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Cited by 728Sexual Differentiation and DisordersGenetic and Clinical Aspects of Sex Determination and Chromosomal AbnormalitiesSex and Gender in Healthcare

Reframing sexual differentiation of the brain

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McCarthy, Margaret M, Arnold, Arthur P·2011·Nature Neuroscience
DOI 10.1038/nn.2834PMC PMC3165173
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Abstract

In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.

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Crossref · 10.1038/nn.2834

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  • Perinatal testosterone treatment of females defeminizes the brain and prevents adult female reproductive behaviors.

    “In the rodent, the absence of testosterone during a critical perinatal period results in the expression of the default program of the brain, which is female-like (McCarthy & Arnold, 2011), whereas perinatal treatment of females with testosterone will defeminize the brain and prevent the expression of female reproductive behaviors in adulthood.”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as McCarthy & Arnold, 2011

    The citation is attached to the first clause, about a female-like brain developing without perinatal testosterone, rather than to the later claim about testosterone treatment. The “Classic model: hormone-mediated organization/activation” section describes testosterone’s developmental masculinizing effects, but the “Parallel hormonal effects on diverse pathways and circuits” section says estradiol is required for normal female brain development. The source therefore does not support describing female brain development simply as a default program. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • In rodents, absence of testosterone during a critical perinatal period leads to expression of the default female-like brain program.

    “In the rodent, the absence of testosterone during a critical perinatal period results in the expression of the default program of the brain, which is female-like (McCarthy & Arnold, 2011), whereas perinatal treatment of females with testosterone will defeminize the brain and prevent the expression of female reproductive behaviors in adulthood.”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as McCarthy & Arnold, 2011

    The 'Classic model: hormone-mediated organization/activation' section says embryonic testosterone masculinizes the brain, and the paper describes a perinatal period of hormonal sensitivity. But 'Parallel hormonal effects on diverse pathways and circuits' says estradiol is required for normal female brain development, so the source does not support describing female-like development as simply a default program expressed in testosterone's absence. No page numbers are available in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The masculinizing effects of steroids are region-specific and diverse, ranging from epigenetic modifications to cell genesis, cell death, synaptogenesis, synaptic pruning, axonal and dendritic growth and branching, myelination, and neurochemical phenotype.

    “The masculinizing effects of steroids are region-specific and quite diverse, ranging from epigenetic modifications to cell genesis, cell death, synaptogenesis, synaptic pruning, axonal and dendritic growth and branching, myelination, and neurochemical phenotype (McCarthy & Arnold, 2011).”

    From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as McCarthy & Arnold, 2011

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The study of sex differences in the brain has revealed similarities and dissimilarities in neuronal development mechanisms between the sexes.

    “The study of sex differences in the brain has unveiled similarities and dissimilarities in the mechanism of neuronal development between sexes (Amateau & McCarthy, 2004; McCarthy & Arnold, 2011; Schwarz, Liang, Thompson, & McCarthy, 2008).”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as McCarthy & Arnold, 2011

  • Estrogen can exert an organizational effect on CNS and behavior in higher vertebrates during early stages of development.

    “It is well known that estrogen can exert an organizational effect on CNS and behavior in higher vertebrates during the early stages of development see [8–10].”

    From Developmental exposure to low levels of ethinylestradiol affects social play in juvenile male rats (2020) · cites this paper as [10]

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Research works printed but not linked: 84

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Cited by

Sorted by citations

Authors
McCarthy, M. M., & Arnold, A. P.
Affiliations
  • University of Maryland, Baltimore (US)
  • University of California, Los Angeles (US)
Corresponding author
McCarthy, Margaret M
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2011-05-25
Volume
14
Issue
6
Pages
677-683
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2834
PMC
PMC3165173
OpenAlex
W2057987333
Cited by
728
References
7
Citations by year
2026: 28 · 2025: 34 · 2024: 46 · 2023: 30 · 2022: 82 · 2021: 54 · 2020: 62 · 2019: 51 · 2018: 40 · 2017: 40 · 2016: 64 · 2015: 38 · 2014: 54 · 2013: 54 · 2012: 44
FWCI
4.62
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R29MH052716, MH 52716, R01MH052716)
  • National Institute on Deafness and Other Communication Disorders (DC 000217, R01DC000217)
  • National Institute of Neurological Disorders and Stroke (NS050525, NS 043196, R01NS043196, R56NS050525, R01NS050525)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Keywords
sexual differentiation of the brain, sex differences, gonadal hormones, genetic sex, serial model, brain regions, molecular pathways
MeSH terms
Animals, Brain, Female, Humans, Male, Models, Biological, Neural Pathways, Sex Differentiation, Sexual Development

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