Leptin in reproduction
Susann Blühera and Christos S. Mantzorosb
Purpose of review
Leptin, a key hormone in energy homeostasis and
neuroendocrine function, has a permissive role in initiating
puberty and is crucial in the pathogenesis of reproductive
dysfunction in several disease states of energy imbalance.
KiSS1 neurons have recently been suggested to mediate
leptin’s effect on the reproductive system. New insights
from recent animal studies and clinical trials are discussed.
Recent findings
Alterations in the expression profile of the KiSS1 gene and
the kisspeptin receptor have been linked to reproductive
dysfunction in leptin-deficient states. Neuroendocrine,
including reproductive, dysfunction can be restored in
humans and animals by leptin-replacement therapy. These
insights have significantly advanced our understanding of
hormonal systems needed to maintain normal reproduction.
These data, if confirmed, also suggest a role for leptin as a
novel therapeutic approach in several disease states.
Summary
Recent proof-of-concept studies involving leptin
administration to humans underline the critical role of leptin
not only in regulating energy homeostasis, but also in
maintaining normal reproductive function. Leptinreplacement therapy is currently under intensive
investigation as a potential novel therapeutic option for
several conditions associated with reproductive
dysfunction due to hypoleptinemia.
Abbreviations
FSH
GnRH
HPG axis
IGF-I
LH
Ob-R
PCOS
r-metHuLeptin
follicle-stimulating hormone
gonadotropin-releasing hormone
hypothalamo-pituitary-gonadal axis
insulin-like growth factor I
luteinizing hormone
leptin receptor
polycystic ovary syndrome
recombinant human methionyl-leptin
ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
1752-296X
Introduction
Leptin, an adipocyte-secreted hormone with pleiotropic
effects, was originally thought to be an antiobesity
hormone [1]. Extensive research over the last 13 years
has shown that leptin conveys information about the body’s
energy stores to the brain and that it is a crucial endocrine
factor for regulating several physiologic processes, including inflammation, angiogenesis, hematopoiesis, immune
function, and reproduction [2,3 –5]. Accumulating
evidence suggests that leptin abundance or deficiency
contributes to the pathogenesis of reproductive abnormalities. This review focuses on the role of leptin in the
physiology/pathophysiology of reproduction, in particular
taking into account data from the past 12 months.
Leptin: the prototype adipokine
Keywords
gonadotropin, infertility, leptin, puberty, reproductive
function
Curr Opin Endocrinol Diabetes Obes 14:458–464.
ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins.
a
Children’s Hospital, University of Leipzig, Leipzig, Germany and bDivision of
Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, Massachusetts, USA
Correspondence to C.S. Mantzoros, MD, Division of Endocrinology, ST 816, Beth
Israel Deaconess Medical Center, Harvard Medical School, 33 Brookline Avenue,
Boston, MA 02215, USA
Tel: +1 617 667 8630; fax: +1 617 667 8634;
e-mail: [email protected]
Current Opinion in Endocrinology, Diabetes & Obesity 2007, 14:458–464
The discovery of leptin through positional cloning of the
ob gene [1] has not only renewed our understanding of
hormonal regulation of energy homeostasis, but has also
changed substantially our view on adipose tissue.
The adipose tissue is now recognized as an endocrine
organ producing several bioactive peptides (adipokines)
and inflammatory/anti-inflammatory molecules [6].
Leptin is the prototype adipokine that may exert direct
effects in metabolically active tissues and/or indirect
effects by binding and activating specific leptin receptors
in the hypothalamus. Leptin promotes an anorexigenic
response and alters glucose and fat metabolism [7,8].
Additional effects include the regulation of several neuroendocrine and reproductive functions, including inhibition of glucocorticoids and enhancement of thyroxine
and sex hormone concentrations in human and mice
[2,7,8,9].
Leptin physiology
Leptin, a 167-amino-acid protein, is primarily expressed
in white adipose tissue but also in the placenta [10],
458
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Leptin in reproduction Blüher and Mantzoros 459
mammary gland [11], testes [12], ovary [13], endometrium [14], stomach [15], hypothalamus [16], pituitary
[17], and elsewhere. Leptin circulates in a free form
(the biologically active form) and also bound to leptinbinding proteins. The hormone is secreted in a pulsatile
fashion with significant diurnal variation. Leptin’s
pulsatility characteristics are similar in lean and obese
subjects with the only exception being pulse amplitude,
which is higher in obese subjects. Leptin’s pulsatility is
synchronous to the pulsatility of serum luteinizing hormone (LH) and estradiol levels in healthy women, implying a role for leptin in the regulation of reproductive
hormones [2,4,9].
Leptin secretion can be stimulated by insulin, glucocorticoids, and cytokines (i.e. tumor necrosis factor a),
whereas catecholamines, free fatty acids, cold exposure
and thyroid hormones inhibit leptin release [18,19].
Estrogens induce leptin production whereas androgens
suppress it, providing an explanation for the sexual
dimorphism in serum leptin levels [19]. Although
anthropometric and clinical features (gender, fat mass/
fat distribution, hormones and cytokines) may influence
the secretion pattern of leptin, the crucial factor in
regulating serum leptin levels seems to be caloric intake
and the amount of energy stored in adipocytes [5].
Leptin acts by activating leptin receptors (Ob-Rs).
Several isoforms of the receptor, resulting from alternative splicing, convey differing biological activity and
are involved in mediating leptin’s actions in the brain and
peripheral organs. The long isoform (Ob-Rb) is expressed
abundantly in the hypothalamic arcuate, ventromedial,
and dorsomedial nuclei and is the predominant signaling
form of the receptor [20]. The short isoforms of the leptin
receptor (Ob-Ra, Ob-Rc–Ob-Rf) are distributed in
almost all peripheral tissues, including the ovary, prostate
and testis, suggesting direct effects of leptin on these
organs.
Serum leptin levels rise in proportion to body fat mass.
Obese subjects are hyperleptinemic and appear to be
resistant to the central hypothalamic effects of leptin [21].
This so-called leptin resistance involves deficits in leptin
signal transduction, associated with increased lipid
storage in muscle, liver, and other tissues. However,
the exact mechanisms of central and peripheral leptin
resistance in obesity are still poorly understood [19,22].
A recent study has proven that insulin signaling in the
liver plays an important role in leptin homeostasis and
fine modulation of leptin action [23].
The dense presence of leptin receptors at all levels of the
hypothalamo-pituitary-gonadal (HPG) axis implies that
nutrition is a key factor regulating reproduction and that
this complex network involves, among others, leptin as
one signal that acts at several levels to regulate the HPG
axis in a paracrine or endocrine fashion.
Regulation of the hypothalamo-pituitarygonadal axis by leptin
Data derived from leptin-deficient animals or humans
have highlighted the importance of leptin in reproductive
function and have suggested direct effects of leptin at the
pituitary level to control reproduction. Leptin-deficient
ob/ob mice are morbidly obese and sterile. However,
fertility can be fully restored by leptin-replacement
therapy [24]. Hypothalamic expression of the leptin
receptor (Ob-Rb) is significantly increased in ob/ob mice
and decreased in obese, hyperleptinemic mice put on a
high-fat diet, suggesting that the expression pattern of
the leptin receptor may be dynamically influenced by
serum leptin levels [25].
In humans, leptin proteins are present in subsets of
corticotropes, somatotropes, thyrotropes and gonadotropes, and the percentage of leptin-bearing cells may
vary within the reproductive state [26]. In addition,
neurons secreting gonadotropin-releasing hormone
(GnRH) express leptin receptors, and the GnRH pulsatility in arcuate hypothalamic neurons regulating the
release of gonadotropins is stimulated by leptin [27].
Leptin may also directly stimulate LH and folliclestimulating hormone (FSH) release from the pituitary
gland [28].
It has been recently shown that leptin is expressed in rat
pituitary, depending on gender and phase of cycle, and
that it can be regulated by GnRH via estrogen feedback.
The highest basal and GnRH-mediated leptin secretion
was found in pituitary cells from female proestrous or
pregnant rats [26].
Leptin and ghrelin have opposing effects on pulsatile
GnRH secretion after administration in vivo, whereas
they both seem to have stimulatory effects in vitro.
The effect of both hormones seems to be mediated via
the melanocortin system [29].
Subjects with congenital leptin deficiency and/or loss of
leptin function due to leptin mutations/leptin receptor
mutations have clinical evidence of hypogonadotropic
hypogonadism with low levels of FSH and LH and
complete loss of LH pulsatility, lack of pubertal
growth spurt, and reduced expression of secondary
sexual characteristics. Additional disturbances include
primary or secondary amenorrhea [30]. Hypothalamic
hypogonadism and associated disturbances can be
corrected by leptin administration in replacement
doses [31]. In contrast, high serum leptin levels seen
in morbid obesity may also have an inhibitory effect on
the gonads [4].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
460 Reproductive endocrinology
All these data underline a pivotal role of leptin in
regulating reproductive function and strengthen the
hypothesis that leptin is one of the factors mediating
reproductive abnormalities in several diseases states. Our
present understanding of leptin’s role in the pituitary
suggests that leptin serves as a signal to convey information to the brain that the metabolic resources as well as
body fat stores are adequate, since a threshold level of
energy and body fat mass is mandatory for the onset of
puberty and normal fertility. Leptin thus acts as permissive signal to activate the reproductive axis and to
maintain normal reproductive function [2,4,5].
Effect of leptin on the gonads
Ovarian follicular cells and testicular Leydig cells express
a functional leptin receptor, and leptin mRNA is synthesized in granulosa and cumulus cells of preovulatory
human follicles [12,13]. Endocrine and/or direct paracrine
effects of leptin on the gonads include antagonism of
the stimulating effects of several growth factors and
hormones [insulin-like growth factor I (IGF-I), insulin,
glucocorticoids] on gonadotropin-stimulated steroidogenesis in ovarian cells as well as inhibition of testosterone production in Leydig cells [12]. In contrast, leptin
deficiency results in down-regulation of the HPG axis,
resulting in low levels of circulating sex steroids [30]. In
summary, both leptin deficiency and excess are associated with reproductive abnormalities at both the central
and the gonadal levels [4,30].
Role of leptin in reproductive function
Puberty is defined as achievement of reproductive maturity and is associated with accelerated linear growth, rapid
increase of muscle mass, and mineralization of the
skeleton. It is closely related to hypothalamic activation,
which subsequently leads to stimulation of the gonads.
Activation of several hormonal axes, including the gonadal and the growth hormone/IGF-I axis, initiate and
complete the complex process of puberty [2].
Physiological and endocrine aspects of puberty
For more than 40 years it had been postulated that a
critical body weight, a critical fat mass and/or critical
levels of metabolites linked to fat mass have to be
achieved before puberty can occur [32,33]. Leptin is at
least one of these factors, as observational studies in
both genders indicate that leptin levels rise prior to
the initiation of puberty and trigger the onset of puberty
in humans [34]. The onset of puberty is characterized by
a significant change in the pulsatile characteristics of
the hypothalamic ‘gonadostat’. The pulsatile amplitude
of hypothalamic GnRH neurons is increased, leading to a
substantial rise in nocturnal FSH, and then to a rise in
LH pulsatile release by the pituitary. This results in a
remarkably higher output of sex steroids by the gonads,
which has also been linked to an increased production of
growth hormone and IGF-I. The combined increase in
growth hormone and IGF-I affects linear growth, muscle
bulk, and mineralization of the skeleton. Although the
secretion of growth hormone, its effector peptide IGF-I,
the growth-hormone-dependent IGF-I carrier protein
IGF-BP3, and the sex steroids peaks through midpuberty, leptin levels already increase during prepuberty,
suggesting an interaction between leptin and the gonadotropins in late childhood [2,4,5]. These insights
have been further advanced by a recent study showing
that in children approaching and progressing into puberty
leptin is associated with LH and FSH over the same time
frame (although leptin is more tightly related to FSH
than to LH), implying a permissive role for leptin which
acts as an important facilitator of the early phases of
human puberty [35].
Role of kisspeptins in reproductive function
Kisspeptins are encoded by the KiSS-1 gene and play a
crucial role in the neuroendocrine regulation of reproduction. Mutations in the kisspeptin receptor GPR54 are
associated with hypogonadotrophic hypogonadism in
rodents and humans, and intracerebral administration
of kisspeptin to mice potently stimulates GnRH release
[36].
Further insights could be obtained from data showing that
KiSS-1 mRNA is significantly reduced in obese and infertile ob/ob mice compared to wild-type mice and that the
levels of KiSS-1 mRNA in these mice increased after
administration of leptin [36,37]. Almost one-half of
cells expressing KiSS-1 mRNA in the hypothalamic
arcuate nucleus express Ob-Rb [36], implying that
KiSS-1 neurons are direct targets and are regulated by
leptin.
Kisspeptins influence reproductive function by regulating GnRH secretion in the hypothalamus. In addition to
the hypothalamic level, kisspeptins have also been shown
to directly stimulate LH release in male and female rat
pituitary cells [38].
Taking all these data together and taking into account
that kisspeptins directly act at the hypothalamic-pituitary
level, it is tempting to speculate that KiSS-1 neurons may
represent the link between systemic metabolic signals
and central maintenance of reproductive function and
that reproductive deficits associated with leptin-deficient
states may be attributable, at least in part, to diminished
expression patterns of KiSS1 and/or its receptor [36 –
38,39].
Leptin and menarche
Menarche represents an important event in the course of
a girl’s puberty and is initiated by an increase in GnRH
pulsatility and frequency. The age of menarche varies
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Leptin in reproduction Blüher and Mantzoros 461
considerably, is accelerated in obese girls and is delayed
in girls with poor nutritional status. Approximately
16 kg is the critical amount of fat needed to have been
stored during childhood and before puberty to provide
additional energy for a potential pregnancy and lactation
[33,40]. Leptin communicates information about the
amount of fat stored to hypothalamic GnRH-secreting
neurons.
leptin gene or the leptin receptor gene is associated with
reproductive dysfunction/hypothalamic hypogonadism
[30]. The reproductive abnormalities seen in either
leptin-deficient humans or mice can be corrected by
administration of leptin in replacement doses, supporting
the causative role of leptin in the pathophysiology of
hypogonadism-induced infertility [3,30].
Leptin’s role in obesity-related reproductive dysfunction
The strong relation between leptin and menarche has
been further underlined by the fact that age at menarche
in young women is inversely related to leptin levels.
Circulating leptin levels increase about 28% during the
first 6 months preceding menarche, and leptin levels are
much more related to gluteofemoral than upper-body
fat, highlighting the importance of body-fat distribution
[40].
Sexual dimorphism in circulating leptin levels
Leptin levels are significantly higher in female than in
male subjects in childhood and adolescence. This divergence increases with proceeding Tanner stages of pubertal development [4,34].
In boys, leptin levels rise by approximately 50% just
before the onset of puberty and reach their peak immediately after the initiation of puberty [34]. The increase in
testosterone levels with the evolution of puberty is
associated with progressively declining leptin levels.
Adult males show a significant negative correlation
between circulating testosterone and leptin levels, which
is not present in females.
Similar to boys, girls show a progressive increase of leptin
levels from prepuberty into early puberty. However,
unlike boys, leptin levels in girls continue to increase
up to late puberty. The increase of leptin with the
progression of puberty is 40% greater in girls compared
to boys and correlates with fat accumulation [41]. The
significantly higher leptin levels in females compared
to males persist from late puberty into adulthood
[2,19,41]. In postpubertal adolescent girls, leptin is
related to growth-hormone concentrations across the
body mass index spectrum from lean to overweight,
and growth-hormone pulsatile secretion seems to be
greater in girls with later age at menarche [42].
In summary, the sexual dimorphism in circulating leptin
concentrations seems to be attributable to the higher
amount of subcutaneous fat mass in females, inhibition
of leptin by androgens, and stimulation by estrogens
[19,43,44].
Leptin in states of reproductive dysfunction
Animal studies and clinical observations in humans have
shown that obesity caused by either a mutation in the
With the exception of rare cases of gene mutations,
human obesity is normally associated with hyperleptinemia (leptin resistance) rather than leptin deficiency.
Increasing obesity is positively correlated to the numbers
of anovulatory cycles, and high leptin levels directly
inhibit ovarian steroidogenesis, leading to ineffective
follicular maturation [45]. In perimenarcheal and young
adult girls, LH and FSH responses to GnRH are negatively correlated with body mass index and circulating
leptin levels. Decreased LH and FSH responses to
GnRH are associated with increased degree of obesity
and hyperleptinemia. Obese girls reach menarche at an
earlier age compared with girls of normal weight. The
fact that age of menarche is inversely correlated with
prepubertal serum leptin levels [39] is consistent with
the critical weight hypothesis proposed by Frisch and
Revelle [33].
In summary, obesity affects reproductive function in
many ways. High circulating leptin levels commonly seen
in obesity and the underlying leptin resistance interact
with the HPG axis at several levels, leading to reproductive dysfunction.
Role of leptin in polycystic ovary syndrome
The heterogenous polycystic ovary syndrome (PCOS) is
defined as a syndromal complex consisting of hirsutism/
hyperandrogenism, chronic anovulation, menstrual disturbances, and features of the metabolic syndrome such
as obesity, insulin resistance, dyslipidemia, and endothelial dysfunction [20]. It results from an abnormal
secretory pattern of GnRH and leads to a high LH/FSH
ratio and a hyperandrogenic state. It has been recently
proposed as a state of chronic low-grade inflammation,
mainly characterized by a modest rise in serum C-reactive
protein [22].
Although the literature available so far shows some discrepancy in terms of leptin levels in PCOS, most studies
agree that serum leptin concentrations in women with the
syndrome are similar to those in weight- and age-matched
controls [22,46]. Recent findings showing a direct inhibitory effect of leptin on ovarian steroidogenesis in conditions of increased body fat mass and the subsequent
shift of interest from serum to follicular fluid leptin levels
have changed the approach to the study of the pathophysiology of PCOS. In summary, leptin’s role in PCOS
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
462 Reproductive endocrinology
needs to be elucidated with more detailed and (preferably) interventional studies in the future.
Role of leptin in anorexia nervosa
It is not only extremely obese adolescents who show
delayed puberty and impaired development of the reproductive system along with other neuroendocrine dysfunctions. This is also the case for subjects with low body fat
mass. From the evolutionary point of view, hormonal
adaptation processes in response to starvation are in
general considered protective, since through most of
these mechanisms energy is saved for functions ensuring
immediate survival. However, after a certain point the
decrease in hormones of the HPG axis as well as other
regulatory endocrine axes becomes critical since physiologal processes are significantly disturbed [3].
Eating disorders such as anorexia nervosa, a condition
with drastically decreased food intake, which leads to
progressive weight loss, are associated with significantly
lower serum leptin levels compared to healthy, normal
weight controls. However, leptin levels still correlate
with body weight and percentage of body fat mass
[47]. Circulating leptin levels are also significantly lower
in patients with anorexia nervosa compared with subjects
with constitutional thinness, which might help to distinguish between these two conditions of severe underweight [48].
In anorexia nervosa, a relatively higher amount of leptin
is transported to the cerebrospinal fluid compared with
healthy controls. Upon refeeding leptin levels in cerebrospinal fluid increase and return to normal in the
circulation before body mass index raises [47]. In accordance, patients with eating disorders and women athletes
have higher levels of soluble leptin receptor, the main
binding protein for leptin, which results in a reduced
free-leptin index [49]. Anorexia nervosa is associated
with hypothalamic amenorrhea and other neuroendocrine disturbances. In female patients with anorexia
nervosa, dietary treatment leading to weight gain causes
an increase in leptin levels and serum LH/FSH. Leptin
represents the factor needed for the resumption of
menses in these patients [2,47,48,49,50].
However, amenorrheic and eumenorrheic female subjects with anorexia nervosa frequently show no difference
in serum leptin concentrations, implying either that there
are significant interindividual differences with respect to
responsiveness to leptin or that other endocrine axes,
such as the growth hormone/IGF-I axis, also play an
important role in normalizing reproductive function in
this disease [50]. Similarly, in male patients with anorexia
nervosa, changes in leptin levels during weight gain are
significantly correlated with changes in gonadotropins,
testosterone, and free androgen index, implying a crucial
role for leptin in regulating the HPG axis in both genders
with this disease. More specifically, leptin-replacement
therapy with recombinant human methionyl-leptin
(r-metHuLeptin) to women with anorexia nervosa
restored the reproductive and hormonal abnormalities
seen in these patients, which has provided initial proof
of the concept that low leptin levels are directly responsible for the neuroendocrine dysfunctions associated with
anorexia nervosa [31]. Additional studies are warranted to
fully elucidate the therapeutic role of leptin replacement.
Role of leptin in other conditions of hypothalamic
amenorrhea
Hypothalamic amenorrhea is characterized by cessation
of ovulation and menstrual cycles due to disturbances in
the HPG axis leading to impaired secretion patterns of
LH/FSH despite normal ovarian function. It is one of
the cardinal features of anorexia nervosa, as discussed
above, but is also present in states of strenuous exercise,
morbid stress, and other features involving negative
energy balance.
Extreme exercise, as commonly seen in elite athletes or
ballet dancers, frequently results in very low body fat
mass and low circulating leptin levels, resembling energy
deficit. The result is secondary dysfunction of the HPG
axis, leading to hypothalamic amenorrhea. Female elite
gymnasts often have delayed menarche and amenorrhea
resulting from the suppression of GnRH pulsatility with
low estrogen levels. Female athletes not only present
with hypoleptinemia, but also with absence of diurnal
rhythm in leptin pulsatility and disturbances of other
neuroendocrine axes. Interventional studies with leptinreplacement therapy to women with hypothalamic amenorrhea have proven this concept, as r-metHuLeptin
replacement restored GnRH pulsatility and neuroendocrine as well as reproductive function, including ovulation and ovarian parameters measured by ultrasound
[31]. Leptin-replacement therapy might prove to be a
therapeutic option for patients with disorders that are
associated with disruptive HPG axis, but further studies
in this area are needed [51].
Conclusion
Leptin communicates information on the body’s energy
reserves to the brain, triggers the onset of puberty, and
contributes to maintaining normal reproductive in postpubertal life. Several conditions with energy imbalance
are associated with altered serum leptin levels and
abnormalities in reproductive function. Our understanding how leptin affects neuroendocrine axes has been
advanced substantially by recent animal studies and
observational/interventional studies in humans, ranging
from pharmacokinetic studies to leptin-replacement
therapy in patients with hypothalamic amenorrhea
[31,51]. Similar to the hormone-deficiency syndromes,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Leptin in reproduction Blüher and Mantzoros 463
a leptin-deficiency syndrome may exist in humans. The
role of r-metHuLeptin as a new potentially useful medication that could be added to our therapeutic armamentarium is currently under intense investigation.
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