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March 2001, Volume 51, Issue 3

Review Articles

Leptin’s Implications in Reproduction: Current Understandings

G. R. Lakho  ( Departments of Physiology. Jinnah Medical College, Karachi. )
M. A. Qureshi  ( Department of Physiology, University of Karachi, Karachi. )

Since the identification and sequencing of ob-gene and its product leptin (146 amino acids chain; 16 KD protein) secreted from adipocytes1, its role in body weight regulation and energy expenditure was extensively studied in rodents and humans2-7. It is hypothesized that leptin plays a central role in energy homeostasis and human obesity7-10. It has been postulated as a feedback regulator of adiposity leading to appetite suppression and catabolic effects11-13. Leptin is known to act through interaction with receptors in the hypothalamus to induce a complex response involving fat mass regulation, and energy homeostasis13-16.
Clinical aspects of leptin and its involvement in the pathophysiology of various disorders have also been discussed which emphasize its dual regulatory role in human physiology16,18. Its relation with other peripheral and neural mechanisms involved in variety of physiological processes other than body weight regulation are being considered and are affected by its multifunctional diversity e.g. hematopoiesis. cardiovascular, immunity, proinflammatory responses and reproduction, including puberty and pregnancy19-26. Leptin concentration and / or expression with certain metabolic indices and endogenous hormones e.g. GH, insulin, ACTI-I, CRH, CART, sex hormone, thyroid hormones and with certain disease conditions associated with obesity e.g. Prader-Willi Syndrome. D.M, obese diabetics, Cushing’s Syndrome, aging and in women with anorexia have been reported27-39.
Evidence is accumulating that leptin has pleiotropic activities, exerting effect not only on appetite and metabolic rate but also on reproductive events8,10,25,40-46. Thus, a putative role for leptin in human and rodent pregnancy and reproduction and importantly, in sexual maturation has been suggested43,44,47,48. Body weight and adipocyte appear to play a critical role in the timing of puberty and increasing adiposity is associated with rise of leptin. Further, experimental evidence suggests that leptin is the signal that informs the brain about sufficiency of energy stores to support the high energy demands of reproduction and may be a major determinant of the timing of puberty40. Leptin deficiency in ob/ob mouse is associated with hypogonadism and administration of recombinant leptin restores fertility23,41,49. Leptin administration accelerated puberty in normal mice23,40,50 and prevented the delay in ovulation induced by starvation in female mice51. It was demonstrated that normal pubertal mice after leptin administration had earlier maturation of reproductive tract and earlier reproduction, despite inhibition of growth rate23. It is well known that low body fat disrupts the reproductive system, denionstrated by fall in testosterone levels associated with increased LH secretion in men and the changes have been accounted by the drop in leptin production25 which suggests leptin action on hypothalamic-pituitary axis51,52 The observation of increased ovarian steroid synthesis in vitro as well as increased primary and Graffian follicle numbers provided further evidence for trophic action of leptin which stimulates GnRH41,53,54. In vivo, administration of estrogen increases circulating leptin in rodents and humans55. Leptin is shown to interact directly or indirectly with both the adrenal and gonadal axes and its levels are higher in women than in men56,57. Leptin inhibits CRH and hence ACTH and potentiates activity of GnRH neurons stimulating adrenal and gonadal functions, respectively10,58,59. Synthesis of leptin from human pre-ovulatory follicles and relationship of leptin with gonadal hormones have also been reported43,60. it was also found that that there is a slight decrease of leptin levels in postmenopausal (hypoestrogenem ic) compared to premenopausal women55,61. Rise in leptin levels at the onset of puberty62 and fall in postmenopausal women and its relationship with gonadotroph ins suggests an association of leptin’s changing concentrat ion with reproductive events. Oopherectomy of adult rats cause a significant decline in circulating leptin concentration that is reversed by estradiol supplementation65. Estradiol increases in vitro leptin production in omental adipose tissue of women but not men63. Circulating concentration of estradiol and testosterone have been reported to be significantly correlated with plasma leptin concentration in adult women64, but not in female children or adolescents65. Leptin concentration was negatively correlated with circulating testosterone in men. Circulating plasma leptin concentrations normalized to body weight mass index are significantly increased in hypogonadal as compared to eugonadal men. Leptin concentration is lowered in hypogonadal men after administration of testosteronebô. Circulating leptin’s sexual dimorphism has been reported61. Thus, leptin increase may be involved in either control or onset of puberty, known to be linked to the fat acquisition40,67-69. All these direct or indirect evidences therefore support the hypothesis that leptin may be the signal responsible for triggering the onset of pubescence in human beings70. The data suggests that leptin. acts as a signal to trigger puberty, thus supporting the hyp9 Thesis that fat accumulation enhances maturation of the reproductive tract. Thus. leptin may be one of the hormonal signals to the brain when the body is ready for maturation.
The relationship between leptin levels, steroid hormones and gonadotrophin concentrations during the menstrual cycle has been studied71-73. Plasma leptin level was found to increase during the late follicular and luteal phases of the menstrual cycle. Changes in circulating leptin levels were associated with menstrual phases and peak levels during luteal phases correlated with high progesterone levels. The cause of this relationship remains unknown. It may be that augmented adipocyte production of leptin in response to increased caloric intake occurs. Alternatively, there may be release of hypothalamic neuropeptide Y or release of leptin from mature ovarian follicles. A large body of evidence now supports the existence of a negative feedback system regulating food intake, leptin secretion and hypothalamic neuropeptide NPY expression52,74,75. The role of leptin in regulation of menstrual cycle and in preparing the body for the metabolic demands of pregnancy has been suggested72. Relationship between leptin and human reproduction is well documented. The possible role of leptin in various conditions like puberty, polycystic ovary syndrome and pregnancy as well as in ovarian functions and relationship with gonadal steroids has been reviewed54,60,70,71. However, physiological significance of many of these processes remains unclear.
Pregnancy is a physiological state associated with the alterations in food intake, energy expenditure, body weight and metabolism. The mechanisms by which maternal weight is regulated during pregnancy, particularly during the third trimester are poorly understood. One of the well known factors that increase the body weight during pregnancy is an increase in body fat tissue mass, providing the researchers with the assumption that leptin level increases during pregnancy. Scarce data exists with respect to leptin levels and its potential role during human pregnancy at term, data regarding relationship between maternal leptin and neonatal leptin levels is controversial in many aspects76,77. Although increased levels of leptin during pregnancy have been documented71,73,76,81, the functional significance, the sources and stimuli of leptin in maternal physiology are still not clear. However, the changes in circulating leptin parallel the process of fat accumulation and mobilization. Leptin has been found to correlate positively with weight, BMI, body fat mass and percentage of fat mass3,5,76,79. On the other hand, no correlation was found between maternal serum leptin levels and BMI77. Thus, at term, it remains controversial.
However, study in Pakistani subjects showed positive correlation between serum leptin levels and BMI at delivery81. In another study on humans, leptin concentration was increased progressively during the first two trimesters peaking at 28th week. The levels also correlated significantly with maternal weight and BMI26. Significant increase in leptin between the first two trimesters of pregnancy but not between second and third trimesters were also demonstrated73, suggesting that several hormones of pregnancy may contribute to increased leptin secretion. In pregnancy, appetite is increased and low leptin levels would be expected. In fact, the opposite is true and leptin levels in pregnancy are high. Leptin increase significantly during early pregnancy before any change in body fat and resting metabolic rate suggesting that pregnancy might represent a leptin resistance state82, while evaluating longitudinal changes in maternal leptin concentration, body composition and metabolic rate during early and late pregnancy in comparison to the pre-pregnancy state. In another study hyperleptinemia in pregnancy was attributable to binding of leptin to a form of leptin receptor secreted by the placenta83. Rise in leptin during pregnancy was due to expression of a binding protein, which was found to have sequence identity to the extracellular domain of the leptin receptors. The placenta was found to produce large amount of the ob-Re isoform of leptin receptors mRNA, while encodes a soluble binding protein. Binding of the leptin by a secreted form of the leptin receptors (from placenta) may be the cause of extreme hyperleptineamia of late pregnancy83. Placental basis for leptin production has also been documented through expression studies84. The placenta as a major source of leptin in fetal circulation is also supported by higher leptin levels in umbilical cord veins than in umbilical cord arteries and marked decrease during the neonatal period85. Increased concentration of leptin during pregnancy and in newborn infants supports contribution of placenta to the high levels of leptin found in umbilical cord suggesting a role of leptin in intrauterine growth and development80.
Although a relationship between leptin and the reproductive, processes clearly exists, the precise regulatory role of leptin in the menstrual cycle and pregnancy is not understood. Studies have suggested mechanisms by which
leptin may effect hypothalamic-pituitary-ovarian axis, this includes hypothalamic neuropeptide Y expression and/or presence of receptors in ovaries, which awaits confirmation.


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