RESUMO
Fetal or neonatal androgen exposure has a programming effect on ovarian function inducing a polycystic ovarian syndrome-like condition. Its effects on uterine structure and function are poorly studied. The aim of this work was to characterize the temporal course of changes in the rat uterine structure induced by neonatal exposure to aromatizable or not aromatizable androgens. Rats were daily treated with testosterone, dihydrotestosterone or vehicle during follicle assembly period (postnatal days 1 to 5). Uterine histoarchitecture, hormonal milieu, endometrial stromal collagen and capillary density were analyzed at prepubertal, pubertal and adult ages. Our data shows that neonatal androgen exposure induces early and long-lasting deleterious effects on uterine development, including altered adenogenesis and superficial epithelial alterations and suggest a role for altered serum estradiol levels in the maintenance and worsening of the situation. Our results suggest that alterations of the neonatal androgenic environment on the uterus could be responsible for alterations in the processes of implantation and maintenance of the embryo in women with polycystic ovary syndrome.
Assuntos
Androgênios , Síndrome do Ovário Policístico , Humanos , Feminino , Ratos , Animais , Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Testosterona/farmacologia , Síndrome do Ovário Policístico/induzido quimicamente , Útero , VirilismoAssuntos
Humanos , Feminino , Oócitos , Criopreservação , Preservação da Fertilidade/métodos , Embrião de MamíferosRESUMO
Androgens are relevant in order to achieve a normal growth and maturation of the follicle and oocyte, since both excess and absence of androgens may affect the correct ovarian function. The current study analyzes the impact of neonatal androgenization in the first ovulation and oocyte maturation in response to exogenous gonadotrophin stimulation. Neonatal rats were daily treated with testosterone, dihydrotestosterone, or vehicle during follicle assembly period (days 1 to 5). At juvenile period, rats were stimulated sequentially with PMSG and hCG. Ovulation, ovarian histology, hormonal milieu, morphological characteristics of meiotic spindle, and in vitro fertilization rate in oocytes were analyzed. Our data shows that oocytes from androgenized rats displayed a major proportion of aberrant spindles and altered meiotic advance that control animals. These alterations were accompanied with an increase in both fertilization rate and aberrant embryos after 48 h of culture. Our findings showed a direct impact of neonatal androgens on oocyte development; their effects may be recognized at adulthood, supporting the idea of a programming effect exerted by neonatal androgens. These results could be relevant to explain the low fertility rate seen in polycystic ovary syndrome patients after in vitro fertilization procedures.
Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Testosterona/toxicidade , Virilismo/induzido quimicamente , Animais , Animais Recém-Nascidos , Técnicas de Cocultura , Feminino , Masculino , Oócitos/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Ovulação/efeitos dos fármacos , Ovulação/fisiologia , Gravidez , Ratos , Ratos Wistar , Virilismo/patologiaRESUMO
This study analyzes the effects of neonatal androgenization on follicular growth and first ovulation in response to gonadotrophins, using a model of exogenous stimulation or the use of subcutaneous ovary grafts in castrated animals to replace the hypothalamus-pituitary signal. Neonatal rats (days 1-5) were treated with testosterone, dihydrotestosterone or vehicle. At juvenile period, rats were stimulated with PMSG, hCG (alone or combined) or used as ovarian donors to be grafted on castrated adult female rats. Ovulation and ovarian histology were analyzed in both groups. Animals treated with vehicle or dihydrotestosterone stimulated with gonadotrophins (pharmacological or by using an ovary graft) ovulated, showing a normal histological morphology whereas rats exposed to testosterone and injected with the same doses of gonadotrophins did not it. In this group, ovulation was reached using a higher dose of hCG. Ovaries in the testosterone group were characterized by the presence of follicles with atretic appearance and a larger size than those observed in control or dihydrotestosterone groups. A similar appearance was observed in testosterone ovary grafts although luteinization and some corpora lutea were also identified. Our findings suggest that neonatal exposure to aromatizable androgens induces a more drastic signalling on the ovarian tissue that those driven by non-aromatizable androgens in response to gonadotrophins.
Assuntos
Androgênios/farmacologia , Gonadotropinas/farmacologia , Ovário/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Gonadotropina Coriônica/farmacologia , Di-Hidrotestosterona/farmacologia , Feminino , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Ovulação/efeitos dos fármacos , Ratos , Testosterona/farmacologiaRESUMO
The effects of neonatal testosterone or dihydrotestosterone exposure on ovarian follicular dynamics were analysed at prepubertal, pubertal or adult age in Wistar rats. Both androgens induced a transitory increase on follicular endowment that was partially corrected at puberty. At adult age testosterone prevented ovulation, without significant modifications on follicular dynamics. An increased number of cystic structures were observed from puberty to adult age. However, ovaries of rats treated with dihydrotestosterone showed follicles with evident morphological alterations in granulosa and thecal layers although several corpora lutea were observed. A significant increase in preantral follicles and few cystic structures were detected at advanced adulthood. The size of cyst increased with age. No immunohistochemical changes on growth factors or enzymes related to steroidogenesis in growing follicles were obvious in any group. In both androgenized groups, cysts shared immunohistochemical characteristics exhibited by preovulatory follicles but they were unable to ovulate spontaneously. Our results provide an insight into the role of different androgens in female reproductive system development, indicating a direct effect of dihydrotestosterone on ovarian tissues whereas a central effect would be the main feature of neonatal testosterone exposure. Heterogeneous clinical manifestations seen in pathologies such as polycystic ovary syndrome among women could be associated with subtle hormonal changes during follicular population development.
Assuntos
Androgênios/metabolismo , Folículo Ovariano/fisiologia , Animais , Biomarcadores , Di-Hidrotestosterona/metabolismo , Ciclo Estral , Feminino , Imuno-Histoquímica , Folículo Ovariano/citologia , Ovário/citologia , Ovário/fisiologia , Ratos , Testosterona/metabolismoRESUMO
Estradiol is a key hormone in the regulation of reproductive processes acting both on peripheral organs and sympathetic neurons associated to reproductive function. However, many of its regulatory effects on the development and function on the sympathetic neurons have not been completely clarified. Sympathetic neurons located in the celiac ganglion projects to visceral, vascular and glandular targets, and contribute to ovarian innervation, being the main source of sympathetic fibers. In the present study, we analyze the effects of elevated levels of exogenous estrogen during the prepubertal period in post-ganglionic sympathetic neurons. Estrogen exposure induced a significant increase in sympathetic celiac neuronal size and modified the expression of neurotrophin receptor p75. This change affected mainly small and medium size neurons. The effect of estrogens on innervation of celiac target organs was heterogeneous, inducing a significant increase in catecholaminergic innervation of the ovary, but not of the pyloric muscular layers. These findings further support the role of estrogen as a modulator of neuronal plasticity and suggest that estrogen could modify some features involved in the relation between sympathetic immature peripheral neurons and their target organs throughout a neurotrophin-dependent mechanism.
Assuntos
Estrogênios/administração & dosagem , Gânglios Simpáticos/metabolismo , Neurônios/metabolismo , Ovário/inervação , Receptor de Fator de Crescimento Neural/biossíntese , Maturidade Sexual/fisiologia , Animais , Feminino , Gânglios Simpáticos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Masculino , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ratos , Ratos Wistar , Receptor de Fator de Crescimento Neural/genética , Maturidade Sexual/efeitos dos fármacosRESUMO
The present study analyses the participation of ovarian innervation during reproductive senescence. We use the model of acute peripheral pharmacological sympathetic denervation with guanethidine in young (3 months old), middle-aged (12 months old) or old (18 months old) rats with spontaneous or induced ovulation. Ovarian levels of norepinephrine (NE) were measured by HPLC and the oestrous cycle, the number of ovulating animals and the percentage of atretic follicles were also assessed. Aged animals showed a progressive reduction in ovulatory capacity and an increase in ovarian NE content. Acute denervation increased the percentage of healthy follicles in 12- and 18-month-old rats compared with control adult animals. Combined treatment of denervation plus stimulation with gonadotrophins doubled the number of ova shed in young adult rats and restablished a partial ovulation in 12-month-old rats. The results suggest that ovarian noradrenergic innervation plays a modulator role in ovarian physiology during the ageing ovary process. The action of ovarian noradrenergic innervation seems to be associated with folliculogenesis and the ovarian response to gonadotrophins.
Assuntos
Envelhecimento/fisiologia , Ciclo Estral/fisiologia , Ovário/inervação , Ovulação/fisiologia , Ratos/fisiologia , Simpatectomia Química/métodos , Animais , Feminino , Gonadotropinas/farmacologia , Guanetidina , Análise Multivariada , Norepinefrina/metabolismo , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Ovário/fisiologia , Ovulação/efeitos dos fármacos , Ratos Wistar , SimpatolíticosRESUMO
The innervation of the uterus is remarkable in that it exhibits physiological changes in response to altered levels in the circulating levels of sex hormones. Previous studies by our group showed that chronic administration of estrogen to rats during the infantile/prepubertal period provoked, at 28 days of age, an almost complete loss of norepinephrine-labeled sympathetic nerves, similar to that observed in late pregnancy. It is not known, however, whether early exposure to estrogen affects uterine cholinergic nerves. Similarly, it is not known to what extent development and estrogen-induced responses in the uterine cholinergic innervation are affected by the absence of sympathetic nerves. To address this question, in this study we analyzed the effects of infantile/prepubertal chronic estrogen treatment, chronic chemical sympathectomy with guanethidine, and combined sympathectomy and chronic estrogen treatment on developing cholinergic nerves of the rat uterus. Cholinergic nerves were visualized using a combination of acetylcholinesterase histochemistry and the immunohistochemical demonstration of the vesicular acetylcholine transporter (VAChT). After chronic estrogen treatment, a well-developed plexus of cholinergic nerves was observed in the uterus. Quantitative studies showed that chronic exposure to estrogen induced contrasting responses in uterine cholinergic nerves, increasing the density of large and medium-sized nerve bundles and reducing the intercept density of fine fibers providing myometrial and perivascular innervation. Estrogen-induced changes in the uterine cholinergic innervation did not appear to result from the absence/impairment of sympathetic nerves, because sympathectomy did not mimic the effects produced by estrogen. Estrogen-induced responses in parasympathetic nerves are discussed, considering the direct effects of estrogen on neurons and on changes in neuron-target interactions.