Menopausal Medicine: For clinicians who provide care for women

Tissue selective estrogen complex: A new paradigm for menopausal therapy

Assistant Vice President, Clinical Research, Wyeth Research, Philadelphia, Pennsylvania

Our knowledge of estrogen receptor action has developed considerably from the “lock and key” model of 40 years ago. Anti-estrogens were later called selective estrogen receptor modulators (SERMs) when it was recognized that, although working through the estrogen receptor, they possessed both agonist and antagonist activity. Estrogens were also shown to have different activity profiles, even when corrected for receptor binding affinity. Hence, it became important to understand how estrogens and SERMs, working through the same receptor, could have similar effects in one tissue and different effects in other tissues. The fact that there were 2 estrogen receptors (ERα and ERβ) with their own distribution was only part of the story. The activity and distribution of coactivators and corepressors and other transcription-related events also helped to explain how conformational changes of the estrogen receptor, induced by specific receptor-ligand interactions, played a role in the tissue-related agonist/antagonist profiles of estrogens and SERMs.

The understanding that estrogens and SERMs exist on a continuum of tissue-specific, estrogen receptor-mediated agonist/antagonist activity has led to the evaluation of estrogen/SERM pairings in treating the effects of menopausal estrogen deficiency. Although hormone therapy (HT) has been proven highly effective for treating vasomotor symptoms and vulvovaginal atrophy associated with menopause and preventing postmenopausal osteoporosis, the clinical profile of some estrogen/SERM pairings may enhance tolerability while maintaining the efficacy seen with HT. In particular, amenorrhea rates and an incidence of breast tenderness that are similar to placebo would be an improvement. This article reviews the phase 2 clinical data for a new paradigm for menopausal treatment—the tissue selective estrogen complex (TSEC), the next-generation menopausal therapy.

Tissue selective estrogen complexes

A TSEC partners a SERM with other estrogens to achieve a more favorable clinical profile than either therapy alone, based on their blended tissue selective activity profiles. The appropriate pairing of an estrogen and a SERM must provide endometrial protection and be effective for other menopausal indications. Not just any estrogen/SERM combination will provide a favorable clinical profile. This was recently illustrated in a report of oral estradiol given with raloxifene.¹ Although the combination effectively relieved hot flushes, it did not fully protect against estrogenic stimulation of the endometrium.¹

Both preclinical and clinical evidence support the pairing of the SERM bazedoxifene with conjugated estrogens (CE). On a cellular level, in the rat uterus, bazedoxifene by itself did not influence wet weight or histology, unlike raloxifene or lasofoxifene.^2-6 Additionally, when bazedoxifene was added to CE, the proliferative effects of CE on the uterus were blocked.⁷ On a molecular level, estrogens and SERMs have been shown to elicit unique gene expression profiles both independently and when combined, such that when bazedoxifene was partnered with CE, the gene expression profile was distinct from that of the individual components.⁷ Preliminary clinical data are consistent with these cellular and molecular data.

Preliminary clinical trial of a TSEC

A phase 2 study randomized 412 healthy, postmenopausal women (aged 40 to 65 years) to 6 different doses of bazedoxifene/CE for 84 days: bazedoxifene, 5 mg, 10 mg, or 20 mg with either CE, 0.3 mg or 0.625 mg. Controls included placebo, CE 0.3 mg, CE 0.625 mg, CE/medroxyprogesterone acetate (MPA) 0.625 mg/2.5 mg, and bazedoxifene 5 mg. Study participants had to experience an average of 4 hot flushes per day and have an intact uterus with an endometrial thickness less than 5 mm, as measured by transvaginal ultrasound. Participants could not have taken any hormone-containing medications within 8 weeks prior to study entry. Endometrial thickness, rates of amenorrhea, hot flush incidence and severity, vaginal maturation, and N-telopeptide levels were examined.

Demographic and baseline characteristics were similar among all treatment groups at baseline. The average age was approximately 54 years, the majority of women were white, the average body mass index was 25.4, and the mean time since their last menstrual period was 4.3 years. The results of this study are presented here.

Endometrial protection

Endometrial hyperplasia, a surrogate marker for endometrial cancer, is a well-documented side effect of unopposed estrogen therapy.^8,9 To date, only the addition of a progestin to estrogen therapy has been shown to prevent estrogen-induced endometrial hyperplasia.^8,9 In this preliminary study, the effect of 84 days of bazedoxifene/CE on endometrial thickness (as a measure of endometrial stimulation) was assessed by transvaginal ultrasound (FIGURE 1).

As expected, endometrial thickness increased in women who received CE 0.3 mg or CE 0.625 mg alone, which was statistically significant versus placebo at a dose of 0.625 mg (P < .05).⁸ Also as expected, CE/MPA significantly reduced the CE-induced increase in endometrial thickness (P < .05), although the change from baseline with CE/MPA was still higher than that with placebo (P < .05).

By itself, bazedoxifene at 5 mg did not increase endometrial thickness but, rather, resulted in a non-significant decrease in uterine thickness. When added to either CE 0.3 mg or CE 0.625 mg, bazedoxifene dose-dependently inhibited the CE-induced increase in endometrial thickness. A dose of bazedoxifene 20 mg significantly lowered the increases in endometrial thickness observed with CE alone at 0.3 mg or 0.625 mg (P < .05). In fact, bazedoxifene 20 mg almost completely blocked the endometrial increase observed with CE 0.3 mg alone.

When bazedoxifene 20 mg was added to CE 0.625 mg alone, the increase in endometrial thickness was less than half that observed with CE/MPA. Likewise, the increase in endometrial thickness with bazedoxifene 10 mg plus CE 0.625 mg was comparable to that with CE/MPA, and was significantly lower (P < .05) than that with CE 0.625 mg alone. When bazedoxifene 10 mg was paired with CE 0.3 mg, the CE-induced increase in endometrial thickness was less than half, but not significantly less, than that with CE 0.3 mg alone. Bazedoxifene at 5 mg was not enough to reduce an increase in endometrial thickness observed with either CE 0.3 mg or CE 0.625 mg.

Collectively, these effects of bazedoxifene with and without CE on the endometrium are consistent with preclinical and clinical studies examining the effects of bazedoxifene alone, and preclinical studies of bazedoxifene/CE in the rat.^2,7,10 When tested in the rat uterus, or when tested at various doses in studies of postmenopausal women, bazedoxifene alone did not elicit a proliferative endometrial response.^2,10 Also in a model of the rat uterus, bazedoxifene blocked CE-induced increases in uterine wet weight.⁷ However, raloxifene significantly increased uterine wet weight versus control.² Preclinical results with raloxifene, then, are consistent with the recently reported finding that raloxifene did not fully prevent endometrial stimulation with estradiol plus raloxifene.¹

Achieving amenorrhea

Additional effects on the endometrium can be indicated by endometrial bleeding. Irregular bleeding is one of the limitations of HT as menopausal treatment. Comparing bleeding incidence between different therapies is difficult based on inconsistent bleeding definitions with each study. However, irregular bleeding has been consistently demonstrated with various HTs, although bleeding incidence has improved with the advent of lower doses of HT.^11-16 Bleeding is also a common reason that women discontinue HTs—approximately 12% to 23% of women discontinue HT because of bleeding.^17,18 An improved menopausal therapy would have a rate of amenorrhea (no bleeding or spotting) comparable to that in either untreated postmenopausal women or women given placebo.

In this study of bazedoxifene/CE, the incidence of vaginal bleeding was recorded by study participants on daily diary cards. The incidence of amenorrhea with the various treatment regimens throughout the study is presented in FIGURE 2. All 6 bazedoxifene/CE combinations had amenorrhea rates similar to placebo (92%), and better than HT (43%; P < .05). The incidence of amenorrhea with bazedoxifene 20 mg with CE 0.625 mg or CE 0.3 mg was 89% to 92%. Thus, amenorrhea and bleeding rates with bazedoxifene/CE approach the goal of improved tolerability for a next-generation menopausal therapy.

Treating menopausal hot flushes and vaginal atrophy

Hot flushes and symptoms of vaginal atrophy are commonly reported by postmenopausal women and are a primary reason they seek therapy. Whereas estrogen and HTs reduce hot flush frequency and severity and treat vulvar and vaginal atrophy, raloxifene—approved for postmenopausal osteoporosis prevention and treatment—can exacerbate hot flushes and vaginal atrophy.^19,20

The incidence of hot flushes was collected from patient daily diary cards so that occurrence of hot flushes at weeks 9 to 12 with bazedoxifene/CE could be compared with placebo. The median numbers of hot flushes per week at screening and at weeks 9 to 12 are shown in FIGURE 3. All treatment groups showed numeric reductions in the median number of hot flushes at weeks 9 to 12 compared with screening. As expected, both doses of CE alone and CE/MPA significantly reduced hot flushes compared with placebo (P < .05). Hot flush frequency also significantly decreased with all doses (5, 10, and 20 mg) of bazedoxifene added to CE 0.625 mg, and bazedoxifene 5 mg plus CE 0.3 mg compared with placebo. Bazedoxifene alone at 5 mg did not influence the median number of hot flushes compared with placebo. Overall results were similar for hot flush severity.

The vaginal maturation index (VMI) was also measured at baseline and after 84 days of treatment. Descriptive statistics were used to summarize VMI data and showed that all treatment groups, except for bazedoxifene 5 mg, bazedoxifene 20 mg plus CE 0.3 mg, and placebo, resulted in a change in VMI that was reflective of an increase in superficial cells, consistent with estrogenization.

Unlike raloxifene, bazedoxifene alone did not worsen hot flushes or vaginal maturation, supporting its use in combination with CE. These preliminary results suggest that bazedoxifene at an appropriate dose with CE will not block the beneficial effects of CE on hot flushes or vaginal atrophy.

Bone protection

Bone loss is greatest during the initial years of menopause.²¹ About 20% of lifetime femoral neck loss and 30% of trochanteric loss occurs in the early menopausal period.²² Thus, in addition to treatment of menopausal symptoms during the early menopausal period, it may also be important to prevent bone loss.

Preliminary, short-term effects of the bazedoxifene/CE combinations on bone physiology were evaluated by examining N-telopeptide and other bone markers. The median change from baseline to day 84 for urinary N-telopeptide was analyzed. Compared with placebo, both doses of CE and CE/MPA significantly reduced urinary N-telopeptide, as expected (P < .05). With the addition of all doses of bazedoxifene to either CE 0.3 mg or 0.625 mg, significant reductions in N-telopeptide versus placebo were achieved (P < .05). With CE 0.625 mg alone and when bazedoxifene 10 or 20 mg was added to CE 0.625 mg, the reductions were slightly less than those observed with CE/MPA (P < .05). Similar favorable effects of bazedoxifene/CE were observed on urinary C-telopeptide, urinary deoxypyridinoline, and serum osteocalcin. These preliminary results are consistent with preclinical data in which bazedoxifene has been shown to preserve bone in rats.²

Breast tenderness

Breast symptoms are also a common reason why menopausal women (about 9% to 13%) discontinue HT.^17,18 Breast pain or tenderness is a common treatment-emergent side effect reported in clinical studies of various HTs.^11-13,23 In this study of bazedoxifene/CE, no significant differences in breast tenderness were observed between any of the bazedoxifene doses with CE 0.625 mg versus placebo. Consistent with previous reports, a significant increase in breast tenderness was found with CE 0.625 mg (46%; P = .011) and CE/MPA (43%; P = .020) compared with placebo (17%). No significant differences between placebo and either bazedoxifene 5 mg or CE 0.3 mg were observed. In conjunction with the amenorrhea rates observed with bazedoxifene/CE, these results indicate an improved tolerability for this new paradigm of menopausal therapy.

Conclusion

Preliminary clinical data with bazedoxifene/CE demonstrate a favorable tissuespecific profile. The pairing of estrogens and a SERM in this TSEC protected the endometrium, and at the same time significantly reduced frequency and severity of hot flushes, improved vaginal maturation, and had favorable effects on bone physiology. Importantly, bazedoxifene/CE provided exceptional tolerability, as demonstrated by rates of amenorrhea and breast tenderness similar to that of placebo.

The effects of bazedoxifene/CE on the endometrium indicate that, at appropriate doses, its effects were comparable to those of standard HT with regard to preventing endometrial stimulation and improved amenorrhea rates. In contrast, the pairing of estradiol and raloxifene, another potential TSEC, did not protect the endometrium.¹ This study also demonstrates that the appropriate dose combination of bazedoxifene and CE is important to ensure that the therapy protects the endometrium, and at the same time treats vasomotor symptoms. For example, bazedoxifene 20 mg added to CE 0.625 mg effectively prevented endometrial stimulation and reduced hot flush frequency and severity. Preclinical data also demonstrate the importance of the right estrogen/SERM combination and dose. In a rat model of hot flushes, bazedoxifene at its bonesparing dose did not antagonize the lowering of tail temperature with estrogen, whereas raloxifene at its bonesparing dose antagonized estrogen’s tail temperature reduction.³

In conclusion, the unique pharmacology of this TSEC containing bazedoxifene/CE provides a clinical profile that has the potential to provide a nextgeneration menopausal therapy with improved tolerability and to change the way women and physicians approach menopausal therapy.

Disclosure

Dr Pickar reported the following potential conflicts of interest: he is an employee of Wyeth Research and is a board member of the International Menopause Society.

The author appreciates the assistance of Kathleen Ohleth, PhD, for manuscript preparation.

Sexuality, Reproduction & Menopause ©2008 Quadrant HealthCom Inc.