leptin and Anovulation

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

Mares have an annual reproductive rhythm, with a phase of inactivity in midwinter. The aim of this study was to determine the impact of food restriction on physiological and metabolic hallmarks of this rhythm.. Over three successive years, 3 groups of 10 mares were kept under natural photoperiod. A 'well-fed' group was fed to maintain the mares in good body condition; a 'restricted' group received a diet calculated to keep the mares thin and a 'variable' group was fed during some periods like the 'restricted' group and during some other periods like the 'well-fed' group, with the aim of mimicking the natural seasonal variation of pasture availability, but a few months in advance of this natural rhythm.. Winter ovarian inactivity always occurred and was long in the restricted group. In contrast, in the 'well-fed' group, 40% of mares showed this inactivity, which was shorter than in the other groups. Re-feeding the 'variable' group in autumn and winter did not advance the first ovulation in spring, compared with the 'restricted' group. Measurements of glucose and insulin concentrations in mares from the 'restricted' group during two 24 h periods of blood sampling, revealed no post-prandial peaks. For GH (Growth hormone), IGF-1 and leptin levels, large differences were found between the 'well-fed' group and the other groups. The glucose, insulin, GH and leptin levels but not melatonin level are highly correlated with the duration of ovulatory activity.. The annual rhythm driven by melatonin secretion is only responsible for the timing of the breeding season. The occurrence and length of winter ovarian inactivity is defined by metabolic hormones.

Topics: Adiposity; Animals; Anovulation; Blood Glucose; Body Weight; Caloric Restriction; Circadian Rhythm; Female; France; Growth Hormone; Horses; Insulin; Insulin-Like Growth Factor I; Leptin; Melatonin; Ovulation; Photoperiod; Seasons; Subcutaneous Fat, Abdominal; Time Factors

Disruptions in hypothalamic-gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalamic amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea.. Eight women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean (+/-SD) of 8.5+/-8.1 months.. Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of three months. Three patients had an ovulatory menstrual cycle (P<0.05 for the comparison with an expected rate of spontaneous ovulation of 10 percent); two others had preovulatory follicular development and withdrawal bleeding during treatment (P<0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corticotropin, or urinary N-telopeptide.. Leptin administration for the relative leptin deficiency in women with hypothalamic amenorrhea appears to improve reproductive, thyroid, and growth hormone axes and markers of bone formation, suggesting that leptin, a peripheral signal reflecting the adequacy of energy stores, is required for normal reproductive and neuroendocrine function.

Topics: Adult; Alkaline Phosphatase; Amenorrhea; Anovulation; Body Composition; Bone Remodeling; Collagen; Collagen Type I; Exercise; Female; Hormones; Humans; Hypothalamic Diseases; Leptin; Osteocalcin; Peptides; Prospective Studies; Thinness

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

Polycystic ovary syndrome is the classic example of loss of functional cyclicity and anomalous feedback. In this case, the excessive extra-glandular production and conversion of androgens to estrogens are the pathophysiological basis of the chronic anovulation. The literature describes an experimental model of the polymicrocystic ovary in obese diabetic mice with insulin resistance. The fact that these animals exhibit obesity, insulin resistance, and infertility demonstrates their skill as an experimental model for polycystic ovary. A recent study using long protocol for up to 40 weeks showed that anovulatory and obese mice transplanted with adipose tissue from animals with normal weight have multiple changes in their phenotype. These changes include reduction of body weight, prevention of obesity, insulin level normalization, and insulin tolerance tests, preventing the elevation of steroids and especially the reversal of fertility restoration with anovulation. Considering that there are close relationships between the ovulation process and the central nervous system, we propose to evaluate the gene expression levels of 84 different genes involved in neurotransmission and insulin pathways in addition to examining the neurolipidosis differential murine brain before and after reversal of anovulation. The present study showed changes in gene expression of molecular markers in brain tissue of animals for brain neurotransmission pathways as well as pathways for insulin. GABAergic genes, muscarinic, serotonin receptors, receptor tyrosine kinase, and genes of interleukin 6 showed overexpression profile. There was also a change in the lipid content in anovulatory brain, obesity, and insulin resistant mice (Ob-/Ob-) compared with controls. The re-introduction of leptin in these animals appears to reverse, at least in part, this profile.

Topics: Animals; Anovulation; Brain; Female; Interleukin-6; Leptin; Lipid Metabolism; Mice; Mice, Obese; Receptor Protein-Tyrosine Kinases; Receptors, GABA; Receptors, Muscarinic; Receptors, Serotonin; Synaptic Transmission

The mechanisms regulating postpartum anovulation (PPA) are not well understood, although poor nutritional status and "intense" breastfeeding behaviors are associated with longer durations.. This study was designed primarily to investigate the hypothesis that higher body fat and leptin concentrations are related to shorter PPA in healthy, lactating US women. Nutrient intake, breastfeeding behaviors, prolactin, and insulin levels were also evaluated.. Fasting serum was collected during the third trimester of pregnancy, at 2 and 4 weeks postpartum, and every 4 weeks until the occurrence of the first postpartum menses. Body composition and breastfeeding behaviors were assessed at the same times postpartum. Women (n = 13) were categorized based on initial percentage body fat and timing of first postpartum menses.. There were no consistent relationships between body composition, leptin, or breastfeeding behaviors and duration of PPA. However, there was an interaction (P = .005) between ovulation group and time on adiposity; earlier ovulating women had less percentage body fat in early lactation than did later ovulating women. There was also an interaction (P = .1) between ovulation group and time postpartum on leptin, such that leptin concentrations tended to be greater in later than earlier ovulating groups beginning at 12 weeks postpartum.. In summary, although baseline percentage body fat and leptin were not related to duration of PPA, fertility returned earlier in women who lost greater percentage body fat during the early postpartum period.

Topics: Adipose Tissue; Adult; Anovulation; Body Composition; Breast Feeding; Female; Humans; Infant, Newborn; Insulin; Leptin; Postpartum Period; Pregnancy; Prolactin; United States; Women's Health; Young Adult

To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function.. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake.. High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, -10.6 to -2.5) and luteal phase progesterone (-22.1%; -36.2 to -4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4).. High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women.

Topics: Aged; Anovulation; Cohort Studies; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leisure Activities; Leptin; Linear Models; Luteinizing Hormone; Menstrual Cycle; Middle Aged; Motor Activity; New York; Premenopause; Progesterone

The aim was to analyze the effect of adipose tissue transplantation on growth differentiation factor-9 (GDF-9), insulin growth factor 1 receptor (IGF1R), and leptin receptor (LEPR) protein expression in ovaries of obese anovulatory mice. Leptin-deficient female (ob/ob) and wild-type mice were divided into untreated ob/ob mice and gonadal white adipose tissue transplanted ob/ob mice, with evaluation after 7, 15, and 45 days and compared to control wild-type mice. The corporal weight and glycemia levels increased in the obese group concomitant with polymicrocyst formation and abundant estrone, mimicking anovulatory disease. In the treated group after 45 days, glycemia, weight, ovarian size, and number of follicles were decreased and corpora lutea were decreased. The analysis of GDF-9 revealed that, whereas control ovaries presented follicular localization, the obese ovary lacked this protein. On the other hand, obese ovaries showed elevated expression of IGF1R that was normalized after the transplantation. Finally, LEPR was reduced in obese ovaries, and adipose tissue transplantation was efficient in returning it to normal levels. In conclusion, the adipose tissue transplantation, especially after 45 days, seems to stimulate ovulation, supported by the fact that several proteins involved in ovulation returned to basal levels.

Topics: Animals; Anovulation; Corpus Luteum; Female; Fertility; Growth Differentiation Factor 9; Intra-Abdominal Fat; Leptin; Mice; Mice, Knockout; Mice, Obese; Obesity; Organ Size; Ovary; Ovulation; Polycystic Ovary Syndrome; Receptor, IGF Type 1; Receptors, Leptin; Subcutaneous Tissue; Transplantation, Heterotopic

To assess the plasma levels of the inflammatory markers such as C-reactive protein (CRP), leptin, and glycosaminoglycans (GAGs) during the menstrual cycle.. Eighteen healthy volunteers were divided into two groups according to the presence of ovulatory or anovulatory menstrual cycles. Blood samples were collected at different time points: at the menstrual phase (days 2-3), periovulatory phase (days 12-13), and luteal phase (days 23-24). CRP and leptin concentrations were measured by enzyme immunoassay. GAGs were isolated using ion-exchange chromatography on DEAE-Sephacel and quantified as hexuronate. The structural characterization of chondroitin sulfate (CS) isomers was performed by fluorophore-assisted carbohydrate electrophoresis (FACE).. In the women with ovulatory cycles, plasma GAG levels differed significantly during menstrual cycle, with increased values at the periovulatory with respect to the menstrual phase. No significant differences in CRP and leptin concentrations were observed through the menstrual cycle in both the examined cycles, but inter-group analysis revealed significant differences of CRP and leptin levels between the ovulatory and anovulatory cycles with higher values at periovulatory phase in the ovulatory cycles.. There are no fluctuations of both total GAG concentration and CS isomer content during menstrual cycle in the anovulatory cycles. A significant correlation between CRP and gonadotrophins was found. There is no significant difference in CRP across the menstrual cycle among ovulatory cycles, but there is a trend toward higher CRP at the periovulatory than the other phases, consistent with the significant difference in CRP between ovulatory and anovulatory cycles at the periovulatory phase. Both the trend and the significant result suggest an elevation in CRP with ovulation. These observations provide additional evidences to the hypothesis that the ovulation is an inflammatory-like phenomenon.

Topics: Adult; Anovulation; C-Reactive Protein; Estradiol; Female; Follicle Stimulating Hormone; Glycosaminoglycans; Humans; Leptin; Luteinizing Hormone; Menstrual Cycle; Ovulation; Progesterone; Young Adult

Central fat distribution is increased in anovulatory women with polycystic ovary syndrome (PCOS) compared with ovulatory PCOS and matched controls. Among secreted adipocytokines, this is reflected mainly in lower levels of adiponectin.

Topics: Adipokines; Adiponectin; Adult; Anovulation; Body Fat Distribution; C-Reactive Protein; Case-Control Studies; Female; Humans; Insulin Resistance; Leptin; Lipids; Nicotinamide Phosphoribosyltransferase; Ovulation; Phenotype; Polycystic Ovary Syndrome; Retinol-Binding Proteins, Plasma; Waist Circumference

The aim of the study was to evaluate the seasonal variation in serum leptin levels in a natural population of the female bat, Scotophilus heathi and their relationship to the changes in the body mass, serum insulin level, and ovarian activity. Circulating leptin level varied significantly over the season and correlated positively with the changes in body mass, and circulating insulin and androstenedione (A4) levels. Circulating leptin concentrations showed two peaks; one coincides with the maximum fat accumulation prior to winter dormancy, whereas the second shorter peak coincides with late pregnancy. The in vivo study in S. heathi showed that the increased circulating leptin level during winter dormancy coincides with the decreased expression of ovarian steroidogenic acute regulatory (StAR) protein, and low circulating estradiol (E2) level. At the same time, increased circulating leptin level coincides with increased expression of ovarian insulin receptor and high circulating A4 level. The low circulating leptin level during preovulatory period coincides with the increase in StAR protein but decrease in insulin receptor protein. The in vitro study confirmed the in vivo observations of inhibitory effect of leptin on LH induced StAR expression and E2 production, whereas the stimulatory effect of leptin (high dose) on LH induced expression of insulin receptor protein and A4 production. However, pharmacological dose of leptin produced inhibitory effect on the expression of insulin receptor protein. The results of the present study thus suggest that high circulating leptin level during winter dormancy promotes adiposity and impairs ovarian activity by suppressing StAR-mediated E2 production as well as by enhancing insulin receptor-mediated A4 synthesis thereby contributing anovulatory condition of delayed ovulation in S. heathi.

Topics: Adiposity; Androstenedione; Animals; Anovulation; Cells, Cultured; Chiroptera; Dose-Response Relationship, Drug; Estradiol; Female; Hibernation; Immunoblotting; Insulin; Leptin; Luteinizing Hormone; Ovary; Phosphoproteins; Pregnancy; Progesterone; Receptor, Insulin

A chronic negative energy balance due to low nutritional intake or increased energy expenditure alters several neuroendocrine axes. The reproductive and thyroid axes are inhibited while the adrenal axis is stimulated. In primates, anovulation resulting from a chronic negative energy balance is a condition often referred to as nutritional amenorrhea. The objective of the current study was to determine if hypoleptinemia induced by dietary restriction is responsible for these neuroendocrine changes, particularly anovulation. Five rhesus monkeys had their dietary intake gradually reduced to inhibit ovulation. Dietary restriction inhibited follicle-stimulating hormone (FSH) and triiodothyronine (T(3)) secretion and stimulated cortisol release. Recombinant human leptin (rhleptin) administered by continuous infusion into the lateral ventricle for 16 weeks inhibited cortisol secretion but failed to stimulate FSH, T(3) or ovulation. An immune response to rhleptin was noted after 3 weeks of leptin administration. Realimentation resulted in weight gain and reversed all endocrine responses to dietary restriction, including ovulation. These results do not support a role for reduced leptin secretion in anovulation induced by dietary restriction. The inability of rhleptin to reverse anovulation induced by a negative energy balance in monkeys is in contrast to its stimulatory effect on ovulation in women with functional hypothalamic amenorrhea. Different outcomes may be attributed to the degree of negative energy balance, the immune response generated by interspecies leptin administration, and/or other experimental variables such as dose or route of administration. Attributing opposing outcomes to species differences is unwarranted until these variables can be further examined.

Topics: Adaptation, Physiological; Amenorrhea; Analysis of Variance; Animals; Anovulation; Caloric Restriction; Disease Models, Animal; Energy Metabolism; Female; Follicle Stimulating Hormone; Humans; Hydrocortisone; Injections, Intraventricular; Leptin; Macaca mulatta; Nutritional Status; Ovulation; Recombinant Proteins; Triiodothyronine

To investigate the functional role of leptin in human ovulation, we measured serum leptin, LH, FSH and estradiol in 16 young adult women suffering from ovulatory dysfunction with BMI ranging from 17.5 to 24.5 (group A). The control subjects included 12 women with regular ovulation and matched age and BMI (group B). We found that serum leptin concentration in group A subjects was significantly lower than that in group B subjects (4.1+/-0.5 vs. 6.1+/-0.4 ng/ml, p<0.01). The percent body fat, estradiol, LH and FSH concentrations in groups A and B were not significantly different. These results indicate that anovulatory young adult women have lower leptin concentration than women with regular ovulation, thus suggesting a key role for leptin in regular ovulation or ovulatory dysfunction.

Topics: Adult; Anovulation; Female; Humans; Leptin

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.

Topics: Animals; Anovulation; Diestrus; Drug Implants; Eating; Energy Metabolism; Female; Hyperphagia; Injections, Intraventricular; Injections, Subcutaneous; Lactation; Leptin; Rats; Rats, Wistar; Vagina; Weight Gain