Oral Contraceptives and Autism

Oral Contraceptives and Autism
The mechanisms by which oral contraceptives instigate neurodevelopmental changes is slowly emerging. It appears that in addition to preventing pregnancy, synthetic hormones like ethinylestradiol, used in most birth control formulations, initiate epigenetic alterations in the oocytes (eggs) causing persistent changes in expression of the estrogen receptor beta gene (ERβ). When those eggs become fertilized and conception ensues, the changes in the estrogen receptor gene impact the expression of autism and other neurodevelopmental disorders.
Ethinylestradiol is an Endocrine Disruptor
Ethinylestradiol is a known endocrine disruptor. Anything that disrupts endogenous hormones can be considered an endocrine disruptor. Evidence is emerging that ethinylestradiol may trigger what is called DNA methylation of the estrogen receptor gene. This then causes decreased messenger RNA resulting in impaired brain estrogen signaling in offspring [2]. Let’s think more deeply about this.
Methylation means that, by way of a chemical process, a gene is turned on (hypomethylation) or turned off (methylation) by an enzyme or protein. Researchers believe that methylation is one of a number of mechanisms by which environmental interactions influence genetic activity. In this case, ethinylestradiol silences or turns off some important processes that are associated with estrogen signaling, namely receptor activity.
Methylation and other epigenetic reactions influence health and disease processes across generations. This is called transgenerational transmission. So, I suspect that the deleterious effects of ethinylestradiol on the estrogen receptor gene are transgenerational. This is possible because the estrogen receptor gene may be an imprinted gene. Imprinting is a dynamic epigenetic phenomenon by which certain genes are expressed in a parent-of-origin manner. If the allele, an alternative form of the same gene, inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed. If the allele from the mother is imprinted, then only the allele from the father is expressed.

Study: The link between oral contraceptive use and prevalence in autism spectrum disorder
Autism spectrum disorder (ASD) is a group of developmental disabilities that include full syndrome
autism, Asperger’s syndrome, and other pervasive developmental disorders. The identified prevalence of ASD has increased in a short time period across multiple studies causing some to conclude that it has reached epidemic proportions in the U.S.
Many possible explanations for the rise in numbers of individuals diagnosed with ASD have been offered and yet, causes and contributing factors for ASD are inadequately understood. Current evidence suggests that both genetics and environment play a part in causing ASD.
One possible risk factor for the increase in prevalence has been profoundly overlooked in the existing biomedical and epidemiologic literature. As the prevalence of ASD has risen in the last sixty years, so has the prevalence of the usage of the oral contraceptives and other modern hormonal delivery methods. In 1960 about one million American women were using oral contraceptives, today close to 11 million women in the U.S. use oral contraceptives. Eighty-two percent of sexually active women in the U.S. have used oral contraceptives at some point during their reproductive years. Thus, the growth in use of progesterone/estrogen-based contraceptives in the United State has reached near-ubiquitous levels among women in the child-bearing age range.
The suppression of ovulation produced by estrogen–progesterone is an indisputable abnormality. It is logical to consider the outcome of the ovum that would have been normally released from the ovary during ovulation. To date there is no comprehensive research into the potential neurodevelopmental effects of oral contraceptive use on progeny. The issue has been only sparsely considered in the biomedical literature. This article hypothesizes that the compounds, estrogen and progesterone, used in oral contraceptives modify the condition of the oocyte and give rise to a potent risk factor that helps explain the recent increase in the prevalence of ASD’s.
This hypothesis does not propose to delineate the cause of autism. Rather, it attempts to explain the recent dramatic increase in prevalence and point the way for further study that will lead to causal examination

Study: An epigenetic basis for autism spectrum disorder risk and oral contraceptive use
In the United States 1 in 68 children are diagnosed with autism spectrum disorder (ASD). Although the etiology is unknown, many scientists believe ASD is caused by a combination of genetic and environmental factors and/or epigenetic factors. The widespread use of oral contraceptives is one environmental risk factor that has been greatly overlooked in the biomedical literature. Oral contraceptives, synthetic hormones created to imitate natural human hormones and disrupt endogenous endocrine function to inhibit pregnancy, may be causing the harmful neurodevelopmental effects that result in the increased prevalence of ASD.
It is conceivable that the synthetic hormones repeatedly assault the oocyte causing persistent changes in expression of the estrogen receptor beta gene. Ethinylestradiol, a known endocrine
disruptor, may trigger DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in impaired brain estrogen signaling in progeny. In addition, it is possible the deleterious effects are transgenerational as the estrogen receptor gene and many of its targets may be imprinted and the methylation marks protected from global demethylation and preserved through fertilization and beyond to progeny generations. This article will delineate the hypothesis that ethinylestradiol activates DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in diminished brain estrogen signaling in offspring of mothers exposed to oral contraceptives. Considering the detrimental epigenetic and transgenerational effects proposed, it calls for further study.

Potential Link between Oral Contraceptives and Autism
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.

Update: Oral Contraceptive Use and Autism
In the realm of environmental risk factors, the oral contraceptive hypothesis I first proposed is compelling. As a group of agents, there are explicit documented mechanisms through which oral contraceptives can impact the oocyte and/or the developing embryo. Additional reasons for considering the role of oral contraceptives and autism include:

The exposure concentration is directly administered and pharmacologically effective.
The exposure to the endocrine disruptor may be of larger magnitude than other environmental exposures that mostly occur through passive secondary means.
A temporal correlation exists between the increased prevalence of oral contraceptive use and the increased prevalence of autism spectrum disorders over the last fifty years.
The possibility exists that the effects of EE2 could intensify over generations due to transgenerational transmission of altered epigenetic programming.
Continued exposure across generations could possibly impart sensitivity to developing autism spectrum disorders.

Do We Really Understand Oral Contraceptives?
While researching my hypothesis linking oral contraceptive use to the development of autism in children, I wondered about why so many women are still using a drug that has dangerous side-effect and could cause neurodevelopmental disorders in offspring. The simple answer seems to be lack of accurate medical information. Not only do individual women lack critical information about the pill, but the support systems women depend on for advice and help with decision-making also seem to lack information about the pill.
All health choices are complex and influenced by multiple variables that all interact. There are multiple levels, underlying determinants of health behaviors, which are relevant for understanding why oral contraceptives are still the primary method of choice in the United States. The following influencing factors are not exhaustive, but do shed light on why pill use is so prevalent in the U.S. Simply put, we don’t know better.

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