Prenatal and postnatal hormone effects on the human brain and cognition

Abstract This review examines the role of hormones in the development of social and nonsocial cognition and the brain. Research findings from human studies designed to elucidate the effects of both prenatal and postnatal exposure to hormones in children and young adults are summarized. Effects are found to be both time and dose dependent, with exposure to abnormal hormone levels having a limited impact outside the "critical window" in development. Particular attention is given to the role of prenatal hormone exposure, which appears to be vital for early organization of the brain. In later life, measurements of circulating hormone levels and the administration of testosterone and oxytocin are found to predict behavior, but the effect is thought to be one of "activation" or "fine-tuning" of the early organization of the brain. Possible directions for valuable future research are discussed. Keywords Prenatal testosterone . Postnatal testosterone . Testosterone administration . Oxytocin . Sex differences . Amniotic fluid . Amniocentesis . Puberty Hormones are some of the most important chemicals that our bodies manufacture. They are the messengers that we use to regulate and control virtually all our physiological processes, from metabolism (e.g., adrenaline, insulin) to activation of the immune system (e.g., erythropoietin) and the regulation of mood (e.g., oxytocin). They are also essential in the processes of reproduction (e.g., testosterone, estrogen), and growth and development (e.g., somatotropin) Animal studies on the effects of hormones have been conducted for over half a century and provide some of the clearest evidence for the role of various hormones in our bodies. In particular, manipulation of glands producing particular hormones can have startling effects on physical development as well as later behavior (e.g., While the effects of testosterone on nonhuman mammal sexual behavior have been extensively studied, there is now increasing evidence that this and other hormones also have a substantial effect on aspects of human social and emotional behavior The timing of hormonal effects is crucial when studying lasting effects on development. There are generally thought to be two types of hormonal effects: organizational and activational Animal research has indicated that the critical period for sexual differentiation of the brain occurs when differences in serum testosterone are highest between sexes In addition to the fetal surge, two other periods of elevated testosterone have been observed in typical males. The first takes place shortly after birth and reaches a peak when the child reaches approximately 3-4 months Prenatal hormone effects in humans Studies in clinical conditions Some naturally occurring clinical conditions render the human hormone environment abnormal. As we consider artificial manipulation of the hormone environment during critical periods of development to be unethical, such conditions are a natural starting point for evaluating the impact of androgens and other hormones on development. One such condition is congenital adrenal hyperplasia (CAH), a genetic disorder which causes excess adrenal production of androgen hormones (including testosterone and other hormones thought to be responsible for the development of masculinizing features) beginning prenatally in both males and females Studies of individuals with CAH have generally found that girls with the condition show masculinization of behavioral performance in activities such as spatial orientation, visualization, targeting, personality, cognitive abilities, and sexuality While CAH provides an opportunity to investigate the effects of additional androgen exposure, the relatively rare occurrence of CAH makes it difficult to obtain large-enough groups for generalization of research findings to the wider population. Researchers have also suggested that CAHrelated disease characteristics, rather than prenatal androgen exposure, could be responsible for the atypical cognitive profiles observed in this population Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and affects an estimated 1 in 15 women worldwide. It is a heterogeneous disorder generally characterized by disruption of the ovulation cycle, a number of small cysts around the edge of their ovaries (polycystic ovaries), and excessive production and/or secretion of androgens (masculinizing hormones) referred to as "hyperandrogenism" Studies using amniotic fluid measurements Amniocentesis is the process of extracting a sample of amniotic fluid during the second trimester of pregnancy to detect clinical abnormalities in mothers thought to be at risk. Amniocentesis is typically performed during a relatively narrow time window which is thought to coincide with the hypothesized critical period for human sexual differentiation (between approximately weeks 8 and 24 of gestation, see A number of studies have linked elevated levels of FT in the amniotic fluid with the masculinization of certain behaviors, beginning shortly after birth. In particular, the Cambridge Child Development Project is an ongoing longitudinal study investigating the relationship between prenatal hormone levels and the development of later behaviors [15, Eye contact at 12 months Reduced eye contact is a characteristic common in children with autism [96, Vocabulary size at 18-24 months Another study of 87 children focused on the relationship between vocabulary size in relation to FT and estradiol levels from amniocentesis. Vocabulary size was measured at both 18 and 24 months of age using the Communicative Development Inventory, a self-administered checklist of words for parents to complete Autistic traits in toddlers at 18-24 months Autism spectrum conditions (ASCs) are a group of related conditions characterized by impairments in reciprocal social interaction and communication, alongside strongly repetitive behaviors and unusually narrow interests The Q-CHAT questionnaire was administered to mothers who had also undergone amniocentesis, providing measurements of FT level and fetal estradiol (FE)-a second hormone which forms prenatally from testosterone and is considered to be the most biologically active estrogen The relationship between FT and Q-CHAT score was also visible within the subset of children who participated in the follow-up study measuring PT levels at 3-4 months. However, no relationships between FE, PT levels, and Q-CHAT scores were observed. In addition, FE and PT levels showed no sex differences or relationships with FT levels Use of mental and affective language at 4 years The Cambridge Child Development study has also completed much longer-term studies, with participants recruited at amniocentesis being followed up 4-5 years after birth. This has provided the opportunity to establish a much greater understanding of how FT levels could affect behavioral development in later life. Thirty-eight children completed a "moving geometric shapes" task at age 4. The children were asked to describe cartoons with two moving triangles whose interaction with each other suggested social relationships and psychological motivations Social relationships and narrow interests at age 4 years A separate follow-up study at 4 years of age utilized the Children's Communication Checklist-a questionnaire designed to screen for communication difficulties in children 4-16 years of age Levels of FT were also associated with a subscale for narrower interests when the sexes were combined and also within boys Gender-typical play at 6-9 years At 6-9 years of age, the children from the Cambridge Child Development Project were followed up using the PreSchool Activities Inventory (PSAI). This is a standardized questionnaire measure of gender-typical play in both boys and girls. The PSAI includes 24 items and is completed by a parent to describe the child's behavior. Higher scores reflect more male-typical behavior, and females with CAH obtain elevated (more male-typical) scores in the PSAI [72], suggesting sensitivity to the effects of prenatal androgen exposure. A significant relationship was found between FT levels and sexually differentiated play behavior in both girls and boys Gender-role behavior at 6-9 years The Bem Sex Role Inventory (BSRI) is a questionnaire developed to measure feminine and masculine personality traits on the basis of cultural definitions of sex-typed social desirability many times a day a few times a day a few times a week less than once a week never • How easy is it for you to get eye contact with your child? very easy quite easy quite difficult very difficult impossible BSRI when boys and girls were examined together and when girls were examined alone. No relationships were found between FT levels and scores in the femininity scale. Within-sex results suggest that girls exposed to higher testosterone levels in utero are perceived as exhibiting more masculinized behavior Mind reading at 6-9 years Results from this study revealed a significant negative correlation with FT-with higher levels predicting lower mind reading capability. Within-sex analyses revealed a significant negative correlation between FT and the eyes test within both the boys' and girls' groups Empathy and systemizing at 6-9 years Empathy has been described as the drive to identify another person's emotions and thoughts and to respond to these appropriately Systemizing has been defined as the drive to analyze, explore, and construct a system The Cambridge Child Development study has developed parental questionnaires to assess a child's capability in the above dimensions: the Empathy Quotient (EQ-C) and Systemizing Quotient (SQ-C). These questionnaires are based on similar versions for adolescents and adults, which have consistently identified significant differences between males and females Girls generally scored higher than boys on the EQ-C at ages 6-8 years. When scores were compared with prenatal measurements of FT, a significant negative correlation between FT levels and EQ-C score was observed when the sexes were combined and also within boys Results for the SQ-C showed that boys scored significantly higher than girls on this scale. A significant positive association was found between SQ-C and FT levels when boys and girls were examined together. When sexes were examined together, the only significant predictor was FT. Sex was not included in the final regression model, suggesting that FT levels could play a greater role than the child's sex in terms of differences in systemizing preference The dimensions of Empathizing and Systemizing are also useful to our understanding of autism. Administration of a wide variety of tasks measuring the ability to empathize has demonstrated that individuals with an ASC are much weaker in this area. Conversely, there is some evidence that some individuals with an ASC are better at tasks that involve systemizing. Autistic traits at 6-9 years of age In order to further evaluate the potential effects of prenatal exposure to testosterone on the development of autistic behaviors in later life, FT measurements were directly evaluated against a child's score on the Childhood Autism Spectrum Test (CAST) FT levels were positively associated with higher scores (indicating greater number of autistic traits) on both the CAST and the AQ-Child. For the AQ-Child, this relationship was seen within both the male and female groups as well as when the sexes were combined, suggesting that this is an effect of FT rather than an effect of sex. The relationship between CAST scores and FT was also seen within boys, but not girls Summary of the Cambridge Child Development Projec