neuropeptide-y and Infertility--Female

Apart from the abnormalities of tubal anatomy, the main concern linked to infertility is impaired tubal motility associated with hydrosalpinx, which is thought to be controlled by hormones and nerves. The objective of this study was to determine the distribution of nerve fibers in the oviduct isthmus in women with and without hydrosalpinx. Histological sections of the oviduct isthmus tissue were obtained from 18 women undergoing salpingectomy for hydrosalpinx, and from 15 women undergoing hysterectomy and salpingectomy for benign gynecologic diseases. The tissues were immunohistochemically stained for protein gene product (PGP) 9.5, protein S100, neuropeptide tyrosine (NPY), and vasoactive intestinal peptide (VIP) to reveal all nerve fibers, as well as sympathetic and parasympathetic nerve fibers, in the oviduct isthmus. We detected the presence of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus in all study subjects. However, the densities of PGP9.5, S100, VIP, and NPY-immunoreactive nerve fibers in the oviduct isthmus were all significantly decreased in women with hydrosalpinx compared with those in women without hydrosalpinx (P<0.01). Our results suggest that reduced nerve fibers in the oviduct isthmus in women with hydrosalpinx compared with women without hydrosalpinx may have an important function in the mechanism of hydrosalpinx-associated infertility.

Topics: Adult; Autonomic Nervous System Diseases; Biomarkers; Fallopian Tubes; Female; Humans; Hysterectomy; Infertility, Female; Nerve Fibers; Neuropeptide Y; S100 Proteins; Salpingectomy; Salpingitis; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide; Young Adult

Nutritional infertility is very common in societies where women fail to eat enough to match their energy expenditure and such females often present as clinical cases of anorexia nervosa. The cellular and molecular mechanisms that link energy balance and central regulation of reproduction are still not well understood. Peripheral hormones such as estradiol, testosterone and leptin, as well as neuropeptides like kisspeptin and neuropeptides Y (NPY) play a potential role in regulation of reproduction and energy balance with their primary target converging on the hypothalamic median eminence-arcuate region. The present study was aimed to explore the effects of negative energy state resulting from intermittent fasting dietary restriction (IF-DR) regimen on complete hypothalamo-hypophysial-gonadal axis in Wistar strain young female and male rats. Significant changes in body weight, blood glucose, estrous cyclicity and serum estradiol, testosterone and LH level indicated the negative role of IF-DR regimen on reproduction in these young animals. Further, it was elucidated whether serum level of metabolic hormone, leptin plays a mechanistic role in suppressing hypothalamo-hypophysial-gonadal (HPG) axis via energy regulators, kisspeptin and NPY in rats on IF-DR regimen. We also studied the effect of IF-DR regimen on structural remodeling of GnRH axon terminals in median eminence region of hypothalamus along with the glial cell marker, GFAP and neuronal plasticity marker, PSA-NCAM using immunostaining, Western blotting and RT-PCR. Together these data suggest that IF-DR regimen negatively influences reproduction in young animals due to its adverse effects on complete hypothalamus-hypophysial-gonadal axis and may explain underlying mechanism(s) to understand the clinical basis of nutritional infertility.

Topics: Animals; Anorexia Nervosa; Estradiol; Estrous Cycle; Fasting; Female; Gonads; Humans; Hypothalamus; Infertility, Female; Leptin; Male; Neuronal Plasticity; Neurons; Neuropeptide Y; Pituitary Gland; Rats; Rats, Wistar; Reproduction; Testosterone

Obesity is strongly associated with female infertility, but the mechanisms underlying this relationship are largely unknown.. We investigated the effect of increasing dietary fat percentage upon body mass, hypothalamic neuropeptide gene expression, adipose hormone secretion and fertility in females of the inbred mouse strains C57BL/6J and DBA/2J. To assess the effect of obesity independent of dietary influence, we also compared these parameters in wild-type female C57BL/6J mice to those congenic for the obesogenic mutations ob/ob and A(y)/a.. After 24 weeks, rather than exhibiting an obese, leptin-resistant phenotype like their female DBA/2J counterparts, wild-type female C57BL/6J mice remained lean, fertile and manifested increased hypothalamic LEPR-B expression. Although both mutant genotypes were associated with obesity and subfertility, ob/ob mice demonstrated significantly increased hypothalamic LEPR-B expression, whereas A(y)/a mice had a significant reduction. Interestingly, wild-type female C57BL/6J mice were noted to manifest significantly higher and lower levels of adiponectin and tissue plasminogen activator inhibitor-1 (tPAI-1), respectively, than weight-matched wild-type female DBA/2J mice.. We conclude that (1) resistance to the obese-infertile phenotype in female C57BL/6J mice is associated with increased hypothalamic leptin receptor expression and alterations in adipokine levels consistent with decreased adipose tissue inflammation and (2) that long-standing hyperleptinemic obesity in mice is associated with a downregulation of the hypothalamic leptin receptor.

Topics: Adiponectin; Agouti-Related Protein; Animals; Body Weight; Dietary Fats; Female; Gonadotropin-Releasing Hormone; Hypothalamus; Infertility, Female; Insulin; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Pro-Opiomelanocortin; Receptors, Cell Surface; Receptors, Leptin; Resistin; Tissue Plasminogen Activator

We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.

Topics: Agouti-Related Protein; Alleles; Animals; Blood Glucose; Body Composition; Body Weight; Cold Temperature; Diabetes Mellitus; DNA, Complementary; Female; Fertility; Gene Expression Regulation; Genetic Therapy; Genotype; Glucose; Homeostasis; Homozygote; Hypothalamus; In Situ Hybridization; Infertility; Infertility, Female; Infertility, Male; Insulin; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Obesity; Peptides; Phenotype; Phosphopyruvate Hydratase; Polymerase Chain Reaction; Pro-Opiomelanocortin; Promoter Regions, Genetic; Protein Isoforms; Proteins; Rats; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Synapsins; Time Factors; Tissue Distribution; Transgenes

The effects of diet and adiposity have been implicated in disturbances of female reproductive function. In an effort to better elucidate the relationship between obesity and female fertility, we analyzed the effect of increasing dietary fat content on body composition, insulin sensitivity, and pregnancy rates in two common inbred mouse strains, DBA/2J and C57BL/6J. After 16 wk, females of both strains on the high fat diet developed glucose intolerance and insulin resistance, but only the female DBA/2J mice developed dietary-induced obesity and hyperleptinemia. The high fat diet was associated with more than a 60% decrease in natural pregnancy rates of female DBA/2J mice, whereas the fertility of female C57BL/6J mice was unaffected. Despite developing a similar degree of obesity, insulin resistance, and hyperleptinemia, male DBA/2J mice did not manifest diminished fertility. Obese female DBA/2J mice achieved normal ovulatory responses and pregnancy rates after exogenous gonadotropin stimulation, suggesting their fertility defect to be central in origin. Real-time PCR quantification of hypothalamic cDNA revealed a 100% up-regulation of neuropeptide Y and a 50% suppression of GnRH expression accompanied by a 95% attenuation of leptin receptor type B expression in obese female DBA/2J mice. These findings suggest that obesity-associated hyperleptinemia, and not insulin resistance or increased dietary fat per se, gradually induces central leptin resistance, increases hypothalamic neuropeptide Y-ergic tone, and ultimately causes hypothalamic hypogonadism. The data establish high fat-fed female DBA/2J mice as a wild-type murine model of obesity-related infertility.

Topics: Animals; Body Composition; Dietary Fats; Female; Gene Expression; Hyperinsulinism; Hypothalamus; Infertility, Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuropeptide Y; Obesity; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Repressor Proteins; Species Specificity; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors

Several conditions that inhibit female sexual behavior are thought to be associated with altered corticotropin-releasing hormone (CRH) activity in the brain. The present experiments examined the hypothesis that endogenous CRH receptor signaling mediates the inhibition of estrous behavior by undernutrition and in other instances of sexual dysfunction. Intracerebroventricular (ICV) infusion of CRH or urocortin inhibited estrous behavior in ovariectomized steroid-primed hamsters. Conversely, ICV infusion of the CRH receptor antagonist astressin prevented the suppression of estrous behavior by food deprivation or by ICV administration of neuropeptide Y. Astressin treatment also induced sexual receptivity in nonresponders, animals that do not normally come into heat when treated with hormones, and this effect persisted in subsequent weekly tests in the absence of any further astressin treatment. Activation of the hypothalamo-pituitary-adrenocortical axis was neither necessary nor sufficient to inhibit estrous behavior, indicating that this phenomenon is due to other central actions of CRH receptor agonists. This is the first direct evidence that CRH receptor signaling may be a final common pathway by which undernutrition and other conditions inhibit female sexual behavior.

Topics: Animal Nutritional Physiological Phenomena; Animals; Corticosterone; Corticotropin-Releasing Hormone; Cricetinae; Eating; Estrous Cycle; Female; Hydrocortisone; Hypothalamo-Hypophyseal System; Infertility, Female; Injections, Intraventricular; Mesocricetus; Neural Inhibition; Neuropeptide Y; Neuroprotective Agents; Peptide Fragments; Pituitary-Adrenal System; Receptors, Corticotropin-Releasing Hormone; Sexual Behavior, Animal; Urocortins

In lactating rats, food restriction potentiates the already high levels of hypothalamic neuropeptide Y (NPY). To investigate the role that high levels of NPY might play in the prolongation of lactational infertility that typically accompanies a food restricted lactation we investigated the effects of chronic central infusions of NPY in ad libitum-fed lactating females. First, we compared the effects of intracerebroventricular (icv) infusion of NPY from Days 12-19 postpartum at a dose of 14.4 microg/day with a similar treatment in nonlactating females. In subsequent experiments we examined the effects of NPY infusions into the lateral ventricle at doses of 6 or 20 mug/day or unilaterally into the medial preoptic area at a dose of 1 microg/day from either Days 12-19 or 7-21 postpartum. Effects on food intake; female body weight; and, where appropriate, litter weight and length of lactational diestrus were compared between NPY and vehicle-treated females. As expected NPY infusion produced a robust increase in body weight and food intake in nonlactating females that was accompanied by a suppression of cyclicity. By contrast NPY treatment in lactating rats resulted in a marked decrease in litter growth and an earlier termination of lactational diestrus.

Topics: Animals; Animals, Suckling; Eating; Female; Infertility, Female; Injections, Intraventricular; Lactation; Neuropeptide Y; Preoptic Area; Prolactin; Rats; Rats, Wistar; Weight Gain

To explore the effect of Tiangui Recipe (TGR) on obesity and anovulation in androgen-sterilized rats (ASR) from the gene transcription level.. In situs hybridization and autoradiography were adopted, using alpha-32 P-radiolabelled leptin receptor (OB-R) and neuropeptide Y (NPY) oligonucleotides probes and integrating with image pattern analysis, to observe the effect of TGR on changes of OB-R, NPY mRNA expression in the hypothalamic arcuate nucleus (ARC).. Compared to the normal rats, the levels of hypothalamic OB-R mRNA expression decreased, NPY mRNA expression elevated significantly in ASR (P < 0.01). ASR characterized by obesity and anovulation. There was no significant difference in hypothalamic OB-R, NPY mRNA expressions between normal rats and ASR with TGR administration.. The increased hypothalamic NPY and decreased OB-R mRNA expression may be important contributing factors to the development of obesity and anovulation in ASR. TGR may play a role in reducing weight and inducing ovulation by regulating NPY/OB-R mRNA expression.

Topics: Animals; Animals, Newborn; Arcuate Nucleus of Hypothalamus; Carrier Proteins; Drugs, Chinese Herbal; Female; Hypothalamus; Infertility, Female; Neuropeptide Y; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Testosterone

Obese Zucker rats are hyperphagic, overweight, and infertile. It has been postulated that neuropeptide Y (NPY) overproduction may contribute to obesity and infertility in these animals. To test this hypothesis, ovariectomized, adult obese Zucker rats were implanted with cannulae in the third ventricle and subsequently injected with NPY antisera or normal rabbit sera (NRS) 6, 4 and 2 h before experimental observation. Steroid-treated females injected with NPY antisera were significantly more receptive and were more likely to show proceptive behaviors than after treatment with NRS (e.g., lordosis quotient: NPY antisera, 65.5+/-6.9%; NRS, 30.9+/-11.6%, P < 0.02; 91% displaying proceptivity after NPY antisera injection vs. 36% after NRS, P < 0.03). Injection of NPY antisera also curbed food intake and weight gain (24 h food intake: NPY antisera, 10.5+/-2.1 g; NRS, 20.5+/-1.7 g, P < 0.01; 24 h weight gain: NPY antisera, -5.4+/-2.2 g; NRS, 5.8+/-0.7 g, P < 0.01). Locomotor activity was similar after NRS and NPY antisera treatment (P > 0.5) suggesting that general malaise was not responsible for the effects of NPY antisera on food intake or body weight. These data suggest that endogenous neuropeptide Y contributes to excessive feeding and weight gain, and suppressed reproductive behaviors in obese Zucker female rats.

Topics: Animals; Antibodies; Feeding Behavior; Female; Infertility, Female; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Ovariectomy; Rabbits; Rats; Rats, Zucker; Sexual Behavior, Animal; Weight Gain