leptin and Infertility--Female

Polycystic ovary syndrome (PCOS) is the most common cause of female endocrine infertility. Insulin resistanсе is supposed to be one of the essential factors of this disease pathways. At the same time, the mechanisms of PCOS development in insulin-resistant patients have not been completely established. Leptin and Peroxisome Proliferator-Activated Receptor γ(PPARγ) are involved in carbohydrate metabolism and reproduction function regulation. It indicates that leptin and PPARγ possibly play a role in the pathways of PCOS. This article is a review of publications on this issue. The purpose of this review was to systematize the available information on the molecular mechanisms that determine the role of leptin and PPARγ in the development of PCOS. The literature search was carried out from 04/05/2020 to 05/17/2020 using the scientific literature databases: NCBI PubMed (foreign sources) and Cyberleninka (domestic sources). We analyzed publications for the period 1990-2020.The review presents the current understanding of the possible role of leptin and PPARγ in the regulation of endocrine, immune systems, and reproductive function, as well as in the development of PCOS. Currently, no studies cover the mechanisms of interaction between leptin and PPARγ in the pathways of this syndrome. The available studies indicating the individual contribution and association of leptin and PPARγ with PCOS are conflicting and have many limitations. Therefore, more studies of direct and indirect interaction of leptin and PPARγ, as well as their role in PCOS pathways, are needed.

Topics: Female; Humans; Infertility, Female; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; PPAR gamma

As the global mean Body Mass Index (BMI) is on the rise, the importance of understanding exactly how female fertility is impacted by once outlier BMI values, becomes ever more important. Studies have implicated abnormal BMI on the female reproductive system by contributing to anovulation, irregular menses, adverse oocyte quality, endometrial alterations, and hormonal imbalances. These well ultimately result in female infertility, which could complicate natural conception efforts and request considering assisted reproductive technology (ART) in such couples. With an increase in the demand for ART, it is crucial to understand what factors can be altered by the female BMI in order to maximize the opportunity for successful pregnancy. The current manuscript aimed to review the information about the effect of BMI on the female fertility and ART outcomes. The complex nature of the female reproductive system leaves space for multiple factors to adversely affect its processes. Imbalances in the hypothalamus-pituitary-ovarian axis can impede efforts for couples to conceive. Leptin and estrogen are two hormones that have been implicated in regulating BMI as well as reproductive physiology. Lifestyle modifications prior to, and during ART have shown promise in enhancing fecundity. The intricacies in female reproductive system leaves much to the unknown, and often with conflicting results. Further research is required to fully elucidate what aspects of female fertility are influenced by BMI, and how the healthcare provider can facilitate successful outcomes. The current review will enable a better consultation and treatment.

Topics: Body Mass Index; Endometrium; Estrogens; Female; Fertility; Humans; Infertility, Female; Leptin; Obesity; Overweight; Ovulation; Pregnancy; Reproductive Techniques, Assisted

Leptin, an adipose hormone, has been shown to control energy homeostasis and food intake, and exert many actions on female reproductive function. Consequently, this adipokine is a pivotal factor in studies conducted on animal models and humans to decipher the mechanisms behind the infertility often observed in obese women.. A systematic PubMed search was conducted on all articles, published up to January 2015 and related to leptin and its actions on energy balance and reproduction, using the following key words: leptin, reproduction, infertility, IVF and controlled ovarian stimulation. The available literature was reviewed in order to provide an overview of the current knowledge on the physiological roles of leptin, its involvement in female reproductive function and its potential interest as a prognostic marker in IVF cycles.. Animal and human studies show that leptin communicates nutritional status to the central nervous system and emerging evidence has demonstrated that leptin is involved in the control of reproductive functions by acting both directly on the ovaries and indirectly on the central nervous system. With respect to the clinical use of leptin as a biomarker in IVF cycles, a systematic review of the literature suggested its potential interest as a predictor of IVF outcome, as high serum and/or follicular fluid leptin concentrations have correlated negatively with cycle outcome. However, these preliminary results remain to be confirmed.. Leptin regulates energy balance and female reproductive function, mainly through its action on hypothalamic-pituitary-ovarian function, whose molecular and cellular aspects are progressively being deciphered. Preliminary studies evaluating leptin as a biomarker in human IVF seem promising but need further confirmation.

Topics: Animals; Biomarkers; Energy Metabolism; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Leptin; Obesity; Ovary; Ovulation Induction; Reproduction

Obesity is a growing worldwide problem and is associated with a wide range of adverse effects on the female reproductive system. The endocrinological changes in obesity that may cause these adverse effects are complex and include changes in circulating adipokines and sex steroids as well as insulin resistance. Considerable evidence suggests an adverse effect of obesity on the risk of miscarriage and other maternal and fetal complications. Obese patients are also more prone to infertility. The most important single method to improve reproductive performance in obese women is weight loss that can be achieved with lifestyle changes and diet. Antiobesity drugs may also be used and, in severe cases, bariatric surgery.

Topics: Abortion, Spontaneous; Adiponectin; Anti-Obesity Agents; Bariatric Surgery; Endocrinology; Female; Fertilization in Vitro; Ghrelin; Humans; Infertility, Female; Leptin; Obesity; Pregnancy; Resistin; Risk

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.

Topics: Androgens; Animals; Female; Humans; Hyperinsulinism; Infertility, Female; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Reproduction

The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS.

Topics: Adipose Tissue; Adult; Cannabinoid Receptor Modulators; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Male; Menstruation Disturbances; Obesity; Phenotype; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects

Obesity is associated with a diverse set of metabolic disorders, and has reproductive consequences that are complex and not well understood. The adipose tissue-produced leptin has dominated the literature with regards to female fertility complications, but it is pertinent to explore the likely role of other adipokines--adiponectin and resistin--as our understanding of their biological functions emerge. Leptin influences the developing embryo, the functioning of the ovary and the endometrium, interacts with the release and activity of gonadotrophins and the hormones that control their synthesis. In this review such biological actions and potential roles of the adipokines leptin, adiponectin and resistin are explored in relation to female fertility and the complexity of the obese metabolic state.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Female; Humans; Infertility, Female; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Obesity; Pregnancy; Resistin

Anovulatory infertility affects a large proportion of reproductive-aged women. Major improvements in successful clinical treatment of this prevalent disorder in women's health have been made possible because of biomedical research employing nonhuman primates. Experiments on female rhesus monkeys were the first to demonstrate that the key hypothalamic neurotransmitter, gonadotropin-releasing hormone, involved in stimulating pituitary gonadotropin synthesis, storage, and release was bioactive only when released in approximately hourly bursts. This breakthrough in understanding gonadotropin regulation enabled identification of hypogonadotropic, apparently normogonadotropic, and hypergonadotropic forms of anovulatory infertility, and development of appropriate stimulatory or inhibitory gonadotropin therapies. Treatments to overcome anovulatory infertility represent one of the major advances in clinical reproductive endocrinology during the last 25 yr. The future promise of nonhuman primate models for human ovulatory dysfunction, however, may be based on an increased understanding of molecular and physiological mechanisms responsible for fetal programming of adult metabolic and reproductive defects and for obesity-related, hyperinsulinemic impairment of oocyte development.

Topics: Animals; Anovulation; Disease Models, Animal; Female; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Hypothalamus; Infertility, Female; Leptin; Ovarian Diseases; Primates; Stress, Physiological; Time Factors

The debate on metformin use in polycystic ovary syndrome (PCOS) has mainly focused on its treatment for infertility in ovulation induction and menstrual cyclicity. Here we will summarize the data supporting the effect of metformin on improving hyperandrogenaemia and hyperinsulinaemia in PCOS patients. We propose that metformin benefits PCOS patients undergoing gonadotrophin therapy and IVF as well as ovulation induction. We also advocate the use of insulin sensitizing drugs to reduce miscarriage rates, and risks associated with coronary artery disease, gestational diabetes and obesity.

Topics: Androgens; Cardiovascular Diseases; Female; Fertilization in Vitro; Gonadotropins; Humans; Hypoglycemic Agents; Infertility, Female; Insulin; Insulin Resistance; Leptin; Menstrual Cycle; Metformin; Ovulation Induction; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome

An established fact in the polycystic ovarian syndrome (POS) is an abnormal ovarian steroidogenesis. Though this suggest an intrinsic ovarian defect, the syndrome could also be influenced by factors outside the ovaries. Although of unknown etiology, the POS is one of the most frequent endocrine disorders in the gynecologic practice. The disorder is characterized by ultrasound findings of enlarged polycystic ovaries, hyperandrogenism, menstrual disorders, obesity and including the appearance of infertility. There are a series of mechanisms involved in the extraovarian androgen increase in patients with POS. Among these mechanisms are implicated those of central and peripheral origin, genetic factors and adrenocortical dysfunction. In the same way, the alterations produced could imply genetic, molecular biological, biochemical, physiological and endocrinological factors. Sometimes all these factors could interact at the same time. The high serum androgen level could stop the pituitary gonadotropin production, either as a direct mechanism or as a result of its peripheral conversion. The increased androgens also explain the manifestations of clinical acne, hirsutism, and the detention in follicular ovarian maturation. All these manifestations are related with the menstrual disorders, anovulation, and infertility that these patients develop. The characteristics of the extraovarian POS include the 17-hydroxyprogesterone elevation in response to the ACTH test and the dexamethasone suppression of adrenal androgens. It is possible to improve the ovarian function in some patients with POS. This could be achieved with clomiphene citrate associated with glucocorticoids to induce ovulation.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; 17-alpha-Hydroxyprogesterone; 3-Hydroxysteroid Dehydrogenases; Adrenal Cortex; Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Adult; Androgens; Catecholamines; Clomiphene; Corticotropin-Releasing Hormone; Cortisone; Dexamethasone; Female; Glucocorticoids; Gonadal Steroid Hormones; Humans; Hydroxysteroid Dehydrogenases; Hyperinsulinism; Hyperprolactinemia; Hypothalamo-Hypophyseal System; Infant, Newborn; Infertility, Female; Insulin Resistance; Leptin; Mineralocorticoids; Obesity; Ovary; Ovulation Induction; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Pseudopregnancy; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase; Steroids; Sterol Esterase; Stress, Psychological

The biological aim of the differentiation and maturation of endometrial tissue compartments during any menstrual cycle is the achievement of suitable conditions for blastocyst implantation and the establishment of pregnancy. Infertility and early embryonic loss are frequently caused by insufficient endometrial differentiation. Even any incomplete receptivity stage of the luteal phase endometrium will prevent attachment and implantation. We have studied the physiological changes throughout an endometrial cycle to elucidate causes of endometrial insufficiency leading to subfertility or infertility. Up to now, the histological changes described by Noyes et al. are understood as classical diagnostic approaches. However, evidence is accumulating that molecular deficits of endometrial differentiation are by no means detectable histologically, and consequently ask for the research on new diagnostic methods and parameters. There are histochemical localizations of specific protein molecules, adhesion molecules and cytokines, which permit by far more detailed and significant molecular analyses than any classical morphological means could yield. Moreover, there are convincing arguments to use further biochemical assessments on proteins of the uterine secretions as specific diagnostic parameters. The electrophoretical resolution presents typical protein patterns, which in turn can be interpreted as characteristic reflexions of the functional phases of the endometrial cycle. What is demonstrated as the so-called adequate luteal phase protein pattern clearly is the product of the receptive endometrium, reflecting the "implantation window". This is established already two days after ovulation and persists usually eight further days, if the endometrial cycle is undisturbed (15th to 24th day of the cycle).

Topics: Animals; Carrier Proteins; Cytokines; Embryo Implantation; Endometrium; Female; Humans; Infertility, Female; Leptin; Luteal Phase; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Uteroglobin

Obesity appears to be associated with female reproductive dysfunction and infertility. Women with obesity undergoing in vitro fertilization (IVF) had poor oocyte quality, decreased embryo development, and poor pregnancy outcome. However, the mechanism linking obesity to poor reproductive outcomes is still unclear. Obesity is frequently accompanied with elevated leptin levels. Here we aimed to evaluate the effect of high leptin level in follicular fluid (FF) on the proliferation and apoptosis in granule cells and correlate these findings with poor reproductive outcomes in infertile women with overweight or obesity who underwent IVF treatment. We investigated clinical and ongoing pregnancy rates in 189 infertile women who underwent IVF. Leptin levels were quantified in peripheral blood and FF as well. In vitro cell model was used to explore the potential effect of high leptin on the proliferation and apoptosis in granulosa cells. Results showed reduced clinical and ongoing pregnancy rates in overweight/obesity women who underwent IVF compared to control with normal BMI. On the other hand, leptin levels presented significant increase in peripheral blood and FF in overweight/obese women. Leptin level in FF was negatively correlated to good quality embryo rate. Importantly, in vitro study showed that leptin inhibited cells proliferation and promoted apoptosis by upregulation of caspase-3 and downregulation of Bcl-2 in granulosa cells in a dose dependent manner. These observations suggest that leptin may acts as a local mediator to attenuate embryo development and reduce fertility in obese patients.

Topics: Adult; Apoptosis; Cell Proliferation; Embryonic Development; Female; Fertilization in Vitro; Granulosa Cells; Humans; Infertility, Female; Leptin; Obesity; Pregnancy

To examine epithelial Na(+) channel (ENaC) expression in endometrium of overweight/obese women with polycystic ovary syndrome (PCOS) during the window of implantation, and to explore the mechanism linking leptin-mediated reduction of γ-ENaC to low endometrial receptivity.. Controlled, prospective, clinical, experimental study.. University-based infertility center.. Blood and endometrium samples were collected from 12 control women and 12 overweight/obese PCOS patients. Pregnancy outcomes were obtained from 245 women with male-factor infertility (533 cycles) and 57 infertile women with PCOS (120 cycles) who underwent intrauterine insemination.. Human endometrial biopsies.. Expression of ENaC mRNA and protein in endometrium.. The expression of γ-ENaC decreased in the secretory phase endometrium of PCOS patients who showed increased serum leptin levels. In cultured endometrial cells (Ishikawa cells), leptin dose-dependently down-regulated the expression of γ-ENaC and reduced the JAr spheroid attachment rate, which could be blocked by knockdown of STAT3, a signal in the pathway of leptin receptor activation. The overweight/obese PCOS patients with increased serum leptin levels showed a significantly increased biochemical pregnancy rate, suggesting that high leptin might attenuate endometrial receptivity and increase very early pregnancy loss.. High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating γ-ENaC expression in the endometrium. These results provide valuable new insights into the molecular mechanisms linking abnormal ENaC gene expression to early pregnancy loss in overweight/obese PCOS patients.

Topics: Adult; Down-Regulation; Endometrium; Epithelial Sodium Channels; Female; Humans; Infertility, Female; Leptin; Overweight; STAT3 Transcription Factor

Obesity is related to hormonal disorders that affect the reproductive system. Low-glycemic index (LGI) diets seem to exert a positive effect on weight loss and on metabolic changes that result from obesity.. We investigated the effects of a hypocaloric diet with an LGI and low glycemic load on anthropometric and metabolic variables, ghrelin and leptin concentrations, and the pregnancy rate in overweight and obese infertile women who were undergoing in vitro fertilization (IVF).. The study was a randomized block-design controlled trial in which we analyzed 26 overweight or obese infertile women. Patients were assigned to a hypocaloric LGI-diet group or a control group and followed the protocol for 12 wk. Body weight, body mass index (BMI), percentage of body fat, glucose, insulin, homeostasis model assessment of insulin resistance, serum lipids, reproductive hormones, leptin, acylated ghrelin, number of oocytes retrieved in the IVF cycle, and pregnancy rate were determined.. There were greater reductions in body mass, BMI, percentage of body fat, waist:hip ratio, and leptin in the LGI-diet group than in the control group (P < 0.05). Despite a change of 18% in mean values, there was no significant increase in acylated ghrelin concentrations in the LGI group compared with the control group (P = 0.215). The LGI-diet group had 85.4% more oocytes retrieved than did the control group (7.75 ± 1.44 and 4.18 ± 0.87, respectively; P = 0.039) in the IVF cycle. Three patients (21.4%) in the LGI group experienced a spontaneous pregnancy during the follow-up, which generated 3 live births.. The hypocaloric LGI diet promoted a decrease in BMI, percentage of body fat, and leptin concentrations, which improved oocyte development and pregnancy rate. These results support the clinical recommendation to advise overweight and obese women to lose weight through a balanced diet before being submitted for treatment with assisted reproduction technologies. A hypocaloric diet combined with LGI foods seems to be beneficial for these patients, but additional studies are required before this treatment is recommended. This trial was registered at clinicaltrials.gov as NCT02416960.

Topics: Adiposity; Adult; Body Mass Index; Brazil; Diet, Reducing; Female; Fertilization in Vitro; Follow-Up Studies; Ghrelin; Glycemic Index; Glycemic Load; Humans; Infertility, Female; Insulin Resistance; Leptin; Obesity; Overweight; Pregnancy; Pregnancy Rate; Risk; Waist-Hip Ratio; Weight Loss

To detect the levels of visfatin and leptin in the serum as well as in the follicular fluid (FF) of polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian stimulation and to compare them with the levels found in age- and weight-matched normally ovulating women under IVF treatment.. Prospective study.. Assisted Reproduction Unit, Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece.. Forty patients with diagnosed PCOS and 40 age- and weight-matched non-PCOS control women enrolled in the IVF program.. Blood and FF samples were collected from all subjects at oocyte retrieval.. Visfatin and leptin levels were measured in serum and FF using ELISA.. Serum visfatin levels were significantly increased in women with PCOS, whereas FF visfatin levels, which were lower than serum levels, did not differ between groups. Serum leptin levels did not differ between groups and were lower than FF levels.. Women with polycystic ovaries exhibit significantly increased serum visfatin and decreased FF leptin levels compared with control subjects of similar age and body mass index, indicating a probable role for visfatin in the general state of insulin resistance and a local contribution in the follicle for leptin in patients undergoing IVF treatment.

Topics: Adult; Age Factors; Body Mass Index; Cytokines; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Insulin; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy

Topics: Biomarkers; Cervix Mucus; Collagen Type I; Estradiol; Female; Follicle Stimulating Hormone; Hormones; Humans; Infertility, Female; Leptin; Maternal Age; Matrix Metalloproteinase 1; Oocytes; Risk Factors; Tissue Inhibitor of Metalloproteinase-1

This study was undertaken to evaluate serum leptin concentrations in women with endometriosis during treatment with danazol and with leuprolide depot.. Twenty patients aged 18 to 42 years with regular menses and documented pelvic endometriosis were recruited from a university hospital setting. Treatment was 200 mg danazol 3 times daily for 6 months or 3.75 mg leuprolide depot every 28 days for 6 months. Serum leptin concentrations were measured before, during, and after treatment. A single blood sample was taken from each of 10 control women without endometriosis for comparison. Serum leptin level was measured with a radioimmunoassay kit with human leptin, and analysis of variance and paired t tests were used for statistical analysis.. Serum leptin levels were almost the same among women with endometriosis as in the control group. Leptin levels were higher among women with endometriosis during treatment with danazol and leuprolide(P <.001). Three months after treatment, leptin values remained moderately higher than before treatment.. Danazol and leuprolide increased serum leptin levels. The mechanism of leptin increase is unclear. Further studies are needed to determine whether an adipogonadal axis exists.

Topics: Adolescent; Adult; Danazol; Endometriosis; Estrogen Antagonists; Female; Humans; Infertility, Female; Leptin; Leuprolide

To study whether different hormonal phases affect appetite regulation, food intake, and concentrations of leptin, glucagon-like peptide-1 (GLP-1), and high-sensitivity C-reactive protein (hs-CRP) during a long agonist in vitro fertilization (IVF) protocol.. Fifty-four infertile women were encountered thrice, the first of which was at the beginning of their period (low estradiol). The other two visits were during a gonadotrophin-releasing hormone (GnRH) analog downregulation (low estradiol) and at the end of a follicle-stimulating hormone (FSH) stimulation (high estradiol). The first visit was the reference; the women served as their controls. The concentrations of leptin, GLP-1, and hs-CRP were assessed from plasma. Dietary intake was assessed using food records (FRs). In addition, weight, height, body mass index (BMI), and plasma levels of estradiol, glucose, HbA1c, insulin, and lipids were monitored. Twenty-six of the subjects also had a postprandial test.. During the stimulation protocol, leptin concentrations elevated (P < 0.001), and energy intake decreased (P = 0.03), while estradiol levels increased (P < 0.001). GLP-1 levels unchanged (P = 0.75) and hs-CRP (P = 0.03) concentrations diminished, while estradiol levels increased.. No increased food intake or weight gain occurred during the stimulation protocol; thus, leptin may protect from overeating during high estradiol levels, and leptin resistance may not occur during a short follow-up. Also, a favorable anti-inflammatory effect was detected. During this study, we observed no harmful metabolic effects, which might affect negatively maternal health.

Topics: C-Reactive Protein; Eating; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Infertility, Female; Leptin

Adipokine leptin plays a crucial role in metabolic and reproductive functions. Leptin receptor has a soluble form that binds to leptin, thus modulating its level in the circulation. It has been indicated that the levels of leptin and leptin receptor and also LEP rs7799039 and LEPR rs1137101 polymorphisms are associated with metabolic disorders. In the present study, we assessed the levels of leptin and soluble leptin receptor (sOB-R), and also the frequency of rs7799039 and rs1137101 polymorphisms in healthy fertile women and patients with polycystic ovary syndrome (PCOS), inclusive of PCOS-infertile and PCOS-recurrent pregnancy loss (RPL) subjects.. A total of 324 PCOS patients- including 199 infertile cases and 125 patients with a history of RPL- and 144 healthy controls were enrolled in this study. Biochemical parameters and plasma leptin and sOB-R levels were measured by ELISA and the genotypes of rs7799039 and rs1137101 polymorphisms were determined using PCR- RFLP.. Plasma leptin and sOB-R levels were significantly higher and lower in PCOS, PCOS-infertile and PCOS RPL groups, respectively. The GG genotype frequencies of rs7799039 and rs1137101 polymorphisms were significantly different between PCOS-infertile women and non-PCOS subjects (P = 0.043, OR = 0.47, 95% CI = 0.22-0.97, and P = 0.01, OR = 0.31, 95% CI = 0.12-0.75, respectively). Increased LEP levels were associated with the risk of PCOS and RPL in women with PCOS (P = 0.039, OR = 1.203, 95%CI = [1.009-1.435] and P = 0.012, OR = 1.267, 95% CI = [1.054-1.522], respectively).. Polymorphisms rs7799039 and rs1137101 and circulating leptin and sOB-R levels were associated with infertility in Iranian women with PCOS. Further studies are needed to reveal the role of leptin in PCOS pathogenesis.

Topics: Adult; Female; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome; Pregnancy; Receptors, Leptin

Unexplained infertility (UI) represents about 25%-40% of all infertility and is a formidable obstacle for successful pregnancy for child-bearing aged women. However, up to now, there is no reliable method to predict this condition with high accuracy, thereby hindering early management of this condition.. Our prospective study consists of 84 child-bearing aged women that were clinically diagnosed UI. Forty-four matched healthy fertility (HF) women were served as controls. We examined the profiles of 25 hormones and cytokines that were likely related to pathogeneses and molecular pathways involved in UI with the technique of protein array. The samples were randomly stratified 7:3 into a training set and a testing set. We used the SMOTEboost model with 10 serum proteins in a clinical verification study to identify UI cases.. The predictor had an area under the receiver operating characteristic curve (AUC) of 0.788 with 24 serum protein features. The predictive performance in terms of AUC of the model with the top 10 important serum proteins in the clinical verification study to classify UI cases was 0.809. Three most significantly differentially expressed proteins (DEPs) were prolactin, monocyte chemotactic protein-1 (MCP-1), and leptin.. Examination of serum-based protein profile changes could help to identify child-bearing aged women at risk of UI. This would enable early detection and facilitate development of clinical strategies to treat UI and guide their planned parenthood. It may also give clues to pathogeneses of the condition of test subjects.

Topics: Adult; Biomarkers; Chemokine CCL2; Female; Humans; Infertility, Female; Leptin; Prolactin; Proteomics

Women with obesity usually need larger doses of FSH for ovarian stimulation, resulting in poor outcomes; however, the mechanism is still unclear.. To investigate the molecular regulation of FSH receptor (FSHR) expression associated with obesity.. Case-control study to improve in vitro fertilization (IVF) outcomes.. Women with obesity (82) and women who were overweight (457) undergoing IVF and 1790 age-matched controls with normal weight from our reproductive medicine center.. FSHR expression was decreased in parallel with body mass index (BMI), whereas the estradiol (E2) level on the human chorionic gonadotropin (hCG) trigger day was significantly lower.. FSHR expression in human granulosa cells (hGCs), both mRNA (P = 0.02) and protein (P = 0.001) levels, was decreased in women who were overweight or obese. Both insulin (P < 0.001) and glucose (P = 0.0017) levels were positively correlated with BMI in fasting blood and follicle fluids (FFs) but not with FFs leptin level. We treated human granulosa-like tumor cells (KGN) cells with insulin; E2 production was compromised; the level of phosphorylated (p)-protein kinase B (p-Akt2) decreased, whereas p-glycogen synthase kinase 3 (GSK3) increased; and there were similar changes in hGCs from women with obesity. Stimulated hGCs from women with obesity with compound 21 (CP21), an inhibitor of GSK3β, resulted in upregulated β-catenin activation and increased FSHR expression. CP21 also increased the expression of insulin receptor substrate 1 and phosphatidylinositol 3-kinase (PI3K), as well as p-Akt2.. Women with obesity in IVF were associated with reduced FSHR expression and E2 production caused by a dysfunctional insulin pathway. Decreased FSHR expression in hGCs from women with obesity and insulin-treated KGN cells could be rescued by an inhibitor of GSK3β, which might be a potential target for the improvement of the impaired FSH-stimulation response in women with obesity.

Topics: Adult; Case-Control Studies; Dose-Response Relationship, Drug; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Follicular Fluid; Glycogen Synthase Kinase 3 beta; Granulosa Cells; Humans; Infertility, Female; Insulin; Leptin; Obesity; Ovulation Induction; Receptors, FSH; Treatment Outcome

Anti-Müllerian hormone (AMH), insulin-like growth factor 1 (IGF1) and leptin are produced in the granulosa cells of follicles and play an important role in the growth and maturation of follicles. The aim of our study was to monitor AMH, IGF1 and leptin levels in a group of healthy women and compare them to a group of women with fertility disorders. The second aim was the evaluation of biomarker levels in relation to the identified cause of infertility. Totally, 146 females were enrolled into our study. Seventy-two healthy controls and seventy-four females with fertility disorders were divided into four subgroups: anovulation, endometriosis, fallopian tube damage, unknown reason. IGF1 was the only biomarker with significantly lower levels throughout the entire group with fertility disorders. We did not identify any statistically significant differences for AMH and leptin. Regarding subgroups, significant differences were only observed in the group of anovulatory women. AMH and leptin showed higher levels while IGF1 showed lower levels. In conclusion, levels of AMH, IGF1 and leptin found in follicular fluid are sensitive markers for anovulatory fertility disorders. AMH, IGF1 and leptin levels in follicular fluid have no relation to the fertility disorders caused by endometriosis, fallopian tube damage or disorders with unknown etiology.. AMH: anti-Müllerian hormone; IGF1: insulin-like growth factor 1; PCOS: polycystic ovary syndrome.

Topics: Adult; Anovulation; Anti-Mullerian Hormone; Biomarkers; Case-Control Studies; Female; Follicular Fluid; Humans; Infertility, Female; Insulin-Like Growth Factor I; Leptin; Young Adult

Female reproductive dysfunction occurs in patients with pathological loss of adipose tissue, i.e. lipodystrophy (LD). However, mechanisms remain largely unclear and treatment effects of adipocyte-derived leptin have not been assessed in LD animals.. In the current study, C57Bl/6 LD mice on a low-density lipoprotein receptor knockout background were treated with leptin or saline for 8 weeks and compared to non-LD controls.. The number of pups born was 37% lower in breeding pairs consisting of LD female mice x non-LD male mice (n = 3.3) compared to LD male mice x non-LD female mice (n = 5.2) (p < 0.05). Mean uterus weight was significantly lower in the saline-treated LD group (18.8 mg) compared to non-LD controls (52.9 mg; p < 0.0001) and increased significantly upon leptin treatment (46.5 mg; p < 0.001). The mean number of corpora lutea per ovary was significantly lower in saline-treated LD animals compared to non-LD controls (p < 0.01) and was restored to non-LD control levels by leptin (p < 0.05). Mechanistically, mRNA expression of ovarian follicle-stimulating hormone receptor (p < 0.01) and estrogen receptor β (p < 0.05), as well as of pituitary luteinizing hormone β subunit (p < 0.001) and follicle-stimulating hormone β subunit (p < 0.05), was significantly upregulated in LD mice compared to non-LD controls. In addition, mean time to vaginal opening as a marker of puberty onset was delayed by 12.5 days in LD mice (50.9 days) compared to non-LD controls (38.4 days; p < 0.001).. Female LD animals show impaired fertility which is restored by leptin. Future studies should assess leptin as a subfertility treatment in human leptin-deficiency disorders.

Topics: Animals; Breeding; Estrogen Receptor beta; Female; Gene Knockout Techniques; Humans; Infertility, Female; Leptin; Lipodystrophy; Male; Mice; Mice, Inbred C57BL; Organ Size; Receptors, FSH; Receptors, LDL; Receptors, LH

Obesity is considered detrimental to women's reproductive health. Although most of the attention has been focused on the effects of obesity on hypothalamic function, studies suggest a multifactorial impact. In fact, obesity is associated with reduced fecundity even in women with regular cycles, indicating that there may be local ovarian effects modulating fertility. Here we describe a novel mechanism for leptin actions directly in the ovary that may account for some of the negative effects of obesity on ovarian function. We find that normal cycling, obese, hyperleptinemic mice fed with a high-fat diet are subfertile and ovulate fewer oocytes compared with animals fed with a normal diet. Importantly, we show that leptin induces expression of the neuropeptide cocaine- and amphetamine-regulated transcript (CART) in the granulosa cells (GCs) of ovarian follicles both in vitro and in vivo. CART then negatively affects intracellular cAMP levels, MAPK signaling, and aromatase mRNA expression, which leads to lower estradiol synthesis in GCs and altered ovarian folliculogenesis. Finally, in human samples from patients undergoing in vitro fertilization, we show a significant positive correlation between patient body mass index, CART mRNA expression in GCs, and CART peptide levels in follicular fluid. These observations suggest that, under obese conditions, CART acts as a local mediator of leptin in the ovary to cause ovarian dysfunction and reduced fertility.

Topics: Adult; Animals; Aromatase; Blotting, Western; Body Mass Index; Cyclic AMP; Diet, High-Fat; Estradiol; Female; Follicular Fluid; Granulosa Cells; Humans; Infertility, Female; Leptin; MAP Kinase Signaling System; Mice; Nerve Tissue Proteins; Obesity; Ovarian Follicle; Ovary; Real-Time Polymerase Chain Reaction; RNA, Messenger

Almost 50% of the women with polycystic ovary syndrome (PCOS) are obese. Obesity in PCOS affects reproduction via various mechanisms. Hyperandrogenism, increased luteinizing hormone (LH) and insulin resistance play a pivotal role. Several substances produced by the adipose tissue including leptin, adiponectin, resistin and visfatin may play a role in the pathophysiology of PCOS. Infertility in PCOS is related to anovulation. For induction of ovulation, clomiphene citrate and human gonadotrophins are first- and second-line treatments, respectively. Other treatment modalities include the use of insulin sensitizers, such as metformin as well as aromatase inhibitors and laparoscopic ovarian drilling, while in vitro fertilization is the last resort. Obesity can adversely affect infertility treatment in PCOS. Diet and lifestyle changes are recommended for the obese women before they attempt conception. The use of anti-obesity drugs and bariatric surgery in PCOS require further evaluation.

Topics: Adipokines; Adiponectin; Female; Humans; Hyperandrogenism; Hyperinsulinism; Hypoglycemic Agents; Infertility, Female; Insulin Resistance; Leptin; Life Style; Luteinizing Hormone; Metformin; Nicotinamide Phosphoribosyltransferase; Obesity; Ovulation Induction; Polycystic Ovary Syndrome; Resistin

The aim of this study was to evaluate the leptin levels in the serum and peritoneal fluid (PF) and the protein expression in three different peritoneal ectopic implants in patients who underwent surgery for deep infiltrating endometriosis.. All patients had been treated at the Department of Gynecology of the Pedro Ernesto University Hospital, Rio de Janeiro. The study group consisted of 15 patients who underwent surgery for adnexal masses and infertility, while the control group consisted of ten women who underwent surgery for tubal ligation. Peritoneal fluid and samples tissues were collected during surgery. Serum samples were obtained before anesthesia. In this study, the leptin levels in the serum and peritoneal fluid (PF) were evaluated by ELISA. The protein expression of leptin and its receptors (ObR) and aromatase enzyme were evaluated by Western blot analysis of the intestine, uterosacral ligament and vaginal septum in the ectopic implants. The t-test and one-way ANOVA with Holm-Sìdak post-test were used, and p < 0.05 was considered to be statistically significant.. Compared to the controls, the serum leptin levels (control = 14.7 ng/mL ± 2.63, endometriosis = 19.2 ng/mL ± 1.84, p < 0.0001) were increased, while in PF, there was no difference (control = 6.68 ng/mL ± 0.43, endometriosis = 7.71 ng/mL ± 0.59, p = 0.18). Comparing women with and without ovarian implants, the leptin levels in both the serum and PF were significantly higher in women without ovarian implants (serum: with ovarian implant = 15.85 ± 1.99; without ovarian implant = 23.14 ± 2.60; ng/mL, p = 0.04; PF: with ovarian implant = 4.28 ± 1.30; without ovarian implant = 11.18 ± 2.98;ng/mL, p = 0.048). The leptin, ObR and aromatase protein expression levels were increased in lesions in the vaginal septum and were decreased in the intestine lesions.. This study reports several interesting associations between the leptin levels in serum, peritoneal fluid, and tissue samples and the localization of the ectopic endometrium. Although this study does not provide a clear picture of the role of leptin in the development and progression of peritoneal implants, it contributed new data that might be useful to elucidating the enigma that is the role of leptin in endometriosis disease.

Topics: Adult; Aromatase; Ascitic Fluid; Body Mass Index; Endometriosis; Female; Gene Expression Regulation, Neoplastic; Humans; Infertility, Female; Laparoscopy; Leptin; Peritoneum; Receptors, Leptin; Vagina

A possible mechanism for poor perinatal outcomes in singleton pregnancies conceived following assisted reproductive technologies (ART) and those conceived naturally following a period of infertility (>12 months) is thought to be placental dysfunction. This was investigated by measuring plasma concentrations of biochemical markers: (i) soluble fms-like tyrosine kinase1 (sFlt1); (ii) placental growth factor (PlGF); (iii) leptin; and (iv) plasminogen activator inhibitor 2 (PAI-2), serially at four antenatal time points. Baseline concentrations of each marker after delivery were also measured. The control group was naturally conceived singleton pregnancies with no history of infertility. Non-smoking, age-matched nulliparous women with no significant medical history were recruited to all groups. The ART group had significantly lower mean plasma concentrations of PlGF at all antenatal time points compared to the control group (p < 0.001). The subfertility (SF) group had significantly higher mean serum concentrations of leptin than the other groups at all time points (p < 0.001), even after correction for body mass index. There were no significant differences in sFlt1 and PAI-2 concentrations between the groups. Low plasma PlGF concentrations in the ART group might suggest abnormal placentation and/or abnormal function in ART pregnancies with relevance to pathogenesis of pregnancy complications in these women.

Topics: Adult; Biomarkers; Female; Humans; Infertility, Female; Leptin; Placenta; Placenta Growth Factor; Plasminogen Activator Inhibitor 2; Pregnancy; Pregnancy Proteins; Reproductive Techniques, Assisted; Vascular Endothelial Growth Factor Receptor-1

The present study was designed to evaluate the relationship between serum leptin and infertility in obese young and old men and women. The groups of infertile obese men (n=66) and women (n=30) compared with control obese fertile men (n=60) and women (n=30) with same ages to find the contribution of serum leptin level in causation of fertility. The results revealed that serum leptin were significantly raised in infertile male and female with p<0.001. BMI was also found to be significantly higher (p<0.001) in infertile men and women. Moreover a strong positive correlation was found between BMI and leptin level, and serum leptin and age in both fertile and infertile men and women. The values of correlation coefficients between serum leptin and BMI, and serum leptin and age are statistically significant (r=0.3-0.6, p<0.01-p<0.05). This study has concluded that obesity is associated with infertility in men and women. Sex hormonal imbalance may also be associated BMI and serum leptin in infertility. However further studies are required to determine the exact match by which enhanced BMI and serum leptin levels to female and male infertility.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Humans; Infertility, Female; Infertility, Male; Leptin; Male; Middle Aged; Obesity

This study was designed to investigate leptin levels in the fluid in ovarian endometriomas (OEs) and to compare the expression of leptin and its receptors (OBR) in ovarian tissue affected by endometrioma in infertile women to its expression in the normal ovarian tissue of fertile controls without endometriosis.. In this case-control observational study, ovarian tissue, blood samples and peritoneal fluid were obtained from 20 women (10 fertile controls without endometriosis or any ovarian disease, who were undergoing tubal ligation surgery, and 10 infertile women with severe endometriosis and OE). The ovarian endometriomal fluid (EF) was aspirated, and peritoneal-implant (PI) biopsies were performed. The tissues removed during the surgeries were immediately frozen in liquid nitrogen to determine expression levels by western blot and leptin levels by ELISA.. OBR was expressed at higher levels in the ovarian tissue affected by endometrioma than in the normal ovarian tissue (control = 0.38 ± 0.05, study = 0.60 ± 0.09, p = 0.03), but there was no significant difference in leptin levels between these groups (control = 0.57 ± 0.1, study = 0.35 ± 0.1, p = 0.18). Positive and significant correlations were observed between leptin and OBR in the OE (r = 0.85, p = 0.004) and in the PI (r = 0.87, p = 0.001). ELISA results demonstrate a greater leptin concentration within the EF compared with the serum and the PF (serum = 14.25 ± 1.63, PF = 5.98 ± 2.0, EF = 73.8 ± 16.2, p = 0.0001), but there was no correlation between these variables. A positive, significant and strong correlation was observed between PF leptin levels and the expression of leptin and OBR in PI (leptin: r = 0.78, p = 0.007/OBR: r = 0.68, p = 0.04) and between the EF leptin levels and the expression of leptin and OBR in the OE (leptin: r = 0.88, p = 0.008/OBR: r = 0.89, p = 0.005).. These data suggest that leptin may play an important role in the physiopathology of OE through a modulatory interaction with its active receptor.

Topics: Adult; Ascitic Fluid; Case-Control Studies; Endometriosis; Female; Humans; Infertility, Female; Leptin; Ovarian Diseases; Ovary; Receptors, Leptin; Up-Regulation

People on a diet to lose weight may be at risk of reproductive failure. To investigate the effects of nutrient restriction on reproductive function and the underlying mechanism, changes of reproductive traits, hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis were examined in postpubertal gilts at anestrus induced by nutrient restriction. Gilts having experienced two estrus cycles were fed a normal (CON, 2.86 kg/d) or nutrient restricted (NR, 1 kg/d) food regimens to expect anestrus. NR gilts experienced another three estrus cycles, but did not express estrus symptoms at the anticipated fourth estrus. Blood samples were collected at 5 days' interval for consecutive three times for measurement of hormone concentrations at the 23th day of the fourth estrus cycle. Individual progesterone concentrations of NR gilts from three consecutive blood samples were below 1.0 ng/mL versus 2.0 ng/mL in CON gilts, which was considered anestrus. NR gilts had impaired development of reproductive tract characterized by absence of large follicles (diameter ≥ 6 mm), decreased number of corepus lutea and atrophy of uterus and ovary tissues. Circulating concentrations of IGF-I, kisspeptin, estradiol, progesterone and leptin were significantly lower in NR gilts than that in CON gilts. Nutrient restriction down-regulated gene expressions of kiss-1, G-protein coupled protein 54, gonadotropin-releasing hormone, estrogen receptor α, progesterone receptor, leptin receptor, follicle-stimulating hormone and luteinizing hormone and insulin-like growth factor I in hypothalamus-pituitary-gonadal axis of gilts. Collectively, nutrient restriction resulted in impairment of reproductive function and changes of hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis, which shed light on the underlying mechanism by which nutrient restriction influenced reproductive function.

Topics: Animal Feed; Animals; Caloric Restriction; Estradiol; Estrogen Receptor alpha; Estrus; Female; Gene Expression Regulation; Genetic Fitness; Gonadotropin-Releasing Hormone; Hypothalamo-Hypophyseal System; Hypothalamus; Infertility, Female; Insulin-Like Growth Factor I; Kisspeptins; Leptin; Ovary; Pituitary Gland; Pituitary-Adrenal System; Progesterone; Receptors, G-Protein-Coupled; Swine

The objective of the present study was to evaluate the levels of leptin, ghrelin, interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in peritoneal fluid in patients with endometriosis and infertility, and study their correlation.. This cross-sectional study included women undergoing diagnostic and/or therapeutic laparoscopy for endometriosis with chief complaint of infertility and/or pain at a tertiary care hospital. Based upon laparoscopic and histopathological findings, patients were categorized as with endometriosis and no endometriosis. Of the 50 patients with infertility (age 23-41 years), 19 had endometriosis while 31 had no endometriosis. The markers were assessed using ELISA kits.. The median levels of leptin in patients with endometriosis (10.20 ng/mL) were higher (p = 0.04) and median levels of ghrelin in patients with endometriosis (150.4 pg/mL) were lower (p = 0.037) versus patients with no endometriosis (5.07 ng/mL and 229.6 pg/mL, respectively). The median levels of IL-6 and VEGF in patients with endometriosis were not different between the groups. The correlation analyses showed that leptin levels and IL-6 were positively correlated (p = 0.0001).. The results suggest that ghrelin and leptin might play a key role in pathophysiology of endometriosis, and leptin is associated with inflammation in endometriosis.

Topics: Adult; Ascitic Fluid; Cross-Sectional Studies; Endometriosis; Female; Ghrelin; Humans; Infertility, Female; Interleukin-6; Leptin; Vascular Endothelial Growth Factor A; 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

Pelvic endometriosis is a chronic inflammatory disease with an immunological background. Yet there is paucity of contemporary research exploring both the angiogenic cytokines, leptin and IL-8 for a possible role in its pathophysiology.. To compare levels of both leptin and IL-8 in peritoneal fluid (PF) in women with endometriosis vs. fertile controls and correlate with disease stage, type and symptoms.. PF from 58 women with endometriosis and 28 women undergoing tubal ligation was collected at laparoscopy and leptin and IL-8 levels were measured using ELISA. Results showed significantly higher levels of both cytokines in women with endometriosis. Significantly higher leptin and IL-8 levels were demonstrated in patients with early peritoneal (ASRM stage I and II) and advancing disease (ASRM stage III and IV), respectively. Levels of leptin/IL-8 were significantly lower in patients with endometrioma (4.8 ng/mL/32 pg/mL) vs. implants (13.0 ng/mL/68 pg/mL). There was no correlation of infertility or chronic pelvic pain with these levels.. Both leptin and IL-8 levels are raised in PF of women with endometriosis reflecting inflammation and dysregulated immunomodulation. Higher levels of leptin were seen in early stages; IL-8 seems to stimulate the disease in a dose-dependent manner.

Topics: Adult; Ascitic Fluid; Case-Control Studies; Endometriosis; Female; Humans; Infertility, Female; Interleukin-8; Leptin; Ovarian Diseases; Pelvic Pain; Peritoneal Diseases

To measure the expression of adiponectin, leptin, and their respective receptors in the human endometria of fertile women compared with women with unexplained recurrent implantation failure (IF) during the window of implantation.. Controlled, prospective, clinical study.. Teaching hospital and university research laboratory.. Thirty-one endometrial biopsies from women with IF and 19 fertile controls.. Human endometrial biopsies.. Gene and protein expression of endometrial biopsies.. Endometrial leptin expression was significantly lower in the IF group compared with fertile women. In contrast, leptin receptor (Ob-R) expression was higher in endometria of women with IF. Concerning the adiponectin system, adiponectin was expressed to the same extent in both groups. Conversely, the expression of its two receptors, AdipoR1 and AdipoR2, was reduced in endometria of women with IF compared with fertile women.. Although progesterone resistance seems to be a common state of the endometrium in some human reproductive disorders, such as endometriosis or polycystic ovary syndrome, modification in leptin endometrial expression seems to be specific to IF. These results strongly suggest that changes in Ob-R and AdipoR expression profiles [1] should be implicated in the development of uterine receptivity, and [2] may therefore be potential new targets for prediction of IF.

Topics: Adiponectin; Adult; Biopsy; Case-Control Studies; Embryo Implantation; Embryo Transfer; Endometrium; Female; Fertilization in Vitro; Gene Expression Regulation; Hospitals, Teaching; Humans; Infertility, Female; Leptin; Paris; Pregnancy; Prospective Studies; Receptors, Adiponectin; Receptors, Leptin; RNA, Messenger; Treatment Failure

The objective was to investigate whether the associations between leptin, adiponectin, andadiposity reported in classic polycystic ovary syndrome (PCOS) are also observed in elderly women with a novel putative postmenopausal PCOS phenotype. We studied 713 postmenopausal community-dwelling women. Diagnosis of the novel phenotype required the presence of ≥3 diagnostic features including: 1) a personal history of oligomenorrhea; 2) history of infertility or miscarriage; 3) current or past clinical or hormonal evidence of hyperandrogenism; 4) central obesity; 5) biochemical evidence of insulin resistance. Women in the control group had ≤2 of these components. Mean age (±SD) was 74±8 years for the study cohort. Sixty-six women (9.3%) had the putative PCOS phenotype. Serum leptin was higher (mean 25.70±15.67 vs 14.94+9.89 ng/mL, P<.01) and adiponectin lower (mean 11.72±4.80 vs 17.31±7.45 μg/mL, P<.01) in cases vs controls. Leptin was positively, and adiponectin inversely, associated with an increasing number of phenotype features (P<.01 for linearity). In age-adjusted regression analysis, adjustment for waist circumference eliminated the association between leptin and the PCOS phenotype, but not the association between adiponectin and the PCOS phenotype. In this novel postmenopausal PCOS phenotype, adipocytokine profiles and their associations with adiposity parallel those reported in younger women with classic PCOS. These results support our hypothesis that a putative phenotype analogous to PCOS can be identified in postmenopausal women using clinical and biochemical criteria. Use of this novel phenotype could provide a basis for studies of the delayed consequences of PCOS in older women.

Topics: Abortion, Spontaneous; Adiponectin; Aged; Biomarkers; Body Mass Index; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Medical History Taking; Middle Aged; Obesity; Obesity, Abdominal; Oligomenorrhea; Phenotype; Polycystic Ovary Syndrome; Postmenopause; Premenopause

To explore the roles of leptin, monocyte chemotactic protein (MCP)-1, and tumour necrosis factor (TNF)-α in the peritoneal fluid (PF) in the pathogenesis of endometriosis-associated infertility.. Leptin, MCP-1, and TNF-α levels in the PF from 28 infertile women with endometriosis (study group), 23 women with fallopian-associated infertility (controls), and 24 women with myoma (controls) were determined by performing enzyme-linked immunosorbent assay (ELISA).. Leptin and TNF-α levels in the PF showed no significant difference among three groups. The MCP-1 level in patients with endometriosis was higher than those in fallopian-associated infertility group and myoma group (P < 0.01). There was a positive correlation between leptin and MCP-1 levels in the PF of patients with endometriosis (P < 0.05).. Peritoneal leptin and MCP-1 play important roles in the pathogenesis of infertility in the early stage of endometriosis.

Topics: Adult; Ascitic Fluid; Chemokine CCL2; Endometriosis; Enzyme-Linked Immunosorbent Assay; Fallopian Tubes; Female; Humans; Infertility, Female; Leptin; Myoma; Tumor Necrosis Factor-alpha

Obesity has an overall negative impact on fertility, affecting both women and men. Not only are obese individuals more likely to experience infertility, they are less likely to benefit from fertility treatment. Moreover, achieving pregnancy may place obese women at high risk for serious complications. It is important that obese individuals understand the effects that their obesity can have on reproductive function.

Topics: Adult; Female; Fertility; Humans; Infertility, Female; Insulin Resistance; Leptin; Male; Obesity; Polycystic Ovary Syndrome; Pregnancy

Endometriosis is a leading cause of infertility, and recent studies suggest that leptin and adiponectin may have a role in its causation and progression. This study assessed levels of leptin and adiponectin in serum and peritoneal fluid (PF) in patients with endometriosis and infertility.. This cross-sectional study included women undergoing diagnostic and/or therapeutic laparoscopy for endometriosis with chief complaint of infertility. Following laparoscopy, patients diagnosed with endometriosis served as cases while patients with no endometriosis served as controls. Patients with polycystic ovarian syndrome, diabetes, thyroiditis and patients on prior therapy with danazol or leuprolide were excluded from the study. Leptin and adiponectin levels were analysed in blood and PF using commercially available ELISA kits.. Of the 50 patients (aged 22-41 years), 15 had endometriosis (cases) while 35 had no endometriosis (controls). The median PF leptin level was significantly higher in cases as compared to controls (27.7 vs. 15.6 ng/ml, p = 0.019), and this remained significant even when PF leptin was BMI-normalised (p = 0.004). However, median serum leptin and adiponectin levels remained comparable between the two groups.. This study confirmed the role of PF leptin in causation and progression of endometriosis. However, this would have been definitive if healthy fertile females were included in this study.

Topics: Adiponectin; Adult; Ascitic Fluid; Biomarkers; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Diet, Vegetarian; Disease Progression; Endometriosis; Female; Humans; Infertility, Female; Laparoscopy; Leptin; Menstrual Cycle; Pelvis; Young Adult

Leptin is proposed to participate in the reproductive system of women by acting on either ovaries or hypothalamic-pituitary axis. The objective of the present study is to investigate the leptin concentrations in peritoneal fluid and serum samples of women diagnosed with primary infertility.. A prospective study was carried out in women who underwent laparoscopy within the diagnostic process of primary infertility between January 2005 and January 2007. Leptin concentrations were determined in blood samples obtained before surgery and in peritoneal fluid samples collected during laparoscopy.. Peritoneal fluid was obtained from 112 subjects; 21 with unexplained infertility 28 with polycystic ovary syndrome (PCOS), 30 with bilateral tubal occlusion, and 33 with endometriosis. Subjects with PCOS have significantly higher body weights, BMI values and plasma leptin levels when compared to other study groups. Peritoneal fluid levels of leptin were significantly higher in the endometriosis group compared to other three study groups. A positive correlation was found between peritoneal fluid leptin levels and the endometriosis stage (r=0.51, P=0.01). However, plasma leptin levels were unrelated to the disease extent.. It might be hypothesized that leptin may be an active factor in the pathogenesis of PCOS and endometriosis, which are two major causes of primary infertility. A mild leptin deficiency in peritoneal environment may interrupt follicular development and ultimately lead to PCOS. Leptin has angiogenic and mitogenic properties, which trigger inflammatory cytokines and eventually result in the development of endometriosis implants. Significantly, higher levels of leptin in peritoneal environments of endometriosis subjects strongly imply the important role of this common pathology.

Topics: Adult; Ascitic Fluid; Female; Humans; Infertility, Female; Leptin; Prospective Studies; Statistics, Nonparametric; Young Adult

To assess serum leptin levels in infertile females referred to a tertiary care hospital in Pakistan.. A case control study was carried out at Shifa College of Medicine/Shifa International Hospital Islamabad, Pakistan from January 2005 to August 2005. Serum leptin levels of 44 infertile females were compared with 44 age matched fertile female controls.. The results revealed that serum leptin levels were significantly raised in infertile women (69.7+/-40.2ng/ml) as compared to fertile controls (41.1+/-27.3ng/ml) with p=0.000. Mean body mass index BMI was also found to be significantly higher in infertile women (27.2+/-6.8kg/m2) as compared to fertile females (24.1+/-5.2kg/m2) with p-value of 0.019. Moreover, a strong positive correlation was found between BMI and leptin levels as leptin levels increased with increase in BMI. Mean leptin levels in overweight women were significantly higher (81.4+/-32.4ng/ml) as compared to normal weight women (30.6+/-20.6ng/ml) with p=0.000.. The present study has indicated that overweight accompanied by hyperleptinemia is associated with infertility in females. However, further studies are required to determine the exact mechanism by which enhanced body mass and serum leptin levels lead to female infertility.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Female; Humans; Infertility, Female; Leptin; Matched-Pair Analysis; Overweight; Pakistan

Endometriosis is a common, complex and chronic disease related to ectopic implantation and growth of endometrial tissue that may manifest by pelvic pain, and accounts for over 20% of all cases of infertility in women. Endometriosis may be associated with increased levels of leptin in peritoneal fluid. However, the association of leptin with infertility has not been definitely documented. Therefore, the aim of the present study was to search for a relationship between concentrations of peritoneal-fluid leptin and patients' clinical status. The study included 56 patients being diagnosed for infertility and/or pelvic pain. Peritoneal fluid was aspirated during routine laparoscopic examination. Concentrations of leptin in peritoneal fluid were evaluated by a specific enzyme-linked immunosorbent assay. The results revealed that the levels of peritoneal-fluid leptin did not correlate with different stage of endometriosis. However, they correlated with body mass index. Leptin levels were significantly higher in infertile patients than in patients with pelvic pain (p = 0.0023 by Mann-Whitney U test or p = 0.0045 by analysis of variance). It may suggest that increased leptin levels in the peritoneal fluid may play a role in pathogenesis of infertility.

Topics: Adult; Ascitic Fluid; Body Mass Index; Endometriosis; Female; Humans; Infertility, Female; Leptin; Pelvic Pain; Peritoneal Diseases; Up-Regulation

Women's reproductive potential is closely related to nutritional status. Some of the molecules that participate in ovarian regulation are produced in the adipose tissue, and therefore their production is associated with adiposity.. To determine serum leptin, adiponectin, C-reactive protein, interleukin-6, and tumor necrosis factor alpha in infertile women with or without insulin resistance; and to associate these molecules with adiposity.. Thirty-one infertile women were included. Nutritional status was evaluated through clinical and biochemical parameters. Patients were stratified according with their body mass index and the presence of insulin resistance. For statistics, parametric analyses were conducted.. The prevalence of overweight was 67.5%; high adiposity was present in 92.3% and central distribution of fat in 96.2% of studied women. Hypercholesterolemia was found in 32.3% of patients, hypertriglyceridemia in 25.8%, and 61.3% presented hyperinsulinemia. Overweight women presented lower adiponectin, and higher TNF-alpha and C-reactive protein concentrations, than those with normal body mass index (p < 0.05). Overweight women had also a higher probability for insulin resistance (p = 0.04). These women with insulin resistance presented lower adiponectin and higher C-reactive protein concentrations than non insulin resistance women. Body mass index correlated with leptin (r= 0.41), TNF-alpha (r= 0.41), and C-reactive protein (r= 0.33) concentrations.. The prevalence of overweight, high adiposity, dislipidemias, and IR was high in our population studied. We conclude that adiposity is closely associated with some of the molecules that participate in the reproductive process and that also regulate inflammatory responses.

Topics: Adiponectin; Adolescent; Adult; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Infertility, Female; Insulin Resistance; Interleukin-6; Leptin; Tumor Necrosis Factor-alpha; Young Adult

The aim of this study was to compare serum levels of leptin in women with unexplained infertility with fertile subjects.. Serum leptin levels of 27 infertile and 30 fertile women on day 3 of the menstrual cycle were assessed and compared in this prospective age and body mass index (BMI) comparable controlled study.. The mean age in the infertile group was 29.3 (range, 23-38), while this figure was 28.9 (range, 19-39) in the fertile group; the mean BMIs were 24.5 (range, 20.6-27.8) and 25.0 (range, 21.8-28.7), respectively. The mean serum leptin level was significantly higher in women with unexplained infertility compared with fertile subjects. Considering normal weight subjects, mean serum leptin levels were increased significantly in the unexplained infertile group compared with the fertile group (7.2 (range, 4.3-10.4) versus 3.5 (range, 1.9-6.2)ng/ml, respectively; p<0.0001, Mann-Whitney U-test). The significant increase in serum leptin levels was observed also in overweight patients (6.8 (range, 1.3-5.2) versus 3.3 (range, 4.2-8.9)ng/ml, respectively; p<0.0001, Mann-Whitney U-test).. A significant difference in serum leptin levels between unexplained infertile and fertile women suggests that this cytokine may be involved in pathophysiology of unexplained infertility.

Topics: Adult; Body Mass Index; Female; Fertility; Humans; Infertility, Female; Leptin; Menstrual Cycle; Pregnancy; Prospective Studies

Our objective was to evaluate whether polycystic ovarian syndrome (PCOS)-associated infertility is related to alterations of leptin, leptin receptor (Ob-R), and the phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/suppressor of cytokine signal 3 (SOCS3) system in the ovary.. A case-control study was conducted in a university hospital.. Thirty-one infertile PCOS women with oligoovulation plus polycystic ovarian morphology and 79 infertile women with tubal blockage (control) participated in the study. The subjects were stratified according to in vitro fertilization outcomes: successful and failed subgroups.. Serum and follicular fluid (FF) leptin levels were measured with ELISA. RT-PCR and Western blotting were performed to assess expression of mRNA encoding leptin and Ob-R and proteins of p-STAT3 and SOCS3 in granulosa cells (GCs).. Leptin levels in serum and FF of PCOS women were significantly higher than those of control (P < 0.01). There were no significant differences in expression of leptin mRNA and short and long Ob-Rs between PCOS and control (P > 0.05). The p-STAT3 level was decreased in PCOS compared with control (P < 0.01), whereas SOCS3 remained significantly unchanged (P > 0.05). Further analysis showed that serum and FF leptin levels were significantly higher, whereas p-STAT3 in GCs was lower in the failed subgroup of PCOS than those in the successful subgroup of PCOS (P < 0.05).. Hyperleptinemia and high FF leptin are important pathologies of PCOS with infertility. Lower levels of p-STAT3 in GCs may be related to ovarian leptin resistance and fecundity in PCOS women. Relatively high serum and FF leptin and low p-STAT3 in GCs may account for decreased fertilization, implantation, and pregnancy rates of in vitro fertilization in PCOS women.

Topics: Actins; Adult; Blotting, Western; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Fertility; Fertilization in Vitro; Follicular Fluid; Granulosa Cells; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins

Leptin influences the proinflammatory immune responses and has angiogenic activity in vitro and in vivo. The objective of this study was to evaluate the peritoneal fluid levels of leptin in patients with endometriosis and idiopathic infertility and compare them with a control group of tubal ligation/reanastomosis patients.. In this observational, prospective controlled study, peritoneal fluid from 108 women was obtained while they underwent laparoscopy for pelvic pain, infertility, tubal ligation or sterilization reversal. We measured the concentration of leptin in the peritoneal fluid and compared the levels among women who were divided into groups according to their post-surgical diagnosis. Sixty patients were diagnosed with endometriosis, 10 with idiopathic infertility and 38 had undergone tubal ligation or reanastomosis (control group).. Peritoneal fluid leptin was significantly higher in endometriosis 14.62+/-9.79 (mean+/-SD) ng/ml compared to idiopathic infertility [0.92+/-1.57 ng/ml (P=0.0007)] and to controls [0.78+/-1.94 ng/ml (P<0.0001)]. Leptin levels were positively correlated with the stage of endometriosis (r=0.45; P=0.03), and with pelvic pain in endometriosis patients (r=0.49; P=0.001). Peritoneal fluid leptin levels in patients with idiopathic infertility were comparable to controls.. Higher levels of leptin were observed in peritoneal fluid of patients with endometriosis compared to those without the disease. These data suggest that the proinflammatory and neoangiogenic action of leptin may contribute to the pathogenesis of endometriosis. Moreover, leptin may play a role in endometriosis-associated pain.

Topics: Ascitic Fluid; Biomarkers; Body Mass Index; Endometriosis; Female; Humans; Infertility, Female; Inflammation; Leptin; Pain; Pelvis; Sterilization Reversal; Sterilization, Tubal

Granulosa-cells are able to produce and store leptin, suggesting that this hormone is locally involved in the regulation of follicular growth. In this study, the role of follicular fluid (FF) leptin concentration in predicting oocyte fertilization and embryo quality was evaluated in 35 normogonadotrophic women undergoing controlled ovarian stimulation (COS) for assisted reproductive techniques.. Leptin concentration was measured in 47 consecutively collected FF in which a mature oocyte had been found during the ovum pick-up. Embryos deriving from fertilized oocytes were submitted to quality scoring systems.. Mean leptin concentration was significantly higher in FF whose oocytes showed 2 pronuclei (no. 25) when compared with those with no evidence of fertilization (no. 22) at the 16-18 h check (26.0+/-6.1 vs 15.3+/-10.6 ng/ml, respectively, p<0.01). Follicular mean diameters were similar in the two groups (21.4+/-3.4 and 21.0+/-5.1 mm, respectively). Logistic regression analysis identified FF leptin levels as the best predictive parameter for oocyte fertilization (p<0.001). When receiving operating characteristics curve was employed, a FF leptin concentration of 20.25 ng/ml was the most reliable cut-off in predicting fertilization of oocytes. FF with leptin concentrations higher than this value (no. 27) had an oocyte fertilization rate of 85.7%. In contrast, FF levels < or =20.25 ng/ml (no. 20) were associated with a rate of 16.7% (p<0.05). No correlation emerged between FF leptin and the score attributed to 15 valuable embryos at the zygote stage (r=-0.01) and at 48 h after insemination (r=0.1).. FF leptin levels are a better predictor of oocyte fertilization success rates than follicular diameter. These results underline the relevance of FF variables in developing methods for oocyte selection.

Topics: Adult; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Leptin; Longitudinal Studies; Male; Oocytes; Predictive Value of Tests; Reproductive Techniques, Assisted

To investigate the expression of leptin mRNA in luteinized granulose cells and the leptin level in serum and follicular fluid of non-obese patients with polycystic ovary syndrome (PCOS).. Granulosa cells were collected from the puncture fluid of follicle of 16 obese infertile patients with PCOS to undergo external fertilization. Fasting venous blood was collected while collecting the ova. RT-PCR was used to detect the expression of leptin mRNA in the granulosa cells. ELISA was used to detect the leptin level in the serum and follicular fluid. Twenty normal women undergoing external fertilization because of male infertility of their husbands were used as controls.. The expression of leptin mRNA (A value) was 1.5 +/- 0.4 in the obese infertile patients with PCOS and was 1.8 +/- 0.6 (P > 0.05) in the controls. Both the leptin levels of serum and follicular fluid were not different between the obese infertile patients with PCOS and controls (both P > 0.05). The leptin level in follicular fluid was significantly correlated with both the serum leptin level in the obese infertile patients with PCOS (r(s) = 0.838, P = 0.000) and the control group (r(s) = 0.712, P = 0.000). The expression level of leptin mRNA in the luteinized was not correlated with the leptin level of follicular fluid in both the obese infertile patients with PCOS and the control group (both P > 0.05). The fertility rate was not different between the obese infertile patients with PCOS (7/16) and the controls (9/24) (P = 0.693).. The expression of leptin mRNA is normal in the follicular fluid of the obese infertile patients with PCOS. The leptin levels in serum and follicular fluid of the obese infertile patients with PCOS are similar to those of normal women. The leptin level in follicular fluid depends mainly on the circulating leptin level.

Topics: Adult; Female; Follicular Fluid; Granulosa Cells; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome; RNA, Messenger

Changes in peritoneal fluid (PF) composition may affect fertilization as well as early embryonic development. Leptin, an adipocyte hormone, has been shown to act as a link between adipose tissue and the reproductive system. Therefore, we decided to assess peritoneal and serum leptin levels in infertile endometriotic patients.. Seventy-two women were studied, including 30 fertile and 18 infertile women with ovarian endometriotic cysts and, as a reference group, 24 patients with unexplained infertility.. No significant difference in the peritoneal and leptin levels was found between the studied groups. Significantly higher PF leptin concentration was observed in patients with stages III and IV of endometriosis as compared to those with minimal stage of the disease. In fertile patients with endometriosis a positive correlation has been found between PF and serum leptin concentrations.. No differences in peritoneal or serum leptin levels between infertile and fertile women with endometriosis suggest that this cytokine is not involved in pathophysiology of endometriosis-related infertility.

Topics: Adolescent; Adult; Ascitic Fluid; Endometriosis; Female; Humans; Infertility, Female; Leptin

Adipose tissue affects metabolism by secreting various adipokines. Lipodystropic mice benefit both from leptin replacement therapy and from transplantation of normal fat. Leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice can also be treated with leptin. Surprisingly, there have been no reports of successful treatment of obese ob/ob mice by transplantation of normal white adipose tissue (WAT). If WAT transplantation is ineffective in treating insulin resistance and diabetes in obese individuals, its applicability may be limited in humans as such abnormalities are usually associated with obesity. In the current study, we tested whether WAT transplantation might prevent, and even reverse, abnormalities characteristic of ob/ob mice. To assess the preventive potential, 6-week-old ob/ob mice were transplanted, subcutaneously, with gonadal fat pads from normal mice. Profound effects on multiple physiological phenotypes were achieved despite leptin levels below 25% of those in control mice. WAT from one donor reduced body weight gain, and WAT from 4 or 8 donors prevented obesity in ob/ob mice. Nonfasting insulin levels and insulin tolerance test were normalized. Corticosterone elevation was also prevented. Finally, WAT from 4 donors restored fertility in ob/ob females. The effects of WAT transplantation were long-lasting, with body weight gain suppressed for at least 40 weeks. To assess the therapeutic potential, obese 13-month-old ob/ob mice with a long history of leptin deficiency were used. Their body weight decreased by approximately 50% when transplanted with WAT from 8 donors. As in young recipients, transplantation greatly reduced nonfasting insulin, suggesting normalized insulin sensitivity. Thus, WAT transplantation was effective for both prevention and therapy. In the future, WAT transplantation may become a useful alternative to hormone replacement in treating not only lipodystropy, but also certain types of obesity.

Topics: Adipose Tissue; Animals; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Infertility, Female; Insulin; Insulin Resistance; Leptin; Mice; Mice, Obese; Obesity; Time Factors; Weight Loss

To investigate the concentrations of steroid hormones (estradiol, progesterone), pregnancy-associated protein-A, IGF-binding protein-4 and leptin in the follicular fluid of infertile patients with and without endometriosis.. Follicular fluid of IVF patients with and without endometriosis was aspirated, centrifuged and stored to analyze the above mentioned hormones and to compare their concentrations between women with and without endometriosis.. Follicular fluid estradiol levels were significantly higher in controls than in affected women. The concentrations of the other markers did not differ between the two groups.. Since not only the follicular fluid concentration of estradiol, but also the oocyte quality is decreased in women with endometriosis, we suggest that estradiol can be considered as a marker not only of oocyte maturity but also of oocyte quality.

Topics: Adult; Case-Control Studies; Endometriosis; Estradiol; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Insulin-Like Growth Factor Binding Protein 4; Leptin; Oocytes; Pregnancy-Associated Plasma Protein-A; Progesterone; Treatment Outcome

Topics: Adult; Endometriosis; Endometrium; Female; Humans; Infertility, Female; Leptin

Leptin administration has been shown to prevent the disruptive effects of acute food deprivation on reproductive function in cycling females and lactating females. We examined the ability of intracerebroventricular leptin administration to ameliorate the effects of food restriction for the first 2 wk postpartum on length of lactational infertility. Leptin administration did not reduce the effects of food restriction on reproductive function at either time period (days 8-15 and 15-22 postpartum) or dose (1 and 10 microg/day) administered. Because of the sharp contrast between these results and the ability of leptin to offset the effects of acute food deprivation in lactating rats, the remaining studies investigated the possible causes of this difference. Both central and peripheral leptin administration eliminated food deprivation-induced prolongation of lactational infertility, suggesting that neither route of administration nor dose was a factor. However, we noticed that, whereas chronically food-restricted females continue to deliver milk to their young, acutely food-deprived females do not. To test the hypothesis that the continued energetic drain of milk production and delivery might prevent the ability of exogenous leptin administration to eliminate the effects of undernutrition, leptin was administered to food-restricted, lactating rats prevented from delivering milk. In this situation intracerebroventricular leptin treatment completely eliminated the effects of food restriction on lactational infertility, suggesting that leptin contributes to the maintenance of reproductive function via two pathways: direct binding in the central nervous system and through increasing the availability of oxidizable metabolic fuels.

Topics: Animals; Caloric Restriction; Female; Food Deprivation; Infertility, Female; Injections, Intraperitoneal; Injections, Intraventricular; Lactation; Leptin; Rats; Rats, Wistar; Time Factors

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

To determine the effect of dose of GnRH agonist on the follicular environment in controlled ovarian hyperstimulation (COH) cycles.. Twenty-eight IVF patients with normal ovarian function were divided into three groups: group I received GnRHa (nafarelin acetate/Synarel) intranasally at 200 microg daily, group II received 400 microg daily until hCG injection, and group III was given 400 microg daily before the initiation of ovarian stimulation, then 200 microg daily before the day of hCG injection. Serum estradiol, progesterone, and leptin levels were measured on the day of hCG injection. After aspiration, expression of pregnancy-associated alpha-plasma protein (PAPP)-A in the follicular fluid of dominant follicles (>20 mm) was determined by Western blot analysis.. No significant difference was noted in serum estradiol, progesterone, and leptin levels. But intrafollicular PAPP-A expression was significantly higher in group II compared to other groups (P<0.05).. The dose of GnRHa may have an impact on the intrafollicular environment of dominant follicles in COH cycles.

Topics: Administration, Intranasal; Adult; Blotting, Western; Dose-Response Relationship, Drug; Drug Administration Schedule; Estradiol; Female; Follow-Up Studies; Humans; Infertility, Female; Leptin; Menstrual Cycle; Nafarelin; Ovulation Induction; Pregnancy-Associated Plasma Protein-A; Probability; Progesterone; Prospective Studies; Radioimmunoassay; Risk Assessment; Statistics, Nonparametric

Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3(N-/-)). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3(N-/-) mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db/db and ob/ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.

Topics: Acute-Phase Proteins; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Corticosterone; Diabetes Mellitus; DNA-Binding Proteins; Female; Infertility, Female; Infertility, Male; Intermediate Filament Proteins; Kinetics; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Nestin; Obesity; Rats; STAT3 Transcription Factor; Time Factors; Trans-Activators

To determine serum and follicular fluid leptin levels in patients undergoing controlled ovarian hyperstimulation (COH) for an in vitro fertilization-embryo transfer (IVF-ET) cycle and their possible correlation to COH variables.. Large university-based IVF unit.. 16 consecutive patients undergoing our routine IVF long gonadotrophin-releasing hormone-analog protocol. INTERVENTIONS AIND MAIN OUTCOME MEASURES: Blood was drawn three times during the COH cycle: 1) day on which adequate suppression was obtained (Day-S); 2) day of or prior to human chorionic gonadotrophin (hCG) administration (Day-hCG); and 3) day of ovum pick-up (Day-OPU). Levels of sex steroids and serum and follicular fluid leptin were compared among the three time points. Serum leptin was measured with a commercial two-site immunoradiometric assay.. Results showed significantly higher levels of serum leptin on Day-OPU and Day-hCG than on Day-S, and significantly higher follicular than serum leptin levels on Day-OPU. Though a significant correlation was observed between serum leptin and body mass index (BMI), no correlations were found between serum or follicular fluid leptin and serum sex-steroid levels or IVF treatment variables.. While serum leptin increases during COH for IVF, there is apparently no correlation of serum and follicular leptin levels with sex-steroid levels or IVF outcome.

Topics: Adult; Chorionic Gonadotropin; Female; Fertilization in Vitro; Follicular Fluid; Hormones; Humans; Infertility, Female; Leptin; Longitudinal Studies; Menstrual Cycle; Ovulation Induction; Prospective Studies

To investigate the changes in serum leptin concentration in the conception cycle of severe ovarian hyperstimulation syndrome (OHSS).. Prospective longitudinal study of 66 IVF-ET cycles between May 2000 and June 2002.. Infertility outpatient clinic at a Japanese medical school.. Infertile patients undergoing IVF-ET cycles at the infertility outpatient clinic were divided into three groups consisting of group 1 (conception-cycle patients with severe OHSS, n = 9), and group 2 (conception cycle, non-OHSS, n = 28), and group 3 (nonconception cycle, non-OHSS, n = 29).. Blood samples were collected at five different periods. Period I, on the first day of ovarian stimulation with FSH; period II, at hCG administration before oocyte retrieval; period III, 7 days after oocyte retrieval; period IV, 14 days after oocyte retrieval; and period V, 21 days after oocyte retrieval.. Serum leptin concentration.. The serum leptin concentration was low in the OHSS group compared with that of the non-OHSS groups in all serum samples, with significant levels at periods III (vs. groups 2 and 3; P<.05) and IV (vs. group 3; P<.01). A twofold increase of leptin concentration from period I to period II (P<.05) was observed in all groups.. The change pattern in serum leptin concentration might provide a great contribution to the pathophysiology development of OHSS patients during assisted reproductive treatment.

Topics: Adult; Embryo Transfer; Female; Fertilization in Vitro; Humans; Infertility, Female; Leptin; Longitudinal Studies; Ovarian Hyperstimulation Syndrome

The aim of this study was to investigate the relationships between the serum levels of soluble leptin receptor (SLEPR), and total, free and bound leptin, and the change in the serum SLEPR level during an IVF cycle.. Serum concentrations of leptin and SLEPR were measured in 50 Japanese women of reproductive age, and 20 patients participating in an IVF programme. The total leptin was fractionated into free and bound portions by gel filtration chromatography.. The SLEPR level was negatively correlated with the body mass index (BMI) (r = -0.548, P < 0.0001), total leptin (r = -0.433, P < 0.0001), the percentage of free leptin (r = -0.732, P < 0.0001) and the absolute free leptin concentration (r = -0.506, P < 0.0001). The SLEPR level was positively correlated with the percentage of bound leptin (r = 0.730, P < 0.0001), whereas there was little variation in the absolute bound leptin concentration, regardless of the BMI or SLEPR concentration. During the IVF cycle, total and free leptin elevated during maximal ovarian stimulation, whereas there was no significant difference in the SLEPR concentration.. The results demonstrate a skillful mechanism where a change in the serum SLEPR level regulates, in part, the biological activity of leptin in the circulation.

Topics: Adult; Body Mass Index; Case-Control Studies; Female; Fertilization in Vitro; Humans; Infertility, Female; Leptin; Middle Aged; Osmolar Concentration; Ovulation Induction; Receptors, Cell Surface; Receptors, Leptin; Solubility

The aims of this retrospective study were to investigate whether the quantification of ovarian stromal blood flow and/or leptin concentration are predictive of in vitro fertilization (IVF) outcomes in women after laparoscopic ovarian cystectomy for large endometriomas.. Twenty-two women undergoing IVF after laparoscopic surgery for ovarian endometriomas (> 6 cm) comprised the study group. Twenty-six women with tubal factor infertility constituted the control group. Ovarian stromal blood flow was evaluated by three-dimensional (3D) power Doppler ultrasound imaging using virtual organ computer-aided analysis (VOCAL( trade mark )). Serum and follicular fluid (FF) leptin concentrations were quantified using an enzyme-linked immunosorbent assay kit.. There were significantly decreased ovarian stromal blood flow parameters (including vascularization index, flow index (FI), and vascularization flow index) in the endometriosis group without an evident difference in total ovarian volume on the day of human chorionic gonadotropin. The value of FF leptin demonstrated a negative correlation with ovarian stromal FI in the control group, but there was a loss of this effect in the endometriosis group.. Quantification of ovarian stromal blood flow by 3D power Doppler ultrasound in women with endometriosis may provide an important prognostic indicator in those undergoing IVF.

Topics: Adult; Blood Flow Velocity; Endometriosis; Female; Fertilization in Vitro; Humans; Imaging, Three-Dimensional; Infertility, Female; Leptin; Ovary; Retrospective Studies; Treatment Outcome; Ultrasonography, Doppler, Color

The role of leptin in reproductive processes has received increasing attention. Because leptin has intrinsic angiogenic properties, may be induced by inflammatory cytokines and induces matrix metalloproteinases, we examined peritoneal fluid (PF) leptin concentrations in women with endometriosis.. PF samples were collected from 60 women undergoing laparoscopy for endometriosis, and 18 controls undergoing tubal sterilization. Fifty of the women with endometriosis had received no prior hormonal treatment, while 10 with moderate- severe endometriosis were using GnRH agonists.. Women with untreated endometriosis had significantly higher (mean +/- SD) PF leptin levels (34.9 +/- 7.9 ng/ml) than controls (17.9 +/- 4.1 ng/ml; P < 0.001). However, PF leptin levels were inversely correlated with the stage of disease (r = -0.62; P < 0.001). Nevertheless, women with stage III-IV endometriosis maintained significantly higher PF leptin levels (26.3 +/- 4.8 ng/ml; P < 0.001) than controls. Although PF leptin levels were significantly higher in the secretory versus proliferative phase of the menstrual cycle, they remained higher in both phases in women with untreated endometriosis. PF leptin levels in women on GnRH agonists were similar to controls.. PF leptin levels are elevated in women with endometriosis, but inversely correlated with extent of disease. These findings suggest a potential role for leptin in the pathogenesis of peritoneal endometriosis.

Topics: Adult; Ascitic Fluid; Endometriosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infertility, Female; Laparoscopy; Leptin; Menstrual Cycle; Pelvic Pain

Transketolase (TKT) is a ubiquitous enzyme used in multiple metabolic pathways. We show here by gene targeting that TKT-null mouse embryos are not viable and that disruption of one TKT allele can cause growth retardation ( approximately 35%) and preferential reduction of adipose tissue ( approximately 77%). Other TKT(+/-) tissues had moderate ( approximately 33%; liver, gonads) or relatively little ( approximately 7 to 18%; eye, kidney, heart, brain) reductions in mass. These mice expressed a normal level of growth hormone and reduced leptin levels. No phenotype was observed in the TKT(+/-) cornea, where TKT is especially abundant in wild-type mice. The small female TKT(+/-) mice mated infrequently and had few progeny (with a male/female ratio of 1.4:1) when pregnant. Thus, TKT in normal mice appears to be carefully balanced at a threshold level for well-being. Our data suggest that TKT deficiency may have clinical significance in humans and raise the possibility that obesity may be treated by partial inhibition of TKT in adipose tissue.

Topics: Adipose Tissue; Alleles; Animals; Body Weight; Cornea; Disease Models, Animal; Embryonic and Fetal Development; Energy Metabolism; Eye Proteins; Female; Gene Targeting; Growth Disorders; Growth Hormone; Heterozygote; Infertility, Female; Introns; Leptin; Litter Size; Mice; Mice, Inbred C57BL; Mice, Knockout; Morula; Mutagenesis, Insertional; Organ Size; Phenotype; Pregnancy; Sexual Behavior, Animal; Transketolase

To determine the effect of ovarian stimulation on TH1, TH2 and natural killer (NK) lymphocytes, plasma cytokines, leptin and nitrite levels.. Women with reproductive failure were studied during the implantation window, at baseline (n = 18) and under ovarian stimulation (gonadotropins + progesterone, n = 6).. eight fertile women. Lymphocyte subpopulations and NK function were determined by flow cytometry. Interleukin-2 (IL-2), IL-4, IL-10, IFN-gamma, TNF-alpha, TGF-beta1 and leptin were measured by enzyme immunoassay (EIA); nitrite by the Griess reaction.. At baseline, patients had higher values of NK effectors, NK activity and plasma IFN-gamma and IL-2 than controls. Conversely, TGF-beta1 values were lower. Hormones induced leukocytosis. Under stimulation, THI CD4+ cells, NK effectors and function and plasma IFN-gamma and IL-2 decreased, while transforming growth factor (TGF)-beta1 increased. Other variables did not change.. The abnormal distribution of leukocytes, high TH1 cytokines and a low TGF-beta1 associated with reproductive failure, respond to ovarian stimulation, achieving total or partial normalization.

Topics: Adult; Chorionic Gonadotropin; Cytokines; Cytotoxicity, Immunologic; Female; Humans; Immunophenotyping; Infertility, Female; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-4; Killer Cells, Natural; Leptin; Leuprolide; Lymphocyte Count; Nitrites; Ovulation Induction; Progesterone; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

To establish whether initial screening characteristics of normogonadotropic anovulatory infertile women can aid in predicting live birth after induction of ovulation with clomiphene citrate (CC).. Prospective longitudinal single-center study.. Specialist academic fertility unit.. Two hundred fifty-nine couples with a history of infertility, oligoamenorrhea, and normal follicle-stimulating hormone (FSH) concentrations who have not been previously treated with any ovulation-induction medication.. 50, 100, or 150 mg of oral CC per day, for 5 subsequent days per cycle.. Conception leading to live birth after CC administration.. After receiving CC, 98 (38%) women conceived, leading to live birth. The cumulative live birth rate within 12 months was 42% for the total study population and 56% for the ovulatory women who had received CC. Factors predicting the chances for live birth included free androgen index (testosterone/sex hormone-binding globulin ratio), body mass index, cycle history (oligomenorrhea versus amenorrhea), and the woman's age.. It is possible to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a nomogram. Applying this nomogram in the clinic may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulatory infertility. Alternative first line of treatment options could be considered for some women who have limited chances for success.

Topics: Abortion, Spontaneous; Amenorrhea; Clomiphene; Ejaculation; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Infant, Newborn; Infertility, Female; Insulin-Like Growth Factor I; Leptin; Male; Odds Ratio; Oligomenorrhea; Ovulation; Ovulation Induction; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Probability; Retrospective Studies; Sperm Count; Treatment Outcome

Leptin may play a role in the regulation of menstrual cycle acting either directly on ovaries or at the level of the hypothalamic-pituitary axis. Peritoneal fluid is a biologically active environment that influences ovarian function but, on the other hand, concentration of many substances in peritoneal fluid can reflect the functional status of ovaries. In our study, we estimated leptin concentration in peritoneal fluid in relation to serum leptin concentration in infertile patients. A study group consisted of 31 infertile patients that underwent laparoscopy. In 15 patients, laparoscopy did not solve the problem and they were grouped as unexplained infertility, in eight patients we found endometriosis and eight patients were diagnosed as polycystic ovary syndrome (PCOS). We found significantly higher peritoneal fluid leptin concentrations in patients with unexplained infertility and endometriosis compared to those with PCOS. The plasma leptin concentration did not differ between the groups studied. There was no correlation between peritoneal fluid and plasma leptin concentrations in any patient group. Taking into account our results, the role of leptin in reproduction should be emphasized but further investigation is needed to determine its mechanism of action.

Topics: Adult; Ascitic Fluid; Female; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome

Leptin is an adipocyte-derived hormone which plays a central role in the regulation of body weight and energy homeostasis and in signalling to the brain that adequate energy stores are available for reproduction. Although leptin may affect reproduction by regulating the hypothalamic-pituitary-gonadal axis, recent in-vitro observations indicate that leptin may also have direct intra-ovarian actions. Leptin concentrations were measured in women who succeeded in becoming pregnant within three cycles of in-vitro fertilization (IVF) or gamete intra-fallopian transfer (n = 53), in women who failed to become pregnant within three cycles (n = 50), and in women with polycystic ovarian syndrome (PCOS) (n = 22). It was found that lower follicular fluid leptin concentrations were a marker of assisted reproduction treatment success in normal women. Women with PCOS had higher leptin concentrations than women without such a diagnosis, but this was due to their higher body mass index (BMI). After adjustment for age and BMI, women with PCOS who became pregnant tended to have lower mean follicular fluid leptin concentrations than women with PCOS who did not succeed at becoming pregnant. Further studies exploiting the strengths of the IVF model are needed to assess whether the prognostic role for follicular fluid leptin in human reproduction is independent of other factors, and to elucidate the underlying mechanisms.

Topics: Adult; Biomarkers; Body Weight; Female; Fertilization in Vitro; Follicular Fluid; Humans; Infertility, Female; Leptin; Polycystic Ovary Syndrome; Predictive Value of Tests; Pregnancy; Pregnancy Rate; Reference Values; Reproductive Techniques; Smoking

To assess serum leptin levels based on body habitus and ovarian morphology during controlled ovarian hyperstimulation.. Prospective analysis.. University IVF program.. Women undergoing IVF-ET were divided into two groups, obese ovulatory women (n = 6; mean (+/-SD) body mass index, 30.1 +/- 0.6 kg/m(2)) and lean ovulatory women (n = 20); mean (+/- SD) body mass index 22.0 +/- 0.2 kg/m(2)). Lean women were categorized further according to whether they had polycystic-appearing ovaries (n = 8) or normal-appearing ovaries (n = 12).. Controlled ovarian hyperstimulation and IVF.. Serum estradiol, testosterone, and leptin.. Mean (+/- SD) leptin levels were significantly higher before and after GnRH agonist down-regulation in obese women (41.7 +/- 5.2 pg/mL and 36.1 +/- 5.8 pg/mL, respectively) compared with lean women (8.4 +/- 1.0 pg/mL and 6.9 +/- 1.1 pg/mL, respectively). Mean (+/- SD) leptin levels increased significantly in both groups (54.5 +/- 5.1 pg/mL and 11.7 +/- 1.2 pg/mL, respectively), and the mean (+/-SD) percentage increase was similar (55% +/- 18% and 54.8% +/- 17%, respectively). Mean (+/-SD) leptin levels were similar in women with polycystic-appearing and normal-appearing ovaries before controlled ovarian hyperstimulation, but increased significantly in women with polycystic-appearing ovaries afterward (14.7 +/- 1.8 pg/mL and 9.3 +/- 1.0 pg/mL, respectively).. Significant increases in leptin levels occur during controlled ovarian hyperstimulation, suggesting that leptin plays a role in follicular growth and maturation. The exaggerated response in women with polycystic-appearing ovaries reflects either a greater number of recruited follicles or a predisposition of adipocytes to leptin production.

Topics: Adult; Body Weight; Case-Control Studies; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leptin; Menotropins; Obesity; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Prospective Studies; Testosterone

We have previously demonstrated that obese hyperandrogenic amenorrheic women are less likely to ovulate after clomiphene citrate (CC) medication. The present study was designed to identify whether additional endocrine screening characteristics, all potentially involved in ovarian dysfunction in 182 normogonadotropic oligoamenorrheic infertile women, are associated with ovarian response, which may improve overall prediction of CC-resistant anovulation. Standardized endocrine screening took place before initiation of CC medication (50 mg/day; increasing doses up to 150 mg/day if required) from cycle days 3-7. Screening included serum assays for fasting insulin and glucose, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, free IGF-I, inhibin B, leptin, and vascular endothelial growth factor. Forty-two women (22% of the total group) did not ovulate at the end of follow-up (a total number of 325 cycles were analyzed). Fasting serum insulin, insulin/glucose ratio, IGFBP-1, and leptin were all significantly different in univariate analyses (P < or = 0.02), comparing CC responders vs. nonresponders. Forward stepwise multivariate analyses in combination with factors reported earlier for prediction of patients remaining anovulatory after CC revealed a prediction model including 1) free androgen index (FAI = testosterone/sex hormone-binding globulin ratio), 2) cycle history (oligomenorrhea or amenorrhea), 3) leptin level, and 4) mean ovarian volume. These data suggest that decreased insulin sensitivity, hyperandrogenemia, and obesity, all associated with polycystic ovary syndrome, are prominent factors involved in ovarian dysfunction, preventing these ovaries from responding to stimulation by raised endogenous FSH levels due to CC medication. By using leptin instead of body mass index or waist to hip ratio, the previous model for prediction of patients remaining anovulatory after CC medication could be slightly improved (area under the curve from 0.82-0.85). This may indicate that leptin is more directly involved in ovarian dysfunction in these patients. The capability of insulin and IGFBP-1 to predict patients who remain anovulatory after CC disappears when FAI enters into the model due to a significant correlation between FAI and these endocrine parameters. This suggests that markers for insulin sensitivity (e.g. IGFBP-1 and insulin) are associated with abnormal ovarian function through its correlation with androgens, whereas leptin

Topics: Adult; Amenorrhea; Androgens; Clomiphene; Female; Fertility Agents, Female; Forecasting; Gonadotropins; Humans; Infertility, Female; Leptin; Ovary; Ovulation Induction; Reference Values

To determine whether elevated follicular steroid levels during gonadotropin stimulation cycles are associated with altered circulating leptin concentrations.. Sequential serum samples were collected from women (N = 37) undergoing luteal phase GnRH agonist + FSH treatment cycles prior to oocyte retrieval for in vitro fertilization. Leptin concentrations in serum were measured by radioimmunoassay and compared with serum estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) levels.. Serum leptin concentrations during stimulated cycles were variable between patients and correlated positively (r = .556, P < .01) with body mass index. Serum leptin levels correlated positively (r = .185, P < .05) with estradiol concentrations across all days. Mean serum leptin concentrations on the day gonadotropin treatment began (baseline, 12.9 +/- 2.0 ng/mL) were lower (P < .0001) than on the day peak estradiol levels were reached (18.4 +/- 2.3 ng/mL). Serum leptin concentrations also correlated with DHEAS levels (r = .214, P < .05) but did not correlate with testosterone or the estradiol:testosterone ratio.. Gonadotropin stimulation in women is associated with elevated leptin levels, consistent with an interaction between the reproductive axis and leptin secretion and/or clearance.

Topics: Adult; Female; Fertilization in Vitro; Gonadotropins; Humans; Infertility, Female; Leptin; Menstrual Cycle

Body weight influences fertility and studies in mice have indicated that leptin is one of the mediators of this effect. Leptin is believed to centrally stimulate the hypothalamic-pituitary axis resulting in increased gonadotropin release. Moreover, leptin is present in follicular fluid and the receptor is expressed in the human ovary. The aim of this study was to evaluate the direct effect of leptin on cultured human granulosa cell steroidogenesis.. Granulosa cells were obtained in connection with IVF procedures, and then cultured in a serum-free medium containing androstenedione (1 microM) for a total of 4 days. After 2 days of culture the medium was changed and the hormones under study were added. We tested the effect of leptin (1, 20, 100 ng/ml) on basal, FSH (10-100 ng/ml), and FSH (10-100 ng/ml)+IGF-I (30 ng/ml) stimulated steroidogenesis.. Leptin (20 ng/ml and 100 ng/ml) significantly reduced basal and FSH-stimulated estradiol secretion (p<0.05). Basal and FSH (10 and 30 ng/ml) stimulated progesterone production was significantly inhibited by leptin 20 ng/ml, whereas leptin 100 ng/ml significantly reduced basal but not FSH stimulated progesterone production. Finally, steroidogenesis stimulated by IGF-I alone and in combination with FSH was not influenced by leptin.. These results suggest that leptin acts directly to inhibit basal and FSH stimulated estradiol and progesterone production in cultured human granulosa cells. This raises the possibility that high circulating leptin levels as seen in obese women may compromise fertility through peripheral mechanisms.

Topics: Body Weight; Cell Culture Techniques; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Infertility, Female; Leptin; Progesterone

To investigate the clinical importance of leptin's intraovarian effects, we studied the concentration of leptin and leptin binding activity in the plasma and in the follicular fluid of PCOS patients (n=20; median BMI: 27.1 kg/m2, range 19.7-36.3) undergoing controlled ovarian stimulation with long-term GnRH agonist, recombinant FSH, and in vitro fertilization. Follicular fluid and blood samples were collected during follicle aspiration for IVF. Total leptin concentration was measured by radioimmunoassay, and specific leptin binding activity was accessed by a gel filtration column assay. Follicular fluid and plasma leptin levels were similar (median 1135 pmol/l vs. 1409 pmol/l; p=0.81). Follicular fluid to plasma leptin ratio was independently associated with cumulative FSH dose (r=0.63; p=0.006) and insulin resistance index (r=-0.45; p=0.04). Specific leptin binding activity was higher in the plasma than in the follicular fluid [median 7.94% vs. 3.49%; p<0.001]. When multivariate analysis was used to predict FSH consumption, only follicular fluid leptin levels were significantly associated with cumulative FSH dose (r=0.46; p=0.04). We infer that at least in part by increased intrafollicular leptin levels, obesity directly affects ovarian function in PCOS, and may induce a relative resistance to gonadotropin stimulation. This intraovarian effect of leptin can be even more profound because of low leptin binding activity in the preovulatory follicle of obese patients.

Topics: Adult; Body Mass Index; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Follicular Fluid; Humans; Infertility, Female; Insulin Resistance; Leptin; Ovarian Follicle; Ovulation; Polycystic Ovary Syndrome; Protein Binding; Recombinant Proteins

To explore the effect of Tiangui Recipe (TGR) on obesity and reproductive function in androgen-sterilized rats (ASR).. ASR model was established by subcutaneous injection of testosterone propionate to SD female rats of 9 days age. Change of serum leptin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in model rats of 115 days old before and after feeding TGR was measured by radioimmunoassay (RIA). Meanwhile, criteria of energy state, including diurnal food intake, retroperitoneal fat depot weight and body weight, were measured and evaluated.. ASR had the characteristics of high metabolic rate, energy imbalance and obesity. Serum level of leptin increased and FSH, LH decreased significantly (P < 0.01) in model rats as compared with the normal rats. Significant positive correlation between leptin level and body weight (r = 0.8977, P < 0.001) was observed, and negative correlation was seen between FSH, LH and leptin (r = -0.7517, P < 0.001; r = -0.8444, P < 0.001, respectively). The endocrinous changes of ASR all returned to normal range after the TGR treatment.. Obesity and concerned hypogonadotropic hypogonadal anovulation were expressed in ASR. TGR may play an important role in reducing weight and inducing ovulation.

Topics: Androgens; Animals; Drugs, Chinese Herbal; Female; Gonadotropins, Pituitary; Infertility, Female; Leptin; Phytotherapy; Rats; Rats, Sprague-Dawley

The goals of these experiments were to determine whether lactational anestrus would be prolonged by a 48-h fast at days 13 and 14 postpartum (pp) and, if so, to determine whether this effect could be reversed by treatment with the Ob protein leptin. We found that food deprivation on days 13 and 14 pp prolonged lactational infertility by 7 days and that the nutritional experience of both the dam and her litter contributed to this effect. Leptin administration (2.5 mg . kg-1 . day-1) during food deprivation was sufficient to reduce the length of lactational infertility compared with vehicle-treated food-deprived rats (P < 0.05). Similar leptin treatment in ad libitum-fed animals reduced food intake (P < 0.05) and litter growth (P < 0.05) but had no statistically significant effect on maternal weight gain or length of lactational infertility. Food-deprived lactating animals had lower circulating leptin levels than ad libitum-fed lactating animals on day 15 pp (P < 0.05), as determined by RIA. Levels in nonlactating rats were higher than in either lactating group (P < 0.05).

Topics: Anestrus; Animals; Animals, Newborn; Diestrus; Female; Food Deprivation; Infertility, Female; Lactation; Leptin; Proteins; Rats; Rats, Wistar; Time Factors; Weight Gain

Topics: Animals; Anorexia Nervosa; Female; Infertility, Female; Leptin; Mice; Pheromones; Proteins; Religion and Medicine

The sterility of male and female homozygous ob/ob mice is a recognized feature of the ob mutation (1). Whereas ob/ob males can occasionally reproduce if maintained on a restricted diet, ob/ob females are always sterile (2). Thinning of the ob/ob females to normal weight by diet-restriction failed to correct their sterility. Early sexual development is normal in ob/ob females; however, ovulation never follows and the mice remain prepuberal indefinitely with no occurrence of oestrus cycles. Reproductive hormones are reduced in ob/ob females (3) demonstrating a functional defect from the hypothalamic-pituitary axis (4-6). The ovaries of ob/ob females are capable of producing viable eggs when transplanted into lean female recipients (7). Reconstitution of reproductive functions in the ob/ob female necessitates delivery of hypothalamic extracts to the third ventricle (8) and administration of pituitary extract (9), gonadotropic hormones (10), progesterone (11) and relaxin (12). These previous findings demonstrate that the sterility of ob/ob females is caused by an insufficiency of hormones at the hypothalamic-pituitary level rather than physical hindrance of copulatory activity, pregnancy and parturition caused by excess adipose tissue. We show here that repeated administration of only the recombinant human ob protein, leptin, into homozygous female ob/ob mice can correct their sterility, thus resulting in ovulation, pregnancy and parturition.

Topics: Animals; Base Sequence; DNA Primers; Female; Homozygote; Humans; Infertility, Female; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Sequence Data; Obesity; Polymerase Chain Reaction; Pregnancy; Proteins; Recombinant Proteins

Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Infertility, Female; Leptin; Mice; Mice, Obese; Ovary; Pregnancy; Proteins; Reproduction