Prenatal DES Exposure and Increased Risk of Multiple Sclerosis

Prenatal and Perinatal Factors and Risk of Multiple Sclerosis

2011 Study Abstracts

Background
A potential role of prenatal and perinatal exposures in autoimmunity has been hypothesized, but few studies have examined the relation between various prenatal and perinatal factors and risk of multiple sclerosis (MS).

Methods
The study population included participants in the Nurses’ Health Studies, 2 prospective cohorts that together comprise 238,381 female nurses, who self-reported exposure to prenatal and perinatal factors. In addition, 35,815 nurses’ mothers participated by providing detailed information regarding experiences surrounding their daughter’s birth. The following prenatal and perinatal factors were studied in relation to MS: fetal growth, birth season, preterm birth, mode of delivery, maternal weight gain, medical conditions, medication use, diethylstilbestrol exposure, prenatal health care, maternal activity level, maternal obstetric history, parental age, and prenatal and childhood passive smoke exposure.

Results
The sample included 723 confirmed MS cases, including 383 with diagnosis after reporting prenatal and perinatal factors. Few associations were observed. These included an increased risk among women whose mothers reported late initiation of prenatal care (after the first trimester) (27 cases, rate ratio = 1.6; 95% confidence interval = 1.0–2.4), diabetes during pregnancy (2 cases; 10;2.5–42), and maternal prepregnancy overweight/obesity (20 cases; 1.7; 1.0–2.7). Results also suggested a possible increase in incident MS risk among women with prenatal diethylstilbestrol exposure (9 cases; 1.8; 0.93–3.5).

PMC full text: Epidemiology. Author manuscript; available in PMC3132937 2011 Jul 11.

Conclusions
This study provides modest support for a role of prenatal factors in MS risk. The results should be interpreted cautiously due to the limited statistical power, potential for exposure misclassification, and possibility of chance findings.

Exposure Assessment

For in utero diethylstilbestrol (DES) exposure, assessed in the NHS-II in 1993, a confirmation questionnaire was sent to all nurses who self-reported DES exposure to classify the level of certainty (very certain, somewhat certain, not certain, or not exposed). The current analysis uses a conservative approach and compares those who were very certain of DES exposure with those who self-reported as nonexposed.

Discussion

This is the first study to assess directly the relation between prenatal DES exposure and risk of multiple sclerosis. Small preliminary studies have suggested an increased risk of any autoimmune disease  or, more broadly, of diseases involving impaired immune function, among individuals with prenatal DES exposure. Experimental studies in laboratory animals as well as human case series have also indicated altered immune cell function associated with DES exposure, such as abnormal natural killer cell activity, T cell-mediated immunity, and thymic development. Despite the limited statistical power with this very rare exposure, there was modest support for a positive association. Further examination is warranted, especially because the potential association may be generalized to other prenatal hormone exposures.

  • Download the full study (free access 15 pages PDF) Prenatal and Perinatal Factors and Risk of Multiple Sclerosis, US National Library of Medicine National Institutes of Health, Epidemiology, NCBI PubMed PMC3132937, 2011 Jul 11.
  • Featured image credit medicinenet.
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Prenatal immunotoxicant exposure and postnatal autoimmune disease

Gestational exposure to DES may interfere with normal development of self-tolerance

Abstract

Reports in humans and rodents indicate that immune development may be altered following perinatal exposure to immunotoxic compounds, including chemotherapeutics, corticosteroids, polycyclic hydrocarbons, and polyhalogenated hydrocarbons.

Effects from such exposure may be more dramatic or persistent than following exposure during adult life. For example, prenatal exposure to the insecticide chlordane or to the polycyclic aromatic hydrocarbon benzo[(italic)a(/italic)]pyrene produces what appears to be lifelong immunosuppression in mice.

Whether prenatal immunotoxicant exposure may predispose the organism to postnatal autoimmune disease remains largely unknown. In this regard, the therapeutic immunosuppressant cyclosporin A (CsA) crosses the placenta poorly. However, lethally irradiated rodents exposed to CsA postsyngeneic bone marrow transplant (i.e., during re-establishment of the immune system) develop T-cell-mediated autoimmune disease, suggesting this drug may produce a fundamental disruption in development of self-tolerance by T cells. The environmental contaminant 2,3,7, 8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD) crosses the placenta and produces fetal thymic effects (italic)in vivo(/italic) similar to effects of CsA in fetal thymic organ culture, including inhibited thymocyte maturation and reduced expression of thymic major histocompatability complex class II molecules.

These observations led to the suggestion that gestational exposure to TCDD may interfere with normal development of self-tolerance. Possibly supporting this hypothesis, when mice predisposed to development of autoimmune disease were treated with TCDD during gestation, postnatal autoimmunity was exacerbated. Similar results have been reported for mice exposed to diethylstilbestrol during development.

These reports suggest that prenatal exposure to certain immunotoxicants may play a role in postnatal expression of autoimmunity.

  • Download the full study (free access) Prenatal immunotoxicant exposure and postnatal autoimmune disease, US National Library of Medicine National Institutes of Health, Environ Health Perspectives, NCBI PubMed PMC 1566248, 1999 Oct.
  • Image credit Michelle Robinson.
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Prenatal DES exposure and increased occurrence of autoimmune disease

Can in utero exposure to DES adversely affect the immune system ?

1988 Study Abstract

Soon after recognition of the increased risk of vaginal clear cell adenocarcinoma in women with in utero exposure to diethylstilbestrol (DES), the National Cancer Institute funded a large multicenter epidemiologic cohort study, the DESAD Project. The purpose of this national project was to describe the prevalence of DES-associated genital tract changes among women exposed in utero and to compare these findings with an unexposed control group. Additionally, the study sought to determine the incidence of cancer and other diseases in the exposed and unexposed cohorts. Because of the possibility that prenatal exposure to DES might adversely affect the adult immune system, the participants in the DESAD Project were surveyed to determine the prevalence of autoimmune diseases. The lifetime history of these disease is reported in this preliminary communication.

Discussion

As noted, research in rodents suggests that perinatal exposure to DES can markedly affect the adult rodent immune system,l whereas limited observations in humans raise the possibility of similar changes in the human immune system. The information presented in this preliminary communication also supports the concept that human exposure before birth to DES may subsequently affect the adult immune system. Unfortunately, no detailed serologic studies of the immune status of women exposed to DES in utero have yet been reported in the literature. Thus, it is not possible to identify any specific immune defect or an underlying mechanism for this association.

Although these data suggest that there is an increase in autoimmune disease among women exposed before birth to DES, the authors wish to caution against drawing firm conclusions from these preliminary findings. Although the overall occurrence of autoimmune disease is statistically significant with one-sided chi-square tests, the number of observed events is small, and the confidence intervals are wide. Additionally, the history of autoimmune disease has not yet been documented for all participants. At the present time, only one of the five centers has reviewed the medical histories to validate the questionnaire information. Twenty-four autoimmune diseases were reported by 23 women followed by the Mayo DESAD Center. Six women received all of their medical care outside of Mayo, leaving 18 evaluable cases. Of these 18 reported cases of autoimmune disease, 14 were confirmed. Two of the unconfirmed diseases occurred in an individual with longstanding psychiatric difficulties. Thus, there appeared to be only two cases in which a reliable participant reported a disease that could not be confirmed by examination of medical records.

Although the data reported here are necessarily indirect, they do indicate reason for concern. Consequently, it would seem prudent for investigators exposed women to determine the prevalence (and, it is hoped, incidence) of autoimmune diseases among their exposed cohorts. Additionally, studies should be undertaken to thoroughly investigate the function of the immune system in DES-exposed women by means of appropriate serologic testing.

  • Read and download the full study (free access) Increased occurrence of autoimmune disease among women exposed in utero to diethylstilbestrol, FERTILITY AND STERILITY, Vol. 49, No.6, June 1988.
  • Lifetime History of Autoimmune Diseases Among DES-Exposed Women (Record Review Cases) and Controls – image credit fertstert S0015-0282(16)59965-8.
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Neonatal DES exposure caused the differential expression of 900 genes

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals

Abstracts

“Synthetic estrogens are well known disruptors of uterine structure and function in humans and animals. Consistent with previous studies, recent data indicate that neonatal DES exposure caused endometrial hyperplasia/dysplasia in hamsters and increased uterine adenocarcinoma and uterine abnormalities in Donryu rats. Neonatal DES exposure also caused the differential expression of 900 genes in one or both layers of the uterus. Specifically, DES altered multiple factors in the PPARγ pathway that regulate adipogenesis and lipid metabolism, and it perturbed glucose homeostasis, suggesting that DES affects energy metabolism in the uterus. In the mouse uterus, DES altered the expression of chromatin-modifying proteins and Wnt signaling pathway members caused epigenetic changes in the sine oculis homeobox 1 gene, and decreased the expression of angiogenic factors. DES also altered the expression of genes commonly involved in metabolism or endometrial cancer in mice, and it activated nongenomic signaling in uterine myometrial cells  and increased the incidence of cystic glands in rats.” …

… “The epidemiological data on potential links between EDCs and neurodevelopmental disorders have grown in the past 5 years; although we will focus on recent studies, we will also present results (briefly) from older studies for an historical perspective. The nature of this work generally involves measurements of body burden from maternal media (urine, blood, milk), umbilical cord blood, infant urine, and ultimately, a correlation with some neurodevelopmental measure in the child such as tests of cognitive function.” …

… “What is still very controversial is whether there are direct links among environmental EDCs and specific disorders such as autism spectrum disorders, attention deficit hyperactivity disorders, and others, although the hypothesis has been postulated that EDCs may contribute to the increasing prevalence of these disorders. A recent review has covered the subject of how aberrant prenatal steroid hormone levels produced by the mother, placenta, or fetal adrenal or gonad, along with pharmaceuticals and to a lesser extent EDCs, could affect the developing brain of the fetus in humans.” …

  • Read and download the full study (free access) EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, on the NCBI, PubMed, Endocrine Reviews, PMC4702494, 2015 Dec.
  • Image credit NCBI PubMedPMC4702494/figure/F4.
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Prenatal diethylstilbestrol exposure and autoimmune disease incidence

The results of this 2010 study do not suggest that prenatal DES exposure has an appreciable influence autoimmune disease development

Abstract

OBJECTIVE
Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women.

METHODS
A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed.

RESULTS
Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and rheumatoid arthritis (RA) among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7).

CONCLUSION
Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.

  • Read and download the full study (free access) Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol, on the NCBI, PubMed, J Rheumatology, PMC2988471, 2010 October.
  • Image credit Claire Brosman.
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Prenatal diethylstilbestrol exposure and self-reported immune-related diseases

Prenatally DES-exposed offspring are at a higher risk of immune-based disease

1998 Study Abstract

OBJECTIVE
To compare self-reports of immune-related diseases in diethylstilbestrol (DES) daughters and controls. Prenatal exposure to DES has been associated with several malformations in the lower genital tract, a higher prevalence of adenosis, and increased risk of clear cell adenocarcinoma, and estrogen-dependent tumors. Lately, reports have been published indicating a link between DES exposure and alterations in the immune system. The present study focuses on the possible clinical consequences of an affected immune system.

STUDY DESIGN
DES daughters (n=170) and control women (n=123) completed questionnaires containing lists of immune-related diseases, specified into three categories (i) allergies, (ii) auto-immune disorders, and (iii) infectious diseases.

RESULTS
DES daughters reported significantly more disease conditions than the controls. Analyses for separate disease categories (allergies, auto-immune disorders, infectious disease), yielded a statistically significant difference only for infectious disease. Within this last category, two infectious diseases yielded highly significant differences: bladder infection and measles.

CONCLUSION
The present findings suggest that DES daughters are at higher risk of developing immune-related disease states.

  • Prenatal diethylstilbestrol exposure and self-reported immune-related diseases, NCBI, PubMed, European journal of obstetrics, gynecology, and reproductive biology, PMID: 9578280, 1998 Apr.
  • Image credit nasamarshall.
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Developmental Immunotoxicity, Perinatal Programming, and Noncommunicable Diseases

Early development appears to be a time of increased sensitivity to xenobiotics and risk of adverse immune outcomes that are likely to persist into later life

2014 Study Abstract

Developmental immunotoxicity (DIT) is a term given to encompass the environmentally induced disruption of normal immune development resulting in adverse outcomes. A myriad of chemical, physical, and psychological factors can all contribute to DIT. As a core component of the developmental origins of adult disease, DIT is interlinked with three important concepts surrounding health risks across a lifetime:

  1. the Barker Hypothesis, which connects prenatal development to later-life diseases,
  2. the hygiene hypothesis, which connects newborns and infants to risk of later-life diseases
  3. and fetal programming and epigenetic alterations, which may exert effects both in later life and across future generations.
Diethylstilbestrol

While human immunological studies on diethylstilbestrol (DES) are limited compared with other health-related studies, there are reports suggesting that prenatally-exposed offspring are at a higher risk of immune-based disease.

Overall DES daughters exposed in utero self-reported an increased risk of all immune-based diseases (infections, allergies, and autoimmune conditions). Within specific categories, the women experienced more infectious diseases than non-DES exposed daughters.

In a separate study, Strohsnitter et al. examined the incidence of selected autoimmune conditions among DES daughters. They found no overall increase in disease associations for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), or idiopathic thrombocytopenic purpura (ITP). However, there was a significant increase in the onset of rheumatoid arthritis by 45 years of age in the DES-exposed versus nonexposed groups.

  • Read and download the full study (free access) Developmental Immunotoxicity, Perinatal Programming, and Noncommunicable Diseases: Focus on Human Studies, on the NCBI, PubMed, Advances in Medicine
    Volume 2014, Article ID 867805, PMC4590951, 2014 Jan 23.
  • Image credit Daniel Liporace.
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Prospects for studying epigenetic mediation of exposure–response relationships

2012 Study Abstracts

Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.

Epigenetic effects in neurological disorders

Historically, the field of epigenetics has focused on elucidating mechanisms for maintaining DNA methylation in dividing cells. However, recent work has discovered dynamic DNA methylation changes in non-dividing cells including neurons, motivating studies of effects of environmental exposures on epigenetic marks in relation to neurological disorders.

Alzheimer’s disease, schizophrenia, and autism spectrum disorders show a variety of epigenetic anomalies. An epigenetic mechanism has been proposed to explain the association between famine during the prenatal period and schizophrenia risk, as well as associations between expression of imprinted genes and both autism and schizophrenia. Recent studies, moreover, report associations of both conditions with DNA methylation in additional, non-imprinted genes.

Human studies – Diethylstilbestrol (DES)

Decades ago, human males exposed in utero to DES were found to have excess occurrence of urogenital malformations, including hypospadias, and elevated prevalence of hypospadias was subsequently reported among unexposed boys whose mothers had been exposed in utero to DES. More recently, in a study addressing potential competing effects of measured environmental and genotypic factors, a notable excess of hypospadias was reported among unexposed grandsons of women who had been exposed in utero to DES. One postulated mechanism for these observations is that epigenetic changes in the androgen receptor gene are induced in primordial germ cells of DES-exposed female fetuses at the time that the reproductive system is forming, and subsequently transmitted across generations to affected sons and grandsons. To our knowledge, this mechanism has not been examined at the molecular level.

Multigenerational studies – Diethylstilbestrol offspring

DES is regarded as a potential environmental endocrine disruptor by many researchers because this compound binds steroid hormone receptors and has only exogenous sources. Because exposure occurred only in relatively controlled clinic settings, cohorts of exposed individuals could in theory provide an opportunity to trace any epigenetic effects of exposure among themselves and their descendents to the restricted time periods of their pregnancies or gestation before administration to pregnant women ended in the 1970s. Exposure and comparison group data of varying quality are or could be made available from several sources, the highest quality in theory being participants in trials of DES efficacy conducted in the 1950s, although sample sizes were limited. Nonetheless, the numerous case–control sets, DES-exposed cohorts, and interest groups that subsequently enrolled large numbers of exposed men and women to monitor and investigate health effects of exposed individuals could prove to be valuable resources for investigation of potential epigenetic and transgenerational effects of DES among exposed individuals and their descendents. Initial proof-of-concept studies could include investigation of epigenetic marks postulated to have been disrupted by DES exposures.

  • Read and download the full study (free access) Environmental epigenetics: prospects for studying epigenetic mediation of exposure–response relationships, on the NCBI, PubMed, PMC3432200, 2012 Oct.
  • Image credit Daniel Friedman.
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Exposure to varying levels of sex steroids early in development can lead to permanent changes in behavior

Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring

Disruption of endocrine pathways at critical stages in development may differentially affect non-reproductive behaviors in male and female offspring.

Sexually-dimorphic responses to sex steroids could potentially occur in human brain regions such as the hippocampus, prefrontal cortex, striatum and amygdala, regions that are associated with attention, working memory and emotional regulation.

Attention-deficit/hyperactivity disorder (ADHD) is a sexually-dimorphic clinical disorder that appears to be influenced by hormone-sensitive neural pathways.

We therefore examined sex interactions for behavior outcomes that characterize ADHD: attention, hyperactivity, adaptability (including leadership and social skills), aggression, conduct problems, and externalizing behaviors .

We hypothesized that maternal polymorphisms in the sex steroid pathway may influence these sexually-dimorphic behaviors in offspring.

Abstract

Sex steroids are major modulators of mammalian brain function, regulating neurotransmitters and influencing neuronal differentiation, growth, and synapse formation

Exposure to varying levels of sex steroids early in development can lead to permanent changes in behavior.

Objective
Slight perturbations in maternal sex steroid production and metabolism may interfere with normal fetal neurodevelopment. The balance of maternal estrogens and androgens may have direct fetal effects, may influence the fetal hypothalamic-pituitary-gonadal axis or may alter local hormonal activity within the fetal brain. We investigated maternal functional polymorphisms of CYP17, CYP19 and CYP1B1, which control three major enzymatic steps in sex steroid biosynthesis and metabolism, in relation to childhood behaviors.

Methods
The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic urban pregnancy cohort from 1998–2002 (n = 404). DNA was obtained from maternal blood (n=149) and from neonatal cord blood (n=53). At each visit, mothers completed the Behavior Assessment System for Children (BASC), a parent-reported questionnaire used to evaluate children for behavior problems. We focused on problem behaviors more commonly associated with ADHD (hyperactivity, attention problems, externalizing behaviors, conduct disorder, poor adaptability) to see if maternal genetic variants in sex steroid production and metabolism influence sexually-dimorphic behaviors in offspring.

Results
The more active gene variants were significantly associated with Attention Problems and poorer Adaptive Skills in male compared to female offspring. The CYP19 variant allele was also significantly associated with worse scores for boys on the Hyperactivity, Externalizing Problems Composite and Adaptive Skills Composite scales (p < 0.05).

Conclusion
We found significant associations for maternal polymorphisms known to affect sex steroid synthesis and metabolism with several problem behaviors in male children. These gene-sex interactions appear to be driven by the maternal genotype and not the child genotype. Epidemiologic studies of environmental toxins such as bisphenol A (BPA), polychlorinated biphenyls (PCB), and diethylstilbestrol (DES) demonstrate that low-level exposures to estrogenic compounds during pregnancy can induce abnormal neurodevelopment in offspring. We, therefore, posit that alterations in endogenous levels of estrogens and androgens during vulnerable windows of brain development may tip the estrogen to androgen balance or achieve a threshold level for hormonal effect on fetal tissues including the brain. Future studies should address whether these CYPs have additive effects, non-hormonal effects, or linkage disequilibrium to unidentified functional polymorphisms that may influence behavior. As an exploratory study, ours would be the first to examine behavioral outcomes in offspring in relation to maternal sex steroid polymorphisms. While the effects may be modest, even a 5-point shift in the distribution of BASC scores for all males could significantly increase the proportion of boys that fall beyond the cut-off for clinical disorders such as ADHD.

  • Read and download the full study (free access) Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring, on the NCBI, PubMed, PMC3335953, 2013 Jun 1.
  • Image credit NASA gsfc.
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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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