In 1991, a group of scientists were brought together for a Wingspread conference to discuss whether xenobiotics, non-biological chemicals found in people and animals, disrupt the endocrine system. These experts reached consensus that environmental chemicals could biologically interfere with hormones, leading to the codification of the concept of endocrine disruption. Fast-forward to 2017 and we find a large body of research demonstrating how endocrine-disruptive chemicals (EDCs) damage human health in a myriad of ways. From developmental disorders to neurological disorders, from infertility to metabolic diseases, we are discovering that our dependence on everyday chemicals comes with an overwhelming cost to our health, and potentially to our future.
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A growing concern is the impact of EDCs on the reproductive success of women in the childbearing years. Every year an increased number of women pursue assisted reproductive technology (ART). Since 2003, there has been a 65% increase in the use of IVF for women who are unable to get pregnant.1 These women are experiencing estrous cyclicity abnormalities, increased time-to-pregnancy, increased miscarriage rate, and premature ovarian failure.2 Medicine has rapidly advanced in the field of ART, helping many infertile people conceive a child, but why are so many seeking help? Are EDCs at fault?
A complete infertility assessment and treatment strategy would take multiple factors into consideration. However, I will limit this review to endocrine disruptors and female fertility, leaving out the other half of the fertility equation; the ever-declining sperm count. By doing so, I will also skip the important contribution of xenobiotic oxidation on infertility for both sexes. Other crucial fertility concerns are the epigenetic inheritable impacts of EDCs on the reproductive health of the next generation, the role of age on fertility, chronic stress contribution and the impact of infections and chronic disease. In truth, the "why" of infertility appears to be all of these factors.
Mechanisms of EDCs
EDCs can mimic or block hormones, interfere with receptor binding, alter steroidogenesis, and change the metabolism of hormones. The function of all reproductive hormones can be altered including estrogens, androgens, progesterone, gonadotrophin releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid hormones. Almost every chemical grouping has been implicated in fertility-related endocrine disruption including polycyclic aromatic hydrocarbons, pesticides, heavy metals, phthalates, polybrominated diphenyl ethers, bisphenol-A and BPA alternatives, dioxins, nonylphenols, polychlorinated biphenyls, perfluorinated compounds, triclosan, and parabens. Of concern to the general populace, many of these chemicals are frequently encountered in non-occupational exposure settings.
BPA is one of the world's highest production volume chemicals; ubiquitous in most people's daily lives, it has been recognized as a significant player in reproductive health concerns. BPA is thought to decrease fertility in part by acting as an agonistic to alpha and beta estrogen receptors.3 Because BPA has a weak estrogenic effect at the receptor site, it can mute overall estrogen expression by blocking endogenous estrogens.
Some of the best studies on EDCs and infertility come from ART participants. Unlike live sperm that can easily and inexpensively be studied outside the body, assessment of the ovum is expensive and often invasive. Because families suffering from infertility are willing to invest in this costly testing, we now have a body of research on the etiology of EDC-driven female infertility. Ovarian reserve and ovarian response tests, currently available and well defined, are FSH, LH, inhibin-B, the ovarian antral follicle count (AFC), and anti-Müllerian hormone (AMH). A 2015 study of 209 women undergoing infertility treatments demonstrated a significant trend (p-trend 0.001) of higher BPA associated with lower AFC. BPA affects oocyte maturation by altering the granulosa cells' effectiveness at assisting follicular growth, steroidogenesis, and oocyte nourishment in the intra-ovarian and intra-follicular environment. In this study, the highest documented BPA urinary level in the 4th quartile showed a 17% decrease in AFC. Interestingly, there was a 22% decrease in AFC at the third quartile, which is a lower amount of BPA.4
One of the challenges of EDCs is that their dose response curve can be U-shaped instead of linear; very low doses of a toxicant show endocrine disruption while very high doses show toxicity, via mechanisms such as oxidation. It is important to note that the BPA-free plastics contain chemicals such as BPS and BPF, which have the same mechanism of action on the endocrine system as BPA and are equally linked to infertility.
Polycystic ovarian syndrome (PCOS), one of the most common endocrine disorders of women in the reproductive years, affects 6-21% of women, depending on diagnostic criteria, and is the primary cause of anovulatory infertility. There is an association of PCOS, elevated androgens, and elevated BPA; but causality has not been defined. Two hypotheses have surfaced to explain this observation; elevated androgens impair excretion of BPA or that BPA displaces testosterone from sex hormone binding globulin (SHBG), thereby increasing free testosterone. The relationship between androgens and BPA may indeed be bi-directional, both a cause and a consequence of deregulated androgens and PCOS.5
Discovering the Root of the Problem
I have focused on BPA, a well-studied ubiquitous endocrine disruptor, but what about the other 2,999 chemicals that your infertility patient has likely been exposed to? To further complicate the picture, we know that people are not exposed to chemicals one-by-one, but rather to a constantly fluctuating chemical soup. Where does a clinician start to unravel and treat the cause?
Step one is a thorough environmental health questionnaire with an in-depth look at daily chemical exposures via food, water, air, and topical routes. A complete exposure assessment and education of personal care products, cleaning products, furnishing, building materials, storage of chemicals, car, and workplace can significantly reduce daily contact with EDCs. To assess endogenous sources of xenobiotics, a comprehensive time-line correlating potential chemical exposures in the past to the temporal onset of new symptoms, can help you determine if testing could be fruitful.
While we are still not able to test all 3,000 high-volume environmentally relevant compounds, a growing list of diagnostic tests is available. There are several labs that offer serum, whole blood, and urine tests on phthalates, BPA, parabens, chlorinated and phosphorylated pesticides, PCBs, dioxins, solvents, toxic metals, and glyphosate. When choosing a test, consider the half-life of the compound. For example, the rapid half-life of phthalates and BPA, and even the slightly longer half-life of organophosphate pesticides, indicates that levels reflect current exposure. The prime treatment for chemicals that are quickly metabolized is avoidance. In this case, treat first with assessment and exposure reduction and then test to demonstrate the effectiveness of the avoidance strategy.
For persistent EDCs such as lead, mercury, cadmium, dioxins, PBDE flame-retardants, PCBs, and organochloride pesticides, testing assesses current exposure plus body burden. While it is beyond the scope of this review, it is imperative to use the right test for the compound you are looking for. For example, a urine test is ideal to screen for cadmium overload, whereas whole blood is a more appropriate sample for initial lead testing. In the case of persistent compounds, while avoidance is crucial, it is often not sufficient with significant chemical body burden.
Functional tests indicating inflammation, oxidation, and liver metabolism are alternatives to testing for specific chemicals. These tests are more affordable and therefore more practical for monitoring therapy. My favorite functional test is a hepatic panel including AST, ALT, GGT, and bilirubin. GGT, a known marker of excessive alcohol consumption, has also been proposed as a sensitive biomarker for xenobiotic exposures and body burden.6,7 Moderate elevation of GGT, within its normal range, has been linked to various chemicals including lead, cadmium, organochlorine pesticides, dioxin, and PCBs. Other inexpensive and informative biomarkers of potential body burden and inflammatory or suppressive effects are hs-CPR and CBC assessing for cytopenia.8,9
|AST and ALT
|WBC and RBC
Detoxification of Body Burden of Xenobiotics (Depuration)
A first step in any depuration protocol is avoidance. Reducing daily chemical exposure and eliminating processed foods and alcohol is imperative. Sugar, in particular, should be avoided due to its contribution to inflammation and its displacement of nutrient-dense food. A general cleanup of the home environment is also crucial, particularly the bedroom where healing and detoxification occur during sleep.
Opening the channels of elimination is the next step; mobilization of endogenous xenobiotics without adequate elimination can cause harm. Specific treatment for dehydration/sub-hydration, constipation, anhidrosis (poor or lack of sweating) and shallow breathing is critical. Of all the depuration therapies, sauna is undoubtedly the most extensively studied and validated.10,11 Other physical modalities that have empirically shown benefit are colon hydrotherapy, dry skin brushing, castor oil packs, acupuncture, yoga, and lymphatic massage to name a few.
The third foundational step for any depuration protocol is an adequate protein diet, high in phytonutrient-rich foods and fiber, and low in pesticides and other contaminants. Avoiding animal products, particularly animal fat and mercury-toxic fish, decreases exposure to bioaccumulated compounds. A hypoallergenic diet will help your patient avoid inflammation from food sensitivities.
Once a general depuration plan is in place, you can add specific therapeutics for identified and/or suspected contaminants. The two main chemical forms of endogenous xenobiotics are metals and fat-soluble chemicals. Due to the risks associated with chelation of toxic metals, testing must always be done prior to treatment and, optimally, post-treatment. In addition, an informed consent with a strong recommendation for birth control during treatment of embryo toxic metals is good preventive policy for your practice. Metal testing is most accurate with an unprovoked test using the appropriate sample, comparing the results to the CDC's NHANES data,12 and following with chelation provocation specific to the metal when treatment is indicated.
Elimination of fat-soluble compounds starts with mobilization. Exercise and weight loss are both effective tools. For the overweight or obese infertility patients, weight loss is an effective and important component of treatment. A loss of as little as 5-10% body mass can restore ovulation in anovulatory women.13 However, weight-loss without depuration of mobilized chemicals is a disservice to the health of your patient and their future child. Weight stabilization or weight gain is shown to reduce circulating persistent organic fat-soluble pollutants, which can expose baby in utero as well as the breast-feeding infant. Effective depuration of fat-soluble compounds includes the use of sauna, fiber14 and other binders, lipase-inhibitors,15 and nutrients and herbs supporting phase one and phase two liver enzymes.
The Importance of Preconception Care
I am a champion of preconception care for all pregnancies due to the overwhelming exposure fertile people have to xenobiotics that are associated with long-term health outcomes for children. When infertility is a concern, application of the Precautionary Principle notches up considerably. If we suspect EDCs to be a component of infertility, then we should also be cognizant that these same compounds limiting fertility can also cause harm to gametes, embryos, fetuses, babies, and breast-feeding toddlers. Given the magnitude of chemical exposure in our modern world, I would argue that EDCs have at least some impact on all infertility, even when they are not the roots of the cause. Infertility is a sign that the body is not at optimal health. Helping infertile people to get pregnant at any cost is a core value of ART. Helping people, even those who ultimately choose ART, to become healthier before attempting conception is an investment to the next generation.
Bonnie Nedrow, ND, lectures nationally on environmental medicine and reproductive health, preconception optimization, and the ketogenic diet for metabolic flexibility. She is currently located in Santa Rosa, California, at Farmacopia, where she has a private practice and teaches classes on her programs to the public. In addition, she offers coaching for her ketogenic detoxification program to patients in Oregon and California. She has co-published two books, The Seasonal Cleanse Workbook and The Cleanse Companion Cookbook. Dr. Nedrow is available for case consultations on the ketogenic diet, single nucleotide polymorphisms, and detoxification. For more about her programs and publications, or to contact Dr. Nedrow, go to keto-cleanse.com.