This 2014 review is not intended to be prescriptive but, instead, is a guide for further study
The prenatal brain develops under the influence of an ever-changing hormonal milieu that includes endogenous fetal gonadal and adrenal hormones, placental and maternal hormones, and exogenous substances with hormonal activity that can cross the placental barrier. This review discusses the influences of endogenous fetal and maternal hormones on normal brain development and potential consequences of pathophysiological hormonal perturbations to the developing brain, with particular reference to autism. We also consider the effects of hormonal pharmaceuticals used for assisted reproduction, the maintenance of pregnancy, the prevention of congenital adrenal hypertrophy, and hormonal contraceptives continued into an unanticipated pregnancy, among others. These treatments, although in some instances life-saving, may have unintended consequences on the developing fetuses. Additional concern is raised by fetal exposures to endocrine-disrupting chemicals encountered universally by pregnant women from food/water containers, contaminated food, household chemicals, and other sources. What are the potential outcomes of prenatal steroid perturbations on neurodevelopmental and behavioral disorders, including autism-spectrum disorders? Our purposes here are
- to summarize some consequences of steroid exposures during pregnancy for the development of brain and behavior in the offspring;
- to summarize what is known about the relationships between exposures and behavior, including autism spectrum disorders;
- to discuss the molecular underpinnings of such effects, especially molecular epigenetic mechanisms of prenatal steroid manipulations, a field that may explain effects of direct exposures, and even transgenerational effects;
- and for all of these, to add cautionary notes about their interpretation in the name of scientific rigor.
Exogenous hormones, environmental EDCs, and the developing brain
Both natural and xenobiotic hormones can reach the fetus through placental transfer. Although this concept is widely accepted in humans today, it was only first acknowledged in the early 1960s when severe developmental malformations of infants were linked to maternal use of thalidomide, usually for insomnia, anxiety, or nausea during the first trimester of gestation. In the case of hormonal pharmaceuticals, one of the most compelling and tragic examples of misuse is that of diethylstilbestrol (DES), a potent estrogen prescribed to an estimated 5 to 10 million women in the United States alone, with the intention of averting miscarriage. Ironically, DES was later found to be ineffective for this purpose, yet millions of infants were exposed. Although as infants, these exposed individuals appeared normal from external observation, with the exception of some cases of cryptorchidism in boys, a host of reproductive tract deformities, disorders, and rare cancers were diagnosed later in life, especially, although not exclusively, in females.
Although DES is no longer prescribed to pregnant women, a large number of hormonal pharmaceuticals are currently given to women undergoing assisted reproductive technologies or those with high-risk pregnancies. In addition, of the tens of millions of women who use oral contraceptives, close to half a million have unintended pregnancies. Some of these women, unaware that they are pregnant, continue oral contraceptive use well into the first trimester. These contraceptives typically include an estrogen, usually ethinyl estradiol, together with a progestin, or a progestin alone. Fortunately, doses of pharmaceutical estrogens and progestins have decreased significantly since the pill was first introduced half a century ago. Nevertheless, there is still no doubt that many fetuses continue to be unwittingly exposed to exogenous steroid hormones today, fortunately, mostly at lower concentrations than in the case of DES.
EDC actions: experimental animal studies and wildlife
Research in the last decade has revealed that developmental exposure to even low-level EDCs, especially in the fetus or infancy, can perturb normal brain maturation and subsequent functional outcomes in experimental laboratory animals, with effects on hypothalamic morphology and neuronal phenotypes. As reviewed previously, EDCs including dioxins, BPA, PCBs, and pesticides (methoxychlor), to name a few, cause changes to the developing brain in a sexually dimorphic and region-specific manner. For example, prenatal/perinatal EDCs change the volume of sexually dimorphic hypothalamic regions and affect neural phenotype (eg, expression of proteins or genes for specific receptors, neurotransmitters, and neuropeptides). The SDN-POA is a good example, as is the anteroventral periventricular nucleus, important for the control of ovulation and steroid feedback in females. These regions are altered in their size and volume, including neuron numbers, neurochemistry, and cellular phenotype, after exposures to prenatal EDCs such as PCBs. A common outcome of such exposures was masculinization or defeminization of the female hypothalamus, and demasculinization or feminization of this region in males. Beyond the hypothalamus, developmental EDC exposures also altered neural development. In hippocampus, cortex, amygdala, and brainstem, EDCs altered synaptic plasticity, neural development, and expression of genes and proteins in specific cellular populations. This developmental programming undoubtedly has implications for the subsequent manifestation of behaviors. This is best studied for reproductive behaviors, because the field of endocrine disruption has its roots in initial observations of reproductive failure as early as the 1962 publication of Rachel Carson’s Silent Spring, and much research into reproductive toxicological effects of EDCs has been published. Moreover, the roles of natural hormones in many nonreproductive behaviors implicate EDCs in perturbations of social behaviors, including complex neurodevelopmental disorders in humans, such as ASDs.
Hormones, Sexually Dimorphic Behaviors, and Autism and Autism-Spectrum Disorders
In general, the diagnosis of autism and ASDs in humans is based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) cardinal signs of autistic behavior: impaired social and communication skills, and restricted and/or repetitive behaviors . Other aspects of attention and cognitive profile associated with the autistic phenotype may also be considered in the diagnosis. For a more complete description of the autistic behavioral phenotype based on DSM-IV, see Supplemental Material (note that although DSM-V was recently released, research to date has been based on DSM-IV or earlier criteria). The fact that autism and ASD are approximately 4 times more prevalent in males than females and that Asperger’s syndrome (high-functioning ASD individuals with intact language) is 9 times more prevalent in males than females has led some to propose a role of androgens and/or their estrogenic metabolites in the development of autism. This extreme male brain theory of autism has been invoked to explain sex differences in prevalence due to higher prenatal androgens. However, this is highly controversial. For example, other hormones, including thyroid hormones, have been considered for their possible links to autism and ASDs. Genetic disorders, pathophysiological conditions, and pharmaceutical treatments resulting in changes in the hormonal milieu of the developing fetus have provided some insight into the roles of prenatal hormones, but again, there are some inconsistencies in the relationships between hormones, neurodevelopment, and the autistic phenotype.
Pharmaceutical progestins in pregnancy
Limited studies on behavioral outcomes after prenatal exogenous hormone exposure were reported in the 1970s and 1980s for treatment of pregnancies deemed to be at risk for early fetal loss, toxemia, and premature birth. Results showed an impact of these hormones on sexually dimorphic behaviors (eg, tomboyishness in girls) in the offspring, but little or no effects on cognition and no evidence of autistic features, although the studies at the time were not designed to seek autistic traits. Reinisch examined IQ and personality traits in late childhood after first-trimester gestational exposure to synthetic progestins and estrogens (most commonly Colprosterone, Norlutin, Delalutin, Deluteval, Provera, Provest, and DES), some with androgenizing effects, using unexposed siblings as controls. There was a high degree of variability in which hormones were used and their timing, dosing, and duration. No differences in IQ were found, but differences in personality were significant, with the high-progestin group more independent, individualistic, self-assured, self-sufficient, and sensitive. The high-estrogen group was more group-oriented and group-dependent. None of these children met existing criteria for any disorder, and none were thought to show autistic traits, but again, these were not specifically sought.
- Read and download the full study (free access) Implications of Prenatal Steroid Perturbations for Neurodevelopment, Behavior, and Autism, on the NCBI, PubMed, PMC4234775, 2014 Dec.
- Depiction of the many modes of exposure of a developing fetus to natural hormones or exogenous hormonally active pharmaceuticals and EDCs, image credit NCBI PMC4234775/figure/F1.