Elsevier

Maturitas

Volume 53, Issue 4, 20 March 2006, Pages 413-423
Maturitas

A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness

https://doi.org/10.1016/j.maturitas.2005.07.003Get rights and content

Abstract

Objectives

To study the effect of standard and low-dose estrogen–progestin therapy (EPT), tibolone and raloxifene on the incidence of vaginal spotting/bleeding and endometrial thickness over a 5-year period.

Methods

Seven hundred eighty-six postmenopausal women were studied in an open prospective design. Vaginal spotting/bleeding and endometrial thickness as assessed by transvaginal ultrasonography was compared between six categories of women over a 5-year period: three categories in women on continuous combined estrogen–progestin therapy, one category under tibolone, one category under raloxifene and one under no treatment. More specifically, women received tibolone 2.5 mg (N = 204), raloxifene HCl 60 mg (N = 137), conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5 mg (N = 122), 17β-estradiol 2 mg/norethisterone acetate 1 mg (N = 58), 17β-estradiol 1 mg/norethisterone acetate 0.5 mg (N = 76) or no therapy (controls, N = 189). Women with suspected endometrial pathology were referred for hysteroscopy.

Results

Bleeding/spotting incidence was highest among standard dose EPT users (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5 mg: 40.1%, 17β-estradiol 2 mg/norethisterone acetate 1 mg: 44.8%, p < 0.001 compared to controls). Low-dose EPT associated with lower incidence of spotting/bleeding (34.1%). The incidence under tibolone and raloxifene was 22.5% and 2.9%, respectively, while 3.2% of women not receiving therapy reported vaginal spotting/bleeding. Mean endometrial thickness was not significantly affected in any of the groups studied. The drop-out rate due to spotting/bleeding was higher in the two higher dose EPT regimens. After logistic regression analysis, age at baseline was the only significant predictor of subsequent spotting/bleeding (b = −0.25, S.E. = 0.09, p = 0.006), while menopausal age and pre-treatment serum FSH had marginal significance.

Conclusions

EPT, tibolone and raloxifene do not appear to associate with significant changes in endometrial thickness in the majority of cases. The low-dose EPT regimen associated with a decreased incidence of unscheduled spotting/bleeding compared to the standard dose regimens. Tibolone expressed a favorable endometrial profile, as seen in its effect on unscheduled spotting/bleeding and mean endometrial thickness. Raloxifene associated with the lowest incidence in S/B and the lowest drop-out rate.s

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

References (63)

  • F.J. Cohen et al.

    Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60

    Obstet Gynecol

    (2000)
  • J.E. Heikkinen et al.

    Optimizing continuous-combined hormone replacement therapy for postmenopausal women: a comparison of six different treatment regimens

    Am J Obstet Gynecol

    (2000)
  • D.F. Archer et al.

    Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding

    Fertil Steril

    (2001)
  • D.F. Archer et al.

    Effects of levonorgestrel, medroxyprogesterone acetate, norethindrone, and 17beta-estradiol on vascular endothelial growth factor isomers 121 and 165 in Ishikawa cells

    Fertil Steril

    (2004)
  • G. Christodoulacos et al.

    Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women

    Maturitas

    (2002)
  • P. Fugere et al.

    Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women

    Am J Obstet Gynecol

    (2000)
  • P. Neven et al.

    A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate

    BJOG

    (2003)
  • J. Ginsburg et al.

    Clinical experience with tibolone (Livial) over 8 years

    Maturitas

    (1995)
  • M. Habiba et al.

    Immunohistochemical and hysteroscopic assessment of postmenopausal women with uterine bleeding whilst taking Tibolone

    Eur J Obstet Gynecol Reprod Biol

    (1996)
  • J.H. Meuwissen et al.

    Regression of endometrial thickness in combination with reduced withdrawal bleeding as a progestational effect of tibolone in postmenopausal women on oestrogen replacement therapy

    Maturitas

    (1995)
  • R. Trevoux et al.

    Efficacy and safety of Org OD 14 in the treatment of climacteric complaints

    Maturitas

    (1983)
  • D. De Aloysio et al.

    Use of Org OD 14 for the treatment of climacteric complaints

    Maturitas

    (1987)
  • S.R. Goldstein et al.

    A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium

    Obstet Gynecol

    (2000)
  • G.D. de Azevedo et al.

    Raloxifene therapy does not affect uterine blood flow in postmenopausal women: a transvaginal Doppler study

    Maturitas

    (2004)
  • W. Hanggi et al.

    Comparison of transvaginal ultrasonography and endometrial biopsy in endometrial surveillance in postmenopausal HRT users

    Maturitas

    (1997)
  • E. Chalas et al.

    Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial

    Am J Obstet Gynecol

    (2005)
  • R. Yazigi et al.

    Carcinoma of the endometrium in patients treated with tibolone

    Gynecol Oncol

    (2004)
  • M. Wells et al.

    Effect on endometrium of long term treatment with continuous combined oestrogen–progestogen replacement therapy: follow up study

    BMJ

    (2002)
  • G.L. Anderson et al.

    Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative Randomized Trial

    JAMA

    (2003)
  • V. Beral et al.

    Endometrial cancer and hormone-replacement therapy in the Million Women Study

    Lancet

    (2005)
  • D.W. Sturdee et al.

    The endometrial response to sequential and continuous combined oestrogen–progestogen replacement therapy

    BJOG

    (2000)
  • Cited by (38)

    • Unscheduled bleeding in continuous combined hormone therapy users

      2011, Maturitas
      Citation Excerpt :

      This approach aims to reduce unscheduled bleeding associated with ongoing endogenous ovarian steroid production in perimenopausal women. Tibolone is also unsuitable during the menopause transition, as unscheduled bleeding affects up to 50% of users during the first 5 years [5]. A combined contraceptive will improve vasomotor symptoms and may regulate bleeding.

    • Bleeding with menopausal hormone therapy

      2009, Best Practice and Research: Clinical Obstetrics and Gynaecology
    View all citing articles on Scopus
    View full text