RESUMO
OBJECTIVE: The follicle-stimulating hormone subunit beta gene rs10835638 variant (c.-211G>T) may have detrimental effects on fertility and protective effects against endometriosis. A case-control analysis was performed, aiming to investigate the possible relationship between this variant and the development and/or progression of endometriosis. METHODS: This study included 326 women with endometriosis and 482 controls without endometriosis, both confirmed by inspection of the pelvic cavity during surgery. Genotyping was performed using a TaqMan real-time polymerase chain reaction assay. Genotype and allele frequencies and genetic models were compared between the groups. RESULTS: The genotype and allele frequencies of the rs10835638 variant did not differ between women with and those without endometriosis. Subdividing the endometriosis group into fertile and infertile groups did not result in a significant difference in these frequencies. However, the subgroup with minimal/mild endometriosis had a higher frequency of the GT genotype than the Control Group, regardless of fertility. The T allele was significantly more common in women with minimal/mild endometriosis than in the Control Group in the recessive model. CONCLUSION: The T allele is associated with the development of minimal/mild endometriosis in Brazilian women.
Assuntos
Endometriose , Humanos , Feminino , Endometriose/genética , Brasil , Polimorfismo de Nucleotídeo Único/genética , Subunidade beta do Hormônio Folículoestimulante/genética , Genótipo , Frequência do Gene , Estudos de Casos e ControlesRESUMO
Background: Single nucleotide variants (SNVs) FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A were reported to be associated with the variability in FSH and LH levels, and in vitro fertilization (IVF) outcomes. In this study, we aimed to evaluate the effects of FSHB:c.-211G>T, FSHR:c.919G>A, and FSHR:c.2039G>A variants, alone and combined, on the hormonal profile and reproduction outcomes of women with endometriosis. Methods: A cross-sectional study was performed comprising 213 infertile Brazilian women with endometriosis who underwent IVF treatment. Genotyping was performed using TaqMan real-time PCR. Variables were compared according to the genotypes of each variant and genetic models, and the combined effects of the SNVs were evaluated using the multifactorial dimensionality reduction method. Results: FSHB:c.-211G>T affected LH levels in women with overall endometriosis and minimal/mild disease. FSHR:c.919G>A affected FSH levels in women with overall endometriosis and the number of oocytes retrieved in those with moderate/severe endometriosis. Moreover, the FSHR:c.2039G>A affected FSH levels in women with overall endometriosis, LH levels and total amount of rFSH in those with minimal/mild disease, and number of follicles and number of oocytes retrieved in those with moderate/severe endometriosis. No effect on hormone profile or reproductive outcomes was observed when the genotypes were combined. Conclusions: Variants of the FSHB and FSHR genes separately interfered with the hormonal profiles and IVF outcomes of women with endometriosis.
Assuntos
Endometriose/genética , Subunidade beta do Hormônio Folículoestimulante/genética , Infertilidade Feminina/genética , Polimorfismo de Nucleotídeo Único/genética , Resultado da Gravidez/genética , Receptores do FSH/genética , Reprodução/genética , Adulto , Alelos , Brasil , Estudos Transversais , Feminino , Frequência do Gene/genética , Genótipo , Humanos , GravidezRESUMO
Follicle stimulating hormone (FSH) is produced by the pituitary gland in a coordinated hypothalamic-pituitary-gonadal (HPG) axis event, plays important roles in reproduction and germ cell development during different phases of reproductive development (fetal, neonatal, puberty, and adult life), and is consequently essential for fertility. FSH is a heterodimeric glycoprotein hormone of two dissociable subunits, α and ß. The FSH ß-subunit (FSHß) function starts upon coupling to its specific receptor: follicle-stimulating hormone receptor (FSHR). FSHRs are localized mainly on the surface of target cells on the testis and ovary (granulosa and Sertoli cells) and have recently been found in testicular stem cells and extra-gonadal tissue. Several reproduction disorders are associated with absent or low FSH secretion, with mutation of the FSH ß-subunit or the FSH receptor, and/or its signaling pathways. However, the influence of FSH on germ cells is still poorly understood; some studies have suggested that this hormone also plays a determinant role in the self-renewal of germinative cells and acts to increase undifferentiated spermatogonia proliferation. In addition, in vitro, together with other factors, it assists the process of differentiation of primordial germ cells (PGCLCs) into gametes (oocyte-like and SSCLCs). In this review, we describe relevant research on the influence of FSH on spermatogenesis and folliculogenesis, mainly in the germ cell of humans and other species. The possible roles of FSH in germ cell generation in vitro are also presented.
Assuntos
Hormônio Foliculoestimulante/metabolismo , Células da Granulosa/metabolismo , Ovário/metabolismo , Células de Sertoli/metabolismo , Animais , Dimerização , Feminino , Fertilidade , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Células Germinativas/metabolismo , Gonadotropinas/metabolismo , Humanos , Masculino , Camundongos , Ovário/embriologia , Ovário/crescimento & desenvolvimento , Hipófise/embriologia , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Ratos , Receptores do FSH/metabolismo , Reprodução , Maturidade Sexual , Espermatogênese/genética , Espermatogônias/citologiaRESUMO
CONTEXT: Transient thelarche (TT), that is, the appearance, regression and subsequent reappearance of breast buds, is a frequent phenomenon, but little is known about pubertal transition in these girls. OBJECTIVE: To describe pubertal progression, growth, genotypes, reproductive hormones and growth factors in girls with TT compared to those who do not present TT (non-TT). DESIGN: Retrospective analysis of a longitudinal population-based study. PATIENTS OR OTHER PARTICIPANTS: Girls (n = 508) of the Chilean Growth and Obesity cohort. MEASUREMENTS: Pubertal progression, reproductive hormones, follicle stimulating hormone (FSH) beta subunit/FSH receptor gene single nucleotide polymorphisms and growth. RESULTS: Thirty-seven girls (7.3%) were presented TT. These girls entered puberty by pubarche more frequently (51%) than girls with normal progression (non-TT; n = 471; 23%, P = .005). Girls with TT who were under 8 years old had lower androgens, anti-Müllerian hormone (AMH), luteinizing hormone (LH) and oestradiol (all P < .05) than older girls with TT. At the time of Tanner breast stage 2 (B2), girls with TT had higher androgens, LH, FSH, IGF1, LH, insulin and oestradiol (P < .01) than at the time of TT. TT girls were older at B2 (10.3 ± 1.1 vs. 9.2 ± 1.2 years, P < .001) and menarche (12.3 ± 0.8 vs. 12.0 ± 1.0 years, P = .040) than their counterparts (non-TT). No differences in anthropometric variables or FSHB/FSHR genotypes were detected. CONCLUSION: Transient thelarche is a frequent phenomenon that does not appear to be mediated by hypothalamic-pituitary-gonadal axis activation or by adiposity. Hormonal differences between earlier TT and later TT suggest that their mechanisms are different.
Assuntos
Subunidade beta do Hormônio Folículoestimulante , Hormônio Luteinizante , Feminino , Hormônio Foliculoestimulante , Subunidade beta do Hormônio Folículoestimulante/genética , Genótipo , Humanos , Puberdade , Estudos RetrospectivosRESUMO
Lambari-do-rabo-amarelo Astyanax altiparanae in the wild reproduce during spring and summer, but females undergo vitellogenesis throughout the year, including the non-spawning winter period when water temperatures are low. The present study investigated the physiological role of temperature modulation on the hypothalamus-pituitary-gonads axis of lambari during winter, as well as the effects of gonadotropin releasing hormone agonist (GnRHa) therapy. Captive females were exposed to two different temperatures (20⯰C and 27⯰C) and were injected weekly with GnRHa for 21â¯days during winter (Control, CTR; Low dose; LD and high dose of GnRHa, HD). At the end of the 21-days period gonadosomatic index (GSI), oocyte stage of development and theoretical fecundity were evaluated, together with plasma levels of 17ß-estradiol (E2). Gene expression of the two pituitary gonadotropins follicle-stimulating hormone (fshß) and luteinizing hormone (lhß), as well as hepatic vitellogenin-A (vtgA) expression were also analyzed. At the end of the experimental period, females from the six different experimental conditions were induced to spawn using human chorionic gonadotropin (hCG). Spawning performance parameters and plasma levels of the maturation inducing steroid (MIS) were analyzed. Gene expression of fshß did not change with temperature manipulation, but females exposed to 27⯰C and supplemented with a HD of GnRHa exhibited an increased fshß gene expression, associated with higher E2 levels. The higher water temperature alone was able to increase E2 levels. At both water temperatures GnRHa injections induced a decrease in E2 levels. GnRHa injected females had a lower vtgA gene expression levels at 20⯰C. Even with differences in the gene expression of gonadotropins among the various temperature/GnRHa treatments, GSI and oocyte diameter did not change, but GnRHa enhanced the number of vitellogenic oocytes at 20⯰C. The reproductive performance of lambari induced to spawn with hCG was better after the combined treatment with GnRHa and summer temperature.
Assuntos
Cruzamento , Characidae/fisiologia , Hormônio Liberador de Gonadotropina/farmacologia , Reprodução/efeitos dos fármacos , Estações do Ano , Temperatura , Animais , Characidae/sangue , Estradiol/sangue , Feminino , Fertilidade/efeitos dos fármacos , Subunidade beta do Hormônio Folículoestimulante/genética , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Gametogênese/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Lineares , Hormônio Luteinizante Subunidade beta/genética , Hormônio Luteinizante Subunidade beta/metabolismo , Masculino , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Reprodução/fisiologia , Esteroides/sangue , Vitelogeninas/genética , Vitelogeninas/metabolismoRESUMO
BACKGROUND: Follicle-stimulating hormone (FSH) is essential to the hypothalamic-pituitary-gonadal axis, playing a key role in human reproduction. It is a heterodimer comprised of a hormone-specific ß-chain (FSH-ß) that is associated with an α-chain. It exerts its biological activities by binding to the FSH receptor (FSHR). The ß-subunit, which is encoded by the FSHB gene, is responsible for ensuring binding specificity to the FSHR. There is a promoter polymorphism in this gene, c.-211G>T (rs10835638), upstream of the transcription start site; and in vitro studies have reported that the T allele decreases FSHB transcription in gonadotrophic cells. AIMS: Investigate the possible effects of the FSHB c.-211G/T polymorphism on hormonal profile and in in vitro fertilization (IVF)/intracytoplasmic sperm injection outcomes in normoovulatory Brazilian women. METHODS: A cross-sectional study of 140 women (median age = 33 years [CI: 32-34]) with infertility mainly caused by male (n = 85) or tuboperitoneal (n = 55) factors. In this study we evaluated FSH, estradiol, luteinizing hormone (LH), progesterone, prolactin and anti-Mullerian hormone levels, and antral follicle counting (AFC). Genotyping was performed using the TaqMan real-time polymerase chain reaction methodology. RESULTS: The wild-type allele G was found in 86.4% and the polymorphic allele T in 13.6% of the women respectively. The TT genotype was not found in any women. Women carrying the GT genotype had a poorer response more frequently to controlled ovarian hyperstimulation when compared to individuals with the GG genotype (47.4% vs. 26.5%, p = 0.010), higher LH levels (3.1 IU/mL vs. 2.4 IU/mL, p = <0.001), lower AFC (8.0 vs. 10.0, p = 0.03), oocytes retrieved (3.0 vs. 5.0, p = 0.03), MII (3.0 vs. 4.0, p = 0.02), and embryos (2.0 vs. 3.0, p = 0.02). Despite these findings, no difference was observed in pregnancy rate. CONCLUSION: Our findings suggest that the FSHB c.-211G/T polymorphism may modestly alter some aspects of the female reproductive system, but they are not associated with significantly different IVF outcomes.
Assuntos
Proteínas de Transporte/genética , Glicopeptídeos/genética , Adulto , Alelos , Hormônio Antimülleriano/genética , Brasil , Estudos Transversais , Feminino , Fertilização in vitro , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Subunidade beta do Hormônio Folículoestimulante/genética , Frequência do Gene/genética , Genótipo , Humanos , Hormônio Luteinizante/genética , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Taxa de Gravidez , Regiões Promotoras Genéticas/genética , Receptores do FSH , Saúde ReprodutivaRESUMO
The common gonadotrophic hormone α-subunit (GTHα) has been previously isolated by our research group from A. gigas pituitaries; in the present work the cDNA sequences encoding FSHß and LHß subunits have also been isolated from the same species of fish. The FSH ß-subunit consists of 126 amino acids with a putative 18 amino acid signal peptide and a 108 amino acid mature peptide, while the LH ß-subunit consists of 141 amino acids with a putative 24 amino acid amino acid signal peptide and a 117 amino acid mature peptide. The highest identity, based on the amino acid sequences, was found with the order of Anguilliformes (61%) for FSHß and of Cypriniformes (76%) for LHß, followed by Siluriformes, 53% for FSHß and 75% for LHß. Interestingly, the identity with the corresponding human amino acid sequences was still remarkable: 45.1% for FSHß and 51.4% for LHß. Three dimensional models of ag-FSH and ag-LH, generated by using the crystal structures of h-FSH and h-LH as the respective templates and carried out via comparative modeling and molecular dynamics simulations, suggested the presence of the so-called "seat-belt", favored by a disulfide bond formed between the 3rd and 12th cysteine in both ß-subunits. The sequences found will be used for the biotechnological synthesis of A. gigas gonadotrophic hormones (ag-FSH and ag-LH). In a first approach, to ascertain that the cloned transcripts allow the expression of the heterodimeric hormones, ag-FSH has been synthesized in human embryonic kidney 293 (HEK293) cells, preliminarily purified and characterized.
Assuntos
DNA Complementar/genética , Peixes/genética , Subunidade beta do Hormônio Folículoestimulante/genética , Hormônio Luteinizante Subunidade beta/genética , Animais , Clonagem Molecular , DNA Complementar/metabolismo , Peixes/metabolismo , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Células HEK293 , Humanos , Hormônio Luteinizante Subunidade beta/metabolismo , Hipófise/metabolismoRESUMO
Bisphenol A (BPA) is a synthetic endocrine-disrupting chemical of high prevalence in the environment, which may affect the function of the hypothalamic-pituitary-testis (HPT) axis in adult rats. The aim of the present study was to evaluate whether exposure to BPA during hypothalamic sexual differentiation at doses below the reproductive no observable adverse effect level of the World Health Organization causes changes in the regulation of the HPT axis. For this, 0.5 or 5mgkg-1 BPA was injected subcutaneously to the mothers from gestational day 18 to postnatal day (PND) 5. In adulthood (PND90), the mRNA expression of genes related to HPT axis was evaluated in hypothalamus, pituitary and testis. Hypothalamic expression of gonadotrophin-releasing hormone (Gnrh) and estrogen receptor 2 (Esr2) mRNA was increased in both BPA-treated groups compared to control group. In the pituitary, follicle stimulating hormone beta subunit (Fshb) and androgen receptor (Ar) mRNA expression was increased compared to control group in rats treated with 0.5mgkg-1 of BPA, whereas estrogen receptor 1 (Esr1) mRNA expression was only increased in the group treated with 5mgkg-1of BPA, compared to control group. In the testis, there was increased expression of FSH receptor (Fshr) and inhibin beta B subunit (Inhbb) transcripts only in rats treated with 0.5mgkg-1 of BPA. Serum testosterone and LH concentrations were increased in the group treated with 5mgkg-1of BPA. The results of the present study demonstrate for the first time that perinatal exposure to low doses of BPA during the critical period of hypothalamic sexual differentiation modifies the activity of the HPT axis in the offspring, with consequences for later life in adult rats.
Assuntos
Compostos Benzidrílicos/farmacologia , Disruptores Endócrinos/farmacologia , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Fenóis/farmacologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Gravidez , Ratos , Receptores do FSH/metabolismo , Maturidade Sexual/fisiologia , Testículo/metabolismoRESUMO
Context: Although genetic factors play a pivotal role in male pubertal timing, genome-wide association studies have identified only a few loci. Genetic variation of follicle-stimulating hormone (FSH) action affects adult reproductive parameters and female pubertal timing. Objective: To investigate whether genetic variation affecting FSH action is associated with onset of puberty in boys. Design: Cross-sectional and longitudinal study of two cohorts of healthy boys. Setting: This was a population-based study. Patients or Other Participants: Danish (n = 1130) and Chilean (n = 424) boys were followed through puberty and genotyped for FSHB c.-211G>T, FSHR c.-29A>G, and FSHR c.2039G>A. Main Outcome Measures: Clinical pubertal staging including orchidometry, anthropometry, and serum gonadotropin levels. Results: Although the cohorts differed markedly (e.g., body composition and genotype frequencies), genetic variation affecting FSH production (FSHB c.-211G>T) was associated with age at pubertal onset, as assessed by testicular enlargement, in both cohorts. The effect appeared further modified by coexistence of genetic variation affecting FSH sensitivity (FSHR c.-29G>A): After correcting for body mass index (BMI), boys with a ligand-receptor variant combination resulting in weak FSH action (i.e., FSHB c.-211GT/TT and FSHR c.-29AA) entered puberty 0.64 years [95% confidence interval (CI), 0.12 to 1.17 years; Denmark] and 0.94 years (95% CI, 0.00 to 1.88 years; Chile) later than boys with the most effective FSH action. Effects explained 1.7% (Denmark) and 1.5% (Chile) of the variance. In addition, BMI z score was negatively associated with pubertal timing (ß = -0.35 years in both cohorts), explaining 17.2% (Denmark) and 7.2% (Chile) of the variance. Conclusion: In two ethnically distinct populations, we independently identified an association of two genetic loci with male pubertal timing.
Assuntos
Subunidade beta do Hormônio Folículoestimulante/genética , Puberdade/genética , Receptores do FSH/genética , Testículo/crescimento & desenvolvimento , Adolescente , Fatores Etários , Criança , Pré-Escolar , Chile , Estudos Transversais , Dinamarca , Hormônio Foliculoestimulante/genética , Variação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
This work describes gonadotropic (GtH) cells and their morphological and immunohistochemical changes during the spermatogenic cycle of Serrasalmus maculatus (continuous spermatogenesis) and Pimelodus maculatus (seasonal spermatogenesis). GtH cells, widely distributed in the proximal pars distalis of the adenohypophysis, were characterized as round-shaped cells with eccentric nucleus, and cytoplasm with basophilic secretory granules and a variable number of vacuoles for both species. Immunohistochemistry against ß-follicle-stimulating hormone (Fsh) and ß-luteinizing hormone (Lh) in adjacent sections showed two separated GtH-producing cell populations, and a third population where both GtHs are expressed in the same cell for both species. In the seasonal spermatogenesis of P. maculatus, GtH cells seemed to be more abundant during developing and spawning capable phases. In contrast, no cyclic changes were detected in the continuous spermatogenesis of S. maculatus, except for the strong immunoreaction for Fsh and Lh in males with intense spermiogenesis. We conclude that changes reported here might reflect the type of spermatogenic cycle (seasonal or continuous) which are under different regulatory mechanisms (environmental and internal cues) controlling the reproduction in these species.