Gender differences in leptin levels and physiology: a role for leptin in human reproduction

Leptin, an adipocyte-derived hormone known to play an important role in body-weight regulation, has been shown to be expressed differentially in men and women. These observations are potentially important for the understanding of differences between men and women in regulation of food intake, weight gain, and body fat distribution. Leptin is also involved in female fertility, especially in pubertal development. It may well be the triggering signal for the onset of puberty in girls. Although the exact mechanisms and interactions with sex steroids are not yet fully established, it is clear that leptin plays a role as an endocrine mediator in sexual development and reproduction.     

The significance of leptin for reproduction

Leptin is mainly synthesized by adipocytes and might represent the connecting link between fatty tissue and brain. In reference to reproduction, leptin resistance could play a role particularly in the pathogenesis of the PCO syndrome. However, there exists at present contradictory data on this, so that further clarification is necessary. Leptin interacts with the steroid synthesis to a degree not yet precisely clarified and possesses receptors in numerous tissues, which suggests extensive local and endocrine effects. Its exact significance for the initiation of puberty still remains unknown. The same is true for first data regarding leptin and endometriosis and the interpretation of hyperleptinemia during pregnancy. It is clear that this protein mediates between fatty tissue and the reproductive function. However, the detailed physiologic and pathophysiologic role of leptin in reproduction can only be clarified through further extensive studies. To date there is not yet a practical importance for the measurement of leptin in routine work in reproductive medicine.     

The role of leptin in human reproduction

The article reviews the current literature about leptin, a hormone produced mainly in the adipose tissue, in terms of its role in reproduction. The structure of leptin, its biological activity as well as its influence on secretion of their hormones has been discussed. The leptin concentrations during the ovulatory cycle, pregnancy puerperium and assisted reproduction have been presented. It has been suggested that leptin may have an advantageous effect not only on oocyte and zygote development in the early stages, but also on the process of implantation and therefore its evaluation may be useful for the clinical determination of embryo quality in IVF-ET program.     

The role of the leptin in reproduction

PURPOSE OF REVIEW: Since its discovery in 1994, leptin has appeared to be a pleiotrophic hormone, governing energy homeostasis and affecting many tissues in the body. Numerous pieces of evidence have accumulated showing that leptin potentially plays an important role in the control of the reproductive function. RECENT FINDINGS: This review presents the major concepts for the role of leptin in the modulation of reproductive function. As a marker of the nutritional status, leptin affects the hypothalamo-pituitary-gonadal axis, regulating gonadotrophin-releasing hormone and luteinising hormone secretion, and appears to be a permissive factor in the onset of the puberty. This protein and its receptor have been found in the reproductive tissues, indicating that this system could be also implicated in several processes such as embryo development, implantation and pregnancy. Moreover, disorders of the leptin system have been related to some reproductive pathologies such as pre-eclampsia and polycystic ovary syndrome. However, controversy surrounds several aspects of the action of leptin in reproduction that require a deeper investigation of this system. SUMMARY: Results to date suggest that this system could be implicated in important reproductive processes such as embryonic development and implantation. Moreover, understanding the role of leptin might be useful for new treatments in reproductive pathologies.     

Paracrine/autocrine control of female reproduction

Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition.

During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical ‘gonadal’ products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal–fetal adaptation to gestational diseases.

There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.     

Hormonal regulation of neonatal weight: placental leptin and leptin receptors

Objective To examine whether umbilical and maternal leptin levels correlate with birthweight, placental weight, and maternal weight; and to detect membrane-bound leptin receptors in placental tissue as well as soluble leptin receptors in umbilical and maternal blood.
Design Prospective observational study.
Setting University teaching hospital.
Methods Serum levels of leptin and soluble leptin receptors were analysed in 31 randomly selected mother/newborn pairs at delivery. In addition, placental tissue was assayed for leptin receptors using immunocytochemistry and Western blot.
Results The mean [SD] leptin level in umbilical cord venous blood (7.1 ng/mL [4.0]) was significantly lower (   P < 0.001  ) than in maternal blood (22.5 ng/mL [10.8]). Umbilical cord leptin concentrations correlated significantly with birthweight (   P < 0.001  ), placental weight (   P < 0.005  ) but not with maternal leptin. Maternal leptin concentrations correlated only with maternal weight (   P < 0.001  ). In chorionic villous tissue, trophoblasts stained strongly positive for leptin receptor-like immunoreactivity. Two membrane-bound isoforms of the leptin receptor were also detected in placental tissue. In both umbilical and maternal serum, a soluble leptin receptor was found migrating as broad band at M_r 97,000 D.
Conclusion The present data strongly reinforce the idea that circulating leptin levels may provide a growth-promoting signal for fetal development during late pregnancy. While membrane-bound leptin receptors may be involved in autocrine regulation of placental leptin production, the soluble receptor form may serve as a transport vehicle for leptin to fetal tissues.     

Paracrine/autocrine control of female reproduction.

Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition. During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical 'gonadal' products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal-fetal adaptation to gestational diseases. There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.     

Leptin and reproduction: a review

OBJECTIVE: To review recent advances in understanding the role of leptin in the physiology and pathophysiology of reproduction, with a focus on relevant clinical situations. DESIGN: A MEDLINE computer search was performed to identify relevant articles. RESULT(S): Leptin, an adipocyte hormone important in regulating energy homeostasis, interacts with the reproductive axis at multiple sites, with stimulatory effects at the hypothalamus and pituitary and inhibitory actions at the gonads. More recently, leptin has been shown to play a role in other target reproductive organs, such as the endometrium, placenta, and mammary gland, with corresponding influences on important physiologic processes such as menstruation, pregnancy, and lactation. As a marker of whether nutritional stores are adequate, leptin may act in concert with gonadotropins and the growth hormone axis to initiate the complex process of puberty. Conditions in which nutritional status is suboptimal, such as eating disorders, exercise-induced amenorrhea, and functional hypothalamic amenorrhea, are associated with low serum leptin levels; and conditions with excess energy stores or metabolic disturbances, such as obesity and polycystic ovarian syndrome, often have elevated serum or follicular fluid leptin levels, raising the possibility that relative leptin deficiency or resistance may be at least partly responsible for the reproductive abnormalities that occur with these conditions. CONCLUSION(S): Leptin may act as the critical link between adipose tissue and the reproductive system, indicating whether adequate energy reserves are present for normal reproductive function. Future interventional studies involving leptin administration are expected to further clarify this role of leptin and may provide new therapeutic options for the reproductive dysfunction associated with states of relative leptin deficiency or resistance.     

Neuroendocrine control of reproduction and its therapeutic manipulation with GnRH and its analogs

The hypothalamus mediates the neuroendocrine control of reproduction in both males and females through pulsatile secretion of GnRH. The anterior pituitary gland, in turn, appears to require this episodic GnRH stimulation in order to secrete the gonadotropins LH and FSH in a physiologic fashion. Deficiency of GnRH manifests as a failure to attain puberty in both sexes, and in females it may also produce amenorrhea and/or anovulation. Replacement regimens of GnRH which employ an episodic pattern of delivery correct the deficiency of endogenous GnRH secretion and stimulate gonadotropin secretion, gonadal steroidogenesis and gametogenesis. However, continuous occupancy of the GnRH receptor by native GnRH and/or its long-acting analogs paradoxically inhibits pituitary gonadotropin secretion. GnRH analogs have been synthesized which exhibit greater affinity and prolonged occupancy on the GnRH receptor and can produce pituitary desensitization of gonadotropin secretion. Chronic administration of these GnRH analogs is capable of producting a selective "medical castration." Thus, by altering the frequency of episodic GnRH administration or by utilizing long-acting GnRH analogs it is possible to stimulate or suppress the neuroendocrine control of reproduction. The use of GnRH or its long-acting analogs has demonstrated a profound clinical impact in restoring or inhibiting fertility.     

Obesity and reproduction: impact and interventions

PURPOSE OF REVIEW: To examine the impact of obesity and potential intervention upon human reproduction in the domain of fertility, fertility treatment, pregnancy and its complications. RECENT FINDINGS: The prevalence of obesity in women of reproductive age continues to increase, with recent recognition that visceral obesity is associated with greater metabolic disturbances and reduced fecundity, even in ovulating women. Although the efficacy of infertility treatment is reduced by obesity, this effect is not profound and indeed the argument for weight reduction in young women is better serviced by the obesity-dependent increases in perinatal and maternal risks during pregnancy and potential modification of long-term health. Although lifestyle modification alone can induce significant metabolic improvement, resumption of ovulation and reduction of perinatal risks, greater weight loss, and therefore greater potential benefit, can be achieved in combination with pharmacological agents or bariatric surgery. SUMMARY: Obesity in women has a broad, negative impact upon human reproduction. Specific risks through pregnancy are real and may be addressed by lifestyle modification leading to weight loss and improved insulin sensitivity. Obese women undergoing fertility treatment should be advised of the increased and absolute increased risks they are undertaking, and fertility centres should adopt appropriate strategies.     

Review and update: marijuana and reproduction

Longterm use of marijuana has been found to cause physiological changes that can alter individual reproductive potential. The effects of marijuana depend on the dose and can include death from depression of the respiratory system. Longterm effects are however particularly hard to assess. Marijuana is absorbed rapidly and eliminated very slowly. The active principle, delta-9-tetrahidrocannabinol (delta-9-THC), is highly liposoluble and fixes to the serum proteins, passing to the lungs and liver for metabolization and to the kidneys and liver for excretion. As with estrogens, there is an enterohepatic circuit for reabsorption and elimination. 90% is eliminated in the feces, 65% within 48 hours. Because of the enterohepatic circuit and liposolubility, elimination requires 1 week for completion. The other important biotransformation of the active principle is hydroxilation; the hydroxilated derivatives are responsible for the psychoactivity of cannabis. Cannabis affects both neuroendocrine function and the germ cells. Studies on experimental animals have indicated that THC can cause a decline in the pituitary hormones follicle stimulating hormone, luteinizing hormone, and prolactin, and in the steroids progesterone, estrogen, and androgens. Human studies have shown that chronic users have decreased levels of serum testosterone. Because steroidogenesis can be restimulated with human chorionic gonadotropin, it appears that THC does not directly affect steroid production by the corpus luteum, but that its action is mediated by the hypothalamus. Because of its potent antigonadotropic action, THC is under study as an anovulatory agent. The same animal studies have shown that ovulation returns to normal 6 months after termination of use. High rates of anovulation and luteal insufficiency have been observed in women smoking marijuana at least 3 times weekly. THC accumulates in the milk. Animal studies have shown that THC depresses the enzymes necessary for lactation and causes a diminution in the volume of the mammary glands. In recent studies, significant amounts of the drug have been detected in both mothers' milk and the blood of newborns. Animal studies indicate that THC crosses the placenta, achieving concentrations in the fetus as high as those in the mother. Animal studies also demonstrated increasing frequency of abortions, intrauterine death, and declines in fetal weight. The effects were probably due to an alteration in placental function. A human study likewise showed that marijuana use during pregnancy was significantly related to poor fetal development, low birth weight, diminished size, and decreased cephalic circumference. Congenital malformations have been observed in experimental animals exposed to THC. Declines in sperm volume and count and abnormal sperm motility have been observed in chronic marijuana users. In vitro studies show that THC produces a marked degeneration of human sperm.     

Thyroid dysfunction: reproduction and postpartum thyroiditis

Thyroid function during pregnancy is characterized by changes in circulating thyroid hormone concentrations related to alterations in thyroxine binding globulin (TBG), human chorionic gonadotropin (hCG), and iodine status. The immunology of normal pregnancy shows a reduction in antibody titer during gestation and an increase in T helper-2 (TH2) immune responses. Thyroid dysfunction may cause menstrual disturbances in hyper- and hypothyroidism but less marked disturbances of sexual function in men. Fertility is reduced in hypo- and hyperthyroid females. Accumulating evidence suggests a strong association between the presence of thyroid antibodies and fetal loss, although the data relating to recurrent abortion are not so convincing. Asymptomatic maternal gestational hypothyroidism may occur in up to 2.5% of women; studies have shown a significant impact of this condition in causing a decrease of child IQ, suggesting that screening for maternal hypothyroidism with intervention may be justified. Postpartum thyroid disease occurs in 5 to 9% of women and thyroid dysfunction postpartum is seen in 50% of thyroid peroxidase antibody positive (TPO Ab+ve) women. There is a significant rate of hypothyroidism in long-term follow-up of women who have transient postpartum thyroid dysfunction.     

Obesity and reproduction: a literature review

Obesity is a growing public health problem because of the morbimortality factors linked to it. In obstetrics and gynecology, consequences on fertility and contraception are notable: infertility, low assisted reproductive technologies (ART) results, miscarriages, congenital abnormalities, obstetrical and neonatal complications, low hormonal contraception efficacy. These effects are partially corrected by weight loss which can be achieved by behavioural, medical or surgical treatment. Gynaecologists should always participate in a multidisciplinary management of obesity before hormonal contraception or ART.     

Uterine contractility and reproduction: new perspectives

The contractile activity of the nonpregnant uterus plays an important role in the human reproduction process. Noticeable variation in uterine contractility occurs during the menstrual cycle to meeting some physiologic requirements of the female reproductive system. During the follicular phase, stimulation of uterine contractions by estrogens fosters sperm transport toward the fertilization site. After ovulation, contractility decreases in response to progesterone, a phenomenon that is probably involved in the embryo implantation mechanism. The comprehension of uterine contractility regulation and physiologic roles has been considerably extended during recent years by the development of direct and noninvasive assessment tools, in particular, ultrasound. Today, not only the artificial stimulation of uterine contractions, aiming at promoting sperm transport during the pre-ovulatory phase, but also their attenuation to provide optimum conditions for embryo implantation during the luteal phase, represent innovating, promising issues in the optimization of assisted reproduction treatments.     

Cerebrospinal fluid leptin levels in preeclampsia: relation to maternal serum leptin levels

BACKGROUND: To determine whether cerebrospinal fluid (CSF) and circulating levels of leptin differ between women with preeclampsia and women who had an uncomplicated pregnancy. METHODS: Maternal serum and CSF leptin concentrations obtained in the third trimester of the gestation were compared in 16 women with mild preeclampsia and 23 normotensive pregnant women who underwent cesarean section. Before administering local anesthetic for spinal anesthesia, 2 mL CSF and 4 mL venous blood sample were taken and were stored at -30 degrees C until serum and CSF leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Mean CSF leptin concentrations were not significantly different between the two groups (preeclampsia 9.7 +/- 4.2 ng/mL, normotensive 13.6 +/- 4.3 ng/mL, p = 0.952). Similarly, mean serum leptin concentrations were similar between the two groups (mild preeclampsia 21.7 +/- 7.1 ng/mL, normotensive 18.3 +/- 6.7 ng/mL, p = 0.698). CSF leptin levels are inversely related to the serum leptin concentrations in preeclamptic patients (r = -0.87, p = 0.000). An inverse relationship was also detected between CSF and serum leptin levels in normotensive pregnant subjects (r = -0.66, p = 0.000). CONCLUSIONS: CSF and serum leptin levels were similar in patients with preeclampsia and normotensive pregnant women. However, the CSF leptin was negatively correlated with the serum leptin concentrations in preeclamptic and normotensive control subjects, suggesting that leptin enters the brain by a saturable transport system. Further work is needed to confirm our findings.