Maturitas 51 (2005) 215–218
Case report
Endometrial lesions causing uterine bleeding in postmenopausal women receiving raloxifene T. Tsalikis∗ , L. Zepiridis, M. Zafrakas, K. Dinas, J. Bontis 1st Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Periferiaki Odos Thessalonikis, N. Efkarpia, Thessaloniki 56403, Greece Received 30 October 2003; received in revised form 5 May 2004; accepted 18 May 2004
Abstract It is generally accepted, that raloxifene administration does not have adverse effects on the uterus. We report the cases of two relatively young postmenopausal patients, who presented with vaginal bleeding, due to endometrial pathology, approximately 1 year after the initiation of raloxifene administration. The women were 43 and 44 years old, and received 60 mg/day of oral raloxifene for 11.5 and 10.5 months, respectively. In both cases, raloxifene was given for osteoporosis prevention in the absence of vasomotor symptoms. The first patient underwent Pipelle-biopsy and hysteroscopy with histopathology revealing simple endometrial hyperplasia. The second patient underwent hysteroscopy with removal of an endometrial polyp, with no histopathological signs of malignancy. Continuation of raloxifene administration was decided in both cases, and follow-up did not reveal any sign of recurrence. Uterine bleeding may rarely occur in postmenopausal women under raloxifene therapy. Patients should be encouraged to report bleeding or spotting and appropriate diagnostic and therapeutic management should follow as in any other case. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: SERMs; Endometrial pathology; Menopause
1. Introduction Raloxifene is a selective estrogen receptor modulator (SERM) approved for the prevention of osteoporosis in postmenopausal women, and currently under evaluation in clinical trials for breast cancer chemoprevention in high-risk patients and prevention of cardiovascular disease in postmenopausal women [1–3]. ∗ Corresponding author. Tel.: +30 2310 693131; fax: +30 2310 992890. E-mail address:
[email protected] (T. Tsalikis).
Raloxifene is selective by having estrogen-agonistic effects on bone, vessels and blood lipids while it appears to be antagonistic on mammary tissue. So far, animal [3], as well as studies in humans [4–7] have provided evidence supporting an antagonistic effect of raloxifene on the uterus, particularly on the endometrium. On the other hand, certain animal studies have shown a possible stimulatory effect of raloxifene on the uterus [8,9] while some authors still question the endometrial safety of raloxifene [10]. We present the cases of two relatively young postmenopausal women taking raloxifene for osteoporosis prevention,
0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2004.05.007
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with post-therapy endometrial pathology suggesting a possible stimulatory effect of raloxifene on the endometrium. 1.1. Case 1 A 43-year-old woman, gravida 3, para 2, presented with a long episode of postmenopausal vaginal bleeding. Her last menstrual period was 2 years earlier and menopause was confirmed with measurement of serum levels of FSH and estradiol. The patient had been taking oral raloxifene for the prevention of osteoporosis, on a daily dose of 60 mg during the previous 11.5 months. Her gynecological history was unremarkable, Pre-treatment endometrial thickness measured with transvaginal ultrasound—as routinely done to all women attending our menopause clinics—was 4 mm. Physical and pelvic examination did not raise any abnormal findings other than uterine bleeding. Transvaginal ultrasound examination revealed increased endometrial thickness, measuring now 11 mm, while the ovaries appeared normal. Pipelle endometrial sampling and diagnostic hysteroscopy with endometrial biopsy followed. Histopathology revealed simple endometrial hyperplasia, with no signs of atypia. Continuation of raloxifene administration in the same dose with close patient follow-up was decided. Two and a half years after biopsy, the patient remains asymptomatic and repeated transvaginal ultrasound examinations did not show any signs of recurrence. In particular, the endometrial thickness was 4 mm at 6 months, 3 mm at 12 months and 4 mm at 18 months after the biopsy. 1.2. Case 2 A 44-year-old woman, gravida 3, para 3, presented with postmenopausal vaginal bleeding. Her last menstrual period was 2 years earlier and the menopausal state was confirmed with measurement of serum levels of FSH and estradiol. The patient received 60 mg of oral raloxifene daily for prevention of osteoporosis, for 10.5 months. She had an unremarkable gynecological history. Endometrial thickness, as routinely measured with transvaginal ultrasound before the initiation of treatment, was 3 mm. Uterine bleeding was the only finding on physical and pelvic examination. On transvaginal ultrasound examination, increased en-
dometrial thickness was found, measuring now 16 mm. Diagnostic hysteroscopy followed, revealing an endometrial polyp located in the uterine fundus, while the rest of the endometrial cavity was covered by atrophic endometrium. The polyp was excised and pathology showed a fibroglandular polyp with no signs of malignancy. Continuation of raloxifene in the same dose with close patient follow-up was decided. Two years post-biopsy, the patient remains free of symptoms and repeated transvaginal ultrasound examinations did not show any signs of recurrence. Endometrial thickness was 3 mm at 6 months and 3 mm at 12 months post-hysteroscopy.
2. Discussion Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women [11]. In clinical trials raloxifene had an estrogen-like effect on bone turnover, increasing bone mineral density and reducing the risk of fractures in women with osteoporosis. In addition, it does not seem to adversely affect breast physiology. Furthermore, it positively influences blood lipid markers. Raloxifene is generally well tolerated. The most common adverse effects are hot flashes and leg cramps and the most serious is venous thromboembolism [5,11]. In respect to the effect of raloxifene on the uterus, it appears that it does not have neither adverse nor protective effects. In an animal study [4], it has been shown that the raloxifene analogue LY117018 has a clear antagonistic effect on endogenous estrogen in uterine tissue. In humans, according to a 1-year prospective, randomized, double-blind trial [6] comparing 3 groups of 143 postmenopausal osteoporotic women receiving raloxifene at 60 or 120 mg/day and controls, there were no differences in the occurrence of uterine bleeding or increased endometrial thickness as assessed by ultrasonography. Likewise, no stimulation on the endometrium, the uterus or the uterine blood flow was observed, 6 months after administration of 60 mg/day [12] of oral raloxifene, in another small study that included 34 asymptomatic postmenopausal women. Furthermore, raloxifene exhibited a favorable safety profile on the uterus as expressed by the bleeding-spotting incidence and the ef-
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fect on endometrial thickness and uterine volume according to other authors [13]. However, at least two animal studies have shown that raloxifene does have a stimulatory effect on the uterus [8,9]. A study involving four experiments showed that raloxifene exerts a genuine trophic effect on the rat uterus [8], and a study in mice also showed that raloxifene has a uterotrophic effect [9]. Some authors still question the safety of raloxifene, suggesting that existence of potentially high- and low-risk groups should be taken into account in future clinical trials looking at the endometrial safety of SERMs, including raloxifene [10]. SERMs comprise a category of therapeutic agents that mimic the effect of estrogens in some cells, but act as estrogen antagonists in others. Several in vitro and in vivo studies have provided insights concerning these mechanisms. It has been reported, that tamoxifen, the most widely used SERM, has rarely a stimulatory effect on the endometrium in postmenopausal women and an antagonistic effect in premenopausal women [14]. Likewise, it can be postulated that raloxifene, might have different effects on the endometrium, depending on menopausal status. None of the two patients in the present report had premature menopause, but menopause occurred in a relatively young age, and there was no recurrence with advancing age, despite continuation of raloxifene administration in both cases. Thus, raloxifene might have a stimulatory effect in early menopause but not in later years, and this hypothesis should be evaluated in future studies. Alternatively, bleeding may have been simply caused by a (last) rise in estradiol by the ovaries, stimulated by high FSH-serum levels; in that case the women were perimenopausal instead of postmenopausal. The benign nature of the lesions reported here should by no means lead to divergence from the general guidelines set for the management of postmenopausal uterine bleeding in general and in women on HRT in particular. Since transvaginal ultrasonography does not have 100% sensitivity in detecting endometrial hyperplasia and polyps, further diagnostic measures should be taken in order to establish diagnosis [15,16]. These measures include enhanced ultrasonography, hysteroscopic biopsy or simply D & C followed by histological examination. The clinician should be always prepared to face rare and unexpected phenomena, even after the administration of theoretically safe medications, like raloxifene.
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In conclusion, two cases of hyperplastic benign endometrial lesions causing uterine bleeding in postmenopausal women receiving raloxifene for osteoporosis prevention have been presented, suggesting a possible stimulatory effect of raloxifene on the human endometrium, at least in early menopause. A causal relationship cannot be established based solely on these two cases, particularly since no signs of recurrence were noted, despite continuation of raloxifene administration in both cases. Patients should be encouraged to report bleeding or spotting and appropriate diagnostic and therapeutic management should follow as in any other case.
References [1] Chlebowski RT, Col N, Winer EP, et al. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002;20(15):3328–43. [2] Jordan VC, Gapstur S, Morrow M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst 2001;93(19):1449–57. [3] Erlandsson MC, Jonsson CA, Lindberg MK, Ohlsson C, Carlsten H. Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice. J Endocrinol 2002;175(2):319–27. [4] Dardes RC, Jordan VC. Novel agents to modulate oestrogen action. Brit Med Bull 2000;56(3):773–86. [5] Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med 1999;130(5):431–9. [6] Lufkin EG, Whitaker MD, Nickelsen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13(11):1747–54. [7] Somjen D, Waisman A, Kaye AM. Tissue selective action of tamoxifen methiodide, raloxifene and tamoxifen on creatine kinase B activity in vitro and in vivo. J Steroid Biochem Mol Biol 1996;59(5–6):389–96. [8] Ashby J, Odum J, Foster JR. Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. Regul Toxicol Pharmacol 1997;25(3):226–31. [9] Carthew P, Edwards RE, Nolan BM. Uterotrophic effects of tamoxifen, toremifene, and raloxifene do not predict endometrial cell proliferation in the ovariectomized CD1 mouse. Toxicol Appl Pharmacol 1999;158(1):24–32. [10] Goldstein SR. Controversy about uterine effects and safety of SERMs: the saga continues. Menopause 2002;9(5):381–4. [11] Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm 2000;57(18):1669– 75.
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[12] Chittacharoen A, Theppisai U, Manonai J. Transvaginal color Doppler sonographic evaluation of the uterus in postmenopausal women on daily raloxifene therapy. Climacteric 2002;5(2):156–9. [13] Christodoulacos G, Panoulis C, Botsis D, Rizos D, Kassanos D, Creatsas G. Transvaginal sonographic monitoring of the uterine effects of raloxifene and a continuous combined replacement therapy in postmenopausal women. Maturitas 2002;42(1):77–84. [14] Mourits MJ, De Vries EG, Willemse PH, Ten Hoor KA, Hollema H, Van der Zee AG. Tamoxifen treatment
and gynecologic side effects: a review. Obstet Gynecol 2001;97:855–66. [15] Lindgren R, Mattsson LA, Andersson K, et al. Transvaginal ultrasonography and endometrial histology in peri- and postmenopausal women on hormone replacement therapy. Brit J Obstet Gynaecol 1999;106(5):421–6. [16] Langer RD, Pierce JJ, O’Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. N Engl J Med 1997;337(25):1792–8.
