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Psychological Effects of Tibolone and Sequential Estrogen- Progestogen Therapy in Perimenopausal Women

Posted on: Thursday, 26 May 2005, 03:00 CDT

Abstract

Objective To investigate changes in psychological symptoms before and after continuous tibolone treatment and sequential estrogen- progestogen therapy in perimenopausal women.

Methods In this prospective, randomized, controlled study, perimenopausal women were randomly allocated to treatment with either tibolone 2.5 mg/day for 28 days (n = 28), or 0.625 mg conjugated equine estrogens (CEE) for 25 days plus 5 mg medroxyprogesterone acetate (MPA) daily on days 16-25 (n = 33). The differences in Beck's depression scores and serum lipid profiles before and after 1 year of treatment with both regimens were compared.

Results Both groups were similar with respect to demographic characteristics. The differences in Beck's depression scores before and after treatment were statistically significant in the tibolone group (21.3 vs 17.1, p = 0.038) and also in the group receiving standard sequential estrogen-progestogen treatment (15.7 vs. 13.0, p = 0.040). In the sequential estrogenprogesterone group, a statistically significant increase was measured in high-density lipoprotein (HDL)-cholesterol levels after treatment (49.1 vs. 56.8 mg/dl, p = 0.023).

Conclusion Tibolone is as effective as sequential estrogen- progesterone therapy in alleviating the psychological symptoms of the perimenopause. In addition, CEE + MPA induces favorable changes in HDL-cholesterol.

Keywords: Beck's depression score, hormone replacement therapy, lipid profile, mood, perimenopause, tibolone

Introduction

Menopause is associated with significant hormonal changes, with plasma levels of estrogen, androstenedione, testosterone and progesterone decreasing significantly. Menopausal women frequently also report psychological symptoms such as increased depression, anxiety, irritability, decreased libido and substantial psychological impairment [1-3].

Hormone replacement therapy (HRT) has been shown to be an effective treatment for the control of vasomotor symptoms and vaginal dryness, as well as to offer protection from osteoporosis [4], but the evidence for direct psychological benefits is less convincing. Some studies report benefits of HRT on psychological symptoms; others find no greater effect than a placebo [5-7].

The present study was designed to investigate the psychological effects of two different HRT regimens using a standardized psychological assessment. The aim of the study was to investigate differences in psychological symptoms between a gonadomimetic drug and established standard estrogen-progestogen therapy.

Materials and methods

The study was carried out in our menopause clinic at Ankara Educating and Research Hospital between April 2000 and May 2003. The local ethics committee approved the study. All patients were asked if they would be willing to participate in a 1-year clinical trial of two forms of HRT. Written informed consent was obtained from all patients.

Inclusion criteria were as follows: women with < 1 year since the last menstrual period, with no history of surgical menopause, having menopausal symptoms with blood levels of follicle-stimulating hormone and luteinizing hormone within 20 to 40 TU/ml, and no contraindications to HRT. It was required that the women be in otherwise good general health, have no history of psychiatric disorders, and not be taking any antidepressants or psychotherapeutic agents currently or for the previous 12 months. As a rough control for sociodemographic factors, all patients were selected from an urban community and all were required to be at least a high school graduate.

After taking a detailed history and a physical examination, the following tests were performed on all women in both groups: transvaginal ultrasonography, mammography, cervico-vaginal smear and routine laboratory studies. The latter comprised complete blood sampling, urine analysis, serum lipid profiles (serum levels of cholesterol, triglycerides, high-density lipoprotein (HDL)- cholesterol, low-density lipoprotein (LDL)-cholesterol and very low- density lipoprotein (VLDL)-cholesterol), liver function tests (serum glutamate-oxaloacetate transaminase, serum glutamate-pruvate transaminase and lactate dehydrogenase) and renal function tests (serum creatinine concentration, serum uric acid concentration and blood urea nitrogen).

Eligible women for this study were randomly allocated to receive either tibolone (Livial; Organon, Istanbul, Turkey) 2.5 mg/day for 28 days, or 0.625 mg conjugated equine estrogens (CEE) (Premarin; Wyeth Medica, Ireland) for 25 days plus 5 mg medroxyprogesterone acetate (MPA) (Farlutal; Deva, Istanbul, Turkey) daily on days 16 to 25. Randomization was done using a computer-generated randomization table. A total of 61 women were enrolled in this study; 28 were treated with tibolone and 33 with sequential estrogen and progesterone. The study period was 12 months. The patients served as their own control.

Before starting HRT and after 12 months of treatment, mood scores were determined for all patients by a psychiatrist utilizing the Beck Depression Inventory (BDI). The translated version of the BDI had been tested and approved for the Turkish population [8]. The BDI is a frequently used selfreporting method for assessing severity of depression. It is a 21-item form that requires subjects to indicate the presence and severity of symptoms. Four statements that are scored from O (neutral) to 3 (maximum severity) measure each item.

After 1 year of treatment, repeat physical examination, lipid profiles and Beck's depression score were assessed. Main outcome measures were changes in serum lipid profiles and Beck's depression score before and after treatment.

To detect a 40% difference with 80% power between the scores of depression with the BDI for any two drugs, it was calculated that a minimum of 44 women would be required, with 22 in each group.

Statistical analyses were conducted using SPSS for Windows (version 9.0) software (SPSS Inc., Chicago, IL, USA). For comparisons between the two drugs, the Student t test for independent samples was used. For changes before and after treatment, the paired t test was used. The Mann-Whitney U test was used for comparing the amount of change in the groups before and after treatment. All data are described as mean standard deviation. A p value of 5% or less was considered statistically significant.

Results

A total of 61 women were enrolled in this study. One woman in the tibolone group and two women in the estrogen-progesterone group were excluded from study because of side-effects of the drugs. Two women in the tibolone group and two women in the estrogen-progesterone group were lost to follow-up. Thus 88.5% of the original 61 patients completed the full 1-year trial. There were no statistically significant differences between the two groups with respect to age, gravidity, body mass index before study entry and duration since menopause (Table I).

Serum levels of cholesterol, triglycrides, HDLcholesterol, LDL- cholesterol and VLDL-cholesterol before treatment were similar in both groups. Pretreatment Beck depression scores were 21.3 (95% confidence interval (CI) 17.4-25.2) in the tibolone group and 15.7 (95% CI 12.2-19.2) in the standard sequential estrogen-progesterone treatment group.

There were no significant differences between the two groups in terms of serum lipid profiles, except for HDL-cholesterol in the conventional HRT group. In women receiving sequential estrogen- progesterone treatment, a statistically significant increase in HDLcholesterol levels was measured after 1 year of treatment (49.1 vs. 56.8 mg/dl, p = 0.023).

The differences in Beck depression scores before and after treatment were statistically significant in the tibolone group (21.3 vs 17.1,p = 0.038) and also in the group receiving standard sequential estrogen-progesterone treatment (15.7 vs 13.0, p = 0.040) (Table II).

Table I. Characteristics of the menopausal women participating in the study.

Table II. Main outcome measures.

Discussion

The results of this study show that both tibolone and sequential estrogen-progesterone treatments are effective in terms of mood- enhancing effects. In addition, sequential estrogen and progestogen therapy had a favorable effect on plasma lipoproteins by increasing HDL-cholesterol levels.

Sex steroids play a very important role in female neurobiology. Postmenopausal gonadal hormone withdrawal seems to be of critical importance in mood disorders, reduced libido and cognitive disturbances, which accompany this phase of a woman's life. Therefore women are more vulnerable to a depressed mood during the perimenopausal years. Estrogen replacement therapy has been suggested as a potential treatment for depressed mood during the perimenopause [9]. This mood-elevating effect has also been documented in a placebo comparative study [1O]. Data obtained by Bukulmez and colleagues demonstrated that, with an increase of [^sup 3^H] imipramine binding sites, 3 months of treatment with CEE + MPA and tibolone improved mood as measured by the BDI [11]. In our study of longer duration, the percentage of women reporting psychological symptoms decreased by 19.9% and 17.3% in the tibolone group and conventional HRT (CEE + MPA) group, respectively. The effects of estrogen and estrogen-progestin combinations on mood and behavior may vary according to the actual compoun\ds and host characteristics [12].

Usually, menopause is associated with a reduction in endorphin levels that is believed to be involved in the pathogenesis of mood disorder [13]. The reason for mood improvement may be an increase in plasma endorphin levels, which was shown to be induced with the use of tibolone [10,13], As well as its potential to elevate mood, estrogen may exert its effects partly via the serotonin system [14]. The serotonin receptor has been shown to be increased in rodents following estrogen administration. However, progestin alone or in combination with estrogen was associated with smaller reductions in depressed mood than was estrogen alone [15]. The type of progestin seems to be of importance, because MPA provoked less negative symptoms compared with norethisterone acetate. This effect is inversely dosedependent. In sequential hormonal therapy, the addition of 20 mg MPA surprisingly provoked less negative mood symptoms than did 10 mg. In our study, 10 mg MPA was added for the last 10 days of each treatment cycle. The slightly diminished effect of sequential estrogen and progesterone therapy on mood improvement compared with tibolone might be due to MPA doses and treatment duration.

With regard to the beneficial effects on mood parameters, our data suggest that a slightly better effect was obtained with tibolone than in the comparative group. These findings are compatible with the results of Egarter and associates [16]. This may be due not only to tibolone's positive effect on vasomotor symptoms but also on libido.

In a randomized, controlled, multi-center trial, 1 year of treatment with any of the CEE or CEE/MPA regimens studied increased HDL-cholesterol; the 10% increase in HDL-cholesterol for the CEE 0.45/ MPA 1.5 group was similar to that in the CEE 0.625/ MPA 2.5 group. CEE and CEE/MPA induce favorable changes in lipids [17]. In an analysis of studies published from 1974 to 2000, Godsland reported that the route of estrogen administration and type of progestogen determined differential effects of HRT on lipid and lipoprotein levels [18]. In the present study, after 1 year of treatment, CEE + MPA increased HDL-cholesterol by 15.6%. In contrast to known data of tibolone decreasing HDL-cholesterol, we did not observe any change in HDL-cholesterol levels in the tibolone group. The effect of tibolone on HDL-cholesterol may occur as a result of a change in hepatic lipase activity and nutritional habits.

The obvious methodological limitation of this study was the absence of a placebo arm. secondly, we could not take into account the vasomotor symptoms of menopause in this study. In menopausal women, the psychological benefits of HRT may occur because of the relief of vasomotor symptoms and a reduction in vaginal dryness, and this is known as the 'domino effect'.

In conclusion, tibolone, with its mixed hormonal profile, is as effective as sequential estrogenprogesterone therapy in alleviating the psychological symptoms of the perimenopause. In addition to its favorable effect on psychological symptoms, CEE + MPA also induces favorable changes in HDL-cholesterol.

Acknowledgement

We wish to thank Selma Yrkhan, from Hacettepe University Faculty of Medicine, Department of Physiology, for her professional linguistic revision of the manuscript.

References

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ISMET INAN1, SEFA KELEKCI2, & BLENT YILMAZ2

1 Ministry of Health, Ankara Education and Research Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey, and 2 Zekai Tahir Burak Women's Health, Education and Research Hospital, Ankara, Turkey

(Received 17 December 2003; revised 17 March 2004; accepted 27 March 2004)

Correspondence: S. Kelekci, Bassehir sokak, 16/11 Cebeci 06100, Ankara, Turkey. Tel: 90312319 18 49. Fax: 90312490 80 90. E-mail: sefamed@hotmail.com

Copyright CRC Press Feb 2005

Source: Gynecological Endocrinology

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