Association of Increased Prenatal Estrogen with Risk Factors for Autism

Estrogen Reduces Resistance to Specific Viruses Associated With Autism, Schizophrenia

2011 Study Abstract

The author previously described a theoretical cause of schizophrenia based on the effects of estrogenic endocrine disruption. In the current review, the author describes how increased estrogen during pregnancy increases susceptibility to certain viral infections associated with increased risk for schizophrenia and/or autism.

The review further discusses how prenatal estrogen exposure could explain associations of schizophrenia with autoimmune diseases, urban environments, and stress.

Based on the association of increased estrogen with schizophrenia and/or autism risk factors, the author proposes increased prenatal estrogen as a unifying factor, perhaps the primary event, in the etiology of schizophrenia.

Toxoplasma gondii

T gondii is a strong candidate as an infectious cause of schizophrenia. More than one animal study found that estrogen enhances T gondii infection. Overwhelming, T gondii infection from reduced cell-mediated immunity occurs in mice and guinea pigs after treatment with hexestrol. Pharmacological doses of estrogenic compounds including 17 beta-estradiol, diethylstilbestrol, and alpha-dienestrol also increase susceptibility of mice to T gondii, and female mice are more susceptible to small intestine infection with T gondii. Some T gondii infections have been associated with increased prenatal testosterone rather than estrogen (see online supplementary material where the author discusses these findings and how prenatal estrogen and/or testosterone might cause schizophrenia and/or autism).

The Theoretical Role of Estrogen and Testosterone in Autism

The foregoing section provides a foundation from which to speculate on the possible role of estrogen and testosterone in both schizophrenia and autism. The author’s current paper describes the increased susceptibility to acute infection by T. gondii caused by estrogen. Some human studies suggest that “latent” toxoplasmosis results from high prenatal testosterone rather than estrogen due to finding low second to fourth finger digit ratios in T. gondii infected subjects . Second to fourth finger digit ratios, or so-called 2D:4D ratios, are proposed markers of prenatal androgen exposure.

Low 2D:4D ratios reflect higher prenatal testosterone exposure and high ratios indicate low testosterone compared to estrogen exposure. Low ratios or high prenatal testosterone are often associated with autism and high ratios or relatively higher prenatal estrogen with schizophrenia. Recent research has cast doubt on the reliability of digit ratio to predict individual prenatal androgen exposure although a modest group effect of feminized 2D:4D ratios resulting from complete androgen insensitivity was found in the most sensitive study to date. On a group basis, this tends to support the notion that finding a high 2D:4D ratio in schizophrenia indicates an estrogenized prenatal environment.

The association of high fetal testosterone with autistic traits including the 2D:4D ratio has been controversial. Autism and schizophrenia share certain genetic and biologic pathways and may occur in the same individual. The author speculates that if both the author’s estrogen theory and other researchers’ testosterone theory of autism are correct, an imbalance of estrogen and testosterone results in varying degrees or combinations of schizophrenia and autism.

Imbalance can occur from any of three measurements of exposure: dose, duration and timing of exposure. The theories should therefore not be portrayed only as “excesses” per se of estrogen and/or testosterone but more by “inappropriate” exposures. Considering just high vs. low dose, the author speculates that schizophrenia might result from excess dose of prenatal estrogen, autism from excess prenatal testosterone, and both conditions in the same individual from excess prenatal estrogen and testosterone combined. Whether the absolute dose versus the ratio of doses is more important in the model is an important consideration but adds to further speculation.

The possible combinations of high and low “dose” prenatal estrogen and/or testosterone and their hypothetical outcomes in the author’s paradigm are shown on Table 1. In this particular theoretical construction, the impact of “dose” could be increased or decreased if duration and timing were part of the model, and boundaries between the outcomes could overlap. For example, excessive prenatal estrogen from a failed 11bHSD barrier may occur at a different time as excessive prenatal testosterone/estrogen exposure from aromatization later in development. The author’s model does not predict whether this latter scenario would have the same result as that from simultaneous excessive estrogen and testosterone. Table 1 shows that the author’s model predicts two hormonal environments will lead to schizophrenia, two other environments will lead to autism, and one specific environment leads to a combined state of both conditions. The three environments marked by low levels of one or both hormones are outside the current discussion although theoretically interesting.

  • Read and download the full study (free access) Association of Increased Prenatal Estrogen With Risk Factors for Schizophrenia, on the NCBI, PubMed, PMC3160212, 2011 Sep.
  • Supplementary data is available at PMC3160212/bin/supp_37_5_946.
  • Image credit hepingting.

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