The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation
Open accessAbstract
Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity.
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Together, the coordinated actions of both androgens and estrogens are necessary for complete masculinization of the brain and behavior in rodents.
“Together, the coordinated actions of both androgens and estrogens are necessary for complete masculinization of the brain and behavior in rodents (McCarthy, 2008; Zuloaga et al., 2008).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Zuloaga et al., 2008
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“Guided by observations that ASDs emerge 12 early in life and are substantially more prevalent among males(3), and that males typically score 13 lower than females in tests of cognitive empathy [6], the EMB hypothesis proposes that elevated 14 prenatal exposure to the sex steroid testosterone causes impairments in cogn…”
MethodSakamoto, H., Takanami, K., Zuloaga, D. G., Matsuda, K.-I., Jordan, C. L., Breedlove, S. M., & Kawata, M. (2009) · Endocrinology · doi:10.1210/en.2008-1791 · Cited by 48 · see citing works
“01), confirming several reports that T levels in Tfm male rats are similar to that of Wt males (29).”
ResultSelf-citationIdentification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer
Heemers, H. V., Schmidt, L. J., Sun, Z., Regan, K. M., Anderson, S. K., Duncan, K., Wang, D., Liu, S., Ballman, K. V., & Tindall, D. J. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2512 · Cited by 43 · see citing works
“Independent Gene Ontology Analysis of the probe sets which are expressed differentially between benign and malignant prostate tissues confirmed involvement in musculature and central nervous system (data not shown), both systems in which SRF and AR have been shown to fulfill indispensable roles (47, 48).”
Ayurvedic Genomics, Constitutional Psychology, and Endocrinology: The Missing Connection
Rizzo-Sierra, C. V. (2011) · Journal of Alternative and Complementary Medicine · doi:10.1089/acm.2010.0412 · Cited by 43 · see citing works
“Even though androgens are potentially brain modifiers, identifying and quantifying which alterations are due to androgens or estrogens have been very difficult to measure, although some studies now indicate that androgens by themselves do alter the cerebral structure.(14) Since reproduction is a very relevant function…”
Chin, Y.-T., Yang, S.-H., Chang, T.-C., Chun, C.-G. A., Lai, H.-Y., Fu, E., HuangFu, W.-C., Davis, P., Lin, H.-Y., & Liu, L. F. (2015) · OncoTarget · doi:10.18632/oncotarget.5482 · Cited by 42
“They are the precursor hormones for estrogen biosynthesis in the ovaries and extragonadal tissues [2] and also function directly via androgen receptors (ARs) throughout the body [3].”
McCarthy, M. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-397025-1.00196-2 · Cited by 52 · see citing works
Neuroendocrine underpinning of social recognition in males and females
Aspesi, D., & Choleris, E. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13070 · Cited by 41 · see citing works
Bramble, M. S., Roach, L., Lipson, A., Vashist, N., Eskin, A., Ngun, T. C., Gosschalk, J. E., Klein, S. D., Barseghyan, H., Arboleda, V. A., et al. (2016) · Scientific Reports · doi:10.1038/srep36916 · Cited by 54 · see citing works
Androgen action in the brain and spinal cord for the regulation of male sexual behaviors
MATSUDA, K., Sakamoto, H., & KAWATA, M. (2008) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2008.08.010 · Cited by 40 · see citing works
“However, it was demonstrated that AR deficient mice and testicular feminization mutation mice and rats that produce a nonfunctional AR protein showed impaired male sexual behavior [15,16], suggesting that androgen signaling through AR is also involved in brain masculinization in rodents.”
BackgroundJuster, R., Almeida, D. M., Cardoso, C., Raymond, C., Johnson, P. J., Pfaus, J. G., Mendrek, A., Duchesne, A., Pruessner, J. C., & LUPIEN, S. J. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.06.011 · Cited by 40 · see citing works
“- S. 119-130 https://dx.doi.org/10.1016/j.psyneuen.2016.06.011 ship between androgens, the masculinization of the rodent brain, and sexual behavior (Zuloaga et al., 2008).”
InfluentialJovanović, H., Kocoska-Maras, L., Rådestad, A., Halldin, C., Borg, J., Hirschberg, A., & Nordström, A. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2014.11.003 · Cited by 40 · see citing works
Bobotis, B. C., Braniff, O., Gargus, M., Akinluyi, E. T., Awogbindin, I. O., & Tremblay, M.-È. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110752 · Cited by 40 · see citing works
Jahan, M. R., Kokubu, K., Islam, M. N., Matsuo, C., Yanai, A., Wroblewski, G., Fujinaga, R., & Shinoda, K. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.003 · Cited by 40 · see citing works
“…as determined by immunohistochemistry remains incomplete (Sheng et al., 2004; Karatsoreos et al., 2011); in spite of that mice have become an increasingly valuable species in terms of availability for transgenic or KO models (Zuloaga et al., 2008b; Raskin et al., 2009; Marie-Luce et al., 2013).”
InfluentialExceptional endocrine profiles characterise the meerkat: sex, status, and reproductive patterns
Davies, C. S., Smyth, K. N., Greene, L., Walsh, D. A., Mitchell, J., Clutton-Brock, T., & Drea, C. (2016) · Scientific Reports · doi:10.1038/srep35492 · Cited by 37 · see citing works
Mendell, A. L., Atwi, S., Bailey, C. D. C., McCloskey, D., Scharfman, H., & MacLusky, N. (2016) · Brain Structure and Function · doi:10.1007/s00429-016-1237-6 · Cited by 37 · see citing works
“While the neural basis of these differences remains uncertain (Miller and Halpern 2014), analogous differences exist in experimental animals and a contribution from gonadal hormones thus seems likely (Bachevalier and Hagger 1991; Zuloaga et al. 2008).”
High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice
Raznahan, A., Probst, F. J., Palmert, M. R., Giedd, J. N., & Lerch, J. P. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.07.052 · Cited by 39 · see citing works
“…mice is caused by reduced PAR gene dosage in XO relative to XX mice, then the greater BNST volume in XY vs. XX mice – which both carry two copies of each PAR gene – can be wholly attributed to well described androgenic mechanisms for BNST volume enhancement in XY vs. XX mice (Zuloaga et al., 2008).”
BackgroundInfluentialMembrane androgen receptors may mediate androgen reinforcement
Sato, S. M., Johansen, J. A., Jordan, C. L., & Wood, R. I. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.01.007 · Cited by 39 · see citing works
“Male Tfm rats exhibit an external female phenotype due to insufficient androgenic stimulation during development (Zuloaga et al., 2008b).”
Self-citationBuskens, V., Raub, W., van Miltenburg, N., Montoya, E. R., & van Honk, J. (2016) · Scientific Reports · doi:10.1038/srep27655 · Cited by 35 · see citing works
Developmental origins of sex differences in the neural circuitry of play
VanRyzin, J. W., Marquardt, A. E., & McCarthy, M. M. (2020) · International Journal of Play · doi:10.1080/21594937.2020.1723370 · Cited by 34 · see citing works
Polymorphisms in sex steroid receptors: From gene sequence to behavior
Maney, D. L. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.07.003 · Cited by 38 · see citing works
“…represented one of the only animal models in which the role of AR in a behavior could be tested; they were found to differ from wild-type animals with respect to spatial memory, anxiety-related behavior, aggression, social investigation and vocalization behavior (reviewed by Zuloaga et al., 2008).”
BackgroundSex Steroids and the Organization of the Human Brain
Peper, J. S., & Koolschijn, P. C. M. P. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1012-12.2012 · Cited by 32 · see citing works
“For example, high levels of fetal testosterone (FT) result in brain masculinization in experimental animals, such as enlargements of the volume and soma size of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and ventromedial hypothalamus (Zuloaga et al., 2008).”
BackgroundBandini, E., Corona, G., Ricca, V., Fisher, A. D., Lotti, F., Sforza, A., Faravelli, C., Forti, G., Mannucci, E., & Maggi, M. (2009) · The Journal of Sexual Medicine · doi:10.1111/j.1743-6109.2009.01322.x · Cited by 36 · see citing works
Zuloaga, D. G., Jordan, C. L., & Breedlove, S. M. (2011) · Endocrinology · doi:10.1210/en.2010-1016 · Cited by 33 · see citing works
Self-citationImpacts of Pollutants on Beavers and Otters with Implications for Ecosystem Ramifications
Peterson, E. K., & Schulte, B. A. (2016) · Journal of Contemporary Water Research & Education · doi:10.1111/j.1936-704x.2016.03212.x · Cited by 32 · see citing works
“Reductions in male reproductive organs can potentially feminize males, inducing changes in cognitive processing, stress responses, sexual behaviors, and territorial behaviors, as shown in research in mammalian model systems (von Saal et al. 1995; Zuloaga et al. 2008).”
Keeley, R. J., Trow, J., & McDonald, R. J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.024 · Cited by 33 · see citing works
Sheng, J. A., Tan, S. M. L., Hale, T. M., & Handa, R. J. (2021) · Androgens Clinical Research and Therapeutics · doi:10.1089/andro.2021.0021 · Cited by 30 · see citing works
“the brain and development of sex differences in behavior and hormone release during development.(12) T is”
The Prenatal Hormone Milieu in Autism Spectrum Disorder
Worsham, W., Dalton, S., & Bilder, D. A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.655438 · Cited by 29 · see citing works
“The “aromatization” hypothesis proposes that the roles of estradiol and testosterone in fetal neurodevelopment are intertwined (161), as masculinization of the rodent fetal brain is dependent upon the conversion of testosterone to estradiol by the enzyme aromatase (162, 163).”
BackgroundWei, Y., Han, C., Li, S.-Y., Cui, Y.-Q., Bao, Y.-Z., & Shi, W.-Y. (2020) · Food & Function · doi:10.1039/c9fo02770j · Cited by 29 · see citing works
Androgenic mechanisms of sexual differentiation of the nervous system and behavior
Swift‐Gallant, A., & Monks, D. A. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.04.003 · Cited by 32 · see citing works
Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior.
Swift-Gallant, A., Coome, L. A., Ramzan, F., & Monks, D. A. (2016) · Endocrinology · doi:10.1210/en.2015-1355 · Cited by 28 · see citing works
Brain–spinal cord neural circuits controlling male sexual function and behavior
Sakamoto, H. (2011) · Neuroscience Research · doi:10.1016/j.neures.2011.11.002 · Cited by 29 · see citing works
Prenatal Flutamide Enhances Survival in a Myogenic Mouse Model of Spinal Bulbar Muscular Atrophy
Johansen, J., Troxell-Smith, S. M., Yu, Z.-G., Mo, K., Monks, D., Lieberman, A. P., Breedlove, S., & Jordan, C. L. (2010) · Neurodegenerative Diseases · doi:10.1159/000313682 · Cited by 28
Self-citationComparative neuroimaging of sex differences in human and mouse brain anatomyPreprint
Guma, E., Beauchamp, A., Liu, S., Levitis, E., Ellegood, J., Pham, L., Mars, R., Raznahan, A., & Lerch, J. (2023) · bioRxiv · doi:10.1101/2023.08.23.554334 · Cited by 27 · see citing works
“This species difference aligns with evidence that gonadal steroids masculinize the mouse brain via activation of the estrogen E2 receptor by aromatized testosterone, whereas the masculinizing effects of gonadal steroids on the primate brain are more dependent on direct activation of the androgen receptor by testostero…”
BackgroundCorbin, C. J., Berger, T., Ford, J. J., Roselli, C. E., Sienkiewicz, W., Trainor, B. C., Roser, J. F., Vidal, J. D., Harada, N., & Conley, A. J. (2009) · Biology of Reproduction · doi:10.1095/biolreprod.109.076331 · Cited by 29 · see citing works
“This has potentially important implications for sexual differentiation of the brain, which is increasingly recognized to be influenced by androgenic and estrogenic organization [18].”
BackgroundRaznahan, A., Lue, Y., Probst, F. J., GREENSTEIN, D. K., Giedd, J. N., Wang, C., Lerch, J. P., & Swerdloff, R. S. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0875-9 · Cited by 28 · see citing works
“Some of these XXY-XY differences fall within known sites of androgen-sensitive sexual dimorphism such as the BNST and amygdala (Zuloaga et al. 2008; Wu et al. 2009)—suggesting that although the XXY karyotype does not ablate normative volumetric masculinization of the mouse brain, it can interfere…”
Androgen regulation of behavioral stress responses and the hypothalamic-pituitary-adrenal axis
Zuloaga, D. G., Lafrican, J. J., & Zuloaga, K. L. (2024) · Hormones and Behavior · doi:10.1016/j.yhbeh.2024.105528 · Cited by 29 · see citing works
Self-citationKarlsson, S. A., Studer, E., Kettunen, P., & Westberg, L. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00041 · Cited by 26 · see citing works
- Authors
- Zuloaga, D. G., Puts, D. A., Jordan, C. L., & Breedlove, S. M.
- Affiliations
- Michigan State University (US)
- Pennsylvania State University (US)
- Corresponding author
- Zuloaga, Damian G.
- Venue
- Hormones and Behavior
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 53
- Issue
- 5
- Pages
- 613-626
- ISSN
- 0018-506X (ISSN-L)
- PMC
- PMC2706155
- OpenAlex
- W1990168204
- Cited by
- 236
- References
- 0
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 16 · 2022: 15 · 2021: 10 · 2020: 15 · 2019: 9 · 2018: 9 · 2017: 16 · 2016: 17 · 2015: 18 · 2014: 12 · 2013: 13 · 2012: 12
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hormones and Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (F31MH078273, F31 MH78273)
- National Institute of Neurological Disorders and Stroke (R01NS028421, R01-NS28421, R01NS045195)
- 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
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- androgen receptor, aromatase, estrogen receptor, sex differences in brain, sexual behavior, stress response, cognitive processes, androgen insensitivity syndrome, brain development
- MeSH terms
- Aggression, Animals, Behavior, Animal, Brain, Female, Feminization, Humans, Male, Mutation, Receptors, Androgen, Sex Differentiation, Social Behavior
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