Leptin influences satiety, adiposity, and metabolism and is associated with mechanisms regulating puberty onset, fertility, and pregnancy in various species. Maternal hyperleptinemia is a hallmark of mammalian pregnancy, although both the roles of leptin and the mechanisms regulating its synthesis appear to be taxa specific. In pregnant humans and nonhuman primates, leptin is produced by both maternal and fetal adipose tissues, as well as by the placental trophoblast. Specific receptors in the uterine endometrium, trophoblast, and fetus facilitate direct effects of the polypeptide on implantation, placental endocrine function, and conceptus development. A soluble isoform of the receptor may be responsible for inducing maternal leptin resistance during pregnancy and/or may facilitate the transplacental passage of leptin for the purpose of directly regulating fetal development. The steroid hormones are linked to the regulation of leptin and the leptin receptor and probably interact with other pregnancy-specific, serum-borne factors to regulate leptin dynamics during pregnancy. In addition to its effects on normal conceptus development, leptin is linked to mechanisms affecting a diverse array of pregnancy-specific pathologies that include preeclampsia, gestational diabetes, and intrauterine growth restriction. Association with these anomalies and with mechanisms pointing to a fetal origin for a range of conditions affecting the individual's health in adult life, such as obesity, diabetes mellitus, and cardiovascular disease, reiterate the need for continued research dedicated to elucidating leptin's roles and regulation throughout gestation.

https://bioone.org/journals/Biology-of-Reproduction/volume-74/issue-2/biolreprod.105.045120/Leptin-in-Pregnancy-An-Update1/10.1095/biolreprod.105.045120.pdf

Leptin in Pregnancy: An Update

The secretion of gonadotrophins from the pituitary in women is under ovarian control via negative and positive feedback mechanisms. Steroidal and non-steroidal substances mediate the ovarian effects on the hypothalamic-pituitary system. During the follicular phase of the cycle, estradiol (E(2)) plays a key role, while circulating progesterone (at low concentrations) and inhibin B contribute to the control of LH and FSH secretion respectively. During the luteal phase, both E(2) and progesterone regulate secretion of the two gonadotrophins, while inhibin A plays a role in FSH secretion. The intercycle rise of FSH is related to changes in the levels of the steroidal and non-steroidal substances during the luteal-follicular transition. In terms of the positive feedback mechanism, E(2) is the main component sensitizing the pituitary to GnRH. Activity of a non-steroidal ovarian substance, named gonadotrophin surge-attenuating factor (GnSAF), has been detected after ovarian stimulation. It is hypothesized that GnSAF, by antagonizing the sensitizing effect of E(2) on the pituitary, regulates the amplitude of the endogenous LH surge at midcycle. Disturbances in the feedback mechanisms can occur in various abnormal conditions or after treatment with pharmaceutical compounds that interfere with the production or the action of endogenous hormones.

Ovarian feedback, mechanism of action and possible clinical implications

Leptin is a 16-kDa cytokine secreted in humans primarily but not exclusively by adipose tissues. Its concentration in blood is usually proportional to body fat mass, but is higher in women than in men not only because of a different distribution of and greater fat mass in women, but also because testosterone reduces its level in men. Leptin features in different ways during the life span. It is synthesized in the ovary, transported in the oocyte, and made by both fetus and placenta, particularly during the last month of gestation. It is made by the lactating mammary gland and ingested by the newborn infant in its milk. The prime importance of leptin is realized at puberty when it is necessary for progression to a normal adult reproductive status in females. Fasting and chronic undernutrition result in a lower level of leptin in the blood. Lack of leptin results in hunger, ensuring that the individual eat to survive, and also inhibition of reproduction, until such time as food and fat stores are adequate to supply energy for pregnancy and lactation. Thus, leptin is important for survival of the individual and survival of the species. Although an extremely rare genetic absence of leptin induces hyperphagia and obesity in humans, as it does in mice, there appears to be little role for leptin in humans in ensuring that fat stores are not in excess of adequate, that is, in preventing obesity. The mouse differs from humans in many respects, in particular in the far more drastic ways it conserves energy when it very rapidly adapts to lack of food. These include not only suppression of reproduction but also lowering of its body temperature (torpor), suppressing its thyroid function, suppressing its growth, and increasing secretion of stress hormones (from the adrenal). This review concentrates on roles of leptin in human physiology and pathophysiology but also discusses why some observations on actions of leptin in mice are not applicable to humans.

Physiological roles of the leptin endocrine system: differences between mice and humans.

Pelvic endometriosis is an immune-related chronic inflammatory disease, characterized by ectopic implants of endometrium in the peritoneal cavity and associated with increased secretion of proinflammatory cytokines and neoangiogenesis. Leptin, the adipocyte-derived hormone, has been shown to have a role in food intake, basal metabolism, and reproductive function. Leptin levels are dynamically regulated, being elevated by inflammatory mediators and reduced by starvation. Leptin itself can influence the proinflammatory immune responses of CD4+ T lymphocytes, and reports have also shown this hormone to be an angiogenic factor in vitro and in vivo. We investigated whether leptin concentrations in serum and peritoneal fluid (PF) differed between 13 patients with different stages of endometriosis and 15 age- and body mass index-matched controls. We found a statistically significant (P < 0.05) increase in leptin levels in serum (30.3 +/- 14.8 ng/mL) and PF (35.9 +/- 17.4 ng/mL) of patients with endometriosis, compared with our control population (serum, 15.6 +/- 8.4; PF, 17.5 +/- 7.2 ng/mL). Regression equations, relating leptin to body mass index, were also significantly different in endometriosis patients, compared with controls. Higher levels of leptin were observed in the earlier stages of endometriosis than advanced-stage disease. These data suggest that the proinflammatory and neoangiogenic actions of leptin may contribute to the pathogenesis of endometriosis.

/pdf/increased-leptin-levels-in-serum-and-peritoneal-fluid-of-1nccel32rz.pdf

Increased leptin levels in serum and peritoneal fluid of patients with pelvic endometriosis.

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 is directly involved in ovarian dysfunction.

https://repub.eur.nl/pub/54872/10690875.pdf

Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

To study the relationships between gonadal steroids and leptin, 20 women with normal cycles were investigated during the postoperative period following a laparotomy. Fourteen women underwent bilateral ovariectomy plus total hysterectomy either in the mid- to late follicular phase (n = 7, group 1) or in the early to midluteal phase (n = 7, group 2). The remaining six of the 20 women underwent cholocystectomy in the early to midfollicular phase of the cycle and were used as controls (group 3). In all three groups, serum leptin values decreased rapidly up to post-operative day 4. Then, leptin values increased significantly only in group 3 (P < 0.05). Leptin values before and after the operation showed significant positive correlations with body mass index (BMI), oestradiol and progesterone. However, with multiple regression analysis, BMI was the only parameter significantly correlated with leptin in group 3 (days 0 and 4-7), whereas in groups 1 and 2 progesterone and BMI showed independent significant correlations with leptin (days 0 and 8, r = 0.601 and r = 0.602 respectively). These results demonstrate for the first time a significant reduction in leptin concentrations in normal women following bilateral ovariectomy. Although BMI seems to be the predominant factor, it is also suggested that oestradiol and progesterone may participate in the control of leptin production during the human menstrual cycle.

Leptin concentrations in normal women following bilateral ovariectomy

(P < 0.01) and were significantly higher than in the other two groups (P < 0.05). Body mass index (BMI) was the Patients most important variable accounting for the changes in The study included 21 normally ovulating women who volunteered leptin values post-operatively, but in the oestradiol plus for the study and gave written informed consent. Approval for the progesterone group progesterone correlated significantly study was obtained from the local ethical committee. Clinical and with leptin independently of BMI. These results suggest endocrine characteristics of the women are shown in Table I. There were no significant differences in the age, body mass index (BMI), that progesterone and cortisol can stimulate leptin secretion FSH, luteinizing hormone (LH), leptin and cortisol values between in women regardless of oestradiol concentrations.

/pdf/treatment-of-normal-women-with-oestradiol-plus-progesterone-2h5pkzylno.pdf

Treatment of normal women with oestradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy

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Leptin concentrations in normal women following bilateral ovariectomy

Treatment of normal women with oestradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy