Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens exert a wide range of biological effects in both sexes also on non-reproductive systems and organs. Human congenital estrogen deficiency, due to an inactivating mutation of the aromatase gene, leads to the lack of the estrogen synthesis, with gonadotropins and circulating testosterone ranging from normal to elevated. The aromatese-deficient females show hyperandrogenism and virilization at birth with ambiguous genitalia. During childhood there are a dysfunction in the LHRH-LH/FSH axis and a progressive delay in bone age. At puberty they show primary amenorrhea, no breast development, worsening of the virilization and the absence of growth spurt. The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment. These phenotypes suggest the physiological role of estrogens on the skeleton, on pituitary function, on the reproductive system, on glucose metabolism, being the precise mechanism on each of these functions not yet known in detail. The estradiol replacement treatment leads to a complete epiphyseal closure and to the skeletal maturation. Moreover, the increasing knowledge on the role of estrogen in several metabolic pathways could be important for a better management of several metabolic diseases.
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PMID:Human models of aromatase deficiency. 1844 29

In Japanese quail, estrogen's effects on sexual behavior can be divided into three classes based on the underlying mechanisms and time-course of action and release. During embryonic life, the embryonic ovary secretes large amounts of estrogens. In contrast to what is observed in mammals where sexual differentiation essentially proceeds via masculinization of the males, in quail, females are demasculinized by their endogenous ovarian estrogens, an effect that can be blocked by injection of an aromatase inhibitor and mimicked in male embryos by an injection of estradiol. In adulthood, testosterone secreted by the testes is converted into estrogens by the preoptic aromatase. Locally produced estrogens activate male sexual behavior largely through the activation of estrogen receptors resulting in the transcription of a variety of genes, including brain aromatase (genomic effect). Both changes in estrogen production and action are observed within latencies ranging from a few hours to a few days, and are completely reversible. Additionally, brain aromatase activity can be modulated within minutes by calcium-dependent phosphorylations, triggered by variations in glutamatergic neurotransmission. These rapid changes in aromatase activity affect with relatively short latencies (10-15 min) the expression of male sexual behavior in quail and also in mice. Overall, the effects of estrogens on sexual behavior can thus be categorized into three classes: organizational (irreversible genomic action during ontogeny), activational (reversible genomic action during adulthood) and rapid nongenomic effects. Rapid and slower changes in brain aromatase activity match well with the two modes of estrogen action on behavior and provide temporal variations in the estrogens' bioavailability that should be able to support the entire range of established effects for this steroid.
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PMID:Estradiol, a key endocrine signal in the sexual differentiation and activation of reproductive behavior in quail. 1848 Dec 66

Aromatase is a steroidogenic enzyme that catalyzes the conversion of androgens to estrogens in vertebrates. Modulation of this enzyme's activity by xenobiotic exposure has been shown to adversely affect gonad differentiation in a number of diverse species. We hypothesized that exposure to the aromatase inhibitor, fadrozole, during the larval development of the tropical clawed frog, Xenopus tropicalis, would result in masculinization of the developing female gonad. Tadpoles were exposed to fadrozole at nominal concentrations from 1 to 64 microg/L in a flow-through system from < 24 h post-fertilization (Nieuwkoop Faber (NF) stage 15-20) to metamorphosis (NF stage 66). At metamorphosis, morphologically examined gonads indicated complete masculinization of all tadpoles at concentrations of 16 microg/L and above and a significant bias in sex ratio towards males at concentrations of 1 microg/L and above. No effects on time to metamorphosis, body mass, or body length were observed. A random subsample of frogs was raised to reproductive maturity (39 weeks post-fertilization) in control water. All frogs exposed as tadpoles to 16 microg/L fadrozole or greater possessed testes at sexual maturity. Intersexed gonads characterized by the presence of both testicular and ovarian tissue were observed in 12% of frogs in the 4 microg/L treatment. No differences in estradiol, testosterone, or vitellogenin plasma concentrations were observed in exposed males or females compared to controls. Females in the 4 microg/L treatment possessed a significantly greater percentage of pre-vitellogenic oocytes than controls and were significantly smaller in body mass. No differences in sperm counts were observed in exposed males compared to controls. Results from this study demonstrate that larval exposure to an aromatase inhibitor can result in the complete masculinization of female gonads. These masculinized females are phenotypically indistinguishable from normal males at adulthood. Lower levels of aromatase inhibition resulted in intersexed gonads and possible female reproductive impairment at adulthood. These results indicate that exposure of amphibians to xenobiotics capable of inhibiting aromatase would result in adverse reproductive consequences.
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PMID:Sex reversal of the amphibian, Xenopus tropicalis, following larval exposure to an aromatase inhibitor. 1880 92

The objective of this study was to contribute to our understanding of the role of sex steroids in fish sex differentiation and male maturation. Sexually undifferentiated sea bass were administered 17alpha-methyldihydrotestosterone (MDHT), estradiol-17beta (E(2)), fadrozole (Fz), cyproterone acetate (CPA) or tamoxifen (Tx). MDHT produced 100% males whereas E(2) and Tx resulted in 100% females. Fz produced 95% males while CPA did not alter sex ratios. E(2) treatment did not affect gonadal aromatase (cyp19a) expression levels, supporting the possibility that the feminizing effect of exogenous E(2) are not directly related to cyp19a regulation. Both MDHT and Fz decreased cyp19a expression. Moreover, androgen receptor (ar) expression levels increased during development in all but the MDHT group, suggesting that early exposure to an androgen down-regulates subsequent ar expression in males and that Fz does not interact with the androgen receptor. Together, these observations indicate that although MDHT and Fz result in a similar phenotype, the molecular pathways involved are likely different, and show that Fz masculinization is the consequence of inhibited ovarian differentiation rather than of a direct androgenic effect. Further, since CPA did not alter sex ratios when administered during the period of highest androgen sensitivity, we suggest that androgens are not required for initial testicular differentiation in the sea bass. MDHT and Fz did not alter the number of precocious males but reduced and increased, respectively, their gonadosomatic index (GSI). In addition, Fz had lasting effects on the GSI of precocious and non-precocious males, probably due to alterations of estrogen function in the testis.
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PMID:Masculinization of the European sea bass (Dicentrarchus labrax) by treatment with an androgen or aromatase inhibitor involves different gene expression and has distinct lasting effects on maturation. 1898 44

The pejerrey (Odontesthes bonariensis) is a teleost fish with strong temperature-dependent sex determination (TSD). Several studies have shown that dmrt1 and gonadal aromatase (cyp19a1) are implicated in the sex differentiation process in teleosts but little is known on the expression balance and endocrine regulation of these two genes during TSD. This study was designed to clarify the expression patterns of both genes during gonadal sex differentiation of pejerrey reared at female-, male- and mixed-sex-producing temperatures (FPT, MPT, and MixPT, respectively). The expression of dmrt1 was found to be significantly higher during gonadal sex differentiation at MPT compared to FPT. Conversely, cyp19a1 expression clearly increased during differentiation at FPT but not at MPT. The expression of both genes at MixPT showed a dimorphic profile with individual values resembling either those at the MPT or FPT. Administration of exogenous 17beta-estradiol down- and up-regulated the expression of dmrt1 and cyp19a1, respectively, regardless of temperature, and rescued the female phenotype at the MPT. However, treatment with the aromatase inhibitor Fadrozole caused masculinization without changing the pattern of gene expression. These results are strong evidence of the involvement of both genes in the gonadal differentiation process of pejerrey. The involvement of estradiol is discussed.
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PMID:Dimorphic expression of dmrt1 and cyp19a1 (ovarian aromatase) during early gonadal development in pejerrey, Odontesthes bonariensis. 1927 34

The present review focuses on the roles of estrogens and aromatase (Cyp19a1a), the enzyme needed for their synthesis, in fish gonadal sex differentiation. Based on the recent literature, we extend the already well accepted hypothesis of an implication of estrogens and Cyp19a1a in ovarian differentiation to a broader hypothesis that would place estrogens and Cyp19a1a in a pivotal position to control not only ovarian, but also testicular differentiation, in both gonochoristic and hermaphrodite fish species. This working hypothesis states that cyp19a1a up-regulation is needed not only for triggering but also for maintaining ovarian differentiation and that cyp19a1a down-regulation is the only necessary step for inducing a testicular differentiation pathway. When considering arguments for and against, most of the information available for fish supports this hypothesis since either suppression of cyp19a1a gene expression, inhibition of Cyp19a1a enzymatic activity, or blockage of estrogen receptivity are invariably associated with masculinization. This is also consistent with reports on normal gonadal differentiation, and steroid-modulated masculinization with either androgens, aromatase inhibitors or estrogen receptor antagonists, temperature-induced masculinization and protogynous sex change in hermaphrodite species. Concerning the regulation of fish cyp19a1a during gonadal differentiation, the transcription factor foxl2 has been characterized as an ovarian specific upstream regulator of a cyp19a1a promoter that would co-activate cyp19a1a expression, along with some additional partners such as nr5a1 (sf1) or cAMP. In contrast, upstream factors potentially down-regulating cyp19a1a during testicular differentiation are still hypothetical, such as the dmrt1 gene, but their definitive characterization as testicular repressors of cyp19a1a would strongly strengthen the hypothesis that early testicular differentiation would need active repression of cyp19a1a expression.
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PMID:Ovarian aromatase and estrogens: a pivotal role for gonadal sex differentiation and sex change in fish. 1928 25

Release of testosterone during early development is necessary for masculinization of brain structures in rodents. Wu et al. (2009) now elucidate the neuronal changes caused by aromatase-mediated conversion of testosterone into estrogen in perinatal mice and the ensuing effects on adult behavior.
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PMID:Sex on the brain. 1980 54

Sex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate extensive sexual dimorphism in the number and projections of aromatase-expressing neurons. The masculinization of these cells is independent of AR but can be induced in females by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.
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PMID:Estrogen masculinizes neural pathways and sex-specific behaviors. 1980 47

In vertebrates, sex is normally determined by genotype. However, in poikilothermal vertebrates, including reptiles, amphibians, and fishes, sex determination is greatly influenced by environmental factors, such as temperature. Little is known about the molecular mechanisms underlying environmental sex determination in these species. The Japanese flounder (Paralichthys olivaceus) is a teleost fish with an XX/XY sex determination system. However, XX flounder can be induced to develop into predominantly either phenotypic females or males, by rearing at 18 or 27 C, respectively, during the sex differentiation period. Therefore, the flounder provides an excellent model to study the molecular mechanisms underlying temperature-dependent sex determination. We previously showed that an aromatase inhibitor, an antiestrogen, and 27 C treatments cause masculinization of XX flounder, as well as suppression of mRNA expression of ovary-type aromatase (cyp19a1), a steroidogenic enzyme responsible for the conversion of androgens to estrogens in the gonads. Furthermore, estrogen administration completely inhibits masculinization by these treatments, suggesting suppression of cyp19a1 mRNA expression, and the resultant estrogen biosynthesis may trigger masculinization of the XX flounder induced by high water temperature. Here, we demonstrated that cortisol causes female-to-male sex reversal by directly suppressing cyp19a1 mRNA expression via interference with cAMP-mediated activation and that metyrapone (an inhibitor of cortisol synthesis) inhibits 27 C-induced masculinization of XX flounder. Moreover, cortisol concentrations in 27 C-reared juveniles were significantly higher than in 18 C-reared fishes during sexual differentiation. These results strongly suggest that masculinization by high water temperature is ascribable to elevation of cortisol concentration during gonadal sex differentiation in the flounder.
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PMID:Cortisol is involved in temperature-dependent sex determination in the Japanese flounder. 2053 25

In many vertebrate species, sex is determined at fertilization of zygotes by sex chromosome composition, knows as genotypic sex determination (GSD). But in some species-fish, amphibians and reptiles-sex is determined by environmental factors; in particular by temperature-dependent sex determination (TSD). However, little is known about the mechanisms involved in TSD and GSD. How does TSD differ from GSD? As is well known, genes that activated downstream of sex-determining genes are conserved throughout all classes of vertebrates. What is the main factor that determines sex, then? Sex steroids can reverse sex of several species of vertebrate; estrogens induce the male-to-female sex-reversal, whereas androgens do the female-to-male sex-reversal. For such sex-reversal, a functioning sex-determining gene is not required. However, in R. rugosa CYP19 (P450 aromatase) is expressed at high levels in indifferent gonads before phenotypic sex determination, and the gene is also active in the bipotential gonad of females before sex determination. Thus, we may predict that an unknown factor, a common transcription factor locates on the X and/or W chromosome, intervenes directly or indirectly in the transcriptional up-regulation of the CYP19 gene for feminization in species of vertebrates with both TSD and GSD. Similarly, an unknown factor on the Z and/or Y chromosome probably intervenes directly or indirectly in the regulation of androgen biosynthesis for masculinization. In both cases, a sex-determining gene is not always necessary for sex determination. Taken together, sex steroids may be the key-factor for sex determination in some species of vertebrates.
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PMID:The mechanism of sex determination in vertebrates-are sex steroids the key-factor? 2062 3


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