RESUMO
Autonomic innervation is important to regulate homeostasis in every organ of the body. The sympathetic nervous system controls several organs associated with metabolism and reproduction, including adipose tissue, the liver, and the ovaries. The sympathetic nervous system is controlled within the central nervous system by neurons located in the hypothalamus, which in turn are regulated by hormones like leptin. Leptin action in the hypothalamus leads to increased sympathetic activity in the adipose tissue. In this short report, we propose that leptin action in the brain also controls the sympathetic innervation of other organs like the liver and the ovary. We performed two experiments: We performed an intracerebroventricular (ICV) injection of leptin and measured norepinephrine levels in several organs, and we used a validated model of overnutrition and obesity to evaluate whether an increase in leptin levels coexists with high levels of norepinephrine in the liver and ovaries. Norepinephrine was measured by ELISA in adipose tissue and by HPLC-EC in other tissues. Leptin was measured by ELISA. We found that the ICV injection of leptin increases norepinephrine levels in several organs, including the liver and ovaries. Also, we found that diet-induced obesity leads to an increase in leptin levels while inducing an increase in norepinephrine levels in the liver and ovaries. Finally, since hyperactivity of the sympathetic nervous system is observed both in non-alcoholic fatty liver disease and polycystic ovary syndrome, we think that an increase in norepinephrine levels induced by hyperleptinemia could be involved in the pathogenesis of both diseases.
Assuntos
Leptina , Norepinefrina , Feminino , Tecido Adiposo/metabolismo , Dieta , Leptina/metabolismo , Norepinefrina/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático , Animais , RatosRESUMO
Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.
Assuntos
Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Feminino , Hipoglicemiantes/farmacologia , Lactação , Metformina/farmacologia , Obesidade/complicações , Ovário/metabolismo , Síndrome do Ovário Policístico/etiologia , Gravidez , Complicações na Gravidez , Ratos Sprague-DawleyRESUMO
Recently, the influence of adrenergic activity over ovarian function, and thus fertility, has begun to gain importance. Previous studies have shown that adrenergic activity through norepinephrine (NE) participates in the control of follicular development and steroidal secretion from the ovary, among other functions. To examine this phenomenon, the denervation of the gonad has been widely used to observe changes in the ovary's performance. Nevertheless, the effect of the absence of adrenergic nerves in the ovary has only been studied in short times periods. In the present work, we used guanethidine (a drug that produces an irreversible sympathectomy) during the infantile period of rats, and we observed its effects in the adult rat (6 months old). Our results indicate that ovarian NE content is recovered at 6 months old, alongside with an increase of the adrenal content of NE and a dysfunctional celiac ganglion. Together, these results suggest that the recovery of ovarian NE does not come from a neural origin. In addition, ovarian performance was impaired because the changes in follicular development and steroidal secretion are not recovered despite the recovery of ovarian NE content. In conclusion, these results suggest that the nerve-ovarian connections, which are established during infantile development, are necessary for the accurate response of the ovary to sympathetic stimulation.
Assuntos
Estradiol/metabolismo , Norepinefrina/metabolismo , Folículo Ovariano/citologia , Simpatectomia , Sistema Nervoso Simpático/cirurgia , Animais , Feminino , Guanetidina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/cirurgia , Ratos , Ratos Sprague-Dawley , Simpatolíticos/farmacologiaRESUMO
Previous work has demonstrated that the increase in the activity of sympathetic nerves, which occurs during the subfertility period in female rats, causes an increase in follicular cyst development and impairs follicular development. In addition, the increase in ovarian sympathetic activity of aged rats correlates with an increased expression of kisspeptin (KISS1) in the ovary. This increase in KISS1 could participate in the decrease in follicular development that occurs during the subfertility period. We aimed to determine whether the blockade of ovarian sympathetic tone prevents the increase in KISS1 expression during reproductive aging and improves follicular development. We performed 2 experiments in rats: (1) an in vivo blockade of beta-adrenergic receptor with propranolol (5.0 mg/kg) and (2) an ovarian surgical denervation to modulate the sympathetic system at these ages. We measured Kisspeptin and follicle-stimulating hormone receptor (FSHR) mRNA and protein levels by qRT-PCR and western blot and counted primordial, primary and secondary follicles at 8, 10 and 12 months of age. The results showed that ovarian KISS1 decreased but FSHR increased after both propranolol administration and the surgical denervation in rats of 8, 10 and 12 months of age. An increase in FSHR was related to an increase in the number of smaller secondary follicles and a decreased number of primordial follicles at 8, 10 and 12 months of age. These results suggest that intraovarian KISS1 is regulated by sympathetic nerves via a beta-adrenergic receptor and participates locally in ovarian follicular development in reproductive aging.
Assuntos
Envelhecimento/metabolismo , Regulação da Expressão Gênica , Kisspeptinas/metabolismo , Ovário/metabolismo , Sistema Nervoso Simpático/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Feminino , Kisspeptinas/genética , Ovário/efeitos dos fármacos , Propranolol/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do FSH/genética , Receptores do FSH/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Successful reproduction is the result of a myriad interactions in which the ovary and the ovarian follicular reserve play a fundamental role. At present, women who delay maternity until after 30 years of age have a decreased fertility rate due to various causes, including damaged follicles and a reduction in the reserve pool of follicles. Therefore, the period just prior to menopause, also known as the subfertile period, is important. The possibility of modulating the follicular pool and the health of follicles during this period to improve fertility is worth exploring. We have developed an animal model to study the ovarian ageing process during this subfertile period to understand the mechanisms responsible for reproductive senescence. In the rat model, we have shown that the sympathetic nervous system participates in regulating the follicular development during ovarian ageing. This article reviews the existing evidence on the presence and functional role of sympathetic nerve activity in regulating the follicular development during ovarian ageing, with a focus on the subfertile period.Free Spanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/153/2/R61/suppl/DC1.
Assuntos
Envelhecimento , Fertilidade/fisiologia , Ovário/fisiologia , Reprodução/fisiologia , Animais , Ciclo Estral , Feminino , Humanos , Kisspeptinas/fisiologia , Camundongos , Modelos Animais , Folículo Ovariano/fisiologia , Ovário/inervação , Pré-Menopausa/fisiologia , Ratos , Sistema Nervoso Simpático/fisiologiaRESUMO
Maternal obesity during pregnancy has been related with several pathological states in offspring. However, the impact of maternal obesity on reproductive system on the progeny is beginning to be elucidated. In this work, we characterize the effect of maternal obesity on puberty onset and follicular development in adult offspring in rats. We also propose that alterations in ovarian physiology observed in offspring of obese mothers are due to increased levels of estradiol during early development. Offspring of control dams and offspring of dams exposed to a high-fat diet (HF) were studied at postnatal days (PND) 1, 7, 14, 30, 60, and 120. Body weight and onset of puberty were measured. Counting of ovarian follicles was performed at PND 60 and 120. Serum estradiol, estriol, androstenedione, FSH, LH, and insulin levels were measured by ELISA. Hepatic CYP3A2 expression was determined by Western blot. HF rats had a higher weight than controls at all ages and they also had a precocious puberty. Estradiol levels were increased while CYP3A2 expression was reduced from PND 1 until PND 60 in HF rats compared to controls. Estriol was decreased at PND60 in HF rats. Ovaries from HF rats had a decrease in antral follicles at PND60 and PND120 and an increase in follicular cysts at PND60 and PND120. In this work, we demonstrated that maternal obesity in rats alters follicular development and induces follicular cysts generation in the adult offspring. We observed that maternal obesity produces an endocrine disruption through increasing endogenous estradiol in early life. A programmed failure in hepatic metabolism of estradiol is probably the cause of its increase.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Estradiol/sangue , Fígado/metabolismo , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Androstenodiona/sangue , Animais , Peso Corporal/fisiologia , Dieta Hiperlipídica , Estriol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Insulina/sangue , Hormônio Luteinizante/sangue , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologiaRESUMO
BACKGROUND: Depletion of ovarian follicles is associated with the end of reproductive function in ageing females. Recently, it has been described that this process parallels increases in the concentration of norepinephrine (NE) in the rat ovary. In sexually mature rats, experimentally-induced increases in the sympathetic tone of the ovary is causally related to ovarian cyst formation and deranged follicular development. Thus, there is a possibility that increased ovarian NE concentrations represent changes in the activity of sympathetic nerves, which consequently participate in the process of ovarian cyst formation observed during ageing in the human and experimental animal models. METHODS: Sprague-Dawley rats between 6 and 14 months old were used to analyse the capacity of the ovary to release 3H-NE recently incorporated under transmural depolarisation in relation to changes in the ovarian follicular population. Morphometric analysis of ovarian follicles and real time PCR for Bcl2 and Bax mRNA were used to assess follicular atresia. RESULTS: From 8 months old, the induced release of recently incorporated 3H-norepinephrine (3H-NE) from the ovary and ovarian NE concentrations increased, reaching their peak values at 12 months old and remained elevated up to 14 months old. Increases in sympathetic nerve activity paralleled changes in the follicular population, as well as disappearance of the corpus luteum. In contrast, luteinised follicles, precystic follicles, and cystic follicles increased. During this period, the relationship between Bax and Bcl2 mRNAs (the proapoptotic/antiapoptotic signals) increased, suggesting atresia as the principal mechanism contributing to the decreased follicular population. When NE tone was increased, the mRNA ratio favoured Bcl2 to Bax and antiapoptotic signals dominated this period of development. Thus, these changing ratios could be responsible for the increase in luteinised follicles, as well as precystic and cystic follicles. CONCLUSION: These data suggest that the ageing process in the ovary of the Sprague-Dawley rat is accompanied by an increased sympathetic tone of the ovary. Consequently, this sympathetic change could be related to a neuroendocrine-driven formation of a polycystic condition similar to that observed in the sympathetic-activated adult ovary.