The Role of Endogenous Sex Hormones in the Development of Type 2 Diabetes

lady-sun-thinking-sm
For more info visit www.mhicn.com

Hormonal balance is recognized as a factor in the development of non-communicable diseases, such as type 2 diabetes. The topic is of particular interest regarding the health of peri- and post-menopausal women who experience changes in hormone levels during the menopausal transition and also have increased risk of developing non-communicable diseases, such as cardiovascular disease and diabetes, as they age.

It is known that post-menopausal women have elevated glucose and elevated insulin response, compared to adiposity-matched pre-menopausal women, so it is possible that changes in the levels of specific sex hormones due to the menopausal transition play a role in increasing women’s risk of developing diabetes. Glucose and insulin response increased following a glucose challenge in ERα-knockout mice, mice lacking functional estrogen receptor-α, mice which can serve as a useful model for humans for endocrine research and the role of estrogen on the body. These results indicate that ERα is important for regulating adipose tissue in women. Furthermore, in an eight-year longitudinal cohort study, the Study of Women’s Health Across the Nation (SWAN), women who experienced vasomotor symptoms like hot flashes during the menopausal transition had a higher HOMA index, a measure of insulin resistance, and somewhat higher glucose than those who did not experience vasomotor symptoms. Furthermore, as women experience the menopausal transition, they often gain subcutaneous abdominal fat and may also have a significant increase in visceral and subcutaneous abdominal fat, accompanied by a decrease in fat oxidation, all of which may predispose post-menopausal women to obesity, more frequent vasomotor symptoms, elevated glucose, elevated insulin response, and diabetes.

These findings suggest a relationship between endogenous female sex hormones, insulin, and diabetes in menopause, particularly in women experiencing the menopausal transition who are overweight or obese. In an abstract at the 2015 European Society of Cardiology Congress, our colleagues from Erasmus MC presented results from the Rotterdam Study indicating that two female sex hormones were associated with the risk of diabetes among women. Sex-hormone binding globulin (SHBG) was inversely associated with the risk of diabetes, while the free androgen index (FAI), the ratio of total testosterone to SHBG, was positively associated with the risk of diabetes in women. The findings regarding the inverse relationship between SHBG levels and incidence of type 2 diabetes in women were also shown in a 2009 study published in the New England Journal of Medicine and a 2006 meta-analysis published in the Journal of the American Medical Association.

The interaction of endogenous sex hormones and menopausal-associated increases in adiposity suggest something of a “vicious cycle” in which elevated insulin levels reduce levels of SHBG, increasing levels of testosterone and the FAI, and increasing visceral and abdominal adiposity, restarting the cycle again.

Hormone replacement therapy (HRT) may alleviate the symptoms of menopause, but are not meant to reduce the risk of developing diabetes, for example. Current guidelines recommend that clinicians discuss the potential benefits and risks of HRT, and that treatments are reviewed every three months to assess efficacy of therapies and tolerability of symptoms. It has been concluded in the guidelines that taking HRT is not associated with an increased risk of developing type 2 diabetes, but ongoing investigations into the associations of sex hormones with various health outcomes may yield changes in the menopausal health guidelines for women. In the meantime, however, healthy lifestyle behaviors like improved nutrition, sleep, and physical activity are recommended to reduce weight gain and its impact on hormonal health during and beyond the menopausal transition.

References

Bessesen, DH; KA Cox-York; TL Hernandez; CB Erickson, H Wang; MR Jackman; RE Van Pelt. Postprandial triglycerides and adipose tissue storage of dietary fatty acids: impact of menopause and estradiol. Obesity (2015) 23(1):. 145-153.

Ding, EL; Y Song; JE Manson; DJ Hunter; CC Lee; N Rifai; JE Buring; M Gaziano; S Liu. Sex Hormone-Binding Globulin and Risk of Type 2 Diabetes in Women and Men. The New England Journal of Medicine (2009); 361:1152-1163.

Ding, EL; Y Song; VS Malik; S Liu. Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis. Journal of the American Medical Association (2006) 295 (11): 1288-1299.

Heine, PA; JA Taylor; GA Iwamoto; DB Lubahn; PS Cooke. Increased adipose tissue in male and female estrogen receptor- α knockout mice. PNAS (2000) 97 (23):12729-12734.

Lovejoy, JC; CM Champagne; L de Jonge; H Xie; SR Smith. Increased Visceral Fat and Decreased Energy Expenditure During the Menopausal Transition. Int J Obes (Lond) (2008) 32 (6): 949-958.

Muka, T; C Meun; L Jaspers; A Hofman; JSE Laven; M Kavousi; OH Franco. Association of sex hormone-binding globulin, testosterone and estradiol with the risk of type 2 diabetes among middle-aged men and women: the Rotterdam Study. European Heart Journal (2015) 36 (Abstract Supplement): 118.

Thurston, RC; SR El Khoudary; K Sutton-Tyrrell; CJ Crandall; B Sternfeld; H Joffe; EB Gold; F Selzer; KA Matthews. Vasomotor symptoms and insulin resistance in the Study of Women’s Health Across the Nation. Journal of Clinical Endocrinal Metabolism (2012) 97 (10): 3487-3494.

Walker, VR; KS Korach. Estrogen Receptor Knockout Mice as a Model for Endocrine Research. ILAR J (2004) 45 (4): 455-461.

Wallace, TM; JC Levy; DR Matthews. Use and Abuse of HOMA Modeling. Diabetes Care (2004) 27 (6): 1487-1495.

Triclosan: Friend or Foe?

A thought-provoking article in the July 22 2016 Issue of Science posed the question “Is triclosan harming your microbiome?”1 The article concludes that the data is still mixed about the effects of triclosan on the microbiome, but begs some broader questions such as, “what is triclosan?” and “are there safety risks associated with it?”

Triclosan, 2,4,4’ –trichloro-2’-hydroxydiphenyl ether, is a synthetic, broad-spectrum, antibacterial and antifungal agent found in many oral and topical body care products, cosmetics, and even plastic toys, clothing and furniture. In toothpaste, antibacterial soaps and body washes, triclosan is considered an over-the-counter drug and is regulated by the Food and Drug Administration (FDA).2 Also regulated by the Environmental Protection Agency (EPA) as an antimicrobial pesticide, “triclosan is used as a preservative in industrial, institutional, and residential settings to protect items from odor and stain-causing bacteria, fungi, mold, and mildew.”3

Used liberally for decades by many industries, triclosan can be found ubiquitously in us and around us. In a National Health and Nutrition Examination Survey (NHANES) study published in 2008, 75% of twenty-five hundred adults and children in the US general population tested positive for triclosan in their urine.4 Triclosan also permeates our waterways; in a survey of 139 streams in 30 US states, 57.6% tested positive for triclosan.5 It is a common drinking water contaminant.6

Triclosan is everywhere, but is it harmful? At this point, the scientific community hasn’t yet reached a firm consensus, but there is increasing evidence that it MAY be harmful. Triclosan is absorbed through the skin and oral cavity into the bloodstream. In addition to blood and urine, breast milk may contain triclosan; levels correlate to use by consumers.7

Although not considered acutely toxic, triclosan poses several health concerns. It acts as an endocrine disruptor and has androgenic and antiestrogenic activities.8 A study in sub-fertile men showed that urinary triclosan levels were associated with increased luteinizing hormone (LH) levels, which the authors speculated may negatively affect Leydig cell function.9 Structurally similar to thyroxine, triclosan may disrupt thyroid hormone homestasis.7 Animal studies have demonstrated that triclosan decreases blood levels of T4; unfortunately, data in humans is lacking.7 A recent review suggested that it may play a role in cancer development due to xenoestrogenic activity and a recent rodent study demonstrated that triclosan promotes liver tumoriogenesis.10,11

Triclosan may negatively alter the microbes in hands-washour guts and our environment. A recent rodent study showed that triclosan disrupted the gut microbiome and reduced the Firmicutes/Bacteroidetes ratio.12 A major public health concern, microbial resistance to triclosan and cross-resistance to additional antimicrobials have been demonstrated.13

In 2010, a petition to ban triclosan was submitted to the EPA by over 80 consumer and environmental advocacy groups. In it, the petitioners cite several concerns regarding the impact of triclosan on human health and the environment.3 The same year the petition was submitted, the EPA announced their intention to “accelerate the schedule” for the triclosan registration review process to begin in 2013, “ten years earlier than originally planned.”14 In 2015, five years after the petition was submitted, the EPA responded that they would not be cancelling the registration of triclosan, but that they are “currently engaged in reevaluating the risks posed by triclosan including a review of the human health and ecological risks.”

Since at least 2013, the FDA and EPA have taken the position that they are “closely collaborating on science and regulatory issues related to triclosan.”15 The position of the Centers for Disease Control and Prevention (CDC) is that “human health effects from exposure to low environmental levels of triclosan are unknown.”16 Unfortunately, it may take years before our public health policymakers are in a position to make recommendations regarding the safety of triclosan.

In the meantime, studies have shown that triclosan-containing soaps do not have significantly increased efficacy over non-“antimicrobial” soaps.13 Additionally, a Cochrane Review concluded that the benefit of adding triclosan to toothpaste to reduce gingivitis may not even be clinically meaningful.17

With questionable health benefits, unknown long-term health effects, and mounting evidence that it may do more harm than good, you may want to advise your patients to reduce their exposure to triclosan and that of their families by carefully checking the labels of toothpastes, mouthwashes, body care products, hand soaps, and other products, especially if they are labelled as “antibacterial.”

Jennifer R. Ryan, ND MS

Find this blog and others at www.MHICN.com

  1. Yee BAL, Gilbert JA. Is triclosan harming your microbiome? 2016;(June).
  2. Triclosan: What Consumers Should Know. http://www.fda.gov/forconsumers/consumerupdates/ucm205999.htm. Accessed July 27, 2016.
  3. EPA Responds to Citizen Petition for a Ban on Triclosan. https://www.epa.gov/pesticides/epa-responds-citizen-petition-ban-triclosan.
  4. Calafat AM, Ye X, Wong L, Reidy JA, Needham LL. Urinary Concentrations of Triclosan in the U . S . Population : 2003 – 2004. 2008;116(3):2003-2004.
  5. Kolpin DW, Meyer MT. Pharmaceuticals , Hormones , and Other Organic Wastewater Contaminants in U . S . Streams , 1999 – 2000 : A National Reconnaissance. 2002;36(6):1202-1211.
  6. Bedoux G, Roig B, Thomas O, Dupont V, Bot B Le. Occurrence and toxicity of antimicrobial triclosan and by-products in the environment. 2012:1044-1065.
  7. Dann AB, Hontela A. Triclosan : environmental exposure , toxicity and mechanisms of action. 2011;(September 2010):285-311.
  8. Kravchenko J, Corsini E, Williams MA, et al. Chemical compounds from anthropogenic environment and immune evasion mechanisms : potential interactions. 2015;36:111-127.
  9. Hond E Den, Tournaye H, Sutter P De, et al. Human exposure to endocrine disrupting chemicals and fertility : A case – control study in male subfertility patients. Environ Int. 2015;84:154-160.
  10. Dinwiddie MT, Terry PD, Chen J. Recent Evidence Regarding Triclosan and Cancer Risk. 2014:2209-2217.
  11. Chen S, Evans RM, Hammock BD, et al. The commonly used antimicrobial additive triclosan is a liver tumor promoter. 2015;112(48).
  12. Hu J, Raikhel V, Gopalakrishnan K, et al. Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model. Microbiome. 2016:1-11.
  13. Giuliano CA, Rybak MJ. Efficacy of Triclosan as an Antimicrobial Hand Soap and Its Potential Impact on Antimicrobial Resistance : A Focused Review. 2015. doi:10.1002/phar.1553.
  14. Pesticides: Reregistration: Triclosan Facts. https://archive.epa.gov/pesticides/reregistration/web/html/triclosan_fs.html. Accessed July 27, 2016.
  15. FDA Taking Closer Look at “Antibacterial” Soap. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm378393.htm. Accessed July 27, 2016.
  16. National Biomonitoring Program: Factsheet: Triclosan. http://www.cdc.gov/biomonitoring/Triclosan_FactSheet.html. Accessed July 27, 2016.
  17. P R, T. L. Triclosan/copolymer containing toothpastes for oral health. Cochrane Database Syst Rev. 2013.

 

NICE New Guidelines for Menopausal Health

Menopause represents the end of a woman’s reproductive life. It is a gradual process, known as the menopausal transition, and is associated with depletion of estrogen levels in the body. In western countries, the average age of menopause is 51 years, but the age of menopause can vary widely depending on several factors. Smoking, for example, is associated with early menopause.

The National Institute for Health and Care Excellence (NICE) in the UK released guidelines for healthcare professionals who care for women in menopause and for women who are experiencing menopause. The first guideline is regarding individualized care and emphasizes the fact that the menopausal transition can differ greatly among individuals. Clinicians are urged to take an “individualized approach at all stages of diagnosis, investigation and management of menopause.”

Despite the need for an individualized approach to managing the menopausal transition, NICE indicates that eight out of ten womenexperience some symptoms during the menopausal transition, “typically lasting about four years after the last period, but continuing for up to twelve years in about 10% of women.” The American National Institute on Aging indicates that symptoms of menopause can include irregular periods, hot flashes, vaginal dryness, bladder control problems, difficulty sleeping, and changes in mood. These symptoms can vary widely, making it somewhat difficult to diagnose perimenopause when the menopausal transition begins.

All of these guidelines are focused on helping women to achieve and maintain “healthy” menopause. Researchers at Erasmus MC, a research university in Rotterdam, the Netherlands proposed a conceptual framework for healthy menopause, which emphasizes that menopause is a dynamic state “characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a woman’s desired ability to adapt and capacity to self-manage.”

As with many of the top health conditions facing menopausal women, healthy menopause can be achieved by adopting and maintaining healthy lifestyle behaviors. Recommendations from the National Institute on Aging include:

  • Do not smoke
  • Eat foods that are low in fat, high in fiber, with fruits and vegetables, whole grains, important vitamins and minerals
  • Get enough calcium and vitamin D
  • Maintain a healthy weight
  • Do weight-bearing exercise at least three days each week.

 

Hormone replacement therapy (HT) can be an option for women experiencing menopausal symptoms, but carries some risk. Using HT does increase the risk of venous thromboembolism compared with baseline population risk, but it does not increase cardiovascular disease risk when started in women aged less than 60 years, it is not associated with increased risk of developing type 2 diabetes, and it may reduce the risk of fragility fractures. Regarding breast cancer, HT with estrogen alone is associated with little to no change in the risk of breast cancer, though HT with estrogen and progestogen can be associated with an increased in the risk of breast cancer.

Others of the NICE guidelines relate to managing short-term symptoms of menopause and diagnosis and management of premature ovarian insufficiency. A part of the NICE guidelines that is often overlooked in guidelines regarding clinical care is the section on information and advice, that is, communicating with patients about menopause. Healthcare providers are encouraged to provide information on the stages and symptoms of menopause, the health implications of menopause, and potential treatment options for their symptoms. As the National Institute on Aging emphasizes, menopause is part of life, like puberty, and should be discussed openly and with support from healthcare providers. By following these guidelines and engaging their patients in their individualized care, healthcare providers will be able to guide women through their menopausal transition and into older age healthfully.

Jenna Troup, MPH

Jaspers, L; et al. “Health in Middle-Aged and Elderly Women: A Conceptual Framework for Healthy Menopause.” Maturitas. 2015: 81(1):93-98.

http://www.maturitas.org/article/S0378-5122(15)00058-4/references

Lu, S; et al. “Meta-analysis Suggests That Smoking is Associated with an Increased Risk of Early Natural MenopauseMenopause. 2012;19(2):126-132.

http://www.medscape.com/viewarticle/757803

van Dijk, G; et al. “Health Issues for Menopausal Women: The Top 11 Conditions have Common Solutions.” Maturitas. 2015: 80(1):24-30.

http://www.maturitas.org/article/S0378-5122(14)00300-4/abstract

Clinical Application: Managing Menopausal Symptoms with Plant-Based Therapies – Part 1

From Erasmus Clinical Team

woman-book-beach
Visit www.mhicn.com for more information

Between 50-82% of menopausal women report hot flashes or night sweats, and managing menopausal symptoms is notoriously difficult. Indeed, symptoms often last for around four years after a woman’s last menstrual period, which occurs at age 51 on average in Western countries but can vary widely depending on lifestyle and ethnicity.

Concerns among women and healthcare providers about potential adverse health outcomes have led many to use non-hormonal complementary therapies. Recent research and care guidelines have indicated that estrogen-only HRT has little or no increase in the risk of breast cancer, HRT with estrogen and progestogen/progesterone can be associated with an increase in the risk of breast cancer, but any increased risk reduces after stopping HRT. Despite conclusive evidence about potential negative health outcomes associated with HRT, 40-50% of women in Western countries use complementary therapies to manage menopausal symptoms. Complementary therapies can include plant-based product solutions like phytoestrogens, Chinese herbs, acupuncture, behavioral therapies
like yoga and cognitive behavioral therapy, and others.

Erasmus LogoA systematic review and meta-analysis published today in the Journal of the American Medical Association by MHICN collaborators at Erasmus MC found that in 62 trials including 6,653 menopausal women, plant-based therapies reduced the number of daily hot flashes and reduced vaginal dryness, but the effect did not extend to night sweats. Plant-based therapies include eating soy-rich foods, and taking phytoestrogen supplements. The study also assessed newer herbal remedies such as ERr 731 (Rheum rhaptonicum), the active ingredient in Metagenics’ ERr 731/Rhaponticin, and reported associations with improvements in the number of hot flashes in 24 hours as assessed by the Kupperman Index. Metagenics also funded the analysis.

In the table below, see the mean difference in hot flashes and vaginal dryness between women who took phytoestrogens versus those who did not.

Phytoestrogens versus control Mean Difference Confidence interval
Hot flashes -1.32 (-2.02 – -0.61)
Vaginal dryness -0.31 (-0.51 – -0.10)

We should note that the most recent guidelines on care for menopausal women, the 2015 National Institute for Health and Care Excellence Guidelines from the United Kingdom, indicate that clinicians should:

  • Offer women hormone replacement (HRT) for hot flashes and night sweats after discussing risks and benefits
  • Consider HRT to ease low mood
  • Explain that estrogen-only HRT has little or no increase in the risk of breast cancer, while HRT with estrogen and progestogen can be associated with an increase in the risk of breast cancer, but any increased risk reduces after stopping HRT
  • Note that women with cardiovascular risk factors should not automatically be excluded from taking HRT; women and healthcare providers should understand that HRT does not increase cardiovascular disease risk when started in women under 60 years of age, and it does not affect the risk of dying from cardiovascular disease

These points, and others. were covered in our November 2015 blog post on the topic. A companion paper on the association between vasomotor symptoms (hot flashes) and cardiovascular disease was also published recently in PLOS One. We encourage you to read both of the papers and our accompanying blog post here as well.

J. Troup, MPH

Clinical Application: Managing Menopausal Symptoms with Plant-Based Therapies – Part 2

From Erasmus Clinical Team

lady-flower
Visit www.mhicn.com for more information

Between 50-82% of menopausal women report vasomotor symptoms like hot flashes or night sweats, and managing menopausal symptoms is notoriously difficult. Indeed, symptoms often last for around four years after a woman’s last menstrual period, which occurs at age 51 on average in Western countries but can vary widely depending on lifestyle and ethnicity.

Concerns among women and healthcare providers about potential adverse health outcomes have led many to use non-hormonal complementary therapies. Despite inconclusive evidence about potential negative health outcomes associated with HRT, 40-50% of women in Western countries use complementary therapies, including oral plant-based supplements and other treatments to manage menopausal symptoms.

A systematic review and meta-analysis published this Erasmus Logoweek in the Journal of the American Medical Association by MHICN collaborators at Erasmus MC and Cambridge University found that in 62 trials including 6,653 menopausal women, plant-based therapies reduced the number of daily hot flashes and reduced vaginal dryness. In addition to phytoestrogens, soy isoflavones, and red clover, the study also assessed newer herbal remedies such as ERr 731, the active ingredient in Metagenics’ Estrovera, and reported associations with improvements in the number of hot flashes in 24 hours as assessed by the Menopausal Rating Scale. Metagenics also funded the analysis.

ERr 731 Results Breakout

The findings from the two papers on ERr 731 paint a compelling picture of the positive effect that the extract can have on menopausal symptoms. The two papers, based on a multicenter, prospective, randomized, double-blind, placebo-controlled, clinical trial of 109 women who received either ERr 731 or a placebo for 12 weeks. In the first 12 weeks of the study, women taking ERr 731 experienced a significant reduction in all their menopausal symptoms, as assessed by the Menopause Rating Scale II. It was also found to be safe and well tolerated.

In a longer-term evaluation of the efficacy and safety of ERr 731, 51 of the original 109 women from the study took ERr 731 (23 from the original ERr group and 28 from the placebo group) for 48 weeks. Over the 48 weeks, women who had taken ERr 731 experienced a further reduction in their menopausal symptoms, and women who had taken the placebo also reported a reduction in their symptoms. At the end of the long-term study, all women had an average of less than 1.4 slight hot flashes per day. A further benefit of plant-based products is that they can be used during the menopausal transition and earlier in the peri-menopausal stage.

Overall Effect of Plant-Based Therapies on Hot Flashes

In the table below (recreated from data from the published paper as well as analyses not included in the publication), note the effects of a variety of plant-based supplements on hot flashes, night sweats, and vaginal dryness. The “mean difference” indicates the average difference in number of hot flashes in 24 hours, for example, between women who used the therapy and those who did not. In most cases, treatment was done for 12 weeks.

Product Ingredient
Menopausal Symptom
ERr 731 Mean Difference Confidence interval Clinical Application
Hot flashes -1.62 (-2.28 to -0.96) Significant reduction in hot flashes. Clinical use  effective.
Phytoestrogens Overall Mean Difference Confidence interval Clinical Application
Hot flashes -1.31 (-2.02 to -0.61) Significant reduction in hot flashes. Clinical use may be effective.
Night sweats -2.14 (-5.57 to 1.29) Reduction in night sweats, wide confidence interval indicates unclear effectiveness.
Vaginal dryness -0.31 (-0.51 to -0.10) Small reduction in vaginal dryness.
Dietary and Supplements of Soy Isoflavones Difference Confidence interval Clinical Application
Hot flashes -0.79 (-1.35 to -0.23) Small reduction in number of hot flashes.
Supplements and Extracts of Soy Isoflavones Mean Difference Confidence interval Clinical Application
Hot flashes -1.09 (-1.96 to -0.22) Significant reduction in hot flashes. Clinical use may be effective.
Vaginal Dryness -0.26 (-0.48 to -0.04) Small reduction in vaginal dryness.
Dietary Soy Isoflavones Mean Difference Confidence interval Clinical Application
Hot flashes -0.48 (-1.23 to -0.73) Small reduction in number of hot flashes.
Red Clover Mean Difference Confidence interval Clinical Application
Hot flashes -1.84 (-3.89 to 0.19) Reduction in hot flashes, wide confidence interval indicates unclear effectiveness.
Night Sweats -3.9 (-4.50 to -3.30)* Significant reduction in night sweats. Clinical use may be effective.
Black Cohosh Mean Difference Confidence interval Clinical Application
Hot flashes -0.71 (-2.51 to 1.08) Possible reduction in hot flashes, wide confidence interval indicates unclear effectiveness.
Chinese Herbs Mean Difference Confidence interval Clinical Application
Hot flashes 0.52 (-1.13 to 2.17)* Possible increase in hot flashes, wide confidence interval indicates unclear effectiveness.
Night sweats 2.7 (0.35 to 5.05)* Indicates increase in night sweats possible.
St. John’s Wort Mean Difference Confidence interval Clinical Application
Hot flashes -0.85 (-1.07 to -0.63)* Small reduction in number of hot flashes.
Evening Primrose Mean Difference Confidence interval Clinical Application
Hot flashes -0.4 (-1.03 to 0.23)* Reduction in hot flashes, wide confidence interval indicates unclear effectiveness.
Flaxseed Mean Difference Confidence interval Clinical Application
Hot flashes 1.2 (-0.75 to -3.15)* Possible increase in hot flashes, wide confidence interval indicates unclear effectiveness.

While healthcare providers and women undergoing the menopausal transition may have concerns about risks associated with HRT or any therapy for menopausal symptoms, recent care guidelines have indicated that estrogen-only HRT has little or no increase in the risk of breast cancer, and that HRT with estrogen and progestogen/progesterone can be associated with an increase in the risk of breast cancer, but any increased risk reduces after stopping HRT.

The Role of Hormone Replacement Therapy for Menopausal Symptoms

While healthcare providers and women experiencing the menopausal transition may have concerns about the risks associated with HRT or any therapy for menopausal symptoms, recent care guidelines have indicated that estrogen-only HRT has little or no increase in the risk of breast cancer, and that HRT with estrogen and progestogen/progesterone can be associated with an increase in the risk of breast cancer, but any increased risk reduces after stopping HRT.

The most recent guidelines on care for menopausal women, the 2015 National Institute for Health and Care Excellence Guidelines from the United Kingdom, indicate the following, among other recommendations that clinicians should take a personalized approach to recommending any therapy, whether it is hormonal or not, and that clinicians and patients should have a detailed discussion of the risks and benefits of all treatments.

They should also note that women with cardiovascular risk factors should not automatically be excluded from taking HRT. Women and healthcare providers should note that HRT does not increase cardiovascular disease risk when started in women under 60 years of age, and it does not affect the risk of dying from cardiovascular disease.

These points and others were covered in our November 2015 blog post on the topic. A companion paper on the association between vasomotor symptoms (hot flashes) and cardiovascular disease was also published recently in PLOS One. We encourage you to read both of the papers and our accompanying blog post here as well.

J. Troup, MPH

References

Franco OH, Chowdhury R, Troup J, et al. Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis. JAMA. 2016;315(23):2554-2563. doi:10.1001/jama.2016.8012.

Hasper I; Ventskovskiy BM; Rettenberger R; Heger PW; Riley DS; Kaszkin-Bettag M. Long-term Efficacy and Safety of the Special Extract ERr 731 of Rheum Rhaponticum in Perimenopausal Women with Menopausal Symptoms. Menopause. 2009;16(1):117-31. doi:10.1097/GME.0b013e3181806446.

Heger M; Ventskovskiy BM; Borzenko I; Kneis KC; Rettenberger R; Kaszkin-Bettag M; Heger PW. Efficacy and Safety of a Special Extract of Rheum Rhaponticum (ERr 731) in Perimenopausal Women with Climacteric Complaints: A 12-week Randomized, Double-Blind, Placebo-Controlled Trial. Menopause. 2006;13(5):744-59.

Muka T, Oliver-Williams C, Colpani V, Kunutsor S, Chowdhury S, Chowdhury R, et al. (2016) Association of Vasomotor and Other Menopausal Symptoms with Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis. PLoS ONE 11(6): e0157417. doi:10.1371/journal. pone.0157417.

 

Naked Mole Rat, You’re My Detox Hero!

There’s no disputing these guys are homely at best, hideous at worst. They’re wrinkled, beady-eyed, hairless (except for whiskers), subterranean rodents with massive protruding front teeth. When one was spotted in Africa in 1842 by German naturalist, Eduard Ruppell, he mistakenly described it as diseased. Poor little NMR!

Kara_Fitzgerald
For more from Dr Kara Fitzgerald visit www.drkarafitzgerald.com

But NMRs don’t need your pity. Learn a little more about these guys, and their beauty emerges: they tolerate oxygen deprivation better than Houdini. They live forever, feel no pain, and they don’t get cancer.

They live healthily well into their rodent-year 90s, still reproducing, and participating in NMR society. They maintain muscle mass, fat mass, bone density, cardiac health and neuron numbers. (American Academy of Anti-aging Medicine, watch out!) Rumor has it that by the time they’re 90, naked mole rats have read all the classics, speak six rodent languages and have mastered at least three instruments, including the French horn.

Some advice: Don’t get into a hot pepper eating contest with a Naked Mole Rat. They feel no pain — seriously! While naked mole rats have the nerve fibers that transmit pain, they make none of the pain neuropeptide Substance P. This ensures that they don’t experience the burn of acid like we do, enabling them to live comfortably in a low oxygen, high CO2 environment. (C02 is acidic — think of the feeling of soda bubbles on your lip or in your nose.) They also don’t mind capsaicin — the hot stuff in peppers — even directly injected into their hairless little foot…

But what makes NMRs so super-cool? They don’t get cancer. In fact, you can spike an NMR with all the cancer cells and cancer-inducing toxins that you can think of, and NO RESPONSE. You can nail them with ray beam after ray beam of ionizing radiation, and NO response. It doesn’t even seem to induce DNA damage. And, they rapidly render toxic metals harmless. Far more is required to kill an NMR cell than a mouse cell.

Really?
Vast swaths of NMR DNA are devoted to DETOXIFICATION and DNA REPAIR genes. These cute little buggers protect their DNA which then in turn produce lots of detox proteins which protect them from toxin exposures. This is probably why they sail through life into their 90s, all happy and healthy. They break down bad cells (autophagy) and problem proteins (using the ubiquitin proteasome system) rapidly.

A few more plot twists: NMRs tolerate a ton of oxidative stress for a long time (20+ years!) without impairment. That’s right — no aging, no disease. (So long free radical theory of aging.) They also have SHORT telomeres and low telomerase activity, which flies in the face of our understanding that LONG telomeres and high telomerase activity are associated with longevity. To those of you gulping down your resveratrol-laced red wine hoping for the fountain of youth through robust telomere preservation: maybe the more primary effect is on glutathione activity? And finally, the subterranean NMRs are naturally very vitamin D deficient.*

What can we learn from these ungainly subterranean masters of the universe?
As we speak, pharma is embracing the NMR, attempting to coax out their secrets in hopes of new block busters for pain, longevity, and anticancer therapy.

Perhaps DETOXIFICATION is THE fundamental issue in wellness.
But how do we integrative clinicians think about using the wisdom of NMR physiology? Well, off the top of my head, I’d say we should continue our focus on detoxification, detoxification, detoxification, as a fundamental issue to wellness. Even if it is an area still deemed “emerging.” I’ll take the risk. Could it be that many treatments of integrative therapy that work, do so through some degree of stimulation of detoxification pathways? NMR physiology might suggest that support for robust Phase I, II and III detoxification pathways are important to wellness, cancer prevention and longevity. Maybe stimulating detoxification is the key mechanism of resveratrol? Where’s my glass of red wine — I’m heading underground.

NOTE: I very liberally borrowed from the much better, reference article on naked mole rats, entitled “Underground Supermodels,” by Dr. Thomas Park in the June, 2012, issue of Scientist Magazine. In fact, I have been carrying that issue around in my roller bag since June intending to author this blog. I can finally take it out. http://www.the-scientist.com/

Kara Fitzgerald, ND

*Gen Comp Endocrinol. 1993 Jun;90(3):338-45.

This blog is from our collaborator Kara Fitzgerald, ND at the Sandy Hook Clinic in Newtown, CT with full permissions.

Findings from the American Diabetes Association Scientific Sessions: Impressive Reduction in A1C and Body Weight when Medical Nutrition Therapy includes a Diabetes-Specific Medical Food and Structured Meal Plan

From June 10-14, diabetes clinicians and researchers are meeting in New Orleans for the 2016 American Diabetes Association Scientific Sessions. One of the most exciting new scientific innovations and discoveries at the conference comes from MHICN collaborators at the Joslin Diabetes Center in Boston, MA. Their poster and abstract entitled “Effects of 3 Different Models of Medical Nutrition Therapy on A1C and Body Weight in Overweight and Obese Patients with Type 2 Diabetes: A Randomized Clinical Study” sheds new light on the opportunities to use medical foods in association with medical nutrition therapy (MNT) to significantly decrease A1C levels.

take control edit
Visit www.mhicn.com for more info

The goal of MNT is, “To decrease the risk of diabetes and cardiovascular disease (CVD) by promoting healthy food choices and physical activity leading to moderate weight loss that is maintained.” As of 2008, the Medical Nutrition Therapy recommendations from the American Diabetes Association include that the patient engage with a registered dietitian (RD) to develop an individualized eating plan. Until this study, it has been unclear that individualized eating plans alone are the most effective way to improve the health of diabetic patients.

The study conducted by Joslin researchers, including frequent MHICN.com contributor Dr. Osama Hamdy, sought to evaluate the effect of three models of MNT on A1C levels, body weight, waist circumference, visceral fat, and lipid profile. The 108 patients who were enrolled had had diabetes for an average of 11 years, an average BMI of approximately 35, and an average A1C percentage above 8% were randomized to three groups.

Group A Group B Group C
Meet RD Meet RD Meet RD
Individualized meal plan Structured Meal Plan Structured Meal Plan
    Weekly Coaching from RD

Group A received the standard of MNT care, while Groups B and C were given a structured meal plan, including a diabetes-specific nutritional formula, or medical food, to aid with glucose control. The structured meal plan also included a food log and book of 17 menu options with detailed ingredients, cooking instructions, and nutrition facts. The groups followed their respective protocols for a total of 16 weeks, and had a follow-up visit with their initial RD after eight weeks for nutritional counseling.

Compared to the baseline, Group A had no change in A1C levels, while Groups B and C had significant reductions in A1C levels. Indeed, Group B experienced a change of -0.63% A1C and Group C experienced a change of  -0.67% A1C. The change remained significant even after controlling for duration of diabetes, age, and body weight. Furthermore, body weight did not change in Group A, but decreased significantly in Groups B and C, in which patients lost an average of 3.49kg and 2.73kg, respectively. Groups B and C also experienced reductions in abdominal adiposity.

These impressive findings indicate that current MNT strategies of individualized meal plans are less effective than a structured meal plan with a diabetes-specific medical food. Clinicians should consider implementing structured meal plans with medical foods for their diabetic patients for reductions in body weight, A1C levels, abdominal adiposity, and improvements in lipid profile.

These clinically significant results provide new and compelling information for practitioners and patients alike including implications for management of blood glucose and use of medical nutrition including,  1. Specialized medical foods provide important transitional support for patients not achievable by diet alone or use of simple guidelines including those of the ADA,  2. Organized medical nutrition therapy programs provide an effective and convenient therapeutic regimen to improve HbA1c levels that is far superior to food or exercise alone and 3. The magnitude of clinical outcomes is as good or better when compared to reported outcomes in the use of medications like the DPP IV inhibitors.

Today medical nutrition therapy programs can easily be integrated into primary care practitioner officers and effectively used by patients.  Not only do these programs help manage diabetes but as importantly help maintain healthy HbA1c levels and normal blood glucose levels in prediabetics and in all patients that are challenged by carbohydrate intolerance and at high risk of chronic disease.

by John Troup, PhD

References:

American Diabetes Association. Nutrition Recommendations and Interventions for Diabetes. Diabetes Care. 2008 Jan; 31 (Supplement 1): S61-S78. <http://care.diabetesjournals.org/content/31/Supplement_1/S61&gt;.

Mottalib, A; V Salsberg; BN Mohd-Yusof; W Mohamed; C Johnson; P Carolan; D Pober; J Mitri; O Hamdy. Effects of 3 Different Models of Medical Nutrition Therapy on A1C and Body Weight in Overweight and Obese Patients with Type 2 Diabetes: A Randomized Clinical Study. ADA Conference Abstract & Poster. 2016.

 

Dietary Recommendations Based on Nutrigenomics — The Future of Personalized Nutrition

Recommendations and guidelines for a heart healthy diet are growing in prevalence as consumers become less interested in weight loss and more interested in overall wellness. Many of the recommendations are, indeed, applicable to large swaths of the population, such as engaging in more physical activity, eating a variety of fruits and vegetables, whole grains, nuts, and limiting red meats and processed, nutrient-poor foods. The 2015-2020 Dietary Guidelines for Americans also incorporate new scientific findings into their recommendations, such as limiting consumption of meats in general, especially for men and boys and adopting a dietary pattern in the Mediterranean or vegetarian style. They also take some personalization factors into condition: acknowledging differences in social and cultural norms, access to nutritious foods, and individual factors that contribute to food consumption including personal preferences, food preparation skills, and personal health status.

The field of nutrigenomics is growing, and so is the possibility of further personalizing dietary recommendations. Researchers at the Center for Restorative Medicine, International Heart and Lung Institute in Palm Springs, CA propose tailoring dietary intake, physical activity levels and amounts, and dietary supplements to patients based on their genetic markers. Dr. Steven Gundry presented an abstract at the 11th International Congress of Update in Cardiology and Cardiovascular Surgery in March 2015, entitled, “Twelve Year Followup for Managing Coronary Artery Disease Using a Nutrigenomics Based Diet and Supplement Program with Quarterly Assessment of Biomarkers.” He and his colleagues followed 978 patients with known coronary artery disease (CAD) for up to 12 years (mean 9 years) as they followed a diet- and dietary supplement-based physician-coached program.

The participants all underwent genotyping, specifically for the APOE gene. This specific gene provides instructions for making a protein that combines with lipids to form lipoproteins, which carry cholesterol through the bloodstream. There are at least three polymorphisms of the APOE gene, one of which, e3, is found in more than half of the population. The e4 allele of APOE is associated with an increased risk of developing Alzheimer’s disease and cardiovascular disease. In Gundry’s study, those participants with the e4 allele were encouraged to eat large amounts of shellfish and to avoid animal fats and cheeses.

lettuce-811962_1280
For more info visit www.mhicn.com

For all participants, the dietary component of the program emphasized:

  • leafy green vegetables
  • olive oil
  • limiting grains, nightshades, commercial poultry, and fruits
  • four ounce portions of animal proteins, including shellfish, wild fish, grass-fed meats

Everyone enrolled in the study was instructed to take 2000-4000 mg of high DHA fish oil, 200 mg of grape seed extract, and 50 mg of Pycnogenol per day. These supplement amounts were tailored specifically to each individual based on individual cardiovascular risk marker tests. Most impressive were the results that were reported in the abstract. The data revealed that the total rate of cardiovascular events over the 12 years of follow-up was 1.6% – only 16 cardiovascular events in 978 patients! We look forward to the publication of Dr. Gundry’s paper to gain further insights and details about this fascinating study.

Further research into the various genes that respond to dietary changes is necessary to create even more precise nutrition and lifestyle plans for patients. We have written previously about dietary personalization and the role that genes can play in the body’s response to specific dietary patterns and are optimistic about the opportunity to create fully personalized dietary and lifestyle plans based on the results of genetic testing. While Dr. Gundry’s abstract does not go into great detail about the role of APOE in the outcomes of the study, it is clear that the patients enrolled in the dietary intervention have seen remarkably good health outcomes, particularly among individuals who had known CAD at the time of their enrollment. In the meantime, we should continue to encourage clinicians to work with their patients to implement a dietary pattern that includes leafy greens, heart-healthy oils, and small portions of meats. Gene sequencing and blood testing can also be helpful for identifying patients that will experience even greater benefit, particularly when those patients have a history of CAD.

Jenna Troup, MPH

 

Proteome, Metabolome, Microbiome, Exposome: Glancing into the OMES

Kara Fitzgerald, ND.jpg
For more info visit www.mhicn.com

Dr. Richard S. Lord, nutritional biochemist extraordinaire and Chief Science Officer at Metametrix Clinical Laboratory (now Genova) recently retired after 25 years. Richard was the director of the Medical Education team when I was in Atlanta at the lab. Richard was and continues to be, my teacher. There has been no greater influence on my thinking as a clinician and scientist than Dr. Lord. He inspired me to always question, embrace the uncertainty, trust the data, and argue my point (with evidence, of course!)

When I interviewed for the postdoctorate position at Metametrix Clinical Laboratory in 2004, I was a bright-eyed student finishing my final year in naturopathic medical school. I was nervous and excited. The lab was a marvel of glass and metal. Gleaming rows of instruments: LC MS/MS, GC/MS, HPLCs and on…. Lots of machines that go “bing” as Monty Python said. There was a library with thousands of journals and almost as many textbooks – and a librarian, Cathy Morris, dedicated to obtaining full text article requests.

I know, you’re a good integrative clinician, and low plasma homocysteine is old hat to you at this point. But at the time, virtually no one was thinking about its relevance as an essential precursor to glutathione, taurine and sulfate; that low levels of homocysteine suggested that the body’s ability to respond to oxidative stress with glutathione and to engage in phase II biotransformation, was at serious risk. If we thought about homocysteine at all, it was as a cardiovascular risk marker, where only high levels were considered relevant. Now, transmethylation and transsulfuration are key pathways memorized by all students of integrative and functional medicine. Methylated folate, B12, n-acetyl cysteine are prescribed routinely.

Dr. Richard Lord put low homocysteine on the map and educated us as to its relevance.

I was moved by the magic, the power, of nutritional biochemistry and the intellectual journeys I took with Richard. It seemed to me then–and it still does today–that the solution is present in understanding as fully as possible the question. We could look “under the biochemical hood” of the individual, piece together their metabolic story and correct it with pinpointed nutritional and dietary interventions—and it worked!

We could effectively reduce disease risk, oxidative stress, and inflammation; improve mitochondrial function, energy, mood, sleep; identify and reduce toxic burden and reverse neurological deficits and tweak the gut microbiome. Sometimes, we could turn the disease process around completely, uncover and successfully treat genetic conditions otherwise missed. Nothing was outside our reach of investigation: It was a grail quest.

I remember consulting with a doctor regarding a patient’s organic acid results. This individual had a seizure disorder, onset at 16, which was non-responsive to any medication. Her organic acids revealed a very elevated beta hydroxyisovalerate (BHIV), a catabolic intermediate compound derived from the amino acid valine that accumulates with a biotin deficiency. In her case, given the severity of her condition, there was likely a mutation in the biotin-dependent carboxylase enzymes required to metabolize BHIV.  The mutation wasn’t apparent at birth, when organic acids are routinely tested, looking for inborn errors of metabolism.  It was too mild to be seen with the broad reference ranges able to identify only the severest cases. She wasn’t symptomatic until 16 years of age.  It took the more sensitive reference ranges we employed at the lab to identify it. The young woman was treated safely with high doses of biotin, which pushed the faulty carboxylase enzymes to function. And her seizures resolved.

Another great case involved a young man with Melnick-Needles Syndrome. MNS is an extremely rare condition caused by a mutation in the gene that codes for filamin A, a protein that provides structure for cells. Being such a fundamental player in sustaining life, a filamin A mutation is often fatal shortly after birth. We carefully individualized his nutrient intake of amino acids, fatty acids, vitamins, minerals to meet his exact needs by looking at his laboratory data every six months. It worked for him. At the time of my last consultation regarding this patient, he was graduating high school. He was the oldest known living individual with MNS.

“Proteome, microbiome, metabolome, exposome,” these are the sexy, current terms used when Dr. Andy Bralley began measuring plasma amino acids – the first steps of an investigation into the proteome. With Dr. Lord, our lab was the first to launch an organic acids test sensitive enough to pick up subtle nutrient perturbations correctible with diet and nutrient interventions: insight into the metabolome. With the launch of DNA analysis of gut bacteria, fungi and parasites, we could look into an individual’s microbiome.Taking everything together, including looking at toxic compounds, we were, and are, glancing into the exposome.

The Medical Education department, led by Dr. Lord,  knew its work was essential, important, reflecting the company’s mission statement: To improve health worldwide by providing clinical laboratory testing services in the areas of nutrients, toxicants, hormonal imbalances, biotransformation and detoxification, gastrointestinal function, and the microbiome.

Contributing writer: Kara Fitzgerald, ND

Vascular Disease and SPMs

spm-ASPEN-banner-crop
For more info on SPMs visit www.mhicn.com

Coronary Artery Disease (CAD) is the most common form  of heart disease and is a leading cause of death in the United States among both men and women. Indeed, in 2012, 17.5 million people died from heart disease worldwide, and 7.4 million of those died from CAD. CAD develops when plaque forms in the coronary arteries, limiting and blocking blood flow. Another cause of CAD, in addition to arterial plaques, is arterial inflammation. A 2014 publication by Libby et al. in Circulation Research explains in great detail how, “inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis.” In addition to traditional therapies for prevention and management of CAD, a new study by Tarec K. Elajami and colleagues, published in April 2016 has found resolution of inflammation in the body may also lead to clot remodeling and reduce the incidence of CAD and coronary events in at risk patients.

The resolution phase of inflammation is facilitated in the body by specialized proresolving mediators (SPMs) which include lipoxins, resolvins, protectins, and maresins which enhance microbial clearance as well as a variety of other functions including tissue remodeling, host defense, and others. Studies with patients with chronic inflammatory diseases such as cystic fibrosis, metabolic syndrome, asthma, and periodontal disease have lower levels of SPMs than do control participants. With regards to vascular disease,  it has also been found that patients with peripheral arterial disease have significantly lower levels of 17-HDHA than healthy subjects. These examples show that levels of SPMs may be lower in patients with chronic inflammatory diseases. Accordingly, Elajami et al. hypothesized  patients with CAD might also have lower levels of SPMs, which would subsequently prevent them from resolving arterial inflammation and ultimately lead to the progression of CAD.

In the study conducted by Elajami et al., six men with stable CAD and lower than normal SPM levels were randomly assigned to take 3.36 g of an FDA-approved pharmacological therapy comprised of EPA and DHA, (n-3 fatty acids that are the precursors of SPMs), daily for a year, along with a statin and aspirin. EPA and DHA have been shown to reduce the risk of cardiovascular events. After one year of this EPA/DHA treatment, the men had a significant reduction in triglycerides. Furthermore, those patients who took EPA/DHA treatment, had twice the levels of proresolving and anti-inflammatory mediators as did those who did not take EPA/DHA treatment, and lower levels of prostaglandins compared to those who did not take EPA/DHA treatment. Other relevant findings included favorable shifts in SPM profiles and enhancement of human macrophage clot phagocytosis in those who took EPA/DHA treatment, compared to those who did not, findings which were identified in a principle component analysis.

After one year of supplementation, CAD patients had more favorable SPM profiles, including improvements in lipid mediation and specific SPM biosynthesis. While the resolution properties of SPMs are known.  This study indicates that a year of high-dose supplementation of EPA/DHA is more effective than short-term, low-dose supplementation. The results of this study indicate that supplementing the diet with EPA/DHA may reduce the progression of atherosclerosis and CAD.

Recently standardized SPM were introduced into the market. These SPM supplements are standardized to level of SPMs and activity. SPMs have a strong potential as new therapeutic strategies for inflammatory diseases, including CAD. Learn more about SPMs at MHICN.com.

J. Troup

References

Elajami, TK; RA Colas; J Dalli; N Chiang; CN Serhan; FK Welty. Specialized Proresolving Lipid Mediators in Patients with Coronary Artery Disease and their Potential for Clot Remodeling. FASEB Journal. 2016 Apr 27. http://www.fasebj.org/content/early/2016/04/27/fj.201500155R.abstract

Fredman, G; SF Oh; S Ayilavarapu; H Hasturk; CN Serhan; TE Van Dyke. Impaired phagocytosis in localized aggressive periodontitis: rescue by Resolvin E1. PLoS One. 2011; 6(9). http://www.ncbi.nlm.nih.gov/pubmed/21935407

Ho, KJ; M Spite; CD Owens; H Lancero; AH Kroemer; R Pande; MA Creager; CN Serhan; MS Conte. Aspirin-triggered lipoxin and resolving E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am J Pathol. 2010; 177(4):2116-23. http://www.ncbi.nlm.nih.gov/pubmed/20709806

Karp, CL; LM Flich; KW Park; S Softic; TM Greer; R Keledijan; R Yang; J Uddin; WB Guggino; SF Atabani;  Y Belkaid; Y Xu; JA Whitsett; FJ Accurso; M Willis-Karp; NA Petasis. Defective Lipoxin-Mediated Anti-Inflammatory Activity in the Cystic Fibrosis Airway. Nat Immunol. 2004;5(4):388-92. http://www.ncbi.nlm.nih.gov/pubmed/15034576

Levy, BD; C Bonnans; ES Silverman; LJ Palmer; G Marigowda; E Israel; Severe Asthma Research Program, National Heart, Lung, and Blood Institute. Diminished Lipoxin Biosynthesis in Severe Asthma. Am J Respir Crit Care Med. 2005;172(7):824-30. http://www.ncbi.nlm.nih.gov/pubmed/15961693

Libby, P; I Tabas; G Fredman; EA Fisher. Inflammation and Its Resolution as Determinants of Acute Coronary Syndromes. Circ Res. 2014 Jun 6; 114(12):1867-79.

http://www.ncbi.nlm.nih.gov/pubmed/24902971

Serhan, CN. Pro-resolving Lipid Mediators are Leads for Resolution Physiology. Nature. 2014 Jun 5; 510(7503):92-101. http://www.ncbi.nlm.nih.gov/pubmed/24899309