Advances IN ORTHOMOLECULAR RESEARCH Advances IN ORTHOMOLECULAR RESEARCH VOLUME 4 ISSUE 5 advances IN ORTHOMOLECULAR RESEARCH advances IN ORTHOMOLECULAR RESEARCH ADVANCES IN ORTHOMOLECULAR RESEARCH Women’s Health Health Concerns Faced by Women Today

IN ORTHOMOLECULAR RESEARCH FREE RESEARCH-DRIVEN BOTANICAL INTEGRATIVE ORTHOMOLECULAR INNOVATIVE Better Bones, Naturally Advanced Bone Protection Reduces bone loss Increases bone mineral density Stimulates bone building cells and collagen production

Just one fast acting capsule a day An Introduction to the The Breast Cancer- 4 HPG Axis 17 Connection The hypothalamic– The risk of breast cancer pituitary–gonadal is thought to be closely axis (HPG axis) plays related to the balance of an important role in estrogen hormones in a the development and women’s body; there are regulation of a number several ways to reduce this of the body’s systems risk. involved in women’s health.

Menopause Parts 1 & 2: Hidden Dangers in Our 6 Natural substances such as 22 Modern World can help are a to balance hormones and significant source of ease the transition into estrogen that can affect a . Lifestyle and women’s hormone balance. dietary modifications can Supporting the body’s also be both helpful and detoxification processes healthful in managing and reducing exposure is or eliminating these important. symptoms.

Is it Really My Thyroid? Control PCOS: Control 14 Hypothyroid Explored 25 Your Life Thyroid health is a key PCOS is a poorly ingredient to managing understood condition energy, weight, aging, and that is also linked to overall well-being. Hypo- other concerning health thyroid (low-thyroid) problems. Learn more conditions can benefit from about how you can evaluate food sourced nutrients and control PCOS. as well as supplemental support.

Published in Canada by Advances in Orthomolecular Research Advanced Orthomolecular Research Inc. is distributed through integrative physicians, health care practitioners, and progressive health food retailers. Publisher/Editor-in-Chief Jaime Thomas, BSc The content of this magazine is provided for informational purposes only, and is not intended Research & Writing as medical advice for individuals, which can only Dr. Colin O’Brien, ND be provided by a healthcare professional. Contents Dr. Paul Hrkal, ND and design © 2013 AOR. Any reproduction in whole Dr. Cameron McIntyre, ND or part and in print or electronic form without Dr. Chantal Ann Dumas, ND (Qc) express permission is strictly forbidden. Permission Mariam Al-Kawally, BSc to reproduce selected material may be granted by Justine Florence, BSc contacting the publisher. Jaime Thomas, BSc

Graphic Design/Art Production Volume 4 Issue 5 Neil Bromley Alvin Cha email: [email protected]

Digital versions of this magazine and back issues are available online at www.AOR.ca ADVANCED ORTHOMOLECULAR RESEARCH Advances 3 variety of other emotional and physical An Introduction to the health conditions. HPG axis refers to the effects of the Hypothalamic–Pituitary–Gonadal Axis hypothalamus, pituitary gland, and gonads as if these separate endocrine The hypothalamic–pituitary–gonadal (polycystic ovary syndrome). glands were a single entity acting as a axis (HPG axis) plays an important role Female hormones affect reproductive whole. Since the glands often function in the development and regulation organs and also influence several in cooperation, endocrinologists of a number of the body’s systems, other body functions by interacting and physiologists find it more simple such as the immune and reproductive with major neuro-endocrine systems and descriptive to refer to them as a systems. Fluctuating hormone levels including thyroid hormones, stress single system. The HPG axis controls cause changes in the hormones that are hormones, and the autonomic nervous reproduction, development, and produced by each gland and as a result system. The HPA (hypothalamic- aging. The hypothalamus produces have a variety of widespread and local pituitary-adrenal) axis is affected gonadotropin-releasing hormone effects in the body. The HPG axis can by similar factors as the HPG axis (GnRH). The anterior portion of the be influenced by lifestyle and dietary and involves the hypothalamus, pituitary gland produces luteinizing factors such as stress, inadequate pituitary and adrenal glands as well hormone (LH) and follicle-stimulating sleep, illness, the use of certain as the hormones CRH (corticotropin- hormone (FSH), and the gonads medications including hormones, as releasing hormone), ACTH produce estrogen and . well as poor dietary habits. This axis (adrenocorticotropic hormone) and the The hypothalamus is located in can also be subject to disorders such stress hormone known as cortisol which the brain and secretes GnRH. GnRH as hypothalamic–pituitary failure or is necessary to survive. Therefore, a lack moves down the anterior portion of dysfunction, as occurs in ovulation of normal functioning of the female the pituitary and binds to the secretory disorders, one example being PCOS reproductive system impacts a wide cell receptors of the anterior pituitary.

4 Advances In response to stimulation from GnRH, these cells then produce LH and FSH, which enters into the blood stream. Autonomic Nervous System These two hormones have a significant role in communicating to the gonads. Hypothalamus FSH and LH act primarily to activate Sympathetic Parasympathetic the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle in females. HPA Axis HPG Axis Symptoms of HPG Axis Dysfunction Stress The most common cause of hot Hypothalamus Trauma Hypothalamus flashes in menopausal women is CRH GnRH changing levels of estrogen in the body. Sleep Diminished amounts of estrogen have a direct effect on the hypothalamus, the part of the brain responsible for Pituitary Pituitary controlling appetite, sex hormones, ACTH LH, FSH sleep, and body temperature. Lowered levels of estrogen confuse the hypothalamus, causing it to inaccurately sense that the body is overheating. This provokes an internal chain of reactions that women experience as Adrenal Cortex “hot flashes”. Sudden weight gain in Cortisol women may also be caused by hormone imbalance. Since the hypothalamus is responsible for metabolism and body Ovaries temperature, when the hypothalamus , isn’t functioning normally, this can Progesterone slow metabolism, also causing the thermogenic process for fat burning to slow, thus causing significant weight increase. HPG Axis’ Role in Female Reproduction and Development One of the most important functions of the HPG axis is to regulate reproduction influence the menstrual cycle initiating changes are caused by the activation of by influencing the ovarian and uterine the proliferation phase to prepare for estrogen and testosterone. After being cycles. In females, a positive feedback ovulation, the secretory phase after activated, the HPG axis functions in loop between luteinizing hormone ovulation, and menstruation when men for the rest of their life but becomes and estrogen assists in preparing the conception does not occur. HPG axis deregulated in women which leads to follicle in the ovary and the uterus for activation in both males and females menopause. The deregulation is caused ovulation and implantation. At the time during puberty also causes individuals mainly by the reduction in oocytes that the egg is released, the ovary starts to to gain secondary sex characteristics. normally produce estrogen to create produce progesterone to inhibit the HPG axis activation and deactivation the positive feedback loop. Over many hypothalamus and the anterior pituitary, also helps to regulate life cycles. FSH years, HPG axis activity decreases and therefore stopping the estrogen-LH and LH levels are elevated at birth, women cease to be fertile. Balancing the positive feedback loop. If conception and females have a lifetime supply HPG axis throughout life is important does occur, the fetus will assume the role of the primary cells from which an since it significantly affects temperature of secreting progesterone; causing the egg develops (oocytes). These levels regulation, metabolism, weight control, mother to be unable to ovulate again. decrease and remain lower throughout mood and also the aging process. If conception does not occur, reduced childhood. At puberty the HPG axis Lifestyle factors and dietary choices as progesterone excretion will allow the is activated by estrogen secreted from well as supplements and medications hypothalamus to restart secretion of the ovaries or testosterone from the can all profoundly affect the functioning GnRH. These hormone levels also testes. Physiological and psychological of this system.

Advances 5 Menopause

provide relief for symptoms such as hot What Are My Natural Options? flashes and night sweats and protection against bone loss, evidence exists to Menopause is a normal, natural and intense sweating and flushing of the suggest that HRT may also increase the inevitable event that affects all women face and chest and are experienced by risk of heart attacks, coronary attacks, reaching middle to late adulthood. In a as many as 75% of menopausal women.2 strokes and even breast cancer (see page very basic sense, menopause occurs as a Night sweats and difficulty sleeping 17 for information on breast cancer). result of aging. Changes in the structure appear to be the next most common An online survey of 166 menopausal and function of the female ovaries concerns,3 although psychological women showed that 27% of respondents lead to a drastic drop in estrogen distress, anxiety, mood changes, stopped or didn’t use HRT at all because levels and permanent cessation of concentration difficulties and bone loss of these safety concerns.5 menses. Unfortunately, its associated are all frequent concerns as well. The With all of this in mind, it’s no symptoms can make this process quite average age of onset is 51, but there is surprise that menopausal women uncomfortable for many women and quite a wide age range (40-58 years of experiencing discomfort want safe and can negatively impact their social life, age) for any individual woman to enter alternative solutions. The good news is psychological health and overall well- menopause.1 that there are many effective options. being.1 The most common conventional Let’s take a closer look at some of the The most common concern in treatment used to address the concerns best alternative therapies available postmenopausal women are hot flashes; of menopause is hormone replacement for the most common menopausal these cause an episodic feeling of heat, therapy (HRT). While this therapy may symptoms:

6 Advances Exercise various menopause-related symptoms related quality of life” (HR-QOL) in Exercise has long been considered and overall health. As many people 44 post-menopausal women. Only 3 a beneficial treatment for easing are aware, these improved health hours per week of moderate aerobic the transition into menopause, outcomes include better cognitive exercise led to an increased HR-QOL most notably through reducing function, sleep patterns, mood, bone and decreased severity of menopausal the frequency and intensity of density, cardiovascular function and symptoms (including hot flashes, hot flashes. It is proposed that the energy levels.6 Observational studies insomnia, nervousness, headaches and exercise-induced production of beta- confirm this notion. joint pains) after a period of six months. endorphins (the “happy” chemical In a survey of over 66,000 menopausal While the groups receiving only associated with a sense of euphoria) women in Italy, those that reported the HRT and no exercise showed similar combats the natural decrease in lowest level of regular exercise were decreases in menopausal symptoms, β-endorphins seen with decreasing significantly more likely to experience they did not experience the similar estrogen levels in aging women.6 more severe symptoms such as hot increase in HR-QOL that exercising These peptides act on many areas of flashes.7 A recent 2012 study found that women exhibited.2 the brain and ultimately may help to symptoms of anxiety and depression Finally, there is also strong evidence stabilize the thermoregulatory centre experienced by menopausal women that menopausal symptoms such as of the hypothalamus, an area crucial could be alleviated by a controlled hot flashes may be reduced and a more to temperature regulation.6 physical exercise regimen.8 positive mental outlook obtained with Multiple studies have reported that A 2008 study examined the effects of the increased sense of accomplishment physical activity has positive effects on physical exercise and HRT on “health- and self-esteem associated with

Advances 7 exercise.6,9 This is supported by the distinct dietary patterns and allocated have shown to be risk factors for idea that yoga, an exercise form that each woman into a category for increased vasomotor symptoms as equally requires physical activity and subsequent analysis. Both night sweats well. Specifically, women with a higher mental focus, has also been suggested and hot flashes were assessed for each body mass index (BMI, a measure of to improve menopausal symptoms woman every 3 years throughout the body weight relative to height) are at an when practiced regularly.10 Regardless follow-up.11 increased risk.11 A 2012 study actually of the mechanism, all forms of regular Findings of this study identified one showed that menopausal women who exercise should be considered safe specific type of diet that appeared to lost 10 lbs or more through increased and effective methods to reduce the aggravate menopause symptoms, and fruit and vegetable intake and reduced frequency and intensity of hot flashes, two diet types that decreased the risk fat intake were more likely to eliminate improve sleep and balance mood of menopause symptoms. Diets high their hot flashes and night sweats throughout menopause. in fat and sugar noticeably worsened completely after 1 year.12 Interestingly, Diet hot flashes, while diets higher in many women who adopted this new It’s no secret that diet affects many fruit and diets closely resembling a dietary regimen but did not lose weight aspects of our health. Menopausal Mediterranean diet (greater proportions also found some benefit in the form of symptoms are no exception to this rule of garlic, peppers, mushrooms, salad reduced hot flashes and night sweats. and many women have seen firsthand greens, pasta and red wine) appear to be This shows that dietary interventions that dietary factors can influence protective of the same symptom. Diets and weight loss both independently menopausal symptoms for better or for high in meat, dairy and vegetables did improve these menopause concerns.12 worse. A very recent 2013 prospective not show any trend in either direction.11 As a final note on dietary and lifestyle cohort study found this exact association Other studies have also found that factors, women who smoke cigarettes between diet and menopause symptom high fibre and low fat intakes may be regularly and those with a higher complaints by monitoring 6040 women associated with reduced menopause consumption of alcohol have both over a period of 9 years (from 2001 to symptoms.11 shown to be at an increased risk for 2010). After gathering baseline dietary Many other modifiable lifestyle experiencing hot flashes.11 If you have data, researchers were able to define six factors that are closely tied to diet been trying to quit smoking or reduce

8 Advances your alcohol consumption, here is yet another reason why it may be time! Black Cohosh Black Cohosh (also known as Actea racemosa or Cimicifuga racemosa) is one of the most promising herbal preparations for reducing menopausal symptoms and which also has a long history of use in traditional medicine for treating menstrual irregularities and pain associated with childbirth.13 Unlike other commonly used herbs to treat menopausal discomforts, black cohosh is not just a (see page 10 for an explanation of Phytoestrogens) but rather a substance that increases dopamine and serotonin levels in the body. Additionally, it appears that black cohosh has an affinity for bone protection as it selectively activates estrogen receptors in the skeletal system.14 In a randomized, double-blind, placebo-controlled trial involving 304 healthy, postmenopausal women in Germany, a standardized extract of black cohosh was found to be beneficial in alleviating menopausal concerns after 12 weeks of treatment. Specifically, improvements in sleep disorders, hot flashes, memory, irritability, depression and vaginal dryness were seen. It should be noted Other interventions for treating menopausal concerns that concomitant use of HRT or any other herbal supplements were Acupuncture: A systematic to improvements in psychological prohibited during the study. With this review on acupuncture and distress and depressive symptoms in mind, the positive results can be 13 menopausal symptoms suggest of menopausal women. solely attributed to the black cohosh. that acupuncture is an effective Supplementation did not, however, The safety profile of black cohosh treatment option for vasomotor show any benefit over placebo in has been a controversial issue over symptoms and improving health- menopausal women suffering from the years, with previous case reports related quality of life.16 a major depressive episode.18 suggesting a possible relationship between black cohosh use and liver Massage: Both aromatherapy Ginseng: Panax ginseng produced toxicity. However, review of these massage and non-aroma massage significant benefit over placebo reports has determined that these have been shown to benefit overall for menopausal depression and cases were not properly assessed for menopausal symptoms after only overall well-being (according to the causality and, in fact, there were many 4 weeks of 30-minute treatment Psychological General Well-Being sessions twice a week. While both Index [PGWB]).19 confounding variables present that massage forms provided relief, may have been responsible for the Qigong: A 12-week study found aromatherapy massage was most unwanted side effect.15 A much larger that menopausal symptoms and beneficial.17 body of evidence exists to suggest sleep quality improved as women that black cohosh is extremely safe,15 Omega-3 Fatty Acids: Eight practiced and became better however, the monitoring of liver health weeks of supplementation with versed in this form of meditative by physicians prescribing black cohosh Eicosapentaenoic acid (EPA) leads exercise.20 is still a prudent approach.

Advances 9 References 1. Shapiro M. Menopause practice: a clinician’s guide.. 4th ed. Mayfield Heights, Ohio: North American Menopause Society, 2010. 2. Moriyama C et al. A randomized, placebo-controlled trial of the effects of physical exercises and estrogen therapy on health-related quality of life in postmenopausal women. Menopause 2008;15(4):613–18. 3. Wylie-Rosett J. Menopause, micronutrients, and hormone therapy. Am J Clin Nutr 2005;81(suppl):1223S-1231S. 4. Huntley A and Ernst E. A systematic review of herbal medicinal products for the treatment of menopausal symptoms. Menopause 2003;10(5):465- 476. 5. Pitkin J. Alternative and complementary therapies for menopause. Menopause Int 2012;18:20-27. 6. Daley A et al. Exercise for vasomotor menopausal symptoms (Review). The Cochrane Library 2011. 7. Di Donato P et al. Factors associated with climacteric symptoms in women around menopause attending menopause clinics in Italy. Maturitas. 2005;52(3-4):181-9. 8. Villaverde G et al. Influence of exercise on mood in postmenopausal women. J Clin Nurs. 2012;21(7-8):923-8. 9. Bedell S et al. The pros and cons of plant estrogens for menopause. J Biochem Mol Biol. 2013. 10. Joshi S et al. Effect of yoga on menopausal symptoms. Menopause Int. 2011;17(3):78-81. 11. Herber-Gast G and Mishra G. Fruit, Mediterranean-style, and high-fat and -sugar diets are associated with the risk of night sweats and hot flashes in midlife: results from a prospective cohort study. Am J Clin Nutr 2013;97(5):1092-9. 12. Kroenke C et al. Effects of a dietary intervention and weight change on vasomotor symptoms in the Women’s Health Initiative. Menopause 2012;19:980–8. 13. Ross MR. A stanbdardized isopropanolic black cohosh extract (remifemin) is found to be safe and effective for menopausal symptoms. Holist Nurs Pract 2012;26(1):58-61. 14. Volker V et al. Black cohosh: just another phytoestrogen? TRENDS in Endocrinology and Metabolism 2005; 16(5): 214-221. 15. Thomsen M and Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case report not sufficiently substantiated. J Altern Complement Med. 2003;9(3):337-40. 16. Baumelou A et al. Perspectives in clinical research of acupuncture on menopausal symptoms. Chin J Integr Med. 2011;17(12):893-7. 17. Darsareh F et al. Effect of aromatherapy massage on menopausal symptoms: a randomized placebo-controlled clinical trial. Menopause. 2012;19(9):995-9. 18. Lucas M et al. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr 2009;89:641–51. 19. Wirklund I et al. Effects of a standardized ginseng on the quality of life and physiological parameters in a symptomatic postmenopausal women: a double-blind, placebo-controlled trial. Int J Clin Pharm Res 1999; XIX: 89-99. 20. Yeh S and Chang M. The effect of Qigong on menopausal symptoms and quality of sleep for perimenopausal women: a preliminary observational study. J Altern Complement Med. 2012;18(6):567-75. 21. Cramer H et al. Effectiveness of yoga for menopausal symptoms: a systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med. 2012. 22. Akazawa N et al. Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res. 2012;32(10):795-9.

now commonly known phytoestrogen Phytoestrogens Explained sources,2 although when it comes to natural health products, their labels will Menopausal women searching estrogen”. In the 1950’s, this estrogenic often only list the active phytoestrogenic for safe and effective alternatives activity was discovered in plants when ingredient from each plant. See Figure to hormone replacement therapy researchers investigated the cause 1 for a list of common phytoestrogenic (HRT) will inevitably come across of infertility in a specific group of plants, their corresponding Latin “phytoestrogens”, either in their whole Australian sheep.1 Researchers noticed names and their most active estrogenic food form or as a concentrated extract that these infertile sheep were grazing in constituents. in a supplement. But what exactly are pastures of clover, subsequently labeling Despite the literal translation to “plant phytoestrogens and how do they work as the active ingredient and estrogen”, it’s important to note that no in the human body? Are they even safe? the constituent responsible in clover actual estrogen exists in phytoestrogenic Many answers remain unknown to the for having estrogen-like activity. Since plants (the principle human estrogen, general public and the literature can this discovery, hundreds of foods have 17β-, is not present). offer mixed results as well. Let’s clear up been identified as phytoestrogens, each Instead, plants that are described as some of the confusion. possessing varying potencies. Soy, hops, phytoestrogens simply have effects in The term “phytoestrogen” canflaxseeds, legumes, lentils, chickpeas, the human body similar to the effects literally be translated into “plant beans, alfalfa sprouts and red clover are of our bodies’ natural estrogen.1 In the

10 Advances most basic sense, all phytoestrogenic Figure 1: Popular phytoestrogens plants contain active ingredients with a similar chemical structure to estrogen. Common name Latin name Active ingredients The ingredients actually interact with Soy Genistein and and activate estrogen receptors. The Alfalfa Medicago sativa human body interprets this chemical signal in the same way that it would Red Clover Trifolium Coumestrol if natural estrogen had triggered the pratense receptor. In other words, the switch gets Flaxseed Linum usitatis- turned on regardless of what initiated simum the action. Hops Humulus lupulus 8-Prenylnaringenin It is also very important to recognize that, even though phytoestrogens activate estrogen receptors, they do so Hops assessment tools all revealing beneficial in a much weaker manner. Using our Hops (Humulus lupulus) can effects in such a short duration shows on/off switch analogy, phytoestrogens be considered a relatively “new” great promise for hops as a treatment simply turn on fewer switches than phytoestrogen as the active estrogenic intervention. Considering the large true estrogen because they don’t ingredient, 8-prenylnaringenin (8-PN) proportion of menopausal women bind strongly enough to the switch.2 was only recognized in 1999.3 While with sleep disturbances and hot flashes, This results in similar physiological the hops plant is now acknowledged hops is an ideal ingredient to target responses that are much milder. for its ability to influence menopausal this population for its estrogenic and Lastly, to fully understand the action symptoms and other conditions of sedative properties.1 In addition, 8-PN of phytoestrogens we must recognize estrogen imbalance, traditionally has been shown to exhibit estrogenic that there are two different types hops has been used for its sedative effects on bone metabolism, thereby of estrogen receptors in the body: properties.3 providing another menopausal benefit alpha-estrogen receptors (ER-α) and Comparison against the active by possibly reducing bone loss.4 beta-estrogen receptors (ER-β). Each ingredients found in other Nevertheless, more research is needed receptor is distributed more heavily phytoestrogens (such as genistein and to fully reveal all of the benefits that in certain tissues (for example bone daidzein from soy) show that 8-PN hops have to offer for menopausal versus breast tissue). This is important is actually one of the most potent!3 women. because all phytoestrogens are actually Moreover, 8-PN actually binds ER-α Soy “selective modulators” stronger than it binds ER-β, a quite Soy is one of the most well-known (SERMs), meaning they affect either the unique property when comparing phytoestrogens, the most researched ER-α or ER-β preferentially.2 phytoestrogenic activities.1 Perhaps and also the most controversial. Many Research examining the ability of this partially explains why hops has research studies have found soy (or phytoestrogens to alleviate menopausal shown such positive research for the active ingredients isolated from ailments is positive, yet still mixed. menopausal concerns. soy; see figure 1) to have no benefit Beneficial results have been shown for Two clinical studies using over placebo on menopausal hot improving hot flashes, vaginal dryness, standardized hops extracts have been flashes.5,6 Yet, other studies show great sleep disturbances, cognition and conducted, both of which elucidated benefit in specific populations. For bone density in menopausal women. the rapid and effective relief of hot example, one study found that soy However, many studies have also shown flashes. One study examined the effects derived isoflavones improved mood very little or no effect of phytoestrogens of supplemental hops for 12 weeks in and hot flashes in menopausal women on menopausal symptoms. With this in 67 menopausal women while the most with high body mass index (BMI) mind, it’s important to know that there recent study in 2010 only examined measurements.7 Another study found is a tremendous amount of variability in 36 menopausal women, but over a that genistein decreased all severities terms of the amount of active ingredient longer duration of 16 weeks. Both of hot flashes in women entering used in each study. Moreover, individual studies measured scores on a modified menopause within the past 12 months differences in intestinal microflora can Kupperman Index (an assessment tool with higher BMI’s.8 further lead to mixed results by altering to rate the intensity of hot flashes, A 2011 report by the North American the ability to break down and use insomnia, headaches, vaginal dryness Menopause Society states that soy-based phytoestrogens in the human body.2 etc.) on a patient questionnaire.4 isoflavones are “modestly effective in Let’s take a closer look at some of While the relatively small number relieving menopausal symptoms”.9 the most popular and most potent of participants in each study may be This statement is significant because phytoestrogens: considered a limitation, the various the report literally evaluated hundreds

Advances 11 after 12 months.10 This suggests that perhaps a synergistic effect is present between the two phytoestrogens. This is supported by the fact that vaginal atrophy has also shown improvement through the combined use of lignans and flaxseeds.11 Lignans and flaxseeds have shown improvements in the areas of cognition and bone health, while also possibly showing a protective effect against breast cancer.12 Specifically, high dietary intake has been associated with better performance in processing capacity, processing speed and executive function,12 while the alpha-linolenic acid (an omega fatty acid) content of flaxseeds are theorized to benefit bone health by decreasing prostaglandin synthesis.13 The suggested protective effect of lignans on breast cancer has only been observed in dietary observational analysis and therefore the proposed benefit is plausible but far from definitive.2 A major shortcoming of the use of studies using soy supplementation amount of lignans, the active of flaxseeds clinically is that there for menopause and found benefit for ingredient responsible for their is currently no long-term research its use. Specifically, better results were estrogenic activity. However, lignans evaluating their efficacy as a sole found in whole food consumption must be converted by the bacteria in intervention.2 Perhaps studies of and in products that provided high the human digestive tract in order duration longer than 12 weeks proportions of genistein.9 To add to become “activated”.2 These active would ascertain whether flaxseed is support to the argument that metabolites actually help the liver to indeed beneficial or not in alleviating supplementation does play a positive make sex-hormone binding globulin menopausal symptoms. role in alleviating menopausal (SHBG), a hormone that decreases the Are phytoestrogens safe? symptoms, a comprehensive 2013 clearance of circulating estrogens, and One of the greatest attributes of review evaluating the efficacy of the metabolites also act as SERM’s with phytoestrogens is their extremely isoflavones, and lignans an affinity for ER-α.2 The end result high safety profile. A literature review found that current research sufficiently of both of these processes is more in 2010 analyzed twenty years of soy concludes that the findings are positive.2 estrogen activity in the body. research and found that there were Increased dietary soy consumption Almost all trials assessing the no serious side effects – only a slightly has also been shown to decrease effectiveness of flaxseeds or lignans higher incidence of gastrointestinal endometrial and breast cancer risk in alone in the treatment of hot flashes disturbances (such as gas or bloating) observational studies, perhaps making have produced insignificant effects. in those consuming higher amounts soy a more attractive option for treating To be more specific, research has of dietary soy.2 Similarly, there have menopause. In addition, possible found quite a large proportion of flax been studies examining the safety protective effects on the cardiovascular interventions to reduce hot flashes, but of soy consumption for up to 3 years system, cognition and bone health have the corresponding placebo groups have in length that failed to expose any been suggested, although research in proven to be so powerful that there is serious adverse effects. Research on these areas is much farther from being actually very little difference in the the use of lignans from flaxseeds, conclusive.9 efficacy between groups. However, one 8-prenylnaringenin from hops and Flaxseed study examining the use of isoflavones coumestrol from both alfalfa and red Of all the known phytoestrogenic in conjunction with lignans found clover have all shown comparable plants, flaxseeds contain the highest significant improvements in hot flashes safety profiles.2, 3

12 Advances Some research has raised concerns surrounding the use of soy and its possible negative effects on thyroid health.14 It’s important to clarify that: research has only shown that genistein from soy can exacerbate low thyroid function in individuals with pre- existing suboptimal thyroid function (specifically deficient in iodine).14 There is currently no evidence to suggest that healthy people consuming soy are at increased risk for hypothyroidism. As aforementioned, HRT has also raised various concerns regarding their use and possible risk of increased blood clotting, liver disease and certain term use and at reasonable dosages, as However, as the mixed evidence cancers. Interestingly, phytoestrogens long-term use over a period of years of suggests, each phytoestrogen doesn’t have been found to decrease the risk high-potency extracts have not been necessarily work for everyone – it’s of endometrial cancer, but also some explicitly studied. clear that the type and potency of studies actually suggest a possible In summary, there are many different phytoestrogen alters the physiological protective effect for this type of cancer.2,9 phytoestrogens, in varying capacities, effects on the body. Numerous active Also, soy consumption has actually been that have shown to be beneficial for ingredients, inadequate potency and found in many human populations to menopausal complaints including variations in individual metabolisms be protective against breast cancer.2, 9 hot flashes, vaginal dryness, sleep may lead to mixed results, but many All in all, phytoestrogens appear to be disturbances, cognition and bone women have found tremendous relief a very safe substitute for HRT that can density and the safety profile for from menopausal ailments by using alleviate women’s health concerns and phytoestrogens is good. phytoestrogens, and much of the aid their transition into menopause. Phytoestrogens in dietary form or research supports this claim. You must Still, to be cautious, it is advised to standardized extracts may be beneficial find the combination or product that only utilize phytoestrogens for shorter- for your menopausal symptoms. works best for you.

References 1. Chadwick L et al. The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties. Phytomedicine 2006;13:119- 131. 2. Bedell S et al. The pros and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol. 2013. 3. Erkkola R et al. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine 2010;17:389-396. 4. Heyerick A et al. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006;54: 164-175. 5. Levis S et al. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med. 2011;171(15):1363-9. 6. St Germain A et al. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause. 2001;8(1):17-26. 7. Chedraui P et al. The effect of soy-derived isoflavones over hot flashes, menopausal symptoms and mood in climacteric women with increased body mass index. Gynecol Endocrinol. 2011;27(5):307-13. 8. Ferrari A. Soy extract phytoestrogens with high dose of isoflavones for menopausal symptoms. J Obstet Gynaecol Res. 2009;35(6):1083-90. 9. Clarkson BT et al. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H Utian Translational Science Symposium in Chicago, IL. Menopause: The Journal of the North American Menopause Society. 2011;18(7): 732-753. 10. Yoles I et al. Efficacy and safety of standard versus low-dose Femarelle (DT56a) for the treatment of menopausal symptoms. Clinical and Experimental Obstetrics and Gynecology 2004;31(2):123–126. 11. Nachtigall M et al. A prospective study of DT56a (Femarelle) for the treatment of postmenopausal vaginal atrophy, Menopause 2011;18(12):1365. 12. Kreijkamp-Kaspers S et al. Dietary phytoestrogen intake and cognitive function in older women. Journals of Gerontology A: Biological Sciences and Medical Sciences 2007:62(5); 556–562. 13. Kim Y and Ilich JZ. Implications of dietary a-linolenic acid in bone health. Nutrition 2011:27(11–12);1101–1107. 14. Marini H et al. Update on genistein and thyroid: an overall message of safety. Front Endocrinol (Lausanne). 2012;3:94.

Advances 13 pregnancy, low blood sugar or insulin resistance. These stressors tax the pituitary so it no longer signals the thyroid to release hormone. With this pattern, individuals will experience hypothyroid symptoms but have a normal to low normal TSH (1.8-3.0 mlU/L). 2. Underconversion of T4 to T3 – T4 (thyroxine) is the inactive form of the hormone and it must be converted to T3 (triiodothyronine) before it can be used in the body. Common reasons for underconversion are inflammation and high cortisol levels. Inflammatory chemicals (cytokines) damage the cell membranes and impair the conversion of T4 to T3.2 Elevated cortisol also suppresses the conversion of T4 to T3.3 This Is it Really my Thyroid? results in hypothyroid symptoms but normal values of TSH, T4 and a low Hypothyroidism Explored T3 reading (if tested). 3. Elevated TBG – TBG (thyroid Hypothyroid is also known as In addition to the many contributing binding globulin) is the protein low or underactive thyroid. This factors for hypothyroid, the list of transporter for thyroid hormone. condition occurs when the gland fails potential symptoms is also numerous. When thyroid hormone is bound to to produce proper amounts of the Please see Table 1. Symptoms TBG, it is inactive and unavailable thyroid hormones (T3 and T4) to meet and Disorders Associated With to the tissues. Elevated TBG can be the body’s needs. Thyroid disease is Hypothyroidism. caused by high estrogen levels (from estimated to affect 200 million people Conventional testing for hypothyroid estrogen-containing birth control worldwide, with recent studies showing involves a blood test that primarily pills, or hormone replacement that as many as 1 in 10 Canadians are investigates TSH (thyroid stimulating therapy). Thus, with high TBG, affected. Of those affected with thyroid hormone). If this measurement is levels of unbound thyroid hormone dysfunction the majority are women, elevated (>5.5 mlU/L), then a diagnosis will be low, leading to hypothyroid of which an estimated 50% remain of hypothyroid is given and patients are symptoms.4 With this pattern, TSH undiagnosed. usually placed on thyroid medication; and T4 will be normal. T3 if tested There are numerous factors that may this shuts down the stimulation of the will be low and TBG will be high. contribute to low thyroid function hypothalamus/pituitary, decreases 4. Decreased TBG – the reverse of including: your TSH, and “normalizes” your above. When TBG levels are low, free • Autoimmune disease (known as blood test (see Figure 1). While this thyroid levels are high. Intuitively Hashimoto’s thyroiditis) can be helpful for some individuals, you would think this would cause • Hyperthyroid treatment (using two main issues are left unaddressed. high thyroid function, but with radioactive iodine or thyroid The first is that the laboratory values high thyroid levels circulating, the suppressing medications) for appropriate thyroid level are based tissues develop a resistance, causing • Thyroid surgery on a bell curve of diseased individuals, hypothyroid symptoms instead. • Radiation therapy of the head and and not what a healthy optimum level Decreased TBG can be caused neck regions should be. Second, the blood test does by high testosterone levels, often • Medications such as birth control, not investigate potential roots of the associated with PCOS (polycystic hormone replacement, and problem concerning hypothyroidism. ovarian syndrome) in women.5 This antidepressants Six Patterns of Hypothyroid to pattern reveals normal TSH and T4 • Pregnancy Consider and high T3. • Iodine deficiency 1. Pituitary dysfunction – caused by 5. Thyroid resistance – in this pattern • Pituitary tumor chronic stress during which high both the thyroid and pituitary are • Congenital defects levels of cortisol1 are secreted, functioning, but the hormones are

14 Advances not getting into the cells where they are needed. Possible mechanisms that block uptake of hormone include high cortisol from chronic stress, as well as high homocysteine which is a marker for inflammation.6,7 Note, all lab markers in this pattern will likely be normal as there is no measure for cellular resistance. 6. Hashimoto’s thyroiditis – an autoimmune disease where the immune system develops antibodies that then attack thyroid tissue. Potential causes include: genetic predisposition, infections, toxins, nutrient deficiencies, food allergies (gluten) and medications. Here the TSH will be high, but can also swing too low. General recommendations for treatment is to keep the TSH under 3.0 mlU/L for stabilization of symptoms. Subclinical Hypothyroid This means that with respect to laboratory testing, your values are within range. However, your clinical history and physical symptoms may all point to hypothyroid; therefore a course of thyroid treatment should still be considered. Basal Body Temperature Patients with suspected hypothyroidism that have normal lab values may get additional information about their condition by measuring basal body temperature. This test is performed by placing a thermometer deep in the armpit for 10 minutes, levothyroxine (synthroid). Additional hormone. It is interesting to note that immediately upon waking and before options are triiodothyronine and tyrosine is also the building block for getting out of bed. Typically the dessicated thyroid compounds. While the stress hormones epinephrine and temperatures are taken over 5 days these medications may be clinically norepinephrine. Thus, when under and the results are averaged. Women effective and relieve symptoms, there stress, thyroid production can be should begin taking their temperature are also some natural compounds reduced, as tryrosine is utilized for on the second day of menstruation, worth considering. They are all found the production of stress hormones which is the time in the cycle when the in the AOR product ThyroSupport. instead. body temperature is the lowest. If the This formula is designed to provide Iodine: Numerous studies have temperature averages below 36• C, then nutrients needed by the thyroid and to shown that normal thyroid status this could be a clue that a hypothyroid help in the stimulation and production is dependent on the presence of condition is possible. Basal body of thyroid hormones. It does not many trace elements for both the temperature is an estimate of basal act like a drug and take over for an synthesis and metabolism of thyroid metabolic rate, which is intimately underfunctioning thyroid, but rather hormones. Iodine is most important linked to thyroid function. provides the necessary nutrients to as a component of the hormones Treatment Options ensure your body’s own thyroid success. thyroxine and 3,3’,5-triiodothyronine Conventional treatment for Tyrosine: An amino acid that when (T3), and iodine deficiency can be a hypothyroid is almost unanimously combined with iodine, makes thyroid key factor in hypothyroidism.

Advances 15 Coleus Forskohlii: The Ayurvedic Table 1. Symptoms and Disorders Associated with Hypothyroidism herb Coleus forskohlii, and its active constituent forskolin, can raise the General • Premenstrual syndrome production and release of thyroid • Fatigue • Menstrual irregularities – hormones in animal and in-vitro • Weight gain amenorrhea or menorrhagia studies.8 • Weakness • Dermatological Bacopa monnieri: Studies in male • Headache • Course, dry, thinning hair mice showed that Bacopa possesses • Muscle aches • Hair loss (clue – loss of lateral 1/3 benefical thyroid-stimulating effects, • Constipation margin of eyebrows) increasing T4 concentration by 41% • Cold intolerance • Dry, rough skin after supplementation for 15 days when Psychiatric • Eczema/Psoriasis 9 compared to non-treated mice. • Depression • Hives Copper: Copper plays an important • Memory loss Cardiovascular role in thyroid metabolism, especially • Poor concentration • Angina pectoris in hormone production and absorption. Gynecological • Atherosclerosis Copper stimulates the production • Fibrocystic breasts • Hypercholesterolemia of the thyroxine hormone (T4), and • Infertility • Blood pressure irregularities prevents over-absorption of T4 in the • Polycystic ovarian syndrome blood cells by controlling calcium levels in the body. Zinc: Zinc plays an essential role are likely to have an underactive thyroid overall well-being. Low thyroid function in thyroid hormone function. In fact, gland. can be something that may fly under the without the presence of zinc, the thyroid Selenium: Is essential for normal radar of regular medical checkups, or may gland cannot transform the inactive thyroid hormone metabolism, it is a be tested and deemed fine by laboratory hormone T4 into the active hormone cofactor for various iodothyronine standards. This article has attempted T3. Furthermore, the hypothalamus deiodinases (enzymes) that control to highlight that this screening is not also requires zinc to make the hormone the synthesis and degradation of the always sufficient, and your physical and it uses to signal the pituitary gland to biologically active thyroid hormone, T3.10 emotional symptoms should be taken activate the thyroid. All of this means Thyroid health is a key ingredient to into account with equal consideration as that people with insufficient zinc levels managing energy, weight, aging, and there may be other factors at play.

References 1. Bartalena L et al. Eur J Endocrinol. Interleukin 6 effects on the pituitary-thyroid axis in the rat. 1994;131(3):302-6. 2. Corssmit E et al. J Clin Endocrinol Metab. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. 1995;80(11):3140-4. 3. Ann N et al. Acad Sci. Neuroendocrinology and pathophysiology of the stress system.1995; 771(29):1-18. 4. Ben-Rafael Z et al. Fertil Steril. Changes in thyroid function tests and binding globulin associated with treatment by gonadotropin. 1987;48(2):318-20. 5. Bisschop P et al. Eur J Endocrinol. The effects of sex-steroid administration on the pituitary-thyroid axis in transsexuals. 2006;155(1):11-6. 6. Williams G et al. Lancet. Thyroid hormone receptor expression in the “sick euthyroid” syndrome. 1989: 23-30;2(8678-8679):1477-81. 7. Limpach A et al. Exp Cell Res. Homocysteine inhibits retinoic acid synthesis: a mechanism for homocysteine-induced congenital defects. 2000:10;260(1):166-74. 8. Ammon H et al. “Forskolin: From an Ayurvedic Remedy to a Modern Agent,” Planta Med Dec.6. 1985: 473-7. 9. Kar A et al. Relative efficacy of three medicinal plant extracts in the alteration of thyroid hormone concentrations in male mice. J Ethnopharmacol. 2002;81(2):281-5. 10. Arthur J et al. Thyroid function. Br Med Bull. 1999;55(3):658-68. 11. Chanoine J. Selenium and thyroid function in infants, children and adolescents. Biofactors. 2003;19(3-4):137-43. Review.

Additional Sources www.thyroid.ca/thyroid_disease.php www.milwaukeethyroid.com/images/thyroid_diagram_large.jpg www.milwaukeethyroid.com/patterns.html www.thyroid.about.com/cs/testsforthyroid/a/labs2003.htm www.thyroid.org/what-is-hypothyroidism Dong, B. How medications affect thyroid function. West J Med. 2000 February; 172(2): 102–106. Gaby, A.R., MD. Nutritional Medicine. 2011. P. 28-39.

16 Advances levels of activity. Estrogens exist in the body in 3 different primary forms, (E1), 17β-estradiol (E2), and 16α- (E3).4 E2 is produced in the ovaries and is considered the most potent estrogen. E2 is approximately 12 times more potent than E1 and over 80 times more potent than E3.4 Estrone (E1) is produced primarily in adipose tissue, especially after menopause. Estriol (E3) is formed in the liver through the conversion of E2 and E1.4 Unfortunately, a number of harmful foods, environmental toxins, and chemicals can block this conversion and therefore result in increased levels of E2, which can promote breast cancer growth.3 Since E3 is the weakest form of estrogen, it acts in a similar fashion to a plant phytoestrogen and blocks the estrogen receptor from being stimulated by the more potent E2 or xenoestrogens. Higher levels of E3 have been associated with lower breast cancer risk, while Balanced Hormones for Breast higher levels of E2 have shown increased cancer risk.4 Cancer Prevention During the metabolism of E2 and E1 in the liver, 3 main estrogen metabolites Breast cancer is the most common the healthy function and metabolism are formed: 2-hydroxyestrone (2- cancer in North American women. of estrogen and other hormones. This OHE1), 4-hydroxyestrone (4-OHE1), It makes up almost 30% of all female article will discuss the positive and and 16α-hydroxyestrone (16α-OHE1).5 cancers and is the leading cause of negative forms of estrogen including See Figure 1 for a diagram of death among women 40-55 years old.1 phytoestrogens and xenoestrogens and estrogen metabolism in the liver. The There are numerous risk factors that are how they relate to breast cancer. It will 16α-OHE1 metabolites have a very associated with breast cancer. However, also address key dietary factors that help potent stimulatory effect on estrogen one of the most well established is reduce breast cancer risk and promote receptors and they promote cell growth, increased exposure to estrogen.2 hormonal balance. which increases cancer risk.5 4-OHE1 Women that experience early menarche Understanding estrogens accumulates in the breast tissue and and a later onset menopause have a Estrogens are an essential family causes DNA mutations and suppresses higher risk of breast cancer due to the of hormones that regulate many the activity of p53, an anti-cancer gene.5 lengthened exposure to estrogen during important functions, especially in the 2-hydroxyestrone opposes the effects their lifetime.3 External sources of female reproductive system. While of the other 2 estrogen metabolites estrogen such as hormone replacement they are important, estrogen receptors and appears to have a protective effect therapy and the birth control pill have often become saturated and over in breast cancer.5 Recent studies have also been linked to increased breast stimulated due to excess production, looked at the ratio of 2-OHE1 to cancer rates.3 Awareness about the poor metabolism and exposure to 16α-OHE1 in urine and have found that impact and importance of estrogen is environmental chemicals that have higher ratios may have protective effects quickly growing because there are so similar functions. This leads to the in breast cancer, but more studies are many factors that can lead to increased excessive promotion of cell growth, needed to confirm this ratio as a risk exposure. Not only is estrogen made which ultimately contributes to cancer assessment tool.6,7 within the body, many chemicals found cell growth. To fully understand Xenoestrogens in the environment act like estrogen the role of estrogen in breast cancer Xenoestrogens are a group of and also prevent its proper breakdown development, we must look at the environmental chemicals which and metabolism. Fortunately, there are a various forms and their actions since mimic estrogen in the body. This number of dietary factors that promote there is wide range of functions and family of molecules has been linked

Advances 17 strongly to ER-β than ER-α.13 ER-β receptors have been linked to increasing cancer cell apoptosis and are often down regulated in hormone sensitive cancers. Conversely, many xenoestrogens activate ER-α, which are present on 75% of breast cancer tumors.14 The fact that plant compounds such as selectively bind ER-β receptors suggests that some phytoestrogens may be useful in promoting cancer cell death.12 A large number of population studies that assess soy consumption found that higher intakes do not increase breast cancer risk. Some studies even showed a protective effect.15 After considering all the studies, a daily intake of 10g of soy protein had the optimal protective effect.15 These results are opposed by a number of test tube studies that have shown phytoestrogens in soy to stimulate estrogen receptors and breast to the development and promotion of these compounds that contribute to cancer cell growth. The difference in hormonally sensitive cancers. As of detrimental estrogenic activity in the the results highlights the complexity in 2003 there were over 160 xenoestrogens body. phytoestrogen activity. One important that may be involved in breast cancer Phytoestrogens and breast cancer point to consider is that individual development.8 For a list of the most It is impossible to talk about breast differences in intestinal microflora common xenoesterogens and where cancer and estrogen without briefly in humans promote the formation of they are found please see Table 1 on discussing phytoestrogens. There is a fair various phytoestrogen metabolites page 23. Cancer types associated with amount of confusion about the safety such as , which has a noted cancer environmental chemical exposure and effectiveness of phytoestrogens, protective effect.16 New data suggests and that have been well documented even among medical professionals. that equol could possibly enhance the in literature include those of the Phytoestrogens are a group of effect of in the prevention reproductive system, breast, lung, compounds found in certain plants of breast cancer.17 These factors are not kidney, pancreas, and brain.9 There that have an estrogen-like effect in the considered in test tube studies and may is evidence that the xenoestrogens human body. These compounds interact be responsible for the negative results. play a role in in all phases of cancer with estrogen receptors, but they are While there still is more research to development including initiation, much weaker than estradiol (E2) or be done, population studies suggest that transformation, and invasion.10 For most xenoestreogens.4 Due to their moderate dietary consumption does example, a number of studies have now relative weakness, phytoestrogens may not increase the risk of breast cancer. confirmed that a chemical (a polycyclic actually bind to the estrogen receptor It may even be protective, especially aromatic hydrocarbon) produced without actually activating it, therefore if the person has consumed soy since during meat frying and grilling strongly preventing E2 or xenoesteogens from childhood. It’s also important to increases DNA damage in breast cells activating the receptor. This would remember that not all phytoestrogens and promotes breast cancer growth.11 explain the fact that the majority of are the same and some may offer a There is still more research to be done studies have shown phytoestrogens to greater protective effect than others. to fully understand the broad health be protective against breast cancer, while The Influence of Diet on Estrogen and impact of xenoestrogens, but the elevated levels of human or synthetic Breast Cancer Risk Reduction emerging evidence is very concerning estrogen increases the risk.12 From a dietary perspective, cruciferous due to their widespread prevalence and It is also important to recognize that vegetables have demonstrated the pervasiveness in our food products, there are two different types of estrogen most powerful anti-cancer effect. water supply, and environment. As part receptors in the body: alpha-estrogen One study found that increasing the of a hormonal balancing and breast receptors (ER-α) and beta-estrogen cruciferous vegetable intake of healthy cancer prevention plan, it is paramount receptors (ER-β). This is important postmenopausal women for four weeks to consider reducing the exposure to because most phytoestrogens bind more increased urinary 2-OHE1:16α-OHE1

18 Advances ratios, suggesting that high intakes of cruciferous vegetables can shift estrogen metabolism.18 Theses vegetables contain a group of natural compounds called glucosinolates (which are later converted to biologically active isothiocyanates) that support liver detoxification and hormone elimination pathways. Two of the most promising isothiocyanates with potential hormonal balancing activity include indole-3-carbinol (I3C) and sulforaphane.19 Sulforaphane Sulforaphane is a compound with a unique ability to stimulate the phase 2 liver detoxification system.20 The phase 2 pathway is very important since it is the final stage for the removal of harmful compounds, detoxification products, and excess estrogens. Sulforaphane also has an impressive range of anti-cancer activity beyond stimulating phase 2 detoxification including stimulation and broccoli sprouts.19 Studies show Supplementation with 108 mg/day of of cancer cell suicide, preventing that just 1 cup of raw broccoli sprouts DIM also increased urinary 2-OHE1 replication, reducing tumor spreading contains enough sulforaphane (200 levels in postmenopausal women and inhibiting blood supply to cancer µmol) to penetrate breast tissue and suggesting that is has a positive effect on cells.21 Numerous studies have shown stop cancer growth.23 estrogen balance.27 One advantage DIM that sulforaphane can prevent the Indole-3-Carbinol (I3C) has over I3C is that it is a more stable growth of various cancer cells of the I3C is another compound found in molecule which leads to enhanced prostate, colon and breast.21 Perhaps the the cruciferous vegetable family, which biological activity.28 most exciting recently discovered action has an impact on estrogen levels and Essential Fatty Acids is that it may actually inhibit breast breast cancer risk. Like sulforaphane, The omega-3 and omega-6 class cancer stem cells which are responsible I3C possesses multiple anti-cancer of polyunsaturated fatty acids exert for continued tumor growth and disease mechanisms including the up- a modulating action on estrogen relapse.22 Another promising anti-cancer regulation of detoxification enzymes and metabolism. High intake of omega-6 effect is the ability of sulforaphane to increasing the 2-OHE1 form of estrogen fatty acids - linoleic acid (LA) and reduce inflammation right at the genetic in the liver.5 In controlled clinical trials, arachidonic acid (AA) - interferes level by stimulating a control protein oral supplementation with 300–400 mg/ with the detoxification of estrogens. called nuclear factor 2 (Nrf2).19 day of I3C has consistently increased Omega-3 fatty acids refer to a group From a practical perspective, urinary 2-OHE1 levels and urinary of three fats: alpha-linolenic acid cruciferous vegetables contain high 2-OHE1:16α-OHE1 ratios in women.24,25 (ALA), eicosapentaenoic acid (EPA) amounts of glucoraphanin (also referred I3C supplementation also reversed a and docosahexaenoic acid (DHA). to as sulforaphane glucosinolate or SGS), form of early cervical cancer after just Hydroxylation is an important which is then converted to biologically 12 weeks of supplementation.26 biochemical process necessary for active sulforaphane by an enzyme called Once I3C is ingested it forms detoxification. EPA has been shown to myrosinase. Myrosinase is released several metabolites, but the majority increase 2-hydroxylation of E2 at the when the plant is chewed or processed is converted to diindolylmethane expense of C-16α hydroxylation, while or produced in the gut by bacteria.19 See (DIM), which is considered the most DHA decreases the binding of estrogens Figure 2 for a diagram of sulforaphane active metabolite. Like I3C, DIM has to the ERs. breakdown. Unfortunately, cooking also demonstrated an improvement in Dietary Fibers partially destroys this enzyme, estrogen metabolism, however it does Dietary fibers are parts of a plant that limiting sulforaphane production. not have the same volume of clinical do not break down in our stomach, and Glucoraphanin is abundant in broccoli, research as I3C does. A number of cell pass through our system undigested. cauliflower, cabbage, and kale, with the studies have shown that it prevents Soluble fibers dissolve in water, while highest concentration found in broccoli the growth of breast cancer cells.5 insoluble fibers do not. Insoluble fibers

Advances 19 polymorphisms (SNPs) which interfere with their ability to metabolize certain vitamins to their active form utilized by the body. For example, it is estimated that between 10 and 15% of North American Caucasians, and >25% of Hispanics present a polymorphism affecting 5,10-methylenetetrahydrofolate reductase (MTHFR), the enzyme needed for the conversion of folic acid to 5-methyltetrahydrofolate (5-MTHF), the primary circulatory form of folate. Since SNPs can affect any other enzymes involved in the metabolism of vitamins, choosing a nutritional supplement containing the metabolically active form of folate (5-MTHF) and other B vitamins (P-5-P, methylcobalamin, etc.) will help ensure that you obtain adequate levels of these crucial nutrients. Green Tea Green tea has a large range of potential anti-cancer actions including reducing the growth of cancer cells and the blood vessels that feed them. For a more detailed discussion on green tea and cancer please see the article in Advances: Cancer. A recent study added another benefit to the long list when it such as lignins are found in flaxseeds dietary fibers per day, but the average found that green tea actually blocked and in the bran layer of grains, beans, American’s daily intake of dietary breast cancer growth associated with and seeds. Fruits and vegetables provide fiber averages only 12–18 grams. a powerful called PhIP most of the soluble fibers. Both types of Partially hydrolyzed guar gum (PHGG) (found in grilled or fried meats).29 This fibers are equally important for health, constitutes an excellent way to increase is so important because xenoestrogens digestion, and preventing various soluble fibers in your diet, and a good may be responsible for up to 85% of diseases. Soluble fibers are readily alternative to other highly allergenic spontaneous breast cancers.29 fermented in the colon into gases and alternatives such as wheat fibers or corn- Glucaric Acid physiologically active byproducts, while based products. This tasteless, odourless Glucaric acid is found in many insoluble fibers increase bulk, soften supplement dissolves completely in fruits and vegetables, with the highest stool, and shorten transit time through water and it has been better tolerated concentrations in oranges, apples, the intestinal tract. and preferred by patients in clinical grapefruit, and cruciferous vegetables. Recent studies demonstrate that trials. Oral supplementation of calcium- 16α-OHE1 levels are affected by B vitamins D-glucarate (a salt form of glucaric fiber intake. Soluble fibers favorably The important role of vitamins B6, acid) has been shown to inhibit beta- modulate the 2/16α ratio while B12, and folate as cofactors for enzymes glucuronidase, an enzyme produced insoluble fibers sequester endogenous involved in the methylation of catechol by gut bacteria that prevents phase II estrogens within the gut, decreasing estrogens (2-OHE1 and 4-OHE1) to liver detoxification.30 Elevated beta- their circulation within the body, their less harmful metabolites has already glucuronidase activity is associated with resulting availability to target tissues, been mentioned. However, obtaining an increased risk for various cancers, and improving their elimination via B vitamins solely from the diet can particularly hormone-dependent feces. represent quite a challenge, especially cancers such as breast, prostate, and Current recommendations from the for the increasing number of individuals colon cancers.30 Calcium-D-glucarate’s United States National Academy of adhering to a gluten-free diet. A inhibition of beta-glucuronidase Sciences, Institute of Medicine suggest significant portion of the population activity allows the body to excrete that adults consume 20–35 grams of presents single nucleotide genetic hormones such as estrogen before they

20 Advances can become reabsorbed. In support normally produced in the body or found balance by binding estrogen receptors of this action, supplementation with in the environment have been linked and increasing the elimination of calcium-D-glucarate has been shown to to higher breast cancer risk. Increasing excess estrogen. Cruciferous vegetables, lower serum estrogen levels in rats by 23 elimination and lowering exposure organic soy products and green/white percent.31 to these forms should be a primary tea stand out in the research as the most Pulling it all together goal in reducing risk and achieving beneficial. Incorporating these foods There is little doubt that estrogen plays healthy estrogen balance. Various into your diet can help to promote a large role in breast cancer development natural substances found in plants and healthy estrogen balance and to help and growth. Certain forms of estrogen vegetables can promote healthy estrogen reduce breast cancer risk.

References 1. “World Cancer Report”. International Agency for Research on Cancer. 2008. Retrieved 2013-07-20. 2. Feigelson H and Henderson B. Review Estrogens and breast cancer. Carcinogenesis. 1996; 17(11):2279-84. 3. Russo J and Russo I. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 2006;102(1-5):89-96. 4. Kaur A and Dean C. The Complete Natural Medicine Guide to Women’s Health. Robert Rose inc. Toronto, 2002. 5. Lord R et al. Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Altern Med Rev. 2002;7(2):112-29. 6. Dallal C and Taioli E. Urinary 2/16 estrogen metabolite ratio levels in healthy women: a review of the literature. Mutat Res. 2010;705(2):154-62 7. Obi N et al. Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? Int J Womens Health. 2011;3:37-51. 8. Brody J and Rudel R. Review Environmental pollutants and breast cancer. Environ Health Perspect. 2003; 111(8):1007-19. 9. Fucic A et al. Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain. Environ Health. 2012;11 Suppl 1:S8. 10. Fernandez S and Russo J. Estrogen and xenoestrogens in breast cancer. Toxicol Pathol. 2010;38(1):110-22. 11. Rohrmann S et al. Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue. Mutagenesis. 2009;24(2):127-32. 12. McKinney N Naturopathic Oncology. An encyclopedic guide for patients & physicians. 2nd edition. Liasion Press: Vancouver; 2012. 13. Turner J et al Molecular aspects of phytoestrogen selective binding at estrogen receptors. J Pharm Sci. 2007;96 (8): 1879–1885. 14. Bennion B et al. PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor. Chem Res Toxicol. 2005; 8(10):1528-36. 15. Kazor T. The Effects of Soy Consumption on Breast Cancer Prognosis: A review of the literature. The Natural Medicine Journal. 2012. 16. Jackson R et al. Emerging evidence of the health benefits of S-equol, an estrogen receptor β agonist. Nutr Rev. 2011;69(8):432-48. 17. Charalambous C et al. Equol enhances tamoxifen’s anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells. BMC Cancer. 2013;13:238. 18. Ho G et al. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore. 1998;27:294–9. 19. Sulforaphane Glucosinolate Monograph. Altern Med Rev 2012;15(4): 352-360. 20. Fahey J and Talalay P. Antioxidant functions of sulforaphane: a potent inducer of phase II detoxifi- cation enzymes. Food Chem Toxicol 1999;37:973-97. 21. Clarke J et al. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett. 2008;269(2):291-304. 22. Li Y et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16(9):2580- 90. 23. Cornblatt B et al. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007;28:1485-1490. 24. Higdon J et al. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224- 36. 25. Michnovicz J and Bradlow H. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst.1990;82:947-949. 26. Bell M et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-9. 27. Dalessandri K et al. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004; 50(2):161-7. 28. Bradlow H Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo. 2008;22(4):441-5. 29. Choudhary S et al. Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis. 2012;33(4):876-85. 30. Calcium-D-glucarate. Altern Med Rev. 2002;7(4):336-9. 31. Walaszek M et al. Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis. Carcinogenesis 1986;7:1463-1466.

Advances 21 shown that even minute exposure to Xenoestrogens: these chemicals can cause endocrine or reproductive harm if they happen Hidden Dangers in our Modern World at a critical developmental stage.3 In addition, the strange cases of some Xenoestrogens or “foreign estrogens” fibroids, endometriosis, fibrocystic of these chemical compounds are are chemical compounds that mimic breast disease, polycystic ovarian shown to be more toxic at low dose the effects of estrogen in our bodies. syndrome, and cancers have shown a exposure rather than high dose Sources come from almost all walks relationship to xenoestrogen exposure. exposures.4 of our modern lives, from industry, While there are numerous factors 5. Transgenerational (epigenetic) water sources, agriculture, clothing/ that will govern how significant these effects - perhaps the scariest to textiles, furniture, home cleaning exposures will be to your health, here consider, these chemicals may products, make-up, skin care products, are five worth consideration: not only affect those exposed, but contraceptives, sunscreens, insecticides, 1. Age at exposure - it has been shown the children born in subsequent food dyes, electrical oils, emulsifiers, that exposure to these chemicals in generations.5 paints; the list is almost endless. An utero or as a child has the potential All of this information can be additional list of common sources of for more harm than if exposed as an daunting and potentially depressing, xenoestrogens can be seen in Table 1. adult.1 however there are ways to minimize While these chemicals have 2. Latency due to exposure - there can your exposure to xenoestrogens as can systemic effects in our bodies, there be a time lag between exposure and be seen in Table 2. are certain areas that will concentrate manifestation of symptoms which To utilize all of the ideas in this xenoestrogens and demonstrate more may make it difficult to determine table may not be feasible, however significant issues due to exposure. when or where the exposure any movement to apply even some of These areas include the brain (pituitary, occurred. these suggestions will go a long way hypothalamus), thyroid, cardiovascular 3. Mixed exposure - due to to reducing overall exposure level. system, breasts, pancreas, ovaries, contamination of environment, we In addition there are some natural uterus and adipose tissue. are rarely exposed to just one of compounds that will also work With targeted uptake of chemical these chemicals. Thus the effects synergistically with these suggestions. concentration into these tissues, of multiple xenoestrogens may be *Sulforaphane - This natural conditions such as hypothyroid, additive and possibly synergistic.2 compound is found in cruciferous heart disease, diabetes, early puberty, 4. Dose response dynamics - It has been (green, leafy) vegetables and has been

22 Advances shown to protect our DNA from toxic demonstrates protection against toxins In addition, it may also be associated chemicals, act as an anticancer agent, and poisons.9 with the reduction of breast cancer.12 stimulate our immune system and *Diindolylmethane (DIM) - Another These natural compounds can be activate our phase II liver detoxification natural compound from cruciferous found in the AOR products Cellular enzymes.6 vegetables like broccoli, DIM promotes Detox, Liver Support and Estro Adapt. *Calcium-D-glucarate - Shown to the production of the healthy “2-OH” *For additional information on these inhibit the detoxification enzyme beta- estrogen, and reduces the production compounds please see the article on page glucaronidase, allowing toxins to be of unhealthy “16-OH” estrogen. This 17. effectively neutralized and excreted aids in reducing the formation of In our modern world, chemical from the body before they can do reproductive system diseases and exposure is part of life. If we can significant damage.7 estrogen sensitive cancers.10 make conscious decisions to limit our Milk Thistle - A liver protector and Hops - The active ingredientxenoestrogen exposure as best we can detoxifier, this herbal remedy acts to 8-prenylnaringenin (8PN), may help to by making clean choices with our diet, neutralize the harmful chemicals we reduce breast cancer metastasis as well how we clean and care for our bodies are exposed to and also protects the as tumor formation.11 and our homes, as well as by utilizing liver from damage even in cases of Choline - A natural compound shown some natural compounds as mentioned hepatitis and cancer.8 to support the liver via its contribution above to assist in detoxification, we limit N-acetyl cysteine (NAC) - The as a cofactor in the methylation process our total chemical load and thereby amino acid precursor to glutathione of detoxification - a key detoxification reduce the potential for complications (body’s premier antioxidant) NAC pathway for dealing with xenoestrogens. with our health.

Table 1 - Common Xenoestrogens and Environmental Sources Xenoestrogen Source Polycyclic aromatic hydrocarbons Formed when meat is cooked at high temperatures such as grilling or Heterocyclic amines barbecuing, and in smoked fish

Dioxins Mainly found in meats and animal products, especially fish, chicken, cheese and eggs (PCB) Found in paints, plastics, rubbers, dyes, and flame resistant clothes. They also accumulate in farmed fish, poultry, milk and dairy products, and fruits and vegetables Dichlorodiphenyl-trichlorethane that is now banned but still present in the water system (DDT) (DES) A drug that is now banned used to prevent miscarriages A preservative found in cosmetics such as creams and shampoos

Phthalates Found in plastics, medical equipment, baby mattresses, paints and personal care products Alkylphenols and PVCs (polyvinyl Found in plastics and perfumes chlorides) (Aluminium Found in anti-perspirants Chlorohydrate) Bispheynol A Leaches from plastics after repeated use. Also found in the inner lining of cans. Butylated hydroxyanisole (BHA) Preservative found in packaged food

Dichlorobenzene Potent chemical found in air fresheners and scents An anti-microbial found in hand soap and tooth pastes Styrene Widely used plastic for food packing Alcohol Even small amounts increases estrogen levels in the body

Advances 23 Table 2: Ideas for Minimizing Your Xenoestrogen Exposure

When Purchasing Household Products and Food or microwaving. • Choose chlorine-free products, unbleached paper • Use glass or ceramics whenever possible to store products and coffee filters. food. • Reduce the use of plastics whenever possible. • Do not leave plastic containers, especially your • Buy food grown locally and in season, organic if drinking water, in the sun. possible. • If a plastic water container has heated up • Buy and use chemical free, biodegradable laundry significantly, throw it away - do not drink the water. and household cleaning products whenever possible. • Don’t refill plastic water bottles. • Avoid freezing water in plastic bottles to drink later. Outside the Home • Peel non-organic fruits and vegetables. • Avoid all , herbicides, and fungicides. • Minimize X-rays whenever possible. Personal Products • Be aware of noxious gas such as from copiers and • Avoid creams and cosmetics that have toxic printers, carpets, fiberboards, and at the gas pump. chemicals and estrogenic ingredients such as parabens and stearal konium chloride. In the Kitchen • Minimize your exposure to nail polish and nail polish • Use filtered water to drink and bathe in to avoid removers. chlorine. • Use naturally based fragrances, such as essential oils. • Whenever possible, choose organic foods. • Read the labels on condoms and diaphragm gels. • Buy hormone free meats and dairy products to avoid • Use chemical free soaps and toothpastes. hormones and pesticides. • Use chlorine free tampons, menstrual pads, toilet • Do not microwave food in plastic containers. paper, paper towel etc. • Avoid the use of plastic wrap to cover food for storing

References 1. Barker D. The developmental origins of adult disease. Eur J Epidemiol. 2003;18:733–736. 2. Crews D et al. Animal models for the study of the effects of mixtures, low doses, and the embryonic environment on the action of endocrine disrupting chemicals. Pure and Applied Chemistry, SCOPE/IUPAC Project Implications of Endocrine Active Substances for Humans and Wildlife. 2003;75:2305–2320. 3. Sheehan D et al. No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much? Environ Health Perspect. 1999; 107:155–159. 4. Vom Saal F et al. Chapel Hill Expert Panel Consensus Statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol. 2007;24:131–138. 5. Anway M et al. Epigenetic trans-generational actions of endocrine disruptors. Endocrinology. 2006;147:S43–S49. 6. Shapiro T et al. Safety, Tolerance, and Metabolism of Broccoli Sprout Glucosinolates and Isothiocyanates: A Clinical Phase I Study. Nutrition and Cancer. 2006;55(1): 53-62. 7. Heerdt A et al. Calcium glucarate as a chemopreventive agent in breast cancer. Isr J Med Sci. 1995; 31(2-3): 101-5. 8. Fried M et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C who failed interferon therapy: a randomized, placebo-controlled trial. JAMA. 2012;308(3):274–282. 9. Manov I et al. Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a study of Hep3B cells. Exp Toxicol Pathol. 2002;53(6):489-500. 10. Hong C et al. 3,3′-Diindolylmethane (DIM) induces a G1 cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21WAF1/CIP1 expression. Carcinogenesis.2002;23(8)1297-1305. 11. Miligan S et al. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) . The Journal of Clinical Endocrinology & Metabolism. 2000; 85(12): 4912-4915. 12. Faseb J. Choline metabolism and risk of breast cancer in a population-based study. 2008 Jun;22(6):2045-52. Additional Sources www.endocrine.org www.organicexcellence.com

24 Advances problems. Finally, there is a higher Control PCOS: Control Your Life prevalence of hirsutism among women of Middle Eastern and Mediterranean Polycystic ovary syndrome (PCOS) not result in irregular menstruation, origin that suffer from PCOS.1 PCOS is considered one of the leading and 2) excessive amounts (or due to the is also associated with other conditions endocrine disorders affecting up to effects) of androgenic hormones, which including Acanthosis nigricans 10% of all women of reproductive age.1 cause hirsutism (excessive facial and (hyperpigmentation of folds in the It is a complex disorder stemming from body hair).2,3 It is not uncommon for skin),11 fatty liver disease, obstructive inappropriate hypothalamic-pituitary- women with PCOS to encounter other sleep apnea, carcinoma (malignant ovarian interaction (see the article difficulties such as infertility, high risk cancer cells), and potentially breast, titled “An introduction to the HPG of miscarriage, accumulation of visceral endometrial or ovarian cancer.5,12 Axis”), thought to be one of the leading fat, obesity, various cardiovascular Interestingly, insulin resistance and causes of infertility. Why and how diseases such as diabetes, dyslipidemia, obesity can further amplify the severity PCOS develops is not yet understood, hypertension, and Metabolic Syndrome of the condition and its symptoms, although accumulating evidence later in life.3-8 The severity of symptoms, creating a vicious cycle where the suggests that it may be mostly genetic.2,3 especially hirsutism and obesity, can symptoms exacerbate the condition Diagnosis, Symptoms and Risks lead to feelings of low self-esteem, and the condition exacerbates the A PCOS diagnosis is based on anxiety, depression and low quality of symptoms.13 menstrual irregularity, excessive life.9 Currently, four categories of PCOS production of androgens Severity of symptoms and related have been identified.14 The first is (masculinizing hormones) or excessive disorders of PCOS vary greatly between characterized by the presence of masculinizing traits (such as balding, individuals, yet there are some trends menstrual irregularities, polycystic excessive body and facial hair), as that have been observed with age and ovaries and hyperandrogenemia well as the presence of ovarian cysts. ethnicity. In younger women with (excessive masculinizing hormones), However, all other possible causes of PCOS, hyperandrogenism (excessive and is present in ~48% of all women with the above mentioned traits have to be androgens) and chronic anovulation PCOS. The second is characterized by excluded for a diagnosis of PCOS to be (lack of ovulation) are the primary the presence of menstrual irregularities made.2,3 There are many connections disturbances, whereas, obesity, insulin and hyperandrogenemia only, and is between the various factors involved in resistance, and metabolic disturbances found in 31% of women with PCOS. the development of PCOS but how they are predominant in older women with The third is characterized by the all fit together has not been conclusively PCOS.10 South Asians with PCOS have presence of hyperandrogenemia and determined.3 a high prevalence of insulin resistance polycystic ovaries only and is present The principal symptoms of PCOS and metabolic syndrome, and are at risk in 10% of women with PCOS. Finally, emerge late in puberty or shortly after, for type 2 diabetes. African American the fourth category is characterized by stemming from two main causes: 1) a and Hispanic women with PCOS are the presence of menstrual irregularities lack of ovulation, which may or may more prone to obesity and metabolic and polycystic ovaries only and is

Advances 25 present in 11% of women with PCOS.14 and change the management routine with PCOS had improved menstrual Panidis and colleagues (2012) identified accordingly. regularity, ovulation and pregnancy the following trends: both lean and Dietary and Lifestyle Changes rates within weeks.18, 19 overweight/obese women in PCOS First line therapy for women with In order to best reduce insulin categories 1 and 2 are at a higher risk for PCOS, and the only therapy incurring resistance and reduce the risk of type insulin resistance than those without lifelong benefits with minimal side 2 diabetes, improve lipid profiles and PCOS, while only obese/overweight effects, is the reduction of central reduce androgen production, diet women in the fourth category share the abdominal fat in all women, and weight recommendations for women with same risk. Overweight women in the loss in overweight and obese women.16 PCOS are similar to those recommended first category, however, have the highest Abdominal fat is the most common fat for type 2 diabetics. A high-fiber, low- risk for insulin resistance. Serum distribution found in women with PCOS glycemic-index diet with adequate androgen levels are highest in both lean whether they’re lean or overweight.17 protein and an emphasis on unsaturated and overweight/obese women in PCOS Visceral fat, especially in obesity, has fatty acids (especially ω-3 fatty acids) is categories one to three compared to been found to increase some features recommended, while also maintaining those in the fourth.14 of PCOS such as infertility, pregnancy a high intake of anti-inflammatory and Management complications and hyperandrogenism antioxidant nutrients such as vitamin E Early diagnosis and preventative including hirsutism, and in and moderate amounts of red wine.20 A measures are of the utmost importance combination with insulin resistance it reduced calorie diet is recommended in promoting long-term health, can increase the risk for type 2 diabetes for obese and overweight women, while decreasing the risk of developing and cardiovascular diseases.17,18 The adequate calories for maintenance are other secondary illnesses, and even reduction of abdominal fat in all more appropriate for lean women.20 An preventing the development of women with PCOS and weight loss in extreme version of a low carbohydrate cardiovascular diseases.15 However, overweight and obese women can also diet called a “ketogenic diet”, in which due to the individualized nature of help prevent long-term complications the ratio of carbohydrates to proteins PCOS, management must be tailored of the condition by improving quality to fat is maintained at 10:30:60, was to target the displayed symptoms and of life, correcting hyperinsulinemia, found to significantly decrease insulin to prevent the risk factors that you improving fertility and improving lipid resistance, free testosterone, and weight may have a predisposition for. It is also and androgen profiles.18 In fact, it has in overweight women with PCOS.21 important to monitor progress and been found that after losing only 5% However it is not recommended the development of new symptoms, of initial body weight, obese women to maintain a ketogenic diet for a

26 Advances prolonged period of time as research on long term safety is lacking; a doctor QUESTIONNAIRE should be consulted prior to starting Should I ask my Doctor if I have PCOS? a ketogenic diet. Timing of caloric Q1 Between the ages of 16 and 40, about how long was your average intake can also have an effect on PCOS menstrual cycle (time from first day of one period to the first day of the symptoms in lean women; it was shown next period)? (select ONE only) that a breakfast with more calories than PS: Do not include any time spent pregnant, receiving birth control pills dinner improved insulin sensitivity or injections, after menopause, or after having both ovaries or the uterus compared to a dinner with more surgically removed: calories than breakfast.22 a) <25 days Lifestyle changes can also have an b) 25-34 days impact on PCOS symptoms. It was c) 35-60 days shown that 1 hour of exercise (aerobic, d) More than 60 days resistance, or endurance) three times e) Totally Variable per week for 12-16 weeks, significantly Q2 During your Menstruating Years (Not including during pregnancy), improved insulin resistance, ovarian did you have a tendency to grow dark, coarse hair on your: (Circle all that hormones, and reproductive applies) 23-26 function. It was also shown that a) Upper Lip the addition of aerobic or combined b) Chin aerobic-resistance exercise to a calorie c) Breasts restricted diet significantly improved d) Chest Between Breasts body composition in overweight and e) Back obese women with PCOS compared to f) Belly 27 those on a low calorie diet only. g) Upper Arms Even if healthy dietary and lifestyle h) Upper Thighs options alone are not enough, a healthy lifestyle can significantly improve the Q3 Were you ever obese or overweight between the ages of 16 and 40? success rate of other supplemental, (Circle one) pharmaceutical and surgical a) Yes interventions. In fact, returning to a less b) No healthy lifestyle and weight gain can Q4 Between the ages of 16 and 40, have you ever noticed a milky easily reverse all the benefits that were discharge from your nipples (not including during pregnancy or recent obtained by exercise and healthy eating. childbirth)? (Circle one) Supplementation a) Yes Some women with PCOS may not b) No achieve adequate symptom relief from Key is at the end of the article. dietary and lifestyle changes alone, and therefore they may seek natural interventions to boost the results of calcium, zinc and copper than women insulin resistance, diabetes, obesity, and healthy lifestyle modifications. without PCOS, and the differences various other metabolic conditions.32,33 Chromium: To reduce the risk were more pronounced in women with It was shown that vitamin D and of developing type 2 diabetes, it is PCOS and insulin resistance.29 calcium supplementation in overweight crucial to reduce insulin resistance. Cinnamon & Gymnema: Cinnamon women with PCOS improved androgen Chromium is a well-known element was also shown to significantly reduce and blood pressure profiles,34 and in that has been found to reduce high insulin resistance in women with PCOS infertile women it improved weight insulin at doses of 200-1000 mcg/day, compared to placebo.30 Additionally, loss, follicle maturation and menstrual and the picolinate salt was found to Gymnema sylvestre, although not yet regularity.35,36 In another study, vitamin be the most bioavailable chromium studied in women with PCOS, is a D supplementation in women with salt.28 Interestingly, circulating serum well-known herb used for lowering PCOS improved glucose metabolism chromium has been found to be low in insulin resistance and supporting the and menstrual frequency.37 women with PCOS, and was directly management of diabetes.31 Folate: Folate (L-5- correlated with fasting insulin levels.29 Vitamin D: Low vitamin D was shown methyltetrahydrofolate, L-5-MTHF) The same study also found that women to be associated with components of is a crucial B vitamin especially for with PCOS had lower serum manganese metabolic syndrome in women with any woman looking to conceive, as it and magnesium, but higher serum PCOS, which include hyperlipidemia, is a simple way to prevent neural tube

Advances 27 significantly reduce liver fat content, thereby preventing or reducing fatty liver disease, in addition to improving serum adiponectin levels (a protein involved in regulating glucose levels as well as fatty acid breakdown), insulin resistance and cholesterol in women with PCOS,49,50 while another group showed that greater plasma polyunsaturated fatty acids, particularly long chain omega-3s, improve the androgenic profile in women with PCOS.51 Anti-androgenic herbs: These can be used to lower androgen levels in women with PCOS, helping to reduce hirsutism and balding. Spearmint herbal tea was shown to have significant anti- androgen effects in polycystic women; however, because hirsutism and balding require more time to resolve in response to lowering androgen levels, the short duration of the trials did not permit them to decrease significantly. However, it is expected that longer defects in developing fetuses. However, quality, mature oocytes (egg cells) term intake of spearmint tea would it can also help reduce homocysteine, has been established.42 It is therefore produce significant results.52,53 While which is associated with recurrent not surprising that supplementing other known anti-androgen herbs pregnancy loss and an increased with myo-inositol (4g/day) during like saw palmetto and standardized risk of cardiovascular disorders in vitro fertilization treatments have pollen extracts have not been studied including dyslipidemia and blood clot been shown to significantly improve in women with PCOS, their well- formation.29,38 Folate intake was shown oocyte quality, improving the chance known anti-androgenic properties are to significantly reduce homocysteine of developing a healthy embryo by expected to reduce symptoms of high levels in women with PCOS 39 at doses improving insulin sensitivity.43-45 androgen levels in women with PCOS. between 400-1000 mcg. However However, evidence on D-chiro-inositol Anti-androgenic supplementation or many women can’t even metabolize supplementation is controversial, with medication must not be taken during regular supplemental folate due to a a recent study even showing worsening pregnancy or when trying to conceive common genetic mutation that makes of oocyte quality and reduced ovarian however, as they have the potential of them unable to convert the folate to its response to fertility treatments.46 feminizing male fetuses. active form, L-5-MTHF. 40 This can be Melatonin: Melatonin supplementation Soy isoflavones: There are many overcome by directly supplementing was also found to improve oocyte options available to manage high with the bioactive folate form, L-5- quality and pregnancy rates in women cholesterol levels and improve the MTHF. undergoing in vitro fertilization.47 body’s lipid profile. Soy isoflavones have Inositol: The development of insulin Melatonin reduces oxidative stress been studied in women with PCOS, resistance may be linked to a deficiency within the follicle. Oxidative stress and an intake of 36 mg/day of genistein in inositol, which is a messenger increases significantly during the for 6 months in dyslipidemic women needed for insulin signaling.41 The ovulatory process and is suspected improved their lipid profiles.54 human body contains two forms to be a cause of poor oocyte quality.48 Other Options of inositol, myo-inositol (the most The addition of 3mg/day of melatonin Some women may opt for prescription abundant form), and D-chiro-inositol; to myo-inositol and folic acid medication, and in severe cases, surgical the ratios of each are different in each supplementation significantly improves intervention may be warranted. It must organ depending on that organ’s needs. oocyte quality and pregnancy outcome be noted however that lifestyle changes, Ovaries require a high level of myo- in women with poor oocyte quality.49 including healthy diet and exercise are inositol - in fact, a link between high Omega-3s: Supplementing with crucial to maintain results, no matter concentrations of myo-inositol and omega-3 fatty acids was shown to what other interventions are used.

28 Advances For hirsutism, there are many Understanding your own symptoms and PCOS. In addition to a healthy lifestyle, available options. Tweezing, waxing, working closely with your doctor are the supplements or medication may be sugaring and shaving are the cheapest first steps toward effective and targeted used to target any other symptoms that methods; however, these only provide therapy. It is crucial to get diagnosed at do not resolve with healthy lifestyle temporary relief. More permanent the earliest stages of the disease in order modifications alone. relief can be provided with electrolysis to have the best chance at reducing the or laser hair removal. Permanent risk of, or even preventing, progression Key to “Should I Ask My Doctor if hair reduction with either laser or of the condition or the development I Have PCOS?” Award 1 point each if you: electrolysis may take up to 2 years to of complications. A healthy lifestyle, Q1: Answered c, d or e Q2: Circled 3 or more sites significantly reduce hair growth. including consistent exercise and a diet Q3: Answered “yes” Being diagnosed with PCOS may high in anti-inflammatory nutrients, For Q4, if you answered “yes”, then subtract 1 point, if you answered “no” then don’t change your seem daunting and overwhelming, antioxidants, fiber and proteins while points. and although it is a lifelong condition low in carbohydrates is the first line of If you get ≥2 points, then you may have PCOS and should speak to your doctor. with no cure, it is highly manageable. therapy toward managing symptoms of

References 1. Zhao Y et al. Ethnic Differences in the Phenotypic Expression of Polycystic Ovary Syndrome. 2013. ; 78(8): 755-760. 2. Robboy S et al. The Female Reproductive System. In: Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1999:1003-1004. 3. Chang RJ. The Reproductive Phenotype in Polycystic Ovary Syndrome. Endocrinology & Metabolism. Jul 2007;3(10):688-695. 4. Ehrmann D et al. Prevalence of Impaired Glucose Tolerance and Diabetes in Women with Polycystic Ovary Syndrome. 1999. Diabetes Care;22(1):141-6. 5. Ehrmann D. Polycystic Ovary Syndrome. 2005. N Eng J Med;352(12):1223-36. 6. Mather K et al. Hyperinsulinemia in Polycystic Ovary Syndrome Correlates with Increased Cardiovascular Risk Independent of Obesity. 2000. Fertil Steril;73(1):150-6. 7. Holte J et al. Elevated Ambulatory Daytime Blood Pressure in Women with Polycystic Ovary Syndrome: A Sign of A Pre-hypertensive State? 1996. Hum Reprod;11:23-8. 8. Badawy A et al. Treatment Options for Polycystic Ovary Syndrome. 2011. Int J Womens Health; 3:25-35 9. Teede H et al. Polycystic Ovary Syndrome: A Complex Condition with Psychological, Reproductive and Metabolic Manifestations that Impacts on Health Across the Lifespan. 2010. BMC Med; 8:41 10. Hsu M. Changes in the PCOS Phenotype with Age. 2013. Steroids; 78(8):761-766. 11. Berbieri R et al. Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans Syndrome: A Common endocrinopathy with Distinct Pathophysiologic Features. 1983. Obstet Gynecol; 147:90-101. 12. Lim S. The Effect of Obesity on Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis. Obes Rev. Feb 2013; 14(2):95-109. 13. Panidis D et al. Insulin Resistance and endocrine Characteristics of the Different Phenotypes of Polycystic Ovary Syndrome: A prospective Study. 2012. Hum Reprod; 27(2):541-549. 14. Huang G et al. Clinical Update on Screening, Diagnosis and Management of Metabolic Disorders and Cardiovascular Risk Factors Associated with Polycystic Ovary Syndrome. 2012. Curr Opin Endocrinol Diabetes Obes; 19(6): 512-519. 15. Cussons A et al. Polycystic Ovarian Syndrome: Marked Differences Between Endocrinologists and Gynaecologists in Diagnosis and Management. 2005. Clin Edocrinol (Oxf); 62(3):289-295. 16. Yildirim B et al. Relation of Intra-Abdominal Fat Distribution to Metabolic Disorders in Non-Obese Patients with Polycystic Ovary Syndrome.2003. Fertil Steril; 79:1358-1364. 17. Stankiewicz M et al. Diagnosis and Management of Polycystic Ovary Syndrome – A practical Guide. 2006. Drugs;66(7):903-912. 18. Motta A. The Role of Obesity in the Development of Polycystic Ovary Syndrome. 2012. Curr Pharm Des; 18(17):2482-2491. 19. Liepa G et al. Polycystic Ovary Syndrome (PCOS) and Other Androgen Excess-Related Conditions; Can Changes in Dietary Intake Make a Difference? 2008. Nutr Clin Pract; 23:63-71. 20. Mavropoulos J et al. The Effects of a Low-Carbohydrate, Ketogenic Diet on The Polycystic Ovary Syndrome: A Pilot Study. 2005. Nutr Metab; 2:35–46. 21. Jakubowicz D et al. Effects of Caloric Intake Timing on Insulin Resistance and Hyperandrogenism in Lean women with Polycystic Ovary Syndrome. 2013. Clinical Science;125:423-432. 22. Harrison C et al. The Impact of Intensified Exercise Training on Insulin Resistance and Fitness in Overweight and Obese women with and without Polycystic Ovary Syndrome. 2012. Clin Endocrinol (Oxf); 76(3):351-357. 23. Joham A et al. Pigment Epithelium-Derived Factor, Insulin Sensitivity, and Adiposity in Polycystic Ovary Syndrome: Impact of Exercise Training. 2012. Obesity (Silver Spring); 20(12):2390-2396. 24. Moran L et al. Exercise Decreases Anti-Müllerian Hormone in Anovulatory Overweight Women with Polycystic Ovary Syndrome: A Pilot Study. 2011. Horm Metab Res. ;43(13):977-9. 25. Nybacka A et al. Randomized Comparison of The Influence of Dietary Management and/or Physical Exercise on Ovarian Function and

Advances 29 Metabolic Parameters in Overweight Women with Polycystic Ovary Syndrome. 2011. Fertil Steril; 96(6):1508-13. 26. Thomson R et al. The Effect of a Hypocaloric Diet with and without Exercise Training on Body Composition, Cardiometabolic Risk Profile, and Reproductive Function in Overweight and Obese Women with Polycystic Ovary Syndrome. 2008. J Clin Endocrinol Metab; 93(9):3373-3380. 27. Power M et al. Alternative and Complementary Treatments for Metabolic Syndrome. 2011. Curr Diab Rep; 11:173-178. 28. Chakraborty P et al. Recurrent Pregnancy Loss in Polycystic Ovary Syndrome: Role of Hyperhomocysteinemia and Insulin Resistance. 2013. PLoS One; 8(5):e64446. 29. Wang J et al. The effect of Cinnamon Extract on Insulin Resistance Parameters in Polycystic Ovary Syndrome: A Pilot Study. 2007. Fertil Steril; 88:240-243. 30. Leach M et al. Gymnema sylvestre for Diabetes Mellitus: A Systematic Review. 2007. The journal of Alternative and Complementary Medicine; 13(9):977-983. 31. Wehr E et al. Association of Hypovitaminosis D with Metabolic Disturbances in Polycystic Ovary Syndrome. 2009. Eur J Endocrinol. 161(4):575-82. 32. Hahn S et al. Low Serum 25-hydroxyvitamin D Concentrations Are Associated With Insulin Resistance and Obesity in Women with Polycystic Ovary Syndrome. 2006. Exp Clin Endocrinol Diabetes;114(10):577-583. 33. Pal L et al. Therapeutic Implications of Vitamin D and Calcium in Overweight Women with Polycystic Ovary Syndrome. 2012. Gynecol Endocrinol; 28(12):965-968. 34. Firouzabadi R et al. Therapeutic Effects of Calcium & Vitamin D Supplementation in Women with PCOS. 2012. Complement Ther Clin Pract. 18(2):85-88. 35. Rashidi B et al. The Effects of Calcium-Vitamin D and Metformin on Polycystic Ovary Syndrome: A Pilot Study. 2009. Taiwan J Obstet Gynecol; 48(2):142-147. 36. Wehr E et al. Effect of Vitamin D3 Treatment on Glucose Metabolism and Menstrual Frequency in Polycystic Ovary Syndrome Women: A Pilot Study. 2011. J Endocrinol Invest; 30(10):757-763. 37. Audeline M et al. Homocysteine and Cardiovascular Disease in Diabetes Mellitus. 2001. Atherosclerosis; 159:497-511. 38. Kazerooni T et al. Effect of Folic Acid in Women with and without Insulin Resistance who have Hyperhomocysteinemic Polycystic Ovary Syndrome. 2008. Int J Gynaecol Obstet; 101(2):156-160. 39. Zhang T et al. Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature. 2013. PLoS One; 8(4):e59570. 40. Huang et al. Chiro-Inositol Deficiency and Insulin Resistance. III. Acute Glycogenic and Hypoglycemic Effects of Two Inositol Phosphoglycan Insulin Mediators in Normal and Streptozotocin-Diabetic Rats in vivo. 1993. Endocrinology; 132:652-657. 41. Chiu T et al. Follicular Fluid and Serum Concentrations of Myo-Inositol in Patients Undergoing IVF: Relationship with Oocyte Quality. 2002 Hum Reprod.17(6):1591-1596. 42. Papaleo E et al. Myo-inositol May Improve Oocyte Quality in Intracytoplasmic Sperm Injection Cycles. A Prospective, controlled, Randomized Trial. 2009. Fertil Steril. 91(5):1750-1754. 43. Unfer V et al. Effects of Myo-Inositol in Women with PCOS: A Systematic Review of Randomized Controlled trials. 2012. Gynecol Endocrinol; 28(7):509-515. 44. Genazzani A et al. Differential Insulin Response to Myo-Inositol Administration in Obese Polycystic Ovary Syndrome Patients. 2012. Gynecol Endocrinol; 28(120):969-973. 45. Isabella R et al. Does Ovary Need D-Chiro-Inositol? 2012. J Ovarian Res; 5:19. 46. Batıoğlu A et al. The Efficacy of Melatonin Administration on Oocyte Quality. 2012. Gynecological Endocrinoliogy; 28(2):91-93. 47. Sugino N. Reactive Oxygen Species in Ovarian Physiology. 2005. Reprod Med;4:31-44. 48. Rizzo P et al. Effect of the Treatment with Myo-Inositol Plus Folic Acid Plus Melatonin in Comparison with a Treatment with Myo-Inositol Plus Folic Acid on Oocyte Quality and Pregnancy Outcome in IVF Cycles. A Prospective, Clinical trial. 2010. Eur Rev Med Pharmacol Sci; 14(6):555-561. 49. Cussons A et a. Omega-3 Fatty Acid Supplementation Decreases Liver Fat Content in Polycystic Ovary Syndrome: A Randomized Controlled Trial Employing Proton Magnetic Resonance Spectroscopy. 2009. J Clin Endocrin Metabo; 94(10)3842-8. 50. Mohammadi E et al. Effects Of Omega-3 Fatty Acids Supplementation on Serum Adiponectin Levels and Some Metabolic Risk Factors in Women with Polycystic Ovary Syndrome. 2012. Asia Pac J Clin Nutr;21(4):511-518. 51. Phelan N et al. Hormonal and Metabolic Effects of Polyunsaturated Fatty Acids in Young Women with Polycystic Ovary Syndrome: Results from a Cross-Sectional Analysis And A Randomized, Placebo-Controlled, Crossover Trial. 2011. Am J Clin Nutr; 93(3): 652-662. 52. Grant P. Spearmint Tea Has Significant anti-Androgen Effects in Polycystic Ovarian Syndrome: A Randomized Controlled Trial. Phtother Res. Feb 2010. 24(2):186-188 53. Akdoğan M et al. Effect of Spearmint (Mentha spicata Labiatae) Teas on Androgen Levels in Women with Hersutism. 2007. Phytother Res; 21(5):444-447. 54. Romualdi D et al. In There a Role for Soy Isoflavones in the Therapeutic Approach to Polycystic Ovary Syndrome? Results from a Pilot Study. 2008. Fertil Steril;90(5):1826-1833. 55. Bates G et al. Medical and Surgical Management of Common Fertility Issues: Polycystic Ovarian Syndrome Management Options. 2012. Obstetrics and Gynecology Clinics; 39(4):495-506. 56. Giallauria F et al. Cardiovascular Risk in Women with Polycystic Ovary Syndrome. 2008. Journal of Cardiovascular Medicine;9(10):987-992. 57. Pedersen SD et al. Polycystic Ovary Syndrome: Validated Questionnaire for Use in Diagnosis. Can Fam Physician. 2007; 53:1041-1047.

30 Advances Supports the Hippocampus

Time to Remember

1.800.387.0177 www.ovos.ca VEIN EASE

A New and Effective Treatment for Chronic Venous Insufficiency (CVI)

ADVANCED ORTHOMOLECULAR RESEARCH