Participation of Estrogens in Female Sexual Differentiation of the Brain; Neuroanatomical, Neuroendocrine and Behavioral Evidence

Döhler, K.-D.; Hancke, Juan L.; Srivastava, S.S.; Hofmann, Cecilia; Shryne, James E.; Gorski, Roger A.

doi:10.1016/s0079-6123(08)64430-1

Cited by 148 publications

(81 citation statements)

References 64 publications

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“…Although our study does not discriminate between the classical and alternative hypotheses, it demonstrates definitively that AFP is required for sexual differentiation of the female hypothalamic-pituitary axis. It is most likely that AFP acts by virtue of its capacity to bind estrogen, because the infertility phenotype of the Afp knockout mice resembles that of female animals exposed perinatally to estrogens or estrogen antogonists (13,32,38). As previously suggested (34,37,38), estrogen may be required for female sexual differentiation of the brain, and this requirement may be quantitative rather than qualitative.…”

Section: Discussionmentioning

confidence: 88%

“…It is most likely that AFP acts by virtue of its capacity to bind estrogen, because the infertility phenotype of the Afp knockout mice resembles that of female animals exposed perinatally to estrogens or estrogen antogonists (13,32,38). As previously suggested (34,37,38), estrogen may be required for female sexual differentiation of the brain, and this requirement may be quantitative rather than qualitative. AFP may ensure this quantitative requirement by providing an ''on call'' source of estrogens (38).…”

Section: Discussionmentioning

confidence: 88%

“…An alternative view is that AFP has more than just a neuroprotective role and possibly serves as a specific estrogen transporter that could protect estrogen from degradation and͞or actively transport estrogen into brain cells (32,37). This hypothesis is partially based on the observation that estrogen antagonists can induce anovulatory sterility in postnatally treated female rats (37)(38)(39). Receptor-mediated endocytosis could allow cell type-specific delivery of AFP, in a similar manner to the renal uptake of the complex formed by the vitamin D binding protein (which is related to AFP) and vitamin D3 (40).…”

Section: Discussionmentioning

confidence: 99%

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Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Gabant

Forrester

Nichols

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The alpha-fetoprotein gene (Afp) is a member of a multigenic family that comprises the related genes encoding albumin, alphaalbumin, and vitamin D binding protein. The biological role of this major embryonic serum protein is unknown although numerous speculations have been made. We have used gene targeting to show that AFP is not required for embryonic development. AFP null embryos develop normally, and individually transplanted homozygous embryos can develop in an AFP-deficient microenvironment. Whereas mutant homozygous adult males are viable and fertile, AFP null females are infertile. Our analyses of these mice indicate that the defect is caused by a dysfunction of the hypothalamic͞ pituitary system, leading to anovulation.A lpha-fetoprotein (AFP) is a serum glycoprotein produced at high levels during fetal life by the liver and the visceral endoderm of the yolk sac and at lower levels by the developing gastrointestinal tract (1, 2). The protein expressed by the embryo is transferred to the maternal blood circulation, and abnormal levels of embryonic AFP in the maternal serum are indicative of spina bifida or Down's syndrome in the fetus (3, 4). The synthesis of AFP decreases dramatically after birth, and only trace amounts are detected in the adult (2). AFP expression has been shown to be regulated by transcriptional mechanisms involving a relatively large promoter (P1) and three distant enhancers (for reviews see refs. 5 and 6). More recently it has been shown that the first intron of the Afp gene contains an enhancer and an alternative promoter called P2 (7). The genes of the albumin family are linked in the mammalian genomes, and this conserved organization has been proposed to be important for the developmental expression switch of the genes of the family after birth (8). Several hypotheses have been proposed for the physiological function of AFP (for reviews see refs. 6, 9, and 10). Because AFP is synthesized during the cell cycle G 1 and S phases, it has been hypothesized that it affects cell growth (11, 12). The observation that AFP is able to bind estrogen led to the suggestion that AFP plays a role in sexual differentiation of the brain by protecting the fetus from the effects of circulating estrogen (13). In addition to binding estrogen, AFP, like albumin, is able to bind other steroids as well as endogenous and exogenous substances such as fatty acids, bilirubin, and various pharmaceutical agents, suggesting that AFP may play a general transportation role (for review see ref. 14). Moreover, because cellular internalization of the protein has been reported, AFP could also interact with cytoplasmic chaperone proteins that normally escort nuclear receptors or transcription cofactors through the cytoplasm toward organelle interfaces (15, 16). AFP has also been proposed to be one protein that protects the embryo against the maternal immune system, on the basis of the observation that addition of purified AFP into the culture of splenic or lymph node mononuclear cells exerts a suppressive effect on ant...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Gabant

Forrester

Nichols

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Other examples suggesting brain-intrinsic sex-determining mechanisms include the sexually dimorphic development of midbrain dopaminergic neurons of rodents in vitro (10) and incomplete sex-reversals of behavior after hormone treatments during early development (11)(12)(13)(14)(15). These examples remain inconclusive because of the impossibility of exactly matching experimental procedures (the exact dosage or timing of endocrine treatments used to modify the hormonal environment during brain development) to individual variation in developmental processes.…”

mentioning

confidence: 99%

Male Japanese quails with female brains do not show male sexual behaviors

Gahr

2003

Proc. Natl. Acad. Sci. U.S.A.

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During embryonic development, gonadal steroid hormones (androgens and estrogens) are thought to organize the sexual differentiation of the brain in the heterogametic sexes of higher vertebrates (males in mammals, females in birds). Brain differentiation of the homogametic sexes is thought to proceed by default, not requiring sex hormones for sex-specific organization. In gallinaceous birds such as the Japanese quail, female brain organization is thought to develop via estrogen-dependent demasculinization of a default male brain phenotype. We performed male donor-tofemale host (MF), female-to-male (FM), male-to-male (MM), and female-to-female (FF) isotopic, isochronic transplantation of the forebrain primordium in Japanese quail embryos before gonadal differentiation had occurred; brain chimeras had a forebrain (including the hypothalamus) originating exclusively from donor cells. MM, FF, and MF chimeras all showed sexual behavior governed by the genetic sex of the host. In contrast, FM chimeras (genetically female forebrain, all other tissues genetically male) showed no mounting and only rudimentary crowing behavior. Although MM, FF, MF, and FM chimeras all showed host-typical production of steroid hormones during embryonic life, only FM chimeras were hypogonadal, had atypical low levels of circulating testosterone in adulthood, and showed reduction (crowing) or absence (mounting) of reproductive behaviors. Morphological features of the medial preoptic nucleus (a sexually dimorphic brain area) also were not male-like in FM males. These data demonstrate a brain-intrinsic, genetically determined component that organizes the sex-typical production of gonadal hormones in adulthood and call for a reevaluation of the mechanisms underlying brain sexual differentiation in other higher-vertebrate species.

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“…Essas alterações do comportamento sexual das fêmeas podem ter sido causadas pela redução nos níveis de estrógeno decorrentes da aplicação do citrato de clomifeno. Esses resultados concordam com Döhler et al (1984), que verificaram que o tratamento pós-natal de ratas com o tamoxifeno, outro antagonista de receptores de estrógeno, defeminiza tanto o controle de gonadrotofinas como o comportamento sexual das fêmeas, enquanto a administração concomitante de doses baixas de estradiol impede estes efeitos.…”

Section: Discussionunclassified

Efeito da administração do citrato de clomifeno durante o período perinatal no comportamento sexual, peso dos órgãos e concentração hormonal de ratos Wistar machos e fêmeas

Oliani

Dias

Naves

et al. 2015

Braz. J. Vet. Res. Anim. Sci.

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ResumoForam investigados os efeitos da exposição perinatal ao citrato de clomifeno no comportamento sexual, peso dos órgãos e concentração hormonal de ratos machos e fêmeas. Os animais receberam quatro doses de 2 mg/mL de citrato de clomifeno, no período perinatal (21 dias de gestação -DG21), nos dias 1 (DN1), 2 (DN2) e 3 (DN3) após o nascimento dos filhotes. O tratamento causou desenvolvimento de ovário policístico em 70% das fêmeas, masculinização do comportamento sexual das fêmeas e alteração do comportamento sexual dos machos evidenciado pela redução no número de ejaculações. Em relação aos níveis hormonais, observou-se diminuição de FSH na prole masculina. Concluiu-se que o citrato de clomifeno interfere na capacidade reprodutiva de ratos machos e fêmeas, e na orientação sexual de fêmeas, quando administrado perinatalmente.Palavras-chave: Desruptores endócrinos. Antiestrogênio. Comportamento homossexual. Ejaculação. AbstractThe effects of prenatal exposure to clomiphene citrate in sexual behavior, organ weight and hormone concentrations of male and female rats was evaluated. The animals received four doses of clomiphene citrate 2 mg/mL each during the prenatal period (21 days of gestation -DG21) on days 1 (DN1), 2 (DN2) and 3 (DN3) after the birth of the puppies. The treatment led to the development of polycystic ovaries in 70% of the females, masculinization of female sexual behavior and changes in sexual behavior of males evidenced by the reduction in the number of ejaculations. In regards to hormone levels, a decrease in the FSH levels in male offspring was observed. It was concluded that clomiphene citrate interferes with the reproductive capacity of male and female rats and female sexual orientation when prenatally administered. Keywords

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Participation of Estrogens in Female Sexual Differentiation of the Brain; Neuroanatomical, Neuroendocrine and Behavioral Evidence

Cited by 148 publications

References 64 publications

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Male Japanese quails with female brains do not show male sexual behaviors

Efeito da administração do citrato de clomifeno durante o período perinatal no comportamento sexual, peso dos órgãos e concentração hormonal de ratos Wistar machos e fêmeas

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