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• July, 2009 •

Tibolone revisited: Still a good treatment option for healthy, early postmenopausal women.

Peter Kenemans

Tibolone is a synthetic steroid that has, through its metabolites, specific effects in different tissues, due to tissue-selective enzyme regulation and steroid receptor activation. At present it is widely used throughout the world for the reduction of menopausal complaints in early postmenopausal women. It has been registered in 90 countries for the treatment of climacteric symptoms and in 55 countries for the prevention of osteoporosis.

Tibolone is taken as one tablet of 2.5 mg daily. After oral intake, tibolone is converted into 3 active metabolites, 2 of which have estrogenic effects, while 1, the delta-4 isomer, has both progestogenic and androgenic properties. Due to its unique mode of action, tibolone has been classified as a selective tissue estrogenic activity regulator, a STEAR (1).

In 2005, an International Consensus Group of experts in the management of the menopause concluded that tibolone has a specific place within the wide range of currently available postmenopausal therapy options (2).

The consensus was that tibolone is a unique drug that provides a valuable treatment option for women with climacteric complaints. It has a good overall tolerability and is associated with a low incidence of vaginal bleeding and breast pain. Tibolone reverses vaginal atrophy and relieves urogenital symptoms. Breast tolerability with tibolone is high, as tibolone causes significantly less breast tenderness and increased mammographic density than with combined hormone therapy (HT). Women are considerably less likely to stop taking tibolone than combined therapy for these reasons. Therefore, tibolone might be preferable to combined HT in women who have not been hysterectomized. In hysterectomized women, tibolone might be preferable to therapy with estrogen alone in those women that are prone to sexual and mood problems. With tibolone, sex hormone binding globuline (SHBG) levels are decreased rather than increased (as seen with estrogen containing therapy). Therefore, free testosterone levels are significantly increased as opposed to the decrease observed with standard HT, which could explain the difference.

The consensus concluded that the level of evidence was inconclusive as to two important items: breast safety and cardiovascular clinical outcomes. For both important clinical endpoints no randomised controlled trials were available and therefore, although many surrogate endpoint studies had been published, no firm conclusions could be drawn regarding benefits or risks.

After publication of these conclusions of the International Tibolone Consensus Group in 2005 (2) various well designed clinical controlled trials have been done, providing a multitude of solid data on various clinical effects of tibolone.

In 2007, the THEBES study (3) confirmed the endometrial safety of tibolone. THEBES is a randomised double-blind parallel group trial of tibolone, compared with continuous combined conjugated equine estrogen (CEE) and medroxy progesteron acetate (MPA) in 3.240 postmenopausal women (mean age 54 years). Amenorrhea was more common with tibolone than with the combined regimen. The primary endpoint in this study is the incidence of abnormal endometrial histology (hyperplasia or carcinoma) after 1 and 2 years of treatment as assessed by histological examination of endometrial tissue specimens obtained by Pipelle suction curette. Endometrial biopsies at endpoint did not show any hyperplasia or carcinoma in the tibolone group and therefore confirmed the endometrial safety of tibolone.

The TOTAL study (4) was a randomised double-blind double-dummy group comparative intervention trial, comparing the vaginal bleeding pattern during administration of tibolone and a low dose continuous combined estradiol (E2) plus norethisterone acetate (NETA) regimen.

In the first 3 months of treatment, the incidence of vaginal bleeding was significant lower with tibolone. This constitutes an important argument for adherence to therapy.

In 2008, two important randomised clinical tibolone studies were published, the LISA study (5) and the LIFT study (6). The LISA study (5) confirmed that tibolone improves sexual function in women with sexual dysfunction. The LIFT study (6) had as primary objective to test the hypothesis that tibolone reduces risk of vertebral fractures. LIFT, Long-term Intervention on Fractures with Tibolone, randomised 4.538 postmenopausal women, mean age 68 years, with a total hip and/or spine BMD T-score of ≤2.5 or ≤2.0 with a vertebral fracture. In this study, tibolone 1.25 mg was randomised to placebo. The results showed a reduced risk of vertebral (reduction of 45%) and non-vertebral (reduction 26%) fractures with tibolone after a median of 34 months of follow-up. In addition, this study showed a reduced risk of breast cancer and an increased risk of stroke. Because of this increased risk of stroke (relative hazard [RH] of 2.19; 95% CI: 1.14-4.23) the study was stopped prematurely. There were no significant differences in risk for either coronary heart disease or venous trombo-embolism between the tibolone group and the placebo group.

The increased risk of stroke with tibolone has also been reported with estrogen therapy, but the biological mechanism is not certain. The authors conclude that as tibolone is associated with an increased risk of stroke, it therefore should not be used in elderly women and women with risk factors for stroke. It should be noted that the risk of stroke rises exponentially with age. In early postmenopausal women, between 50 and 60 years of age, the baseline risk of stroke is low. Nevertheless, tibolone should be avoided in women who have a strong risk factor for stroke, such as hypertension, smoking, diabetes and arterial fibrillation.

In the LIFT study, although the overall numbers of adverse events were small, there was no increased risk of venous trombo-embolism, as has been seen with hormone therapy and SERMs, or an increased risk of coronary events, as has been seen with conjugated estrogen combined with medroxy progesterone.

In the LIFT study, surprisingly tibolone was associated with a reduction in the risk of invasive breast cancer (RH: 0.32; 95% CI: 0.13-0.80), a degree that is similar to that observed for treatment with tamoxifen or raloxifen. The LIFT study is the first and thusfar the only randomised controlled trial to show an effect on breast cancer with tibolone.

In a population based case-control study (7), it had been found that the risk of breast cancer in this population was not increased among women that used exclusively tibolone (relative risk [RR] of 0.86; 95% CI: 0.65-1.13), quite similar to that found for exclusive use of unopposed estrogens (RR: 0.97; 95% CI: 0.86-1.09), while women that used opposed estrogens had an increased risk (RR: 1.38; 95% CI: 1.27-1.49).

Based on these data that were reassuring as to breast safety, the LIBERATE trial was designed to assess the safety and efficacy of tibolone in women with vasomotor symptoms and a history of breast cancer. The results of this large multi-centered randomised double-blind placebo-controlled trial that randomised 3.148 women to either tibolone 2.5 mg daily or placebo at 245 centers in 31 countries, were published recently (8). Unfortunately, the conclusion of this trial was that while relieving vasomotor symptoms and preventing bone loss, tibolone increased the risk of recurrence in breast cancer patients suffering from menopausal symptoms, while using adjuvant therapy. Thus, while tibolone appears to be safe for the breast in healthy, early postmenopausal women, it remains contra-indicated in women with menopausal symptoms induced by  adjuvant treatment for breast cancer.

Based on all new data provided by recent randomised clinical trials, looking at safety and efficacy of tibolone, it can only be concluded that these recent studies (3-8) confirm the earlier conclusion of the International Tibolone Consensus Group (2), that tibolone as a mono-therapy holds a unique place within the large arsenal of currently available postmenopausal therapy options.

Tibolone is a valuable treatment option for healthy early postmenopausal women suffering from climacteric complaints and might be preferable to common combined HT products for women with an intact uterus. In older women, above 65 years, tibolone doubles the relative risk of stroke, while in breast cancer patients suffering from vasomotor symptoms probably risk of recurrence will be increased. In these patient groups tibolone could be best avoided. However, finally each decision in medical practice should be patient-tailored, taken after proper counselling by the patient and the doctor together, based on individual knowledge and personal experience (2).

References

  1. Smith CL, O’ Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004;25:45-71.
  2. Kenemans P, Speroff L. Tibolone: Clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group. Maturitas 2005;51:21-28.
  3. Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, den Hollander W, Stathopoulos V, Helmond FA for the Tibolone Histology of the Endometrium and Breast Endpoints (THEBES) Study Group. Endometrial Effects of Tibolone. J Clinical Endocrinology and Metab 2007, 92, 911-18.
  4. Hammar M, van de Weijer P, Franke H, Pornel B, von Mauw E, Nijland E on behalf of the TOTAL Study Investigators Group. Tibolone and low-dose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability. BJOG 2007;114:1522-1529.
  5. Nijland EA, Weijmar Schultz WCM, Nathorst-Böös J, Helmond FA, van Lunsen RHW, Palacios S, Norman RJ, Mulder RJ, Davis SR for the LISA study investigators. Tibolone and transdermal E2/NETA for the treatment of Female Sexual Dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J Sex Med 2008;5:646-56.
  6. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J, Kerzberg EM, Johnson S, Zanchetta J, Grobbee D, Seifert W, Eastell R, for the LIFT Trial Investigators. The Effects of Tibolone in Older Postmenopausal Women. NEJM 2008;359:21-32.
  7. Opatrny L, Dell’ Aniello S, Assouline S, Suissa S. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 2008;115:169-175.
  8. Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz, B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M, Mulder R, van Os S, Beckmann MW, on behalf of the LIBERATE Study Group. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised non-inferiority trial. Lancet Oncol 2009;10:135-46.

Are there specific subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value?

The International Tibolone Consensus Group looked into this question and identified the following groups: group 1: postmenopausal women with vasomotor symptoms in whom tibolone might have added value, include women with low sex drive or so-called female sexual dysfunction; women with mood disorders; women at risk of accelerated bone loss; women with premenopausal breast tenderness; women with high breast density; and women with fibroids. group 2. Women who might benefit from a switch from conventional HT to tibolone. These women include: women with increase in breast pain or mastalgia on HT, women with an increase in breast density, causing false recalls and unreadable mammograms; women with low sex drive or mood disorders; women with bleeding problems (providing no histopathological reason exists for bleeding). In addition to postmenopausal women with a natural menopause, for younger women with a premature menopause and in women receiving long-term GnRH agonists for endometriosis, the use of tibolone should also be considered.

What are the contra-indications for tibolone use?

The contra-indications for tibolone use should be considered to be the same as those for conventional combined hormone therapy.

Are the results of the LIBERATE Study also relevant for healthy postmenopausal women using tibolone for relief of climacteric symptoms?

The LIBERATE data obtained in breast cancer patients without evidence of disease, but suffering from moderate to severe vasomotor symptoms, caused by their adjuvant treatment for breast cancer, have no relevance for normal women. The population of the LIBERATE study consists of breast cancer patients who have been surgically treated for breast cancer. Primary endpoint of the study is recurrence of breast cancer or newly detected breast cancer in the contra lateral breast. The LIBERATE population differs is various aspects considerably from the normal postmenopausal apparently healthy population. Breast cancer patients have a different risk profile on basis of their different genetic makeup, and/or different hormonal environmental risk factors. Risk for a second breast cancer in the contra lateral breast in this group is 2 to 4 times higher than in a normal population. Breast cancer survivors have a high incidence of occult cancer deposits, so-called dormant metastasis, on which tibolone may act. The effect of tibolone on healthy breast tissue most probably differs from its effect on cancer cells. Moreover, over 80% of breast cancer patients included in the LIBERATE trial used tamoxifen or aromatase inhibitors. Exposure to these drugs that influence the hormonal status of the patient (and in case of tamoxifen also competes also for the estrogen receptor), renders their situation totally different from the situation in normal postmenopausal women.

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