THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 0, Number 0, 2016, pp. 1–7 ª Mary Ann Liebert, Inc. DOI: 10.1089/acm.2015.0021
Original Article
A Selective Estrogen Receptor Beta Agonist for the Treatment of Hot Flushes: Phase 2 Clinical Trial Mary A. Tagliaferri, MD, LAc,1 Margit C. Tagliaferri, MD,1 Jennifer M. Creasman, PhD,2 and William D. Koltun, MD3
Abstract
Objective: The aim of this study was to evaluate the safety, tolerability, and efficacy of a selective estrogen receptor beta (ERb) agonist, Dr. Tagliaferri’s Menopause Formula (MF102), to treat the symptoms of menopause. Methods: An open-label trial of MF102 taken for 12 weeks by 30 postmenopausal women aged 40–65 years, who experienced a minimum of five moderate to severe hot flushes per day. The primary efficacy outcome was a change in the frequency of moderate to severe hot flushes from baseline to week 12. A change in the frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks was a secondary endpoint. Lipid profile and endometrial thickness were also evaluated. Results: Thirty postmenopausal women with an average of nine moderate to severe hot flushes per day were treated with MF102 4 g/day; 27 participants completed the study. The median percent reduction in moderate to severe hot flushes was 71% ( p < 0.001). The median percent reduction in hot flushes that woke participants from their sleep was 54% ( p < 0.001). Low-density lipoprotein (LDL-C) and total cholesterol both declined significantly from baseline. There were no serious adverse events, reports of abnormal uterine bleeding, or significant changes in double-wall endometrial thickness. Conclusions: Treatment with MF102 resulted in a marked decrease in the frequency of moderate to severe hot flushes, was well-tolerated, and demonstrated no safety concerns.
rived by a team of physicians knowledgeable in TCM and estrogen receptor biology for the purpose of developing a natural alternative treatment to hormone therapy. MF102 is a selective estrogen receptor beta (ERb) agonist that does not exhibit transactivation activity for estrogen receptor alpha (ERa; Fig. 1). Thermoregulatory control centers of the brain are rich with ERb receptors. During the menopausal transition, hot flushes may result from fluctuations in stimulation of these receptors, due to the variability of perimenopausal endogenous estrogen levels. ERb-selective agonists may decrease these hot flushes by providing more stable ERb stimulation.8,9 Moreover, stimulation of ERb receptors is not associated with the in vitro and in vivo breast and uterine cell proliferation inherent in ERa stimulation.10–15 Thus, ERb agonists theoretically do not carry the same risks for breast and uterine tumor formation inherent in the use of traditional nonselective ER-based estrogenic treatments.
Introduction
V
asomotor symptoms are reported by 60–80% of menopausal women,1 and approximately one-third of this population reports symptoms severe enough to seek treatment.2 While estrogens are effective in reducing the severity of vasomotor symptoms,3 concerns have been raised about the increased risks of uterine cancer,4 breast cancer, and cardiovascular events associated with use of estrogenbased postmenopausal hormone therapy (HT).5,6 Selective serotonin reuptake inhibitors (SSRIs) have shown modest efficacy in the treatment of hot flushes but have side effects that limit their use.7 Dr. Tagliaferri’s Menopause Formula (MF102) is an over-the-counter combination of 10 botanical agents used in Traditional Chinese Medicine (TCM) to treat yin deficiency heat, a TCM diagnosis often ascribed to menopausal women experiencing vasomotor symptoms. The formula was de1 2 3
Dr. Tagliaferri Formulas, Inc., San Anselmo, CA. Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, CA. Medical Center for Clinical Research, San Diego, CA.
1
2
TAGLIAFERRI ET AL.
FIG. 1. Dose-dependent activation of a minimal thymidine kinase (tk) promoter ERE-tk-Luc with estrogen receptor alpha and estrogen receptor beta.
An open label, uncontrolled trial was performed in healthy, postmenopausal women to investigate the safety, tolerability, and efficacy of the ERb agonist, MF102, in treating moderate to severe hot flushes. Materials and Methods Study design
An open-label, uncontrolled prospective study was conducted to evaluate the safety, tolerability, and efficacy of a selective ERb botanical extract, MF102, for the treatment of postmenopausal hot flushes. The study protocol and informed consent were approved by the Schulman Institutional Review Board (IRB), and this study was conducted in accordance with Good Clinical Practice and the International Conference on Harmonization Guidelines. All study participants were recruited at the Medical Center for Clinical Research in San Diego, CA, from October 2013 to May 2014. Eligible participants were generally healthy postmenopausal women aged 40–65 years who reported either five or more moderate to severe hot flushes per day, or 35 per week. Participants were excluded for the following reasons: history of malignancy (with the exception of nonmelanoma skin cancer or cervical cancer, with diagnosis and treatment completion more than 1 year prior to screening); known carrier of BRCA1 or BRCA2; abnormal mammogram or breast examination suggestive of cancer within 12 months of screening; abnormal Pap smear or pelvic examination suggestive of cancer within 12 months of screening; doublewall endometrial thickness >8 mm on transvaginal ultrasound; or any unexplained uterine bleeding within 6 months prior to screening. In addition, participants were excluded if they had a history of cardiovascular disease or venous thromboembolism, or uncontrolled hypertension. Participants with active liver disease or a history of impaired hepatic function were also excluded. A washout period was required for women using hormone therapy at baseline. Women using herbal or dietary supplements purported to treat hot flushes or dietary supplements with known estrogenic or progestogenic activity within 2 weeks of screening were excluded. At baseline, data regarding demographics, medical and gynecological history, and medication use were captured. All participants had a physical examination, including blood pressure and heart rate, a breast and pelvic exam, laboratory tests (complete blood count, chemistry panel, and cholesterol panel), and, in women with an intact uterus,
a transvaginal ultrasound to measure endometrial doublewall thickness. While on study medication, participants were either contacted by phone or came to the clinic at weeks 2 and 8, and had a clinic visit after 4 and 12 weeks of treatment to collect hot-flush diaries and assess adherence to study medication, and for the patient to report any adverse events. Capsules of MF102 were counted to assess adherence to treatment, and adverse events were elicited and recorded at each visit. Two weeks after discontinuing study medication, participants were contacted by phone to collect information on adverse events. Study medication
MF102 is a spray-dried powder of a purified aqueous extract of 10 botanical species with known ERb selectivity. See Table 1 for a list of botanical agents and their proportions in MF102. MF102 was manufactured in accordance with Food and Drug Administration (FDA) Good Manufacturing Practices, and certificates of analyses were provided to the Shulman IRB and kept on file. During the study, MF102 was delivered as capsules, each containing 500 mg of botanical extract. Participants took four capsules orally twice a day, 30 minutes after meals. Treatment was 4 g/day for 12 weeks.
Table 1. MF102: Per Capsule Content Latin name
Pin yin name
Percent in capsule
mg
Radix rehnmanniae Fructus corni officinalis Radix dioscoreae oppositae Sclerotium poriae cocos Cortex moutan radicis Rhizoma alismatis orientalis Anemarrhena rhizome Glycyrrhiza uralensis Radix astragali Atractylodis macrocephalae rhizoma
Shu Di Huang Shan Zhu Yu Shan Yao
12% 12% 12%
60 60 60
Fu Ling Mu Dan Pi Ze Xie
10% 10% 10%
50 50 50
Zhi Mu Gan Cao Huang Qi Bai Zhu
10% 10% 6% 8%
50 50 30 40
100%
500
MF102, Dr. Tagliaferri’s Menopause Formula.
AN ER BETA AGONIST FOR MENOPAUSAL HOT FLUSHES
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Mechanism of action
Statistical analyses
The effect of estrogen on hot flushes is mediated by estrogen receptors ERa and ERb, both of which are present in the thermoregulatory center of the brain, the hypothalamus. To determine if MF102 regulates ERa or ERb, human U2OS osteosarcoma cells were co-transfected with a classical estrogen response element (ERE) upstream of a minimal thymidine kinase (tk) promoter (ERE-tk-Luc) and expression vectors for human ERa and ERb. The U2OS cell lines were cultured and maintained as previously described.16 A single copy of the vitellogenin A2 ERE upstream of the minimal tk promoter (ERE tk-Luc) was co-transfected into U2OS cells with an expression vector for human ERa or ERb. After transfection, the cells were treated with increasing amounts of MF102, and luciferase activity was measured. The cells were treated with 10 nM E2 or 10–100 lg/mL of MF102 for 18 h and luciferase activity was measured. MF102 produced a dose-dependent activation of ERE-tk-Luc with ERb (Fig. 1), whereas no significant activation was observed with ERa. These results demonstrate that MF102 is an ERb-selective agonist.
All analyses completed for the primary and secondary outcomes were by the intent-to-treat method. Incomplete hot-flush diary data at any given point were imputed using the last observation carried forward method. For example, a participant with missing hot-flush data for days 6 and 7 had hot-flush data from day 5 carried forward through day 7. If a participant did not record at least one day of daily diary hotflush data for a given week, no imputation was performed for that week. All nonmissing observations were included in the analyses. Mixed regression models were used to estimate the change in reported hot flushes over time, employing maximum likelihood estimates to estimate model parameters.18 The hot-flush outcomes were overdispersed, such that the observed variance of number of hot flushes was equal to or greater than the observed mean number of hot flushes. Negative binomial mixed models were fitted to account for the overdispersed outcomes. The primary analysis of efficacy was median percent change from baseline to 12 weeks of treatment in the frequency of moderate to severe hot flushes. The secondary analyses of efficacy were median percent change from baseline to 4 weeks in moderate to severe hot flushes and median percent change in frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks of treatment. p-Values were estimated from negative binomial regression models. All analyses were performed using SAS v9.4 (SAS Institute, Inc., Cary, NC).
Safety and tolerability assessments
To evaluate safety and tolerability, adverse events were captured at weeks 2, 5, 8, 12, and 14. Participants were also advised to contact the clinical site by phone or to schedule an in-person clinic visit at any time during the trial to report adverse events. Physical examinations with vital signs were completed at week 12. In addition, complete blood counts, chemistry panels, lipid panels, and urinalyses were completed at study termination. All blood and urine samples were processed by Enzo Central Laboratories. Endometrial double-wall thickness was assessed at the end of treatment in each participant using transvaginal ultrasound. If a participant reported vaginal spotting or vaginal bleeding, or if the final endometrial double-wall thickness was >8 mm, the plan was to perform diagnostic endometrial biopsies during the study. Adverse events were classified and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) system.
Results Study population
A total of 30 postmenopausal women were enrolled to the study, and 27 participants completed 12 weeks of treatment. The majority of the participants were Caucasian, and their mean age was 56.6 years. At baseline, the average frequency of moderate to severe hot flushes was nine per day, and the average frequency of hot flushes that woke participants from their sleep was 3.2 per night. Baseline demographic and clinical characteristics are described in Table 2. Efficacy outcomes
Efficacy assessments
Hot-flush frequency and severity were recorded in a paper diary modeled after diaries commonly used in previous studies.17 A 7-day diary was completed prior to randomization and during weeks 4, 8, and 12 while on study medication. For each hot flush, severity was rated as 1 (mild), 2 (moderate), or 3 (severe). In addition, participants noted in the diary any hot flush–related awakenings from sleep. Hotflush diaries were reviewed and collected by the study coordinator at the week 5 visit and at the week 12 visit (study completion). The primary efficacy outcome measurement was median percent change in frequency of moderate to severe hot flushes from baseline to 12 weeks of treatment. Secondary endpoints included median percent change in frequency of moderate to severe hot flushes from baseline to 4 weeks of treatment and median percent change in frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks of treatment.
The median percent decrease in the frequency of moderate to severe hot flushes was 54% (95% confidence interval [CI] 49–59; p < 0.001) at 4 weeks and 71% (95% CI 66–76; p < 0.001) at 12 weeks. The median percent reduction in hot flushes awakening participants from sleep from baseline to week 12 was 54% (95% CI 49–59; p < 0.001). Observed median percent changes are presented in Figures 2 and 3. Safety outcomes
During the study, there were no serious adverse events, no reported abnormal vaginal bleeding, and no clinically significant laboratory abnormalities. Three of the 30 participants (10%) reported adverse events that resulted in discontinuation of study treatment (rash, stomach pains, and influenza), and two additional participants reported adverse events (abdominal bloating and bloody nipple exudate) that did not result in discontinuation of study treatment
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Table 2. Baseline and Demographic Characteristics
Median % Reduction in Awakenings from Sleep Due to Hot Flushes 0
MF102 4 g/day (N = 30)
Characteristic
Age, years Mean (SD) 56.6 (4.9) Race, n (%) White 22 (73.3%) Black/African American 8 (26.7%) Ethnicity, n (%) Hispanic or Latino 5 (16.7%) Not Hispanic or Latino 25 (83.3%) Body mass index, kg/m2 Mean (SD) 27.2 (4.5) Length of time experiencing hot flushes, years Mean (SD) 8.0 (4.7) Time since menopause, n (%) 40 mIU/mL, 9 (30.0%) n (%) SD, standard deviation; TVUS, transvaginal ultrasound; FSH, follicle-stimulating hormone.
(Table 3). The nipple exudate could not be demonstrated during a follow-up visit with a surgeon, and a repeat mammogram showed no changes from the mammogram completed prior to enrollment and no suspicious lesions. Of the 30 participants in the study, 21 (70%) who had a uterus underwent measurement of double-wall endometrial thickness via transvaginal ultrasound at baseline and at study end. Mean endometrial thickness was 2.03 mm at baseline and 2.38 mm at 12 weeks; there were no differences in mean endometrial thickness from baseline to study end ( p = 0.16). No participant had an endometrial thickness >8 mm during or at the end of the study. Thus, no endo-
BASELINE
WEEK 4
WEEK 12
-0.1 -0.2 -0.3 -0.4 -0.5
-0.45
-0.6
-0.54
-0.7
FIG. 3. MF102 and median percent change from baseline in the weekly frequency of hot flushes that woke participants from their sleep (intent-to-treat population). p = p-value of change from baseline. metrial biopsies were performed. There were no abnormalities on physical examination, routine laboratory testing, or mammography. Treatment adherence
Treatment adherence was measured by review of diaries at weeks 5 and 12/early termination visits. Mean treatment compliance was 91.1% (range 83–100%). Secondary outcomes
Body mass index (BMI) decreased 1.5% from baseline to 12 weeks ( p = 0.03), total cholesterol decreased 5.3% ( p = 0.01), and low-density lipoprotein (LDL) cholesterol decreased 8% ( p = 0.01; Table 4). Discussion
The emotional and physical distress associated with hot flushes and their attendant sleep disruption and mood changes continues to drive millions of menopausal women to their physicians’ offices every year, seeking prescriptions for relief of symptoms. Additionally, up to 79% of peri- and postmenopausal women between 40 and 60 years of age use over-
Table 3. Number (%) of Participants Reporting Treatment Emergent Adverse Events Median % Reduction in Moderate to Severe Hot Flushes 0 -0.1
0 BASELINE
WEEK 4
WEEK 12
-0.2 -0.3
Adverse event
Gastrointestinal disorders
Abdominal distension/ bloating Gastrointestinal pain Influenza
1 (3.3%)
Rash
1 (3.3%)
Bloody nipple exudate
1 (3.3%)
-0.4 -0.5 -0.6 -0.7 -0.8 -0.9
-0.54 -0.71
FIG. 2. MF102 and median percent change from baseline in the weekly frequency of moderate-to-severe hot flushes (intent-to-treat population). p = p-value of change from baseline.
MF102 4 g/day, n (%)
MedDRA SOC
Infections and infestations Skin and subcutaneous disorders Reproductive system and breast disorders
1 (3.3%) 1 (3.3%)
MedDRA SOC, Medical Dictionary for Regulatory Activities System Organ Class.
AN ER BETA AGONIST FOR MENOPAUSAL HOT FLUSHES
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Table 4. Weight, Body Mass Index, Blood Pressure, and Cholesterol Baseline (N = 30)
Weight (kg) BMI Diastolic blood pressure (mmHg) Systolic blood pressure (mmHg) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL (mg/dL) LDL-C (mg/dL)
End of study (N = 29)
Mean
SD
Mean
SD
p-Value (paired t-test)
73.2 27.2 79.6 118.9 228.0 124.5 66.3 136.4
11.9 4.5 6.3 10.0 40.8 78.6 19.1 35.1
72.3 26.8 79.3 111.6 215.9 140.0 63.7 125.9
11.9 4.5 5.8 9.5 39.6 119.8 18.8 33.5
0.06 0.03 0.68 0.22 0.01 0.26 0.21 0.01
BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation.
the-counter dietary supplements.19 Given the recent evidence that the duration of moderate to severe hot flushes can persist for more than 10 years,20 an urgency exists to bring forth safe and effective novel therapies for vasomotor symptoms. HT, in a variety of different delivery systems and formulations, has been the most frequently prescribed therapy for the symptoms of menopause. However, given the risks of uterine and breast cancer and thrombotic events associated with treatment, a majority of women continue to be reluctant to use HT. Recently, a study of the SSRI paroxetine mesylate (Brisdelle) showed modest efficacy in reduction of hot-flush frequency and led to FDA approval of the drug for treatment of menopausal vasomotor symptoms.21 SSRIs have raised safety concerns, however. Paroxetine mesylate, like its counterpart paroxetine hydrochloride, carries a boxed warning in its package insert for its risk of suicidality. In addition, new studies suggest a link between SSRI use and osteoporosis, and data from the Women’s Health Initiative (WHI) showed an increased risk of stroke and all-cause mortality in postmenopausal women taking SSRIs.22 In previous studies, women have identified a 50% reduction in hot flushes as a clinically meaningful benefit.23,24 Twelve weeks of treatment with MF102, a novel aqueous extract of 10 botanical agents used in TCM, resulted in a statistically significant reduction in the frequency of hot flushes and sleep disturbance. There were no clinically significant adverse events, no reports of abnormal uterine bleeding, and no significant changes in double-wall endometrial thickness. There were small but significant decreases in BMI, total cholesterol, and LDL-C. The women in this trial were carefully monitored for safety and efficacy using well-validated measures. Adherence to study medication and compliance with study procedures were very high, and loss to follow-up was low. Because this trial was small and uncontrolled, the results may be attributed to a placebo effect. However, a 71% reduction in moderate to severe hot flushes is a much greater effect than the observed reductions in placebo groups reported in large, controlled trials of treatments for hot flushes. For example, in the recent placebo-controlled phase 3 trials evaluating paroxetine 7.5 mg daily for hot flushes (recently approved by the FDA for this indication), reductions in moderate to severe hot flushes after 12 weeks of treatment in the placebo groups were 39% and 50%.21 Novel, selective estrogen receptor modulators are needed for treatment of vasomotor symptoms without the deleteri-
ous side effects of menopausal hormone therapy. The effect of estrogens in the treatment of hot flushes is mediated by two estrogen receptors, ERa and ERb, both of which are present in the thermoregulatory center of the brain, the hypothalamus. MF102 acts as a selective ERb agonist and does not cause transactivation of ERa. This selectivity is clinically advantageous; both in vitro and in vivo studies have shown that stimulation of ERa leads to breast and endometrial tissue proliferation, while stimulation of ERb does not induce such proliferation. Moreover, in breast tissue, ERb may inhibit the proliferative effects of ERa.10–14 ERa and ERb are also prominent in cardiovascular tissue. Animal models have shown that the presence of ERb can decrease fibrosis and left ventricular hypertrophy associated with cardiac remodeling due to pressure overload.25 Hence, an ERb agonist such as MF102 may have potential benefit not only in treating menopausal symptoms but also in reducing the cardiac morbidity associated with cardiovascular disease. In the WHI studies, heart-disease risk was greatest among women on HT reporting moderate to severe hot flushes at baseline.22 Moreover, the Study of Women’s Health Across the Nation (SWAN) showed a lower flow-mediated dilation of the brachial artery and more calcified aortic plaques in women with hot flushes.26 The Eindhoven Perimenopausal Osteoporosis Study, including >5523 participants aged 46– 57 years, revealed that women who experience hot flushes and night sweats had higher cholesterol, higher blood pressure, and a higher BMI than women without symptoms did.27 Evidence is thus compelling that hot flushes alone may be a marker of existing cardiovascular disease and/or cardiovascular disease risk factors. If future studies demonstrate that reduction of menopausal hot flushes decreases cardiovascular risk, hot-flush treatment options with minimal untoward side effects would have enormous therapeutic value. MF102 significantly reduced total cholesterol and LDL-C, consistent with the effects of estrogen therapy,28–32 and although this study did not examine the effects of MF102 on clotting factors, other selective ERb agonists derived from botanical agents have not increased coagulation factors. A selective ERb agonist that can decrease vasomotor symptoms and reduce total cholesterol and LDLC while not increasing the risks for breast cancer, uterine cancer, and thromboembolic events would be greatly desired in the clinical setting.
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Given the findings from this study showing the potential for a safer treatment for vasomotor symptoms, research efforts are needed to broaden insight into and support development of MF102 for the treatment of hot flushes and other peri- and postmenopausal women’s health concerns. Conclusions
Treatment with MF102 resulted in a statistically significant and clinically meaningful decrease in the frequency of moderate to severe hot flushes. MF102 was well-tolerated, and its use yielded no safety concerns. These findings support the role of an ERb agonist for treatment of menopausal hot flushes and suggest that MF102 should be evaluated in larger placebo-controlled clinical trials. Author Disclosure Statement
This study was sponsored and funded by Dr. Tagliaferri Formulas, Inc., San Anselmo, CA. Dr. Mary Tagliaferri is a majority owner of Dr. Tagliaferri Formulas, Inc. No competing financial interests exist for the remaining authors.
TAGLIAFERRI ET AL.
12.
13.
14.
15. 16.
17. 18.
References
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Address correspondence to: Mary Tagliaferri, MD, LAc Dr. Tagliaferri Formulas, Inc. 121 San Anselmo Ave, Suite 1634 San Anselmo, CA 94979 E-mail: [email protected]
Original Article
A Selective Estrogen Receptor Beta Agonist for the Treatment of Hot Flushes: Phase 2 Clinical Trial Mary A. Tagliaferri, MD, LAc,1 Margit C. Tagliaferri, MD,1 Jennifer M. Creasman, PhD,2 and William D. Koltun, MD3
Abstract
Objective: The aim of this study was to evaluate the safety, tolerability, and efficacy of a selective estrogen receptor beta (ERb) agonist, Dr. Tagliaferri’s Menopause Formula (MF102), to treat the symptoms of menopause. Methods: An open-label trial of MF102 taken for 12 weeks by 30 postmenopausal women aged 40–65 years, who experienced a minimum of five moderate to severe hot flushes per day. The primary efficacy outcome was a change in the frequency of moderate to severe hot flushes from baseline to week 12. A change in the frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks was a secondary endpoint. Lipid profile and endometrial thickness were also evaluated. Results: Thirty postmenopausal women with an average of nine moderate to severe hot flushes per day were treated with MF102 4 g/day; 27 participants completed the study. The median percent reduction in moderate to severe hot flushes was 71% ( p < 0.001). The median percent reduction in hot flushes that woke participants from their sleep was 54% ( p < 0.001). Low-density lipoprotein (LDL-C) and total cholesterol both declined significantly from baseline. There were no serious adverse events, reports of abnormal uterine bleeding, or significant changes in double-wall endometrial thickness. Conclusions: Treatment with MF102 resulted in a marked decrease in the frequency of moderate to severe hot flushes, was well-tolerated, and demonstrated no safety concerns.
rived by a team of physicians knowledgeable in TCM and estrogen receptor biology for the purpose of developing a natural alternative treatment to hormone therapy. MF102 is a selective estrogen receptor beta (ERb) agonist that does not exhibit transactivation activity for estrogen receptor alpha (ERa; Fig. 1). Thermoregulatory control centers of the brain are rich with ERb receptors. During the menopausal transition, hot flushes may result from fluctuations in stimulation of these receptors, due to the variability of perimenopausal endogenous estrogen levels. ERb-selective agonists may decrease these hot flushes by providing more stable ERb stimulation.8,9 Moreover, stimulation of ERb receptors is not associated with the in vitro and in vivo breast and uterine cell proliferation inherent in ERa stimulation.10–15 Thus, ERb agonists theoretically do not carry the same risks for breast and uterine tumor formation inherent in the use of traditional nonselective ER-based estrogenic treatments.
Introduction
V
asomotor symptoms are reported by 60–80% of menopausal women,1 and approximately one-third of this population reports symptoms severe enough to seek treatment.2 While estrogens are effective in reducing the severity of vasomotor symptoms,3 concerns have been raised about the increased risks of uterine cancer,4 breast cancer, and cardiovascular events associated with use of estrogenbased postmenopausal hormone therapy (HT).5,6 Selective serotonin reuptake inhibitors (SSRIs) have shown modest efficacy in the treatment of hot flushes but have side effects that limit their use.7 Dr. Tagliaferri’s Menopause Formula (MF102) is an over-the-counter combination of 10 botanical agents used in Traditional Chinese Medicine (TCM) to treat yin deficiency heat, a TCM diagnosis often ascribed to menopausal women experiencing vasomotor symptoms. The formula was de1 2 3
Dr. Tagliaferri Formulas, Inc., San Anselmo, CA. Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, CA. Medical Center for Clinical Research, San Diego, CA.
1
2
TAGLIAFERRI ET AL.
FIG. 1. Dose-dependent activation of a minimal thymidine kinase (tk) promoter ERE-tk-Luc with estrogen receptor alpha and estrogen receptor beta.
An open label, uncontrolled trial was performed in healthy, postmenopausal women to investigate the safety, tolerability, and efficacy of the ERb agonist, MF102, in treating moderate to severe hot flushes. Materials and Methods Study design
An open-label, uncontrolled prospective study was conducted to evaluate the safety, tolerability, and efficacy of a selective ERb botanical extract, MF102, for the treatment of postmenopausal hot flushes. The study protocol and informed consent were approved by the Schulman Institutional Review Board (IRB), and this study was conducted in accordance with Good Clinical Practice and the International Conference on Harmonization Guidelines. All study participants were recruited at the Medical Center for Clinical Research in San Diego, CA, from October 2013 to May 2014. Eligible participants were generally healthy postmenopausal women aged 40–65 years who reported either five or more moderate to severe hot flushes per day, or 35 per week. Participants were excluded for the following reasons: history of malignancy (with the exception of nonmelanoma skin cancer or cervical cancer, with diagnosis and treatment completion more than 1 year prior to screening); known carrier of BRCA1 or BRCA2; abnormal mammogram or breast examination suggestive of cancer within 12 months of screening; abnormal Pap smear or pelvic examination suggestive of cancer within 12 months of screening; doublewall endometrial thickness >8 mm on transvaginal ultrasound; or any unexplained uterine bleeding within 6 months prior to screening. In addition, participants were excluded if they had a history of cardiovascular disease or venous thromboembolism, or uncontrolled hypertension. Participants with active liver disease or a history of impaired hepatic function were also excluded. A washout period was required for women using hormone therapy at baseline. Women using herbal or dietary supplements purported to treat hot flushes or dietary supplements with known estrogenic or progestogenic activity within 2 weeks of screening were excluded. At baseline, data regarding demographics, medical and gynecological history, and medication use were captured. All participants had a physical examination, including blood pressure and heart rate, a breast and pelvic exam, laboratory tests (complete blood count, chemistry panel, and cholesterol panel), and, in women with an intact uterus,
a transvaginal ultrasound to measure endometrial doublewall thickness. While on study medication, participants were either contacted by phone or came to the clinic at weeks 2 and 8, and had a clinic visit after 4 and 12 weeks of treatment to collect hot-flush diaries and assess adherence to study medication, and for the patient to report any adverse events. Capsules of MF102 were counted to assess adherence to treatment, and adverse events were elicited and recorded at each visit. Two weeks after discontinuing study medication, participants were contacted by phone to collect information on adverse events. Study medication
MF102 is a spray-dried powder of a purified aqueous extract of 10 botanical species with known ERb selectivity. See Table 1 for a list of botanical agents and their proportions in MF102. MF102 was manufactured in accordance with Food and Drug Administration (FDA) Good Manufacturing Practices, and certificates of analyses were provided to the Shulman IRB and kept on file. During the study, MF102 was delivered as capsules, each containing 500 mg of botanical extract. Participants took four capsules orally twice a day, 30 minutes after meals. Treatment was 4 g/day for 12 weeks.
Table 1. MF102: Per Capsule Content Latin name
Pin yin name
Percent in capsule
mg
Radix rehnmanniae Fructus corni officinalis Radix dioscoreae oppositae Sclerotium poriae cocos Cortex moutan radicis Rhizoma alismatis orientalis Anemarrhena rhizome Glycyrrhiza uralensis Radix astragali Atractylodis macrocephalae rhizoma
Shu Di Huang Shan Zhu Yu Shan Yao
12% 12% 12%
60 60 60
Fu Ling Mu Dan Pi Ze Xie
10% 10% 10%
50 50 50
Zhi Mu Gan Cao Huang Qi Bai Zhu
10% 10% 6% 8%
50 50 30 40
100%
500
MF102, Dr. Tagliaferri’s Menopause Formula.
AN ER BETA AGONIST FOR MENOPAUSAL HOT FLUSHES
3
Mechanism of action
Statistical analyses
The effect of estrogen on hot flushes is mediated by estrogen receptors ERa and ERb, both of which are present in the thermoregulatory center of the brain, the hypothalamus. To determine if MF102 regulates ERa or ERb, human U2OS osteosarcoma cells were co-transfected with a classical estrogen response element (ERE) upstream of a minimal thymidine kinase (tk) promoter (ERE-tk-Luc) and expression vectors for human ERa and ERb. The U2OS cell lines were cultured and maintained as previously described.16 A single copy of the vitellogenin A2 ERE upstream of the minimal tk promoter (ERE tk-Luc) was co-transfected into U2OS cells with an expression vector for human ERa or ERb. After transfection, the cells were treated with increasing amounts of MF102, and luciferase activity was measured. The cells were treated with 10 nM E2 or 10–100 lg/mL of MF102 for 18 h and luciferase activity was measured. MF102 produced a dose-dependent activation of ERE-tk-Luc with ERb (Fig. 1), whereas no significant activation was observed with ERa. These results demonstrate that MF102 is an ERb-selective agonist.
All analyses completed for the primary and secondary outcomes were by the intent-to-treat method. Incomplete hot-flush diary data at any given point were imputed using the last observation carried forward method. For example, a participant with missing hot-flush data for days 6 and 7 had hot-flush data from day 5 carried forward through day 7. If a participant did not record at least one day of daily diary hotflush data for a given week, no imputation was performed for that week. All nonmissing observations were included in the analyses. Mixed regression models were used to estimate the change in reported hot flushes over time, employing maximum likelihood estimates to estimate model parameters.18 The hot-flush outcomes were overdispersed, such that the observed variance of number of hot flushes was equal to or greater than the observed mean number of hot flushes. Negative binomial mixed models were fitted to account for the overdispersed outcomes. The primary analysis of efficacy was median percent change from baseline to 12 weeks of treatment in the frequency of moderate to severe hot flushes. The secondary analyses of efficacy were median percent change from baseline to 4 weeks in moderate to severe hot flushes and median percent change in frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks of treatment. p-Values were estimated from negative binomial regression models. All analyses were performed using SAS v9.4 (SAS Institute, Inc., Cary, NC).
Safety and tolerability assessments
To evaluate safety and tolerability, adverse events were captured at weeks 2, 5, 8, 12, and 14. Participants were also advised to contact the clinical site by phone or to schedule an in-person clinic visit at any time during the trial to report adverse events. Physical examinations with vital signs were completed at week 12. In addition, complete blood counts, chemistry panels, lipid panels, and urinalyses were completed at study termination. All blood and urine samples were processed by Enzo Central Laboratories. Endometrial double-wall thickness was assessed at the end of treatment in each participant using transvaginal ultrasound. If a participant reported vaginal spotting or vaginal bleeding, or if the final endometrial double-wall thickness was >8 mm, the plan was to perform diagnostic endometrial biopsies during the study. Adverse events were classified and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) system.
Results Study population
A total of 30 postmenopausal women were enrolled to the study, and 27 participants completed 12 weeks of treatment. The majority of the participants were Caucasian, and their mean age was 56.6 years. At baseline, the average frequency of moderate to severe hot flushes was nine per day, and the average frequency of hot flushes that woke participants from their sleep was 3.2 per night. Baseline demographic and clinical characteristics are described in Table 2. Efficacy outcomes
Efficacy assessments
Hot-flush frequency and severity were recorded in a paper diary modeled after diaries commonly used in previous studies.17 A 7-day diary was completed prior to randomization and during weeks 4, 8, and 12 while on study medication. For each hot flush, severity was rated as 1 (mild), 2 (moderate), or 3 (severe). In addition, participants noted in the diary any hot flush–related awakenings from sleep. Hotflush diaries were reviewed and collected by the study coordinator at the week 5 visit and at the week 12 visit (study completion). The primary efficacy outcome measurement was median percent change in frequency of moderate to severe hot flushes from baseline to 12 weeks of treatment. Secondary endpoints included median percent change in frequency of moderate to severe hot flushes from baseline to 4 weeks of treatment and median percent change in frequency of hot flushes that woke participants from their sleep from baseline to 12 weeks of treatment.
The median percent decrease in the frequency of moderate to severe hot flushes was 54% (95% confidence interval [CI] 49–59; p < 0.001) at 4 weeks and 71% (95% CI 66–76; p < 0.001) at 12 weeks. The median percent reduction in hot flushes awakening participants from sleep from baseline to week 12 was 54% (95% CI 49–59; p < 0.001). Observed median percent changes are presented in Figures 2 and 3. Safety outcomes
During the study, there were no serious adverse events, no reported abnormal vaginal bleeding, and no clinically significant laboratory abnormalities. Three of the 30 participants (10%) reported adverse events that resulted in discontinuation of study treatment (rash, stomach pains, and influenza), and two additional participants reported adverse events (abdominal bloating and bloody nipple exudate) that did not result in discontinuation of study treatment
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TAGLIAFERRI ET AL.
Table 2. Baseline and Demographic Characteristics
Median % Reduction in Awakenings from Sleep Due to Hot Flushes 0
MF102 4 g/day (N = 30)
Characteristic
Age, years Mean (SD) 56.6 (4.9) Race, n (%) White 22 (73.3%) Black/African American 8 (26.7%) Ethnicity, n (%) Hispanic or Latino 5 (16.7%) Not Hispanic or Latino 25 (83.3%) Body mass index, kg/m2 Mean (SD) 27.2 (4.5) Length of time experiencing hot flushes, years Mean (SD) 8.0 (4.7) Time since menopause, n (%) 40 mIU/mL, 9 (30.0%) n (%) SD, standard deviation; TVUS, transvaginal ultrasound; FSH, follicle-stimulating hormone.
(Table 3). The nipple exudate could not be demonstrated during a follow-up visit with a surgeon, and a repeat mammogram showed no changes from the mammogram completed prior to enrollment and no suspicious lesions. Of the 30 participants in the study, 21 (70%) who had a uterus underwent measurement of double-wall endometrial thickness via transvaginal ultrasound at baseline and at study end. Mean endometrial thickness was 2.03 mm at baseline and 2.38 mm at 12 weeks; there were no differences in mean endometrial thickness from baseline to study end ( p = 0.16). No participant had an endometrial thickness >8 mm during or at the end of the study. Thus, no endo-
BASELINE
WEEK 4
WEEK 12
-0.1 -0.2 -0.3 -0.4 -0.5
-0.45
-0.6
-0.54
-0.7
FIG. 3. MF102 and median percent change from baseline in the weekly frequency of hot flushes that woke participants from their sleep (intent-to-treat population). p = p-value of change from baseline. metrial biopsies were performed. There were no abnormalities on physical examination, routine laboratory testing, or mammography. Treatment adherence
Treatment adherence was measured by review of diaries at weeks 5 and 12/early termination visits. Mean treatment compliance was 91.1% (range 83–100%). Secondary outcomes
Body mass index (BMI) decreased 1.5% from baseline to 12 weeks ( p = 0.03), total cholesterol decreased 5.3% ( p = 0.01), and low-density lipoprotein (LDL) cholesterol decreased 8% ( p = 0.01; Table 4). Discussion
The emotional and physical distress associated with hot flushes and their attendant sleep disruption and mood changes continues to drive millions of menopausal women to their physicians’ offices every year, seeking prescriptions for relief of symptoms. Additionally, up to 79% of peri- and postmenopausal women between 40 and 60 years of age use over-
Table 3. Number (%) of Participants Reporting Treatment Emergent Adverse Events Median % Reduction in Moderate to Severe Hot Flushes 0 -0.1
0 BASELINE
WEEK 4
WEEK 12
-0.2 -0.3
Adverse event
Gastrointestinal disorders
Abdominal distension/ bloating Gastrointestinal pain Influenza
1 (3.3%)
Rash
1 (3.3%)
Bloody nipple exudate
1 (3.3%)
-0.4 -0.5 -0.6 -0.7 -0.8 -0.9
-0.54 -0.71
FIG. 2. MF102 and median percent change from baseline in the weekly frequency of moderate-to-severe hot flushes (intent-to-treat population). p = p-value of change from baseline.
MF102 4 g/day, n (%)
MedDRA SOC
Infections and infestations Skin and subcutaneous disorders Reproductive system and breast disorders
1 (3.3%) 1 (3.3%)
MedDRA SOC, Medical Dictionary for Regulatory Activities System Organ Class.
AN ER BETA AGONIST FOR MENOPAUSAL HOT FLUSHES
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Table 4. Weight, Body Mass Index, Blood Pressure, and Cholesterol Baseline (N = 30)
Weight (kg) BMI Diastolic blood pressure (mmHg) Systolic blood pressure (mmHg) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL (mg/dL) LDL-C (mg/dL)
End of study (N = 29)
Mean
SD
Mean
SD
p-Value (paired t-test)
73.2 27.2 79.6 118.9 228.0 124.5 66.3 136.4
11.9 4.5 6.3 10.0 40.8 78.6 19.1 35.1
72.3 26.8 79.3 111.6 215.9 140.0 63.7 125.9
11.9 4.5 5.8 9.5 39.6 119.8 18.8 33.5
0.06 0.03 0.68 0.22 0.01 0.26 0.21 0.01
BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation.
the-counter dietary supplements.19 Given the recent evidence that the duration of moderate to severe hot flushes can persist for more than 10 years,20 an urgency exists to bring forth safe and effective novel therapies for vasomotor symptoms. HT, in a variety of different delivery systems and formulations, has been the most frequently prescribed therapy for the symptoms of menopause. However, given the risks of uterine and breast cancer and thrombotic events associated with treatment, a majority of women continue to be reluctant to use HT. Recently, a study of the SSRI paroxetine mesylate (Brisdelle) showed modest efficacy in reduction of hot-flush frequency and led to FDA approval of the drug for treatment of menopausal vasomotor symptoms.21 SSRIs have raised safety concerns, however. Paroxetine mesylate, like its counterpart paroxetine hydrochloride, carries a boxed warning in its package insert for its risk of suicidality. In addition, new studies suggest a link between SSRI use and osteoporosis, and data from the Women’s Health Initiative (WHI) showed an increased risk of stroke and all-cause mortality in postmenopausal women taking SSRIs.22 In previous studies, women have identified a 50% reduction in hot flushes as a clinically meaningful benefit.23,24 Twelve weeks of treatment with MF102, a novel aqueous extract of 10 botanical agents used in TCM, resulted in a statistically significant reduction in the frequency of hot flushes and sleep disturbance. There were no clinically significant adverse events, no reports of abnormal uterine bleeding, and no significant changes in double-wall endometrial thickness. There were small but significant decreases in BMI, total cholesterol, and LDL-C. The women in this trial were carefully monitored for safety and efficacy using well-validated measures. Adherence to study medication and compliance with study procedures were very high, and loss to follow-up was low. Because this trial was small and uncontrolled, the results may be attributed to a placebo effect. However, a 71% reduction in moderate to severe hot flushes is a much greater effect than the observed reductions in placebo groups reported in large, controlled trials of treatments for hot flushes. For example, in the recent placebo-controlled phase 3 trials evaluating paroxetine 7.5 mg daily for hot flushes (recently approved by the FDA for this indication), reductions in moderate to severe hot flushes after 12 weeks of treatment in the placebo groups were 39% and 50%.21 Novel, selective estrogen receptor modulators are needed for treatment of vasomotor symptoms without the deleteri-
ous side effects of menopausal hormone therapy. The effect of estrogens in the treatment of hot flushes is mediated by two estrogen receptors, ERa and ERb, both of which are present in the thermoregulatory center of the brain, the hypothalamus. MF102 acts as a selective ERb agonist and does not cause transactivation of ERa. This selectivity is clinically advantageous; both in vitro and in vivo studies have shown that stimulation of ERa leads to breast and endometrial tissue proliferation, while stimulation of ERb does not induce such proliferation. Moreover, in breast tissue, ERb may inhibit the proliferative effects of ERa.10–14 ERa and ERb are also prominent in cardiovascular tissue. Animal models have shown that the presence of ERb can decrease fibrosis and left ventricular hypertrophy associated with cardiac remodeling due to pressure overload.25 Hence, an ERb agonist such as MF102 may have potential benefit not only in treating menopausal symptoms but also in reducing the cardiac morbidity associated with cardiovascular disease. In the WHI studies, heart-disease risk was greatest among women on HT reporting moderate to severe hot flushes at baseline.22 Moreover, the Study of Women’s Health Across the Nation (SWAN) showed a lower flow-mediated dilation of the brachial artery and more calcified aortic plaques in women with hot flushes.26 The Eindhoven Perimenopausal Osteoporosis Study, including >5523 participants aged 46– 57 years, revealed that women who experience hot flushes and night sweats had higher cholesterol, higher blood pressure, and a higher BMI than women without symptoms did.27 Evidence is thus compelling that hot flushes alone may be a marker of existing cardiovascular disease and/or cardiovascular disease risk factors. If future studies demonstrate that reduction of menopausal hot flushes decreases cardiovascular risk, hot-flush treatment options with minimal untoward side effects would have enormous therapeutic value. MF102 significantly reduced total cholesterol and LDL-C, consistent with the effects of estrogen therapy,28–32 and although this study did not examine the effects of MF102 on clotting factors, other selective ERb agonists derived from botanical agents have not increased coagulation factors. A selective ERb agonist that can decrease vasomotor symptoms and reduce total cholesterol and LDLC while not increasing the risks for breast cancer, uterine cancer, and thromboembolic events would be greatly desired in the clinical setting.
6
Given the findings from this study showing the potential for a safer treatment for vasomotor symptoms, research efforts are needed to broaden insight into and support development of MF102 for the treatment of hot flushes and other peri- and postmenopausal women’s health concerns. Conclusions
Treatment with MF102 resulted in a statistically significant and clinically meaningful decrease in the frequency of moderate to severe hot flushes. MF102 was well-tolerated, and its use yielded no safety concerns. These findings support the role of an ERb agonist for treatment of menopausal hot flushes and suggest that MF102 should be evaluated in larger placebo-controlled clinical trials. Author Disclosure Statement
This study was sponsored and funded by Dr. Tagliaferri Formulas, Inc., San Anselmo, CA. Dr. Mary Tagliaferri is a majority owner of Dr. Tagliaferri Formulas, Inc. No competing financial interests exist for the remaining authors.
TAGLIAFERRI ET AL.
12.
13.
14.
15. 16.
17. 18.
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Address correspondence to: Mary Tagliaferri, MD, LAc Dr. Tagliaferri Formulas, Inc. 121 San Anselmo Ave, Suite 1634 San Anselmo, CA 94979 E-mail: [email protected]
