Role Of Leptin In Reproduction Research Articles

Role of Leptin in Reproduction

Role of Leptin in Reproduction

Role of the adipocyte-derived hormone leptin in reproductive control.

Achievement of sexual maturation and maintenance of fertility in adulthood are functions that are sensitive to the metabolic status of the organism, particularly the magnitude of fat reserves. In this sense, the adipocyte-derived hormone, leptin, plays a major role in linking metabolic cues and the control of multiple neuroendocrine axes. The hypothalamus is a key site mediating leptin actions, including those involved in the modulation of the hypothalamus-pituitary-gonads (HPG) axis at different stages of development and in different environmental conditions. In the present review, we provide an update of the role of leptin in reproduction and discuss its interactions with neurons, neurotransmitters and downstream targets of the reproductive axis, with a special emphasis on the actions of leptin in the central nervous system. We hope this review will contribute to the understanding of the mechanisms whereby metabolic signals, especially leptin, influence the reproductive neuroendocrine axis modulating its activity in different nutritional states. Special attention will be given to recent advances in the identification of key hypothalamic sites and signaling pathways relevant to leptin's action in reproductive control.

Obesity and Male Reproductive Potential

Obesity and Male Reproductive Potential

Role of leptin in reproduction.

This article focuses on recently gained knowledge concerning the different emerging aspects of the role of leptin in reproduction, through both its central hypothalamus-mediated and peripheral actions. As delineated in murine models, STAT3-independent signals triggered by the leptin receptor are clearly important in fertility, and candidate pathways such as those via phosphatidylinositol-3 kinase and extracellular signal-related kinase are implicated in leptin-regulated cascades. Another aspect whose importance has recently been revealed is that of the bioavailability of leptin in general, and the fate and action of carrier-bound versus free leptin at central and peripheral sites in particular. Besides the well-established role of leptin in the control of appetite and energy expenditure in humans and animals, evidence for a major involvement of the hormone in the function of the reproductive system is rapidly accumulating through physiological and molecular genetic approaches. Powerful animal models that facilitate the dissection of increasingly complex pathways, together with detailed studies in man, will soon delineate in detail the diverse roles of leptin in biological regulation. The development of therapeutic agents primarily directed against obesity must therefore take into consideration the consequences of treatment not only on the amelioration of leptin resistance, but also on the bioactivity of leptin in the context of growth, glucose homeostasis, and last but not least, fertility.

Leptin exists in tubuli seminiferi and in seminal plasma.

Leptin is a 167-amino acid protein that stimulates gonadotrophin-releasing hormone secretion and exerts indirect effects on the gonads via neuropeptide Y, NPY. Recent research has suggested that leptin may also have an effect on testosterone secretion. To investigate the role of leptin in reproduction, leptin in testicular tissue and seminal plasma was examined in relation to leptin in serum, semen sample qualities and vasectomy. Seminal plasma and serum of 64 infertility patients, and 15 individuals after vasectomy, were assayed for leptin using a competitive 'in house' radioimmunoassay. The concentration of leptin in seminal plasma was significantly lower in the 'normal' semen sample group than in the 'pathological' group (Mean +/- SEM; 1.45 +/- 0.18 vs. 3.19 +/- 0.57 ng ml-1; P < 0.05), and showed a significantly negative correlation with percentage of motile spermatozoa (r = -0.46; P = 0.0005) and with the velocity straight line, VSL, (r = -0.30; P = 0.029). In contrast, leptin concentration in serum did not show any relationship with the spermiogram parameters. In testicular tissue, leptin was preferentially found within the tubuli seminiferi using anti-leptin polyclonal antibody, Ob A-20 Sc 842. The amount of leptin per ejaculate did not significantly change after vasectomy, and was not correlated to fructose, zinc or neutral alpha glucosidase in seminal plasma (P > 0.05). These results suggest that the amount of leptin in the genital tract, including the tubuli seminiferi, may influence the mechanisms involved in the motility development of spermatozoa.

The role of leptin in reproduction: experimental and clinical aspects

The discovery of the adipocyte-produced hormone leptin has greatly changed the field of obesity research and future treatment as well as our understanding of energy homeostasis in man. In addition to its relevant role as a metabolic adaptor to overweight and fasting states, new and previously unsuspected neuroendocrinological roles have emerged for leptin. In reproduction, leptin is implicated in fertility regulation and appears as a permissive factor for puberty. In particular, various sets of data suggest that leptin may serve as a signal to the central nervous system (CNS) with information on the critical amount of adipose tissue stores that is necessary for gonadotropin-releasing hormone (GnRH) secretion and pubertal activation of the hypothalamic-pituitary-gonadal axis. Leptin also acts at the periphery, directly on the ovary and testis where it may control steroidogenesis, although the exact role of intragonadal action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated. Furthermore, relevant gender-based differences in leptin levels exist, with higher levels in women, even at birth, and which persist throughout life. In adult life, there is experimental evidence that leptin is a permissive factor for the menstrual cycle, with a regulatory role exerted at hypothalamic, pituitary and gonadal levels, and with severe changes in pregnancy and postpartum. Moreover, leptin is present in both human and commercial milk, and may play a role in the adaptive responses of the newborn.

Leptin and reproduction.

Since the cloning of leptin by Friedman's laboratory in 1994, over 3000 papers have been published on leptin, making it one of the most active research areas in all of science. Leptin appears to be a pleiotrophic hormone affecting many different tissues in the body. This review focuses on the role of leptin in reproduction. Evidence is accumulating that leptin potentially has roles in the regulation of GnRH and LH secretion, puberty, pregnancy, and lactation. Reciprocal regulation of leptin and its receptors by gonadal hormones and the implications and controversies thereof are also discussed in the review. Signaling pathways utilized by leptin are starting to become more clear, particularly JAK/STAT, MAPK, and SOCS3 have been implicated as mediators/modulators of leptin effects at the cellular level. At the hypothalamic level, there is also evidence that CART (cocaine and amphetamine-related transcript) is involved as a downstream mediator of leptin effects, especially with regards to control of GnRH secretion. While leptin clearly has many effects upon the reproductive axis, defining its precise roles is not without controversies. This review presents both pro and con findings, thereby demarking controversial areas that undoubtedly will be fertile ground for future investigation.

Peritoneal fluid leptin concentration in infertile patients

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.

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.

Role of leptin in reproduction.

Leptin is a 16-kDa adipocyte-secreted protein the serum levels of which reflect mainly the amount of energy stores but are also influenced by short-term energy imbalance as well as several cytokines and hormones. Leptin, by binding to specific receptors, alters the expression of several hypothalamic neuropeptides that regulate neuroendocrine function as well as energy intake and expenditure. More specifically, accumulating evidence suggests that this hormone may serve to signal to the brain information on the critical amount of fat stores that are necessary for LHRH secretion and activation of the hypothalamic-pituitary-gonadal axis. Rising leptin levels have been associated with initiation of puberty in animals and humans and normal leptin levels are needed for maintenance of menstrual cycles and normal reproductive function. Moreover, circadian and ultradian variations of leptin levels are associated with minute to minute variations of LH and estradiol in normal women. Falling leptin levels in response to starvation result in decreased estradiol levels and amenorrhea in subjects with anorexia nervosa or strenuously exercising athletes. In addition, leptin has a potentially important role during pregnancy and in the physiology of the neonate. Finally, recent evidence suggests that leptin may influence ovarian steroidogenesis directly, but the exact role of intraovarian leptin action in the physiology and pathophysiology of the human reproductive system needs to be further elucidated.