Brain Aromatization: Classic Roles and New Perspectives

ABSTRACT

Aromatization of testosterone to estradiol by neural tissue has classically been associated with the regulation of sexual differentiation, gonadotropin secretion, and copulatory behavior. However, new data indicate that the capacity for aromatization is not restricted to the endocrine brain and demonstrate roles for locally formed estrogens in neurogenesis and in responses of brain tissue to injury. This article summaries our current understanding of the distribution and regulation of aromatase in the brain and describes the classic and novel roles it plays. A better understanding of brain aromatization could shed new light on its physiologic and pathologic functions and someday lead to new, centrally acting drug therapies.

KEYWORDS

Cytochrome P450 aromatase - CYP19 - LH - sexual behavior - sexual partner preference - brain ischemia

REFERENCES

• 1 Naftolin F, Ryan K J, Davies I J et al.. The formation of estrogens by central neuroendocrine tissues.  Recent Prog Horm Res. 1975;  31 295-319
• 2 Naftolin F. Brain aromatization of androgens.  J Reprod Med. 1994;  39 257-261
• 3 Lephart E D. A review of brain aromatase cytochrome P450.  Brain Res Brain Res Rev. 1996;  22 1-26
• 4 Roselli C E, Abdelgadir S E, Ronnekleiv O K, Klosterman S A. Anatomic distribution and regulation of aromatase gene expression in the rat brain.  Biol Reprod. 1998;  58 79-87
• 5 Naftolin F, Ryan K J, Davies I J et al.. The formation of estrogens by central neuroendocrine tissues.  Recent Prog Horm Res. 1975;  31 295-319
• 6 Abdelgadir S E, Resko J A, Ojeda S R, Lephart E D, McPhaul M J, Roselli C E. Androgens regulate aromatase cytochrome P450 messenger ribonucleic acid in rat brain.  Endocrinology. 1994;  135 395-401
• 7 Roselli C E, Horton L E, Resko J A. Distribution and regulation of aromatase activity in the rat hypothalamus and limbic system.  Endocrinology. 1985;  117 2471-2477
• 8 Simerly R B, Chang C, Muramatsu M, Swanson L W. The distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.  J Comp Neurol. 1990;  294 76-95
• 9 Hojo Y, Hattori T A, Enami T et al.. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons.  Proc Natl Acad Sci U S A. 2004;  101 865-870
• 10 MacLusky N J, Walters M J, Clark A S, Toran-Allerand C D. Aromatase in the cerebral cortex, hippocampus, and mid-brain: ontogeny and developmental implications.  Mol Cell Neurosci. 1994;  5 691-698
• 11 Evrard H C. Estrogen synthesis in the spinal dorsal horn: a new central mechanism for the hormonal regulation of pain.  Am J Physiol Regul Integr Comp Physiol. 2006;  291 R291-R299
• 12 Stoffel-Wagner B, Watzka M, Schramm J, Bidlingmaier F, Klingmuller D. Expression of CYP19 (aromatase) mRNA in different areas of the human brain.  J Steroid Biochem Mol Biol. 1999;  70 237-241
• 13 Horvath T L, Wikler K C. Aromatase in developing sensory systems of the rat brain.  J Neuroendocrinol. 1999;  11 77-84
• 14 Lavaque E, Mayen A, Azcoitia I, Tena-Sempere M, Garcia-Segura L M. Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and aromatase in the olivocerebellar system.  J Neurobiol. 2006;  66 308-318
• 15 Kretz O, Fester L, Wehrenberg U et al.. Hippocampal synapses depend on hippocampal estrogen synthesis.  J Neurosci. 2004;  24 5913-5921
• 16 Tanapat P, Hastings N B, Gould E. Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner.  J Comp Neurol. 2005;  481 252-265
• 17 Naftolin F, Horvath T L, Jakab R L, Leranth C, Harada N, Balthazart J. Aromatase immunoreactivity in axon terminals of the vertebrate brain - an immunocytochemical study on quail, rat, monkey and human tissues.  Neuroendocrinology. 1996;  63 149-155
• 18 Peterson R S, Yarram L, Schlinger B A, Saldanha C J. Aromatase is pre-synaptic and sexually dimorphic in the adult zebra finch brain.  Proc Biol Sci. 2005;  272 2089-2096
• 19 Veney S L, Rissman E F. Co-localization of estrogen receptor and aromatase enzyme immunoreactivities in adult musk shrew brain.  Horm Behav. 1998;  33 151-162
• 20 Tsuruo Y, Ishimura K, Hayashi S, Osawa Y. Immunohistochemical localization of estrogen receptors within aromatase-ummunoreactive neurons in the fetal and neonatal rat brain.  Anat Embryol (Berl). 1996;  193 115-121
• 21 Balthazart J, Foidart A, Surlemont C, Harada N. Neuroanatomical specificity in the co-localization of aromatase and estrogen receptors.  J Neurobiol. 1991;  22 143-157
• 22 Ronnekleiv O K, Malyala A, Kelly M J. Membrane-initiated signaling of estrogen in the brain.  Semin Reprod Med. 2007;  25 165-177
• 23 Balthazart J, Ball G F. Is brain estradiol a hormone or a neurotransmitter?.  Trends Neurosci. 2006;  29 241-249
• 24 Martinez-Cerdeno V, Noctor S C, Kriegstein A R. Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex.  Eur J Neurosci. 2006;  24 3475-3488
• 25 Götz M, Barde Y A. Radial glial cells: defined and major intermediates between embryonic stem cells and CNS neurons.  Neuron. 2005;  46 369-372
• 26 Mouriec K, Pellegrini E, Anglade I et al.. Synthesis of estrogens in progenitor cells of adult fish brain: evolutive novelty or exaggeration of a more general mechanism implicating estrogens in neurogenesis?.  Brain Res Bull. 2008;  75 274-280
• 27 Yague J G, Munoz A, Monasterio-Schrader P, DeFelipe J, Garcia-Segura L M, Azcoitia I. Aromatase expression in the human temporal cortex.  Neuroscience. 2006;  138 389-401
• 28 Yague J G, Wang A CJ, Janssen W GM et al.. Aromatase distribution in the monkey temporal neocortex and hippocampus.  Brain Res. 2008;  1209 115-127
• 29 Garcia-Segura L M, Wozniak A, Azcoitia I, Rodriguez J R, Hutchison R E, Hutchison J B. Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair.  Neuroscience. 1999;  89 567-578
• 30 Peterson R S, Saldanha C J, Schlinger B A. Rapid upregulation of aromatase mRNA and protein following neural injury in the zebra finch (Taeniopygia guttata).  J Neuroendocrinology. 2001;  13 317-323
• 31 Carswell H VO, Dominiczak A F, Garcia-Segura L M, Harada N, Hutchison J B, Macrae I M. Brain aromatase expression after experimental stroke: topography and time course.  J Steroid Biochem Mol Biol. 2005;  96 89-96
• 32 McCullough L D, Blizzard K, Simpson E R, Oz O K, Hurn P D. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection.  J Neurosci. 2003;  23 8701-8705
• 33 Wynne R D, Walters B J, Bailey D J, Saldanha C J. Inhibition of injury-induced glial aromatase reveals a wave of secondary degeneration in the songbird brain.  Glia. 2008;  56 97-105
• 34 Hoyk Z, Parducz A, Garcia-Segura L M. Dehydroepiandrosterone regulates astroglia reaction to denervation of olfactory glomeruli.  Glia. 2004;  48 207-216
• 35 Azcoitia I, Sierra A, Garcia-Segura L M. Aromatase expression by reactive astroglia is neuroprotective.  Ann N Y Acad Sci. 2003;  1007 298-305
• 36 Garcia-Segura L M, Veiga S, Sierra A, Melcangi R C, Azcoitia I. Aromatase: a neuroprotective enzyme.  Prog Neurobiol. 2003;  71 31-41
• 37 Wynne R D, Saldanha C J. Glial aromatization decreases neural injury in the zebra finch (Taeniopygia guttata): influence on apoptosis.  J Neuroendocrinol. 2004;  16 676-683
• 38 Balthazart J, Ball G F. New insights into the regulation and function of brain estrogen synthetase (aromatase).  Trends Neurosci. 1998;  21 243-249
• 39 MacLusky N J, Naftolin F. Sexual differentiation of the central nervous system.  Science. 1981;  211 1294-1302
• 40 Lauber M E, Lichtensteiger W. Pre- and postnatal ontogeny of aromatase cytochrome P450 messenger ribonucleic acid expression in the male rat brain studied by in situ hybridization.  Endocrinology. 1994;  135 1661-1668
• 41 Zhao C, Fujinaga R, Tanaka M, Yanai A, Nakahama K, Shinoda K. Region-specific expression and sex-steroidal regulation on aromatase and its mRNA in the male rat brain: immunohistochemical and in situ hybridization analyses.  J Comp Neurol. 2007;  500 557-573
• 42 Connolly P B, Roselli C E, Resko J A. Aromatase activity in developing guinea pig brain: ontogeny and effects of exogenous androgens.  Biol Reprod. 1994;  50 436-441
• 43 Roselli C E, Resko J A. Effects of gonadectomy and androgen treatment on aromatase acitivity in the fetal monkey brain.  Biol Reprod. 1986;  35 106-112
• 44 Roselli C E, Resko J A, Stormshak F. Estrogen synthesis in fetal sheep brain: effect of maternal treatment with an aromatase inhibitor.  Biol Reprod. 2003;  68 370-374
• 45 Peruffo A, Cozzi B, Ballarin C. Ontogenesis of brain aromatase P450 expression in the bovine hypothalamus.  Brain Res Bull. 2008;  75 60-65
• 46 Wallen K, Baum M J. Masculinization and defeminization in altricial and precocial mammals: comparative aspects of steroid hormone action. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT Hormones, Brain and Behavior. San Diego, CA; Elsevier Science 2002: 385-423
• 47 Forger N G, Rosen G J, Waters E M, Jacob D, Simerly R B, de Vries G J. Deletion of Bax eliminates sex differences in the mouse forebrain.  Proc Natl Acad Sci U S A. 2004;  101 13666-13671
• 48 Toran-Allerand C D. Sex steroids and the development of the newborn mouse hypothalamus and preoptic area in vitro: implication for sexual differentiation.  Brain Res. 1976;  106 407-412
• 49 Roselli C E, Resko J A. Sex differences in androgen-regulated expression of cytochrome P450 aromatase in the rat brain.  J Steroid Biochem Mol Biol. 1997;  61 365-374
• 50 Balthazart J, Baillien M, Charlier T D, Cornil C A, Ball G F. Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level.  J Steroid Biochem Mol Biol. 2003;  86 367-379
• 51 Callard G V, Tchoudakova A V, Kishida M, Wood E. Differential tissue distribution, developmental programming, estrogen regulation and promoter characteristics of cyp19 genes in teleost fish.  J Steroid Biochem Mol Biol. 2001;  79 305-314
• 52 Roselli C E, Resko J A. Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance.  J Steroid Biochem Mol Biol. 2001;  79 247-253
• 53 Veney S L, Rissman E F. Immunolocalization of androgen receptors and aromatase enzyme in the adult musk shrew brain.  Neuroendocrinology. 2000;  72 29-36
• 54 Honda S, Harada N, Takagi Y. Novel exon 1 of the aromatase gene specific for aromatase transcripts in human brain.  Biochem Biophys Res Commun. 1994;  198 1153-1160
• 55 Reddy V VR, Naftolin F, Ryan K J. Aromatization in the central nervous system of rabbits: effects of castration and hormone treatment.  Endocrinology. 1973;  92 589-594
• 56 Roselli C E. Synergistic induction of aromatase activity in the rat brain by estradiol and 5α-dihydrotestosterone.  Neuroendocrinology. 1991;  53 79-84
• 57 Gardner L, Anderson T, Place A R, Dixon B, Elizur A. Sex change strategy and the aromatase genes.  J Steroid Biochem Mol Biol. 2005;  94 395-404
• 58 Bulun S E, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters.  J Steroid Biochem Mol Biol. 2003;  86 219-224
• 59 Sasano H, Takahashi K, Satoh F, Nagura H, Harada N. Aromatase in the human central nervous system.  Clin Endocrinol (Oxf). 1998;  48 325-329
• 60 Kato J, Yamada-Mouri N, Hirata S. Structure of aromatase mRNA in the rat brain.  J Steroid Biochem Mol Biol. 1997;  61 381-385
• 61 Cornil C A, Ball G F, Balthazart J. Functional significance of the rapid regulation of brain estrogen action: where do the estrogens come from?.  Brain Res. 2006;  1126 2-26
• 62 Cooke B, Hegstrom C D, Villeneuve L S, Breedlove S M. Sexual differentiation of the vertebrate brain: principles and mechanisms.  Front Neuroendocrinol. 1998;  19 323-362
• 63 Bakker J, Baum M J. Role for estradiol in female-typical brain and behavioral sexual differentiation.  Front Neuroendocrinol. 2008;  29 1-16
• 64 Karsch F J, Dierschke D J, Knobil E. Sexual differentiation of pituitary function: apparent difference between primates and rodents.  Science. 1973;  179 484-486
• 65 McEwen B S, Lieberburg I, Chaptal C, Krey L C. Aromatization: important for sexual differentiation of the neonatal rat brain.  Horm Behav. 1977;  9 249-263
• 66 Vreeburg J TM, van der Vaart P DM, Van Der Schoot P. Prevention of central defeminization but not masculinization in male rats by inhibition neonatally of oestrogen biosynthesis.  J Endocrinol. 1977;  74 375-382
• 67 Baum M J, Carroll R S, Tobet S A. Steroidal control of behavioural, neuroendocrine and brain sexual differentiation: studies in a carnivore, the ferret.  J Neuroendocrinol. 1990;  2 401-418
• 68 Roselli C E, Schrunk J M, Stadelman H L, Resko J A, Stormshak F. The effect of aromatase inhibition on the sexual differentiation of the sheep brain.  Endocrine. 2006;  29 501-512
• 69 Gorski R A, Gordon J H, Shryne J E, Southam A M. Evidence for a morphological sex difference within the medial preoptic area or the rat brain.  Brain Res. 1978;  148 333-346
• 70 Dohler K D, Coquelin A, Davis F, Hines M, Shryne J E, Gorski R A. Pre- and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats.  Brain Res. 1984;  302 291-295
• 71 Houtsmuller E J, Brand T, De Jonge F H, Joosten R NJMA, Van De Poll N E, Slob A K. SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD.  Physiol Behav. 1994;  56 535-541
• 72 Schwarz J M, McCarthy M M. Cellular mechanisms of estradiol-mediated masculinization of the brain.  J Steroid Biochem Mol Biol. 2008;  109 300-306
• 73 Simerly R B. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain.  Annu Rev Neurosci. 2002;  25 507-536
• 74 Arendash G W, Gorski R A. Effects of discrete lesions of the sexually dimorphic nucleus of the preoptic area or other medial preoptic regions on the sexual behavior of male rats.  Brain Res Bull. 1983;  10 147-154
• 75 De Jonge F H, Louwerse A L, Ooms M P, Evers P, Endert E, Van De Poll N E. Lesions of the SDN-POA inhibit sexual behavior of male Wistar rats.  Brain Res Bull. 1989;  23 483-492
• 76 Paredes R G, Baum M J. Altered sexual partner preference in male ferrets given excitotoxic lesions of the preoptic area anterior hypothalamus.  J Neurosci. 1995;  15 6619-6630
• 77 Paredes R G, Nakagawa Y, Nakach N. Lesions of the medial preoptic area/anterior hypothalamus (MPOA/AH) modify partner preference in male rats.  Brain Res. 1998;  813 1-8
• 78 Vasey P L. Same-sex sexual partner preference in hormonally and neurologically unmanipulated animals.  Annu Rev Sex Res. 2002;  13 141-179
• 79 Perkins A, Roselli C E. The ram as a model for behavioral neuroendocrinology.  Horm Behav. 2007;  52 70-77
• 80 Roselli C E, Larkin K, Resko J A, Stellflug J N, Stormshak F. The volume of a sexually dimorphic nucleus in the ovine medial preoptic area/anterior hypothalamus varies with sexual partner preference.  Endocrinology. 2004;  145 478-483
• 81 Roselli C E, Stadelman H, Reeve R, Bishop C V, Stormshak F. The ovine sexually dimorphic nucleus of the medial preoptic area is organized prenatally by testosterone.  Endocrinology. 2007;  148 4450-4457
• 82 LeVay S. A difference in hypothalamic structure between heterosexual and homosexual men.  Science. 1991;  253 1034-1037
• 83 Adkins-Regan E, Mansukhani V, Thompson R, Yang S. Organizational actions of sex hormones on sexual partner preference.  Brain Res Bull. 1997;  44 497-502
• 84 Brand T, Kroonen J, Mos J, Slob A K. Adult partner preference and sexual behavior of male rats affected by perinatal endocrine manipulations.  Horm Behav. 1991;  25 323-341
• 85 Bakker J, Honda S, Harada N, Balthazart J. Sexual partner preference requires a functional aromatase (Cyp 19) gene in male mice.  Horm Behav. 2002;  42 158-171
• 86 Resko J A, Perkins A, Roselli C E, Fitzgerald J A, Choate J VA, Stormshak F. Endocrine correlates of partner preference behavior in rams.  Biol Reprod. 1996;  55 120-126
• 87 Carani C, Qin K, Simoni M et al.. Effect of testosterone and estradiol in a man with aromatase deficiency.  N Engl J Med. 1997;  337 91-95
• 88 Carani C, Granata A RM, Rochira V et al.. Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism.  Psychoneuroendocrinology. 2005;  30 413-417
• 89 DuPree M G, Mustanski B S, Bocklandt S, Nievergelt C, Hamer D H. A candidate gene study of CYP19 (aromatase) and male sexual orientation.  Behav Genet. 2004;  34 243-250
• 90 Hull E M, Meisel R L, Sachs B D. Male sexual behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT Hormones, Brain and Behavior. San Diego, CA; Academic Press 2002: 3-137
• 91 Sodersten P. Estrogen-activated sexual behavior in male rats.  Horm Behav. 1973;  4 247-256
• 92 Bonsall R W, Clancy A N, Michael R P. Effects of the nonsteroidal aromatase inhibitor, fadrozole, on sexual behavior in male rats.  Horm Behav. 1992;  26 240-254
• 93 Vagell M E, McGinnis M Y. The role of aromatization in the restoration of male rat reproductive behavior.  J Neuroendocrinol. 1997;  9 415-421
• 94 Beyer C, Morali G, Naftolin F, Larsson K, Perez-Palacios G. Effect of some antiestrogens and aromatase inhibitors on androgen induced sexual behavior in castrated male rats.  Horm Behav. 1976;  7 353-363
• 95 Roselli C E, Cross E, Poonyagariyagorn H K, Stadelman H L. Role of aromatization in anticipatory and consummatory aspects of sexual behavior in male rats.  Horm Behav. 2003;  44 146-151
• 96 Fisher C R, Graves K H, Parlow A F, Simpson E R. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp 19 gene.  Proc Natl Acad Sci U S A. 1998;  95 6965-6970
• 97 Honda S, Harada N, Ito S, Takagi Y, Maeda S. Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene.  Biochem Biophys Res Commun. 1998;  252 445-449
• 98 Toda K, Okada T, Takeda K et al.. Oestrogen at the neonatal stage is critical for the reproductive ability of male mice as revealed by supplementation with 17beta-oestradiol to aromatase gene (Cyp19) knockout mice.  J Endocrinol. 2001;  168 455-463
• 99 Matsumoto T, Honda S, Harada N. Alteration in sex-specific behaviors in male mice lacking the aromatase gene.  Neuroendocrinology. 2003;  77 416-424
• 100 Bakker J, Honda S, Harada N, Balthazart J. Restoration of male sexual behavior by adult exogenous estrogens in male aromatase knockout mice.  Horm Behav. 2004;  46 1-10
• 101 Alsum P, Goy R W. Actions of esters of testosterone, dihydrotestosterone, or estradiol on sexual behavior in castrated male guinea pigs.  Horm Behav. 1974;  5 207-217
• 102 Phoenix C H. Effect of dihydrotestosterone on sexual behavior of castrated male rhesus monkeys.  Physiol Behav. 1974;  12 1045-1055
• 103 Zumpe D, Clancy A N, Bonsall R B, Michael R P. Behavioral responses to depo-provera, fadrozole, and estradiol in castrated, testosterone-treated cynomolgus monkeys (Macaca fascicularis): the involvement of progestin receptors.  Physiol Behav. 1996;  60 531-540
• 104 Gooren L J. Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone, and dihydrotestosterone.  Arch Sex Behav. 1985;  14 539-548
• 105 Sharma T P, Blache D, Blackberry M A, Martin G B. Role of peripheral and central aromatization in the control of gonadotrophin secretion in the male sheep.  Reprod Fertil Dev. 1999;  11 293-302
• 106 Hayes F J, Seminara S B, Decruz S, Boepple P A, Crowley Jr W F. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback.  , [In Process Citation] J Clin Endocrinol Metab. 2000;  85 3027-3035
• 107 Couse J F, Korach K S. Estrogen receptor null mice: what have we learned and where will they lead us?.  Endocr Rev. 1999;  20 358-417
• 108 Jones M EE, Chin B W, Proietto J, Simpson E R. Of mice and men: the evolving phenotype of aromatase deficiency.  Trends Endocrinol Metab. 2006;  17 55-64
• 109 Ellinwood W E, Hess D L, Roselli C E, Spies H G, Resko J A. Inhibition of aromatization stimulates luteinizing hormone and testosterone secretion in adult male rhesus monkeys.  J Clin Endocrinol Metab. 1984;  59 1088-1096
• 110 Roselli C E, Stadelman H, Horton L E, Resko J A. Regulation of androgen metabolism and luteinizing hormone-releasing hormone content in discrete hypothalamic and limbic areas of male rhesus macaques.  Endocrinology. 1987;  120 97-106
• 111 Schnorr J A, Bray M J, Veldhuis J D. Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men.  J Clin Endocrinol Metab. 2001;  86 2600-2606
• 112 Bagatell C J, Dahl K D, Bremner W J. The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol.  J Androl. 1994;  15 15-21
• 113 Boyar R M, Moore R J, Rosner W et al.. Studies of gonadotropin-gonadal dynamics in patients with androgen insensitivity.  J Clin Endocrinol Metab. 1978;  47 1116-1122
• 114 Veldhuis J D, Urban R J, Dufau M L. Evidence that androgen negative feedback regulates hypothalamic gonadotropin-releasing hormone impulse strength and the burst-like secretion of biologically active luteinizing hormone in men.  J Clin Endocrinol Metab. 1992;  74 1227-1235
• 115 Pitteloud N, Dwyer A A, Decruz S et al.. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men.  J Clin Endocrinol Metab. 2008;  93 784-791
• 116 Hall E D, Pazara K E, Linseman K L. Sex differences in postischemic neuronal necrosis in gerbils.  J Cereb Blood Flow Metab. 1991;  11 292-298
• 117 Alkayed N J, Harukuni I, Kimes A S, London E D, Traystman R J, Hurn P D. Gender-linked brain injury in experimental stroke.  Stroke. 1998;  29 159-166
• 118 Alkayed N J, Murphy S J, Traystman R J, Hurn P D. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats.  Stroke. 2000;  31 161-168
• 119 Carswell H V, Anderson N H, Clark J S et al.. Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat.  Hypertension. 1999;  33 681-685
• 120 McCullough L D, Blizzard K, Simpson E R, Oz O K, Hurn P D. Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection.  J Neurosci. 2003;  23 8701-8705
• 121 Li X, Blizzard K K, Zeng Z, DeVries A C, Hurn P D, McCullough L D. Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender.  Exp Neurol. 2004;  187 94-104
• 122 Bramlett H M, Dietrich W D. Neuropathological protection after traumatic brain injury in intact female rats versus males or ovariectomized females.  J Neurotrauma. 2001;  18 891-900
• 123 Hurn P D, Macrae I M. Estrogen as a neuroprotectant in stroke.  J Cereb Blood Flow Metab. 2000;  20 631-652
• 124 Morrison J H, Brinton R D, Schmidt P J, Gore A C. Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women.  J Neurosci. 2006;  26 10332-10348
• 125 Bryant D N, Sheldahl L C, Marriott L K, Shapiro R A, Dorsa D M. Multiple pathways transmit neuroprotective effects of gonadal steroids.  Endocrine. 2006;  29 199-207
• 126 Vagnerova K, Koerner I P, Hurn P D. Gender and the injured brain.  Anesth Analg. 2008;  107 201-214
• 127 Azcoitia I, Sierra A, Veiga S, Honda S, Harada N, Garcia-Segura L M. Brain aromatase is neuroprotective.  J Neurobiol. 2001;  47 318-329
• 128 Garcia-Segura L M, Azcoitia I, DonCarlos L L. Neuroprotection by estradiol.  Prog Neurobiol. 2001;  63 29-60
• 129 Veiga S, Azcoitia I, Garcia-Segura L M. Extragonadal synthesis of estradiol is protective against kainic acid excitotoxic damage to the hippocampus.  Neuroreport. 2005;  16 1599-1603
• 130 Garcia-Ovejero D, Veiga S, Garcia-Segura L M, DonCarlos L L. Glial expression of estrogen and androgen receptors after rat brain injury.  J Comp Neurol. 2002;  450 256-271
• 131 Jones M EE, Thornburn A W, Britt K L et al.. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity.  Proc Natl Acad Sci U S A. 2000;  97 12735-12740
• 132 Simpson E R, Clyne C, Rubin G et al.. Aromatase–a brief overview.  Annu Rev Physiol. 2002;  64 93-127
• 133 Oz O K, Zerwekh J E, Fisher C et al.. Bone has a sexually dimorphic response to aromatase deficiency.  J Bone Miner Res. 2000;  15 507-514
• 134 Liu M, Hurn P D, Roselli C E, Alkayed N J. Role of P450 aromatase in sex-specific astrocytic cell death.  J Cereb Blood Flow Metab. 2007;  27 135-141
• 135 Liu M, Oyarzabal E A, Yang R, Murphy S J, Hurn P D. A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture.  J Neurosci Methods. 2008;  171 214-217
• 136 Toung T K, Hurn P D, Traystman R J, Sieber F E, Faraci F M. Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type 1 diabetes mellitus: editorial comment.  Stroke. 2000;  31 2701-2706
• 137 Vannucci S J, Willing L B, Goto S et al.. Experimental stroke in the female diabetic, db/db, mouse.  J Cereb Blood Flow Metab. 2001;  21 52-60
• 138 Alkayed N J, Murphy S J, Traystman R J, Hurn P D, Miller V M. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats.  Stroke. 2000;  31 161-168