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Kula wrote a very important Polish paper, is a summary of what
about the brain differentiation and gender identity. We know a little bit more than
that, we think, about transsexuality, he do not says nothing about....but all he says
is very helpfull as a summary.
Samodzielna Pracownia Andrologii i Endokrynologii Plodnosci, Centrum Ksztalcenia Klinicznego Europejskiej, Akademii Andrologii, Akademii Medycznej w Lodzi.
Normal human development requires the compatibility between genetic sex (sex chromosomes), sex of gonades (tests or ovaries), genitalia (external and internal sex organs), somatic features (body characteristics) and psychic sex. The psychic sex, called frequently gender, consist of gender identity (self-estimation), gender role (objective estimation) and sexual orientation (hetero- or homosexual). It was believed that the psychic gender depends only on socio-environmental influences such as rearing, learning and individual choice. Although, the process of sexual differentiation of human brain is not completely elucidated, it has became recently evident that endogenous hormones more then socio-environmental factors influence gender differences. Experimental studies on animals revealed that transient action of sex steroids during perinatal period of life is crucial for the dymorphism of sexual behavior (male or female) in adulthood. It seems, that also in the human male neonates testosterone produced by testes perinatally takes the main role in the irreversible masculinization of the brain i.e. creation of the differences vs. female brain. The evaluation of patients with disturbances of sexual differentiation of external genitalia (the lack of the testosterone transformation into 5-alpha dihydrotestosterone in peripheral tissues of men or the inborn excess of androgens in women with the congenital adrenal hyperplasia) has served as a useful clinical model for understanding factors, affecting the formation of gender. In these individuals the formal sex established according to genetic sex and somatic sex may be incompatible with gender identity and role. However, it has been found that the female gender identity is most frequently associated with the presence of ovaries or the lack of gonads (gonadal dysgenesis), while the male gender identity appear most frequently in the presence of testicular tissue irrespective of female or hermaphrodite (intersex) phenotype. In genetic men with the absence of male genitalia formation, caused by the aberrant function of androgen receptor, the gender identity depends on the severity of the disorder: female gender identity in the complete androgen insensitivity syndrome and female or male gender identity in the complete androgen insensitivity syndrome and female or male in the partial androgen insensitivity. These clinical observations confirm the experimental data indicating androgen role in the male gender identity creation. This knowledge is necessary for the decision of the direction of surgical correction of sex organs in children with ambiguous genitalia, which should not depend on the expected efficiency to perform sexual intercourse, but mostly on the expected or already present individual gender identity.
Abnormal sexual development and psychosexual issues.
Department of Psychology, City University, London, UK.
Animal models of gonadal hormone influences on the sexual differentiation of brain and behaviour are reviewed and discussed as a basis for predicting hormonal influences on human neurobehavioural development. Behavioural outcomes in clinical intersex cases, including congenital adrenal hyperplasia, androgen insensitivity syndrome, enzymatic deficiencies and situations in which hormones have been prescribed during pregnancy are reviewed. It is concluded that the prenatal or neonatal hormone environment contributes to the development of human behaviours that show sex differences, particularly childhood play behaviour, sexual orientation and core gender identity. There also is some evidence for influences on aggression and cognition. It is also concluded that additional research is needed to determine why some intersex patients assigned and reared as girls are not successful in this identity and role.
Etiology, clinical profile, gender identity and long-term follow up of patients with ambiguous genitalia in India.
Ammini AC, Gupta R, Kapoor A, Karak A, Kriplani A, Gupta DK, Kucheria K.
Department of Endocrinology, All India Institute of Medical Sciences, New Delhi. firstname.lastname@example.org
There is little information on the profile of children with ambiguous genitalia in India. Presented here is an analysis of patients with ambiguous genitalia registered in a general endocrine clinic during the last 2 decades. Seventy-four patients (age 4 months to 36 years) were registered during this period. Fifty-two were more than 5 years old at the time of registration. Thirty-five were reared as females, 29 as males; nine children (4 months to 1 year old) were brought for sex assignment, and one (with epispadias) was brought for correction of urinary incontinence. Investigations revealed 28 patients with congenital adrenal hyperplasia, 14 dysgenetic male pseudohermaphroditism, ten true hermaphroditism, six partial androgen insensitivity, four castration and one epispadias. There were eight patients with perineal hypospadias with normal Leydig cell reserve (normal LH, FSH and testosterone response to LHRH). Sex of rearing and gender identity were concordant in all except the patients with perineal hypospadias with normal Leydig cell response. These observations support the theory that prenatal androgen exposure masculinizes the brain.
PMID: 12008689 [PubMed - indexed for MEDLINE]
Some very important papers showing the aromatization of T in the brain basal areas (hypothalamus and amygdalas), and its relation with agressivity and male sexual behavior in primates, non primates, and other species.
Sexual behaviour of rams: male orientation and its endocrine correlates.
Resko JA, Perkins A, Roselli CE, Stellflug JN, Stormshak FK.
Department of Physiology and Pharmacology, School of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA.
The components of heterosexual behaviour in rams are reviewed as a basis for understanding partner preference behaviour. A small percentage of rams will not mate with oestrous females and if given a choice will display courtship behaviour towards another ram in preference to a female. Some of the endocrine profiles of these male-oriented rams differ from those of heterosexual controls. These differences include reduced serum concentrations of testosterone, oestradiol and oestrone, reduced capacity to produce testosterone in vitro, and reduced capacity to aromatize androgens in the preoptic-anterior hypothalamus of the brain. Our observation that aromatase activity is significantly lower in the preoptic-anterior hypothalamic area of male-oriented rams than in female-oriented rams may indicate an important neurochemical link to sexual behaviour that should be investigated. The defect in steroid hormone production by the adult testes of the male-oriented ram may represent a defect that can be traced to the fetal testes. If this contention is correct, partner preference behaviour of rams may also be traceable to fetal development and represent a phenomenon of sexual differentiation.
Testosterone metabolism in brain cells and membranes.
Celotti F, Melcangi RC, Negri-Cesi P, Poletti A.
Institute of Endocrinology, University of Milan, Italy.
The central nervous system (CNS) is considered a target structure for the action of all the classes of hormonal steroids produced by the organism. Well-characterized genomic and less well-understood membrane mechanisms of action are probably involved in the steroid modulation of brain activities. Moreover, some classes of steroids need to be converted into "active" metabolites before interacting with their effector systems. In particular, testosterone (T) exerts many of its effects after conversion to 5 alpha-dihydrotestosterone (DHT) and estrogens. The CNS possesses both the 5 alpha-reductase, the enzyme which produces DHT and the aromatase which transforms T into estrogens; however, the relative role and distribution of these enzymes in the various structural components of the CNS has not been clarified so far. The 5 alpha-reductase has been found to be present in high concentrations in brain white matter structures because these are particularly rich in myelin membranes, to which the enzymatic activity appears to be associated. This membrane localization might suggest a possible involvement of steroidal 5 alpha-reduced metabolites in membrane-mediated events in the CNS. Moreover, the distribution of 5 alpha-reductase was studied in neurons, astrocytes and oligodendrocytes isolated from the brain of male rats by density gradient ultracentrifugation, as well as in neurons and glial cells grown in culture. The aromatase activity was also evaluated in neurons and glial cells grown in culture and in isolated oligodendrocytes. Among the three cell types isolated, neurons appear to be more active than oligodendrocytes and astrocytes, respectively, in converting T into DHT. Also, in cell culture experiments, neurons are more active in forming DHT than glial cells. Only neurons possess aromatase activity, while glial cells are apparently unable to aromatize T.
Cytochrome P450 aromatase (CYP19) in the non-human primate brain: distribution, regulation, and functional significance.
Roselli CE, Resko JA.
Department of Physiology and Pharmacology, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA. email@example.com
In adult male primates, estrogens play a role in both gonadotropin feedback and sexual behavior. Inhibition of aromatization in intact male monkeys acutely elevates serum levels of luteinizing hormone, an effect mediated, at least partially, within the brain. High levels of aromatase (CYP19) are present in the monkey brain and regulated by androgens in regions thought to be involved in the central regulation of reproduction. Androgens regulate aromatase pretranslationally and androgen receptor activation is correlated with the induction of aromatase activity. Aromatase and androgen receptor mRNAs display both unique and overlapping distributions within the hypothalamus and limbic system suggesting that androgens and androgen-derived estrogens regulate complimentary and interacting genes within many neural networks. Long-term castrated monkeys, like men, exhibit an estrogen-dependent neural deficit that could be an underlying cause of the insensitivity to testosterone that develops in states of chronic androgen deficiency. Future studies of in situ estrogen formation in brain in the primate model are important for understanding the importance of aromatase not only for reproduction, but also for neural functions such as memory and cognition that appear to be modulated by estrogens.
Identification of multiple CYP19 genes encoding different cytochrome P450 aromatase isozymes in brain and ovary.
Tchoudakova A, Callard GV.
Department of Biology, Boston University, Massachusetts 02215, USA.
Evidence to date indicates that the gene encoding cytochrome P450 aromatase (P450arom) in humans is a single member of the CYPl9 family, but multiple CYPl9 loci and isoforms have been identified in pigs. Here we report the cloning and characterization of a second member of the CYP19 family in goldfish. A search for P450arom variants was prompted by studies showing that a full-length P450arom complementary DNA (cDNA) isolated from a goldfish brain cDNA library hybridizes with a high abundance 3 kb transcript in brain RNA but fails to detect a message in ovarian RNA. A stepwise PCR cloning strategy led to isolation of a 1.9-kb cDNA, which encodes a protein of 518 amino acids and has a predicted mol wt of 58.7K. The ovary-derived P450arom (-A) shares 68-72% sequence identity with ovarian aromatases of other fish species, but only 62% identity with the homologous brain-derived P450arom (-B). Amino acid differences are distributed throughout the two goldfish P450arom forms, but presumptive functional domains are highly conserved. Both P450aromA and -B are able to aromatize [3H]androgen to [3H]estrogen when expressed in nonsteroidogenic COS cells. Southern analysis and PCR-restriction analysis of genomic DNA using discriminating probes and primers indicates that a single locus encodes the brain-derived P450aromB (CYPl9B), whereas one or two different loci encode the ovarian form (CYPl9A). Northern blot analysis revealed two P450aromA messenger RNAs (1.9 >> 3.0 kb) in ovary. Simultaneous PCR amplification with A- and B-specific primer pairs confirms that P450aromA is the only form expressed in ovaries, but shows overlapping expression of the two genes in neural tissues. Whereas P450aromB messenger RNA predominates in brain (B/A, approximately 14:1), the ratios are reversed in retina (B/A, approximately 1:25). Further studies are required to resolve the evolutionary and functional implications of multiple CYPl9 genes and P450arom isozymes in goldfish, their differential expression in brain and ovary, and whether observations can be generalized to other vertebrates.
Changes in aromatase activity in the rat brain during embryonic, neonatal, and infantile development.
George FW, Ojeda SR.
We assessed the activity of the aromatase enzyme complex in slices of brain from rats by measuring the release of 3H2O from [1 beta-3H]testosterone. In hypothalami from 12-day-old rats, the rate of aromatase activity was linear with time and amount of tissue. The reaction was saturated at a substrate concentration of 0.1 microM, and the apparent Km of the reaction was 27 nM. The production of 3H2O was inhibited by 4-hydroxyandrostenedione, with an apparent Ki of 20 nM. Aromatase activity was first detected in the diencephalon of 16-day-old fetuses and reached maximum rates in hypothalamic tissue between days 18 and 20 of gestation. The highest rate of activity per mg protein (approximately 4.8 pmol h-1 mg protein-1) was observed in the preoptic area (POA) on the 20th day of embryonic development. However, when expressed as a rate per tissue fragment, aromatase activity was as high in the medial basal hypothalamus as in the POA. After day 20 of gestation aromatase activity rapidly decreased in the POA and medial basal hypothalamus of both males and females. The lowest levels were observed between postnatal days 16 and 20. Aromatase activity was not detectable in cerebral cortex and cerebellum at any age studied. Since serum testosterone was higher in males than females during the first 4 days of postnatal life, and since aromatase activity is elevated in the hypothalamus at this time, our results support the current concept that local formation of estrogen mediates testosterone-induced masculinization of the brain during the neonatal period. However, our results also indicate that failure of the rat brain to undergo complete sexual differentiation before birth cannot be due to an inability of the fetal hypothalamus to aromatize androgens, since aromatase activity was higher in the hypothalamus than in any other fetal tissue.
PMID: 7094885 [PubMed - indexed for MEDLINE]
1: Environ Health Perspect. 2002 Jun;110 Suppl 3:423-8.
The parvocellular vasotocin system of Japanese quail: a developmental and adult model for the study of influences of gonadal hormones on sexually differentiated and behaviorally relevant neural circuits.
Panzica GC, Bakthazart J, Pessatti M, Viglietti-Panzica C.
Department of Anatomy, Pharmacology, and Forensic Medicine, Laboratory of Neuroendocrinology, Rita Levi Montalcini Center for Brain Repair, University of Torino, c.so M. D'Azeglio 52, I-10126 Turin, Italy. firstname.lastname@example.org
Vasotocin (VT; the antidiuretic hormone of birds) is synthesized by diencephalic magnocellular neurons projecting to the neurohypophysis. A sexually dimorphic system of VT-immunoreactive (ir) parvocellular elements has been described within the male medial preoptic nucleus (POM) and the nucleus of the stria terminalis, pars medialis (BSTm). VT-ir fibers are present in many diencephalic and extradiencephalic locations, and quantitative morphometric analyses demonstrated their sexually dimorphic distribution in regions involved in the control of different aspects of reproduction. Moreover, systemic or intracerebroventricular injections of VT markedly inhibit the expression of some aspects of male sexual behavior. In adult animals, circulating levels of testosterone (T) have a profound influence on the VT immunoreactivity within BSTm, POM, and lateral septum. Castration markedly decreases the immunoreaction, whereas T-replacement therapy restores a situation similar to the intact birds. We observed no changes in gonadectomized females treated with T. These changes parallel similar changes in male copulatory behavior (not present in castrated male quail, fully expressed in castrated, T-treated males). The restoration by T of the VT immunoreactivity in castrated male quail could be fully mimicked by a treatment with estradiol (E(2)), suggesting that the aromatization of T into E(2) may play a key limiting role in both the activation of male sexual behavior and the induction of VT synthesis. This dimorphism has an organizational nature: administration of E(2) to quail embryos (a treatment that abolishes male sexual behavior) results in a dramatic decrease of the VT immunoreactivity in sexually dimorphic regions. Conversely, the inhibition of E(2) synthesis during embryonic life (a treatment that stimulates the expression of male copulatory behavior in treated females exposed in adulthood to T) results in a malelike distribution of VT immunoreactivity. The VT parvocellular system of the Japanese quail can therefore be considered an accurate marker of the sexual differentiation of brain circuits mediating copulatory behavior and could be a very sensitive indicator of the activity of estrogenlike substances on neural circuits.
Phosphorylation processes mediate rapid changes of brain aromatase activity.
Balthazart J, Baillien M, Ball GF.
Research Group in Behavioral Neuroendocrinology, Center for Cellular and Molecular Neurobiology, 17 Place Delcour (Bat. L1), University of Liege, B-4020, Liege, Belgium. email@example.com
The enzyme aromatase (also called estrogen synthase) that catalyzes the transformation of testosterone (T) into estradiol plays a key limiting role in the action of T on many aspects of reproduction. The distribution and regulation of aromatase in the quail brain has been studied by radioenzyme assays on microdissected brain areas, immunocytochemistry, RT-PCR and in situ hybridization. High levels of aromatase activity (AA) characterize the sexually dimorphic, steroid-sensitive medial preoptic nucleus (POM), a critical site of T action and aromatization for the activation of male sexual behavior. The boundaries of the POM are clearly outlined by a dense population of aromatase-containing cells as visualized by both immunocytochemistry and in situ hybridization histochemistry. Aromatase synthesis in the POM is controlled by T and its metabolite estradiol, but estradiol receptors alpha (ERalpha) are not normally co-localized with aromatase in this brain area. Estradiol receptor beta (ERbeta) has been recently cloned in quail and localized in POM but we do not yet know whether ERbeta occurs in aromatase cells. It is therefore not known whether estrogens regulate aromatase synthesis directly or by affecting different inputs to aromatase cells as is the case with the gonadotropin releasing hormone neurons. The presence of aromatase in presynaptic boutons suggests that locally formed estrogens may exert part of their effects by non-genomic mechanisms at the membrane level. Rapid effects of estrogens in the brain that presumably take place at the neuronal membrane level have been described in other species. If fast transduction mechanisms for estrogen are available at the membrane level, this will not necessarily result in rapid changes in brain function if the availability of the ligand does not also change rapidly. We demonstrate here that AA in hypothalamic homogenates is rapidly down-regulated by exposure to conditions that enhance protein phosphorylation (addition of Ca2+, Mg2+, ATP). This inhibition is blocked by kinase inhibitors which supports the notion that phosphorylation processes are involved. A rapid (within minutes) and reversible regulation of AA is also observed in hypothalamic explants incubated in vitro and exposed to high Ca2+ levels (K+-induced depolarization, treatment by thapsigargin, by kainate, AMPA or NMDA). The local production and availability of estrogens in the brain can therefore be rapidly changed by Ca2+ based on variation in neurotransmitter activity. Locally-produced estrogens are as a consequence available for non-genomic regulation of neuronal physiology in a manner more akin to the action of a neuropeptide/neurotransmitter than previously thought.
Steroid control and sexual differentiation of brain aromatase.
European Graduate School for Neuroscience, Laboratory of Biochemistry, University of Liege, Belgium. firstname.lastname@example.org
Brain aromatase (ARO) activity in the quail is markedly enhanced by testosterone (T). This effect only becomes detectable after several hours and reaches its maximum within a few days, which suggests enzymatic induction at the genomic level. This idea is reinforced by the fact that T also increases the ARO protein, as observed by immunocytochemistry (ICC) and the ARO mRNA, as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). These changes can be mimicked by the administration of estrogens and therefore presumably require T aromatization. In our first test, injection of the non-steroidal ARO inhibitor, R76713 (racemic vorozole), unexpectedly revealed an increase in ARO immunoreactivity in the preoptic area (POA) of treated birds. This property of R76713 was shared by another non-steroidal inhibitor, fadrozole, but not by two steroidal inhibitors, androstatrienedione (ATD) and 4-hydroxy-androstenedione (OHA). These last two compounds markedly decreased the concentration of brain ARO as estimated by ICC. In parallel, ATD and OHA decreased ARO mRNA concentration measured by RT-PCR but vorozole and fadrozole had no effect on these concentrations in the POA, and only caused them to decrease slightly in the posterior hypothalamus. Together, these data indicate that the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO, presumably at the transcriptional level. Additional regulatory mechanisms apparently take place after the injection of non-steroidal inhibitors and probably include increased half-life of the protein. The induction of ARO activity by steroids appears to be greater in males than in females, but this difference has been difficult to localize and confirm by assay methods. We therefore analysed by ICC the tridimensional distribution of ARO-ir neurons in the POA of males and females that were sexually mature or gonadectomized and treated with T-filled or control empty implants. Localized sex differences and effects of T were detected in this way. In particular, males had more ARO-ir cells than females in the lateral POA but a difference in the opposite direction was evident in the medial part of this area. These sex differences are largely activational (i.e. caused by the higher T levels in males) but they may also reflect organizational effects of neonatal steroids. Castration decreased ARO-ir cell numbers in the lateral POA, but increased it in the periventricular region. This anatomically specialized control by T may be mediated by three potential mechanisms that are discussed and comparatively evaluated: a migration of ARO neurons towards the ventricle after castration; a differential colocalization of ARO with estrogen receptors or a differential modulation of ARO neurons by catecholaminergic inputs.
Sex-specific aromatization of testosterone in mouse hypothalamic neurons.
Beyer C, Wozniak A, Hutchison JB.
AFRC BABRAHAM Institute, MRC Neuroendocrine Development and Behaviour Group, Cambridge, UK.
Conversion of androgens to oestrogens by neural aromatase during brain development appears to be a prerequisite for sexual differentiation of the mammalian central nervous system. In order to investigate the pre- and perinatal patterns of testosterone (T) aromatization in the male and female mouse brain, aromatase activity (AA) was measured in hypothalamic and cerebral homogenates of embryonic day (ED) 17 fetuses and neonates using an in vitro 3H2O product formation microassay. In addition, AA was examined in gender-specific neuronal cell cultures prepared from ED 15 mouse cerebral hemisphere and hypothalamus at 3 and 6 days in vitro (DIV), and this was compared with enzyme activities in homogenates. The aromatase has also been evaluated in glial-enriched cultures from ED 20 mouse hypothalamus and cortex as well as in ED 15 cultures treated with the neurotoxin kainic acid in order to localize AA to neurons and/or glial cells. Significant sex differences in AA were observed in hypothalamic tissue homogenates as early as ED 17, becoming even more distinct in neonates, AA being always higher in males compared to females. Similar AA was also found in cells from both sexes from cultured ED 15 hypothalamus after 3 DIV. However, significantly higher AA was observed after 6 DIV in ED 15 male hypothalamic cultures compared to female. ED 20 glial-enriched hypothalamic cultures (purity > 95%) from both brain regions exhibited very low AA after 6 DIV, and no sex differences were found.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of the nonsteroidal aromatase inhibitor, fadrozole, on the sexual behavior of male cynomolgus monkeys (Macaca fascicularis).
Zumpe D, Bonsall RW, Michael RP.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322.
In many vertebrates, castration and hormone replacement and, more recently, the use of aromatase inhibitors, have shown that male sexual activity is mediated by the aromatization of testosterone (T) to estradiol (E2). In macaques, however, the systemic administration of E2, either alone or in combination with androgen, failed either to maintain or to restore the sexual activity of castrated males. The present study examines the effects of administering the nonsteroidal aromatase inhibitor, Fadrozole, either alone or combined with E2, to castrated, T-treated male cynomolgus monkeys at a dose of 0.25 mg/kg/day. This dose inhibited by over 98% the conversion of T to E2 and the subsequent accumulation of the latter in hypothalamic cell nuclei. Castrated males bearing sc Silastic impants of T were each tested with an ovariectomized, E2-treated female partner before, during, and after being given minipumps delivering either Fadrozole or water (240 1-hr tests). Within 2 weeks, Fadrozole significantly reduced ejaculatory activity and male sexual motivation in the absence of changes in plasma T levels, which remained in the upper range for intact males. Additional estradiol treatment produced small but significant increases in ejaculations by three of the six males only, and measures of male sexual motivation remained unchanged (120 tests). The present results, which stand in contrast to our previous findings in macaques, support the view that aromatization of T is important for ejaculatory activity and sexual motivation in a male primate. They also suggest that exogenous E2, which reaches the brain from the systemic circulation, does not fully duplicate the behavioral effects of E2 produced locally in the brain by the aromatization of T.
Estrogen synthesis in fetal sheep brain: effect of maternal treatment with an aromatase inhibitor.
Roselli CE, Resko JA, Stormshak F.
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97201-3098, USA. email@example.com
The aim of the present study was to determine whether the fetal lamb brain has the capacity to aromatize androgens to estrogens during the critical period for sexual differentiation. We also determined whether administration of the aromatase-inhibitor 1,4,6-androstatriene-3,17-dione (ATD) could cross the placenta and inhibit aromatase activity (AA) in fetal brain. Eight pregnant ewes were utilized. On Day 50 of pregnancy, four ewes were given ATD-filled Silastic implants, and the other four ewes received sham surgeries. The fetuses were surgically delivered 2 wk later (Day 64 of gestation). High levels of AA (0.8-1.4 pmol/h/mg protein) were present in the hypothalamus and amygdala. Lower levels (0.02-0.1 pmol/h/mg protein) were measured in brain stem regions, cortex, and olfactory bulbs. The Michaelis-Menten dissociation constant (K(m)) for aromatase in the fetal sheep brain was 3-4 nM. No significant sex differences in AA were observed in brain. Treatment with ATD produced significant inhibition of AA in most brain areas but did not significantly alter serum profiles of the major sex steroids in maternal and fetal serum. Concentrations of testosterone in serum from the umbilical artery and vein were significantly greater in male than in female fetuses. No other sex differences in serum steroids were observed. These data demonstrate that high levels of AA are found in the fetal sheep hypothalamus and amygdala during the critical period for sexual differentiation. They also demonstrate that AA can be inhibited in the fetal lamb brain by treating the mother with ATD, without harming fetal development.