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Leptin in reproduction

Susann Bluhera and Christos S. Mantzorosb

Purpose of review Abbreviations


Leptin, a key hormone in energy homeostasis and FSH follicle-stimulating hormone
neuroendocrine function, has a permissive role in initiating GnRH gonadotropin-releasing hormone
HPG axis hypothalamo-pituitary-gonadal axis
puberty and is crucial in the pathogenesis of reproductive IGF-I insulin-like growth factor I
dysfunction in several disease states of energy imbalance. LH luteinizing hormone
Ob-R leptin receptor
KiSS1 neurons have recently been suggested to mediate PCOS polycystic ovary syndrome
leptins effect on the reproductive system. New insights r-metHuLeptin recombinant human methionyl-leptin

from recent animal studies and clinical trials are discussed.


Recent findings 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Alterations in the expression profile of the KiSS1 gene and 1752-296X
the kisspeptin receptor have been linked to reproductive
dysfunction in leptin-deficient states. Neuroendocrine,
including reproductive, dysfunction can be restored in Introduction
humans and animals by leptin-replacement therapy. These Leptin, an adipocyte-secreted hormone with pleiotropic
insights have significantly advanced our understanding of effects, was originally thought to be an antiobesity
hormonal systems needed to maintain normal reproduction. hormone [1]. Extensive research over the last 13 years
These data, if confirmed, also suggest a role for leptin as a has shown that leptin conveys information about the bodys
novel therapeutic approach in several disease states. energy stores to the brain and that it is a crucial endocrine
Summary factor for regulating several physiologic processes, includ-
Recent proof-of-concept studies involving leptin ing inflammation, angiogenesis, hematopoiesis, immune
administration to humans underline the critical role of leptin function, and reproduction [2,3 5]. Accumulating
not only in regulating energy homeostasis, but also in evidence suggests that leptin abundance or deficiency
maintaining normal reproductive function. Leptin- contributes to the pathogenesis of reproductive abnorm-
replacement therapy is currently under intensive alities. This review focuses on the role of leptin in the
investigation as a potential novel therapeutic option for physiology/pathophysiology of reproduction, in particular
several conditions associated with reproductive taking into account data from the past 12 months.
dysfunction due to hypoleptinemia.
Leptin: the prototype adipokine
Keywords The discovery of leptin through positional cloning of the
gonadotropin, infertility, leptin, puberty, reproductive ob gene [1] has not only renewed our understanding of
function hormonal regulation of energy homeostasis, but has also
changed substantially our view on adipose tissue.
Curr Opin Endocrinol Diabetes Obes 14:458464.
2007 Wolters Kluwer Health | Lippincott Williams & Wilkins.
The adipose tissue is now recognized as an endocrine
a
Childrens Hospital, University of Leipzig, Leipzig, Germany and bDivision of organ producing several bioactive peptides (adipokines)
Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, Massachusetts, USA
and inflammatory/anti-inflammatory molecules [6].
Leptin is the prototype adipokine that may exert direct
Correspondence to C.S. Mantzoros, MD, Division of Endocrinology, ST 816, Beth
Israel Deaconess Medical Center, Harvard Medical School, 33 Brookline Avenue, effects in metabolically active tissues and/or indirect
Boston, MA 02215, USA effects by binding and activating specific leptin receptors
Tel: +1 617 667 8630; fax: +1 617 667 8634;
e-mail: cmantzor@bidmc.harvard.edu in the hypothalamus. Leptin promotes an anorexigenic
response and alters glucose and fat metabolism [7,8].
Current Opinion in Endocrinology, Diabetes & Obesity 2007, 14:458464
Additional effects include the regulation of several neuro-
endocrine and reproductive functions, including inhi-
bition 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 Bluher and Mantzoros 459

mammary gland [11], testes [12], ovary [13], endome- one signal that acts at several levels to regulate the HPG
trium [14], stomach [15], hypothalamus [16], pituitary axis in a paracrine or endocrine fashion.
[17], and elsewhere. Leptin circulates in a free form
(the biologically active form) and also bound to leptin- Regulation of the hypothalamo-pituitary-
binding proteins. The hormone is secreted in a pulsatile gonadal axis by leptin
fashion with significant diurnal variation. Leptins Data derived from leptin-deficient animals or humans
pulsatility characteristics are similar in lean and obese have highlighted the importance of leptin in reproductive
subjects with the only exception being pulse amplitude, function and have suggested direct effects of leptin at the
which is higher in obese subjects. Leptins pulsatility is pituitary level to control reproduction. Leptin-deficient
synchronous to the pulsatility of serum luteinizing hor- ob/ob mice are morbidly obese and sterile. However,
mone (LH) and estradiol levels in healthy women, imply- fertility can be fully restored by leptin-replacement
ing a role for leptin in the regulation of reproductive therapy [24]. Hypothalamic expression of the leptin
hormones [2,4,9]. receptor (Ob-Rb) is significantly increased in ob/ob mice
and decreased in obese, hyperleptinemic mice put on a
Leptin secretion can be stimulated by insulin, glucocor- high-fat diet, suggesting that the expression pattern of
ticoids, and cytokines (i.e. tumor necrosis factor a), the leptin receptor may be dynamically influenced by
whereas catecholamines, free fatty acids, cold exposure serum leptin levels [25].
and thyroid hormones inhibit leptin release [18,19].
Estrogens induce leptin production whereas androgens In humans, leptin proteins are present in subsets of
suppress it, providing an explanation for the sexual corticotropes, somatotropes, thyrotropes and gonado-
dimorphism in serum leptin levels [19]. Although tropes, and the percentage of leptin-bearing cells may
anthropometric and clinical features (gender, fat mass/ vary within the reproductive state [26]. In addition,
fat distribution, hormones and cytokines) may influence neurons secreting gonadotropin-releasing hormone
the secretion pattern of leptin, the crucial factor in (GnRH) express leptin receptors, and the GnRH pulsa-
regulating serum leptin levels seems to be caloric intake tility in arcuate hypothalamic neurons regulating the
and the amount of energy stored in adipocytes [5]. release of gonadotropins is stimulated by leptin [27].
Leptin may also directly stimulate LH and follicle-
Leptin acts by activating leptin receptors (Ob-Rs). stimulating hormone (FSH) release from the pituitary
Several isoforms of the receptor, resulting from alter- gland [28].
native splicing, convey differing biological activity and
are involved in mediating leptins actions in the brain and It has been recently shown that leptin is expressed in rat
peripheral organs. The long isoform (Ob-Rb) is expressed pituitary, depending on gender and phase of cycle, and
abundantly in the hypothalamic arcuate, ventromedial, that it can be regulated by GnRH via estrogen feedback.
and dorsomedial nuclei and is the predominant signaling The highest basal and GnRH-mediated leptin secretion
form of the receptor [20]. The short isoforms of the leptin was found in pituitary cells from female proestrous or
receptor (Ob-Ra, Ob-RcOb-Rf) are distributed in pregnant rats [26].
almost all peripheral tissues, including the ovary, prostate
and testis, suggesting direct effects of leptin on these Leptin and ghrelin have opposing effects on pulsatile
organs. GnRH secretion after administration in vivo, whereas
they both seem to have stimulatory effects in vitro.
Serum leptin levels rise in proportion to body fat mass. The effect of both hormones seems to be mediated via
Obese subjects are hyperleptinemic and appear to be the melanocortin system [29].
resistant to the central hypothalamic effects of leptin [21].
This so-called leptin resistance involves deficits in leptin Subjects with congenital leptin deficiency and/or loss of
signal transduction, associated with increased lipid leptin function due to leptin mutations/leptin receptor
storage in muscle, liver, and other tissues. However, mutations have clinical evidence of hypogonadotropic
the exact mechanisms of central and peripheral leptin hypogonadism with low levels of FSH and LH and
resistance in obesity are still poorly understood [19,22]. complete loss of LH pulsatility, lack of pubertal
A recent study has proven that insulin signaling in the growth spurt, and reduced expression of secondary
liver plays an important role in leptin homeostasis and sexual characteristics. Additional disturbances include
fine modulation of leptin action [23]. primary or secondary amenorrhea [30]. Hypothalamic
hypogonadism and associated disturbances can be
The dense presence of leptin receptors at all levels of the corrected by leptin administration in replacement
hypothalamo-pituitary-gonadal (HPG) axis implies that doses [31]. In contrast, high serum leptin levels seen
nutrition is a key factor regulating reproduction and that in morbid obesity may also have an inhibitory effect on
this complex network involves, among others, leptin as the gonads [4].

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460 Reproductive endocrinology

All these data underline a pivotal role of leptin in growth hormone and IGF-I. The combined increase in
regulating reproductive function and strengthen the growth hormone and IGF-I affects linear growth, muscle
hypothesis that leptin is one of the factors mediating bulk, and mineralization of the skeleton. Although the
reproductive abnormalities in several diseases states. Our secretion of growth hormone, its effector peptide IGF-I,
present understanding of leptins role in the pituitary the growth-hormone-dependent IGF-I carrier protein
suggests that leptin serves as a signal to convey infor- IGF-BP3, and the sex steroids peaks through mid-
mation to the brain that the metabolic resources as well as puberty, leptin levels already increase during prepuberty,
body fat stores are adequate, since a threshold level of suggesting an interaction between leptin and the gon-
energy and body fat mass is mandatory for the onset of adotropins in late childhood [2,4,5]. These insights
puberty and normal fertility. Leptin thus acts as permis- have been further advanced by a recent study showing
sive signal to activate the reproductive axis and to that in children approaching and progressing into puberty
maintain normal reproductive function [2,4,5]. leptin is associated with LH and FSH over the same time
frame (although leptin is more tightly related to FSH
Effect of leptin on the gonads than to LH), implying a permissive role for leptin which
Ovarian follicular cells and testicular Leydig cells express acts as an important facilitator of the early phases of
a functional leptin receptor, and leptin mRNA is syn- human puberty [35].
thesized in granulosa and cumulus cells of preovulatory
human follicles [12,13]. Endocrine and/or direct paracrine Role of kisspeptins in reproductive function
effects of leptin on the gonads include antagonism of Kisspeptins are encoded by the KiSS-1 gene and play a
the stimulating effects of several growth factors and crucial role in the neuroendocrine regulation of reproduc-
hormones [insulin-like growth factor I (IGF-I), insulin, tion. Mutations in the kisspeptin receptor GPR54 are
glucocorticoids] on gonadotropin-stimulated steroido- associated with hypogonadotrophic hypogonadism in
genesis in ovarian cells as well as inhibition of testoster- rodents and humans, and intracerebral administration
one production in Leydig cells [12]. In contrast, leptin of kisspeptin to mice potently stimulates GnRH release
deficiency results in down-regulation of the HPG axis, [36].
resulting in low levels of circulating sex steroids [30]. In
summary, both leptin deficiency and excess are associ- Further insights could be obtained from data showing that
ated with reproductive abnormalities at both the central KiSS-1 mRNA is significantly reduced in obese and infer-
and the gonadal levels [4,30]. tile ob/ob mice compared to wild-type mice and that the
levels of KiSS-1 mRNA in these mice increased after
Role of leptin in reproductive function administration of leptin [36,37]. Almost one-half of
Puberty is defined as achievement of reproductive matur- cells expressing KiSS-1 mRNA in the hypothalamic
ity and is associated with accelerated linear growth, rapid arcuate nucleus express Ob-Rb [36], implying that
increase of muscle mass, and mineralization of the KiSS-1 neurons are direct targets and are regulated by
skeleton. It is closely related to hypothalamic activation, leptin.
which subsequently leads to stimulation of the gonads.
Activation of several hormonal axes, including the gona- Kisspeptins influence reproductive function by regulat-
dal and the growth hormone/IGF-I axis, initiate and ing GnRH secretion in the hypothalamus. In addition to
complete the complex process of puberty [2]. the hypothalamic level, kisspeptins have also been shown
to directly stimulate LH release in male and female rat
Physiological and endocrine aspects of puberty pituitary cells [38].
For more than 40 years it had been postulated that a
critical body weight, a critical fat mass and/or critical Taking all these data together and taking into account
levels of metabolites linked to fat mass have to be that kisspeptins directly act at the hypothalamic-pituitary
achieved before puberty can occur [32,33]. Leptin is at level, it is tempting to speculate that KiSS-1 neurons may
least one of these factors, as observational studies in represent the link between systemic metabolic signals
both genders indicate that leptin levels rise prior to and central maintenance of reproductive function and
the initiation of puberty and trigger the onset of puberty that reproductive deficits associated with leptin-deficient
in humans [34]. The onset of puberty is characterized by states may be attributable, at least in part, to diminished
a significant change in the pulsatile characteristics of expression patterns of KiSS1 and/or its receptor [36
the hypothalamic gonadostat. The pulsatile amplitude 38,39].
of hypothalamic GnRH neurons is increased, leading to a
substantial rise in nocturnal FSH, and then to a rise in Leptin and menarche
LH pulsatile release by the pituitary. This results in a Menarche represents an important event in the course of
remarkably higher output of sex steroids by the gonads, a girls puberty and is initiated by an increase in GnRH
which has also been linked to an increased production of pulsatility and frequency. The age of menarche varies

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Leptin in reproduction Bluher and Mantzoros 461

considerably, is accelerated in obese girls and is delayed leptin gene or the leptin receptor gene is associated with
in girls with poor nutritional status. Approximately reproductive dysfunction/hypothalamic hypogonadism
16 kg is the critical amount of fat needed to have been [30]. The reproductive abnormalities seen in either
stored during childhood and before puberty to provide leptin-deficient humans or mice can be corrected by
additional energy for a potential pregnancy and lactation administration of leptin in replacement doses, supporting
[33,40]. Leptin communicates information about the the causative role of leptin in the pathophysiology of
amount of fat stored to hypothalamic GnRH-secreting hypogonadism-induced infertility [3,30].
neurons.
Leptins role in obesity-related reproductive dysfunction
The strong relation between leptin and menarche has With the exception of rare cases of gene mutations,
been further underlined by the fact that age at menarche human obesity is normally associated with hyperleptine-
in young women is inversely related to leptin levels. mia (leptin resistance) rather than leptin deficiency.
Circulating leptin levels increase about 28% during the Increasing obesity is positively correlated to the numbers
first 6 months preceding menarche, and leptin levels are of anovulatory cycles, and high leptin levels directly
much more related to gluteofemoral than upper-body inhibit ovarian steroidogenesis, leading to ineffective
fat, highlighting the importance of body-fat distribution follicular maturation [45]. In perimenarcheal and young
[40]. adult girls, LH and FSH responses to GnRH are nega-
tively correlated with body mass index and circulating
Sexual dimorphism in circulating leptin levels leptin levels. Decreased LH and FSH responses to
Leptin levels are significantly higher in female than in GnRH are associated with increased degree of obesity
male subjects in childhood and adolescence. This diver- and hyperleptinemia. Obese girls reach menarche at an
gence increases with proceeding Tanner stages of pub- earlier age compared with girls of normal weight. The
ertal development [4,34]. fact that age of menarche is inversely correlated with
prepubertal serum leptin levels [39] is consistent with
In boys, leptin levels rise by approximately 50% just the critical weight hypothesis proposed by Frisch and
before the onset of puberty and reach their peak immedi- Revelle [33].
ately after the initiation of puberty [34]. The increase in
testosterone levels with the evolution of puberty is In summary, obesity affects reproductive function in
associated with progressively declining leptin levels. many ways. High circulating leptin levels commonly seen
Adult males show a significant negative correlation in obesity and the underlying leptin resistance interact
between circulating testosterone and leptin levels, which with the HPG axis at several levels, leading to reproduc-
is not present in females. tive dysfunction.

Similar to boys, girls show a progressive increase of leptin Role of leptin in polycystic ovary syndrome
levels from prepuberty into early puberty. However, The heterogenous polycystic ovary syndrome (PCOS) is
unlike boys, leptin levels in girls continue to increase defined as a syndromal complex consisting of hirsutism/
up to late puberty. The increase of leptin with the hyperandrogenism, chronic anovulation, menstrual dis-
progression of puberty is 40% greater in girls compared turbances, and features of the metabolic syndrome such
to boys and correlates with fat accumulation [41]. The as obesity, insulin resistance, dyslipidemia, and endo-
significantly higher leptin levels in females compared thelial dysfunction [20]. It results from an abnormal
to males persist from late puberty into adulthood secretory pattern of GnRH and leads to a high LH/FSH
[2,19,41]. In postpubertal adolescent girls, leptin is ratio and a hyperandrogenic state. It has been recently
related to growth-hormone concentrations across the proposed as a state of chronic low-grade inflammation,
body mass index spectrum from lean to overweight, mainly characterized by a modest rise in serum C-reactive
and growth-hormone pulsatile secretion seems to be protein [22].
greater in girls with later age at menarche [42].
Although the literature available so far shows some dis-
In summary, the sexual dimorphism in circulating leptin crepancy in terms of leptin levels in PCOS, most studies
concentrations seems to be attributable to the higher agree that serum leptin concentrations in women with the
amount of subcutaneous fat mass in females, inhibition syndrome are similar to those in weight- and age-matched
of leptin by androgens, and stimulation by estrogens controls [22,46]. Recent findings showing a direct inhibi-
[19,43,44]. tory effect of leptin on ovarian steroidogenesis in con-
ditions of increased body fat mass and the subsequent
Leptin in states of reproductive dysfunction shift of interest from serum to follicular fluid leptin levels
Animal studies and clinical observations in humans have have changed the approach to the study of the patho-
shown that obesity caused by either a mutation in the physiology of PCOS. In summary, leptins role in PCOS

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462 Reproductive endocrinology

needs to be elucidated with more detailed and (prefer- role for leptin in regulating the HPG axis in both genders
ably) interventional studies in the future. with this disease. More specifically, leptin-replacement
therapy with recombinant human methionyl-leptin
Role of leptin in anorexia nervosa (r-metHuLeptin) to women with anorexia nervosa
It is not only extremely obese adolescents who show restored the reproductive and hormonal abnormalities
delayed puberty and impaired development of the repro- seen in these patients, which has provided initial proof
ductive system along with other neuroendocrine dysfunc- of the concept that low leptin levels are directly respon-
tions. This is also the case for subjects with low body fat sible for the neuroendocrine dysfunctions associated with
mass. From the evolutionary point of view, hormonal anorexia nervosa [31]. Additional studies are warranted to
adaptation processes in response to starvation are in fully elucidate the therapeutic role of leptin replacement.
general considered protective, since through most of
these mechanisms energy is saved for functions ensuring Role of leptin in other conditions of hypothalamic
immediate survival. However, after a certain point the amenorrhea
decrease in hormones of the HPG axis as well as other Hypothalamic amenorrhea is characterized by cessation
regulatory endocrine axes becomes critical since physio- of ovulation and menstrual cycles due to disturbances in
logal processes are significantly disturbed [3]. the HPG axis leading to impaired secretion patterns of
LH/FSH despite normal ovarian function. It is one of
Eating disorders such as anorexia nervosa, a condition the cardinal features of anorexia nervosa, as discussed
with drastically decreased food intake, which leads to above, but is also present in states of strenuous exercise,
progressive weight loss, are associated with significantly morbid stress, and other features involving negative
lower serum leptin levels compared to healthy, normal energy balance.
weight controls. However, leptin levels still correlate
with body weight and percentage of body fat mass Extreme exercise, as commonly seen in elite athletes or
[47]. Circulating leptin levels are also significantly lower ballet dancers, frequently results in very low body fat
in patients with anorexia nervosa compared with subjects mass and low circulating leptin levels, resembling energy
with constitutional thinness, which might help to dis- deficit. The result is secondary dysfunction of the HPG
tinguish between these two conditions of severe under- axis, leading to hypothalamic amenorrhea. Female elite
weight [48]. gymnasts often have delayed menarche and amenorrhea
resulting from the suppression of GnRH pulsatility with
In anorexia nervosa, a relatively higher amount of leptin low estrogen levels. Female athletes not only present
is transported to the cerebrospinal fluid compared with with hypoleptinemia, but also with absence of diurnal
healthy controls. Upon refeeding leptin levels in cere- rhythm in leptin pulsatility and disturbances of other
brospinal fluid increase and return to normal in the neuroendocrine axes. Interventional studies with leptin-
circulation before body mass index raises [47]. In accord- replacement therapy to women with hypothalamic ame-
ance, patients with eating disorders and women athletes norrhea have proven this concept, as r-metHuLeptin
have higher levels of soluble leptin receptor, the main replacement restored GnRH pulsatility and neuroendo-
binding protein for leptin, which results in a reduced crine as well as reproductive function, including ovu-
free-leptin index [49]. Anorexia nervosa is associated lation and ovarian parameters measured by ultrasound
with hypothalamic amenorrhea and other neuroendo- [31]. Leptin-replacement therapy might prove to be a
crine disturbances. In female patients with anorexia therapeutic option for patients with disorders that are
nervosa, dietary treatment leading to weight gain causes associated with disruptive HPG axis, but further studies
an increase in leptin levels and serum LH/FSH. Leptin in this area are needed [51].
represents the factor needed for the resumption of
menses in these patients [2,47,48,49,50]. Conclusion
Leptin communicates information on the bodys energy
However, amenorrheic and eumenorrheic female sub- reserves to the brain, triggers the onset of puberty, and
jects with anorexia nervosa frequently show no difference contributes to maintaining normal reproductive in post-
in serum leptin concentrations, implying either that there pubertal life. Several conditions with energy imbalance
are significant interindividual differences with respect to are associated with altered serum leptin levels and
responsiveness to leptin or that other endocrine axes, abnormalities in reproductive function. Our understand-
such as the growth hormone/IGF-I axis, also play an ing how leptin affects neuroendocrine axes has been
important role in normalizing reproductive function in advanced substantially by recent animal studies and
this disease [50]. Similarly, in male patients with anorexia observational/interventional studies in humans, ranging
nervosa, changes in leptin levels during weight gain are from pharmacokinetic studies to leptin-replacement
significantly correlated with changes in gonadotropins, therapy in patients with hypothalamic amenorrhea
testosterone, and free androgen index, implying a crucial [31,51]. Similar to the hormone-deficiency syndromes,

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Leptin in reproduction Bluher and Mantzoros 463

a leptin-deficiency syndrome may exist in humans. The 18 Considine RV. Regulation of leptin production. Rev Endocr Metab Disord
2001; 2:357363.
role of r-metHuLeptin as a new potentially useful medi-
19 Ahima R, Qi Y, Singhal NS, et al. Brain adipocytokine and metabolic regula-
cation that could be added to our therapeutic armamen-  tion. Diabetes 2006; 55 (suppl 2):S145S154.
tarium is currently under intense investigation. This comprehensive work summarizes available data on peripheral and central
mechanisms of adipose-tissue-secreted hormones (adipokines), steroid
hormones, proinflammatory cytokines, vasoactive peptides, and coagulation/
complement proteins. Understanding these actions will provide further insight
References and recommended reading into the pathogenesis and treatment of obesity and related diseases.
Papers of particular interest, published within the annual period of review, have
been highlighted as: 20 Heretier A, Charnay Y, Aubert ML. Regional distribution of mRNA encoding
 of special interest the long form of receptor in mouse brain. Neurosci Res Commun 1997;
 of outstanding interest 21:113118.
Additional references related to this topic can also be found in the Current 21 Munzberg H, Bjornholm M, Bates SH, Myers MG Jr. Leptin receptor action
World Literature section in this issue (p. 502). and mechanisms of leptin resistance. Cell Mol Life Sci 2005; 62:642652.
22 Xita N, Papassotiriou I, Georgiou I, et al. The adiponectin-to-leptin ratio in
1 Zhang Y, Proenca M, Maffei M, et al. Positional cloning of the obese gene and
 women with polycystic ovary syndrome: relation to insulin resistance and
its human homologue. Nature 1994; 372:425432.
proinflammatory markers. J Metabol Clin Exper 2007; 56:766771.
2 Bluher S, Mantzoros CS. The role of leptin in regulating neuroendocrine The authors describe the adiponectin/leptin ratio as a potential biomarker of both
function in humans. J Nutr 2004; 134:2469S2474S. insulin resistance and low-grade inflammation, providing the link between these
3 Brennan AM, Mantzoros CS. Drug insight: the role of leptin in human cardiovascular risk factors in women with PCOS.
 physiology and pathophysiology emerging clinical applications. Nat Clin 23 Cohen SE, Kokkotou E, Biddinger SB, et al. High circulating leptin receptors
Pract Endocrinol Metab 2006; 2:318327.  with normal leptin sensitivity in liver-specific insulin receptor knockout (LIRKO)
This review outlines recent advantages in leptins physiology and its involvement in mice. J Biol Chem 2007; 282:2367223678.
several pathophysiological states. Emerging applications for its therapeutic use in This study shows for the first time that insulin signaling in liver plays an important
humans are also discussed. role in leptin homeostasis and fine modulation of leptin action.
4 Chan JL, Matarese G, Shetty GK, et al. Differential regulation of metabolic, 24 Chebab F, Lim M, Lu R. Correction of the sterility defect in homozygous obese
 neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci female mice by treatment with human recombinant leptin. Nat Genet 1996;
USA 2006; 103:84818486. 12:318320.
This paper suggests the existence of a leptin deficiency syndrome with a definable
25 Tortoriello DV, McMinn JE, Chua SC. Increased expression of hypothalamic
threshold for low leptin levels. Acute and chronic leptin deficiency seems to have
 leptin receptor and adiponectin accompany resistance to dietary-induced
different effects on various neuroendocrine axes.
obesity and infertility in female C57BL/6J mice. Int J Obes 2007; 31:395
5 Kelesidis T, Mantzoros CS. The emerging role of leptin in humans. Pediatr 402.
 Endocrinol Rev 2006; 3:239348. This work advances our understanding towards leptin resistance in obesity as the
In this review, the current understanding of leptins role in various physiologic and authors show that hyperleptinemic obesity in mice is associated with downregula-
pathophysiologic states in humans as well as potential future therapeutic indica- tion of the hypothalamic leptin receptor.
tions of leptin are discussed.
26 Akther N, Johnson BW, Crane C, et al. Anterior pituitary leptin expression
6 Laclaustra M, Corella D, Ordovas JM. Metabolic syndrome pathophysiology:  changes in different reproductive states: stimulation, in vitro, by gonadotropin
 the role of adipose tissue. Nutr Metab Cardiovasc Dis 2007; 17:125 releasing hormone (GnRH). J Histochem Cytochem 2007; 55:151166.
139. This study proves that leptin is expressed by the pituitary and that expression
It is suggested by the authors that a functional capacity of the adipose tissue patterns are dependent on gender and menstrual cycle.
exists, which varies among subjects explaining the incomplete overlapping among
27 Lebrethon MC, Vandersmissen E, Gerard A, et al. In vitro stimulation of the
the metabolic syndrome and obesity. Variations at multiple gene loci may be partly
prepubertal rat gonadotropin-releasing hormone pulse generator by leptin
responsible for these interindividual differences.
and neuropeptide Y through distinct mechanisms. Endocrinology 2000;
7 Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: 141:14641469.
 an update. Clin Endocrinol (Oxf) 2006; 64:355365.
28 Yu WH, Walczewska A, Karanth S, McCann SM. Nitric oxide mediates leptin-
This review summarizes our current understanding of the pathophysiology and
induced luteinizing hormone-releasing hormone (LHRH) and LHRH and
molecular actions of adipokines.
leptin-induced LH release from the pituitary gland. Endocrinology 1997;
8 Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. 138:50555058.
 Curr Diab Rep 2007; 7:12.
29 Lebrethon MC, Aganina A, Fournier M, et al. Effects of in vivo and in vitro
In this paper the latest insights of the physiology and pathophysiology leptin and
 administration of ghrelin, leptin and neuropeptide mediators on pulsatile
adiponectin are discussed, taking especially into consideration their role in
gonadotrophin-releasing hormone secretion from male rat hypothalamus
diabetes.
before and after puberty. J Neuroendocrinol 2006; 19:181188.
9 Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal Leptin and ghrelin show opposing effects on pulsatile GnRH secretion in vivo,
human physiology and clinical implications for hypothalamic amenorrhoea and whereas they have stimulatory effects in vivo. The melanocortin system appears to
anorexia nervosa. Lancet 2005; 366:7485. mediate the effects of both hormones.
10 Masuzaki H, Ogawa Y, Sagawa N, et al. Nonadipose tissue production of 30 Farooqi S, Wangensteen T, Collins S, et al. Clinical and molecular genetic
leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997;  spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007;
3:10291033. 356:237247.
11 Smith-Kirwin SM, OConnor DM, De Johnston J, et al. Leptin expression in This significant paper investigates circulating leptin levels in congenital leptin-
human mammary epithelial cells and breast milk. J Clin Endocrinol Metab receptor deficiency in humans. The rare mutation and associated hormonal
1998; 83:18101813. dysfunctions are discussed.

12 Caprio M, Isidori AM, Carta AR, et al. Expression of functional leptin receptors 31 Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with
in rodent Leydig cells. Endocrinology 1999; 140:49394947. hypothalamic amenorrhea. N Engl J Med 2004; 351:987997.

13 Karlsson C, Lindell K, Svensson E, et al. Expression of functional leptin 32 Kennedy GC, Mitra J. Body-weight and food intake as initiating factors for
receptors in the human ovary. J Clin Endocrinol Metab 1997; 82:4144 puberty in the rat. J Physiol 1963; 166:375381.
4148. 33 Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of
critical body weights and adolescent events. Science 1970; 169:397399.
14 Kitawaki J, Koshiba H, Ishihara H, et al. Expression of leptin receptor in human
endometrium and fluctuation during the menstrual cycle. J Clin Endocrinol 34 Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and
Metab 2000; 85:19461950. physical alterations during normal puberty in boys. Rising leptin levels may
signal the onset of puberty. J Clin Endocrinol Metab 1997; 82:10661070.
15 Bado A, Levasseur S, Attoub S, et al. The stomach is a source of leptin. Nature
1998; 394:790793. 35 Maqsood AR, Trueman JA, Whatmore AJ, et al. The relationship between
 nocturnal urinary leptin and gonadotrophins as children progress towards
16 Morash B, Li A, Murphy PR, et al. Leptin gene expression in the brain and puberty. Horm Res 2007; 68:225230.
pituitary gland. Endocrinology 1999; 140:59955998. Leptin is an important facilitator of the early phases in human puberty. In children
17 Jin L, Zhang S, Burguera BG, et al. Leptin and leptin receptor expression in rat approaching and progressing into puberty, leptin is associated with LH and FSH
and mouse pituitary cells. Endocrinology 2000; 141:333339. levels.

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464 Reproductive endocrinology

36 Smith JT, Acohido BV, Clifton DK, Steiner RA. Kiss-1 neurones are direct 43 Flier JS. Obesity wars: molecular progress confronts an expanding epidemic.
 targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006; 18:298303. Cell 2004; 116:337350.
This paper shows for the first time that KiSS-1 neurons in the hypothalamus
express Ob-Rb and are direct targets for leptin, offering a causative explanation for 44 Audi L, Mantzoros CS, Vidal-Puig A, et al. Leptin in relation to resumption
reproductive deficits associated with leptin-deficient states. of menses in women with anorexia nervosa. Mol Psychiatry 1998; 3:544
547.
37 Luque RM, Kineman RD, Tena-Sempere M. Regulation of hypothalamic
 expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using 45 Duggal PS, Van Der Hoek KH, Milner CR, et al. The in vivo and in vitro effects
mouse models and a cell line. Endocrinology 2007 (epub ahead of print). of exogenous leptin on ovulation in the rat. Endocrinology 2000; 141:1971
This paper outlines the significant role of leptin as one of the putative key mediators 1976.
of the metabolic regulation of the hypothalamic KiSS-1 system. 46 Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations in the polycystic ovary
38 Gutierrez-Pascual E, Martinez-Fuentes AJ, Pinilla L, et al. Direct pituitary syndrome. J Clin Endocrinol Metab 1997; 82:16871691.
 effects of kisspeptin: activation of gonadotrophs and somatotrophs and 47 Mantzoros CS, Flier JS, Lesem MD, et al. Cerebrospinal fluid leptin in anorexia
stimulation of luteinising hormone and growth hormone secretion. J Neuro- nervosa: correlation with nutritional status and potential role in resistance to
endocrinol 2007; 19:521530. weight gain. J Clin Endocrinol Metab 1997; 82:18451851.
This paper provides evidence that kisspeptin exerts direct effects in the pituitary in
peripubertal male and female rats and modulates directly the gonadotrophic axis. 48 Germain N, Galusca B, LeRoux CW, et al. Constitutional thinness and
 lean anorexia nervosa display opposite concentrations of peptide YY,
39 Navarro VM, Castellano JM, Carcia-Galiano D, Tena-Sempere M. Neuroendo-
glucagon-like peptide 1, ghrelin, and leptin. Am J Clin Nutr 2007; 85:967
 crine factors in the initiation of puberty: the emergent role of kisspeptin. Rev
971.
Endocr Metab Disord 2007; 8:1120.
Circulating leptin levels are significantly lower in patients with anorexia nervosa
This review summarizes recent findings in the activation of the reproductive axis by
compared with subjects with constitutional thinness, which might help to distin-
hypothalamic KiSS-1 neurons during puberty.
guish between these two conditions of severe underweight.
40 Lassek WD, Gaulin SJC. Menarche is related to fat distribution. Am J Physiol
 Anthropol 2007; 133:11471151. 49 Kratzsch J, Lammert A, Bottner A, et al. Circulating soluble leptin receptor and
In this paper, new insights about leptins role in the onset of menarche are free leptin index during childhood, puberty, and adolescence. J Clin Endo-
presented. Special attention is drawn to the role of fat distribution during puberty. crinol Metab 2002; 87:45874594.

41 Molina-Carballo A, Fernandez-Tardaguila E, Uberos-Fernandez J, et al. Long- 50 Audi L, Mantzoros CS, Vidal-Puig A, et al. Leptin in relation to resumption
 itudinal study of the simultaneous secretion of melatonin and leptin during of menses in women with anorexia nervosa. Mol Psychiatry 1998; 3:544
normal puberty. Horm Res 2007; 68:1119. 547.
In this work the authors suggest that melatonin and leptin do not interact in the 51 Chan JL, Wong SL, Orlova C, et al. Pharmacokinetics of recombinant
initiation or progression of human pubertal development.  methionyl human leptin after subcutaneous administration: variation of con-
42 Kasa-Vubu JZ, Ye W, Borer KT, et al. Twenty-four hour growth hormone and centration-dependent parameters according to assay. J Clin Endocrinol
 leptin secretion in active postpubertal adolescent girls: impact of fitness, Metab 2007; 92:23072311.
fatness, and age of menarche. J Clin Endocrinol Metab 2006; 91:39353940. Novel data on leptin pharmacokinetic parameters after subcutaneous r-metHu-
This paper introduces ghrelin as a biomarker of individual differences in energy Leptin administration are discussed, which will be relevant for the future ther-
balance during the menstrual cycle and across ethnicities. apeutic use of r-metHuLeptin.

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