Catholic Medical Quarterly

The Journal of the Catholic Medical Association (UK)

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Catholic Medical Quarterly Volume 74(3) Aug 2024

News

The effects of Hormone-Based Contraceptives on development of Autism Spectrum Disorder in offspring

The first synthetic oestrogen called diethystilbestrol (DES) was developed in 1930s in the United States and used to prevent early miscarriage or premature labour. Three decades later the US Food and Drug Administration (FDA) banned its use due to a clear risk of adenocarcinoma of vagina and cervix which was present not only in the directly exposed offspring but also in subse- quent generations. The side effects of newer for- mulations of synthetic oestrogen called ethinyl oestradiol (EE) used in hormonal contraception of various forms are also notable. Women taking synthetic oestrogen alone or with progesterone are at a greater risk of heart attack due to blood clot formation, they suffer from decreased libido and mood swings that can even lead to depression (Segarra et al., 2023). The list of the side effects due to hormone-based contraceptives (HBC) is still expanding and is a reason why 61% of women discontinue their use and seek alternative methods of contraception and turn to modern fertility awareness based methods (FABMs) of family planning (Segarra et al., 2023). Not many users of the HBC know that their adverse effects also effects the next generation. It has been hypothesized and partially proven using animal models, that the follicles of the female taking HBC can undergo epigenetic changes that can impact health of her future babies (Streitfert, 2014).

There is a potential causal link between increased usage of HBC and rises in instances of Autism Spectrum Disorders (ASDs) worldwide. The Centre for Disease control published a report in 2014, where it demonstrated 20- to 30-fold in- crease in the prevalence of ASD compared to thefirst epidemiologic studies conducted in 1960s (Donhauser, 2020). This indicates that besides heritability and genetic background, other factors might be implicated in development of ASDs, particularly environmental factors that influence the central nervous system (CNS) development. Several toxic compounds have been linked to ASD risk, such as heavy metals, air pollutants or pesticides. However, the increased usage of HBC is thought to be one of the main drivers of the significant rise in the prevalence of ASD. The first potential mechanism includes a direct effect of synthetic hormones during prenatal life by continuation of HBC in early pregnancy. In the US alone, up to 100,000 women may get pregnant while continuing to take some form of HBC after oocyte fertilization. Those embryos would then be directly exposed to pharmacologic doses of synthetic oestrogen and/or progesterone during early development of the embryo. Another possibility of a direct foetal exposure to synthetic hormones is through consumption of contami- nated food, especially fish, or water, which is now a global problem (Zou et al., 2017; Li et al., 2018). In China, for example, combined oral contraceptives are widely used by the seafood industry for pregnancy prevention in fish and shrimps because they can grow faster and become fatter if they do not lay eggs. In a large population-based case-control epidemiology study in China scientists found that the use of progestin to prevent threatened abortion, use of progestin contraceptives at the time of conception, and prenatal consumption of progestin-contaminated seafood during the first trimester of pregnancy were significantly associated with the risk of autism (Li et al., 2018). Additionally, they confirmed these findings by conducting in vivo experiments in rats. Generally, exposures at critical windows of early development (foetal, birth, puberty) have the most dramatic impact on later life disease development or abnormal physiology.

The second possible mechanism by which the HBC influence development of ASD is indirect and related to the duration of taking the HBC. Taking oral contraceptives for longer than 3 years showed a statistically significant risk for children subsequently developing ASD (Lyall et al., 2011). There are two possible explanations to this. Firstly, it is known that the body re-distributes vitamins and other materials, including folate and vitamin B12 (key in brain development), to the uterus and amniotic sac during pregnancy for foetal development, thus less available for use by the mother’s own body. It is thought that HBC produce physiological responses that mimic becoming pregnant to a limited extent. Prolonged usage of HBC can lead to low levels of vitamin B12 and folate during foetus development, which could be a contributing factor for ASD develop- ment (Donhauser 2020). Secondly, HBC can cause changes in epigenetic mechanisms in follicles leading to reduced expression of oestrogen receptor type beta (ERβ) and other genes, which result in presentation of ASD in offspring. This hypothesis was first stated by a public health researcher Kim Strifert in 2014.

Strong motivation for this epigenetic hypothesis came from a study comparing postmortem brains (areas of middle frontal gyrus) of ASD individuals with controls (Crider et al., 2014). They determined a significant decrease in expression of oestrogen receptor type β (ERβ) at the level of gene and protein, which provides a strong evidence that oestrogen receptors (ERs) signalling in the brain can be impaired in people with ASD. The importance of oestrogen receptors, especially ERβ was also confirmed in studies using animal models. In rats, prenatal exposure to synthetic progesterone alone or in combination with synthetic oestrogen inhibited ERβ expression in the amygdala through increased methylation of its promoter (Zou et al., 2017). Down-regulation of ERβ expression in the amygdala during neuro-development may contribute to autism-like behaviour. It was hypothesised by Strifert (2014) that not only ERβ is silenced by methylation, but also other genes, which expression is normally regulated by oestrogen receptors. When HBC activate oestrogen receptors in the oocyte and/or developing embryo, the oestrogen receptor binds to DNA increasing methylation at many sites across the genome. This causes long-term decrease in oestrogen receptor function leading to impaired brain oestrogen signalling. This hypothesis has been first tested four years ago in mice, which were treated with low doses of synthetic oestrogen in the absence or presence of synthetic proges- terone, similarly to contraceptive pills, for 90 days prior to pregnancy (Garbett et al., 2020). Female mice treated with the synthetic hormones demon- strated reduced expression of ERβ in ovaries even following the treatment. Additionally, mice treated with low dose of synthetic oestrogen in the presence or absence of progesterone prior to pregnancy produced less offspring and offspring with altered gene expression patterns in frontal cortex. Behavioural tests in specialized cages, revealed that young adult male mice from mothers treated with both synthetic oestrogen and progesterone prior to pregnancy exhibited hyper- active ADHD-like locomotor behaviour. The effects of synthetic hormones are sex specific, more prominently seen in males. Author’s speculate that treatment of females with low doses of synthetic oestrogen and progesterone altered the epigenetic landscape of oocytes that later led to neurodevelopmental adaptations and presentation of ADHD-like behaviors in male offspring, which come under the umbrella of ASD.

Conclusion

There is an emerging body of evidence in the literature of the causal link between the increase in the prevalence of Autism Spectrum Disorders and rise in Hormone-Based Contraceptive usage. There is a need for more epidemiological studies to confirm this association and experimental research to determine the exact mechanism by which HBC increase the risk of ASD in offspring.

We are grateful to the National Asssociaton of NFP teachers for permission to publish this article.