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1.
Ecotoxicol Environ Saf ; 181: 362-369, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31212184

RESUMO

DEHP is reported to cause precocious puberty of females in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of DEHP on the pathogenesis of sexual precocity. Prepubertal female rats were treated with DEHP for 4 weeks. Key organs were analyzed in control conditions and after exposure to 0.2, 1, and 5 mg/kg/day DEHP in pubertal female rats. To determine the role of the IGF-1/PI3K/Akt/mTOR signaling pathway in DEHP-induced female precocious puberty, 36 rats were treated with 5 mg/kg/day DEHP to establish a model of female precocious puberty. And we investigated the expression of genes and proteins related to IGF-1 pathway in rat hypothalamus after treatment with inhibitors. In the present study, we observed that DEHP treatment resulted in earlier vaginal opening time, higher number of Nissl bodies in the hypothalamus neurons, lower apoptosis of hypothalamic cells, higher IGF-1 and GnRH levels in the serum and hypothalamus. DEHP could also upregulated the expression of IGF-1/PI3K/Akt/mTOR pathway and GnRH in the hypothalamus of adolescent female rats, and inhibition of IGF-1R and mTOR in hypothalamus could block the activation of Kiss-1, GPR54, and GnRH by DEHP. In summary, our study suggested that DEHP might activate the hypothalamic GnRH neurons prematurely through the IGF-1 signaling pathway and promote GnRH release, leading to the initiation of female sexual development. Our results provide a new molecular mechanism underlying reproductive and developmental toxicity in pubertal female rats induced by DEHP.


Assuntos
Dietilexilftalato/toxicidade , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Puberdade Precoce/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Puberdade Precoce/enzimologia , Puberdade Precoce/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
2.
Clinics (Sao Paulo) ; 74: e836, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241662

RESUMO

OBJECTIVE: Follow-up studies of girls with premature adrenarche have reported the development of polycystic ovary syndrome, insulin resistance, and dyslipidemia and a propensity to cardiovascular disease. The aim of this study was to analyze the presence of these conditions in patients previously treated at the Universidade Federal do Triângulo Mineiro. METHODS: A total of 130 medical records reported premature adrenarche. One hundred and twenty-two patients were invited to participate, of whom 54 accepted; 34 patients were selected, as they had reached their final height. Anthropometric, blood glucose, insulin, and lipid and hormonal profile (LH, FSH, estradiol, 17α-OH-progesterone, androstenedione, dehydroepiandrosterone sulfate, testosterone) data were obtained, the HOMA-IR index was calculated, and pelvic ultrasonography was performed. To characterize polycystic ovary syndrome and metabolic syndrome, the Rotterdam and International Diabetes Federation criteria, respectively, were used. Data were analyzed according to measures of dispersion, frequency and correlations of interest. RESULTS: The age of the participants ranged from 15.2 to 28.2 years/months; 23.5% of the patients were overweight, 11.8% were obese, 29.4% had a large waist circumference, and 8.8% were hypertensive. None of the patients had altered glucose levels, and insulin levels and HOMA-IR were elevated in 29.4% and 38.2% of the participants, respectively; 14.7% of the patients exhibited acanthosis nigricans. The lipid profiles of the participants were variable, and one patient (2.9%) had metabolic syndrome. Polycystic ovary syndrome was found in 41.2% of patients. CONCLUSION: The percentage of patients with polycystic ovary syndrome who also had overweight, obesity and insulin resistance corroborates the literature data about the need for follow-up aiming at interventions, especially for conditions associated with cardiometabolic risk.


Assuntos
Adrenarca/metabolismo , Síndrome do Ovário Policístico/etiologia , Puberdade Precoce/complicações , Puberdade Precoce/metabolismo , Adolescente , Adulto , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Colesterol/sangue , Dislipidemias/etiologia , Dislipidemias/metabolismo , Feminino , Hormônios/sangue , Humanos , Resistência à Insulina , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Sobrepeso/etiologia , Sobrepeso/metabolismo , Síndrome do Ovário Policístico/metabolismo , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
3.
J Pediatr Endocrinol Metab ; 32(4): 403-407, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30849047

RESUMO

Context Germ cell tumours (GCTs) secreting ß-human chorionic gonadotropin (ß-HCG) are a rare cause of gonadotropin-independent precocious puberty (GIPP). Case description A 5.7-year-old boy presented with GIPP. Investigations to elucidate the underlying cause revealed elevated serum ß-HCG. Ultrasound of the abdomen and testes, urine steroid profile, bone isotope scan, and sequencing of the luteinizing hormone receptor gene (LHCGR) were normal. Despite paired serum and cerebrospinal fluid ß-HCG measurement suggesting local (brain) ß-HCG production, repeated magnetic resonance imaging (MRI) of the brain as well as MRI of the mediastinum did not identify a tumour source of persistently elevated serum ß-HCG. Treatment with cyproterone acetate and spironolactone was unsuccessful. Increase in testicular volumes prompted the addition of a gonadotropin releasing hormone (GnRH) analogue. Due to progressing virilisation and skeletal maturation, treatment was changed to a combination of anastrozole and bicalutamide at the age of 7 years. One year later, serum ß-HCG and testosterone concentrations spontaneously normalised followed by reductions in the height velocity, skeletal maturation and virilisation. The proband achieved his genetic height potential. No medication side effects were observed. The patient subsequently presented with non-secreting pineal GCT at 14 years, 8½ years after his initial presentation with GIPP. Conclusions Our case highlights that GIPP with no definite underlying aetiology at diagnosis should be considered as a prodrome for GCTs, and regular radiological surveillance for earlier tumour identification is warranted. To the best of our knowledge, our case is the first reported case of the use of anastrozole and bicalutamide in the setting of idiopathic GIPP. The good height outcome in our case warrants the trial of anastrozole and bicalutamide in similar cases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hormônio Liberador de Gonadotropina/metabolismo , Puberdade Precoce/patologia , Anastrozol/administração & dosagem , Anilidas/administração & dosagem , Encéfalo/metabolismo , Criança , Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Humanos , Masculino , Nitrilos/administração & dosagem , Prognóstico , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/metabolismo , Compostos de Tosil/administração & dosagem
4.
J Pediatr Endocrinol Metab ; 32(2): 181-186, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30699070

RESUMO

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.


Assuntos
Biomarcadores/análise , Índice de Massa Corporal , Hormônio Liberador de Gonadotropina/análogos & derivados , Resistência à Insulina , Lipídeos/análise , Puberdade Precoce/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Hormônio Liberador de Gonadotropina/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Prognóstico , Estudos Prospectivos , Puberdade Precoce/metabolismo , Puberdade Precoce/patologia , Maturidade Sexual
5.
Exp Clin Endocrinol Diabetes ; 127(4): 234-239, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29506309

RESUMO

BACKGROUND: Luteinizing hormone (LH) is a useful parameter in diagnosing precocious puberty. The pubertal response of serum LH to a GnRH stimulation test is varied, and clinical symptoms of precocious puberty are sometimes disproportionate with serum LH concentrations. Many patients present in a state of precocious puberty that advances rapidly, but the post-GnRH peak LH remains prepubertal. LH receptor mutations are suspected of involvement in the non-classic type of central precocious puberty (CPP). OBJECTIVE: To examine the association between LHCGR polymorphism and non-classic CPP in subjects exhibiting a peak LH<5 IU/L on a GnRH stimulation test. METHODS: In total, 102 girls with non-classic CPP and 100 normal adult women were enrolled. All subjects underwent LHCGR gene analysis by the Sanger method, and patients and controls were compared. Auxological data and gonadotropin concentrations were analyzed in the 102 patients. Of these patients, 75 completed GnRH agonist treatment, and the treatment outcomes were analyzed. RESULTS: A total of seven variants were identified, including two missense mutations (g.48698754 G/A and g.48688613 G/A) that were found in the patient group (no patients contained both mutations). In silico analysis of these missense mutations suggested the possibility of damaging the LHCGR. However, no significant association was found between the identified LHCGR variants and non-classic CPP. GnRH agonist treatment decreased bone age advancement and increased predicted adult height. CONCLUSIONS: LHCGR gene polymorphisms do not appear to be a major causative factor for the relatively low concentration of LH in patients with non-classic CPP. GnRH agonist treatment improved clinical parameters in these patients.


Assuntos
Hormônio Luteinizante/metabolismo , Puberdade Precoce/genética , Puberdade Precoce/metabolismo , Receptores do LH/genética , Adulto , Criança , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Puberdade Precoce/tratamento farmacológico
6.
Stress ; 21(6): 564-568, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29916751

RESUMO

Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a small number of girls. In this cross-sectional study, 82 pre-pubertal children (66 girls and 16 boys) diagnosed with PA, were compared to 63 control children regarding their psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function, as assessed by salivary cortisol measurement. Symptoms of anxiety and depression were assessed by child self-report (Spence Children's Anxiety Scale (SCAS) and Depression self-rating scale for Children (DSRS)) and parent-report (Child Behaviour Checklist (CBCL)) tests validated for the Greek population. Salivary cortisol levels were determined directly after awakening (approximately 7am) and evening (8pm) of the same day. Morning serum DHEAS levels were assessed in PA children. Girls with PA scored significantly higher on anxiety (p = .016) and depression (p =.039) scales than controls. No group differences were noted for parent reports and children's salivary cortisol concentrations. Boys with PA did not demonstrate significant differences in any of the aforementioned parameters. Our findings suggest that girls with PA may be at higher risk for reporting symptoms of anxiety and depression than their non-PA peers. HPA axis dysregulation in this population was not documented.


Assuntos
Adrenarca/psicologia , Ansiedade/psicologia , Depressão/psicologia , Puberdade Precoce/psicologia , Adrenarca/metabolismo , Ansiedade/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Sulfato de Desidroepiandrosterona/metabolismo , Depressão/metabolismo , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário , Masculino , Sistema Hipófise-Suprarrenal , Puberdade Precoce/metabolismo , Saliva/química , Fatores Sexuais
7.
Hormones (Athens) ; 17(3): 415-418, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29943104

RESUMO

Tay-Sachs disease is an autosomal recessive type of lysosomal storage disorder. The disease is very rare in Turkey, with an incidence of 0.54/100,000. The clinical manifestations of Tay-Sachs disease include progressive developmental delay, seizures, deafness, blindness, spasticity, and dystonia, which are caused by the accumulation of gangliosides in the central nervous system. To date, only one case indicating the association between Tay-Sachs disease and central precocious puberty has been reported. Although the mechanism of this association is not clear, it is thought to be due to ganglioside accumulation in the central nervous system or the inhibition of the hypothalamic inhibiting pathway. Herein, we report two patients with genetically proven Tay-Sachs disease who developed central precocious puberty during follow-up. Pubertal development in patients affected by Tay-Sachs disease should be carefully assessed.


Assuntos
Puberdade Precoce/etiologia , Doença de Tay-Sachs/complicações , Criança , Pré-Escolar , Feminino , Humanos , Puberdade Precoce/metabolismo , Doença de Tay-Sachs/metabolismo , Doença de Tay-Sachs/fisiopatologia
8.
J Tradit Chin Med ; 38(5): 740-745, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-32185991

RESUMO

OBJECTIVE: To evaluate the effect of ZiYin Xiehuo granules (ZYXH) and Zishen Qinggan granules (ZSQG) on partial precocious puberty (PPP). METHODS: This was a multicenter, randomized, single-blind, positive-controlled trial. A total of 143 patients were assigned to either the ZYXH group or the ZSQG group using a random number table. The ZYXH group received ZYXH three times daily for 6 months and the ZSQG group received ZSQG three times daily for 6 months. Mammary nucleus diameter; the results of uterus, ovarian, and maximum follicle measures; and Chinese medicine symptom pattern scores were compared at baseline and after 3 months and 6 months of treatment. RESULTS: After 3 months' treatment, there were no significant differences between the two groups in mammary nucleus index changes (left 3.4 ± 3.1 vs 3.5 ± 3.1, P = 0.790; right 3.0 ± 2.9 vs 3.6 ± 3.0, P = 0.719). The uterine volume in the ZYXH group was smaller than that in the ZSQG group (2.1 ± 1.6 vs 2.6 ± 2.2, P = 0.006). There were no significant between-group differences in ovarian volume and maximum follicular diameter on either side (ovarian volume: left 1.2 ± 0.7 vs 1.3 ± 0.6, P = 0.8; right 1.2 ± 0.7 vs 1.4 ± 1.1, P = 0.984; maximum follicular diameter: left 3.9 ± 1.7 vs 3.5 ± 2.2, P = 0.158; right 3.5 ± 1.7 vs 3.9 ± 2.1, P = 0.314). CONCLUSION: ZYXH granules and ZSQG granules both affected the size of the mammary nucleus in girls with PPP, and improved Chinese medicine symptom patterns. ZYXH granules showed slight advantages over ZSQG granules in terms of the decrease in the size of the uterus, ovaries, and ovarian follicles.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Puberdade Precoce/tratamento farmacológico , Criança , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Tamanho do Órgão/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Puberdade Precoce/metabolismo , Puberdade Precoce/fisiopatologia , Método Simples-Cego , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Útero/metabolismo
9.
Reprod Biol Endocrinol ; 15(1): 56, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28738839

RESUMO

BACKGROUND: We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty. METHODS: We conducted a prospective cohort study between 2007 and 2015 with 4-6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8-14 years old and re-assessed after a median follow-up of 5.4 years, at 13-21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DIFSivGTT); and indices of NEFA suppression during FSivGTT (logn-linear slope of NEFA and T50 of NEFA suppression). RESULTS: At follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DIFSivGTT = 1926 vs 1380 (p = 0.44), logn-linear slope = -0.032 vs -0.032 (p = 0.88) and T50NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DIFSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p < 0.05). CONCLUSIONS: Impaired metabolism observed during early puberty in girls predisposed to PCOS remains stable after 5 years whereas control girls deteriorated their metabolic parameters. Therefore, both groups become comparable in late/post-puberty. Early puberty may thus represent a window during which metabolic alterations are transiently apparent in girls at risk of PCOS.


Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico/metabolismo , Puberdade Precoce/metabolismo , Adolescente , Ácidos Graxos não Esterificados/metabolismo , Feminino , Seguimentos , Glucose/metabolismo , Homeostase , Humanos , Adulto Jovem
10.
J Cell Mol Med ; 21(10): 2623-2626, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28338294

RESUMO

The human genome encodes ~750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co-transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders.


Assuntos
Mutação da Fase de Leitura , Mutação com Ganho de Função , Puberdade Precoce/genética , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença/genética , Humanos , Puberdade Precoce/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Deleção de Sequência
11.
Eur J Endocrinol ; 176(6): 747-753, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28348072

RESUMO

OBJECTIVE: Premature thelarche and precocious puberty are frequently diagnosed in girls even below 6 years of age and may be difficult to differentiate in the early stages. A GnRH test is often included in the diagnostic work-up, although interpretation of the GnRH test in girls below 6 years of age is challenging, as no reference interval exists for this age group. The objective is to determine the normal FSH and LH response to a GnRH test in healthy prepubertal girls below 6 years of age. DESIGN AND METHODS: A standardized GnRH test, baseline reproductive hormones, clinical evaluation and bone age were determined in all participants. Forty-eight healthy normal-weight girls aged 3.5 ± 0.2 years (range: 0.8-5.9 years) were included. Serum concentrations of LH and FSH were measured before and 30 min after the gonadorelin injection. RESULTS: The 30-min LH responses (mean ± 2 s.d.) were 5.2 ± 4.0 and 2.9 ± 2.5 IU/L and the FSH responses were 23.3 ± 16.2 and 14.5 ± 10.3 IU/L in girls aged 0.8-3.0 years and 3.0-5.9 years respectively. This corresponds to upper cut-off limits for LH of 9.2 IU/L (<3 years) and 5.3 IU/L (3-6 years). The stimulated LH/FSH ratio was 0.23 ± 0.19 (range 0.06-0.43) and did not correlate with age. CONCLUSIONS: We found that LH increases up to 9.2 IU/L during GnRH test in healthy normal-weight girls below 3 years of age and that the stimulated LH/FSH ratio did not exceed 0.43. Our findings have important implications for appropriate diagnosis of central precocious puberty in girls below 6 years of age.


Assuntos
Desenvolvimento Infantil , Hormônio Foliculoestimulante Humano/metabolismo , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Luteinizante/metabolismo , Algoritmos , Desenvolvimento Ósseo , Pré-Escolar , Estudos de Coortes , Dinamarca , Técnicas de Diagnóstico Endócrino , Feminino , Hormônio Foliculoestimulante Humano/sangue , Hormônio Liberador de Gonadotropina/farmacologia , Hospitais Universitários , Humanos , Lactente , Hormônio Luteinizante/sangue , Distribuição Normal , Puberdade Precoce/sangue , Puberdade Precoce/diagnóstico , Puberdade Precoce/metabolismo , Valores de Referência , Globulina de Ligação a Hormônio Sexual
12.
Toxicol Appl Pharmacol ; 307: 123-129, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27495896

RESUMO

Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, ß-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism.


Assuntos
Dietilexilftalato/toxicidade , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Puberdade Precoce/induzido quimicamente , Processos de Determinação Sexual/efeitos dos fármacos , Animais , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Feminino , Folistatina/genética , Folistatina/metabolismo , Fatores de Transcrição Forkhead/genética , Troca Materno-Fetal , Camundongos Endogâmicos ICR , Ovário/efeitos dos fármacos , Ovário/metabolismo , Fosfoproteínas/genética , Gravidez , Puberdade Precoce/metabolismo , Proteína Wnt4/genética , beta Catenina/genética
13.
Mol Cell Endocrinol ; 437: 62-74, 2016 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-27519634

RESUMO

Sporadic epidemics and several researches in rodents indicated that zearalenone (ZEA) and its metabolites, the prevailing oestrogenic mycotoxins in foodstuffs, were a triggering factor for true precocious puberty development in girls. Nevertheless, the neuroendocrine mechanism through which ZEA mycoestrogens advance puberty onset is not fully understood. To elucidate this issue, hypothalamic kisspeptin-G-protein coupled receptor-54 (GPR54) signaling pathway that regulates the onset of puberty was focused on in the present study. Immature female SD rats were given a daily intragastric administration of corn oil (vehicle control), 50 µg/kg body weight (bw) of 17ß-estradiol (E2, positive control), and 3 doses (0.2, 1 and 5 mg/kg bw) of ZEA for consecutive 5 days starting from postnatal day 15, respectively. Puberty onset was evaluated by detecting the physiological and hormonal responses, and hypothalamic kisspeptin-GPR54 pathway was determined to reveal the neuroendocrine mechanism. As the markers of puberty onset, vaginal opening was significantly accelerated and uterine weight was increased in both E2 and 5 mg/kg ZEA groups. Serum levels of follicle stimulating hormone, luteinizing hormone and estradiol were also markedly elevated by E2 and 5 mg/kg ZEA, which is compatible with the changes in peripheral reproductive organs. The mRNA and protein expressions of hypothalamic gonadotropin-releasing hormone (GnRH) were both obviously elevated by E2 and 5 mg/kg ZEA. GnRH expression changes occurred in parallel with increased expressions of hypothalamic Kiss1 and its receptor GPR54 at both mRNA and protein levels. Most of these changes were also noted in 1 mg/kg ZEA group, but none in 0.2 mg/kg group. Therefore, within the context of this study, the No Observed Adverse Effect Level (NOAEL) for ZEA in terms of oestrogenic activity and puberty-promoting effect in immature female rats was considered to be 0.2 mg/kg bw per day, and the Lowest Observed Adverse Effect Level (LOAEL) was 1 mg/kg bw per day. In conclusion, prepubertal exposure to dietary relevant levels of ZEA induced central precocious puberty in female rats by premature activation of hypothalamic kisspeptin-GPR54-GnRH signaling pathway, followed by the stimulation of gonadotropins release at an earlier age, resulting in the advancement of vaginal opening and enlargement of uterus at periphery.


Assuntos
Estrogênios/toxicidade , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Micotoxinas/toxicidade , Puberdade Precoce/induzido quimicamente , Receptores Acoplados a Proteínas-G/metabolismo , Maturidade Sexual/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/crescimento & desenvolvimento , Genitália Feminina/patologia , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hormônios/sangue , Hipotálamo/efeitos dos fármacos , Masculino , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Puberdade Precoce/sangue , Puberdade Precoce/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de Kisspeptina-1 , Receptores LHRH/genética , Receptores LHRH/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Endocrinology ; 157(8): 3233-41, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27309941

RESUMO

Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments. Another experiment assessed in vitro IGF-1 release in response to Mn and assessed signal transduction pathways in the POA/AVPV region after Mn delivery into the third ventricle. Chronic Mn exposure increased (P < .05) basal expressions of mTOR and kisspeptin proteins. Mn increased protein kinase B (Akt) and Ras homolog enriched in brain, both capable of activating mTOR. Central Mn delivery increased expressions of phosphorylated IGF-1 receptor (IGF-1R) (P < .05) and Akt (P < .01) in the POA/AVPV region. The previous central delivery of JB1, an IGF-1R antagonist, blocked Mn-induced expressions of both phosphorylated IGF-1R and Akt. Downstream to Akt, centrally administered Mn increased tuberous sclerosis complex 2 (P < .05), Ras homolog enriched in brain (P < .01), mTOR (P < .05), and kisspeptin (P < .05). Finally, we observed that the early puberty induced by Mn was blocked by the administration of an mTOR inhibitor. These results suggest that Mn acts, at least in part, through the IGF-1/Akt/mTOR pathway to influence prepubertal kisspeptin and LHRH.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Kisspeptinas/metabolismo , Manganês/farmacologia , Proteína Oncogênica v-akt/metabolismo , Maturidade Sexual , Serina-Treonina Quinases TOR/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Gravidez , Puberdade Precoce/induzido quimicamente , Puberdade Precoce/metabolismo , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Transdução de Sinais/efeitos dos fármacos
15.
J Clin Res Pediatr Endocrinol ; 8(4): 392-398, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27215137

RESUMO

OBJECTIVE: Girls with precocious puberty have high luteinizing hormone (LH) levels and advanced bone age. Obese children enter puberty at earlier ages than do non-obese children. We analyzed the effects of obesity on LH secretion during gonadotropin-releasing hormone (GnRH) tests in girls with precocious puberty. METHODS: A total of 981 subjects with idiopathic precocious puberty who had undergone a GnRH stimulation testing between 2008 and 2014 were included in the study. Subjects were divided into three groups based on body mass index (BMI). Auxological data and gonadotropin levels after the GnRH stimulation test were compared. RESULTS: In Tanner stage 2 girls, peak stimulated LH levels on GnRH test were 11.9±7.5, 10.4±6.4, and 9.1±6.1 IU/L among normal-weight, overweight, and obese subjects, respectively (p=0.035 for all comparisons). In Tanner stage 3 girls, peak stimulated LH levels were 14.9±10.9, 12.8±7.9, and 9.6±6.0 IU/L, respectively (p=0.022 for all comparisons). However, in Tanner stage 4 girls, peak stimulated LH levels were not significantly different among normal, overweight, and obese children. On multivariate analysis, BMI standard deviation score was significantly and negatively associated with peak LH (ß=-1.178, p=0.001). CONCLUSION: In girls with central precocious puberty, increased BMI was associated with slightly lower peak stimulated LH levels at early pubertal stages (Tanner stages 2 and 3). This association was not valid in Tanner stage 4 girls.


Assuntos
Técnicas de Diagnóstico Endócrino , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Luteinizante/sangue , Obesidade/sangue , Puberdade Precoce/sangue , Índice de Massa Corporal , Peso Corporal , Criança , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/metabolismo , Análise Multivariada , Obesidade/metabolismo , Sobrepeso , Puberdade Precoce/diagnóstico , Puberdade Precoce/metabolismo , Fatores de Tempo
16.
J Pediatr Endocrinol Metab ; 29(6): 723-9, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27054594

RESUMO

BACKGROUND: We aimed to examine the associations of adipocytokines and circulating bone metabolism markers with bone mineral parameters in early pubertal boys with different physical activity level. METHODS: Eighty-six early pubertal boys were divided into active and non-active boys according to the accumulated moderate-to-vigorous physical activity (MVPA) level. Body composition and bone mineral parameters were assessed and testosterone, leptin, adiponectin, osteocalcin (OC), and C-terminal telopeptide of type I collagen (CTX) were measured. RESULTS: Active subjects had significantly lower (p<0.05) body mass, body mass index (BMI), fat mass (FM), leptin, and sedentary time values, while non-active subjects had lower (p<0.05) vigorous physical activity level and femoral neck bone mineral density (FN-BMD). OC contributed to the models in physically active group and explained 6.6% and 9.7% of variance in whole body (WB) [F(5,44)=10.847; p<0.001] and lumbar spine bone mineral content (LS-BMC) [F(5,44)=4.158; p=0.004], respectively. No other biochemical parameters were found to be related to bone mineral parameters in either the active or non-active group. CONCLUSIONS: Bone metabolism markers were positively correlated with bone mineral values only in active pubertal boys. Leptin and adiponectin were not related to bone mineral parameters in active and non-active pubertal boys.


Assuntos
Adipocinas/sangue , Densidade Óssea , Osso e Ossos/metabolismo , Exercício , Puberdade Precoce/metabolismo , Criança , Colágeno Tipo I/sangue , Humanos , Masculino , Osteocalcina/sangue , Peptídeos/sangue
17.
J Pediatr Endocrinol Metab ; 29(11): 1241-1248, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26887034

RESUMO

BACKGROUND: Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer therapy. This is the first study in patients with CPP. METHODS: The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2-8 years for girls and 2-9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed. RESULTS: Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported. CONCLUSIONS: The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.


Assuntos
Hormônio Liberador de Gonadotropina/agonistas , Hormônio Luteinizante/antagonistas & inibidores , Puberdade Precoce/tratamento farmacológico , Substâncias para o Controle da Reprodução/administração & dosagem , Pamoato de Triptorrelina/administração & dosagem , Biomarcadores/sangue , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Chile , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/uso terapêutico , Esquema de Medicação , Estradiol/sangue , Estradiol/química , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante Humano/antagonistas & inibidores , Hormônio Foliculoestimulante Humano/sangue , Hormônio Foliculoestimulante Humano/metabolismo , Humanos , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , México , Osteogênese/efeitos dos fármacos , Puberdade Precoce/sangue , Puberdade Precoce/metabolismo , Substâncias para o Controle da Reprodução/efeitos adversos , Substâncias para o Controle da Reprodução/uso terapêutico , Testosterona/antagonistas & inibidores , Testosterona/sangue , Testosterona/metabolismo , Pamoato de Triptorrelina/efeitos adversos , Pamoato de Triptorrelina/uso terapêutico , Estados Unidos
18.
Clin Endocrinol (Oxf) ; 84(3): 394-401, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26426700

RESUMO

OBJECTIVE: Precocious pubarche (PP) has been linked to higher prevalence of metabolic disturbances and polycystic ovary syndrome (PCOS). The aim of the study was to assess echocardiographic parameters in PP girls and to analyse their relationship with androgens and insulin resistance (IR). DESIGN: Case-control study. PATIENTS: Thirty-five PP girls and 35 healthy age-matched controls. MEASUREMENTS: Clinical, hormonal and metabolic profiles, echocardiography, body composition and oral glucose tolerance test. RESULTS: Chronological age (10·04 ± 2·6 years in PP vs 10·13 ± 2·56 years in controls, P = 0·227), and pubertal stage at the time of the study were similar between the groups. PP girls had higher free androgen index (FAI) [1·39 (0·48-3·64) vs 1·06 (0·39-1·7), P = 0·005] and QUICKI (0·58 ± 0·08 vs 0·63 ± 0·12, P = 0·021). However, HOMA-IR was not significantly different between the groups [2·79 (1·84-4·05) vs 2·15 (1·09-3·23), P = 0·085]. After adjusting for total body fat, left ventricular mass (LVM) was higher in the PP group (97·31 ± 33·37 vs 81·25 ± 19·06 g, P = 0·017) as well as A' wave (5·66 ± 1·34 vs 5·09 ± 0·98 cm/s, P = 0·025), a measurement of diastolic function. FAI and total body fat were independent predictors of higher LVM and together with HOMA-IR contributed 72% of LVM variability in the PP group. CONCLUSION: In this study with PP girls, greater LVM, associated with higher androgen levels, IR and total body fat, occurred early in pubertal development.


Assuntos
Adiposidade , Androgênios/metabolismo , Resistência à Insulina , Puberdade Precoce/fisiopatologia , Adolescente , Composição Corporal , Estudos de Casos e Controles , Criança , Ecocardiografia , Feminino , Teste de Tolerância a Glucose , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hormônios/metabolismo , Humanos , Modelos Lineares , Análise Multivariada , Puberdade Precoce/metabolismo , Função Ventricular Esquerda
19.
Endocr Relat Cancer ; 23(1): R1-14, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26407873

RESUMO

Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.


Assuntos
Glândulas Endócrinas/metabolismo , Glândulas Endócrinas/patologia , Hormônios Ectópicos/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adulto , Criança , Feminino , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Hipertireoidismo/congênito , Hipertireoidismo/genética , Hipertireoidismo/metabolismo , Hipertireoidismo/patologia , Masculino , Glândulas Paratireoides/metabolismo , Glândulas Paratireoides/patologia , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/patologia , Gravidez , Puberdade Precoce/genética , Puberdade Precoce/metabolismo , Puberdade Precoce/patologia
20.
Mol Biol (Mosk) ; 49(5): 707-15, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26510589

RESUMO

Kisspeptin (KISS1) and its receptor (KISS1R) are important regulators of the reproductive function, along with gonadoliberin (GnRH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), and sex steroid hormones. Mutations of their genes alter sexual maturation. The p.P74S, p.H90D, and p.P110T missense mutations of KISS1 are associated with central precocious puberty (CPP); and the p.G35S, p.C53R, and p.F117L mutations, with delayed puberty and isolated hypogonadotropic hypogonadism (IHH). The p.P196H and p.R386P mutations of KISS1R are also associated with CPP. However, a greater number of KISS1R mutations are associated with IHH, as is the case with p.L102P, p.L148S, p.E232Q, p.R297L, p.Y313H, pX399R, and more complex mutations, such as the 155-bp deletion that removes the acceptor splice site of intron 4 and part of exon 5, a deletion of the GCA triplet in position-2 ...-4 of intron 2, and an ACCGGCT insertion in the same site. The heterozygous compound mutations p.C223R/p.R297L and p.R331X/X399R and the 1-bp insertion 1001_1002insC of KISS1R are similarly associated with IHH. Leptin-dependent activation of KISS1 in hypothalamic neurons was observed in mice and sheep, being especially evident after puberty. Leptin exerts a permissive effect in regulating fertility and facilitate the induction of puberty by hypothalamic KISS1 and GnRH and pituitary LH and FSH, which support the reproductive function during further life.


Assuntos
Fertilidade/genética , Hipogonadismo/genética , Kisspeptinas/genética , Leptina/genética , Puberdade Precoce/genética , Receptores Acoplados a Proteínas-G/genética , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Regulação da Expressão Gênica , Hormônios Esteroides Gonadais/genética , Hormônios Esteroides Gonadais/metabolismo , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/patologia , Kisspeptinas/metabolismo , Leptina/metabolismo , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Mutação , Puberdade Precoce/metabolismo , Puberdade Precoce/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Kisspeptina-1 , Maturidade Sexual/genética , Transdução de Sinais
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