It is estimated that 1 in 68 children are diagnosed with ASD in the United States. Increasing awareness and the rapidly growing number of cases of Autism Spectrum Disorder (ASD) have caused national alarm, compelling scientists to search for clues about the causes and contributing factors of ASDs. Many explanations for the rise in prevalence of ASD have been offered and yet, causal factors for ASD are still inadequately understood. Scientists agree that ASD is a complicated disorder thought to be due to interactions between genes and the environment, but as yet, there is no known cause that explains the increase in prevalence of autism and autism spectrum disorders.
Oral contraception use is one possible risk factor for the increase in prevalence that has been profoundly overlooked in the biomedical and epidemiologic literature. Interestingly, as the prevalence of ASD has risen over the last fifty years, so has the prevalence of the usage of oral contraceptives. Usage of oral contraceptives in the United States has increased from 1 million women in 1962 to almost 11 million women today. Because oral contraceptives were created to mimic natural human hormones and disrupt endogenous endocrine function to inhibit pregnancy, there is good reason for concern that the synthetic hormonal components may be causing the harmful neurodevelopmental effects that lead to the increase in ASDs.
Oral Contraceptives are Endocrine Disruptors
One of the compounds found in oral contraceptives is the synthetic estrogen called Ethinylestradiol (EE2). EE2 is a known endocrine disrupting compound (EDC) capable of causing harm to the endocrine system and to progeny. Studies show that EDCs have the potential to do harm by adversely affecting the sensitive hormonal pathways that regulate reproductive function in a variety of species including humans. The National Institute for Environmental Health Sciences (NIEHS) reports that EDCs may disturb the endocrine system and produce adverse developmental, reproductive, neurological, and immune effects in humans and wildlife. The NIEHS indicates that research also shows that the highest risk of endocrine disruption occurs during prenatal and early postnatal development. Humans might be exposed to EDCs through foods, beverages, pesticides, and cosmetics, but the case with EE2 is particularly striking because EE2 exposure in female humans occurs at a pharmacologically effective dose, administered every day, for extended periods of time.
Hormones and their signaling pathways are essential to normal functioning of all tissues and organs in invertebrate and vertebrate species. Normal communication of the endocrine system can be disrupted by exogenous substances like EDCs, which have the same attributes as endogenous hormones. EDCs possess the ability to be active at low concentrations and like endogenous hormones, they are able to bind to receptors at very low concentrations. Therefore, endocrine disruption can occur from low-dose exogenous hormone exposure or from hormonally active substances that interfere with receptors for other hormonally assisted processes. In addition, some EDCs are able to interact with multiple hormone receptors concurrently. They can work simultaneously to create additive or synergistic effects not observed with the individual compounds. EDCs can act on a number of physiological processes in a tissue specific manner. And, as with endogenous hormones, it is often not feasible to extrapolate low-dose effects from the high-dose effects of EDCs. Thus the mimicry of estradiol (E2) and the information that such compounds can cause harmful effects on reproduction and the endocrine system provide mechanistic evidence that EE2 found in oral contraceptives may adversely affect the oocyte or developing embryo.
Disrupting Hormones Chronically: Is This Safe?
Exposure timing is of interest and importance. When does exposure to the endocrine disruptor EE2 in oral contraceptives disrupt the endocrine system? Oral contraceptives were designed to disrupt the endocrine system throughout the month to keep a woman from becoming pregnant. During this disruption, what happens to follicles or the oocytes? As they are repeatedly exposed to the compound EE2, does this modify or change either or both of them? It is conceivable that with contraceptive EE2 exposure alteration in follicles or oocytes occurs, since data from animal models suggest that hormonal compounds do cause changes in follicular, embryonic, and fetal development. Does repeated exposure to the synthetic hormone EE2 cause harmful changes to human follicles and/or oocytes as well? If so, in this case, the adverse effects of disruption would happen even before fertilization occurs.
Becoming Pregnant while on Oral Contraceptives: Potential Dangers
Oral contraceptives are reported to be 99.9% effective if used properly. Less than 1 out of 100 women will get pregnant each year if they always take the pill each day as directed. Moreover, about 9 out of 100 women will get pregnant each year if they don’t always take the pill each day as directed. That means that out of the 11 million U.S. women using oral contraceptives, up to 100,000 may get pregnant while continuing to take EE2 after oocyte fertilization. Those embryos would then be directly exposed to pharmacologic doses of EE2. It is conceivable that exposure to EE2 could adversely affect the developing embryo. And, the time-frame for oral contraceptive wash-out is not clear even after discontinued use of the pills. Even if there is full drug wash-out, persisting toxicological, genetic, and epigenetic effects are possible. Harmful EE2 exposure could then occur after fertilization and during early development of the embryo.
There is also the potential for some EDCs to produce effects that can cross generations, meaning that exposure may affect not only the development of the first offspring but also their offspring over generations. This means that effects of EDCs could increase over generations due to both transgenerational transmission of the modified epigenetic programming, and the continued exposure across generations possibly imparting disease sensitivity later in time. Thus, the ability of ancestral exposures to promote disease susceptibility greatly complicates the possible threat to the health of subsequent generations, through exposure to EDCs such as EE2.
Autism and Oral Contraceptives: Is there a Connection?
The need for human epidemiological investigation into the link between oral contraceptive use and ASD is motivated by the firmly grounded hypothesis that oral contraceptive use is a risk factor for ASD in offspring. In the realm of environmental risk factors this hypothesis is compelling due to several considerations. First, as a category of agents there are specific documented mechanisms through which oral contraceptives can affect the oocyte and/or developing embryo. Second, exposure concentration is directly administered and by definition pharmacologically effective. And, it may be of greater magnitude than other environmental exposures that largely occur through passive secondary mechanisms. The possibility exists that the effects of EE2 could intensify over generations due to transgenerational transmission of altered epigenetic programming and the continued exposure across generations possibly imparting sensitivity to developing ASDs. Lastly, the specific demographic at risk, women who are likely to have children, is the exact demographic that is taking oral contraceptives, specifically during child-bearing years (“first principles”).
If, as I have hypothesized, epidemiological investigation establishes a link between oral contraceptives and ASD, this information would be invaluable to women of child-bearing age evaluating birth control options. Considering the increased prevalence of ASD, the increasing usage of oral contraceptives and the striking lack of research in this area, this information has a sense of urgency for those women and their progeny.
To read more about possible connections between autism and oral contraceptives see: The link between oral contraceptive use and the increase in the prevalence of autism spectrum disorder.
About the Author: Kim Strifert has an MA and is currently a student of Public Health at the Graduate School, School of Public Health, University of Alabama at Birmingham. She was previously employed as a healthcare administrator at the Mayo Clinic and Baylor College of Medicine.
Armenti AE, Zama AM, Passantino L, Uzumcu M (2008) Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats. Toxicology and Applied Pharmacology 233: 286–296.
Csoka, A B, Szyf, M (2009) Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology (Article). Medical Hypotheses. Vol. 73, Issue 5, 2009, 770-780.
Denslow ND, Bowman CJ, Ferguson RJ, Lee HS, Hemmer MJ, and Folmar LC (2001) Induction of gene expression in sheepshead minnow (Cyprinodon variegates) with 17β-estradiol, diethylstilbestrol, or ethinylestradiol: The use of mRNA fingerprints as an indicator of gene regulation. General Comparative Endocrinology 121:250-260.
Gandolfi F, Pocar P, Brevini TAL, Fischer B (2002) Impact of endocrine disrupters on ovarian function and embryonic development. Domestic Animal Endocrinology 23: 189–201.
Jobling, S, Coey S, Whitmore JG, et al. (2002) Wild intersex roach (Rutilus rutilus) have reduced fertility. Biology of Reproduction 67: 515-524.
Kasan P, Andrews J (1980) Oral contraception and congenital abnormalities. British Journal of Obstetrics and Gynaecology 87(7):545-51.
Kerdivel G, Habauzit D, Pakdel F (2013) Assessment and Molecular Actions of Endocrine-Disrupting Chemicals That Interfere with Estrogen Receptor Pathways. International Journal of Endocrinology 2013:501851.
Larkin, P, Folmar LC, Hemmer MJ, Poston AJ, Denslow ND (2003) Expression profiling of estrogenic compounds using a sheepshead cDNA macroarray. Environmental Health Perspectives 111:839-846
Leese HJ, Baumann CG, Brison DR, McEvoy TG, Sturmey RG (2008) Metabolism of the viable mammalian embryo: quietness revisited. Molecular Human Reproduction 14:667–672.
Leese HJ, Sturmey RG, Baumann CG, McEvoy TG (2007) Embryo viability and metabolism: obeying the quiet rules. Human Reproduction 22:3047–3050.
Martínez NA, Pereira SV, Bertolino FA, Schneider RJ, Messina GA, Raba J (2012) Electrochemical detection of a powerful estrogenic endocrine disruptor: ethinylestradiol in water samples through bioseparation procedure. Analytica Chimica Acta Apr 20;723:27-32.
Metcalfe CD, Metcalfe T L, Kiparissis Y, et al. (2001) Estrogenic potency of chemicals detected in sewage treatment plant effluents as determined by in vivo assays with Japanese medaka (Oryzias latipes). Environmental Toxicology and Chemistry 20:297-308.
National Institute of Environmental Health Sciences (2014) Accessible at: www.niehs.nih.gov/health/topics/agents/endocrine
Skinner M (2014) Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Molecular and Cellular Endocrinology Jul 31. pii: S0303-7207(14)00223-8.
The Collaborative on Health and the Environment’s Learning and Developmental Disabilities Initiative (2008) issued the “Scientific Consensus Statement on Environmental Agents Associated with Neurodevelopmental Disorders”. Accessible at: www.healthandenvironment.org/initiatives/learning. (accessed 10, December 2014)
Tilton SC, Foran CM, Benson WH (2004) Relationship between ethinylestradiol-mediated changes in endocrine function and reproductive impairment in Japanese medaka (Oryzias latipes). Environmental Toxicology and Chemistry 24:352-359.
Vaiserman A (2014) Early-life Exposure to Endocrine Disrupting Chemicals and Later-life Health Outcomes: An Epigenetic Bridge? Aging and Disease Jan 28;5(6):419-29.
World Health Organization (2012) State of the Science of Endocrine Disrupting Chemicals 2012 Summary for Decision-Makers. Available at: www.who.int/ceh/publications/endocrine/en/