The effect of tibolone versus 17␤-estradiol on climacteric symptoms in women with surgical menopause: A. Somunkiran , C.T. Erel , F. Demirci , M.L. Senturk a Abant Izzet Baysal University, Duzce Medical School, Department of Obstetrics and Gynecology, b Istanbul University, Cerrahpasa Medical School, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Turkey Received 19 December 2005; received in revised form 25 May 2006; accepted 4 June 2006 Abstract
Objective: To compare the effectiveness of tibolone and 17␤-estradiol on climacteric symptoms, in a randomized, single-blind,cross-over study in surgically menopausal women.
Material and methods: Forty surgically menopausal women were divided randomly into two groups. Group A received treatmentwith tibolone for 6 months, while group B received 17␤-estradiol. After 3 weeks washout period, treatment protocols wereexchanged for another 6 months. The climacteric symptoms were assessed with Greene Climacteric Scale at baseline, duringwashout and after the treatments. Statistical analysis was done with the Wilcoxon’s Sign Rank test.
Results: Both treatments significantly improved the scores of all subscales with respect to baseline. However, the improvementin psychological, somatic and sexual subscales were significantly superior in the tibolone group compared with 17␤-estradiolgroup. Both treatments showed comparable improvements in the relief of vasomotor symptoms.
Conclusion: Our findings suggest that tibolone may improve mood, libido and somatic symptoms in surgically menopausalwomen to a greater extent than estrogen therapy alone.
2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Surgical menopause; Tibolone; 17␤-Estradiol; Greene Climacteric Scale 1. Introduction
flushes, sweating, changes in mood and libido are someimportant outcomes affecting the quality of life (QoL) The decline in circulating estrogen levels in the during climacterium in women. Quality of life covers perimenopause results in climacteric symptoms. Hot physical, functional, emotional, social and cognitivevariables menopause-associated symptoms can impair these major aspects of QoL for many women.
Corresponding author. Tel.: +90 532 6346799; After the results of The Women’s Health Initiative E-mail address: (A. Somunkiran).
(WHI) study, to improve the quality of life in women 0378-5122/$ – see front matter 2006 Elsevier Ireland Ltd. All rights reserved.
A. Somunkiran et al. / Maturitas 56 (2007) 61–68 during the menopausal transition period is the main The climacteric scale constructed by Greene, is indication for estrogen plus progestin based hormone based on factor analysis studies This scale inde- therapy (HT) Another issue is the quality of life pendently measures psychological, somatic, vasomotor in women undergoing surgical menopause. Since and sexual symptoms and is used as a quality of life the circulating sex steroids abruptly decrease, the measurement in estrogen replacement trials climacteric symptoms are more severe and disturb- and in a population-based study to obtain normative ing in women undergoing bilateral oophorectomy.
data for climacteric symptoms A recently pub- Estrogen replacement therapy (ERT) improves the lished study by Lam et al. investigated the effect of complaints and in turn, quality of life. But ERT arm of tibolone on menopause symptoms, psychological well- the WHI study was terminated prior to the scheduled being and dyadic relationships. In this randomized close-out interval, because of increased risk of stroke, placebo-controlled crossover study the menopausal and the likelihood that neither cardioprotection nor symptoms were assessed by Greene Climacteric Scale breast cancer risk would be demonstrated in the remaining intervention period s a result hormone In the present study, we conducted a randomized therapies, estrogen plus progestin or estrogen alone, cross-over trial to compare the effects of tibolone and are appropriate for the relief of vasomotor symptoms, 17␤-estradiol on climacteric symptoms, in women with and primarily recommended for the prevention of surgical menopause, with a standardized scale.
menopausal symptoms for the shortest possibletime. The effects of alternatives to HRT, such astibolone, phytoestrogens or SERMs, need to be 2. Material and methods
Tibolone is a tissue specific compound, struc- A randomized, controlled, cross-over trial was con- turally related to 19-nortestosterone derivatives, which ducted at Department of Obstetrics and Gynecology, exhibits weak estrogenic, progestagenic and andro- Duzce School of Medicine to compare the effects of genic activities In a number of studies, it has tibolone and 17␤-estradiol in climacteric symptoms been shown that tibolone provided relief of vasomotor in women with surgical menopause. The study pro- symptoms without stimulating endometrium and breast tocol was approved by the Medical Ethics Committee tissue The success of this relatively new com- of Duzce Medical School and conformed to the ethical pound, tibolone, in treating climacteric symptoms after guidelines of the 1975 Helsinki Declaration. Informed natural/surgical menopause, has not been addressed written consent was obtained from each woman before by well-designed studies. Albertazzi et al. reviewed the studies in which tibolone was used for climac-teric symptoms. According to them the problems with study designs were; the randomized double blind stud-ies were not cross-over, in the cross-over studies there Forty women who had been subjected to hysterec- were no washout periods, and measurement of symp- tomy and bilateral oophorectomy for benign gyneco- logical conditions in our clinic were enrolled to the The effect of tibolone versus estrogen on climac- study. All of the patients were in the perimenopausal teric symptoms in women with surgical menopause was period before the operation and none of them had been the subject of two previous studies but both of treated with hormones for their climacteric complaints them used the Blatt–Kupperman Indices to measure cli- before the operation. The initial screening included macteric symptoms/complaints. The Blatt–Kupperman medical history, physical and gynecological exami- Index has severe limitations such as; the symptoms are nation, measurement of systolic and diastolic arterial highly selected, the scales have no psychometric prop- blood pressures, height and weight and a mammogra- erties and they are derived from biased samples. It is phy if not performed during the previous 12 months.
argued that this index should be replaced by standard- Complete blood count, urine analysis and blood bio- ized scales that have reported properties of reliability chemistry were done. All analysis was found to be in the normal range. Any women who had hypertensive A. Somunkiran et al. / Maturitas 56 (2007) 61–68 disorders (systolic BP > 170 mmHg and/or diastolic teric symptoms. GCS was performed at baseline, after BP > 105 mmHg), active liver disease, cerebrovascular the washout and after the treatments. A different author or thromboembolic disorders, diabetes mellitus, thy- (AS), blind to the type of treatment, was responsible for roid disorders, any malignancies and chronic disease which may affect the quality of life, were excludedfrom the study.
The Greene Climacteric Scale measures a total of 21 symptoms. Each symptom is rated by the woman Cross-over study design was used to define whether herself according to its severity using a four-point the treatment with tibolone was effective, with respect rating scale: (0, not-at-all; 1, a little; 2, quite a bit; to estrogen for each woman. Patients were randomly 3, extremely). Symptoms 1–11 address psychological allocated into two groups, group A or group B, accord- symptoms divided in a measure of anxiety (a sum of ing to a computer-generated list of random num- symptoms 1–6) and of depression (a sum of symptoms ber groups, and were followed for 1 year 7–11). Somatic aspects are addressed in symptoms The time interval between the surgery and the study 12–18 and vasomotor symptoms in symptom 19 and was 3 weeks. Patients assigned to group A received 20. Symptom 21 is a probe for sexual dysfunction.
tibolone 2.5 mg/day (Livial®, NV Organon, Holland) The total Greene climacteric score is the sum of all for the first 6 months of study, and for the remain- ing 6 months they received 17␤-estradiol (Estrofem®,Novo-Nordisk, Denmark) 2 mg/day. Patients allocated to group B received 17␤-estradiol 2 mg/day for the firsthalf of the study, and tibolone 2.5 mg/day for latter The mean score of each symptom is calculated by half of the study. There was a 3-week washout period the sum of all individual scores divided by the number between treatments. One author (FD) was responsible of subjects. The score of the clusters are given as the for the randomization and the same author also assessed sum of the mean scores of the symptoms within that the subjects’ compliance to the study medication by checking the empty boxes, and counting the unused For comparisons between baseline, tibolone and drugs. A patient was considered non-compliant if, on 17␤-estradiol the non-parametric Wilcoxon Sign Rank at least 4 days within a period (28 days) no tablets were Test was used. Results were analyzed using the SPSS for Windows statistical package (SPSS/PC software, The Greene Climacteric Scale (GCS) questionnaire Chicago, IL). p-Value of <0.05 was accepted as statis- was used to detect the efficacy of treatments on climac- 3. Results
After randomization 20 patients were assigned to group A and 20 to group B. There were no significantdifferences in the baseline demographic and clinicalcharacteristics between the two groups ( ws the mean scores of the 21 items of the Greene Climacteric Scale at baseline, and the changesof the scores from baseline according to the treatment,and the efficacy of tibolone and 17␤-estradiol. Dataindicate that, both 17␤-estradiol and tibolone signif-icantly improved palpitations, nervousness, sleeping Fig. 1. Design of the study; GCS: Greene Climacteric Scale.
disorders, excitability, concentration, tiredness, loss of A. Somunkiran et al. / Maturitas 56 (2007) 61–68 Table 1Basal characteristics of the patients a Data are presented as mean and S.D.
b NS, Non-statistically significant.
interest in most things, feeling unhappy or distressed, The scores of the several subscales (psychological, crying spells, irritability, parts of body feel numb or somatic, vasomotor and sexual) at baseline and after tingling, muscle and joint pains, hot flushes, night sweats and libido with respect to baseline. Neverthe- baseline, all subscores improved in both groups during less, with regard to the improvement of nervousness, treatment. Tibolone treatment, however, produced sig- sleeping disorders, concentration, tiredness, loss of nificantly greater improvements in all subscores, except interest in most things, feeling unhappy or distressed, for vasomotor subscore, which were similar in both crying spells and libido a significant between group differences was observed. A significant better improve- In order to investigate the carryover effect Wilcoxon ment was observed in the above parameters during Sign Rank Test was performed between the baseline tibolone usage with respect to 17␤-estradiol. More- GCS and after the washout GCS. None of the parame- over, headaches significantly improved during the use ters were statistically significant between baseline and of tibolone in comparison to 17␤-estradiol.
Table 2Mean score of the 21 items of the Greene Climacteric Scale during the treatment with tibolone and 17␤-estradiol A. Somunkiran et al. / Maturitas 56 (2007) 61–68 Table 3Mean score ± S.D. of the symptoms clusters of the Greene Climacteric Scale during the treatment with tibolone and 17␤-estradiol * Number of items of the cluster in parentheses.
Two women in the tibolone/estrogen group (group Tibolone also significantly lowers SHBG and A) withdrew because of a change in employment, while increases circulating free testosterone, further adding they were taking estrogen pills. Their last GCS was performed by phone calls. Other than these two, all Tibolone has been shown to improve vasomotor subjects were compliant and completed the study.
symptoms, emotional reactions, sleep disturbances During the use of tibolone, two women experi- enced hirsutism, both in the estrogen/tibolone sequence (group B) of assumption and there were no other This study was focused on the effects of two differ- ent forms of hormone replacement therapy on climac-teric symptoms in surgically menopausal women. Bothtibolone and 17␤-estradiol showed improvements in 4. Discussion
the relief of climacteric symptoms. Tibolone treatment,however, produced significantly greater improvements After menopause, a progressive decline in both in psychological, somatic and sexual symptoms com- ovarian and adrenal androgen production occurs. This effect is most dramatic in women undergoing bilat- The findings of the studies examining the effects eral oophorectomy. In women who undergo surgical of tibolone on mood are not consistent. Meeuwsen menopause, serum testosterone and androstenedione et al. found an improvement in emotional reactions levels fall acutely, by approximately 50% Surgi- and sleep disturbances with 12 months of tibolone cal menopause is associated with a more acute onset therapy. But in that placebo-controlled trial, in the of menopausal symptoms and deterioration in sexual placebo group, an unexpected significant better score life than natural menopause Furthermore, use was observed in the physical mobility parameter, with of estrogen replacement further decreases the amount regard to tibolone In a double blind placebo- of bioavailable androgens by increasing the levels of controlled crossover study by Lam et al., tibolone sex hormone binding globulin (SHBG), thereby fur- treatment and placebo showed the same improvements ther lowering the amount of bioavailable testosterone on the psychological well-being in GCS In a Thus, even adequately estrogenized, surgically double-blind, cross-over placebo-controlled study of menopausal women are at risk for androgen deficiency.
20 oophorectomized women, Crona et al. found that Tibolone is a synthetic steroid that has estrogenic, tibolone and estradiol valerate reduced hot flushes and androgenic, and progestagenic properties. Tibolone improved mood to a similar degree and both com- itself has no biological activity; its effects are the results pounds were effective than placebo. But the study of the activity of its metabolites on various tissues. Its period was too short (6 weeks for each preparation) and 4-isomer has androgenic effects on brain and liver there was no washout period in the above mentioned A. Somunkiran et al. / Maturitas 56 (2007) 61–68 study Albertazzi et al., in a very small sample Although there are studies favoring estrogen in the sized study, found no effect of tibolone and continuous relief of vasomotor symptoms our finding is in combined estradiol–norethisterone acetate therapy on agreement with other studies that found tibolone to be mood et al. compared the effects of tibolone as clinically effective in controlling vasomotor symp- and CEE-MPA on QoL in 501 naturally menopausal women, and in that double blind, randomized trial they Four of the items in the somatic subscale were absent found no difference in total GCS score and psycho- at the baseline and they remained unchanged during the logical subscore between the tibolone and CEE-MPA treatment period. Of the three items present at baseline, two (parts of body feel numb or tingling, and muscle As mood improvement can be induced by andro- and joint pains) were improved by both treatments.
gens, the significantly greater improvement in psy- Alleviation in headache was achieved with tibolone chological symptoms in the tibolone group compared only. Improvement in headache with tibolone was also with 17␤-estradiol group, in the present study, may be cantly improvement in somatic subscale with tibolone formed in the brain. Genazzani et al. found that tibolone compared with estrogen is the result of the improve- increased ␤-endorphin levels in the plasma and pitu- ment in headache only. The present study gives further itary, and proposed that this might contribute to the support to the study of Lam et al., which showed that improved mood in postmenopausal women. However, tibolone treatment as compared with placebo treatment mood was not directly assessed in their trial had a significant beneficial effect on the somatic symp- better improvement of tibolone in well-being in the present study may also be attributed to the effects of One limitation of this prospective randomized cross- over study was that the treatment packages of tibolone Although both medications improved libido, and estrogen were not identical, so the patients were tibolone therapy was superior to 17␤-estradiol in the aware that their treatment medication changed after the current study. Several other studies of tibolone consis- washout. But the women in the groups did not have any previous knowledge about whether these drugs might Although understanding of the role played by andro- have any effect on sexual functions, psychological and gens in female sexual function remains incomplete, it somatic symptoms and we did not give any information is widely accepted that androgens exert an important about those either. We aimed to assess the effect of two influence on sexual function trials in post- different treatments on QoL in surgically menopausal menopausal women have consistently demonstrated women. Concern can arise that hysterectomy may that addition of androgens to estrogen replacement also affect the QoL. But, in the patients enrolled to results in a significant improvement of sexual func- the study, hysterectomy and bilateral oophorectomy tion, particularly sexual desire In the end, was performed for benign gynecological conditions, to the effect of tibolone on libido may be the result of enhance the quality of life. Research shows that in most its androgenic activity, as well as its SHBG lowering women suffering from gynecological disorders, quality of life is improved within a month after hysterectomy; An internet held study reported that vasomo- the surgery does not produce any psychological distur- tor symptoms were overwhelmed by psychosomatic bances in otherwise psychologically healthy women symptoms, like; feeling tired/worn out, feeling lack of energy and muscle and joint aches the symp- In conclusion tibolone as well as 17␤-estradiol toms “hot flushes” and “sweating at night” were the improves psychological, somatic, sexual and vaso- highest scored symptoms in the present study. This data motor symptoms in surgically menopausal women.
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