A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness
Introduction
Hormone therapy (HT) is given to postmenopausal women for the relief from climacteric symptoms and the prevention of urogenital atrophy. Furthermore, prolonged HT administration has been associated with an osteoprotective effect [1]. In non-hysterectomized women estrogen is combined with a progestin (EPT), so as to offset the proliferative effect of estrogen on the endometrium and minimize the risk for hyperplasia-cancer. In fact, this combined regimen given continuously eventually induces endometrial atrophy and amenorrhea [2], [3], [4]. The recently published results from the Million Women Study indicate a reduced risk of endometrial cancer in women under continuous combined EPT [5]. However, endometrial safety during long-term EPT is still not established and even an optimal estrogen/progestin dose ratio may expose the endometrium to pathology. Sporadic cases of endometrial cancer have been reported among women on continuous EPT [6], [7], [8].
Continuous EPT may cause vaginal spotting/bleeding (S/B) mainly during the initial 6–9 months of therapy in up to 60% of women [9], [10]. Although unscheduled S/B during EPT is not necessarily an indicator or predictor of endometrial pathology [11], [12], its absence does not always exclude the presence of a lesion [13]. Monitoring the endometrium under long-term EPT is advisable in women presenting with S/B. Routine invasive evaluation of the endometrium in HT users is not indicated, for it will affect their decision to initiate or adhere to therapy. Transvaginal sonography (TVS) is a non-invasive and reliable method for evaluating the uterus and endometrium at baseline and for monitoring the effect of HT on endometrium particularly in the presence of unscheduled S/B [12], [13].
The results of WHI [14] have led to a re-appraisal of the indications for HT and the reported effect on breast cancer and cardiovascular disease incidence has obliged us to consider HT regimens of lower dose than that administered in WHI, as well as alternative therapies to deal with the consequences of estrogen depletion. Tibolone is a synthetic steroid with tissue-specific action. Following rapid conversion to the 3α- and 3β-hydroxy-metabolites and the Δ4 isomer, tibolone may engage either the ER-α, expressing estrogenic activity or the progesterone and androgen receptors and act as a progestogen–androgen [15]. As such tibolone has been extensively administered in Europe as an effective alternative to HT in treating climacteric symptoms and vaginal atrophy, in improving libido and in preventing bone loss [16], while having minimal stimulatory effect on the breast [17], [18] and endometrium [19], [20]. This data, however, comes from observational studies, while results from randomized controlled trials are still missing.
Raloxifene, a non-steroid benzothiophene derivative is classified as a selective estrogen receptor modulator (SERM). Although devoid of any action on climacteric symptoms and vaginal atrophy, raloxifene expresses an estrogen-agonist effect on the skeleton [21], [22] and cardiovascular risk factors [21], [23], [24], [25], while being an estrogen antagonist on the breast [26], [27] and endometrium [21], [22], [28]. Raloxifene administration in osteoporotic women with a high-risk profile for cardiovascular disease appears to decrease the incidence of cardiovascular events compared to the placebo group [29].
The purpose of this study was to assess the effect of various continuous EPT regimens, tibolone and raloxifene on the incidence of unscheduled S/B and endometrial thickness.
Section snippets
Materials and methods
Seven hundred eighty-six postmenopausal women with an intact uterus aged 42–66 years were included in the study. Subjects were recruited from the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital between September 1997 and December 1999. Patients were at least 9 months postmenopausal. Women who were past users of HT, tibolone or raloxifene were not included in the study unless they had been off-therapy for at least 3 months.
Before
Results
Baseline demographic characteristics of the 786 women originally enrolled in the study are presented in Table 1. Women in the raloxifene group were older and had a longer duration of menopause compared to the other groups. Women did not differ between groups with respect to age at menopause, BMI, hormone levels or lifestyle parameters.
Baseline characteristics of the 422 women who completed the 5-year study and who were fully compliant in keeping the S/B diary cards are presented in Table 2.
Discussion
The purpose of administering EPT in a continuous mode is to prevent scheduled bleeding so as to improve compliance among women wishing to remain amenorrhoeic. However, women on continuous EPT may still develop unscheduled S/B, a serious and for the woman disturbing adverse event which influences her decision to initiate or adhere to treatment [30]. Accepted treatment modalities have been re-evaluated in varying estrogen–progestin dose ratio and alternative therapies have been considered in an
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Bleeding with menopausal hormone therapy
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