Sex Steroid-related Genes Research Articles

Thyroid hormones and androgens differentially regulate gene expression in testes and ovaries of sexually mature Silurana tropicalis

A series of ex vivo exposures using testicular and ovarian tissues of sexually mature Western clawed frogs (Silurana tropicalis) were designed to examine molecular mechanisms of thyroid hormone (TH) and androgen crosstalk sans hypophyseal feedback as well as investigate potential sex-specific differences. Tissues were exposed ex vivo to either triiodothyronine (T3), iopanoic acid (IOP), one co-treatment of IOP + 5α-dihydrotestosterone (5α-DHT), 5α-DHT, 5β-dihydrotestosterone (5β-DHT), or testosterone (T). Direct exposure to different androgens led to androgen specific increases in thyroid receptor and deiodinase transcripts in testes (trβ and dio1) but a decrease in expression in ovaries (trβ and dio3), suggesting that male and female frogs can be differently affected by androgenic compounds. Moreover, exposure to select androgens differentially increased estrogen-related transcription (estrogen receptor alpha (erα) and aromatase (cyp19)) and production (estradiol) in ovaries and testes indicating the activation of alternate metabolic pathways yielding estrogenic metabolites. Sex-steroid-related transcription (i.e., steroid 5α-reductase type 2 (srd5α2) and erα) and production (i.e., 5α-DHT) were also differentially regulated by THs. The presence and frequency of transcription factor binding sites in the putative promoter regions of TH- and sex steroid-related genes were also examined in S. tropicalis, rodent, and fish models using in silico analysis. In summary, this study provides an improved mechanistic understanding of TH- and androgen-mediated actions and reveals differential transcriptional effects as a function of sex in frogs.

Influence of DEHP on thyroid, sex steroid-related genes and gonadal differentiation in Rana chensinensis tadpoles.

In the present study, responses of the Chinese brown frog (Rana chensinensis) to exposure to di-2-ethylhexyl phthalate (DEHP), a common plasticizer, during the larval period were characterized. The effects of DEHP on metamorphosis rate, thyroid hormone, thyroid histology and the expression of genes involved in the steroid hormone synthesis in gonad were investigated. Metamorphosis rate and 50 percent of the tadpoles to reach Gosner stage 42 (T0.5 ) were significantly slower in all DEHP groups. The thyroid glands of the tadpoles exposed to DEHP clearly exhibited colloid depletion. In addition, decreased concentrations of T4 and T3 were observed in the tadpoles exposed to DEHP. Moreover, the highest DEHP exposure (10 µmol/L DEHP) showed increased ratio of females significantly. Also, up-regulation significantly of transcripts of cytochrome P450 aromatase (CYP19) gene was detected in male tadpoles exposed to DEHP. The present results indicate that this increase in estrogens could lead to female-biased sex ratio in DEHP exposure group. Taken together, the present study indicates that DEHP disrupt thyroid hormone and sex steroid signaling in R. chensinensis tadpoles. Our present observations support evidence of a crosstalk between TH and sex steroids in gonad differentiation.

Further investigations of the relation between polymorphisms in sex steroid related genes and autistic-like traits

Autism spectrum disorders (ASDs) are more prevalent in boys than in girls, indicating that high levels of testosterone during early development may be a risk factor. Evidence for this hypothesis comes from studies showing associations between fetal testosterone levels, as well as indirect measures of prenatal androgenization, and ASDs and autistic-like traits (ALTs). In a recent study we reported associations between ALTs and single nucleotide polymorphisms (SNPs) in the genes encoding estrogen receptor 1 (ESR1), steroid-5-alpha-reductase, type 2 (SRD5A2) and sex hormone-binding globulin (SHBG) in a subset (n=1771) from the Child and Adolescent Twin Study in Sweden (CATSS). The aim of the present study was to try to replicate these findings in an additional, larger, sample of individuals from the CATSS (n=10,654), as well as to analyze additional SNPs of functional importance in SHBG and SRD5A2. No associations between the previously associated SNPs in the genes ESR1 and SRD5A2 and ALTs could be seen in the large replication sample. Still, our results show that two non-linked SNPs (rs6259 and rs9901675) at the SHBG gene locus might be of importance for language impairment problems in boys. The results of the present study do not point toward a major role for the investigated SNPs in the genes ESR1 and SRD5A2 in ALTs, but a possible influence of genetic variation in SHBG, especially for language impairment problems in boys, cannot be ruled out.

Associations between polymorphisms in sex steroid related genes and autistic-like traits

Sex differences in psychiatric disorders are common, which is particularly striking in autism spectrum disorders (ASDs) that are four times more prevalent in boys. High levels of testosterone during early development have been hypothesized to be a risk factor for ASDs, supported by several studies showing fetal testosterone levels, as well as indirect measures of prenatal androgenization, to be associated with ASDs and autistic-like traits (ALTs). Further, the importance of sex steroid related genes in ASDs is supported by studies reporting associations between polymorphisms in genes involved in sex steroid synthesis/metabolism and ASDs and ALTs. The aim of the present study was to investigate possible associations between 29 single nucleotide polymorphisms (SNPs) in eight genes related to sex steroids and autistic features. Individuals included in the study belong to a subset (n=1771) from The Child and Adolescent Twin Study in Sweden (CATSS), which are all assessed for ALTs. For two SNPs, rs2747648 located in the 3'-UTR of ESR1 encoding the estrogen receptor alpha and rs523349 (Leu89Val) located in SRD5A2 encoding 5-alpha-reductase, type 2, highly significant associations with ALTs were found in boys and girls, respectively. The results of the present study suggest that SNPs in sex steroid related genes, known to affect gene expression (rs2747648 in ESR1) and enzymatic activity (Leu89Val in SRD5A2), seem to be associated with ALTs in a general population. In conclusion, the current findings provide further support for a role of sex steroids in the pathophysiology of ASDs.

Developmental expression of sex steroid- and thyroid hormone-related genes and their regulation by triiodothyronine in the gonad-mesonephros of a Neotropical frog, Physalaemus pustulosus

Gonadal differentiation in frogs is affected by sex steroids and thyroid hormones (THs); however, the genes controlling differentiation and the molecular effects of THs in the gonad are not clear and have only been investigated in a few anuran species. In this study, we established developmental profiles and TH regulation of sex steroid- and TH-related genes in the gonad-mesonephros complex (GMC) of the túngara frog (Physalaemus pustulosus), and compared the results to our previous research in another tropical frog, Silurana tropicalis. The developmental profiles allowed us to identify three genes as markers of ovarian development. During metamorphosis, aromatase (cyp19), estrogen receptor α, and steroid 5α-reductase 1 (srd5alpha1) were higher in the GMC of putative and morphological females. Acute exposure to triiodothyronine (T3) decreased GMC expression of srd5alpha1 and cyp19, while increasing TH-related genes in premetamorphic tadpoles. The regulation of sex steroid-related genes differed significantly from our previous study in S. tropicalis. P. pustulosus and S. tropicalis share ecological, developmental, and reproductive characteristics; however, they are not closely related. These results along with our previous research in the tadpole brain support the hypothesis that evolutionary convergence is not important in understanding differences in the effects of TH on sex steroid-related genes in frogs. Finally, we propose that T3 induces male gonadal development but this can be achieved through different mechanisms depending on the species.

P1-507 Polymorphisms in genes related to sex steroid transport and signalling modulate menopausal hormone therapy effect on risk of colorectal cancer

IntroductionMenopausal hormone therapy (MHT) has been associated with reduced colorectal cancer (CRC) risk. Since the underlying biological mechanisms of MHT effects on CRC are unknown, we investigated whether single nucleotide...

Transcript profiles and triiodothyronine regulation of sex steroid- and thyroid hormone-related genes in the gonad–mesonephros complex of Silurana tropicalis

In amphibians, the main role of thyroid hormones (THs) is to regulate metamorphosis; however, there is evidence that THs also affect gonadal sexual differentiation. In this study, Silurana ( Xenopus) tropicalis tadpoles were exposed to triiodothyronine (T3; 0, 0.5, 5 and 50 nM), the bioactive form of THs for 48 h. Real-time RT-PCR analyses in the gonad–mesonephros complex (GMC) revealed that TH- and androgen-related genes were positively regulated, while estrogen receptor β was negatively regulated by T3. Together, these results are in agreement with the masculinizing effect of THs in amphibians. Profiles of TH- and sex steroid-related genes in the GMC during metamorphosis of S. tropicalis suggest that THs are important regulators of sex steroid-related gene expression in the GMC. This study provides evidence that the GMC is a target of THs but that a complex interplay exists between THs and sex steroids during gonadal sexual development.

Regulation of thyroid hormone-, oestrogen- and androgen-related genes by triiodothyronine in the brain of Silurana tropicalis.

Amphibian metamorphosis is an excellent example of hormone-dependent control of development. Thyroid hormones (THs) regulate almost all aspects of metamorphosis, including brain development and larval neuroendocrine function. Sex steroids are also important for early brain function, although little is known about interactions between the two hormonal systems. In the present study, we established brain developmental profiles for thyroid hormone receptors (tralpha and trbeta), deiodinases (dio1, dio2 and dio3), aromatase (cyp19) mRNA and activity, oestrogen receptors (eralpha and erbeta), androgen receptor (ar) and 5α-reductases (srd5alpha1 and srd5alpha2) mRNA during Silurana (Xenopus) tropicalis metamorphosis. Real-time reverse transcriptase-polymerase chain reaction analyses revealed that all of the genes were expressed in the brain and for most of the genes expression increased during development, with the exception of dio2, srd5alpha1 and srd5alpha2. The ability of premetamorphic tadpoles to respond to exogenous THs was used to investigate the regulation of TH- and sex steroid-related genes in the brain during development. Exposure of premetamorphic tadpoles to triiodothyronine (T3; 0, 0.5, 5 and 50 nm) for 48 h resulted in concentration-dependent increases in trbeta, dio2, dio3, eralpha and erbeta. Expression of srd5alpha2 showed large increases (six- to 7.5-fold) for all three concentrations of T3. No changes were detected in dio1, ar and cyp19 transcript levels; however, cyp19 activity increased significantly at 50 nm T3. The results obtained suggest that expression of TH-related genes and er during development could be regulated by rising levels of THs, as previously documented in Lithobates (Rana) pipiens. The positive regulation of srd5alpha by T3 in the brain suggests that endogenous TH levels help maintain or control the rate at which srd5alpha mRNA levels decrease as metamorphosis progresses. Finally, we have identified sex steroid-related genes that are responsive to T3, providing additional evidence of crosstalk between THs and sex steroids in the tadpole brain.

2061 GENETIC POLYMORPHISM INFLUENCES INDIVIDUAL VARIATIONS IN SERUM TESTOSTERONE LEVELS IN PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 20102061 GENETIC POLYMORPHISM INFLUENCES INDIVIDUAL VARIATIONS IN SERUM TESTOSTERONE LEVELS IN PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY Shintaro Narita, Kazuyuki Numakura, Takashi Obara, Hiroshi Tsuruta, Mitsuru Saito, Yohei Horikawa, Norihiko Tsuchiya, and Tomonori Habuchi Shintaro NaritaShintaro Narita More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Takashi ObaraTakashi Obara More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Yohei HorikawaYohei Horikawa More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2108AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Individual variations in serum testosterone levels after androgen deprivation therapy (ADT) have been reported. The objectives of this study were to assess changes in serum testosterone levels after administration and cessation of luteinizing hormone-releasing hormone agonist (LHRHa) and to investigate prognostic factors for testosterone recovery including genetic variations in sex steroid-related genes in prostate cancer (PCa) patients treated with ADT. METHODS A total of 26 localized PCa patients treated with ADT and external beam radiotherapy were enrolled. A neoadjuvant maximal androgen blockade was given for 2 months, and LHRHa was continued for 1 year after radiation therapy. Serum testosterone levels were measured every 3 months. Castrate testosterone levels were defined as 50 ng/dL or less. Testosterone recoveries to supracastrate levels and to the normal range were estimated using the Kaplan-Meier method. Prognostic factors for testosterone recovery, including clinical parameters and six single nucleotide polymorphisms in five genes (VDR, SRD5A2, CYP17, CYP19, and GnRHR), were examined. RESULTS At 9 months after LHRHa cessation, serum testosterone levels returned to supracastrate levels in 14 (53.8%) and to the normal range in 10 (38.5%) of the 26 patients. The median duration of serum testosterone recoveries to supracastrate levels was 10.6 months. The duration of testosterone recoveries to supracastrate levels in patients aged≥72 years was significantly longer than that in patients aged <72 years (14.5±2.7 vs. 9.4±0.8 months,p=0.027). Pretreatment serum testosterone levels and LHRHa type were not associated with testosterone recovery. Patients carrying the bb genotype of the BsmI polymorphism in VDR had a significantly longer testosterone recovery time than that taken by those carrying the Bb genotype (12.0±2.0 vs. 8.2±0.7 months, p=0.045). CONCLUSIONS Variations in the testosterone recovery after LHRHa cessation were found in PCa patients treated with LHRHa followed by external beam radiotherapy. Older age and the bb genotype of the BsmI polymorphism in VDR influenced the slow testosterone recovery in patients with PCa. Akita, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e801 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita More articles by this author Kazuyuki Numakura More articles by this author Takashi Obara More articles by this author Hiroshi Tsuruta More articles by this author Mitsuru Saito More articles by this author Yohei Horikawa More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Genetic Variations in Sex Steroid-Related Genes as Predictors of Serum Estrogen Levels in Men

Genetic Variations in Sex Steroid-Related Genes as Predictors of Serum Estrogen Levels in Men

Expression and T3 regulation of thyroid hormone- and sex steroid-related genes during Silurana ( Xenopus) tropicalis early development

In amphibians, thyroid hormones (THs) are the primary regulators of metamorphosis; however, their physiological role during embryogenesis remains unclear. First, we established complete developmental profiles for TH receptors ( tralpha and trbeta), deiodinases ( dio; types 1, 2, 3), estrogen receptors ( eralpha and erbeta) and androgen receptor ( ar) mRNA levels during embryogenesis and early larval stages in Silurana ( Xenopus) tropicalis (from Nieuwkoop and Faber (NF) stage 2 until NF 46). Real-time RT-PCR analyses in whole embryos and larvae revealed that all transcripts except tralpha were detected throughout development; tralpha only appears after gastrulation. The first significant increase in the expression of tralpha and trbeta was observed before hatching, between NF 21 and NF 27 (2.5- and 11-fold, respectively). In order to test if these genes could be regulated by THs during early larval development, embryos were exposed to triiodothyronine (T3; 0.5, 5.0, 50 nM) from NF 27 to NF 46. T3 exposure caused a dose-dependent increase relative to control in the expression of tralpha, trbeta, dio (types 2 and 3), ar, and 5α-reductase type 1 in whole larvae. These results indicate that in S. tropicalis, tr and dio can be induced by T3 as early as NF 46, a response that had only been characterized later during frog metamorphosis. In addition, T3 also affected androgen-related gene expression, supporting our hypothesis that THs are involved in male development in frogs.

Genetic Variations in Sex Steroid-Related Genes as Predictors of Serum Estrogen Levels in Men

The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids. The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men. Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 +/- 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 +/- 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 +/- 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry. The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 x 10(-6)). This association was confirmed both in the MrOS Sweden study (P = 9 x 10(-7)) and in the MrOS US study (P = 1 x 10(-4)). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 x 10(-14)) and E1 (P = 8 x 10(-19)) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05). rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.

Sex steroid-related genes and male-to-female transsexualism

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.