Jurnal Menopause Ku

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Mini review

Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide Santiago Palacios a∗ , Heather Currie b , Tomi S. Mikkola c , Erika Dragon d a

Instituto Palacios, Madrid, Spain NHS Dumfries & Galloway, Dumfries, Scotland, United Kingdom Helsinki University Central Hospital, Helsinki, Finland d Pfizer, Global Innovative Pharma, Europe, Paris, France b c

a r t i c l e

i n f o

Article history: Received 30 October 2014 Received in revised form 9 January 2015 Accepted 11 January 2015 Available online xxx Keywords: Menopause Hot flashes Postmenopausal hormone replacement therapy Selective estrogen receptor modulators (SERMs) Bazedoxifene Osteoporosis

a b s t r a c t Current guidelines recommend that hormone therapy (HT) in postmenopausal women with a uterus include a progestin to protect against endometrial hyperplasia. However, many concerns relating to HT use appear to be related to the progestin component, including cardiovascular risk, breast stimulation, and irregular vaginal bleeding. Conjugated estrogens (CE) combined with the selective estrogen receptor modulator bazedoxifene (BZA) is a new progestin-free HT option for alleviating estrogen deficiency symptoms in postmenopausal women with a uterus for whom treatment with progestin-containing therapy is not appropriate. Five double-blind, randomized, placebo-controlled, phase 3 studies, known as the Selective estrogens, Menopause, And Response to Therapy (SMART) trials have investigated the efficacy of CE/BZA for relieving vasomotor symptoms (VMS), and effect on bone mass, as well as endometrial and breast safety in postmenopausal women. In a 12-week study, CE 0.45 mg/BZA 20 mg significantly reduced the number and severity of hot flushes compared with placebo at weeks 4 and 12. Unlike estrogen-progestin therapy (EPT), CE 0.45 mg/BZA 20 mg did not increase breast density compared with placebo. In clinical trials up to 2 years, CE/BZA had a favorable tolerability profile, demonstrated by amenorrhea rates similar to placebo. Vascular disorders including venous thromboembolic events (pulmonary embolism, retinal vein thrombosis, deep vein thrombosis, and thrombophlebitis) were rare events, occurring in less than 1 per 1000 patients. CE/BZA was associated with significantly higher incidences of amenorrhea and lower incidences of bleeding compared with CE/medroxyprogesterone acetate in 2 comparative trials. Therefore, CE 0.45 mg/BZA 20 mg provides an effective, well-tolerated, progestin-free alternative to EPT for postmenopausal women with a uterus. © 2015 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Efficacy of CE/BZA in phase 3 clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safety and tolerability concerns and contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appropriate candidates for CE/BZA therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author. Tel.: +34 915780517; fax: +34 914319951. E-mail address: [email protected] (S. Palacios). http://dx.doi.org/10.1016/j.maturitas.2015.01.003 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hormone therapy (HT) is established as the most effective therapy for vasomotor symptoms (e.g., hot flushes, night sweats) in women younger than 60 years [1]. The addition of a progestogen to systemic estrogen (estrogen-progestin therapy [EPT]) is recommended for nonhysterectomized women to prevent endometrial cancer [2]. Many concerns about HT appear to be related to the progestin component, as coronary heart disease risk, increased mammographic breast density, breast cancer risk, breast pain, and irregular vaginal bleeding occur more frequently with EPT than with estrogen therapy (ET) [3–6]. Thus, there is a need for progestinfree treatment options that protect the endometrium, with a clinically evidenced efficacy and improved tolerability/safety profile. Conjugated estrogens (CE)/bazedoxifene (BZA) (CE/BZA; Duavive® , Duavee® ) is a novel tissue selective estrogen complex (TSEC) combining estrogens with a selective estrogen receptor modulator (SERM). The rationale for TSEC development was that the SERM component would minimize adverse estrogenic effects on the endometrium and breast, while maintaining the beneficial effects of estrogens on menopausal symptoms [7]. BZA was specifically selected as this SERM because it showed favorable preclinical effects on the skeleton, vasomotor activity, and lipid metabolism, as well as mammary and uterine safety [8]. Gene expression profiling of CE in combination with 3 different SERMs (BZA, raloxifene, and lasoxifene) showed differential patterns of gene expression, indicating that different SERM/CE combinations may have distinct clinical activities [9]. Preclinical data have shown that whereas CE alone stimulates proliferation of MCF-7 and T47D human breast cancer cells and reduces cell apoptosis, the addition of BZA at an adequate dose level abrogates these effects [10]. In a separate analysis, BZA was also shown to be a more potent inhibitor of CE-dependent in vitro breast cancer cell proliferation than raloxifene and lasoxifene. A phase 3 study of BZA alone in postmenopausal women with osteoporosis demonstrated a favorable long-term safety profile in the endometrium, breast, and reproductive tract over 7 years [11]. 2. Efficacy of CE/BZA in phase 3 clinical trials CE 0.45 mg/BZA 20 mg once daily tablet (Duavive® ) was recently approved in the European Union for treatment of estrogen deficiency symptoms in postmenopausal women with a uterus (≥12 months since last menses) for whom treatment with progestincontaining therapy is not appropriate [12]. CE 0.45 mg/BZA 20 mg is also approved in the United States (Duavee® ) for treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause and prevention of postmenopausal osteoporosis [13]. Safety and efficacy of CE/BZA are supported by 5 double-blind, randomized, placebo- and active-controlled, phase 3 Selective estrogens, Menopause, And Response to Therapy (SMART) trials (Table 1) [14–20]. In SMART-2, CE 0.45 mg/BZA 20 mg significantly reduced the mean daily number of moderate to severe hot flushes by 74% at week 12, and significantly reduced hot flush severity during weeks 3 through 12 (p < 0.001 vs placebo) [15]. In SMART-3, CE 0.45 mg/BZA 20 mg significantly increased superficial cells, decreased parabasal cells, and reduced vaginal dryness compared with placebo in postmenopausal women with moderate to severe symptoms of vulvar-vaginal atrophy (VVA) at baseline;

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however, the most bothersome VVA symptom and vaginal pH were not statistically significantly affected versus placebo [16]. In the 1year SMART-5 study, CE 0.45 mg/BZA 20 mg showed an increase of 0.24% from baseline in lumbar spine BMD at month 12 compared with a decrease of 1.28% for placebo—a significant (p < 0.01) difference of +1.52% [18]. CE/BZA also exhibited beneficial effects on sleep parameters and menopause-related quality of life [18,20,21].

3. Safety and tolerability concerns and contraindications CE/BZA was well tolerated in the SMART trials; rates of discontinuation due to adverse events were low and similar to placebo (Fig. 1 [SMART-5]) [15–19]. Higher breast density has been shown to be associated with lower mammographic sensitivity (i.e., ability to detect cancer at screening) [22]. In the SMART-5 study, mean mammographic breast density decreased to a comparable extent from baseline to 1 year with CE/BZA (−0.38%) and placebo (−0.44%) while HT (CE/MPA) significantly (p < 0.001) increased breast density (+1.60%) from baseline compared with placebo [23]. Similar reductions in breast density were reported for CE/BZA and placebo at 2 years in an ancillary study to SMART-1 [24]. Incidence of breast cancer was low and similar to placebo during up to 2 years of use in the SMART trials [23,24]. The incidence of breast pain/tenderness among women treated with CE/BZA was similar to placebo across SMART trials [15–19] and significantly lower than with CE/MPA in SMART-4 and SMART-5 [17,18]. The addition of BZA to CE reduces the risk of endometrial hyperplasia that can occur with estrogen-only use [12]. Through 12- and 24-month follow-up in the SMART trials, there was no increased risk of endometrial hyperplasia with CE 0.45 mg/BZA 20 mg [14,18]. Incidences of uterine bleeding and spotting were low and similar to placebo [17,18,25]. In SMART-4 and SMART-5, CE 0.45 mg/BZA 20 mg was associated with a significantly higher rate of amenorrhea (Fig. 2 [SMART-5]) and lower incidence of bleeding compared with CE/MPA [17,18]. In one study, amenorrhea was reported in 97% of the women who received CE 0.45 mg/BZA 20 mg during months 10 to 12 [12]. As with other HT, abnormal bleeding requires diagnosis before initiating CE/BZA, and any persistent/recurrent bleeding during treatment warrants investigation to rule out malignancy. Although CE and BZA individually have been linked to increased venous thromboembolism (VTE) risk [26,27], there appears to be no added risk of combining the two. Across all the phase 3 studies, VTE was a rare event, affecting less than 1 person per 1000 patients [12]. There were few VTEs in the SMART studies (CE 0.45 mg/BZA 20 mg: n = 3; placebo: n = 1; all deep vein thromboses) [15–19,28]. Although the rates of myocardial infarction with CE/BZA were similar to placebo in the SMART trials, effects of CE/BZA (Fig. 2) on the cardiovascular system require further data collection and analysis. In nonhuman primates (postmenopausal monkeys) fed a high-fat, high-cholesterol diet, CE modestly reduced the severity of atherosclerosis and complicated plaques in the common carotid artery; the addition of BZA did not significantly attenuate these benefits [29]. Statistical power to evaluate VTE and cardiovascular risks is limited by the small number of such events and lack of long-term follow-up data from the SMART trials. If prolonged immobilization is anticipated following elective surgery, CE/BZA should be stopped temporarily beginning 4 to 6 weeks before surgery [12]. Treatment should not be restarted until the woman is completely mobilized [12].

Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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Table 1 Study designs of the SMART trials.

N (randomized)

SMART-1 [14]

SMART-2 [15]

SMART-3 [16]

SMART-4 [17]

SMART-5 [18]

3544

332

652

1083

1886

Key eligibility criteria Aged 40 to 75 years

Postmenopausal women with a uterus Aged 40 to 65 years Aged 40 to 65 years Aged 40 to 65 years ≥1 moderate to severe ≥7 moderate to severe daily hot flushes VVA symptoms 12 weeks 12 weeks 1 year (1-year extension)

Aged 40 to 65 years

Study duration

2 years

Treatments administered (once-daily oral doses)

• CE 0.625 or 0.45 mg each with BZA 10, 20, or 40 mg • Raloxifene 60 mg • Placebo

• CE 0.45 mg/BZA 20 mg • CE 0.625 mg/BZA 20 mg • Placebo

• CE 0.45 mg/BZA 20 mg • CE 0.625 mg/BZA 20 mg • BZA 20 mg • Placebo

• CE 0.45 mg/BZA 20 mg • CE 0.625 mg/BZA 20 mg • CE 0.45 mg/MPA 1.5 mg • Placebo

• CE 0.45 mg/BZA 20 mg • CE 0.625 mg/BZA 20 mg • BZA 20 mg • CE 0.45 mg/MPA 1.5 mg • Placebo

Primary endpoints

• Incidence of endometrial hyperplasia

• Frequency/severity of hot flushes

• Vaginal maturation • Vaginal pH • Most bothersome symptom

• Incidence of endometrial hyperplasia • Bone mineral density

• Incidence of endometrial hyperplasia • Bone mineral density

Secondary endpoints

• Bone mineral density • Bone turnover markers • Frequency/severity of hot flushes • VVA measures • Sleep • Menopause-specific quality of life

• Sleep • Menopause-specific quality of life • Breast pain

• Individual VVA symptoms (dryness, itching/irritation, dyspareunia) • Sexual function • Satisfaction with treatment • Menopause-specific quality of life

• Amenorrhea profile • Breast pain

• Osteoporosis parameters • Bleeding • Breast density • Breast tenderness • Sleep • Menopause-specific quality of life

1 year

SMART, Selective estrogens, Menopause, And Response to Therapy; VVA, vulvar-vaginal atrophy; BZA, bazedoxifene; CE, conjugated estrogens; MPA, medroxyprogesterone acetate.

CE/BZA had favorable effects on lipid profile in the SMART trials, significantly lowering total and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol, compared with placebo [15,16,19]. CE/BZA had minimal effects on coagulation profile, consisting of small decreases from baseline in fibrinogen and plasminogen activator inhibitor type 1 activities, and small increases in plasminogen activity [19]. In pooled analyses

of the SMART trials, CE/BZA was not associated with increases in body weight or body mass index compared with placebo [30]. 4. Appropriate candidates for CE/BZA therapy CE/BZA was studied in healthy nonhysterectomized postmenopausal women, on average 53 to 56 years of age

Fig. 1. Summary of selected safety and tolerability parameters in SMART-5 [18]. a Overall p < 0.05. bazedoxifene; MPA, medroxyprogesterone acetate; TEAE, treatment-emergent adverse event.

b

Overall p < 0.001. AE, adverse event; CE, conjugated estrogens; BZA,

Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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Fig. 2. Rates of cumulative amenorrhea for cycles 1 to 13 among postmenopausal women taking CE/BZA, BZA, CE/MPA, or placebo in SMART-5. Reprinted with permission from endocrine society [18]. a P < 0.001 vs all other treatment groups. CE, conjugated estrogens; BZA, bazedoxifene; MPA, medroxyprogesterone acetate.

Table 2 Characteristics of women enrolled in the SMART trials [14–18,20]. Characteristic Age BMI Race Time since last natural menstrual period Vasomotor symptoms (SMART-2) Vulvar-vaginal atrophy symptoms (SMART-3)

Average participanta

Eligibility criteria Healthy women postmenopausal women with intact uterus 40 to 65 years (SMART-1: 40 to 75 years) ≤34 kg/m2 (≤32.2 kg/m2 in SMART-1) All ≥12 months or ≥6 months with appropriate FSH level ≥7 moderate to severe hot flushes per day or 50 hot flushes per week ≥1 moderate to severe vulvar-vaginal symptom (vaginal dryness, irritation/itching, or pain with intercourse)

Vaginal cytological smear: ≤5% superficial cells Vaginal pH: >5 a

53 to 56 years 25 to 26 kg/m2 Caucasian: 76% to 94% ∼4 to 8 years ∼10 moderate and severe hot flushes per day Most bothersome symptom: Pain with intercourse: 43% to 59% Vaginal dryness: 30% to 41% Vaginal itching or irritation: 11% to16% 0.8% to 1.0% superficial cells Vaginal pH: ∼6.2

BMI, body mass index; FSH, follicle stimulating hormone; SMART, Selective estrogens, Menopause, And Response to Therapy Trial. Based on mean baseline characteristic across groups.

(Table 2) [14–18]. Efficacy of CE/BZA for VMS has been demonstrated in women experiencing at least 7 moderate to severe hot flushes per day at baseline [15]. Thus, we recommend CE/BZA for women with frequent, bothersome hot flushes. CE/BZA can be considered in women for whom progestins are inappropriate or for whom the benefit-risk profile is assessed as favorable compared with progestin-containing HT. Recommendations about which to use cannot be made based on efficacy, as there are few direct comparisons between CE/BZA and EPT. CE/BZA may be considered for women who have experienced bothersome vaginal bleeding or breast pain/tenderness, or other intolerable side effects of progestin-containing therapy (e.g., nausea, hirsutism, headache, dizziness, weight gain). In addition, exogenous progestins have been associated with cyclical mild depression and mood symptoms similar to those of premenstrual syndrome or premenstrual dysphoric disorder in postmenopausal women [31,32]. Oral progestin-containing therapy is associated with decreased glucose tolerance and increased insulin resistance [33,34]. Unlike ET, EPT has been associated with increased breast density [4,35], which may impede mammographic detection of breast cancer and serve as an independent risk factor for breast cancer [36]. Furthermore, given the Women’s Health Initiative trial results showing an increased risk of breast cancer in women taking EPT compared with ET [3], some women may decline progestin-containing HT based on concerns about breast cancer risk. Such women may wish to

consider progestin-free treatment with CE/BZA, with the understanding that long-term data on breast cancer risk are not currently available. 5. Conclusion CE/BZA is an effective, progestin-free treatment for menopauserelated hot flushes. Unlike EPT, CE/BZA does not increase breast density. At 10 to 12 months, amenorrhea was reported in about 97% of the women who received CE/BZA, a rate similar to placebo [12]. Across all the phase 3 studies, VTE was a rare event affecting less than 1 person per 1000 patients. Thus, CE/BZA fills an important need for a progestin-free alternative to traditional EPT for nonhysterectomized postmenopausal women who cannot tolerate progestin-containing therapy or who wish to avoid potential safety concerns associated with progestins. However, when comparing the safety profiles of progestin-containing therapy versus CE/BZA, it should be kept in mind that long-term safety data for CE/BZA are not yet available. 6. Practice points • CE/BZA is a novel, progestin-free treatment option for managing symptoms of estrogen deficiency in nonhysterectomized postmenopausal women.

Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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• CE/BZA should not be used in women with undiagnosed abnormal bleeding, known or suspected breast cancer, or spontaneous venous or arterial thromboembolism. • Unlike EPT, CE/BZA does not increase breast density. • CE/BZA can be considered in women for whom progestins are inappropriate or for whom the benefit-risk profile is assessed as favorable compared with progestin-containing HT (e.g., women with depression, insulin resistance, those who experienced bothersome side effects on progestin-containing therapy).

[2]

[3]

[4]

[5]

7. Research agenda • Menopausal symptoms are chronic and often treated for ≥5 years. Data on breast cancer risk and other safety outcomes of CE/BZA use beyond 2 years are needed. • Further study on VTE risk is needed to confirm the low incidence seen in the SMART studies. • Further comparative randomized controlled trials of CE/BZA vs EPT are needed to inform treatment selection.

Disclosures S Palacios has been a symposium speaker or advisory board member for Servier, Pfizer, GSK, Abbott, Ferrer, Bioiberica, Shionogi and Amgen and has received research grants and/or consulting fees from Pfizer, Servier, Amgen, MSD, Preglem, Leon Farma, and Gynea. H Currie has received educational grants and speaker fees, and has been an advisory board member for several pharmaceutical and nonpharmaceutical companies. T Mikkola has been a speaker and/or received consulting fees from AMS, Astellas Pharma, Bayer, Boston Scientific, Novo Nordisk, and Pfizer. E Dragon is an employee of Pfizer Inc.

[6] [7] [8]

[9]

[10]

[11]

[12] [13] [14]

[15]

Contributors Santiago Palacios, Heather Currie, Tomi S. Mikkola, and Erika Dragon contributed equally to the conception of this paper, critically revised it for important intellectual content, and approved the final version submitted. Competing interest S Palacios has been a symposium speaker or advisory board member for Servier, Pfizer, GSK, Abbott, Ferrer, Bioiberica, Shionogi and Amgen and has received research grants and/or consulting fees from Pfizer, Servier, Amgen, MSD, Preglem, Leon Farma, and Gynea. H Currie has received educational grants and speaker fees, and has been an advisory board member for several pharmaceutical and nonpharmaceutical companies. T Mikkola has been a speaker and/or received consulting fees from AMS, Astellas Pharma, Bayer, Boston Scientific, Novo Nordisk, and Pfizer. E Dragon is an employee of Pfizer Inc. Provenance and peer review

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

Provenance and peer review: Commissioned and externally peer reviewed. This is a mini review.

[24]

Acknowledgments

[25]

Medical writing assistance was provided by Lela Creutz, PhD and Lauren Cerruto, of Peloton Advantage, LLC (supported by Pfizer).

[26]

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Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003

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Please cite this article in press as: Palacios S, et al. Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide. Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.01.003