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The role of the leptin in reproduction
Article in Current Opinion in Obstetrics and Gynecology · July 2006
Impact Factor: 2.07 · DOI: 10.1097/01.gco.0000193004.35287.89 · Source: PubMed





6 authors, including:
Ana Cervero

Francisco Domínguez


University of Valencia





Antonio Pellicer

Carlos Simón

Instituto Valenciano de Infertilidad IVI

Instituto Valenciano de Infertilidad IVI





Available from: Francisco Domínguez
Retrieved on: 14 April 2016

Guadassuar 1 bajo 46015. understanding the role of leptin might be useful for new treatments in reproductive pathologies. However. C. Nonetheless. It has recently been described [6••] how a transgene containing the long form of the leptin receptor under a neurone-specific promoter partially corrects the obese phenotype. Summary Results to date suggest that this system could be implicated in reproductive processes such as embryonic development and implantation. Keywords embryo. endometrium. University of Valencia. and functions in implantation and pregnancy as well as in some reproductive disorders. # 2006 Lippincott Williams & Wilkins. Spain Tel: +34 963455560. causing altered function with altered body weight [5]. and has been implicated in the regulation of reproductive function. Jose´ A. regulating gonadotrophin-releasing hormone and luteinising hormone secretion. leptin receptor Curr Opin Obstet Gynecol 18:000–000. Leptin concentrations in the plasma have been shown to be directly related to the amount of body fat. these results do not rule out the possibility that leptin exerts peripheral actions. and appears to be a permissive factor in the onset of the puberty.GCO 200063 (CMW) The role of the leptin in reproduction Ana Cervero. suggesting a link between adipose tissue and the reproductive system. The exogenous administration of leptin restored the fertility in these ob/ob animals. implantation. Moreover. 18:000–000 Abbreviation LIF leukaemia inhibitory factor # 2006 Lippincott Williams & Wilkins 1040-872X Introduction Leptin. Horcajadas. acting at endocrine and paracrine levels [4•]. Leptin has been found to be expressed by different tissues. This protein and its receptor have been found in the reproductive tissues. Fundacio´n IVI. indicating that this system could be also implicated in several processes such as embryo development. Numerous pieces of evidence have accumulated showing that leptin potentially plays an important role in the control of the reproductive function. controversy surrounds several aspects of the action of leptin in reproduction that require a deeper investigation of this system. Fundacion IVI. Instituto Universitario IVI. fertility and ability to lactate of the db/db mice. implantation and pregnancy. Valencia. The leptin receptor gene and protein have been shown to be expressed in immortalized gonadotrophin-releasing hormone neurones that secrete gonadotrophin- . Antonio Pellicer and Carlos Simo´n Purpose of review Since its discovery in 1994. Neuroendocrine effects of leptin The size of the body fat stores is known to influence fertility.2] related to the reproductive role of leptin was that ob/ob mice (which lack functional leptin) and db/db mice (which lack a functional leptin receptor) are obese and infertile. embryonic development and the endometrium. disorders of the leptin system have been related to some reproductive pathologies such as pre-eclampsia and polycystic ovary syndrome. This indicates that obesity is not the sole cause of infertility and that leptin is required for normal reproductive function. including reproductive tissues. Spain Correspondence to C Simo´n. The purpose of this review is to summarise recent developments in the biology of the leptin system. One of the first pieces of evidence [1. which are important aspects in the reproductive field. Alicia Quin˜onero. leptin has appeared to be a pleiotrophic hormone governing energy homeostasis and affecting many tissues in the body. leptin affects the hypothalamo-pituitary-gonadal axis. e-mail: csimon@ivi. Recent findings This review presents the major concepts for the role of leptin in the modulation of reproductive function. focusing on how leptin regulates the neuroendocrine-gonadal axis. Full restoration of all functions is produced when two leptin receptor transgenes with different promoters are employed at the same time [6••]. Moreover. the product of ob gene. was discovered as an adipocyte hormone and was initially linked to food consumption and energy balance [1].es Current Opinion in Obstetrics and Gynecology 2006. Francisco Domı´nguez. As a marker of the nutritional status. whereas dietary restriction alone was ineffective in correcting fertility [3]. glucose metabolism. fax: +34 963455512. It is therefore possible that leptin provides a peripheral signal indicating the adequacy of nutritional status to the reproductive system. leptin.

In mice. suggesting that this protein could exert a direct effect on the gonads. the negative influence of nutritional restriction on the hypothalamic-pituitary axis could be produced through a decrease in luteinizing hormone release. with higher doses of leptin inhibiting follicular development [22]. In support of this idea. and clinical observations [14] indicate that the menarche is reached earlier in obese than in normal-weight girls. the administration of human recombinant leptin increases levels of luteinizing hormone and oestradiol [9••]. leptin seems to be important in mediating deficits in reproductive function induced by undernutrition. In this sense. oestradiol and testosterone in cultured follicles. leptin stimulated the production of progesterone. Despite this. Nevertheless. the aforementioned studies do not rule out a direct effect on the gonads. However. Injection of exogenous leptin restores fertility to these mice [10]. leptin treatment during bovine oocyte maturation improved the ability of the oocyte to sustain embryonic development. and is probably also present in bovine oocytes [27•]. Similarly. characterized by hypothalamic amenorrhoea. With respect to its predominant role as a signal of starvation. are lower than those of normal-weight controls [11••]. serum leptin concentrations in women with anorexia nervosa. to a lesser extent. In this study. whereas supraphysiological concentrations of leptin produce the opposite effect. leptin has been shown to attenuate the insulin-like growth factor-1 augmentation of oestradiol synthesis in human granulosa cells through nitric oxide.16] have not found changes in leptin concentration with the onset of puberty. Subsequently. This apparent contradiction may be due to differences in the culture systems and doses used. hence leptin could be permissive for and not necessarily an initiator of puberty. Similarly. and decreased the number of apoptotic cells in the blastocysts [27•]. follicle-stimulating hormone release [8]. Leptin receptor mRNA has been found in murine [24]. Role of leptin in preimplantation embryo The first data implicating leptin in embryonic development described the presence of leptin receptors . and leptin receptors are present on several cell types in the human ovary [19]. It has been reported that leptin activation causes STAT3 (signal transducers and activators of transcription-3) phosphorylation in mouse oocytes [28] and also enhances nuclear maturation in porcine oocytes via activation of the mitogen-activated protein kinase pathway [26•]. human [25••] and porcine [26•] oocytes. Moreover. the absence of leptin mRNA in mature mouse and human oocytes led us to think that this leptin came from an exogenous source and could be transported into the oocyte by means of an unidentified mechanism. In man. some studies [15. decreasing oestradiol production. Effects of leptin on the ovary Leptin has been found in follicular fluid [18]. women with lipoatrophic diabetes have a normal reproductive function despite their low leptin levels. culturing follicles in the presence of recombinant leptin resulted in a significant decrease in follicle growth rate. In this study [22]. in women with hypothalamic amenorrhoea. leptin has been immunolocalized in a polarized manner in murine and human oocytes [23]. as well as in severely food-restricted rats [13]. Moreover. Moreover. leptin enhances gonadotropin liberation through a pituitary and/or hypothalamic site of action. it has been reported [22] that the presence of leptin at different concentrations has no effect on mouse germinal vesicle breakdown. It has been hypothesized that leptin could be an important signal in the onset of puberty. another study [21] has demonstrated that leptin increases oestrogen production in cultures of human granulosa cells. Leptin treatment produces an advance in puberty in normal mice [12] and allows puberty to start in mice lacking leptin. the lack of reproductive function coincides with the fall of plasma leptin level and several neuroendocrine changes. leptin seems to play a regulatory role in the oocyte. More interesting information about influence of leptin in the oocyte maturation has recently been published. which is in turn the result of a reduction in GnRH secretion [9••]. In starved mice. In recent work. however. A plausible hypothesis is that low-dose leptin stimulates steroidogenesis and follicular maturation. The rate of germinal vesicle breakdown in mouse oocytes cultured within preovulatory follicles has been reported to be increased by leptin [19]. which induces a dose-related increase in luteinizing hormone and. Moreover. Therefore. This result [20•] suggests that nitric oxide induced by leptin might inhibit aromatase activity. it is known that a critical body weight is necessary to start puberty. owing to the absence of adipose tissue [17]. the procurement of follicles is a crucial process that we have to take into account because there are critical interactions with surrounding cumulus cells that compromise developmental competence.2 Fertility releasing hormone under leptin stimulation [7].

blastocyst. other work [33•] has recently reported that leptin protein.29.29•] . with a significantly greater effect in trophectoderm cells [24. In this latter study [31]. as well as different methodologies. Leptin Leptin receptor Mouse BT [24] •• •• Mouse from OO to BT [24. in a dosedependent manner. from the two-cell stage to the blastocyst stage. It has.25.34••] to be present the in the human and murine endometrium. leukaemia inhibitory factor (LIF) alone had no effect on the hatching of blastocysts and on the rate of apoptosis. In addition. leptin mRNA was found in the endometrium as well as in cultured endometrial epithelial cells using nested-PCR. Leptin system in endometrium The leptin receptor and its long form have been shown [25. and further studies are necessary to validate these results. or the embryo in a paracrine manner. another [33•] did not find Table 1 Studies showing leptin and leptin receptor expression at the RNA and protein level in uterus and preimplantation embryos of different species Uterus mRNA Protein Preimplantation embryo Leptin Leptin receptor Mouse uterus and oviduct [24. However. Whereas one study found the highest expression in the early secretory phase.25••].32] Human BT [25 ] Porcine OO [26•] Mouse uterus and oviduct [24.33•] Human endometrium [25 . its expression throughout the menstrual cycle is controversial. suggesting that this molecule might be a marker of viability. the presence of leptin in murine endometrium remains controversial. Two different works [24. others [25••] have described that leptin receptor expression is lowest during the early secretory phase and higher during the late secretory phase (Fig.28] Human from OO to BT [25••] Porcine OO and from 4 cells to BT [26•.23. leptin has found [24.33•.1 and HuB219.29•].32] Pregnant pig oviduct [29•] Mouse uterus [30. such as the embryo culture medium. Furthermore. In a recent work [25••] on this topic. leptin increased the total number of cells in the blastocyst. Whereas one study [24] showed that leptin mRNA appeared in the oviduct and endometrium of the pregnant mouse. Murine and human preimplantation embryos express leptin mRNA exclusively at the blastocyst stage [24. oocyte. the rate-scoring of embryonic development and the concentration of exogenous leptin.29•] have shown that the addition of leptin to mouse or porcine embryos promotes development. human blastocysts were[32] discovered to secrete higher levels of leptin in the conditioned media than the arrested embryos. also been reported that leptin has no effect on the development of mouse embryos [22]. is found in mouse blastocysts.29•] Bovine at BT [27•] Mouse from OO to BT [19. to be present in the oviduct of the pregnant mouse. These differences in result might derive from the differ- ent species used. These experimental conditions are very important in assessing the role of leptin in preimplantation embryonic development. man [25••] and pig [29•]. This discrepancy can be attributed to the use of different strains of mice. 1). 28] Human from OO to BT [23] Porcine from OO to BT [26•. HuB219. There are discrepancies regarding the expression of leptin mRNA in the human uterus [4•]. 30] Human endometrium [25••.30]. as well as in the human and porcine uterus.Leptin in reproduction Cervero et al. the leptin receptor is available in the human and murine endometrium in order to be activated by its ligand at the moment of implantation. A reasonable explanation for such differences is that leptin expression is very low and only detectable by means of nested-PCR or overloading cDNA. suggesting a putative role for this system in this process. however. Controversial data exist describe the influence of leptin in preimplantation embryonic development. Different works showing the presence of leptin and the leptin receptor in preimplantation embryos are included in Table 1.3. and even that leptin decreases their development and produces a higher rate of cellular apoptosis [31]. BT. Therefore.34••] Human endometrium [32] Mouse uterus [30. but not mRNA. Moreover. whereas the addition of leptin together with LIF promoted the embryonic development. short isoforms of the leptin receptor. In addition. 33•. Similarly. 3 throughout all the preimplantation stages in mouse [24]. This new endometrial leptin could affect the endometrium in an autocrine manner. only detectable by nested-PCR. Nonetheless. and also to the low leptin mRNA expression. have been also detected in the human endometrium with a similar expression pattern to that of the long form [25••].34••] Mouse from OO to BT [23] Human endometrium [32] Human from OO to BT [23] Porcine OO [26•] OO.

it has been shown [25••] that the presence of a human blastocyst does not increase the mRNA expression of the long form of the leptin receptor and the short . it. In this way.4 Fertility Figure 1 mRNA expression of leptin and leptin receptor in human preimplantation embryos and human endometrium during the menstrual cycle Leptin receptor mRNA is found along preimplantation development from oocyte to blastocyst stage. Endometrial. leptin mRNA is expressed at low levels. and leptin receptor mRNA presents a variation throughout the cycle. Figure 2 Hypothesis relating to human leptin system interactions established at the maternal-embryonic interphase during the preimplantation and implantation phases From Cervero et al. whereas leptin is detected only at the blastocyst stage. In human endometrium. [25] Copyright 2004. Table 1 shows the studies that found leptin and leptin receptor expression in the uterus. regulating receptivity and/or facilitating the implantation process (Fig. 2). embryonic or endocrine leptin could trigger a ligand–receptor-mediated effect through the endo- metrial leptin receptor. with its lowest expression in the early secretory phase and a peak in the late secretory phase. The Endocrine Society.

Leptin levels are increased before clinical establishment of the disease. it has been found that leptin promotes mouse blastocyst adhesion and blastocyst outgrowth on fibronectin [30]. The reported effects could also be due to a blockade of leptin signalling in the embryo. especially in women with the condition.Leptin in reproduction Cervero et al. the pregnancy rate dramatically decreased [37]. Regulatory role of leptin in pregnancy Leptin concentrations are higher during pregnancy in both mouse and man [39]. Although hyperleptinaemia in these patients has been related to higher levels of the soluble leptin receptor [45]. IL-1 receptor tI and β3 integrin levels. however. a diminished transport of leptin into the brain may also contribute to pregnancy-induced leptin resistance. preventing the blastocyst from acquiring the capability to implant and/or secreting essential factors for the implantation process. leptin is not required for the maintenance of pregnancy once implantation has been achieved. However. Elevated serum leptin levels correlate significantly with the development of pre-eclampsia [42. as well as LIF and LIF receptor [36]. This idea is reinforced by a study [41••] in which the long isoform of leptin receptor mRNA was found to be reduced in the ventromedial nucleus of the hypothalamus during pregnancy compared with non-pregnant controls. Leptin . Therefore. The higher leptin levels and lower trophoblastic invasion in preeclampsia suggest that this protein could be an inhibitor of embryonic invasion in this situation. This study consisted of mating ob/ob mice that had been previously treated with recombinant leptin and withdrawing the treatment at various stages of pregnancy. Temporal and spatial expression of the leptin receptor could be a mechanism for establishing crucial molecular crosstalk between the endometrium and the blastocyst at the moment of implantation. been reported [38•] that. Leptin system during implantation There is much evidence on the relevance of leptin in murine implantation. and given that leptin is related to obesity. Moreover. a study [37] showed that a lack of leptin prevents implantation. in cultured endometrial cells. Women with polycystic ovary syndrome are frequently obese and insulin-resistant. there are papers [46] that report contrary findings. Conclusion The effect of leptin on control of reproduction has been intensely studied for several years. impaired mouse embryo implantation and LIF receptor. Nevertheless. vascular endothelial growth factor receptor 2. Therefore. Hence. new experiments need to be performed in order to elucidate the role of leptin in the inadequate placentation found in pre-eclampsia. we have to keep in mind that the contribution of leptin via the embryo cannot be discarded. In the mouse. This trophoblast invasion can be prevented by an metalloproteinase inhibitor.3 in cultured endometrial epithelial cells. Using in-vitro culture models for studying embryo implantation. In this sense. the adipose tissue has been described as the source of this leptin [40]. A significant increase in leptin level has been [47] found during ovarian stimulation in assisted reproductive technology programmes.43•]. It has. Pregnancy seems to be a leptin-resistance state resulting from a decreased transduction signalling in the hypothalamus. it has been speculated that this protein could be implicated in the pathophysiology of polycystic ovary syndrome. The high leptin levels seen during pregnancy indicate that there could be a state of leptin resistance associated with impaired leptin signalling in the hypothalamus. the leptin receptor and its long form have been found to be differentially regulated in implantation sites and interimplantation sites. Several years ago. at least in vitro. reduced levels of the soluble isoform of leptin receptor have been found in the choroid plexus of pregnant rats. indicating that leptin may play an important role during early pregnancy and that this function is dependent on metalloproteinase activity. showing that this protein might play an important role in the process at different levels. using leptin peptide antagonists or antibody to the leptin receptor. Further studies are necessary in order to clarify these results. Another study [34••] recently described how the disruption of leptin signalling in the endometrium. This finding indicates that this is the hypothalamic site involved in pregnancy-induced leptin resistance. When leptin treatment was stopped before implantation. 5 isoform HuB219. leptin increases the invasion of the trophoblast from a pre-eclamptic pregnancy. suggesting that leptin level could be used as a marker of pre-eclampsia [44]. There is evidence that leptin interacts with the neuroendocrine axis to signal an appropriate metabolic status for reproduction. other possible indirect actions should be taken into account given that leptin increases levels of interleukin (IL)-1β and the IL receptors type I (IL-1R tI) and IL-1 receptor antagonist (IL-1Ra) [35]. indicating that leptin may play a role in the maintenance of pregnancy. with a lower expression in the former [33•]. as well as stimulating mouse trophoblast cell invasion [38•].

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