- Email: [email protected]
progestogen
M EN OPA U S E
Tibolone reduced menopausal symptoms with less bleeding compared to continuous estrogen/progestogen Hammar M, Christau S, Nathorst-BoK oK s J, Rud T, Garre K. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynecol 1998; 105: 904d911
OBJECTIVE To compare tibolone with continuous combined estrogen/progestogen (17b-estradiol/norethisterone acetate) for the treatment of menopausal symptoms. DESIGN Multicenter, randomized, double-blind, placebo trial. Allocation was by sealed envelopes.
double-
SETTING 44 centers in Denmark, Norway and Sweden. SUBJECTS 437 healthy, non-obese, postmenopausal women with an intact uterus, who complained of menopausal symptoms. Mean age was 55 years. 72% of women completed the study. INTERVENTION 218 women were randomized to receive oral tibolone 2.5 mg daily, and 219 to receive oral 17b-estradiol 2 mg plus norethisterone acetate 1 mg (E2 /NETA) daily, for 48 weeks, plus placebo tablets matching the alternate treatment. MAIN OUTCOME MEASURES Menopausal symptoms scored in severity from 1 (none) to 5 (very severe), vaginal bleeding, assessed at 4, 12, 24 and 48 weeks. MAIN RESULTS At baseline, the mean severity score was 3.1 for hot flushes and sweating episodes, and 2.1 for vaginal dryness, with a significant decrease in severity of all symptoms at each time point, with both treatments. The mean severity of hot flushes was significantly lower in the E2 /NETA group than in the tibolone group at all time points (e.g., at 12 weeks the mean improvement
Commentary Tibolone is a promising new therapeutic agent with efficacy in relieving clinical symptoms of estrogen deficiency, such as hot flushes, sweating episodes and vaginal dryness. This study showed that tibolone (2.5 mg) was comparable to E2/NETA reducing these clinical menopausal symptoms, with a lower incidence of bleeding episodes during the first 6 months, but no difference in bleeding after 6 months. Although the discontinuation rate due to bleeding was lower for tibolone, the overall discontinuation rate of both preparations was high, and the discontinuation rate for other side-effects was similar. The major reason compliance is an issue with regard to menopausal hormonal replacement therapy (HRT) is the associated long-term prevention of osteoporosis and possibly cardiovascular disease. Tibolone (2.5 mg) has been shown in another study to have effects comparable to hormone replacement with oral or transdermal estradiol plus dydrogesterone on bone densitometry of the lumbar spine, upper femur and whole body over a 2 year period.1 However, the effect of tibolone on serum lipids is not as beneficial as conventional HRT regimens. Both tibolone and E2 /NETA reduce high-density lipoprotein (HDL), tibolone reduces plasma triglycerides, whereas only E2 /NETA reduces low-density lipoprotein (LDL).2 When comparing the effects of tibolone on the lipid profile with those of HRT, perhaps it is more appropriate to compare it with estradiol plus micronized progesterone, a progestogen without androgenic activity. In the PEPI trial, treatment with conjugated equine estrogens and micronized progesterone resulted in an increase in HDL levels and a reduction in LDL levels compared to placebo.3 Thus,
96
Evidence-based Obstetrics and Gynecology (1999) 1, 96
was 88%* and 70%*, respectively, p(0.001), but there was no difference between the groups in improvement of sweating (70–80%* improvement from 12 weeks onward) or vaginal dryness (73%* improvement). Vaginal bleeding occurred in 34% of women on tibolone and in 58% of those on E2 /NETA ( p(0.0001). The proportion of women with bleeding was significantly higher in the E2 /NETA group for each of the first 6 months; however, after 6 months, there was no difference. In the tibolone group, 80% of women achieved amenorrhea after the first month, and 90% after the third month, but it took 7 months for 90% of the E2 /NETA group to achieve amenorrhea. 25% of women in the tibolone group withdrew before completion of the study, 2% because of unacceptable bleeding and 14% because of other side effects, compared to 31% in the E2 /NETA group, 13% because of bleeding and 12% because of other side effects ( p"0.14 overall, p(0.0001 due to bleeding). More women on E2 /NETA complained of breast tenderness. CONCLUSION Both tibolone and estrogen/progestogen were effective in reducing menopausal symptoms, although the latter was more effective in reducing hot flushes. With tibolone, fewer women had vaginal bleeding and fewer women discontinued treatment due to unacceptable bleeding. * Numbers calculated from data in article.
neither tibolone nor E2 /NETA is an optimal regimen, with respect to effects on cholesterol metabolism and the lipid profile. How does this information translate into clinical practice? Clearly, in the woman with severe menopausal symptoms who is bothered by unscheduled episodes of uterine bleeding, tibolone is a useful addition to the pharmacologic choices, because it is effective in relieving menopausal symptoms and is less likely to cause troublesome irregular bleeding or spotting. As for osteoporosis, the data appear favorable with regard to maintenance of bone density, but data on fracture reduction are not available. Long-term data on the cardioprotective effects do not exist; however, in women who are at high risk for cardiovascular disease, a regimen with a better overall effect on the lipid profile is advised. Esther Eisenberg, MD Vanderbilt University School of Medicine, Nashville TN, USA
Other sources 1. Lippuner K, Hanggi W, Birkhaeuser MH, et al. Prevention of postmenopausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17 beta-estradiol and dydrogesterone. J Bone Mineral Res 1997; 22: 806-812 2. Hanggi W, Lippuner K, Reisen 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: 708d717 3. The Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273: 199d208
^ 1999 Harcourt Publishers Ltd
Tibolone reduced menopausal symptoms with less bleeding compared to continuous estrogen/progestogen Hammar M, Christau S, Nathorst-BoK oK s J, Rud T, Garre K. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynecol 1998; 105: 904d911
OBJECTIVE To compare tibolone with continuous combined estrogen/progestogen (17b-estradiol/norethisterone acetate) for the treatment of menopausal symptoms. DESIGN Multicenter, randomized, double-blind, placebo trial. Allocation was by sealed envelopes.
double-
SETTING 44 centers in Denmark, Norway and Sweden. SUBJECTS 437 healthy, non-obese, postmenopausal women with an intact uterus, who complained of menopausal symptoms. Mean age was 55 years. 72% of women completed the study. INTERVENTION 218 women were randomized to receive oral tibolone 2.5 mg daily, and 219 to receive oral 17b-estradiol 2 mg plus norethisterone acetate 1 mg (E2 /NETA) daily, for 48 weeks, plus placebo tablets matching the alternate treatment. MAIN OUTCOME MEASURES Menopausal symptoms scored in severity from 1 (none) to 5 (very severe), vaginal bleeding, assessed at 4, 12, 24 and 48 weeks. MAIN RESULTS At baseline, the mean severity score was 3.1 for hot flushes and sweating episodes, and 2.1 for vaginal dryness, with a significant decrease in severity of all symptoms at each time point, with both treatments. The mean severity of hot flushes was significantly lower in the E2 /NETA group than in the tibolone group at all time points (e.g., at 12 weeks the mean improvement
Commentary Tibolone is a promising new therapeutic agent with efficacy in relieving clinical symptoms of estrogen deficiency, such as hot flushes, sweating episodes and vaginal dryness. This study showed that tibolone (2.5 mg) was comparable to E2/NETA reducing these clinical menopausal symptoms, with a lower incidence of bleeding episodes during the first 6 months, but no difference in bleeding after 6 months. Although the discontinuation rate due to bleeding was lower for tibolone, the overall discontinuation rate of both preparations was high, and the discontinuation rate for other side-effects was similar. The major reason compliance is an issue with regard to menopausal hormonal replacement therapy (HRT) is the associated long-term prevention of osteoporosis and possibly cardiovascular disease. Tibolone (2.5 mg) has been shown in another study to have effects comparable to hormone replacement with oral or transdermal estradiol plus dydrogesterone on bone densitometry of the lumbar spine, upper femur and whole body over a 2 year period.1 However, the effect of tibolone on serum lipids is not as beneficial as conventional HRT regimens. Both tibolone and E2 /NETA reduce high-density lipoprotein (HDL), tibolone reduces plasma triglycerides, whereas only E2 /NETA reduces low-density lipoprotein (LDL).2 When comparing the effects of tibolone on the lipid profile with those of HRT, perhaps it is more appropriate to compare it with estradiol plus micronized progesterone, a progestogen without androgenic activity. In the PEPI trial, treatment with conjugated equine estrogens and micronized progesterone resulted in an increase in HDL levels and a reduction in LDL levels compared to placebo.3 Thus,
96
Evidence-based Obstetrics and Gynecology (1999) 1, 96
was 88%* and 70%*, respectively, p(0.001), but there was no difference between the groups in improvement of sweating (70–80%* improvement from 12 weeks onward) or vaginal dryness (73%* improvement). Vaginal bleeding occurred in 34% of women on tibolone and in 58% of those on E2 /NETA ( p(0.0001). The proportion of women with bleeding was significantly higher in the E2 /NETA group for each of the first 6 months; however, after 6 months, there was no difference. In the tibolone group, 80% of women achieved amenorrhea after the first month, and 90% after the third month, but it took 7 months for 90% of the E2 /NETA group to achieve amenorrhea. 25% of women in the tibolone group withdrew before completion of the study, 2% because of unacceptable bleeding and 14% because of other side effects, compared to 31% in the E2 /NETA group, 13% because of bleeding and 12% because of other side effects ( p"0.14 overall, p(0.0001 due to bleeding). More women on E2 /NETA complained of breast tenderness. CONCLUSION Both tibolone and estrogen/progestogen were effective in reducing menopausal symptoms, although the latter was more effective in reducing hot flushes. With tibolone, fewer women had vaginal bleeding and fewer women discontinued treatment due to unacceptable bleeding. * Numbers calculated from data in article.
neither tibolone nor E2 /NETA is an optimal regimen, with respect to effects on cholesterol metabolism and the lipid profile. How does this information translate into clinical practice? Clearly, in the woman with severe menopausal symptoms who is bothered by unscheduled episodes of uterine bleeding, tibolone is a useful addition to the pharmacologic choices, because it is effective in relieving menopausal symptoms and is less likely to cause troublesome irregular bleeding or spotting. As for osteoporosis, the data appear favorable with regard to maintenance of bone density, but data on fracture reduction are not available. Long-term data on the cardioprotective effects do not exist; however, in women who are at high risk for cardiovascular disease, a regimen with a better overall effect on the lipid profile is advised. Esther Eisenberg, MD Vanderbilt University School of Medicine, Nashville TN, USA
Other sources 1. Lippuner K, Hanggi W, Birkhaeuser MH, et al. Prevention of postmenopausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17 beta-estradiol and dydrogesterone. J Bone Mineral Res 1997; 22: 806-812 2. Hanggi W, Lippuner K, Reisen 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: 708d717 3. The Writing Group for the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273: 199d208
^ 1999 Harcourt Publishers Ltd