No_452.pdf

Thai Journal of Obstetrics and Gynaecology
June 2001, Vol.13, No.3, pp. 179-188


REVIEW


Leptin and female reproductive function
Nares Sukcharoen MD.

Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330,
THAILAND

Abstracts
Leptin is mainly synthesized by adipocytes and might represent the connecting link between fatty tissue and brain. It informs neuroendocrine pathways about the status of energy stores in adipose tissue. The integration of this peripheral signal in hypothalamic networks results in activation of peripheral pathways that control energy build-up and expenditure. It is also linked to a variety of reproductive processes in both animals and humans. The relationships between leptin and obesity, puberty, polycystic ovary syndrome, endometriosis, assisted fertility, and menopause are discussed. The role of leptin in fetal physiology and in normal and abnormal fetal growth as well as its role in diabetes, pregnancy, and pregnancy-induced hypertension are also reviewed. Leptin is a protein produced mainly by adipose tissue and plays an important role in the regulation of body weight and food intake.(1) Leptin suppresses the appetite, increases
the metabolic rate and is correlated with fat mass.(2) It has been proposed to be involved in
the control of the reproductive function and the pathophysiology of reproductive process e.g.
anorexia nervosa, polycystic ovary syndrome (PCOS), etc.(3) The present review
concentrates on the basic knowledge of letpin and its implication in the reproductive process.

Leptin, leptin receptor and signal transduction
Leptin is a 16 kDa non-glycosylated polypeptide of 146 amino acids discovered in 1994.(4) Leptin (from Greek leptos : thin) is a product of the ob gene, 18 kb long(5), located in the long arm of chromosome 7 (7q31).(6) This gene encodes a 167 amino acids activated by cleavage of a 21 amino acid residues.(4) Three-dimensional structure of leptin resembles that of cytokines and lactogenic hormones.(7) It is produced mainly by adipose tissue(4), but also by placenta(8), stomach(9) and skeletal muscle.(10) It circulates in the blood (at concentrations paralleling the amount of fat reserves), and acts at the hypothalamic level as a satiety factor. Leptin circulates in biological fluids both as a free protein and in a form that is bound to the soluble isoform of its receptor (Ob-Re)(11). It has a half-life of 30 minutes.(12) Its secretion is pulsatile and shows a circadian rhythm, with a nocturnal rise reaching its peak between 1-2 a.m.(13) This pulsatile pattern is synchronized with that of luteinizing hormone (LH).(14) It is liberated as 3.6 pulses every 24 hours, usually 2 to 3 hours after meals. The main elimination route for leptin is via the kidney.(15) Leptin receptors are the products of the db gene and belongs to the class I cytokine superfamily of receptors. It encodes a protein of variable length. Five different types of receptors have been identified, with ubiquitous locations among tissues, e.g., Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, and Ob-Re.(16) (Figure 1) Only Ob-Rb contains a long intracellular domain and carries both of the protein motifs that are necessary for the activation of the Janus kinase–signal transducers and activators of transcription (JAK–STAT) pathway. Ob-Rb is mainly expressed in the hypothalamus, and its expression is much lower in peripheral tissues, where the prevalent isoform is Ob-Ra.(17) Leptin receptors are found in many areas of the brain, including the hypothalamus, cerebellum, cortex, hippocampus, thalamus, choroid plexus, and brain capillary endothelium. Leptin receptors are also expressed in peripheral tissues, including the lung, kidney, liver, pancreas, adrenals, ovaries, hematopoietic stem cells, and skeletal muscle, whereas the soluble leptin receptor isoform that circulates in the serum functions as a leptin-binding protein.(18)
Fig. 1. Schematic representation of leptin receptor (Ob-R) isoforms. The gene encodes five
different splice variants (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Re). Only Ob-Rb contains
both of the protein motifs (Box 1 and Box 2) that are capable of activating the Janus kinase
(JAK)-signal transducers and activators of transcription (STAT) pathway. (aa : amino acids,
EC : extracellular, IC : intracellular, TM : transmembrane)(17)
Regulation of leptin synthesis and secretion
The regulation of leptin synthesis and secretion is dependent on multiple factors. (Table 1) Women seem to have higher leptin levels than men.(19,20) The gender difference in
leptin levels seems to be explained by differential effects of sex hormones, in particular an
inhibition by testosterone, in addition to the differences in body composition, with women
having more subcutaneous fat, secreting more leptin. Leptin levels increase exponentially
with increasing fat mass(2), and leptin production is higher in subcutaneous fat than in
visceral fat depot.(21)
Table 1. Factors that influence leptin levels
Decrease leptin levels
Prolonged fasting(22)
Isoproterenol, Somatostatin(23)
Cigarette smoking(24)
Thiazolidinediones(25)
Metformin(26)
Diazoxide(27)
Increase leptin levels
Fat mass(2)
Overfeeding(28)
Prolonged insulin infusions or supraphysiologic insulin levels (29-31)
Glucocorticoid administration(32-34)
Before puberty and at the onset of puberty(35,36)
Estrogen(37)
During food excess, energy balance is usually positive, causing anabolic pathways to be activated and glycogen synthesis and triglyceride deposit to occur. Such an energy state
enhances leptin synthesis and liberation from adipocytes. Leptin receptors in hypothalamic
arcuate nuclei induce a satiety state and augment energy expenditure with heat
production.(38) In contrast, during starvation, a negative energy balance ensues with limited
amounts of available substrates. Catabolic pathways are activated that generate glucose
from glycogen, amino acids from proteins, and free fatty acids and glycerol from triglycerides.
In this state, leptin synthesis and secretion are decreased, and the hypothalamus induces
food-seeking behavior. This response is accompanied by a reduction in metabolic rate and
heat-generating mechanisms. These changes enhance energy and substrate preservation in
adverse conditions. (39)

The role of leptin in female reproductive physiology
Leptin and adipose tissue are systemic modulators of the hypothalamus–pituitary– gonadal (HPG) axis. (Figure 2) Leptin acts at multiple levels of the reproductive axis, eliciting different effects on reproduction depending on its concentrations in the blood. The saturable system of leptin transport through the blood–brain barrier prevents high levels of leptin reaching hypothalamic receptors, where leptin exerts stimulatory actions on gonadotropin-releasing hormone (GnRH) and in turn gonadotropin secretion. By contrast, excess levels of leptin have the potential to act on peripheral leptin receptors and exert inhibitory actions on testicular and ovarian steroidogenesis.
Fig. 2. Model for the dual roles of leptin in the regulation of adipose mass and reproduction.
Leptin is secreted from adipocytes and finds its way to the arcuate region of the
hypothalamus where it activates leptin-receptor-expressing neurons. Projections from these
neurons will in turn stimulate melanocortin MC4 receptors and neuropeptide Y (NPY)-
containing neurons to activate the sympathetic nervous system, which controls lipolysis in
white adipose tissue. The firing of gonadotrophin releasing hormone (GnRH)-containing
neurons and secretion of GnRH to the pituitary is elicited by leptin mediated activation of
leptin-receptor-expressing neurons and by other factors, such as growth hormone (GH),
NPY, insulin and others that control the reproductive axis. The ultimate consequences of
leptin activation are the regulation of lipolysis and the firing of the reproductive system. This
oversimplification does not show the projections of other neurons, which might impact on
either pathway stimulated by leptin. Abbreviations: FSH, follicle-stimulating hormone; LH,
luteinizing hormone.(40)

Leptin in childhood and puberty
Because a critical threshold in fat mass has to be reached to initiate puberty and maintenance of menstrual cycles and reproductive ability, leptin may be the signal from
energy storage to the reproductive axis to elicit sexual development.(41,42) In normal children,
leptin levels increase before puberty as body fat mass increases and reach their peak at the
onset of puberty, suggesting that leptin may trigger puberty in humans.(36,43) In contrast,
persons with inactivating mutations of the leptin receptor are morbidly obese, remain
prepubertal, and have hypogonadotrophic hypogonadism.(44) However, leptin may not be
essential to this process; puberty, sexual development, and pregnancy have been observed
in patients with lipoatrophic diabetes.(45)

Leptin levels during the menstrual cycle
Longitudinal studies have found a physiological fluctuation of leptin levels during the menstrual cycle, with lower circulating leptin levels in the early follicular phase, an increase in
leptin in the luteal phase of the cycle, and a pre-ovulatory peak in leptin.(46-48) It may
increase in the follicular phase of superovulated cycles.(49) The changes in leptin are
associated with changes in progesterone(46,47), estrogens(37,50) and LH.(13,51) It is important to
be aware of this variation when studying leptin levels in women, in order to measure leptin at
the same moment of the cycle. In women taking oral contraceptives, leptin levels remain
unchanged throughout the cycle(52), but levels are not different from normally cycling
females.(53)

Leptin in menopause
It has been proposed that a decrease in leptin levels found at menopause was due to the fall in estrogen levels.(54) However, most other studies found no differences in leptin
levels between pre- and postmenopausal women, when matched for BMI.(19,53,55,56) Hormone
replacement therapy (with estrogens and progesterone) does not seem to affect leptin levels
in post-menopausal women either.(53,55,57,58)

Leptin in female reproductive problems
Leptin in polycystic ovarian disease
Women with the polycystic ovary syndrome (PCOS) are hyperandrogenic, with increased plasma androstenedione and testosterone levels, are often characterized by visceral obesity, hyperinsulinaemia, insulin resistance, and anovulation. Leptin status in these women is not clear. Several studies found leptin levels in women with PCOS to be higher than expected for their BMI(59-61), but other studies found leptin levels comparable with age- and weight-matched control women.(62-64) A possible explanation for these different findings could be that the phenotype of PCOS can vary considerably, and that not all women with PCOS are to the same degree (abdominally) obese. The variability in leptin levels can possibly be explained in part by differences in body composition. But even with similar leptin levels, the activity could differ in women with PCOS, for example by a different proportion of bound leptin circulating in the blood, differences in leptin pulsatility, or a reduced sensitivity of the hypothalamic-pituitary-ovary axis in women with PCOS.(65) Furthermore, recent data indicate that locally acting leptin may be more important than circulating leptin in the pathogenesis of the polycystic ovary syndrome and type 2 diabetes.(66,67) To evaluate the importance of leptin in female fertility, serum and follicular fluid leptin values have been measured in different categories of patients – women who succeeded (and
women who failed) in becoming pregnant after assisted reproductive cycles, and patients
with PCOS. It was found that lower follicular fluid leptin concentrations are a predictor of
pregnancy success, both in normal women and in those with PCOS, possibly through direct
ovarian actions resulting in impaired oocyte quality and/or early embryo development.(68,69)
Leptin in endometriosis
Leptin levels in plasma and peritoneal fluid from patients who have endometriosis is higher than normal women, especially peritoneal endometriosis. This may be due to its
angiogenic activity and ability to modulate the immune response through receptors in T cells
(CD4).(71-73)

Leptin in eating disorders
Serum leptin levels in patients with anorexia nervosa, bulimia, nonspecific eating disorders(74,75), and depression(76) are similar to those of healthy persons with comparable
body mass index. However, decreased serum leptin was recently found to be associated
with alterations in eating patterns, metabolic rate, and neuroendocrine regulation in bulimia
nervosa.(77)

Anorexia nervosa
In anorexia nervosa, severe undernutrition is associated with extremely low plasma and cerebrospinal fluid leptin levels, low and apulsatile gonadotropins, altered menstrual
function and amenorrhea.(78) Leptin values below 1.85 ng/ml have been found to associate
with amenorrhea in underweight females with eating disorders(79); in addition, the resumption
of menses is associated with leptin levels above this threshold. However, in underweight
patients the rapid increment in serum leptin with weight gain is not concomitant with
menstruation, which suggests that the normalization of menstrual periods might depend on
additional factors such as the GH–insulin-like growth factor I (IGF-I) axis. These observations
indicate that leptin values above a certain threshold might be necessary, but not sufficient,
for the resumption of menses in anorexia nervosa patients.(80)

Mutations of the genes encoding leptin and its receptor
Mutations of the genes encoding leptin and its receptor have also been found in humans. In adult patients, homozygous missense mutations of the gene encoding the leptin receptor determine severe early-onset obesity, failure to enter puberty, primary amenorrhoea in females and clinical features of hypogonadism in males (no beard, scanty pubic and axillary hair, small penis and testes), with a prepubertal pattern of gonadotropin secretion.(81) The treatment of a nine-year-old patient with congenital leptin deficiency with recombinant leptin for 12 months led to a marked reduction in weight and fat mass, and the appearance of a nocturnal pulsatile secretory pattern of gonadotropins, which is characteristic of early puberty.(82) Similarly, female patients have been described who are homozygous for missense mutations in the db gene that encode a truncated leptin receptor lacking both the transmembrane and the intracellular domains. These patients do not spontaneously enter puberty, have no apparent mammary glands, sparse pubic hair and amenorrhoea, with low basal and human chorionic gonadotropin (hCG)-stimulated concentrations of estradiol, LH and folliclestimulating hormone (FSH). These data clearly indicate that correct signaling through Ob-R is necessary for sexual maturation in women.(83)
Leptin during pregnancy
During pregnancy, plasma leptin levels are elevated(84,85), rising especially during the second trimester(86,87), and dropping sharply after delivery.(88) This increase is correlated with gestational weight gain, and absolute leptin levels are correlated with BMI.(85,86) This hyperleptinemia during pregnancy occurs with the appearance of a circulating form of the leptin receptor, functioning as a binding protein.(87) Another factor contributing to the rise in leptin levels is the production of leptin by placenta(8) and fetus (89), partly secreted into the maternal circulation. During pregnancy, insulin levels are increased during pregnancy, and also gestational hormones like human chorionic gonadotrophin and estrogen can stimulate leptin production
by adipocytes. It is not clear whether leptin synthesized by placenta acts as a growth factor
for the fetus or as a signal of energy status between mother and fetus. However, no
correlation between maternal leptin levels and birth weight was found(86,90), in contrast to cord
serum leptin concentrations and leptin levels in infants at birth, which are correlated with birth
weight.(90,91) Female fetuses have higher levels than males. These differences persist until
early neonatal life.(92) Leptin concentrations also correlate with weight gain.(93) Levels vary
with time of day (higher in morning hours) and seasons (higher in spring and summer).(94)
The drop in leptin levels seen after delivery could play a role in the reduced fertility during the
period of lactation.

Leptin in complicated pregnancy
Fetuses with intrauterine growth retardation have lower leptin levels due to a reduction in fat tissue accretion. In insulin-dependent diabetic pregnancies, leptin receptors
are increased as an expression of leptin resistance.(95) In pregnancy-induced hypertension,
patients have higher leptin levels(96), and placental production of leptin is increased.
Trophoblastic cells that were cultured under hypoxic conditions secreted more leptin than
cultures in a normoxic environment. Leptin may be useful in the future as a marker of
placental ischemia.(97)

Leptin in the neonate
The level of leptin in cord blood derived from both the placenta and fetal tissues, is positively associated with the body weight and fat mass of the neonate, decrease in response to maternal smoking, is lower in preterm infants and those who are small for gestational age, and is higher in those who are large for gestational age.(91,98) Apart from signaling energy reserves to the brain, leptin may regulate growth(99) and promote hematopoiesis and lymphopoiesis in newborn infants.(100,101) Infants of diabetic mothers(102) or those with a family history of obesity on the paternal side(94) also have higher leptin levels. Immunoreactive leptin has been identified in human milk and in mammary epithelial cells. It is well known that many cytokines and growth factors are present in human milk. Thus, it is possible that leptin plays a role in infant development and growth.(103,104) In conclusions Leptin, an adipocyte-derived hormone known to play an important role in body-weight regulation, has been shown to be expressed differentially in men and women. These observations are potentially important for the understanding of differences between men and women in regulation of food intake, weight gain, and body fat distribution. Leptin is also involved in female reproduction and pregnancy, especially a trigger of puberty, and might play a predominant role in conditions with abnormally low plasma concentrations, such as in subjects with very low BMI (anorexia nervosa) or in patients with homozygous mutations of the ob gene. Although the exact mechanisms and interactions with sex steroids are not yet fully established, it is clear that leptin plays a role as an endocrine mediator in sexual development, reproduction and pregnancy.
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