FOR PROFESSIONAL USE ONLY

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1 Natural Approaches to Women s Health Menopause! FOR PROFESSIONAL USE ONLY Prepared By: Rishma Walji, ND, RAc, PhD CCCEP File # I-P Accreditation Date: November 22, 2016 Expiry Date: November 22, 2017 CEUs 0.5

2 Commercial Disclosure This learning activity has received financial support from WN Pharmaceuticals in the form of program development fees. This learning activity has received in-kind support from WN Pharmaceuticals in the form of logistical support. Disclaimer For Professional Use Only This information is provided for educational purposes only and is not intended for self-diagnosis or self-treatment of a condition that should be interpreted by a qualified health care provider. While the information in this document has been carefully reviewed and reflects current clinical and scientific knowledge, it is subject to change. The Author, Expert Reviewers and Presenter declare no real or perceived conflict with the sponsor company.

3 Instructions Carefully watch this lesson. Complete and submit the on-line quiz. Study each question in the post-test and select the answer which you believe to be most correct. To successfully pass this lesson, a grade of 70% is required. Complete and submit the on-line Program Evaluation form. If you pass, you will receive your Statement of Attendance via or mail for your own records. Introduction Throughout a woman s reproductive life menarche to menopause women face health issues that are specific to their hormones and genetic composition. According to Statistics Canada, women make healthier lifestyle choices and are quicker to react to signs of illness. Women are more likely to consider their health when making food choices as well as complementary and alternative health advice.

4 Learning Objectives Goal: To educate pharmacists on the natural treatment options for menopause. Objectives: After completing this session, the pharmacist should be able to: Summarize the prevalence and etiology of menopause. Describe the physical, behavioral, and psychological symptoms associated with menopause. Explain the diet, lifestyle & natural health product options available for the treatment of menopause. Explain the safety and efficacy of these options. Case Menopause GT, a 45-year-old female walks into your pharmacy and discreetly asks for your advice. It seems that she is beginning to experience uncomfortable hot flashes and severe breast pain. She is worried that she may have to go on hormone replacement therapy to control these symptoms. GT s mother died of breast cancer in her early fifties and from what she has read on the internet, she is worried that taking prescription HRT will put her at increased risk of developing breast cancer. She has also read that certain natural options could be a risk for her. She would really like to try natural options before pursuing prescription medications, but wants to be as safe as possible due to her family history. What would your recommendations be and why?

5 Introduction to Menopause Menopause (natural): is recognized to have occurred after 12 months of amenorrhea with no obvious pathologic cause. Perimenopause: The period immediately prior to the menopause (when the endocrinological, biological, and clinical features of approaching menopause commence) up to and including the 12 months of amenorrhea. Natural menopause can occur between age 40 & 58; average age 51. By 2025, 1.1 billion women world-wide will be postmenopausal. (North American Menopause Society (NAMS), 2010; International Menopause Society (IMS), 2013) Etiology, Pathogenesis & Symptoms of Menopause Change in ovarian follicular activity Fluctuating estrogen, progesterone & reduced inhibin production FSH and LH Symptoms & Signs of Menopause Hot flashes/sweating Weight gain Joint pain Mood changes Sore breasts Headache Sleep disturbances Fast heartbeat Osteopenia/osteoporosis Urogenital symptoms Fatigue Decreased libido Irregular periods Dizziness Scalp hair loss/hirsutism (Prior, 1998; Kaur et al., 2005; Elder & Thacker, 2010)

6 Dietary Recommendations for Menopause Consume a diet rich in vegetables, fruits, & fiber. Eat more cruciferous vegetables (kale, cabbage, cauliflower, broccoli etc.) Restrict animal fats & red meat; aim for lean protein (chicken, fish, turkey). Decrease intake of caffeine, alcohol, nicotine, salt. Try the mediterranean diet vasomotor symptoms (hot flashes, night sweats) (Herber-Gast & Mishra, 2013). Restrict sugar & fat: sugar & fat vasomotor symptoms (Herber-Gast & Mishra, 2013). Eat phytoestrogens (soybeans, whole grain cereals, lentils, alfalfa, tofu, tempeh, mung beans, etc.). Increase dietary intake of calcium to protect bones (nuts, green leafy vegetables, dairy products). Lifestyle Recommendations for Menopause Exercising regularly is important for cardiovascular health and maintaining bone density, but may not help vasomotor symptoms (Daley et al., 2011). Yoga may reduce hot flashes (Morrow et al., 2011) Relaxation techniques have been shown to lower sympathetic nervous system tone hot flashes (Morrow et al., 2011). Sleep in a dark room to enhance sleep quality via improved melatonin production (Kaur et al., 2005)

7 NHP Recommendations for Menopause We will review the possible role of the following NHPs in the management of Menopause: Black Cohosh Evening Primrose Oil (EPO) Soy Isoflavones Red Clover Collagen Black Cohosh Introduction (Hoffman, 2003; Pachman et al., 2010; Ross, 2012) Latin name: Cimicifuga racemosa (formerly Actaea racemosa) Common names: black cohosh, black bugbane, black snakeroot, fairy candle, squaw root. Parts used: dried roots & rhizomes. Native Americans used black cohosh to maintain women s reproductive health, relieve pain during menses and childbirth, as a mild sedative. The German Commission E has approved black cohosh as a nonprescription drug for treatment of premenstrual discomfort, dysmenorrhea & menopausal symptoms.

8 Black Cohosh Mechanism of Action (Fritz et al., 2013; Johnson & Fahey, 2012) Early preclinical studies indicated that black cohosh constituents could bind estrogen receptors (ER) in vitro, this is not supported by newer evidence. Several recent in vitro and in vivo studies show there is no estrogenic activity, and indicate there is outright antagonism of estrogen-induced effects selective estrogen receptor modulator (SERM)-like properties. May act on central estrogen (or other) receptors at the level of the hypothalamus, reducing LH surges that can cause hot flashes. May exert effects via dopaminergic and serotonergic pathways to reduce menopausal symptoms. May have analgesic properties. Black Cohosh Evidence Data supporting the efficacy of black cohosh in preventing or reducing the frequency and severity of hot flashes has been mixed: Several RDBPC trials found no significant improvement in vasomotor symptoms in menopausal women (Liske et al., 2002; Newton et al., 2006; Pockaj et al., 2006; Geller et al., 2009; Maki et al., 2009b). Other well-designed studies found the converse to be true black cohosh was found to improve vasomotor and physical symptoms and sleep quality (Frei-Kleiner et al., 2005; Raus et al., 2006; Bai et al., 2007; Oktem et al., 2007; Jiang 2015).

9 Black Cohosh Evidence cont d Cochrane Review evaluating clinical efficacy & safety of black cohosh for treating menopausal symptoms in peri-& postmenopausal women (Leach & Moore, 2012). 16 RCTs, recruiting a total of 2027 perimenopausal or postmenopausal women. All studies used oral monopreparations of black cohosh at a median daily dose of 40 mg (range mg/d), for a mean duration of 23 weeks. There was no significant difference between black cohosh and placebo in the frequency of hot flushes (mean difference 0.07 flushes per day; 95% confidence interval to 0.56 flushes per day;p=0.79; 393 women; three trials) or in menopausal symptom scores (standardized mean difference -0.10; 95% CI to 0.11; P = 0.34; 357 women; four trials). There was insufficient evidence to support the use of black cohosh for menopausal symptoms; further study suggested due to the heterogeneity of studies. Authors noted that evidence does suggest the intervention is probably safe and feasible to implement in clinical practice. Black Cohosh Dosage Average dose: 40 mg/d (Leach & Moore, 2012). Adverse Effects Adverse effects are considered rare, mild and reversible, including: gastrointestinal upset, breast pain/enlargement, infection, vaginal bleeding/ spotting, & musculoskeletal complaints (Leach & Moore, 2012; Ross, 2012). Drug Interactions May decrease clinical efficacy of tamoxifen via inhibition of CYP 2D6 & 3A4 (Li et al., 2011).

10 Black Cohosh Cautions and Contraindications Estrogenic effects: Does not influence circulating levels of estradiol, FSH, or LH, or appear to exert estrogenic effects on breast, endometrial, or vaginal tissues. No apparent effect on recurrence or incidence of breast cancer (Fritz et al., 2013). Hepatotoxicity: Case reports suggested a correlation between black cohosh & liver toxicity. Review of these cases suggests a lack of evidence for causality. Subsequent RCTs & meta-analysis have shown no effect on liver toxicity (Nasr & Nafeh, 2009; Naser et al., 2011). Herbal adulteration may be a factor (Johnson & Fahey, 2012). Caution may still be warranted in individuals with liver conditions. Contraindicated in pregnancy (may cause premature birth in large doses) and lactation (Ross, 2012). Contraindicated in patients with aspirin sensitivity because it contains salicylates. Evening Primrose Oil (EPO) Introduction As discussed in PMS section. Mechanism of Action Unknown in menopause, but likely related to prostagladin synthesis (as discussed in PMS section).

11 Evening Primrose Oil (EPO) Evidence A RDBPC multicenter trial has studied the effects of EPO in menopausal women (n = 56) (Chenoy et al., 1994). For 6 months participants took four capsules twice daily that contained either EPO (500 mg EPO and 10 mg natural vitamin E per capsule = 4000 mg/d EPO & 80 mg vit E) or placebo (parafin). The EPO showed no benefit in treating menopausal flushing compared with placebo. Menopausal women who experience PMS-like symptoms due to latent hyperprolactinemia often experience mastalgia (van Die et al., 2009) and may benefit from EPO (Gateley et al.,1992; Thakur et al., 2010). EPO in menopause Evidence 6 week RCT n=56 menopausal women (Farzaneh 2013) EPO 500mg or placebo Severity of hot flashes improved in EPO arm, and significant improvement in social activities, relations with others, and sexuality compared to placebo.

12 Evening Primrose Oil (EPO) Dosage No benefit was seen with 4000 mg/d for hot flashes (Chenoy et al., 1994) mg/d has been used for mastalgia (Gateley et al., 1992; Thakur et al., 2010). Adverse Effects, Drug Interactions, Cautions and Contraindications As discussed in PMS section. Soy Isoflavones Introduction (Pachman et al., 2010; NAMS, 2011) 10-20% of Asian women experience hot flashes vs % in Western countries. Thought to reflect the predominance of soy-based foods in the Asian diet a potent source of phytoestrogens (similar to endogenous estrogens). Phytoestrogens can be classified into two classes: isoflavones & lignans. The primary isoflavones of soybeans are genistein, daidzein, and glycitein.

13 Soy Isoflavones Mechanism of Action (NAMS, 2011; Panay, 2011; Yang et al., 2012; Taku et al., 2012) Often referred to as natural selective estrogen receptor modulators (SERMs). Compete with estrogen for the same receptors, exerting both estrogenic and anti-estrogenic effects (mixed agonist/antagonist). Preferentially bind to estrogen-β receptors rather than α-receptors, but with much lower affinity than conventional estrogenic compounds. α-receptors occur in the breast and the uterus, where isoflavones may be anti-estrogenic. β receptors occur in bone and blood vessels, where they may exert positive estrogenic effects. Soy Isoflavones Evidence Generally thought that results of studies using soy supplements to relieve menopausal symptoms are conflicting (Jenks et al., 2012). This is largely attributable to 2 major factors: 1. Lack of comparability of agents (e.g., soy protein vs. soy-based diet) and not using extracted/concentrated soy isoflavones (NAMS, 2011). 2. Bioavailability/digestion of isoflavones (NAMS, 2011; Jenks et al., 2012). S-equol is formed from daidzen by intestinal flora & binds with greater affinity than its parent isoflavone to estrogen β receptors. Not all individuals have the ability to produce S-equol. Evidence indicates 20-30% of Western adults vs % of Asian adults can produce S-equol after consuming soy products.

14 Soy Isoflavones Evidence cont d Addressing factor 1: A systematic review & meta-analysis of 19 trials showed that most doubleblind placebo-controlled studies using extracted or concentrated soy isoflavones significantly reduced vasomotor symptoms (Taku et al., 2012). Ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months significantly reduced the frequency of hot flashes by 20.6% and hot flash severity by 26.2% compared with placebo. Isoflavone supplements providing more than 18.8 mg of genistein were more than twice as potent at reducing hot flash frequency than lower genistein supplements. Soy Isoflavones Evidence cont d Addressing factor 2: 8 week randomized, double-blind, trial to compare the efficacy of a supplement containing primarily S(-)-equol (5.0 mg S-equol, 1.0 mg daidzen, 1.1 mg genistein, 2.5 mg glycitein) to a supplement that combined genistein (22 mg), daidzein (24 mg), and glycetin (2.0 mg) (Jenks et al., 2012). 102 postmenopausal women (ages 45-65) with moderate to severe hot flashes were randomized to S(-)-equol at 10, 20, or 40 mg/day or the combination supplement with a total isoflavone dose of 50 mg/day for 8 weeks. Reduction in hot flash frequency was similar in the 10 mg S(-)-equol and combination isoflavone groups. Women in the 20- and 40-mg S(-)-equol groups showed greater reduction in symptoms than those receiving the combination supplement.

15 Soy Isoflavones Dosage Minimum starting dose: 50 mg/d for at least 12 weeks (NAMS, 2011). Longer duration of treatment shows more effect (Li, 2015) Higher proportions (> 15 mg/d) of genistein have shown particular benefit (NAMS, 2011). Initial trials with S(-)-equol are promising at mg/d (NAMS, 2011; Jenks 2012). Adverse Effects Mainly gastrointestinal (Taku et al., 2012). Drug Interactions Theoretical interaction with: estrogen & SERMs (e.g., tamoxifen); aromatase inhibitors (e.g., anastrozole, exemestane); warfarin. Soy Isoflavones Cautions and Contraindications Allergy/hypersensitivity to soy products. Thyroid: Theoretically, isoflavones may interfere with thyroid function. Several studies measured thyroid function as a parameter and no impact of isoflavones was found (Eden, 2012). Estrogenic effects: Initial concerns that isoflavones may effect endometrial thickness, vaginal cytology and breast density, particularly increasing the risk of uterine & breast cancer have not been found in several large RCTs and cohort studies (NAMS, 2011; Eden, 2012). Some studies (meta-analysis & cohort) suggest protective effects (Dong & Qin, 2011; Ollberding, 2011), but longer-term studies are still recommended (NAMS, 2011).

16 Red Clover Introduction Latin name: Trifolium pratense. Common names: Red clover, Beebread, Cow Clover, Cow Grass, Meadow Clover, Purple Clover, Wild Clover. Parts used: Dried and fresh flower heads. Rich source of isoflavones, containing biochanin A and formononetin (Panay, 2011). Mechanism of Action As discussed for soy isoflavones (Panay, 2011). Red Clover Evidence Meta-analysis of 5 randomized, controlled studies showed significant reduction in vasomotor symptoms with red clover isoflavones (40-82 mg/d) over placebo, with a weighted mean difference of 1.5 fewer hot flushes per day (Coon et al., 2007). Randomized, placebo-controlled crossover trial of 109 women given 80 mg red clover isoflavones daily for 3 months (Lipovac et al., 2012). Significant improvement in the overall symptom score (Kupperman index) while women were on red clover isoflavone supplementation. Over 70% reduction in the frequency of hot flushes and night sweats compared to placebo.

17 Red Clover Evidence RPCCT n=72 healthy post menopausal women (Shakeri 2015) 2 capsules of 40mg dried leaves of red clover daily for 12 weeks or placebo Reduction in severity of menopausal symptoms was observed according to the Menopause Rating Scale to in intervention group to in control group Red Clover Dosage mg/d (Coon et al., 2007; Lipovac et al., 2012) Adverse Effects Pooled adverse event data from 15 published clinical trials, including a total of more than 1000 women using red clover isoflavones, have shown no difference compared to placebo (Panay, 2011). Drug Interactions Theoretical concerns, as discussed with soy isoflavones.isoflavonoids may interfere with hormonal agents; avoid use with oral contraceptives, estrogen, or progesterone therapies. Case reports are lacking; however, caution is warranted with concomitant use of tamoxifen or letrozole. May inhibit cytochrome P450 enzymes, especially CYP450 1A2, 2C19, 2C9, and 3A4 (Unger & Frank, 2004). Theoretically, may act synergistically with NSAIDS & anticoagulants, due to content of couramin-like compounds (Abebe, 2002).

18 Red Clover Cautions and Contraindications Allergy/hypersensitivity to red clover or plants of the legume (leguminosae/fabaceae) family. No significant changes in breast density or endometrial thickness observed, but further research required (Powles et al., 2008; Panay, 2011). Contraindicated in patients with hormonal disorders, estrogen-dependent breast cancer (or risk of), and during pregnancy or lactation. Not advised in children younger than 12 years. Collagen Introduction Collagen peptides (CP) Sold in natural health products as Hydrolyzed Collagen Used as bone health supplements. Mechanism of Action Bovine CP compounds increase osteoblast proliferation and plays a positive role in differentiation and mineralized bone matrix formation in mice (Liu, 2014). Hydrolyzed collagen peptides have been shown to improve BMD and BMC by inhibiting bone resorption (Takeda 2013)

19 Collagen Evidence On Rats (Takeda 2013) Moderate dietary hydrolyzed collagen peptides intake increased bone mass during growth period and further promoted the effect of running exercise. On Humans - RCT n=39 (Elam 2015) 5g CC (calcium-collagen chelate with 500mg of elemental calcium and 200IU vitamin D) or control (500mg calcium and 200IU vitamin D) daily for 12 months Whole body BMD was substantially lower than that of the control group Collagen Dosage 5g of calcium-collagen chelate was used in one RCT daily for 12 months (Elam, 2015) More research needed Adverse Effects Unknown Potential for gastrointestinal upset based on data from a combination products used for arthritis (Schauss, 2012) Caution if pregnant or breastfeeding (lack of evidence) Drug Interactions Unknown Possible interaction with Calcium during bone turnover

20 Case Study Review Case Highlights Patient: GT, 45 year old female CCs: Hot flashes, severe breast pain Family History: Mother died of breast cancer in early fifties, fear of HRT risks Social History: Insignificant Current medications: None; seeking natural treatment options Case Study Conclusions Based on GT s history and her presenting symptoms, recommendations should reflect the presence of estrogen-receptor positive breast cancer in her family. Diet GT should consume a diet rich in fruits, veggies & fiber, while minimizing animal fats and red meat. Trying to model her diet after the Mediterranean diet has several health benefits, including cancer reduction & reduced hot flashes. Decrease intake of caffeine, alcohol, salt, sugar. Eating moderate amounts of phytoestrogens (e.g. soy) should not be an issue for GT, as several studies now suggest protective effects against breast cancer, rather than increased risk.

21 Case Study Conclusions Lifestyle Encourage GT to exercise regularly, including yoga, which may control vasomotor symptoms. Ensure she is sleeping in a dark room to maximize melatonin production, which is affected during menopause & with aging, & may contribute to symptoms. Case Study Conclusions NHP Recommendations Although studies now suggest that soy and red clover isoflavones are unlikely to promote breast cancer, and may, in fact, be protective, GT may be apprehensive about their use. Instead, recommending the following may be prudent: Black Cohosh: although results are mixed, Cochrane review suggests 40 mg/d may be beneficial in a clinical setting and mechanism of action is not phytoestrogenic. Evening primrose oil: due to GT s severe mastalgia, she may benefit from mg/d. Although clinical trial found no benefit for hot flashes, empirical evidence suggests relief is possible.

22 Practical Considerations for the Pharmacist Offer advice and recommendations to patients regarding the use of natural health products. Advise the patient to: Inform their health care provider and pharmacist which natural health products they are taking. Maintain a list of natural health products that they are using and take it with them to their medical appointments. If they are contemplating starting to take natural health products, consult with their health care provider and pharmacist to ensure there are no risks of NHP-medication interaction. Conclusions Women face health concerns throughout their lifetime that are unique to their physiology, hormones and genetic composition. Given that women tend to make healthier lifestyle choices, they are also more apt to seek complementary and alternative health advice, often turning to their pharmacists as a first line of information. Although many NHPs do promote and enhance good health, they are only safe when used under the right conditions. As a first line of information for the majority of Canadians, a pharmacist can advise patients if an NHP is right for them on an individualized basis, discussing benefits and risks.