Interplay between nitric oxide and gonadotrophin-releasing hormone in the neuromodulation of the corpus luteum during late pregnancy in the rat.

BACKGROUND: Nitric oxide and GnRH are biological factors that participate in the regulation of reproductive functions. To our knowledge, there are no studies that link NO and GnRH in the sympathetic ganglia. Thus, the aim of the present work was to investigate the influence of NO on GnRH release from the coeliac ganglion and its effect on luteal regression at the end of pregnancy in the rat. METHODS: The ex vivo system composed by the coeliac ganglion, the superior ovarian nerve, and the ovary of rats on day 21 of pregnancy was incubated for 180 min with the addition, into the ganglionic compartment, of L-NG-nitro arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor. The control group consisted in untreated organ systems. RESULTS: The addition of L-NAME in the coeliac ganglion compartment decreased NO as well as GnRH release from the coeliac ganglion. In the ovarian compartment, and with respect to the control group, we observed a reduced release of GnRH, NO, and noradrenaline, but an increased production of progesterone, estradiol, and expression of their limiting biosynthetic enzymes, 3ß-HSD and P450 aromatase, respectively. The inhibition of NO production by L-NAME in the coeliac ganglion compartment also reduced luteal apoptosis, lipid peroxidation, and nitrotyrosine, whereas it increased the total antioxidant capacity within the corpora lutea. CONCLUSION: Collectively, the results indicate that NO production by the coeliac ganglion modulates the physiology of the ovary and luteal regression during late pregnancy in rats.

Neural crest-derived neurons invade the ovary but not the testis during mouse gonad development.

Testes and ovaries undergo sex-specific morphogenetic changes and adopt strikingly different morphologies, despite the fact that both arise from a common precursor, the bipotential gonad. Previous studies showed that recruitment of vasculature is critical for testis patterning. However, vasculature is not recruited into the early ovary. Peripheral innervation is involved in patterning development of many organs but has been given little attention in gonad development. In this study, we show that while innervation in the male reproductive complex is restricted to the epididymis and vas deferens and never invades the interior of the testis, neural crest-derived innervation invades the interior of the ovary around E16.5. Individual neural crest cells colonize the ovary, differentiate into neurons and glia, and form a dense neural network within the ovarian medulla. Using a sex-reversing mutant mouse line, we show that innervation is specific to ovary development, is not dependent on the genetic sex of gonadal or neural crest cells, and may be blocked by repressive guidance signals elevated in the male pathway. This study reveals another aspect of sexually dimorphic gonad development, establishes a precise timeline and structure of ovarian innervation, and raises many questions for future research.

Unilateral section of the superior ovarian nerve induces first ovulation in the Zucker fatty (fa/fa) rat.

Hyperactivity in the sympathetic nervous system has been shown to be related to the development of ovarian pathologies. In addition, obesity has been found to be associated with multiple reproductive anomalies and is considered a chronic stress condition of low intensity with changes in the peripheral sympathetic activity. Therefore, in the present study, we aimed to evaluate if the information reaching the ovaries through the superior ovarian nerve (SON) modifies the ovarian function of Zucker fatty rats. We performed a unilateral section of the SON at 32 days of age and autopsies were carried out on the day of the first vaginal estrus. The results showed that fatty animals do not ovulate on the day of the first vaginal estrus and exhibit an increase in catecholaminergic fibers and the presence of precystic structures in the ovaries, without changes in the onset of puberty or in the secretion of ovarian and hypophyseal hormones. We also found that the section of the right SON resulted in ovulation on the day of the first vaginal estrus, which was accompanied by a decrease in ovarian noradrenaline content. The section of the left SON caused a delay in puberty without changes in the rest of the parameters. These results provide functional evidence that the peripheral sympathetic innervation participates in the regulation of ovarian functions in an animal model of genetic obesity.

Role of the superior ovarian nerve in the regulation of follicular development and steroidogenesis in the morning of diestrus 1.

PURPOSE: Little is known about the role of the superior ovarian nerve (SON) in follicular development during the estrus cycle. The aim of the present study was to analyze the role of neural signals arriving through the SON at the ovaries in the regulation of follicular development and ovarian steroid secretion in diestrus 1 of cyclic rats. METHODS: Cyclic rats were subjected to left, right, or bilateral SON sectioning or to unilateral or bilateral laparotomy at diestrus 1 at 11:00 h. Animals were sacrificed 24 h after surgery. RESULTS: Compared to laparotomized animals, unilateral SON sectioning decreased the number of preovulatory follicles, while bilateral SON sectioning resulted in a decreased number of atretic preantral follicles. An important observation was the presence of invaginations in the follicular wall of large antral and preovulatory follicles in animals with denervation. Furthermore, left SON sectioning increased progesterone levels but decreased testosterone levels, which are effects that were not observed in animals that were subjected to right denervation. CONCLUSIONS: At 11:00 h of diestrus 1, the SON was found to stimulate follicle development, possibly via neural signals, such as noradrenaline and/or vasoactive intestinal peptide, and this stimulation induced the formation of follicle-stimulating hormone receptors. The role of the SON in the regulation of ovarian steroid secretion is asymmetric: the left SON inhibits the regulation of progesterone and stimulates testosterone secretion, and the right nerve does not participate in these processes.

Pharmacological sympathetic denervation prevents the development of polycystic ovarian syndrome in rats injected with estradiol valerate.

BACKGROUND: The injection of estradiol valerate in female rats induces polycystic ovary syndrome, which is characterized by polycystic ovaries, anovulation, and hyperandrogenism. These characteristics have been associated with an increase in the ovarian concentration of norepinephrine, which occurs before establishing the polycystic ovary syndrome. The bilateral section of the superior ovarian nerve restores ovarian functions in animals with polycystic ovary syndrome. The superior ovarian nerve provides norepinephrine and vasoactive intestinal peptide to the ovary. An increase in the activity of both neurotransmitters has been associated with the development of polycystic ovary syndrome. The purpose of the present study was analyzed the participation of the noradrenergic nervous system in the development of polycystic ovary syndrome using guanethidine as a pharmacological tool that destroys peripheral noradrenergic nerve fibers. METHODS: Fourteen-day old female rats of the CIIZ-V strain were injected with estradiol valerate or vehicle solution. Rats were randomly allotted to one of three guanethidine treatment groups for denervation: 1) guanethidine treatment at age 7 to 27-days, 2) guanethidine treatment at age 14 to 34- days, and 3) guanethidine treatment at age 70 to 90- days. All animals were sacrificed when presenting vaginal oestrus at age 90 to 94-days. The parameters analyzed were the number of ova shed by ovulating animals, the ovulation rate (i.e., the numbers of ovulating animals/the numbers of used animals), the serum concentration of progesterone, testosterone, oestradiol and the immunoreactivity for tyrosine hydroxylase enzyme. All data were analyzed statistically. A p-value of less than 0.05 was considered significant. RESULTS: Our results show that the elimination of noradrenergic fibers before the establishment of polycystic ovary syndrome prevents two characteristics of the syndrome, blocking of ovulation and hyperandrogenism. We also found that in animals that have already developed polycystic ovary syndrome, sympathetic denervation restores ovulatory capacity, but it was not as efficient in reducing hyperandrogenism. CONCLUSION: The results of the present study suggest that the noradrenergic fibers play a stimulant role in the establishment of polycystic ovary syndrome.

Ovarian function and reproductive senescence in the rat: role of ovarian sympathetic innervation.

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.

Inhibitory mechanism of l-glutamic acid on spawning of the starfish Patiria (Asterina) pectinifera.

l-Glutamic acid was previously identified as an inhibitor of spawning in the starfish Patiria (Asterina) pectinifera; this study examined how l-glutamic acid works. Oocyte release from ovaries of P. pectinifera occurred after germinal vesicle breakdown (GVBD) and follicular envelope breakdown (FEBD) when gonads were incubated ex vivo with either relaxin-like gonad-stimulating peptide (RGP) or 1-methyladenine (1-MeAde). l-Glutamic acid blocked this spawning phenotype, causing the mature oocytes to remain within the ovaries. Neither RGP-induced 1-MeAde production in ovarian follicle cells nor 1-MeAde-induced GVBD and FEBD was affected by l-glutamic acid. l-Glutamic acid may act through metabotropic receptors in the ovaries to inhibit spawning, as l-(+)-2-amino-4-phosphonobutyric acid, an agonist for metabotropic glutamate receptors, also inhibited spawning induced by 1-MeAde. Application of acetylcholine (ACH) to ovaries under inhibitory conditions with l-glutamic acid, however, brought about spawning, possibly by inducing contraction of the ovarian wall to discharge mature oocytes from the ovaries concurrently with GVBD and FEBD. Thus, l-glutamic acid may inhibit ACH secretion from gonadal nerve cells in the ovary. Mol. Reprod. Dev. 84: 246-256, 2017. © 2017 Wiley Periodicals, Inc.

Histological verification of the prehypogastric and ovarian ganglia confirms a bilaterally symmetrical organization of the ganglia comprising the aortic plexus in female human cadavers.

The aortic plexus is a network of sympathetic nerves positioned along the infrarenal abdominal aorta. Recently, we characterized the aortic plexus and its ganglia (inferior mesenteric, left/right spermatic, and prehypogastric ganglion) in males; however, the literature minimally describes its anatomy in females. In the present study, we conducted the first histological examination of the left and right ovarian ganglia, while also investigating whether females, like males, exhibit a prehypogastric ganglion. The ganglia were dissected from embalmed (n = 32) and fresh (n = 1) human cadavers, and H&E staining was used to confirm the presence of a left ovarian ganglion in 31/31 specimens, a right ovarian ganglion in 29/29 specimens and a prehypogastric ganglion in 25/28 specimens. Comparable to the topographic arrangement in males, there is a bilateral organization of the ganglia comprising the aortic plexus in females. More specifically, the left and right ovarian ganglia were positioned in close relation to their respective ovarian artery, whereas the prehypogastric ganglion was positioned within the right cord of the aortic plexus, contralateral to the inferior mesenteric ganglion. Using immunohistochemistry, it was shown that all ganglia from the fresh cadaver stained positive for tyrosine hydroxylase, thereby confirming their sympathetic nature. Having provided the first topographical and histological characterization of the ovarian and prehypogastric ganglia in females, future studies should seek to determine their specific function.

Physiology of reproductive worker honey bees (Apis mellifera): insights for the development of the worker caste.

Reproductive and behavioural specialisations characterise advanced social insect societies. Typically, the honey bee (Apis mellifera) shows a pronounced reproductive division of labour between worker and queen castes, and a clear division of colony roles among workers. In a queenless condition, however, both of these aspects of social organisation break down. Queenless workers reproduce, forage and maintain their colony operating in a manner similar to communal bees, rather than as an advanced eusocial group. This plasticity in social organisation provides a natural experiment for exploring physiological mechanisms of division of labour. We measured brain biogenic amine (BA) levels and abdominal fat body vitellogenin gene expression levels of workers in queenright and queenless colonies. Age, ovary activation and social environment influenced brain BA levels in honey bees. BA levels were most influenced by ovary activation state in queenless bees. Vitellogenin expression levels were higher in queenless workers than queenright workers, but in both colony environments vitellogenin expression was lower in foragers than non-foragers. We propose this plasticity in the interacting signalling systems that influence both reproductive and behavioural development allows queenless workers to deviate significantly from the typical worker bee reaction norm and develop as reproductively active behavioural generalists.

Oxidative stress and altered steroidogenesis in the ovary by cholinergic stimulation of coeliac ganglion in the first proestrous in rats. Implication of nitric oxide.

An ex-vivo Coeliac Ganglion-Superior Ovarian Nerve-Ovary (CG-SON-O) system from virgin rats in the first proestrous was used to test whether cholinergic stimulation of CG affects oxidative status and steroidogenesis in the ovary. The CG and the O were placed in separate buffered-compartments, connected by the SON, and the CG was stimulated by acetylcholine (Ach). To test a possible role of nitric oxide (NO) in the ovarian response to cholinergic stimulation of CG, aminoguanidine (AG) - an inhibitor of inducible-NO synthase was added to the O compartment. After 180 min incubation, the oxidative status was assessed in O whereas nitrite and steroidogenesis were assessed at 30, 120 and 180 min. Ach in CG decreased the total antioxidant capacity, but increased NO production and protein carbonization in O. Ach stimulation of CG increased estradiol, but decreased progesterone release in O by reducing the mRNAs related to their synthesis and degradation. The addition of AG to the O compartment caused an opposite effect, which was more pronounced in the presence of Ach in the CG compartment than in its absence. These results show that the stimulation of the extrinsic-cholinergic innervation of the O increases the concentration of NO, causes oxidative stress and modulates steroidogenesis in the first rat proestrous.

Prolactin modulates luteal regression from the coeliac ganglion via the superior ovarian nerve in the late-pregnant rat.

There is considerable evidence of the neuroendocrine control involved in luteal regression in the rat. In addition, circulating prolactin (PRL), which increases during the night before parturition, may gain access to the coeliac ganglion (CG), indirectly impacting the physiology of the ovary because of the known connection between the CG and the ovary via the superior ovarian nerve (SON). In this work we investigated in the CG-SON-ovary system and whether PRL added to the CG has an impact, indirectly via the SON, on luteal regression on Day 21 of pregnancy. The system was incubated without (control) or with PRL added to the CG. We measured the ovarian release of progesterone (P), oestradiol and prostaglandin F2 alpha (PGF2α) by radioimmunoassay, and nitrites (NO) by the Griess method. Luteal mRNA expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 20α-HSD, aromatase, inducible nitric oxide synthase (iNOS) and apoptosis regulatory factors was analysed by reverse transcription-polymerase chain reaction. P release, the expression of Bcl-2 and the Bcl-2:Bax ratio was lower than control preparations, while the expression of 20α-HSD and the release of NO and PGF2α were higher in the experimental group. In conclusion, PRL acts at the CG and, by a neural pathway, modulates luteal function at the end of pregnancy.

In the pubertal rat, the regulation of ovarian function involves the synergic participation of the sensory and sympathetic innervations that arrive at the gonad.

BACKGROUND: The present study investigates sectioning the superior ovarian nerve (SON) in rats with functional sensorial denervation induced by capsaicin administration at birth and the effects on the establishment of puberty, ovulation, serum progesterone, and estradiol concentrations. METHODS: The animals were allotted randomly to one of the following experimental groups. Groups of 8-10 rats were injected at birth with capsaicin or vehicle, and on day 20 or 28 of life, they were submitted to a sham operation (SO). Other groups of 8-10 rats were injected at birth with capsaicin or vehicle, and on day 20 or 28 of life, they were submitted to the uni-or bilateral SON sectioning. The animals were killed at the first estrus. Serum concentration of progesterone (ng/ml) and estradiol (pg/ml) were measured using a radioimmunoassay. RESULTS: Animals treated with capsaicin and subjected at 20 days of life to the left or bilateral section of SON had a delayed age of vaginal opening. Furthermore, animals with a lack of sensory information and subjected to a SO at 28 days of life had the same delay in the age of vaginal opening. Animals with sensorial innervation intact, subjected to unilateral section of the SON at 20 or 28 days of age, showed diminished ovulation rate and number of ova shed by the denervated ovary. In animals with sensorial denervation, the uni-or bilateral sectioning of the SON did not result in changes in ovulation. Progesterone and estradiol levels were different depending on the age of the animal in which the SON section was performed. CONCLUSIONS: Based on the present results, we suggest that sympathetic innervation regulates ovulation and the secretion of steroid hormones and that the sensory fibers modulate the sympathetic innervation action on ovarian functions.

Exogenous long-term treatment with 17ß-oestradiol alters the innervation pattern in pig ovary.

The aim of the present study was to determine the effect of long-term 17ß-oestradiol (E2) exposure, a simulation of pathological states that occur with oestrogen overproduction, on the innervation patterns of ovaries in adult gilts. The intraovarian distribution and density of nerve fibres immunoreactive (IR) to protein gene product (PGP) 9.5 and containing dopamine-ß-hydroxylase (DBH), neuropeptide Y (NPY), somatostatin (SOM) and galanin (GAL) were determined. From Day 4 of the first oestrous cycle to Day 20 of the second cycle studied, experimental gilts were injected with E2 (1000µg every 12h) whereas control gilts were injected with corn oil. After E2 administration, there was an increase in the number of PGP9.5-, DBH-, NPY- and GAL-IR fibres. Numerous PGP9.5-IR terminals were observed within the ground plexus around secondary follicles and small or medium tertiary follicles. Long-term E2 treatment increased the density of DBH- and NPY-IR fibres in the cortical part of the ground plexus, DBH- and GAL-IR fibres in the medullary part of the ground plexus, DBH-IR fibres near small and medium tertiary follicles and NPY-IR fibres around medullary arteries. The data indicate that long-term exposure of gilts to E2 increases the total number of intraovarian fibres, including sympathetic fibres. These results suggest that elevated E2 levels that occur during pathological states may affect the innervation patterns of ovaries and their function(s).

Effect of prolactin acting on the coeliac ganglion via the superior ovarian nerve on ovarian function in the postpartum lactating and non-lactating rat.

Whether prolactin (PRL) has a luteotrophic or luteolytic effect in the rat ovary depends on the nature of the corpora lutea present in the ovaries and the hormonal environment to which they are exposed. The aim was to investigate the effect of PRL acting on the coeliac ganglion (CG) on the function of the corpora lutea on day 4 postpartum under either lactating or non-lactating conditions, using the CG-superior ovarian nerve-ovary system. The ovarian release of progesterone (P), estradiol, PGF2α, and nitrites was assessed in the ovarian compartment at different incubation times. Luteal mRNA expression of 3ß-HSD, 20α-HSD, aromatase, PGF2α receptor, iNOS, Bcl-2, Bax, Fas and FasL was analysed in the corpus luteum of pregnancy at the end of the experiments. Comparative analysis of control groups showed that the ovarian release of P, nitrites, and PGF2α, the expression of PGF2α receptor, and the Bcl-2/Bax ratio were lower in non-lactating rats, with increased release of estradiol, and higher expression of aromatase, Fas and FasL, demonstrating the higher luteal functionality in ovaries of lactating animals. PRL added to the CG compartment increased the ovarian release of P, estradiol, nitrites and PGF2α, and decreased the Bcl-2/Bax ratio in non-lactating rats; yet, with the exception of a reduction in the release of nitrites, such parameters were not modified in lactating animals. Together, these data suggest that the CG is able to respond to the effect of PRL and, via a neural pathway, fine-tune the physiology of the ovary under different hormonal conditions.

Functional neuronal circuits promote disease progression in cancer.

The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.

The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target?

Polycystic ovary syndrome (PCOS) is a common endocrine condition associated with long-term health risks, including type 2 diabetes and vascular dysfunction in addition to reproductive sequelae. Many of the common features of PCOS, such as central obesity, hyperinsulinaemia and obstructive sleep apnoea (OSA), are associated with chronic sympathetic overactivity, suggesting that sympathoexcitation may be involved in the pathogenesis of this condition. Rodent models of polycystic ovaries have shown that ovarian sympathetic outflow may be increased, accompanied by elevated intra-ovarian synthesis of nerve growth factor (NGF) which may be involved in initiation of ovarian pathology. Patients with PCOS have evidence of increased muscle sympathetic nerve activity (MSNA), altered heart rate variability and attenuated heart rate recovery postexercise, compared with age- and BMI-matched controls, suggesting a generalized increase in sympathetic nerve activity. Active weight loss can reduce MSNA and whole body noradrenaline spillover, whereas low-frequency electroacupuncture decreased MSNA in overweight women with PCOS. Treatment of OSA with continuous positive airways pressure may reduce plasma noradrenaline levels and diastolic blood pressure and improve cardiac sympathovagal balance. Renal sympathetic denervation also reduced MSNA, noradrenaline spillover and blood pressure in two PCOS subjects with hypertension, accompanied by improved insulin sensitivity. The sympathetic nervous system may thus offer a new therapeutic target in PCOS but larger and longer-term studies are needed before these treatments can be considered in clinical practice.

Involvement of the oestrogenic receptors in superior mesenteric ganglion on the ovarian steroidogenesis in rat.

Oestradiol (E(2)) is a key hormone in the regulation of reproductive processes. The aims of this work were a) to examine the distributions of oestrogen receptor α (ERα) and ERß in the neurons of the superior mesenteric ganglion (SMG) in the oestrus stage by immunohistochemistry, b) to demonstrate whether E(2) in the SMG modifies progesterone (P(4)), androstenedione (A(2)) and nitrite release in the ovarian compartment on oestrus day and c) to demonstrate whether E(2) in the ganglion modifies the activity and gene expression in the ovary of the steroidogenic enzymes 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 20α-hydroxysteroid dehydrogenase (20α-HSD). The ex vivo SMG-ovarian nervous plexus-ovary system was used. E(2), tamoxifen (Txf) and E(2) plus Txf were added in the ganglion to measure ovarian P(4) release, while E(2) alone was added to measure ovarian A(2) and nitrites release. Immunohistochemistry revealed cytoplasmic ERα immunoreactivity only in the neural somas in the SMG. E(2) increased ovarian P(4) and A(2) release at 15, 30 and 60 min but decreased nitrites. The activity and gene expression of 3ß-HSD increased, while the activity and gene expression of 20α-HSD did not show changes with respect to the control. Txf in the ganglion diminished P(4) release only at 60 min. E(2) plus Txf in the ganglion reverted the effect of E(2) alone and the inhibitory effect of Txf. The results of this study demonstrate that ERα activation in the SMG has an impact on ovarian steroidogenesis in rats, thus providing evidence for the critical role of peripheral system neurons in the control of ovarian functions under normal and pathological conditions.

Effects on steroid hormones secretion resulting from the acute stimulation of sectioning the superior ovarian nerve to pre-pubertal rats.

In the adult rat, neural signals arriving to the ovary via the superior ovarian nerve (SON) modulate progesterone (P4), testosterone (T) and estradiol (E2) secretion. The aims of the present study were to analyze if the SON in the pre-pubertal rat also modulates ovarian hormone secretion and the release of follicle stimulating hormone (FSH) and luteinizing (LH) hormone. P4, T, E2, FSH and LH serum levels were measured 30 or 60 minutes after sectioning the SON of pre-pubertal female rats. Our results indicate that the effects on hormone levels resulting from unilaterally or bilaterally sectioning the SON depends on the analyzed hormone, and the time lapse between surgery and autopsy, and that the treatment yielded asymmetric results. The results also suggest that in the pre-pubertal rat the neural signals arriving to the ovaries via the SON regulate the enzymes participating in P4, T and E2 synthesis in a non-parallel way, indicating that the mechanisms regulating the synthesis of each hormone are not regulated by the same signals. Also, that the changes in the steroids hormones are not explained exclusively by the modifications in gonadotropins secretion. The observed differences in hormone levels between rats sacrificed 30 and 60 min after surgery reflect the onset of the compensatory systems regulating hormones secretion.

Neonatal programming by immunological challenge: effects on ovarian function in the adult rat.

Neonatal exposure to an immunological challenge (lipopolysaccharide, LPS) increases the activity of hypothalamo-pituitary-adrenal axis and sensitises the GNRH pulse generator to the inhibitory influence of stress in adult rats. We investigated the effects of neonatal exposure to LPS on various reproductive parameters during puberty and into adulthood in female rats. LPS (50 µg/kg, i.p.) or saline was administered on postnatal days 3 and 5. Vaginal opening was recorded, and oestrous cyclicity was monitored immediately post puberty and again at 8-9 weeks of age. At 10 weeks of age, the ovaries were removed and the number of follicles was counted, together with the thickness of the theca interna of the largest antral follicles. Ovarian sympathetic nerve activity was assessed immunohistochemically by measurement of the levels of ovarian low-affinity receptor of nerve growth factor (p75NGFR). In rats exposed to LPS in early life, there was a significant delay in puberty and disruption of oestrous cyclicity immediately post puberty, which persisted into adulthood. The follicle reserve was decreased, the thickness of the theca interna increased and the expression profile of ovarian p75NGFR increased in the neonatal LPS-treated animals. These data suggest that exposure to LPS during early neonatal life can have long-term dysfunctional effects on the female reproductive system, which might involve, at least in part, increased ovarian sympathetic nerve activity.