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The role of the leptin in reproduction

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GCO 200063 (CMW)

The role of the leptin in reproduction

Ana Cervero, Francisco Domnguez, Jose A. Horcajadas, Alicia Quinonero,
Antonio Pellicer and Carlos Simon

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 reproductive processes such as embryonic
development and implantation, which are important
aspects in the reproductive field. Moreover, understanding
the role of leptin might be useful for new treatments in
reproductive pathologies.
Keywords
embryo, endometrium, implantation, leptin, leptin receptor
Curr Opin Obstet Gynecol 18:000000. # 2006 Lippincott Williams & Wilkins.
Fundacion IVI, Instituto Universitario IVI, University of Valencia, Spain
Correspondence to C Simon, Fundacion IVI. C. Guadassuar 1 bajo 46015,
Valencia, Spain
Tel: +34 963455560; fax: +34 963455512; e-mail: csimon@ivi.es
Current Opinion in Obstetrics and Gynecology 2006, 18:000000
Abbreviation
LIF

leukaemia inhibitory factor

# 2006 Lippincott Williams & Wilkins

1040-872X

Introduction
Leptin, the product of ob gene, was discovered as an
adipocyte hormone and was initially linked to food consumption and energy balance [1]. One of the first pieces
of evidence [1,2] 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. The exogenous administration of
leptin restored the fertility in these ob/ob animals,
whereas dietary restriction alone was ineffective in correcting fertility [3]. This indicates that obesity is not the
sole cause of infertility and that leptin is required for
normal reproductive function. Leptin has been found
to be expressed by different tissues, including reproductive tissues, and has been implicated in the regulation of
reproductive function, acting at endocrine and paracrine
levels [4].
The purpose of this review is to summarise recent
developments in the biology of the leptin system, focusing on how leptin regulates the neuroendocrine-gonadal
axis, embryonic development and the endometrium, and
functions in implantation and pregnancy as well as in
some reproductive disorders.

Neuroendocrine effects of leptin

The size of the body fat stores is known to influence
fertility, suggesting a link between adipose tissue and
the reproductive system. Leptin concentrations in the
plasma have been shown to be directly related to the
amount of body fat. It is therefore possible that leptin
provides a peripheral signal indicating the adequacy of
nutritional status to the reproductive system, causing
altered function with altered body weight [5].
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, glucose metabolism, fertility and ability to
lactate of the db/db mice. Full restoration of all functions
is produced when two leptin receptor transgenes with
different promoters are employed at the same time
[6]. Nonetheless, these results do not rule out the possibility that leptin exerts peripheral actions.
The leptin receptor gene and protein have been shown
to be expressed in immortalized gonadotrophin-releasing hormone neurones that secrete gonadotrophin-

Fertility

releasing hormone under leptin stimulation [7]. Moreover, leptin enhances gonadotropin liberation through a
pituitary and/or hypothalamic site of action, which
induces a dose-related increase in luteinizing hormone
and, to a lesser extent, follicle-stimulating hormone
release [8]. Similarly, in women with hypothalamic amenorrhoea, the administration of human recombinant leptin increases levels of luteinizing hormone and oestradiol [9]. Therefore, the negative influence of
nutritional restriction on the hypothalamic-pituitary
axis could be produced through a decrease in luteinizing
hormone release, which is in turn the result of a reduction in GnRH secretion [9].
With respect to its predominant role as a signal of starvation, leptin seems to be important in mediating deficits
in reproductive function induced by undernutrition. In
starved mice, the lack of reproductive function coincides
with the fall of plasma leptin level and several neuroendocrine changes. Injection of exogenous leptin restores
fertility to these mice [10]. Similarly, serum leptin concentrations in women with anorexia nervosa, characterized by hypothalamic amenorrhoea, are lower than those
of normal-weight controls [11].
It has been hypothesized that leptin could be an important signal in the onset of puberty. Leptin treatment
produces an advance in puberty in normal mice [12]
and allows puberty to start in mice lacking leptin, as
well as in severely food-restricted rats [13]. In man, it
is known that a critical body weight is necessary to
start puberty, and clinical observations [14] indicate
that the menarche is reached earlier in obese than in
normal-weight girls.
Nevertheless, the aforementioned studies do not rule
out a direct effect on the gonads, hence leptin could
be permissive for and not necessarily an initiator of
puberty. In support of this idea, some studies [15,16]
have not found changes in leptin concentration with
the onset of puberty. Moreover, women with lipoatrophic diabetes have a normal reproductive function
despite their low leptin levels, owing to the absence of
adipose tissue [17].

Effects of leptin on the ovary

Leptin has been found in follicular fluid [18], and leptin
receptors are present on several cell types in the human
ovary [19], suggesting that this protein could exert a
direct effect on the gonads.
In recent work, leptin has been shown to attenuate the
insulin-like growth factor-1 augmentation of oestradiol
synthesis in human granulosa cells through nitric oxide.
This result [20] suggests that nitric oxide induced by

leptin might inhibit aromatase activity, decreasing oestradiol production. However, another study [21] has
demonstrated that leptin increases oestrogen production
in cultures of human granulosa cells. A plausible hypothesis is that low-dose leptin stimulates steroidogenesis
and follicular maturation, whereas supraphysiological
concentrations of leptin produce the opposite effect.
In mice, culturing follicles in the presence of recombinant leptin resulted in a significant decrease in follicle
growth rate, with higher doses of leptin inhibiting follicular development [22]. In this study [22], leptin stimulated the production of progesterone, oestradiol and testosterone in cultured follicles.
Moreover, leptin seems to play a regulatory role in the
oocyte. In this sense, leptin has been immunolocalized
in a polarized manner in murine and human oocytes
[23]. Despite this, 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.
Leptin receptor mRNA has been found in murine [24],
human [25] and porcine [26] oocytes, and is probably
also present in bovine oocytes [27]. 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]. More interesting information about influence of leptin in the
oocyte maturation has recently been published. In this
study, leptin treatment during bovine oocyte maturation
improved the ability of the oocyte to sustain embryonic
development, and decreased the number of apoptotic
cells in the blastocysts [27].
The rate of germinal vesicle breakdown in mouse
oocytes cultured within preovulatory follicles has been
reported to be increased by leptin [19]. Subsequently,
however, it has been reported [22] that the presence of
leptin at different concentrations has no effect on mouse
germinal vesicle breakdown. This apparent contradiction may be due to differences in the culture systems
and doses used. Moreover, 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.

Role of leptin in preimplantation embryo

The first data implicating leptin in embryonic development described the presence of leptin receptors

Leptin in reproduction Cervero et al. 3

throughout all the preimplantation stages in mouse [24],

man [25] and pig [29]. In addition, leptin has found
[24,25,29,30]. to be present in the oviduct of the pregnant mouse, as well as in the human and porcine uterus.
Controversial data exist describe the influence of leptin
in preimplantation embryonic development. Two different works [24,29] have shown that the addition of leptin to mouse or porcine embryos promotes development,
from the two-cell stage to the blastocyst stage, in a dosedependent manner. Furthermore, leptin increased the
total number of cells in the blastocyst, with a significantly greater effect in trophectoderm cells [24,29]. It
has, however, also been reported that leptin has no
effect on the development of mouse embryos [22], and
even that leptin decreases their development and produces a higher rate of cellular apoptosis [31]. In this latter study [31], leukaemia inhibitory factor (LIF) alone
had no effect on the hatching of blastocysts and on the
rate of apoptosis, whereas the addition of leptin together
with LIF promoted the embryonic development. This
discrepancy can be attributed to the use of different
strains of mice, as well as different methodologies,
such as the embryo culture medium, the rate-scoring of
embryonic development and the concentration of exogenous leptin. These experimental conditions are very
important in assessing the role of leptin in preimplantation embryonic development, and further studies are
necessary to validate these results.
Murine and human preimplantation embryos express
leptin mRNA exclusively at the blastocyst stage
[24,25]. In addition, human blastocysts were[32] discovered to secrete higher levels of leptin in the conditioned media than the arrested embryos, suggesting that
this molecule might be a marker of viability. Nonetheless, other work [33] has recently reported that leptin
protein, but not mRNA, is found in mouse blastocysts.
These differences in result might derive from the differ-

ent species used, and also to the low leptin mRNA

expression, only detectable by nested-PCR. Different
works showing the presence of leptin and the leptin
receptor in preimplantation embryos are included in
Table 1.

Leptin system in endometrium

The leptin receptor and its long form have been shown
[25,34] to be present the in the human and murine
endometrium. However, its expression throughout the
menstrual cycle is controversial. Whereas one study
found the highest expression in the early secretory
phase, others [25] have described that leptin receptor
expression is lowest during the early secretory phase and
higher during the late secretory phase (Fig. 1). Moreover, short isoforms of the leptin receptor, HuB219.1
and HuB219.3, have been also detected in the human
endometrium with a similar expression pattern to that
of the long form [25]. Therefore, the leptin receptor
is available in the human and murine endometrium in
order to be activated by its ligand at the moment of
implantation, suggesting a putative role for this system
in this process.
There are discrepancies regarding the expression of leptin mRNA in the human uterus [4]. In a recent work
[25] on this topic, leptin mRNA was found in the
endometrium as well as in cultured endometrial epithelial cells using nested-PCR. A reasonable explanation for
such differences is that leptin expression is very low and
only detectable by means of nested-PCR or overloading
cDNA. This new endometrial leptin could affect the
endometrium in an autocrine manner, or the embryo in
a paracrine manner.
Similarly, the presence of leptin in murine endometrium
remains controversial. Whereas one study [24] showed
that leptin mRNA appeared in the oviduct and endometrium of the pregnant mouse, 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,

30]
Human endometrium [25,32]
Pregnant pig oviduct [29]

Mouse uterus [30,33]

Human endometrium [25 ,32]

Human BT [25 ]
Porcine OO [26]

Mouse uterus and oviduct [24,

33,34]
Human endometrium [32]

Mouse uterus [30,33,34]

Mouse from OO to BT [23]

Human endometrium [32]

Human from OO to BT [23]

Porcine OO [26]

OO, oocyte; BT, blastocyst.

Leptin

Leptin receptor

Mouse BT [24]

Mouse from OO to BT [24,28]

Human from OO to BT [25]
Porcine OO and from 4 cells to
BT [26,29]
Bovine at BT [27]
Mouse from OO to BT [19,23,
28]
Human from OO to BT [23]
Porcine from OO to BT [26,29]

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, whereas leptin is detected only at the blastocyst stage. In human endometrium, leptin
mRNA is expressed at low levels, and leptin receptor mRNA presents a variation throughout the
cycle, with its lowest expression in the early secretory phase and a peak in the late secretory
phase.

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. [25] Copyright 2004, The Endocrine Society.

it. Table 1 shows the studies that found leptin and leptin receptor expression in the uterus.
Endometrial, embryonic or endocrine leptin could trigger a ligandreceptor-mediated effect through the endo-

metrial leptin receptor, regulating receptivity and/or

facilitating the implantation process (Fig. 2). In this
way, 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

Leptin in reproduction Cervero et al. 5

isoform HuB219.3 in cultured endometrial epithelial

cells. Nevertheless, other possible indirect actions
should be taken into account given that leptin increases
levels of interleukin (IL)-1 and the IL receptors type I
(IL-1R tI) and IL-1 receptor antagonist (IL-1Ra) [35], as
well as LIF and LIF receptor [36], in cultured endometrial cells.

Leptin system during implantation

There is much evidence on the relevance of leptin in
murine implantation. Several years ago, a study [37]
showed that a lack of leptin prevents implantation.
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. When leptin treatment was stopped before
implantation, the pregnancy rate dramatically decreased
[37]. Therefore, leptin is not required for the maintenance of pregnancy once implantation has been
achieved.
Another study [34] recently described how the disruption of leptin signalling in the endometrium, using leptin peptide antagonists or antibody to the leptin receptor, impaired mouse embryo implantation and LIF
receptor, vascular endothelial growth factor receptor 2,
IL-1 receptor tI and 3 integrin levels. However, we
have to keep in mind that the contribution of leptin
via the embryo cannot be discarded. The reported
effects could also be due to a blockade of leptin signalling in the embryo, preventing the blastocyst from
acquiring the capability to implant and/or secreting
essential factors for the implantation process.
Using in-vitro culture models for studying embryo
implantation, it has been found that leptin promotes
mouse blastocyst adhesion and blastocyst outgrowth on
fibronectin [30], as well as stimulating mouse trophoblast cell invasion [38]. This trophoblast invasion can
be prevented by an metalloproteinase inhibitor, indicating that leptin may play an important role during early
pregnancy and that this function is dependent on metalloproteinase activity.
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. In this sense, the leptin
receptor and its long form have been found to be differentially regulated in implantation sites and interimplantation sites, with a lower expression in the former [33].

Regulatory role of leptin in pregnancy

Leptin concentrations are higher during pregnancy in
both mouse and man [39], indicating that leptin may

play a role in the maintenance of pregnancy. In the

mouse, the adipose tissue has been described as the
source of this leptin [40].
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.
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. This finding indicates that this is the hypothalamic site involved in pregnancy-induced leptin resistance. Moreover, reduced levels of the soluble isoform
of leptin receptor have been found in the choroid plexus
of pregnant rats. Hence, a diminished transport of leptin
into the brain may also contribute to pregnancy-induced
leptin resistance.
Elevated serum leptin levels correlate significantly with
the development of pre-eclampsia [42,43]. Leptin
levels are increased before clinical establishment of the
disease, suggesting that leptin level could be used as a
marker of pre-eclampsia [44]. Although hyperleptinaemia in these patients has been related to higher
levels of the soluble leptin receptor [45], there are
papers [46] that report contrary findings. Further studies
are necessary in order to clarify these results. The higher
leptin levels and lower trophoblastic invasion in preeclampsia suggest that this protein could be an inhibitor
of embryonic invasion in this situation. It has, however,
been reported [38] that, at least in vitro, leptin increases
the invasion of the trophoblast from a pre-eclamptic
pregnancy. Therefore, new experiments need to be performed in order to elucidate the role of leptin in the
inadequate placentation found in pre-eclampsia.
Women with polycystic ovary syndrome are frequently
obese and insulin-resistant, and given that leptin is
related to obesity, it has been speculated that this protein could be implicated in the pathophysiology of polycystic ovary syndrome. A significant increase in leptin
level has been [47] found during ovarian stimulation in
assisted reproductive technology programmes, especially
in women with the condition.

Conclusion
The effect of leptin on control of reproduction has been
intensely studied for several years, showing that this
protein might play an important role in the process at
different levels. There is evidence that leptin interacts
with the neuroendocrine axis to signal an appropriate
metabolic status for reproduction. Pregnancy seems to
be a leptin-resistance state resulting from a decreased
transduction signalling in the hypothalamus. Leptin

Fertility

also appears to affect the ovary, but further studies are

necessary to verify controversial data and examine them
in more detail. A wide range of factors, such as species,
season and metabolic and steroidal status, need to be
considered in the conduct of such experiments. Increasing data are available supporting the notion that leptin
plays an important role in embryonic development and
implantation. Nevertheless, there are no functional
proofs of this concept in human. Finally, genes regulated by leptin in the reproductive and neuroendocrine
tissues remain almost unknown. Therefore, future
investigations are expected to elucidate and understand
this complex system and potentially provide new alternatives for leptin-related pathologies, as well as to investigate the potential use of leptin in assisted reproductive
technology and embryo culture.

9 Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with
 hypothalamic amenorrhea. N Engl J Med 2004; 351:987997.
A remarkable study in which the administration of recombinant leptin to women
with hypothalamic amenorrhoea improved their reproductive and neuroendocrine
function compared with control subjects who had not been treated.
10 Cunningham MJ, Clifton DK, Steiner RA. Leptins actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 1999; 60:216222.
11 Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal
 human physiology and clinical implications for hypothalamic amenorrhoea
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This nice review outlines the role of leptin in neuroendocrine function and the
importance of this molecule in the pathophysiology of energy-deficient states
such as hypothalamic amenorrhoea and anorexia nervosa.
12 Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in
normal female mice treated with leptin. Science 1997; 275:8890.
13 Gruaz NM, Lalaoui M, Pierroz DD, et al. Chronic administration of leptin into
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14 Jaruratanasirikul S, Mo-suwan L, Lebel L. Growth pattern and age at
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15 Garcia-Mayor RV, Andrade MA, Rios M, et al. Serum leptin levels in normal
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Acknowledgements
This work was supported by FISs 02/1169 from the Spanish Government and Premio Serono de Investigacion from Fundacion Salud
2000. A. C. is a predoctoral fellow sponsored by Programa para la
Formacion de Personal Universitario from the Ministerio de Educacion
y Ciencia of the Spanish Government.

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