Cover Story

Is tibolone a viable alternative to HT?

By Leon Speroff, MD, and Thomas B. Clarkson, DVM

Clinical experience in humans in many countries and studies in monkeys say yes. Tibolone offers the symptom relief and bone benefits of CEE with endometrial safety—without stimulating breast tissue or increasing the risk of CAD.

Tibolone is marketed for postmenopausal hormone therapy in more than 70 countries, and approval is currently pending in the United States. It was first introduced in the Netherlands, the home country of its manufacturer, Organon, which initiated research on this product in the 1960s. Organon began collaborating with Robert Lindsay when he was at Glasgow's Western Infirmary, culminating in the first randomized tibolone trial to demonstrate preservation of bone, published in 1980.¹ Although tibolone was specifically developed to treat osteoporosis, its clinical performance led rapidly to its approval for the treatment of menopausal symptoms and prevention of osteoporosis. In the early studies, tibolone was known by its Organon-assigned number: Org OD 14. Various chemists and clinicians have tried to link tibolone with a popular acronym, but in our view, the generic name is a good one, well established in history and deserving of retention.

Because of its unique metabolism (see "The chemistry of tibolone"), tibolone can exert different hormonal activities at different sites. This unique characteristic is precisely what makes the drug difficult to understand. Summarizing the effect of tibolone on various biologic (and surrogate) endpoints can result in a mixed story. For this reason, this article emphasizes the impact to be expected with postmenopausal use of this drug and concentrates on recent publications.

By now, the important hormonal effects on postmenopausal women are well recognized, and they include the clinical impact on the cardiovascular system, bone, breast tissue, the endometrium, the CNS, menopausal symptoms, and sexuality. This paper provides evidence to show that tibolone relieves hot flushes, prevents bone loss, elevates mood, increases libido, inhibits endometrial proliferation, potentially prevents breast cancer, and probably has no effect on the cardiovascular system. Of most importance, we relate relevant and current clinical observations concerning tibolone's effects on postmenopausal women to the findings from an experimental trial in surgically postmenopausal cynomolgus monkeys. (For detailed information on the monkey data, visit http://www.contemporaryobgyn.net .) In light of recent controversies regarding the risks and benefits of postmenopausal hormone therapy, we place major emphasis on the cardiovascular system and breast.

Menopausal symptoms and quality of life in postmenopausal women

Menopausal symptoms are the main reason women use postmenopausal hormonal therapy. Tibolone must perform well in this area in order to be attractive to clinicians and patients. Clinical studies have established, without question, that tibolone exerts a beneficial estrogenic impact on hot flushing and vaginal dryness.

Hot flushes. Because the average reduction in hot flush frequency with placebo is 51%, a study of flushing must be properly designed: randomized, double-blinded, and placebo-controlled. ² Appropriate studies have documented that tibolone, in a daily dose of 2.5 mg, is as effective as standard postmenopausal hormone regimens in treating hot flushing.^3-9 The 1.25-mg dose takes longer to be more effective, and also has a higher incidence of persistent flushing.¹⁰ Tibolone also is effective for hot flushing associated with GnRH agonist therapy.¹¹

Vaginal dryness and sexuality. Fortunately, tibolone has an estrogenic effect on the vagina. At a dose of 2.5 mg daily, it relieves vaginal dryness and dyspareunia, and in most studies, tibolone is as effective as estrogen.^5-9,12-15

A decided advantage for tibolone can be found in studies examining sexuality. In prospective, randomized trials comparing tibolone with estrogen or estrogen-pro-gestin therapy, tibolone has been associated with a better sexual response.^6,9,16-19 An increase in libido also has been reported in studies comparing tibolone to placebo, and the response has been comparable to that associated with androgen treatment.^15,20 The overall effect has included an increase in sexual interest and sexual performance, specifically fantasies, arousal, and orgasm.

There are two possible mechanisms for tibolone's effect on sexuality: a direct androgenic effect of the

-4 isomer and/or an increase in the circulating level of free testosterone. Tibolone is associated with a profound change in the circulating levels of sex hormone-binding globulin (SHBG)—about a 50% decrease.^15,21 This is undoubtedly due to the

-4 isomer and an androgenic effect on the liver. Tibolone, therefore, produces a decrease in the concentration of total testosterone (bound and unbound), but a substantial increase in the amount of free, unbound testosterone. This is a striking contrast to estrogen, which increases SHBG and decreases both total and free testosterone levels. The androgenic side effects of acne and hirsutism, however, have not been reported with tibolone.

Mental changes. A comparison of women treated with tibolone for 10 years and matched controls showed that the treated women were less clumsy, less anxious in response to mild stress, and were better able to remember facts. They did not, however, differ in memory for events and performed worse on sustained attention and planning.²² Overall, tibolone exerts a positive but modest effect on mood.^21,23 However, this is an area in which it is not easy to achieve consistent effects, a problem often due to differences in measurement tools and definitions. Studying cognition is difficult because of the need to match treated and control groups for intelligence, age, occupation, education, and mental state (for example, depression). Because of this difficulty, the literature on effects of hormone therapy on cognition is inconsistent. This is further complicated by the sensitivity and appropriateness of the assessment tools that are used. For example, two imaging studies reported that estrogen was associated with increased activity in the areas of the brain associated with memory, yet at the same time, no effect could be detected in memory tasks.^24,25 This is an area that requires standardization and new approaches for research, not only for tibolone, but for all pharmacologic treatments that affect the CNS.

Impact on cardiovascular risk factors and CHD

Cholesterol. The impact of tibolone on HDL has been a major concern, but lipid changes associated with treatment are complicated. The effects are mixed, and there are indications that the overall impact is not harmful. Short-term clinical studies uniformly document that tibolone, 2.5 mg per day, reduces HDL levels by about 20%; how-ever, there is also a reduction in total cholesterol (about 10%) and triglycerides (about 20%), and a slight decrease or no change in LDL levels.^17,26-32 In women, tibolone does not increase LDL, and the reduction in HDL is less than that recorded in monkeys. In addition, tibolone decreases LDL oxidation and produces a shift away from small, dense LDL (which is more atherogenic); both changes would be beneficial.³² The potential harmful effects associated with reductions in HDL-cholesterol are further balanced by tibolone-associated reductions in endothelin and lipoprotein(a), anti-ischemic effects detected in women with angina, and improved insulin sensitivity.^31,33-36 In longer-term studies, HDL levels did not come back to baseline at the end of 2 years of treatment, but did return to baseline after 3 years.^31,37-39 And other studies have found that the decrease in HDL is statistically insignificant.^40,41

Reductions in HDL are believed to be potentially harmful because of the important role HDL plays in mediating cholesterol movement from lipid-laden cells and inhibiting LDL oxidation. However, in monkey studies, reduced HDL concentrations did not directly parallel reductions in important HDL functions. One reason for this is the complex nature of HDL lipoproteins, a heterogenous collection of particles that differ in their activities.⁴² An overall change in HDL levels will not reflect specific changes in particles that result in varying biologic activity. Like the results in monkeys, a randomized trial in women demonstrated that significant reductions in HDL levels (average 27%) caused by tibolone, 2.5 mg per day, were due to a decrease in one subclass of HDL particles, and measures of HDL anti-atherogenic functions (reverse cholesterol transport and inhibition of LDL oxidation) were not impaired.³³ Although the study was limited by the length of the treatment (12 weeks), the findings are consistent with those from the 2-year monkey experiment. These human results were confirmed and strengthened by a study of 68 postmenopausal women randomized to daily treatment for 3 months with either 2.5 mg of tibolone or placebo.⁴³ Changes in HDL were associated with an increase in hepatic lipase activity (an androgenic effect), again without impairing the ability of plasma to maintain cholesterol efflux.

C-reactive protein. Tibolone-induced reductions in HDL and SHBG levels indicate an androgenic impact on the liver. However, C-reactive protein (CRP) changes after tibolone treatment are similar to those achieved with standard hormone therapy: about a three- to fourfold increase.^44,45 CRP is synthesized in the liver and was given its name because it reacts with the C-polysaccharide of Streptococcus pneumoniae. Thus the circulating level of CRP increases in response to various inflammatory stimuli, specifically bacterial infections and chronic inflammatory conditions, such as systemic lupus erythematosus. New sensitive assays now detect small increases associated with low-grade inflammation in the vascular system. Are elevated CRP levels specific for cardiac outcomes, or is CRP a more general marker that is elevated in many conditions, even unrelated conditions? Is CRP an independent risk factor for coronary heart disease (CHD)? The increased relative risks are in the range of 1.5 to 2.0, recognized as a weak association that is difficult to separate from confounding factors. The increase in CRP levels may be due to estrogen's well-known stimulation of the hepatic synthesis of proteins. Most importantly, we don't know if the decrease in CRP levels with statins and the increase with estrogen and tibolone are instrumental in clinical outcomes or reflect other effects. Thus, raising or lowering CRP levels will not necessarily increase or decrease the risk of clinical disease. Tibolone does not change homocysteine, another substance in the circulation that has been linked to the risk of coronary artery disease (CAD). ⁴⁶

Results in the monkey model are consistent with an overall neutral impact on the cardiovascular system. A long-term (average of 7.5 years) follow-up of women treated with tibolone found no increase in carotid artery intim

-media thickness and the number of atherosclerotic plaques, results that are consistent with the monkey data.⁴⁷ This neutral impact is further supported by failure to find any effect of tibolone on experimentally-induced brachial artery dilatation or on vascular resistance measured in the carotid and middle cerebral arteries.^40,48 On the other hand, a study of venous dilatation in the hand found an improvement in endothelium-dependent responses after tibolone treatment.⁴⁹ Myocardial infarction and heart failure have been reported to be associated with overactivity of the sympathetic component of the cardiac autonomic nervous system, and tibolone decreases plasma levels of free fatty acids, an effect that results in an improved ratio of cardiac sympathetic to parasympathetic tone.⁵⁰ Another favorable effect connected to tibolone and its metabolites is a direct impact on endothelial cells that results in a beneficial decrease in endothelial-leukocyte adhesion molecules, another human finding similar to that in the monkey trial.⁵¹

Diabetes. The administration of 2.5 mg/day of tibolone to older women with Type II diabetes mellitus produced no significant changes in the lipid profile.⁵² Tibolone is associated with an increase in insulin sensitivity in women with insulin resistance, although there are reports of lack of effect in normal women.^28,33,53,54 Tibolone is an attractive option for postmenopausal women with diabetes mellitus and does not adversely affect the blood pressure in women with established hypertension.²⁹

Venous thromboembolism. Although no increased risk of venous thromboembolism (VTE) has been seen with tibolone despite its use for more than 15 years in many countries, studies in this area are needed. Tibolone's overall effects on the clotting system are consistent with an increase in fibrinolysis and thrombosis (Table 1), but the overall impact of these changes is not known. Does the prothrombotic effect dominate, and is an increase in fibrinolysis a reactive, secondary response? This uncertainty underscores the need for epidemiologic data regarding actual clinical events.

TABLE 1
Tibolone’s effects on clotting factors*

Cardiovascular studies with tibolone in women collectively provide an excellent example of the difficulty in trying to make a clinical conclusion with conflicting data. The results in the monkey trial indicate a neutral impact of tibolone on the cardiovascular system, suggesting that apparently adverse effects are balanced by apparently beneficial effects. Only the results of appropriately designed clinical trials will establish the cardiovascular impact of tibolone.

Endometrial effects

We can state with confidence that tibolone does not cause endometrial proliferation. This is because the predominant, if not exclusive, tibolone metabolite produced within the endometrium, is the

-4 isomer, which binds to the progesterone receptor and protects the endometrium from the agonist effects of the two estrogenic metabolites.^55-58 This protective effect has been documented in long-term (up to 8 years) human studies.^{5,13,14,57-61} Isolated cases of endometrial proliferation have been reported (for example, four of 150 women treated with 2.5 mg daily for 2 years).⁶² In a 5-year follow-up, 47 of 434 women experienced bleeding, and of these, 11 had endometrial polyps and two had fibroids, but there were also two with simple hyperplasia and two with endometrial cancer in situ.⁶³ This underscores the standard clinical principle to investigate persistent vaginal bleeding in any postmenopausal women. Three cases of endometrial cancer were observed in the US trial, but each woman later was found to have preexisting carcinoma.³¹ In the Organon database of 4,269 women who participated in Phase III and Phase IV clinical trials, there were two cases of endometrial cancer in the tibolone-treated women and two in the placebo group.⁶⁴

Reported breakthrough bleeding rates with tibolone have been comparable to treatment with combined, continuous estrogen-progestin therapy,^6,8,27,59 but some reports indicate that the rate has been less with tibolone.^7,9,15,65 In addition, amenorrhea is achieved more rapidly: 90% of tibolone-treated women are amenorrheic by 6 months.^7,63,66 Bleeding is less in older women, and can be greater with the 2.5-mg dose compared to the 1.25-mg dose, but the difference is too small to be detected in some studies.^10,31,67 Importantly, a lack of correlation has been observed between bleeding and endometrial thickness measured by ultrasonography.^67,68 This again emphasizes the need to biopsy tibolone-treated women with persistent bleeding.

Careful evaluations of women with fibroids who have been treated with tibolone have revealed no evidence of myoma growth, with up to 3 years of follow-up.^69-71 Furthermore, add-back treatment with tibolone effectively prevents flushing and bone loss, and does not impair fibroid response to GnRH analogs.⁷²

Breast effects

There is no more pressing issue in regard to postmenopausal hormone therapy than breast cancer. Fear of this disease is prevalent among women and plays a key role in their decision-making. The evidence thus far with tibolone is very encouraging, even raising the possibility of a preventive effect.

The breast is a complicated estrogen factory. Normal and abnormal breast tissue contains all the enzymes necessary for the formation of estrogens (sulfatase, aromatase, and 17ß-hydroxysteroid dehydrogenase) and the conversion of estrogens into their sulfates (sulfotransferase). Estrone sulfate concentrations are high in the breast (higher than in plasma), and even higher in cancerous tissue. This state is achieved in postmenopausal women with very low systemic levels of estrogen, indicating that a local mechanism is operative.

The major pathway of estrogen synthesis in human breast tumor cells, conversion of estrone sulfate to estrone by estrone sulfatase, is more important than the aromatase pathway.⁷³ Aromatase is an enzyme complex that produces irreversible conversion of androgens to estrogens and it acts predominantly in the stromal tissue of the breast. The levels of estrone sulfate and estradiol are higher in tumor than in normal tissue.⁷⁴ Sulfatase activity is higher (130 to 200 times) than aromatase activity in all breast tissues examined, and the sulfatase and aromatase activity is higher in the tumor tissue than in normal tissue. Thus, estrogen concentrations in the breast are higher in women with breast cancer, and formation of estradiol from sulfated estrogen is the primary pathway. Most importantly, this increase in estrogen activity is independent of the estrogen-receptor (ER) status of the tissue. The story is made even more complex by the observation that estradiol is a potent inhibitor of estrone sulfatase, decreasing its own production in breast cancer cells (Figure 1).⁷⁵

Tibolone and its metabolites inhibit estrone sulfatase and 17ß-hydroxysteroid dehydrogenase in normal stromal cells and in hormone-dependent breast cancer cells (MCF-7 and T-47D).^76-79 This inhibits conversion of estrone sulfate to estradiol. In addition, tibolone and its 3-hydroxymetabolites increase conversion of estrone back to estrone sulfate by increasing the activity of sulfotransferase.⁸⁰ Tibolone and all three metabolites inhibit the conversion of estrone to estradiol by 17ß-hydroxysteroid dehydrogenase.⁷⁷ Although these effects resemble progestin activity, tibolone is more potent. Tibolone increases aromatase activity in stromal cells, but only at high concentrations that are beyond in vivo levels.⁷⁸

In the rat and mouse breast cancer models (cancer induced by 7,12-dimethylbena{a}anthracene, DMBA), tibolone exerts protective effects to the same degree as tamoxifen.⁸¹ However, tibolone is not antiestrogenic and does not inhibit aromatase. Therefore, the mechanism is explained by the enzyme effects summarized previously: inhibition of sulfatase and 17ß-hydroxysteroid dehydrogenase and stimulation of sulfotransferase to increase the production of inactive sulfates.⁷⁸ In addition, tibolone increases cellular differentiation and stimulates apoptosis, at least with normal breast cells in vitro.⁸² An increase in apoptosis is an action of the parent tibolone and its

-4 isomer. Thus, tibolone acts like progestins and weak androgens in cell line studies examining proliferation, differentiation, and apoptosis.

Tibolone and its metabolites do not have the same effect as sulfatase activity in all tissues. Strong inhibition of sulfatase is a major feature in breast cells, but tibolone and its metabolites inhibit sulfatase only moderately in the endometrium (contributing to an antiestrogenic action), and provide no inhibition in bone (allowing a greater estrogenic impact).⁸³

Postmenopausal hormone therapy increases breast density on mammography in about 10% to 20% of estrogen users and about 20% to 35% of estrogen-progestin users, an effect that occurs within the first months of treatment. In contrast, tibolone does not increase breast density, and causes far less mastalgia than that seen with estrogen.^{7,19,31,84-88} It is logical to conclude that these favorable responses are a consequence of tibolone's effects on the breast tissue enzymes involved in local estrogen production.

In Phase III and Phase IV studies of tibolone involving 4,537 women, the documented incidence of breast cancer was 1.59 per 1,000 woman-years in the treatment group, compared with 3.15 in the placebo group, but the difference did not achieve statistical significance.⁶⁴

Bone effects

Tibolone prevents bone loss in postmenopausal women as effectively as estrogen or estrogen-progestin therapy.^17,31,89-93 In a large US dose-response study with doses ranging from 0.3 mg to 2.5 mg daily, only the 1.25-mg and 2.5-mg doses produced progressive increases in the femoral neck. Indeed, the impact on bone was essentially the same for the two highest doses: 1.25 mg and 2.5 mg. Although the 1.25-mg dose is acceptable for preventing bone loss, the 2.5-mg dose is more effective for alleviating hot flushes.¹⁰

The beneficial impact on bone can be attributed to the estrogenic metabolites acting through the ER because it is blocked by an antiestrogen, but not by an antiandrogen or an antiprogestin.⁹⁴ Tibolone prevents bone loss associated with GnRH-agonist treatment (and the side effect of hot flushing).^72,95

The results with bone mineral density (BMD) measurements predict that tibolone treatment will reduce the incidence of fractures due to osteoporosis. Although the establishment of tibolone's ultimate effect on fractures awaits the results of a clinical trial, the BMD data are similar to those for hormonal therapy and alendronate, which of course are associated with fracture protection.

Conclusion

Tibolone is an appropriate choice for hormonal therapy, suitable for most postmenopausal women. Because of its unique and varied metabolism, tibolone has different actions in different tissues, which provide an overall favorable risk-benefit profile. Clinically tibolone is as effective as estrogen for menopausal symptoms, including hot flushes and vaginal dryness, and most importantly, improves sexual response. Its endometrial safety and ability to prevent bone loss are comparable to that achieved with continuous combined estrogen-progestin regimens, and with a lower rate of breakthrough bleeding.

The sum of the various biologic effects of tibolone and its metabolites on the cardiovascular system should neither increase nor decrease the risk of CAD. So far, there has been no indication of an increased risk of VTE, but this is a potential side effect that requires epidemiologic study. Tibolone does not stimulate proliferation of breast cells and affects enzyme activity in the breast to lower breast tissue concentrations of active estrogen. Tibolone does not increase breast density on mammography and does not increase the frequency of mastalgia. These effects carry the potential to offer protection against breast cancer, another subject that requires epidemiologic study.

Important clinical trials with tibolone are currently under way. The LIFT Study (Long-term Interventional Fracture study in osteoporotic patients) is assessing the incidence of breast cancer. The OPAL Study (Osteoporosis Prevention and Antiatherosclerosis effects of TiboLone) is directed at both bone and the cardiovascular system. LIBERATE (Livial Intervention following Breast Cancer; Efficacy, Recurrence, and Tolerability Endpoints) is a breast safety study and THEBES (Tibolone Histology of the Endometrium and Breast Endpoints Study) is assessing endometrial response.

Tibolone has been around a long time and is the subject of an enormous amount of investigation. The extensive literature provides a clinical appraisal that is very positive. Patient satisfaction related to effects on menopausal symptoms and sexuality is further enhanced by an excellent side-effect profile. For example, in appropriately designed studies with placebo controls, tibolone has not caused significant weight gain.^31,96 Overall, tibolone would be a welcome addition to the list of hormonal treatments available in the US for postmenopausal women.

Monkey studies described here were supported, in part, by a grant from Organon, NV, The Netherlands, to Wake Forest University. Dr. Speroff has received research grants and consultant fees from: Wyeth, Organon, Galen, Ltd., WomenFirst, Barr Labs.

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52. de Beer F, Smelt AH, Van Vark LC, et al. The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia. J Intern Med. 2002;251:148-155.

53. Prelevic GM, Beljic T, Balint-Peric L, et al. Metabolic effects of tibolone in postmenopausal women with non-insulin dependent diabetes mellitus. Maturitas. 1998;28:271-276.

54. Wiegratz I, Starflinger F, Tetzloff W, et al. Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women. Maturitas. 2002;41:133-141.

55. Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium. J Steroid Biochem. 1990;35:535-541.

56. Tang B, Markiewicz L, Kloosterboer HJ, et al. Human endometrial 3 bet

-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Mol Biol. 1993;45:345-351.

57. Punnonen R, Liukko P, Cortes-Prieto J, et al. Multicentre study of effects of Org OD 14 on endometrium, vaginal cytology and cervical mucus in postmenopausal and oophorectomized women. Maturitas. 1984;5:281-286.

58. Genazzani AR, Benedek-Jaszmann LJ, Hart DM, et al. Org OD 14 and the endometrium. Maturitas. 1991;13:243-251.

59. Ginsburg J, Prelevic G, Butler D, et al. Clinical experience with tibolone (Livial) over 8 years. Maturitas. 1995;21:71-76.

60. Meuwissen JH, Wiegerinck MA, Haverkorn MJ. Regression of endometrial thickness in combination with reduced withdrawal bleeding as a progestational effect of tibolone in postmenopausal women on oestrogen replacement therapy. Maturitas. 1995;21:121-125.

61. Egarter C, Sator M, Berghammer P, et al. Efficacy, tolerability, and rare side effects of tibolone treatment in postmenopausal women. Int J Gynaecol Obstet. 1999;64:281-286.

62. Volker W, Coelingh Bennink HJ, Helmond FA. Effects of tibolone on the endometrium. Climacteric. 2001;4:203-208.

63. Ginsburg J, Prelevic GM. Cause of vaginal bleeding in postmenopausal women taking tibolone. Maturitas. 1996;24:107-110.

64. Helmond FA, Kloosterboer HJ. Safety and tolerability profile of Livial. In: Genazzani AR, ed. Hormone Replacement Therapy and Cancer. The Current Status of Research and Practice. Boca Raton: The Parthenon Publishing Group; 2002:252-256.

65. Wu MH, Pan HA, Wang ST, et al. Quality of life and sexuality changes in postmenopausal women receiving tibolone therapy. Climacteric. 2001;4:314-319.

66. Rymer J, Fogelman I, Chapman MG. The incidence of vaginal bleeding with tibolone treatment. Br J Obstet Gynaecol. 1994;101:53-56.

67. Berning B, van Kuijk C, Benink HJ, et al. Absent correlation between vaginal bleeding and oestradiol levels or endometrial morphology during tibolone use in early postmenopausal women. Maturitas. 2000;35:81-88.

68. Hanggi W, Lippuner K, Riesen W, et al. Long-term influence of different postmenopausal hormone replacement regimens on serum lipids and lipoprotein(a): a randomised study. Br J Obstet Gynaecol. 1997;104:708-717.

69. Fedele L, Bianchi S, Raffaelli R, et al. A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in postmenopausal women with uterine myomas. Eur J Obstet Gynecol Reprod Biol. 2000;88:91-94.

70. Gregoriou O, Konidaris S, Botsis D, et al. Long term effects of tibolone on postmenopausal women with uterine myomas. Maturitas. 2001;40:95-99.

71. Simsek T, Karakus C, Trak B. Impact of different hormone replacement therapy regimens on the size of myoma uteri in postmenopausal period: tibolone versus transdermal hormonal replacement system. Maturitas. 2002;42:243-246.

72. Palomba S, Affinito P, Tommaselli GA, et al. A clinical trial of the effects of tibolone administered with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril. 1998;70:111-118.

73. Santner SJ, Feil PD, Santen RJ. In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus aromatase pathway. J Clin Endocrinol Metab. 1984;59:29-33.

74. Chetrite GS, Cortes-Prieto J, Philippe JC, et al. Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol. 2000;72:23-27.

75. Pasqualini JR, Chetrite G. Paradoxical effect of estradiol: it can block its own bioformation in human breast cancer cells. J Steroid Biochem Mol Biol. 2001;78:21-24.

76. Chetrite G, Kloosterboer HJ, Pasqualini JR. Effect of tibolone (Org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cancer cells. Anticancer Res. 1997;17:135-140.

77. Chetrite GS, Kloosterboer HJ, Philippe JC, et al. Effects of Org OD14 (Livial) and its metabolites on 17-bet

-hydroxysteroid dehydrogenase activity in hormone-dependent MCF-7 and T-47D breast cancer cells. Anticancer Res. 1999;19:261-267.

78. van de Ven J, Donker GH, Sprong M, et al. Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells. J Steroid Biochem Mol Biol. 2002;81:237-247.

79. Purohit A, Malini B, Hooymans C, et al. Inhibition of oestrone sulphatase activity by tibolone and its metabolites. Horm Metab Res. 2002;1:1-6.

80. Chetrite GS, Kloosterboer HJ, Philippe JC, et al. Effect of Org OD14 (LIVIAL) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent McF-7 and T-47D, and the hormone-independent MD

-MB-231, breast cancer cell lines. Anticancer Res. 1999;19:269-275.

81. Kloosterboer HJ. Endocrine prevention of breast: any role for tibolone? Eur J Cancer. 2002;(38 suppl 6):S24-S25.

82. Gompel A, Siromachkova M, Lombet A, et al. Tibolone actions on normal and breast cancer cells. Eur J Cancer. 2000;36:76-77.

83. de Gooyer ME, Kleyn GT, Smits KC, et al. Tibolone: a compound with tissue specific inhibitory effects on sulfatase. Mol Cell Endocrinol. 2001;183:55-62.

84. Valdivia I, Ortega D. Mammographic density in postmenopausal women treated with tibolone, estriol or conventional hormone replacement therapy. Clin Drug Invest. 2000;20:101-107.

85. Colacurci N, Fornaro F, De Franciscis P, et al. Effects of different types of hormone replacement therapy on mammographic density. Maturitas. 2001;40:159-164.

86. Sendag F, Coson Terek M, Õzsener S, et al. Mammographic density changes during different postmenopausal hormone replacement therapies. Fertil Steril. 2001;76:445-450.

87. Lundstrom E, Christow A, Kersemaekers W, et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol. 2002;186:717-722.

88. Egarter C, Eppel W, Vogel S, et al. A pilot study of hormone replacement therapy with tibolone in women with mastopathic breasts. Maturitas. 2001;40:165-171.

89. Berning B, Kuijk CV, Kuiper JW, et al. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a two-year randomized, placebo-controlled study. Bone. 1996;19:395-399.

90. Lippuner K, Haenggi W, Birkhaeuser MH, et al. Prevention of postmenopausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17bet

-estradiol and dydrogesterone. J Bone Miner Res. 1997;12:806-812.

91. Studd J, Arnala I, Kicovic PM, et al. A randomized study of tibolone on bone mineral density in osteoporotic postmenopausal women with previous fractures. Obstet Gynecol. 1998;92:574-579.

92. Milner M, Harrison RF, Gilligan et al. Bone density changes during two years treatment with tibolone or conjugated estrogens and norgestrel, compared with untreated controls in postmenopausal women. Menopause. 2000;7:327-333.

93. Rymer J, Robinson J, Fogelman I. Effects of 8 years of treatment with tibolone 2.5 mg daily on postmenopausal bone loss. Osteoporos Int. 2001;12:478-483.

94. Ederveen AG, Kloosterboer HJ. Tibolone exerts an estrogenic effect on bone leading to prevention of bone loss and reduction in bone resorption in ovariectomized rats. Osteoporos Int. 1999;8:95.

95. Palomba S, Morelli M, Di Carlo C, et al. Bone metabolism in postmenopausal women who were treated with a gonadotropin-releasing hormone agonist and tibolone. Fertil Steril. 2002;78:63-68.

96. Meeuwsen IB, Samson MM, Duursma SA, et al. The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal women. Endocrinology. 2001;142:4813-4817.

Dr. Speroff is Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Ore. Dr. Clarkson is Professor of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, N.C.

The chemistry of tibolone

Tibolone is structurally related to the 19-nortestosterone progestins used clinically in oral contraceptives, but its activity depends on how it is metabolized. Tibolone {7-

,17-

-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one} is metabolized by humans and nonhuman primates into three biologically active metabolites; the 3

-hydroxy (3

-OH) metabolite and the 3ß-hydroxy (3ß-OH) metabolite have estrogen agonist properties, whereas the

-4 ketoisomer has progestogenic and androgenic effects (Figure 1; metabolic conversion of tibolone to its active metabolites).^1,2 Binding studies in in vitro cell preparations indicate the hormonal characteristics of the metabolites (Table 1).

Although tibolone binds to the estrogen receptor (ER), in vivo the activity of the 3-hydroxy metabolites is 100 times greater, with a greater affinity for the

-ER than for the ß-ER.² The loss of the hydroxyl group at position 3 of the A ring eliminates estrogenic activity in the

-4 isomer. The

-4 isomer exerts its androgenic effects primarily in the liver and brain.

TABLE 1
Tibolone's binding affinity for sex steroid receptors*

Tibolone's conversion into metabolites occurs chiefly in the liver and intestine. Metabolism of the parent compound is rapid and very near total, yielding mainly the 3ß-OH and the 3

-OH metabolites in the circulation; the level of the 3

-OH metabolite is three-fold higher than the 3ß-OH metabolite.^3,4 Tibolone and the

-4 isomer can be detected only at peak levels 2 hours after ingestion, and even then, the levels are very low, at the limit of detection. The half-life of the metabolites that predominate in the circulation (the 3

-OH and 3ß-OH metabolites) is approximately 7 to 8 hours, and a steady state is attained by day 5.⁵ Eating does not affect metabolism, and tibolone can be taken at any time of the day.³ The pharmacokinetics of tibolone are not affected by impaired renal function. The metabolites have a very weak effect on cytochrome P450 enzymes, and no interference is to be expected with co-administered drugs.⁴ After the initial metabolism of tibolone, the products are rapidly sulfated, and over 75% of the metabolites circulate as the sulfates, to be activated by tissue sulfatases.⁴

Tibolone is available in two doses: 1.25 mg and the dose usually administered daily, 2.5 mg. There is considerable variability (about 30% to 40%) within and between subjects, but the 1.25-mg and 2.5-mg doses are bioequivalent as measured by maximum levels and areas under the curve for the 3

-OH and 3ß-OH metabolites.⁵ There are differences in clinical responses, however, which influence choice of dose.

Tibolone's metabolism is not limited to the liver and intestine. Important effects are explained by specific local-tissue metabolism. For example, the

-4 isomer is produced primarily within the endometrium, binds to the progesterone receptor, and protects the endometrium from the agonist effects of the two estrogenic metabolites.^6-9

Tibolone reportedly is aromatized to 7-

-methyl-ethinyl estradiol. Blood levels 2 hours after ingesting 2.5 mg were comparable to the levels of ethinyl estradiol (E₂) achieved with an OC containing 30 µg E₂.¹⁰ An evaluation of this metabolite indicated that it is a potent estrogen, approximately 20-fold greater than the 3

-OH and 3ß-OH metabolites.¹¹ However, an analysis of aromatization using a very sensitive bioassay system determined unequivocally that tibolone and its metabolites are not aromatized, a result that is consistent with a failure to find aromatized metabolites in humans.^4,12 We can say with confidence that tibolone's estrogenic activity is mediated by the 3

- and 3ß-hydroxy metabolites.

REFERENCES

1. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol. 2001;76:231-238.

2. de Gooyer ME, Deckers GH, Schoonen WG, et al. Receptor profiling and endocrine interactions of tibolone. Steroids. 2003;68:21-30.

3. Timmer CJ, Huisman JA. Effect of a standardized meal on the bioavailability of a single oral dose of tibolone 2.5 mg in healthy postmenopausal women. Pharmacotherapy. 2002;22:310-315.

4. Vos RM, Krebbers SF, Verhoeven CH, et al. The in vivo human metabolism of tibolone. Drug Metab Dispos. 2002;30:106-112.

5. Timmer CJ, Houwing NS. Dose proportionality of three different doses of tibolone. Pharmacotherapy. 2002;22:6-13.

6. Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestagenic effects of a steroidal drug (Org OD-14) and its metabolites on human endometrium. J Steroid Biochem. 1990;35:535-541.

7. Tang B, Markiewicz L, Kloosterboer HJ, et al. Human endometrial 3 bet

-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Mol Biol. 1993;45:345-351.

8 Punnonen R, Liukko P, Cortes-Prieto J, et al. Multicentre study of effects of Org OD 14 on endometrium, vaginal cytology and cervical mucus in postmenopausal and oophorectomized women. Maturitas. 1984;5:281-286.

9. Genazzani AR, Benedek-Jaszmann L, Hart DM, et al. Org OD 14 and the endometrium. Maturitas. 1991;13:243-251.

10. Wiegratz I, Sanger N, Kuhl H. Formation of 7 alpha-methyl-ethinyl estradiol during treatment with tibolone. Menopause. 2002;9:293-295.

11. Bodine PV, Harris HA, Lyttle CR, et al. Estrogenic effects of 7alpha-methyl-17alpha-ethynylestradiol: a newly discovered tibolone metabolite. Steroids. 2002;67:681-686.

12. de Gooyer ME, Oppers-Tiemissen HM, et al. 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. Steroids. 2003;68:235-243.

Key points

• Evidence to date in humans and animals suggests that tibolone will neither increase nor decrease risk of coronary artery disease.

• In the breast, tibolone affects enzyme activity to lower breast tissue concentrations of active estrogen and does not stimulate proliferation of cells.

• Tibolone is comparable to combined estrogen-progestin in prevention of bone loss and endometrial safety and it also improves sexual response.

• Studies currently under way are further examining tibolone's impact on bone, the cardiovascular system, breast safety, and endometrial response.

 

Leon Speroff. Cover Story: Is tibolone a viable alternative to HT? Contemporary Ob/Gyn Aug. 1, 2003;48:54-68.