February 22, 2019 | Vol. 3
Distributed by the International Institute for Restorative Reproductive Medicine
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Toxic environmental chemicals have negative impacts on reproductive health, particularly during pregnancy and breastfeeding, and consequences of exposure to these chemicals can manifest throughout the lifespan. According to the International Federation of Gynecology and Obstetrics, FIGO, an organization representing OBGYN's from 125 countries and territories, numerous ob/gyn health outcomes are at risk due to these toxic environmental exposures. Miscarriage and stillbirth, impaired fetal growth, decreased sperm quality, congenital malformations, impaired or reduced neurodevelopment and cognitive function, and an increase in cancer, attention problems, ADHD behaviours and hyperactivity are among the long list of poor health outcomes linked to chemicals such as pesticides, air pollutants, plastics and solvents.

In their report (1) FIGO cites some striking statistics:

  • Healthcare and other costs from exposure to endocrine disrupting chemicals in Europe are estimated at a minimum of 157 billion euros a year
  • Cost of childhood diseases in the United States related to environmental toxins and pollutants in their surrounding environment was calculated to be $76.6 billion in 2008
  • Exposure to ambient and household air pollution results in at least 7 million deaths a year worldwide2
  • Close to 800 environmental chemicals are known or suspected to be capable of interfering with hormone receptors, hormone synthesis, or hormone conversion3

This committee opinion piece works through the various issues in play- vulnerable people, communities and populations, and the nature and extent of prenatal and preconception exposure to toxic environmental chemicals. Furthermore there is mounting research showing harms related to endocrine-disrupting chemicals triggering adverse health effects and humans are being exposed to them through food, energy production, industrial emissions, garbage landfill sites, transportation, and even use of consumer and personal care products. Chemical manufacturing has grown rapidly in the last 4 decades, and there is substantial growth in developing countries with estimates that by next year developing countries are expected to lead the world in the growth rate of manufacturing and development of chemicals. In the US alone its estimated over 30 000 pounds of chemicals per person were manufactured or imported in 2012 4, a good many of which haven’t been tested. What’s more, exposure to these chemical during vulnerable times of patient health, such as during pregnancy, can trigger ill-effects that may manifest not only during the pregnancy itself but across the lifespan. 

Health-care professionals can be an effective first-line resource in advocacy and patient education, however, few currently receive any training in environmental health 5. FIGO calls to reproductive health professionals to be aware of the disproportionate effects on more vulnerable populations and advocate for and educate those individuals who may be unaware of the environmental effects on their reproductive health. RRM professionals can be cognizant of the greater risks to those in lower socio-economic groups and help to provide them essential education.
Supplementary Resources for healthcare providers:

1 Renzo, Gian CarRlo Di, Conry, Jeanne A., Blake, Jennifer, DeFrancesco, Mark S., DeNicola, Nathaniel, Martin, James N., McCue, Kelly A., Richmond, David, Shah, Abid, Sutton, Patrice, Woodruff, Tracey J., Poel, Sheryl Ziemin van der, Giudice, Linda C. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. International Journal of Gynecology & Obstetrics. 2015 vol: 131 (3) pp: 219-225.
2 World Health Organization. Burden of disease from ambient and household air pollution. 2015.  http://www.who.int/phe/health_topics/outdoorair/databases/en/
3 World Health Organization, United Nations Environment Programme. State of the science of endocrine disrupting chemicals – 2012.  http://www.who.int/ceh/publications/endocrine/en/ , Published 2013. Accessed September 7, 2015
4 U. S. Environmental Protection Agency. (2014). Fact Sheet: Chemicals Snapshot. https://www.epa.gov/sites/production/files/2014-11/documents/2nd_cdr_snapshot_5_19_14.pdf
5 McClafferty H. 2016. Environmental health: children’s health, a clinician’s dilemma. Curr Probl Pediatr Adolesc Health Care 46(6):184–189, PMID: 26846483, https://doi.org/10.1016/j.cppeds.2015.12.003.
A recent systematic review and meta-analysis evaluated the use of metformin (MET) and myo-inositol (MI) treatment in PCOS patients. Both MET and MI are commonly used by health practitioners in the treatment of PCOS, however the use of MET is sometimes limited due to gastrointestinal adverse effects experienced by patients.

In total 6 trials, containing 355 total subjects, were included in the final review for quality assessment. The researchers used a standardized mean difference to measure the effect size for continuous outcomes and risk ratios for the dichotomous outcome. In the studies doses for MET ranged between 1.5 and 2 g/d and MI between 2 and 4 g/d and a treatment window of 12-24 weeks. The analysis found that there was no difference in fasting insulin between women receiving MET and those receiving MI. They did not find evidence of a difference for HOMA, serum testosterone, androstenedione outcome, or SHBG levels. S tatistically significant heterogeneity for HOMA, SHBG and BMI changes were noted and, as expected, women receiving MET over MI were almost five times as likely to experience side effects.

Such conclusions suggest that as MI could be an an effective treatment for PCOS, particularly as the lack of side-effects will ensure higher patient compliance with the treatment. In the context of RRM, this could help patients with PCOS manage their symptoms without major side effects of the treatment, encouraging them to adhere to the prescribed treatment.

A major weakness of this study is the relatively small number of studies which could be included in the review. While these results seem conclusive, more studies should be done comparing MET and MI treatments independent from a large review, particularly if there can be ways to manage the side effects of MET treatment. The variation between the studies included is also an issue, as there were different doses of MET or MI in different studies or the main outcome of the study was not that which this study sought to understand. Additionally, the long-term effects and outcomes must be studied, as PCOS is a chronic condition which patients work to manage for their lifetimes.

As a provider what do you use as first line treatment in patients presenting with PCOS? Do you use metformin, Myo-inositol (or combination myo-inositol& D-chiro-inositol) or a combined approach of both medications? 
Ref: Fabio Facchinetti, Beatrice Orrù, Giovanni Grandi & Vittorio Unfer (2019) Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials, Gynecological Endocrinology, DOI: 10.1080/09513590.2018.1540578
Obesity has been on the rise over the last 3 decades 1 and as well as a number of other health burdens, reduced sperm quality and male infertility can accompany elevated BMI's. This study suggests that chronic inflammation caused by obesity may harm the male genital tract and contribute to infertility, though more research is still needed to confirm this 2. Obese men and women can experience inflammation in a variety of tissues; however it was unknown if this inflammation influenced fertility.

Researchers in Shanghai, China found increased levels of inflammatory proteins, and lower sperm concentration and motility, in both overweight and obese men. A higher body mass index also correlated with increased levels of inflammatory markers in their seminal fluid and lower sperm quality. The team believes that obesity-related chronic inflammation may also be causing sperm abnormalities and damage to the blood-testes barrie.

Although reducing BMI in obese or overweight patients remains important for overall health, could targeted treatment to reduce chronic inflammation in the male genital tract help prevent damage and improve fertility in the future? How else could this information be used to improve male fertility in RRM?
1 GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years.  N Engl J Med . 2017;377(1):13-27.
2 Weimin Fan, Yali Xu, Yue Liu, Zhengqing Zhang, Liming Lu and Zhide Ding. Obesity or Overweight, a Chronic Inflammatory Status in Male Reproductive System, Leads to Mice and Human Subfertility, Frontiers in Physiology (2018).https://doi.org/10.3389/fphys.2017.01117
In a study looking to identify a common genetic architecture for the different diagnostic criteria used to define polycystic ovary syndrome (PCOS), researchers discovered 14 gene variants. The study itself analyzed seven whole-genome association studies involving more than 10,000 women with PCOS and a control group of 100,000 with European ancestry. It included 2,540 patients diagnosed using the National Institutes of Health criteria, 2,669 patients using the Rotterdam criteria, and 5,184 self-reported cases. 

Among the medical community there has been differing opinions over which diagnostic criteria to use in the diagnosis of PCOS. This analysis demonstrated that regardless of which criteria was used for diagnosis, the genes between the patients were similar, suggesting physicians can be fairly broad in diagnosis and find the same genetic form of PCOS. Of particular interest, the self-reported cases of PCOS also had similar susceptibility genes to the cases clinically diagnosed through the Rotterdam or NIH criteria.

Further analysis also found evidence linking genetic pathways found in this study to other conditions, including obesity, type 2 diabetes, menopause, depression as well as some links to male pattern baldness. The authors hope that this study could eventually lead to new therapies in the treatment of PCOS.
Characteristics of PCOS cases and controls from each cohort included in the meta-analysis (1) .
Ref: Day F, Karaderi T, Jones MR, Meun C, He C, et al. (2018) Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLOS Genetics 14(12): e1007813.
Abstract submissions are now being accepted for the IIRRM's 16th Annual General Meeting and Scientific Assembly, taking place 7 September, 2019 in Dublin, Ireland, as well as for our North American Regional Conference being held in BlueBell, PA on July 17, 2019. 

Abstracts are welcome in any area relevant to Restorative Reproductive Medicine. Visit our website to find out more about the conferences, and to view guidelines for submission.
For any further questions please contact:
Joseph B. Stanford, MD, MSPH, CFCMC
+1 801-587-3331

Missed this webinar? Watch the recording on our website. IIRRM welcomes discussion and comments the RRM Forum!
RRM Research Updates
This week IIRRM welcomed Dr. Serena Del Zoppo, Dr. Michele Barbato, and Dr. Fulvia Pennoni, from Milan, Italy to present on their latest paper, as well as looked at outcomes from a small pilot study looking at patients who chose an an RRM approach vs those that choose an IVF approach. With an increasing mean age over the last 4 decades at which couples are choosing to have children, and increasing trends in infertility they look to how effective could FABMs and RRM-based interventions be for these couples and hope to work towards a more standardized and larger scale study in the future.
Join our colleagues at FACTS:
Interested in learning the latest about Fertility Awareness based methods and their applications for women’s health care?
Facts upcoming conference, Precision Women's Health is just 1 week away. Designed to equip medical and health professionals to offer more holistic healthcare options for women, topics will include:

  • FABM overview and their applications for
  • Achieving and Preventing Pregnancy
  • Adolescence, Postpartum and Peri Menopause
  • PCOS and Endometriosis
  • Fertility Apps
  • The Female Cycle as the 5th Vital Sign
  • Extensive Q&A with our expert panels

For more information or to register visit: https://www.factsaboutfertility.org/learn-more/conferences/. This conference is approved for 6.5 CME credits through the American Academy of Family Physicians
Disclaimer:  The material presented in the Bulletin or Journal Nook are for educational purposes only. Please note that medical information is constantly changing; the information contained in this activity was accurate at the time of publication. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the Author or Institute, which may be helpful to others who face similar situations.

RRM providers often use fertility awareness-based methods to help patients. The IIRRM does not endorse one method over another but supports the use of all validated science-based fertility models. Most commonly recognized methods include Billings, Creighton, FEMM, Neo, SymptoThermal and other mucus sign-based methods. It recommends caution to patients when using simple, unproven or proprietary fertility apps and strongly encourages patients to consult an RRM professional when deciding on the best method for their personal situation.

Restorative Reproductive Medicine (RRM) does NOT use methods that are inherently suppressive, circumventive or destructive, such as ART techniques including IVF, AI, ICSI and others. However, research involving these approaches can sometimes be modified and applied in a restorative manner and is thus reviewed here with that intent. The IIRRM does not use or condone ART or any non-RRM techniques.