■ ORIGINAL ARTICLETibolone ■ Compliance and Efficacy in Women Living in Taiwan

NEW SELECTIVE ESTROGENIC ACTIVITY REGULATOR (STEAR) IN MENOPAUSAL THERAPY IN TAIWAN

Kuan-Chong Chao*, Peng-Hui Wang, Ming-Shyen Yen, Ching-Ying Chang, Chin-Mu Juang, Nae-Fan Twu, Hwa-Shi Wu Department of Gynecology and Obstetrics, Taipei Veterans General Hospital and National Yang-Ming University School of , Taipei, Taiwan.

SUMMARY Objective: The compliance of women living in Taiwan with the selective tissue estrogenic activity regulator (STEAR) has seldom been reported. The purpose of this study was to evaluate the short-term compliance of perimenopausal women living in Taiwan in taking tibolone, and the efficacy of the drug. Materials and Methods: A total of 289 perimenopausal women who had experienced mild to severe climacteric symptoms were enrolled in this study. Every woman was evaluated before (baseline), during (end of the third month), and after therapy (end of the sixth month) with 2.5 mg tibolone daily. Efficacy was assessed from improvement in climacteric symptoms and compliance was also assessed. Results: A total of 275 women were still on tibolone treatment by the end of the study, revealing a high rate (95.2%) of retention. tenderness was significantly reduced, from 26.5% to 2.8%. The reported rate of insomnia was 50.5% at baseline, and had been reduced to 20.4% by the end of the study. Bleeding episodes dropped from 87.4% at baseline to 39.4% at the end of the study. The rate of mood instability was significantly reduced, from 84.1% at baseline to 44.3% at the end of the study. improved from 15.9% at baseline to 61.6% at the end of the study, a unique benefit of tibolone due to the androgenic effect of its b-isomer. Most women (84.1%) had an increase in body weight ranging from 0.5 to 3 kg. Fourteen subjects dropped out for the following reasons: three women had acne and/or allergic reaction, four had a significant increase in body weight and/or water retention, one had , and the other six dropped out for personal reasons. Conclusion: Tibolone can improve the climacteric symptoms of perimenopausal women living in Taiwan. With the exception of increased body weight, no major side-effect was noted during this short-term study. [Taiwanese J Obstet Gynecol 2005;44(4):327–331]

Key Words: climacteric symptoms, menopausal treatment, STEAR, selective tissue estrogenic activity regulator, tibolone

Introduction toms and the prevention of osteoporosis in postmeno- pausal women [1]. Although it is frequently described Tibolone is a new treatment with a unique pharmaco- as a (HT) product, recent research logic profile licensed for the relief of climacteric symp- provides a clearer insight into the mechanism of action of tibolone, which is significantly different from those of conventional HT, such as with or without *Correspondence to: Dr. Kuan-Chong Chao, Department of progestin [2]. Therefore, the clinical profile has led to its Obstetrics and Gynecology, Taipei Veterans General Hospital, classification as a selective tissue estrogenic activity 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. regulator (STEAR) [1]. Tibolone is a synthetic E-mail: [email protected] with tissue-selective estrogenic, progestogenic, and Received: April 1, 2005 Revised: April 4, 2005 androgenic properties. It is metabolized into three main Accepted: April 28, 2005 : the b-4 isomer, and the 3-_ and 3-` hydroxy

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metabolites. Each has different binding to safety profile increases the acceptability of tibolone the estrogenic, progestogenic, and androgenic receptors treatment and improves short- and long-term adher- [3]. The 3-_ and 3-` hydroxy metabolites exert estro- ence to treatment [17]. However, these studies do not genic activity, but in a tissue-selective manner [3–12]. provide data about women living in Taiwan. There- The b-4 isomer shows both androgenic and pro- fore, it is reasonable to evaluate the compliance with gestogenic effects [2], which avoids stimulation of the and efficacy of tibolone in symptomatic perimenopau- [1,11]. Tibolone is easy to use: only a sal women in Taiwan. single containing 2.5 mg tibolone is needed each day [8]. Climacteric symptoms sometimes bother peri- Methods menopausal women, resulting in severe interference in their quality of life, and HT is an effective method of re- Before initiation of the study, approval was granted by lieving most climacteric symptoms. However, concerns the independent ethics committee and institutional have arisen regarding the possible association between review board of the hospital. Women with a natural or and HT. The largest meta-analysis to surgically induced who visited the hospital date, which included more than 90% of the literature between September 2003 and June 2004 due to [13], concluded that HT increases the risk of developing climacteric complaints were recruited into the study, breast carcinoma and that this risk increases with the whether they had received other HT or not. Once re- increasing duration of HT use. Once HT is stopped, this cruited, the case report form was immediately used to risk decreases, and it largely disappears by 5 years after record baseline data, including basic demographic data, cessation. Recent findings from the Women’s Health and the patient was scheduled for follow-up at the end Initiative study show an increased incidence of invasive of the third and sixth months of therapy with 2.5 mg breast cancer during HT [14]. Although menopause is tibolone daily. The case report form was used to record a natural event in women, some women suffer from whether breast tenderness, insomnia, libido changes, symptoms that significantly affect their lives. Al- mood swings, or bleeding episodes occurred during the though circulating levels of estrogen are reduced in study period. Weight was measured at the first visit and postmenopausal women, the breast tissue of post- at the end of the sixth month for comparison. menopausal women is able to synthesize locally, which explains why the risk of breast cancers is not minimized after menopause. In fact, is Results the main factor supporting the growth and evolution of breast cancers. One pathway involved in the A total of 289 women in natural or surgical perimeno- transformation of estradiol is the sulfatase pathway, pause were recruited into this study. Of these, 275 which transforms sulfate to estradiol [9], were still taking tibolone at the end of the study, which especially after menopause. Tibolone and its metabolites demonstrated a high retention rate (95.2%) (Figure 1). are very potent inhibitors of the conversion of estrone The rate of breast tenderness was significantly reduced sulfate to estradiol in the hormone-dependent breast from 26.5% at baseline to 2.8% at the end of the study. cancer cell [9,10]. Tibolone metabolites regulate the activity of local enzymes normally involved in the production of active estrogens in the breast [12]. 100 Tibolone has a different effect from conventional HT in 90 Baseline 80 Month 3 the breast. It does not seem to stimulate breast tissue Month 6 and might have an inhibitory effect on the growth of 70 human breast tumor cells , and animal breast 60 tumors [12], in addition to slowing down the 50 40 proliferation rate and increasing differentiation and Patients (%) 30 apoptosis [9]. In addition to the possibility of no 20 increased risk of breast cancer, tibolone rarely causes 10 breast tenderness and does not increase breast density 0 [3,15]. Tibolone reportedly has a favorable tolerability Breast Insomnia Less Mood Libido tenderness bleeding improvement profile [16]. Only a minority of women treated with tibolone experience , and the bleeding Figure 1. Symptoms and signs at baseline and at the end of 3 is mild and transient [4]. The advantageous tolerability/ and 6 months of tibolone treatment (n = 275).

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The rate of insomnia decreased from 50.5% at baseline [16]. In addition, tibolone shows beneficial effects on to 20.4% at the end of the study, and bleeding episodes mood and sexual wellbeing [5–7,17]. The results of this decreased from 87.4% at baseline to 39.4% at the end of study demonstrate a similar positive effect in improving the study. The rate of mood instability was significantly insomnia, libido, and mood instability and, of most reduced, from 84.1% at baseline to 44.3% at the end importance, there was a high rate of continuous use of the study. Libido (sexual satisfaction) significantly of tibolone. Moreover, a low dose (1.25 mg/day) also improved from 15.9% at baseline to 61.6% at the end seemed to be effective. In this observational study, seven of the study, which is a unique profile of tibolone due women were satisfied with this low-dose treatment, to the androgenic effect of its b-isomer. Thirty women which is in agreement with a previous report showing (10.4%) had improved vaginal dryness. Ten women that tibolone induced a decrease in the frequency and (3.5%) developed an allergic reaction, three of whom intensity of climacteric symptoms, leading to statistic- dropped out of the study. One woman (0.3%) had ally significant differences compared to placebo, at breast tenderness and three (1%) complained of gastro- doses of 1.25 mg and higher [18]. intestinal disturbance. Three women (1%) had an attack Concerning irregular vaginal spotting and/or possi- of acne during therapy. Body weight changes in the ble unwanted pathologic changes to the endometrium, women varied; most women (84.1%) had a weight tibolone therapy is reported to have high rates of increase ranging from 0.5 to 3 kg (Figure 2). Fourteen after 10 years, with minimal evidence of subjects dropped out for the following reasons: three adverse effects on endometrial pathology [19]. In this for acne and/or an allergic reaction; four for intolerable study, we found that irregular bleeding episodes were weight gain and/or water retention; one due to head- markedly decreased both during and at the end of ache and dizziness; and six for other personal reasons. treatment. During the 6-month evaluation period, seven women In terms of biochemical changes in the , (2.4%) had been prescribed a half dose (1.25 mg) for tibolone is reported to lower lipoprotein(a), fibrinogen, personal reasons. No severe adverse events were re- and plasminogen activator inhibitor-1 levels and to ported during the observation period. improve glucose tolerance, insulin sensitivity, and endothelial function. However, it also lowers high- density lipoprotein cholesterol by more than 20% [20]. Discussion Therefore, the long-term impact of tibolone on the risk of coronary heart disease is not known and needs to be Numerous clinical studies have shown that tibolone has studied [20]. We did not evaluate changes in blood beneficial effects in relation to climacteric symptoms biochemistry. However, significantly increased body and vaginal in postmenopausal women; relief weight was noted in this study, in disagreement with a from climacteric symptoms develops within 3–5 weeks, previous report showing that tibolone is not associated and the maximum effect is usually seen by 3 months with weight gain [15]. Due to the short-term follow-up,

40 35 30 25 20

Patients (%) 15 10 5 0

–10 * > 10 0.00~0.99 1.00~1.99 2.00~2.99 3.00~3.994.00~4.99 5.00~5.996.00~6.99 –7.99~–7.00–5.99~–5.00–4.99~–4.00–3.99~–3.00–0.99~–0.01 Weight change (kg)

Figure 2. Weight change from baseline to the end of 6 months of tibolone treatment (n = 275).

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we do not know the long-term effects of the increased be re-evaluated in a future study. Fourthly, this is a de- body weight on these women taking tibolone, but we scriptive study, and we did not use scientific statistics are highly concerned about these changes. We believe, to analyze the data. therefore, that changes in body weight should be further This study shows the efficacy of tibolone in insom- studied and evaluated. nia, mood, and libido improvement, as well as its good Tibolone, compared with conventional HT such as tolerability (less breast tenderness and fewer bleeding estrogen with or without , seems to be a episodes) in postmenopausal women. relatively safe in terms of the risk of breast cancer. The Million Women Study shows that the incidence of breast cancer is significantly increased in References current users of preparations containing estrogen only (adjusted relative risk, 1.30 [95% confidence interval, 1. Kloosterboer HJ, Ederveen AGH. Pros and cons of existing 1.21–1.40]; p < 0.0001), estrogen/progestogen (2.00 treatment modalities in osteoporosis: a comparison between [1.88–2.12]; p < 0.0001), and tibolone (1.45 [1.25– tibolone, SERMs and estrogen (± progestogene) treatments. 1.68]; p < 0.0001), but the magnitude of the associated J Steroid Biochem Mol Biol 2003;83:157–65. 2. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific risk was substantially greater for estrogen/progestogen mode of action. J Steroid Biochem Mol Biol 2001;76:231–8. than for other types of HT (p < 0.0001) [21–23]. An 3. Bruce D, Robinson J, McWilliams S, Reddy M, Rymer J. Long- increase in mammographic density should be regarded term effects of tibolone on mammographic density. Fertil as an unwanted side effect of HT [15]. In contrast to Steril 2004;82:1343–7. estrogen/progestogen treatment, tibolone seems to have 4. Berning B, Bennink HJ, Fauser BC. Tibolone and its effects on little stimulating effect on breast tissue [15]. A recently bone. Climacteric 2001;4:120–36. published paper on the long-term effects of tibolone on 5. Laan E, van Lunsen RH, Everaerd W. The effects of tibolone mammographic density elaborates tibolone’s unique on vaginal blood flow, sexual desire and arousability in post- menopausal women. Climacteric 2001;4:28–41. effects on the breast, and suggests that tibolone seems 6. Nathorst-Boos J, Hammar M. Effect on sexual life—a com- to have a minimal effect on mammographic density [3]. parison between tibolone and a continuous estradiol- All of the above suggest that tibolone has an advantage acetate regimen. Maturitas 1997;26:15–20. over conventional HT in terms of breast cancer risk. 7. Castelo-Branco C, Vicente JJ, Figueras F, et al. Comparative is often used as adjuvant therapy and/or effects of estrogens plus and tibolone on bone, preventive therapy for breast cancer. Unfortunately, lipid pattern and sexuality in postmenopausal women. many women with breast cancer suffer vasomotor Maturitas 2000;34:161–8. symptoms rather than risk recurrence with conventional 8. Rymer J, Robinson J, Fogelman I. Ten years of treatment with tibolone 2.5 mg daily: effects on bone loss in postmenopausal HT. In a small randomized controlled trial in women women. Climacteric 2002;5:390–8. with early breast cancer undergoing adjuvant tamoxi- 9. Chetrite G., Kloosterboer HJ, Pasqualini JR. Effect of tibolone fen treatment, tibolone reduced hot flushes and night (Org OD14) and its metabolites on estrone sulphatase activity sweats and improved quality of life compared with in MCF-7 and T-47D mammary cancer cells. Anticancer Res placebo [24]. Moreover, tibolone prevents the increase 1997;17:135–40. in hot flushes in postmenopausal women given tamoxi- 10. Gompel A, Siromachkova M, Lombet A, Kloosterboer HJ, fen following surgery for breast cancer without unto- Rostene W. Tibolone actions on normal and breast cancer ward effects on the endometrium [25]. cells. Eur J Cancer 2000;36:S76–7. 11. Volker W, Coelingh Bennink HJ, Helmond FA. Effects of Tibolone prevents bone loss and increases bone tibolone on the endometrium. Climacteric 2001;4:203–8. mineral density in early and late postmenopausal women 12. Kloosterboer HJ, Schoonen WG, Deckers GH, Klijn JG. Effects [4,8,26]. Since we did not evaluate bone mineral density of progestagens and Org OD14 in in vitro and tumor during or at the end of tibolone treatment, we do not models. J Steroid Biochem Mol Biol 1994;49:311–8. know the changes in bone mineral density in this short- 13. Breast cancer and hormone replacement therapy: collabo- term evaluation. rative reanalysis of data from 51 epidemiological studies of Some limitations of this study should be clarified. 52,705 women with breast cancer and 108,411 women First, this is a relatively small study population, which without breast cancer. Collaborative Group on Hormonal may not provide strong evidence showing the true Factors in Breast Cancer. Lancet 1997;350:1047–59. 14. Writing Group for the Women’s Health Initiative Investigators. benefits of tibolone. Secondly, prescription behavior Risks and benefits of estrogen plus progestin in healthy was not clearly identified within the scope of the postmenopausal women. JAMA 2002;288:321–33. measurement. Thirdly, increased body weight seems to 15. Lundstrom E, Christow A, Kersemaekers W, et al. Effects of be the major unwanted effect in this trial, and because tibolone and continuous combined hormone replacement of the small sample and dropouts, this issue should therapy on mammographic breast density. Am J Obstet Gynecol

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2002;186:717–22. clinical implications. Treat Endocrinol 2004;3:105–15. 16. Moore RA. Livial: a review of clinical studies. Br J Obstet 21. Beral V; Million Women Study Collaborators. Breast cancer Gynaecol 1999;106(Suppl 19):1–21. and hormone-replacement therapy in the Million Women 17. Gulseren L, Kalafat D, Mandaci H, Gulseren S, Camli L. Study. Lancet 2003;362:419–27. Erratum in: Lancet 2003; Effects of tibolone on the quality of life, anxiety-depression 362:1160. levels and cognitive functions in natural menopause: an 22. Speroff L. The Million Women Study and breast cancer. observational follow-up study. Aust NZ J Obstet Gynaecol 2005; Maturitas 2003;46:1–6. 45:71–3. 23. Crosignani PG. Breast cancer and hormone-replacement 18. Landgren MB, Helmond FA, Engelen S. Tibolone relieves therapy in the Million Women Study. Maturitas 2003;46: climacteric symptoms in highly symptomatic women with at 91–2. least seven hot flushes and sweats per day. Maturitas 2005; 24. Bundred NJ, Turner LE. Postmenopausal hormone therapy 50:222–30. before and after breast cancer: clinical experiences. Maturitas 19. Bruce D, Robinson J, Rymer J. Long-term effects of tibolone 2004;49:S22–31. on the endometrium as assessed by bleeding episodes, 25. Kroiss R, Fentiman IS, Helmond FA, et al. The effect of transvaginal scan and endometrial biopsy. Climacteric 2004; tibolone in postmenopausal women receiving tamoxifen after 7:261–6. surgery for breast cancer: a randomised, double-blind, 20. Vogelvang TE, van der Mooren MJ, Mijatovic V. Hormone placebo-controlled trial. BJOG 2005;112:228–33. replacement therapy, selective modulators, 26. Devogelaer JP. A review of the effects of tibolone on the and tissue-specific compounds: cardiovascular effects and skeleton. Expert Opin Pharmacother 2004;5:941–9.

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