Chemical compound
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. The medication may have greater benefits on libido than standard menopausal hormone therapy, which may be related to its androgenic effects. 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.

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

Tibolone can infrequently produce androgenic side effects such as acne and increased facial hair growth. Possible adverse effects of tibolone include unscheduled vaginal bleeding ( = 2.79; incidence 13–26% more than placebo), an increased risk of breast cancer in women with a history of breast cancer ( = 1.5) although apparently not without a history of breast cancer ( = 0.52), an increased risk of cerebrovascular events (strokes) ( = 1.74) and cardiovascular events ( = 1.38), and an increased risk of endometrial cancer ( = 2.04).

Tibolone possesses a complex pharmacology and has weak estrogenic, progestogenic, and androgenic activity. Tibolone, 3α hydroxytibolone, and 3β hydroxytibolone act as agonists of the estrogen receptors. 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 ), but occur at relatively high concentrations that are sufficient for full and marked estrogenic responses to occur. 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. or "tissue specific receptor and intracrine mediator" (TRIM). Controversy and disagreement followed when other researchers contested the findings however. 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. 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) ( = 0.92), which would not be expected if the medication formed a potent, liver metabolism resistant estrogen similar to ethinylestradiol in important quantities. (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 ( = 4.03).) In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α methylethinylestradiol in small quantities. 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. 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, despite the absence of aromatase in the adult human liver.

Tibolone and δ4 tibolone act as agonists of the progesterone receptor (PR). 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. Its plasma protein binding is 96.3%. 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. The sulfate conjugates can be transformed back into free steroids by steroid sulfatase. 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. Tibolone is the 7α methyl derivative of the progestin noretynodrel (17α ethynyl δ5(10) 19 nortestosterone).

Tibolone is the generic name of the drug and its , , , , and .

Tibolone is used widely in the European Union, Asia, Australasia, and elsewhere in the world, but is not available in the United States.

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