Sex Differences in Brain Function


Sex differences in the brain come in many sizes, shapes and forms. The most robust differences between males and females are not surprisingly those directly relevant to reproduction. The neural underpinnings controlling sex behaviour and control of gonadal function are establishing during a developmental sensitive period by the differential hormonal milieu found in males versus females. Considerable advances have been made in identifying the cellular mechanisms of early organizational effects of testosterone and its metabolite estradiol, which then determine adult physiology and behaviour. These mechanisms are highly region‐specific and impact on cell death, axonal projections and synaptogenesis, resulting in a brain that combines varying degrees of maleness and femaleness. The study of reproductive endpoints is not only valid in its own right but also provides insight into the more subtle sex differences associated with cognition, emotionality, social behaviour and relative risk of neurological disorders and diseases of mental health.

Key Concepts:

  • During development sex‐specific hormones organize the brain into a male or female phenotype which is then activated by hormones in adulthood.

  • The largest magnitude sex differences in the brain are in areas associated with control of reproduction.

  • Hormones regulate growth factors, cell death, cell genesis and synaptogenesis to build sexually dimorphic neural circuits.

  • There are multiple cellular mechanisms of hormonally mediated sexual differentiation which vary by brain region and endpoint.

  • Because of the myriad of mechanisms and the impact of environment and experience, ultimately every brain is a moasic of masculine and feminine in varying degrees.

Keywords: testosterone; estradiol; preoptic area; hypothalamus; sexual differentiation; glutamate; GABA; prostaglandins; synaptogenesis

Figure 1.

Organizational and activational phases of sexual differentiation of the brain. Sexual differentiation of the brain in rodents begins during a perinatal sensitive period when testosterone levels become elevated following active synthesis by the testis of the developing male. High testosterone gains access to the male brain where it is aromatised to estradiol within neurons and subsequently masculinises brain and behaviour. These early effects of hormones are considered organizational and will determine how the brain is activated in adulthood. Females do not have elevated testosterone and therefore the brain is organized into the feminine phenotype. If a female is treated with exogenous testosterone or estradiol during the sensitive period (black arrows), her brain will be masculinised and additional testosterone treatment in adulthood will activate male sexual behaviour. The offset of the sensitive period is defined by the lack of the ability of exogenous hormone treatment to masculinise the female brain (red arrow).

Figure 2.

Control of LH release from the pituitary is sexually differentiated. In adult females estradiol regulates the release of LH from the pituitary by a sequential combination of positive followed by negative feedback effects on GnRH neurons and LH synthesis, resulting in a mid‐cycle surge in LH release that is essential for ovulation. In adult males, the capacity for positive feedback effects of estradiol is lost due to steroid‐mediated sexual differentiation during the perinatal sensitive period. As a result, neither males nor females masculinised by exogenous steroid hormone treatment will exhibit an LH surge or ovulation.

Figure 3.

Estradiol induces a target‐derived diffusible growth factor. The size of the innervation of the anteroperiventricular nucleus (AVPV) by the bed nucleus of the stria terminalis (BNST) is significantly larger in males versus females. Studies by Rich Simerly and colleagues in which explants of the AVPV and the BNST were placed in a culture dish demonstrate that the estradiol induces the synthesis of a diffusible growth factor by the neurons of the AVPV which attracts the growing axons of the BNST. As a result, significantly more axons of male BNST neurons find their way to the AVPV and successfully innervate it, insuring the survival of the BNST neurons.

Figure 4.

Neurons of the POA are masculinised by prostaglandins. Within pre‐optic area (POA) neurons, testosterone derived from the testis is aromatised to estradiol and initiates a signalling cascade that begins with increased transcription of the cyclooxygenase enzymes (COX). The COX enzymes produce prostaglandin E2 (PGE2) from arachadonic acid. PGE2 is released from neurons and appears to have two principle actions. One is to induce release of glutamate from neighbouring astrocytes. The second is to active EP2 and EP4 receptors on the postsynaptic neuron. EP2 and EP4 are linked to adenlyl cyclase and the production of cAMP, which activates protein kinase A (PKA). PKA that is located close to the post‐synaptic density plays a critical role in the trafficking and anchoring of glutamate AMPA receptors to excitatory synapses located on dendritic spines. As a result, the formation and maintenance of dendritic spines synapses is stabilised. Convergent evidence is consistent with the working hypothesis that this combination of events involving two cell types and multiple signalling pathways is the basis for the 2–3 fold higher density of dendritic spine synapses on male POA neurons compared to female. These events occur during a perinatal sensitive period and positively correlate with the capacity to exhibit male sexual behaviour in response to the activational effects of testosterone in adulthood.

Figure 5.

The mature sexually differentiated brain is a mosaic. Steroid hormone‐induced sexual differentiation of the brain is mediated by multiple distinct regionally specific mechanisms and includes many diverse signalling cascades, neurotransmitter systems and steroid hormone receptors. As a result, there are many sources of variability introduced into the process for each brain region and the associated physiological and behavioural endpoints. Therefore from a conceptual standpoint it is appropriate to think of the brain as a mosaic of different regions with varying degrees of masculinisation and feminisation, the preponderance of which will be largely consistent with the overall sexual phenotype of the brain.



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Further Reading

Arnold AP (2003) The gender of the voice within: the neural origin of sex differences in the brain. Current Opinion in Neurobiology 13: 759–764.

Becker JB, Breedlove SM, Crews D and McCarthy MM (2002) Behavioral Endocrinology. Cambridge, MA: MIT Press.

Breedlove SM and Jordan CL (2001) The increasingly plastic, hormone‐responsive adult brain. Proceedings of the National Academy of Sciences of the USA 98: 2956–2957.

Hines M (2004) Brain Gender. New York: Oxford University Press.

McCarthy MM (2008) Estradiol and the developing brain. Physiological Reviews 88: 91–124.

McCarthy MM, de Vries GJ and Forger NG (2009) Sexual differentiation of the brain: mode, mechanisms and meaning. In: Pfaff DW, Etgen AM, Fahrbach SE and Rubin RT (eds) Hormones, Brain and Behavior, pp. 1707–1744. San Diego: Academic Press.

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McCarthy, Margaret M(Dec 2010) Sex Differences in Brain Function. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022344]