Estrogen masculinizes neural pathways and sex-specific behaviors
Open accessAbstract
Sex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate extensive sexual dimorphism in the number and projections of aromatase-expressing neurons. The masculinization of these cells is independent of AR but can be induced in females by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.
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The appetitive and consummatory aspects of sex are regulated by gonadal steroids (estrogen, progesterone, testosterone) as well as by OT, DA, and AVP.
“The appetitive and consummatory aspects of sex are regulated by gonadal steroids (estrogen, progesterone, testosterone) as well as by OT, DA, and AVP [51,119,120,121,122].”
From The Neurobiology of Love and Pair Bonding from Human and Animal Perspectives (2023) · cites this paper as [121]
The Introduction states that testosterone and estrogen are required for male sexual behaviors, and the Results describe estrogen and progesterone injections used to induce estrus in female mice. The paper does not establish that OT, DA, and AVP regulate sex, or frame its findings as regulation of both appetitive and consummatory aspects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIf the brain is exposed to testosterone either from its own testes in males or from an exogenous source in females, it will be masculinized.
“If the brain is exposed to testosterone either from its own testes in males or from an exogenous source in females, it will be masculinized [59–64].”
From Sex differences in metabolic homeostasis, diabetes, and obesity (2015) · cites this paper as [64]
The Results report that testosterone given to neonatal females masculinized aromatase-expressing neural pathways; the Discussion links the neonatal testosterone surge in males to increased brain estrogen through aromatization. The claim is broader than these findings: it does not limit exposure to the neonatal period or masculinization to the pathways studied. The Discussion also reports that adult estrogen administration did not masculinize those neurons or behavior. Page numbers were not supplied for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEarly exposure to estradiol induces masculinization/defeminisation.
“Note that, early exposure to estradiol induces masculinization/defeminisation (280, 281).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [281]
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References 68 · Cited by 404
- Authors
- Wu, M. V., Manoli, D. S., Fraser, E. J., Coats, J. K., Tollkuhn, J., Honda, S.-I., Harada, N., & Shah, N. M.
- Affiliations
- University of California, San Francisco (US)
- Fujita Health University (JP)
- Corresponding author
- Shah, Nirao M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 139
- Issue
- 1
- Pages
- 61-72
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2851224
- OpenAlex
- W2120119174
- Cited by
- 404
- References
- 68
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 22 · 2023: 25 · 2022: 28 · 2021: 27 · 2020: 22 · 2019: 27 · 2018: 39 · 2017: 27 · 2016: 20 · 2015: 20 · 2014: 21 · 2013: 25 · 2012: 13
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS049488)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- aromatase, estrogen, testosterone, androgen receptor, sexual differentiation of the brain, sexual dimorphism, neural circuit development, male aggression, urine marking, territoriality, neonatal estrogen exposure
- MeSH terms
- Animals, Animals, Newborn, Aromatase, Brain, Cell Survival, Estrogens, Female, Male, Neural Pathways, Neurons, Receptors, Androgen, Sexual Behavior, Animal, Sex Characteristics, Territoriality, Mice
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