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The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation
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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 (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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Goddings, A., Mills, K. L., CLASEN, L. S., Giedd, J. N., Viner, R., & Blakemore, S. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.09.073 · Cited by 572
“The smaller increase and earlier peak in testosterone concentration in females compared withmales might explain the differences in trajectories between the two sexes, where the changes in neural structure that are seen are beingmodulated by systemic testosterone concentrations (Zuloaga et al., 2008).”
The genetics of sex differences in brain and behavior
Ngun, T. C., Ghahramani, N., Sánchez, F. J., Bocklandt, S., & Vilain, E. J. N. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.10.001 · Cited by 450
“Humans with Complete AIS are female-typical in their play behavior and sexual orientation [283].”
Backgroundvan Honk, J., Schutter, D. J. L. G., Bos, P. A., Kruijt, A., Lentjes, E. G. W. M., & Baron‐Cohen, S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011891108 · Cited by 332
“, in rodents, brain masculinization depends on circulating testosterone acting on AR receptors and conversely on testosterone converted by the enzyme aromatase into estradiol acting on estrogen receptors (32).”
BackgroundVanRyzin, J. W., Marquardt, A. E., Argue, K. J., Vecchiarelli, H. A., Ashton, S. E., Arambula, S. E., Hill, M. N., & McCarthy, M. M. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.006 · Cited by 272
Raznahan, A., Lee, Y., Stidd, R., Long, R., Greenstein, D., Clasen, L., Addington, A., Gogtay, N., Rapoport, J. L., & Giedd, J. N. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006025107 · Cited by 278
“Second, as far as we are aware, no one has ever longitudinally tested the hypothesis that nonhuman vertebrate models of androgen receptor–dependent structural masculinization of sexually dimorphic brain regions subserving sexually dimorphic behavior (12) also apply to humans.”
BackgroundLINE-1 retrotransposons: mediators of somatic variation in neuronal genomes?
Singer, T., McConnell, M. J., Marchetto, M. C., Coufal, N. G., & Gage, F. H. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.04.001 · Cited by 280
Juntti, S. A., Tollkuhn, J., Wu, M. V., Fraser, E. J., Soderborg, T., Tan, S., Honda, S.-I., Harada, N., & Shah, N. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.03.024 · Cited by 254
“Mice exhibit a large array of behavioral dimorphisms beyond sexual and territorial displays, and it will be important in future studies to determine whether AR function in the nervous system is essential for the appropriate display of such behaviors (Zuloaga et al., 2008a, 2008b).”
Sex differences in prenatal epigenetic programing of stress pathways
Bale, T. L. (2011) · Stress · doi:10.3109/10253890.2011.586447 · Cited by 249
“Recent evidence points to an additional important role of reduced testosterone to 5a-dihydrotestosterone (DHT) and binding of the androgen receptor in this process as well (Sato et al. 2004; Weinstock 2007; Bodo and Rissman 2008; Zuloaga et al. 2008).”
Sex Differences in Autism Spectrum Disorder: Diagnostic, Neurobiological, and Behavioral Features
Napolitano, A., Schiavi, S., Rosa, P. L., Rossi‐Espagnet, M. C., Petrillo, S., Bottino, F., Tagliente, E., Longo, D., Lupi, E., Casula, L., et al. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.889636 · Cited by 286
Sexual orientation and the second to fourth finger length ratio: A meta-analysis in men and women.
Grimbos, T., Dawood, K., Burriss, R. P., Zucker, K. J., & Puts, D. A. (2010) · Behavioral Neuroscience · doi:10.1037/a0018764 · Cited by 271
Self-citationSexual differentiation of the human brain in relation to gender identity and sexual orientation
Savic, I., Garcı́a-Falgueras, A., & Swaab, D. F. (2010) · Progress in brain research · doi:10.1016/b978-0-444-53630-3.00004-x · Cited by 191
“Other brain nuclei, such as the posteromedial amygdala, the ventromedial hypothalamus, and the locus coeru leus were, however, feminized in Tfm male rats (Morris et al., 2005; Zuloaga et al., 2008).”
BackgroundYou’ve got male: Sex and the microbiota-gut-brain axis across the lifespan
Jaggar, M., Rea, K., Spichak, S., Dinan, T. G., & Cryan, J. F. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100815 · Cited by 200
Swain, J., Perkins, S., Dayton, C., Finegood, E. D., & Ho, S. (2012) · Behavioral and Brain Sciences · doi:10.1017/s0140525x12000970 · Cited by 196
“Moreover, androgenic steroids and steroid-like compounds involved in embryonic brain development, stress responses, and behavior can induce L1 activity (Zuloaga et al. 2008).”
BackgroundThe neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination
Hussain, R., Ghoumari, A. M., Bielecki, B., Steibel, J., Boehm, N., Lière, P., Macklin, W. B., Kumar, N., Habert, R., Mhaouty‐Kodja, S., et al. (2013) · Brain · doi:10.1093/brain/aws284 · Cited by 189
“Because in AR Tfm mice the androgen receptor is non-functional in all tissues and males exhibit an abnormal reproductive phenotype with an altered endocrine status (Zuloaga et al., 2008), we examined the specific relevance of brain androgen receptor in testosterone-dependent myelin repair.”
BackgroundThe role of sex and gender socialization in stress reactivity.
Dedovic, K., Wadiwalla, M., Engert, V., & Pruessner, J. C. (2009) · Developmental Psychology · doi:10.1037/a0014433 · Cited by 162
Surprising origins of sex differences in the brain
McCarthy, M. M., Pickett, L. A., VanRyzin, J. W., & Kight, K. E. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.04.013 · Cited by 158
Duarte‐Guterman, P., Navarro‐Martín, L., & Trudeau, V. L. (2014) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2014.03.015 · Cited by 168
Brain sex matters: Estrogen in cognition and Alzheimer’s disease
Li, R., Cui, J., & Shen, Y. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.12.018 · Cited by 143
“Interestingly, the roles of testosterone in sex differentiation during brain development might be mediated by its metabolite estradiol, a conversion process catalyzed by neuronal aromatase [87].”
BackgroundShaping of the Female Human Brain by Sex Hormones: A Review
Rehbein, E., Hornung, J., Poromaa, I. S., & Derntl, B. (2020) · Neuroendocrinology · doi:10.1159/000507083 · Cited by 159
Matsuda, K., Mori, H., Nugent, B. M., Pfaff, D. W., McCarthy, M. M., & Kawata, M. (2011) · Endocrinology · doi:10.1210/en.2011-0193 · Cited by 142
Moore, A. M., Prescott, M., & Campbell, R. E. (2012) · Endocrinology · doi:10.1210/en.2012-1954 · Cited by 153
“Because previous comparisons of dendritic spine density between adult male and female mice revealed no sex differences (53), it appears that the present change does not reflect any masculinizing effects that could be attributed to prenatal DHT exposure (30).”
BackgroundHamson, D. K., Wainwright, S. R., Taylor, J., Jones, B. A., Watson, N. V., & Galea, L. A. M. (2013) · Endocrinology · doi:10.1210/en.2013-1129 · Cited by 128
Estrogen receptors and the aging brain
Maioli, S., Leander, K., Nilsson, P., & Nalvarte, I. (2021) · Essays in Biochemistry · doi:10.1042/ebc20200162 · Cited by 114
Visualising androgen receptor activity in male and female mice
Dart, D. A., Waxman, J., Aboagye, E. O., & Bevan, C. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071694 · Cited by 112
“the sexually dimorphic nucleus of the preoptic area and the anteroventral periventricular nucleus [38].”
BackgroundBordt, E. A., Ceasrine, A. M., & Bilbo, S. D. (2020) · Glia · doi:10.1002/glia.23753 · Cited by 125
Epigenetic impacts of endocrine disruptors in the brain
Walker, D. M., & Gore, A. C. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.09.002 · Cited by 94
“Like ERs, the AR plays a role in sexual differentiation of the brain and behavior [Reviewed in (Zuloaga et al., 2008)] and its actions as a transcription factor in development is thought to impart a “molecular memory” on its targets, presumably through epigenetic mechanisms [Reviewed in (Holterhus, 2011)].”
BackgroundNguyen, T., McCracken, J. T., Albaugh, M. D., Botteron, K. N., Hudziak, J. J., & Ducharme, S. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.09.021 · Cited by 97
Zuloaga, D. G., Heck, A., Guzman, R. M. D., & Handa, R. J. (2020) · Biology of Sex Differences · doi:10.1186/s13293-020-00319-2 · Cited by 99
“Therefore, studies performed in ARdeficient rodents in the past decade have been vital in confirming a critical role of AR in suppressing HPA axis reactivity [106, 108, 137, 138].”
BackgroundSelf-citationComparative Aspects of Pre‐ and Postnatal Development of the Male Reproductive System
Picut, C., Ziejewski, M. K., & Stanislaus, D. (2018) · Birth Defects Research · doi:10.1002/bdr2.1133 · Cited by 82
Chang, C., Yeh, S., Lee, S. O., & Chang, T. (2013) · Nuclear Receptor Signaling · doi:10.1621/nrs.11001 · Cited by 92
“Incidentally, Tfm male mice have been shown to have elevated corticosterone levels and increased stress indices suggesting hyperactivation of the hypothalamic-pituitary-adrenal axis [Zuloaga et al., 2008a].”
BackgroundZuloaga, D., Morris, J. A., Jordan, C. L., & Breedlove, S. (2008) · Hormones and Behavior · doi:10.1016/j.yhbeh.2008.08.004 · Cited by 81
“One model for exploring the role of the AR in the brain and behavior is testicular feminization mutant (Tfm) mice (Zuloaga et al., 2008).”
BackgroundSelf-citationThe Neural Mechanisms of Sexually Dimorphic Aggressive Behaviors
Hashikawa, K., Hashikawa, Y., Lischinsky, J. E., & Lin, D. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.07.001 · Cited by 92
Hormones of choice: the neuroendocrinology of partner preference in animals.
Henley, C., Nunez, A. A., & Clemens, L. G. (2011) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2011.02.010 · Cited by 80
“Tfm males have a dysfunctional androgen receptor [93] and display a female external phenotype due to a lack of androgenization during development.”
Microglia: Driving critical periods and sexual differentiation of the brain
VanRyzin, J. W., Pickett, L. A., & McCarthy, M. M. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22569 · Cited by 97
“Testosterone and its androgenic metabolites are able to sexually differentiate several endpoints in the brain; however, most are driven by estradiol synthesized from testosterone by the aromatase enzyme in the brain (McCarthy, 2008; Zuloaga et al., 2008).”
BackgroundAndrogen Receptors, Sex Behavior, and Aggression
Cunningham, R. L., Lumia, A. R., & McGinnis, M. Y. (2012) · Neuroendocrinology · doi:10.1159/000337663 · Cited by 85
Jordan, K., Fromberger, P., Stolpmann, G., & Müller, J. L. (2011) · The Journal of Sexual Medicine · doi:10.1111/j.1743-6109.2011.02393.x · Cited by 85
Early exposure to low doses of atrazine affects behavior in juvenile and adult CD1 mice
Belloni, V., Dessì-Fulgheri, F., Zaccaroni, M., Di Consiglio, E., De Angelis, G., Testai, E., Santochirico, M., Alleva, E., & Santucci, D. (2011) · Toxicology · doi:10.1016/j.tox.2010.07.002 · Cited by 74
Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors
VanRyzin, J. W., Marquardt, A. E., Pickett, L. A., & McCarthy, M. M. (2019) · Glia · doi:10.1002/glia.23740 · Cited by 84
Animal Homosexuality: A Biosocial Perspective
Poiani, A. (2010) · doi:10.5860/choice.48-4488 · Cited by 74
Sex and pain perception and analgesia.
Palmeira, C. C. D. A., Ashmawi, H. A., & Posso, I. (2011) · Revista Brasileira de Anestesiologia · doi:10.1016/s0034-7094(11)70091-5 · Cited by 73
Masculinization of the Mammalian Cochlea
McFadden, D. (2009) · Hearing Research · doi:10.1016/j.heares.2009.01.002 · Cited by 73
“…estrogen receptors as well because androgen can be aromatized into estradiol (a form of estrogen) in the brain, and estradiol is known to have strongly masculinizing effects in the brains of some mammals (e.g., Zuloaga et al., 2008), although apparently not in humans (see Wallen and Baum, 2002).”
Endocrinology of human female sexuality, mating, and reproductive behavior
Motta‐Mena, N. V., & Puts, D. A. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.11.012 · Cited by 89
“…likely organize sexual orientation, gender identity, and other psychobehavioral traits in humans specifically through binding to ARs in the brain (Zuloaga et al., 2008), rather thanaromatization and binding of estrogen to estrogen receptors (ERs), as in rodents (Bakker et al., 2006; Puts et al.,…”
BackgroundSelf-citationAndrogen Physiology, Pharmacology, and Abuse
Handelsman, D. J. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00138-4 · Cited by 54
The influence of sex-linked genetic mechanisms on attention and impulsivity
Trent, S., & Davies, W. (2011) · Biological Psychology · doi:10.1016/j.biopsycho.2011.09.011 · Cited by 62
Arambula, S. E., Jima, D. D., & Patisaul, H. B. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.10.005 · Cited by 71
Lateralised visual processing in domestic cattle herds responding to novel and familiar stimuli
Robins, A., & Phillips, C. (2010) · Laterality · doi:10.1080/13576500903049324 · Cited by 65
Langlois, V. S., Duarte‐Guterman, P., Ing, S., Pauli, B. D., Cooke, G. M., & Trudeau, V. L. (2009) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2009.11.004 · Cited by 66
Puts, D. A., Pope, L. E., Hill, A. K., Cárdenas, R. A., Welling, L. L. M., Wheatley, J. R., & Breedlove, S. M. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.01.006 · Cited by 76
“In nonhuman animals, androgens such as Tmediatemale-typical sociosexual behavior (Hart, 1974;Martin and Baum, 1986;Money and Ehrhardt, 1971; Xu et al., 2012; Yang and Shah, 2014; Zuloaga et al., 2008).”
BackgroundSelf-citationEpigenetic mechanisms are involved in sexual differentiation of the brain
Matsuda, K., Mori, H., & Kawata, M. (2012) · Reviews in Endocrine & Metabolic Disorders · doi:10.1007/s11154-012-9202-z · Cited by 61
“We note that it has recently been argued that androgen signaling via the androgen receptor also participates in brain masculinization in rodents [14, 15]; and in humans, testosterone mainly regulates masculinization of the brain independently of aromatization [8].”
BackgroundCruz, C. D., & Pereira, O. C. M. (2012) · The Journal of Physiological Sciences · doi:10.1007/s12576-011-0190-7 · Cited by 66
“becomes masculinized and defeminized [11].”
Androgen Decreases Dopamine Neurone Survival in Rat Midbrain
Johnson, M. L., Day, A. E., Ho, C. C., Walker, Q. D., Francis, R., & Kuhn, C. M. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.01965.x · Cited by 57
Zuloaga, D., Poort, J. E., Jordan, C. L., & Breedlove, S. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.07.008 · Cited by 56
“We previously investigated corticosterone responses and anxietyrelated behaviors in response to a mild stressor in wt male and Tfm male mice and found that a dysfunctional AR led to increases in both (Zuloaga et al., 2008b).”
InfluentialSelf-citationDevelopmental effects of androgens in the human brain
Nguyen, T. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12486 · Cited by 64
Postnatal exposure to low-dose bisphenol A influences various emotional conditions
Fujimoto, T., Kubo, K., Nishikawa, Y., & Aou, S. (2013) · The Journal of Toxicological Sciences · doi:10.2131/jts.38.539 · Cited by 49
“Recent reports suggested that not only the estrogen receptor but also androgen receptor was strongly related to the brain masculinization (Garcia-Falgueras et al., 2005; Zuloaga et al., 2008).”
BackgroundChen, C. V., Brummet, J. L., Lonstein, J. S., Jordan, C. L., & Breedlove, S. M. (2014) · Hormones and Behavior · doi:10.1016/j.yhbeh.2014.01.001 · Cited by 57
“To examine whether disabling AR via the Cre/Lox system produces effects on anxiety-like behavior comparable to that seen in sTfm mice (Zuloaga et al., 2008a), castrated WT and iTfm male mice with T or B capsules were tested for anxiety-related behavior on PN 90-120.”
InfluentialSelf-citationNguyen, T., Lew, J., Albaugh, M. D., Botteron, K. N., Hudziak, J. J., Fonov, V., Collins, D. L., Ducharme, S., & McCracken, J. T. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.12.005 · Cited by 66
“Previous investigations using experimental animal models have documented testosterone-related masculinization of limbic brain areas (Zuloaga et al., 2008), and we have previously documented limbic changes related to pubertal maturation in a large, longitudinal human sample (Hu et al., 2013).”
BackgroundInfluentialGene regulatory mechanisms underlying sex differences in brain development and psychiatric disease
Manoli, D. S., & Tollkühn, J. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13564 · Cited by 58
Kumar, R., Atamna, H., Zakharov, M. N., Bhasin, S., Khan, S. H., & Jasuja, R. (2011) · Life Science · doi:10.1016/j.lfs.2011.01.021 · Cited by 50
Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system
Forger, N. G., Strahan, J. A., & Castillo‐Ruiz, A. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.01.001 · Cited by 58
“Conversion of testosterone to estradiol is required for full masculinization of many brain features in rodents (but see Zuloaga et al., 2008), whereas androgens are thought to play the dominant role in sexual differentiation of the brain in primates (Thornton et al., 2009; Wallen, 2005).”
BackgroundProteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy
Rusmini, P., Bolzoni, E., Crippa, V., Onesto, E., Sau, D., Galbiati, M., Piccolella, M., & Poletti, A. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.06.016 · Cited by 49
Abi‐Ghanem, C., Degerny, C., Hussain, R., Lière, P., Pianos, A., Tourpin, S., Habert, R., Macklin, W. B., Schumacher, M., & Ghoumari, A. M. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1007049 · Cited by 56
“Although in AR mice, the absence of functional AR in all tissues is accompanied by endocrine abnormalities, this model has been widely used to probe the role of AR in shaping brain and behavior in rodents [54].”
The Role of Central Androgen Receptor Actions in Regulating the Hypothalamic-Pituitary-Ovarian Axis
Walters, K. A., Edwards, M. C., Tesic, D., Caldwell, A. S. L., Jimenez, M., Smith, J. T., & Handelsman, D. J. (2018) · Neuroendocrinology · doi:10.1159/000487762 · Cited by 58
Nadler, A., Camerer, C. F., Zava, D. T., Ortiz, T. L., Watson, N. V., Carré, J. M., & Nave, G. (2019) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2019.1062 · Cited by 52
“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
“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
“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
“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
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
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
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 41
“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
“- 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).”
InfluentialJovanovic, H., Kočoska-Maraš, L., Rådestad, A. F., Halldin, C., Borg, J., Hirschberg, A. L., & Nordström, A. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.11.003 · Cited by 43
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
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
“…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., Greene, L. K., Walsh, D. A., Mitchell, J. L., Clutton-Brock, T. H., & Drea, C. M. (2016) · Scientific Reports · doi:10.1038/srep35492 · Cited by 40
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
“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 38
“…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
“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
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
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
“…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 34
“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 37
Zuloaga, D. G., Jordan, C. L., & Breedlove, S. M. (2011) · Endocrinology · doi:10.1210/en.2010-1016 · Cited by 33
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
“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
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 32
“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
“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
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
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
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 30
Prenatal Flutamide Enhances Survival in a Myogenic Mouse Model of Spinal Bulbar Muscular Atrophy
Johansen, J. A., Troxell‐Smith, S. M., Yu, Z., Mo, K., Monks, D. A., Lieberman, A. P., Breedlove, S. M., & Jordan, C. L. (2010) · Neurodegenerative Diseases · doi:10.1159/000313682 · Cited by 26
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
“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
“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
“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 30
Self-citationKarlsson, S. A., Studer, E., Kettunen, P., & Westberg, L. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00041 · Cited by 26
Metadata
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › 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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