RESUMO
Mice lacking estrogen receptor alpha in the pituitary gonadotroph (PitEsr1KO) were generated to determine the physiologic role of pituitary estrogen signaling in the reproductive axis. PitEsr1KO female mice are subfertile or infertile and have elevated levels of serum luteinizing hormone (LH) and LH beta subunit gene expression, reflecting a lack of estrogen negative feedback effect on the gonadotroph. While serum LH values are elevated in PitEsr1KO mice, the degree of elevation is much less than that observed in ESR1-null mice, indicating that the hypothalamus must also have an important role in estrogen negative feedback. PitEsr1KO mice also demonstrate a defect in estrogen positive feedback, as surge LH values and estrous cyclicity are absent in these mice. Although sex steroid feedback in the reproductive axis is thought to involve discrete anatomic regions that mediate either a positive or negative estrogen effect, PitEsr1KO mice demonstrate novel evidence that localizes both estrogen positive feedback and estrogen negative feedback to the gonadotroph, which suggests that they may be mechanistically related.
Assuntos
Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Retroalimentação Fisiológica/fisiologia , Infertilidade Feminina/genética , Hipófise/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/sangue , Estrogênios/metabolismo , Ciclo Estral/sangue , Ciclo Estral/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Hormônios Esteroides Gonadais/sangue , Infertilidade Feminina/sangue , Infertilidade Feminina/metabolismo , Infertilidade Feminina/patologia , Hormônio Luteinizante/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos/genética , Ovário/metabolismo , Ovário/patologiaRESUMO
Previous studies have shown that insulin augments GnRH-stimulated LH synthesis and release from primary gonadotrophs. In this study, regulation of LHbeta gene expression by GnRH and insulin was examined in LbetaT2 cells. Endogenous LHbeta mRNA is stimulated 2.4-fold by insulin alone, 2.6-fold by GnRH alone, and 4.7-fold by insulin together with GnRH. This effect of insulin, like GnRH, mapped to sequences -140 to +1 in the mouse LHbeta gene. Insulin together with GnRH stimulates activity of an LHbeta-reporter gene 7.1-fold; whereas, GnRH alone or insulin alone stimulates the reporter activity 2.8- and 3.1-fold, respectively. Blocking the binding of Egr-1 to sequences -51 to -42 in the LHbeta gene inhibits effects of insulin and GnRH. Insulin together with GnRH increases Egr-1 mRNA levels and total Egr-1 binding to LHbeta DNA. These findings indicate that insulin may impact regulation of the reproductive axis at the level of the pituitary.
Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/farmacologia , Insulina/farmacologia , Hormônio Luteinizante Subunidade beta/genética , Animais , Sítios de Ligação , Linhagem Celular , Sinergismo Farmacológico , Proteína 1 de Resposta de Crescimento Precoce/química , Proteína 1 de Resposta de Crescimento Precoce/genética , Hormônio Liberador de Gonadotropina/fisiologia , Hormônio Luteinizante Subunidade beta/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Receptor de Insulina/metabolismo , Transdução de SinaisRESUMO
Polycystic ovary syndrome (PCOS) is a syndrome of variable combinations of menstrual irregularity, hirsutism or acne, and obesity. It can be diagnosed in adolescence and has early childhood antecedents. PCOS is the single most common endocrine cause of an ovulatory infertility and a major risk factor for the metabolic syndrome and, in turn, development of type 2 diabetes mellitus in women. Thus, it appears that PCOS increases a woman's risk of developing cardiovascular disease. Therefore, identifying girls at risk for PCOS and implementing treatment early in the development of PCOS may be an effective means of preventing some of the long-term complications associated with this syndrome. This article reviews the definition, clinical features, diagnosis, and treatment of PCOS.