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Introduction
Menopause is a period in the life cycle of all women and is associated with hormonal changes,12 that presents with different symptoms, including hot flashes, night sweat, vaginal atrophy, stress, apprehension and decreased libido.3 Hormone replacement therapy (HRT) is a widely used therapeutic approaches to deal with menopausal symptoms.4 Based on the report by the Women's Health Initiative (WHI) the risk of cardiovascular events and breast cancer increase following the HRT regimen.5 These serious complication have resulted in reduced desire to use HRT for menopausal women.5
Lack of tissue specificity and distribution of estrogen-related complications within the body, have encouraged the researchers to think about medications with certain estrogen receptor modulating effects like raloxifene.67 Raloxifene as a non-steroidal pentathiophene from the second generation of selective estrogen receptor modulators (SERMs) that acts as a non-hormonal agent binding to the estrogen receptor that present estrogenic impacts on bone and anti-estrogenic impacts on endometrial and breast tissues.89101112 It should be noted that raloxifene was found to have beneficial outcomes on the brain, liver, and kidneys, as well as cardiovascular and musculoskeletal systems.613
According to a recent meta-analysis, tamoxifen can decrease the plasma lipoprotein concentration by 20%.14 Daily administration of raloxifene at a dose of 120 mg has led to 33% reduction in the risk of mild cognition impairment.6 According to the result of a network meta-analysis, raloxifene significantly decreased the risk of breast cancer.15 Based on another meta-analysis, the use of raloxifene resulted in a 50% decrease in the need for prolapse surgery during 3 years follow up.16 On the other hand, some adverse effect such as deep vein thrombosis (DVT) risk and pulmonary edema (PE) was caused by raloxifene.17
Accordingly, it can be claimed that a review of efficacy and complications of taking raloxifene is necessary regarding the extensive and increasing use of raloxifene among menopausal women. Hence, we decided to conduct the current review to summarize the available literature on the advantages and disadvantages of raloxifene in attenuating the menopausal symptoms.
Materials and Methods
This study is a review of relevant publications about the effects of raloxifene on sleep disorder, depression and venous thromboembolism, plasma concentration of lipoprotein and cancer, breast cancer and cognition function among menopausal women.
Results
This mini review assessed the beneficial and adverse effects of raloxifene in menopausal women. Five studies included in this review (Table 1). These studies assessed the effect of raloxifene on sleep disorder, depression, venous thromboembolism, pelvic organ prolapse (POP), plasma concentration of lipoprotein, Cognitive function and breast cancer.
1. Raloxifene and sleep disorder
A part of this systematic review focused on the effect of raloxifene on sleep disorder. Four out of 5 included trials in this systematic review assessed the effect of raloxifene on sleep disorder. Three studies failed to show any difference in efficacy between raloxifene and placebo on sleep disorder.6
2. Raloxifene and depression
This systematic review also focused on the effect of raloxifene on depression. Four out of 5 included trials in this systematic review assessed the effect of raloxifene on depression. Based on the findings of 1 study, raloxifene decreased the score of depression while 3 other studies did not find any beneficial effect for raloxifene in improving of depressive symptoms. Authors of the systematic review concluded that raloxifene had no beneficial effect on depression.6
3. Raloxifene and venous thromboembolism
Adomaityte et al.17 performed a meta-analysis to evaluate the effect of raloxifene on venous thromboembolism among postmenopausal women. Nine trials, involving 24,523 postmenopausal women with mean age of 59.4 years were included in their meta-analysis. Raloxifene was administered as a dose of 60 mg/day in most of the studies and the follow up period was 24 months. The odds ratio (OR) was 1.54 (95% confidence interval [CI], 1.13–2.11; P = 0.006), indicating 54% increase in the risk of DVT while the OR for PE was 1.05, suggesting 91% increase in risk of PE alone (95% CI, 1.05–3.47; P = 0.03).
4. Raloxifene and POP
A meta-analysis was performed to assess the adverse effects of raloxifene and found that treatment with raloxifene was associated with 50% decrease in the need for prolapse surgery during a 3 year follow up period.16
5. Raloxifene and plasma concentration of lipoprotein
A meta-analysis was recently performed on the efficacy of raloxifene on plasma concentration of lipoproteins in postmenopausal women. The result of the meta-analysis showed a significant decline in plasma concentration of lipoproteins in raloxifene group compared to placebo (standardized mean difference [SMD], −0.43; 95 CI, −0.65 to 0.19; 10 trials). Subgroup analysis was performed based on dose and length of treatment. Subgroup analysis based on length of treatment revealed a better effect in studies administering raloxifene for less than 48 weeks compared to raloxifene administration for more than 48 weeks (P = 0.001). Publication bias was detected by Funnel plot. The result of metregression did not show any significant relation between plasma concentrations of lipoprotein with dose of raloxifene (slope of −0.001; P = 0.801). However, lipoprotein lowering effect decreased significantly with the increase in the length of treatment (slope was 0.00 with only a slight asymmetry). Authors concluded that raloxifene can significantly improve plasma concentration of lipoprotein in postmenopausal women.14
6. Raloxifene and cognitive function
Verbal memory improved after daily administration of 60 mg raloxifene. Administration of 120 mg/day of raloxifene decreased the risk of mild cognition impairment by 33%. The authors suggested that it is difficult to draw a certain conclusion based on the current findings and that there is a need for larger studies and higher quality of life.6
7. Raloxifene on breast cancer
A network meta-analysis showed that raloxifene significantly decreased the risk of breast cancer (summary relative risk [RR], 0.572; 95% CI, 0.327–0.881; P = 0.01). Furthermore, the incidence of severe adverse effects was lower in raloxifene compared to aromatase inhibitor (summary RR, 0.85; 95% CI, 0.76–0.95; P = 0.04).15
Discussion
This review aimed to summarize present knowledge regarding the beneficial and adverse effects of raloxifene in menopausal women. In this review, the effects of raloxifene on sleep disorder, depression and venous thromboembolism, along with plasma concentration of lipoprotein, breast cancer and cognition function were assessed in menopausal women. Raloxifene showed no significant effect on depression and sleep disorder. Raloxifene was associated with decreased risk of breast cancer and POP. However, raloxifene was associated with increased risk of DVT and PE.
Lipoprotein alone or in combination with other lipid or non-lipid risk factors may be involved in the increased risk of cardiovascular diseases (CVD).14 The postmenopausal women were reportedly shown to have low level of high-density lipoprotein (HDL) cholesterol and concurrently high levels of low-density lipoprotein cholesterol, triglycerides and cholesterol,18 indicating a probable reduction in the protective effect of HDL against CVD after menopause.19 Recently, a meta-analysis showed a 20% decrease in plasma lipoprotein in patients treated with tamoxifen. The effect of raloxifene on lipoprotein (a) is attributed to estrogen-like properties of raloxifene.14 Yang et al.6 found that raloxifene may act in a dose-dependent manner. They attributed this to the fact that raloxifene can easily cross the blood -brain barrier.
Adomaityte et al.17 concluded that raloxifene could lead to an increased risk of DVT and PE. However, their meta-analysis had several limitations, that made it difficult to draw a conclusion. First, a wide CI was identified in their meta-analysis, second, in all included studies, DVT or PE was assessed as the secondary outcome.14
Future studies should be conducted with a large enough sample size in order to enable researchers conduct subgroup analyses to compare the patients with elevated plasma lipoprotein concentrations and the patient with normal corresponding values. Additionally, the comparison between the effects of raloxifene and other conventional medical therapies should be performed in future studies.
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