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Biology of Reproduction 63, 1219-1228 (2000)
© 2000 Society for the Study of Reproduction, Inc.

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Leptin in Pregnancy

Michael C. Henson,a,b,c,d, and V. Daniel Castracanee,f

a Departments of Obstetrics and Gynecology, b Physiology, and c Structural and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112-2699 d Tulane Regional Primate Research Center, Covington, Louisiana 70433-8915 e Department of Obstetrics and Gynecology, and f the Women's Health Research Institute of Amarillo, Texas Tech University Health Sciences Center, Amarillo, Texas 79106-1797


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 
Leptin is a polypeptide hormone that aids in the regulation of body weight and energy homeostasis and is linked to a variety of reproductive processes in both animals and humans. Thus, leptin may help regulate ovarian development and steroidogenesis and serve as either a primary signal initiating puberty or as a permissive regulator of sexual maturation. Perhaps significantly, peripheral leptin concentrations, adjusted for adiposity, are dramatically higher in females than in males throughout life. During primate pregnancy, maternal levels that arise from adipose stores and perhaps the placenta increase with advancing gestational age. Proposed physiological roles for leptin in pregnancy include the regulation of conceptus growth and development, fetal/placental angiogenesis, embryonic hematopoiesis, and hormone biosynthesis within the maternal-fetoplacental unit. The specific localization of both leptin and its receptor in the syncytiotrophoblast implies autocrine and/or paracrine relationships in this endocrinologically active tissue. Interactions of leptin with mechanisms regulating pre-eclampsia and maternal diabetes have also been suggested. Collectively, therefore, reports suggest that a better understanding of the regulation of leptin and its role(s) throughout gestation may eventually impact those causes of human perinatal morbidity and mortality that are exacerbated by intrauterine growth retardation, macrosomia, placental insufficiency, or prematurity.

conceptus, gene regulation, hormone action, leptin, leptin receptor, placenta, pregnancy, syncytiotrophoblast


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 
Leptin is a 167-amino acid polypeptide hormone originally assumed to be produced only by adipose cells [1]. This product of the obese (ob) gene has been identified as a modulator of feeding behavior and adipose stores [2] and may also be at least partially responsible for regulating food intake in both humans [3] and nonhuman primates [4]. Although the mechanism by which leptin modulates body composition is only partly understood, serum concentrations increase with adipose mass in both rodents and humans (among men, pre- or postmenopausal women, etc.) and probably communicate the status of energy reserves with the central nervous system for the purpose of regulating metabolic stores [5, 6]. In genetically obese, leptin-deficient rodents, administration of the polypeptide results in weight loss by inducing satiety via a specific hypothalamic receptor that is homologous to the cytokine receptor superfamily. The human leptin receptor exists in alternatively spliced isoforms that differ in the length of their intracellular domains and includes OB-RL, a long form that resides in the greatest abundance in the hypothalamus [7], and OB-RS, a short form expressed in the brain [8, 9] and other organs [1, 10–12]. In the mouse, as many as five isoforms are commonly referred to as OB-Ra–e [7]. Although the functions of the short forms are currently unclear, they may augment clearance from cells or act as a circulating leptin-binding protein [3]. Mutations in the ob gene are responsible for an absence of leptin production and for obesity in homozygous (ob/ob) mice [13]. Indeed, although a potential for receptor abnormalities exists, leptin-related human obesity is principally linked to a mutation-induced deficiency of the hormone [14, 15]. Additionally, a propensity toward leptin resistance in the obese may result from a failure in leptin signal transduction, the inability of a putative carrier protein to facilitate leptin delivery across the blood-brain barrier, or in a defect in a yet undefined effector mechanism. In any respect, mechanisms regulating human body weight are complex, as interplay with various hormonal axes probably affect leptin's ability to modulate adiposity [16–18].

Compelling evidence also suggests that leptin influences reproduction [19, 20]. Thus, leptin-treated prepubertal female mice reproduced at an earlier age than did nontreated controls, indicating that leptin may help to trigger puberty [21]. This observation identified leptin as the first peripherally produced molecule to accelerate the maturation of the reproductive axis in normal rodents [22]. Administration is associated with elevated LH concentrations and dramatic changes in ovarian and uterine weights and histology. Expression of leptin receptor mRNA transcripts in the rat ovary, uterus, hypothalamus, and anterior pituitary further demonstrate the potential of reproductive tissues for leptin responsiveness [23]. Importantly, leptin-associated mechanisms appear to be conserved across species, as leptin dose-dependently attenuated insulin-induced steroid production by bovine ovarian granulosa [24] and theca [25] cells. This, in addition to reports that leptin stimulates gonadotropin release in rhesus macaques [26], identifies the polypeptide as a mediator of reproduction in multiple species, from rodents to primates. In the human, mRNA transcripts for both leptin and its receptor are expressed in preovulatory follicles [27]. Transcripts for both the long and short isoforms of the leptin receptor were located in granulosa and theca cell populations [28, 29]. Leptin may also serve as a permissive regulator of human reproductive maturity [30, 31], as increases in peripheral levels are associated with the onset of menarche [32]. Women of reproductive age typically exhibit higher levels than men of comparable age or adiposity [3, 33, 34]. This unique gender dichotomy extends to adolescents, as prepubertal leptin levels in girls, although not in boys, were highly predictive of gains in adipose mass and the initiation of puberty [35]. Similarly, leptin levels in cycling women have been reported by some investigators to be greater than those in postmenopausal women [36], and circulating levels of the polypeptide in female neonates [37–40] and fetuses in utero [41] are higher than in their male counterparts, further implying a relationship with female reproductive development.


   LEPTIN AS A GESTATIONAL HORMONE
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 
In Human Pregnancy

During pregnancy, maternal serum leptin concentrations are greater than those in nonpregnant women [42]. Substantial increases in early pregnancy, before the occurrence of any notable increase in body weight due to progressive gestation, imply that factors other than increased adiposity mediate maternal leptin levels [43]. Numerous studies have demonstrated that maternal peripheral leptin levels are enhanced during pregnancy [38, 41–47] and collectively suggest that leptin concentrations peak in the second trimester and remain elevated until parturition. In many studies, however, the number of samples obtained during pregnancy was quite small, making an accurate evaluation of the leptin profile difficult, especially near term. In order to gain a better perspective of changes in leptin levels throughout gestation, we sampled a large number of women presenting for normal prenatal care, obtaining as many as 20 samples from each subject during pregnancy (unpublished observations). As expected, maternal serum leptin concentrations increased throughout most of pregnancy (Fig. 1). However, following midterm, levels appeared to decline prior to parturition, a decline that was formerly proposed on the conclusions drawn from a smaller data set [48].



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  		FIG. 1. Serum leptin concentrations in women sampled at 4–40 wk of gestation. Each point represents a single determination. The regression line depicted conforms (P < 0.05) to the quadratic (r = 0.581)

Fetal leptin concentrations, although lower than maternal levels, are detectable at term and are probably due to production by fetal adipose tissue [49]. Immunocytochemical staining of developing subcutaneous tissue of human embryos, at 6–10 wk of gestation, indicate that leptin is produced by developing fat cells from the beginning of lipidogenesis and differentiation [50]. Complementary studies in fetal sheep suggest a positive correlation between leptin transcript abundance and fetal body weight in late gestation [51]. Concentrations of the polypeptide are significant in the human fetus [45, 46] and levels in umbilical cord blood [52] at term are highly correlated with birth weight [45, 47, 53–55], although no correlation appears to exist between maternal peripheral concentrations and cord levels [45, 56]. Higher concentrations in umbilical veins than in umbilical arteries [55], combined with a precipitous decline in neonatal levels immediately following birth [57], imply that the placenta may be an important source of leptin in the fetal circulation, although some suggest that fetal adipose tissue is the main contributor to fetal leptin concentrations [41, 45]. Determination of specific leptin mRNA transcripts in placental tissue by reverse transcription-polymerase chain reaction (RT-PCR) at term [58, 59] and by Northern analysis in both first and third trimesters [60] supports a leptin-producing role for the placenta. Intriguingly, the placenta may be both a source of leptin and a target for its action, as leptin [59] and leptin receptor mRNA [10, 61] have been detected in placental trophoblasts. Localization of leptin protein to the syncytiotrophoblast by immunohistochemistry [58, 60] indicates that at least a portion of the increase noted in the maternal periphery with advancing gestation is of placental origin [62].

Recently, we investigated the expression of leptin and leptin receptor mRNA transcripts with advancing human pregnancy [61] and reported that specific transcripts for leptin, as well as for OB-RL and OB-RS receptor isoforms, were expressed in placenta, both early (7–14 wk) in gestation and at term (38 wk). Quantitative assessment of mRNA transcripts for genes of interest was made by competitive RT-PCR. Although no changes in OB-Rs and OB-RL transcript abundance were evident with respect to stage of gestation, the abundance of leptin mRNA transcripts in placental villous tissue decreased significantly (P < 0.005) at term (Fig. 2). Although Northern analysis had previously suggested that placental leptin mRNA transcripts might be present in greater abundance in early gestation [60], accurate quantitative comparisons were problematic due to the paucity of samples available from early pregnancies. Although reasons for the reverse trends evidenced by maternal leptin and placental leptin mRNA are as yet undefined, it may be that both a significant increase in maternal leptin concentrations and a decline in leptin mRNA abundance in syncytiotrophoblast are common features of advancing gestational age in human pregnancy. These findings differ from those of Dotsch et al. [63], however, who recently reported that the leptin/ß-actin or leptin/glyceraldehyde phosphate dehydrogenase ratios were sixfold lower in placentae from premature deliveries than from those at term. Unlike the first study, no comparisons were made between tissues collected at term with those collected early in the first trimester. Perhaps significantly, therefore, in vitro methodologies determined that leptin secretion from first trimester chorionic tissue was 50-fold greater than that from placental tissue collected at term [64]. It is still unclear if increasing leptin levels are primarily of placental or adipose tissue origin, are altered by increasing serum binding proteins or the progress of labor, or if perceived increases in placental leptin production with advancing gestational age are the result of translational, rather than transcriptional mechanisms.



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  		FIG. 2. Leptin mRNA transcripts (attomoles/µg total RNA) for human placental villous tissue collected early in gestation (7–14 wk, n = 6 placentae) and at term (38 wk, n = 5 placentae). Values are mean ± SEM. Different lowercase letters (a, b) indicate a significant difference between means. (Reprinted with permission from the American College of Obstetricians and Gynecologists [61].)

Although leptin receptor transcripts had previously been identified in term placental villous tissue [10], our recent study [61] identified both OB-RL or OB-RS isoforms in early pregnancy placenta. Although the mRNA encoding OB-RL is expressed as the predominant isoform in hypothalamus, it is generally recognized as being much less abundant in most tissues (lung, kidney, etc.) than the transcripts encoding short intracellular domain forms [7]. Our findings indicate that a similar disparity exists in human placental trophoblast. Additionally, in situ hybridization indicated that leptin, OB-RL and OB-RS mRNA transcript expression was exclusive to the endocrinologically active trophoblast, predominantly in the layer of syncytiotrophoblasts covering placental villi. In related studies, human placental cells were enzymatically dispersed and an enriched fraction of cytotrophoblasts sequestered [61]. After attaining syncytiotrophoblastic maturity in culture [65], transcripts for leptin (235 base pairs [bp]), OB-RL (427 bp), and OB-RS (329 bp) were identified by RT-PCR. Transcript expression in cultured cells suggests the suitability of in vitro paradigms for future studies of leptin dynamics in human pregnancy [60, 61].

In Nonhuman Primate Pregnancy

The baboon (Papio sp.) is a proven model for the study of endocrine mechanisms in human pregnancy [66–70]. Therefore, changes in leptin dynamics were evaluated relative to gestational age and similarities with human pregnancy noted [71]. Venous blood samples were obtained from both nonpregnant and pregnant baboons at regular intervals and serum leptin concentrations determined by RIA. Peripheral serum leptin concentrations (mean ± SEM) in pregnant baboons (n = 5), between days 60–160 of gestation (term {approx} 184 days) was 125.2 ± 11.4 ng/ml, as compared to 1.4 ± 0.1 ng/ml in nonpregnant animals in the luteal phase of the menstrual cycle (n = 6) and 1.8 ± 0.1 ng/ml in nonpregnant animals sampled 15–18 days following cesarean delivery (n = 4). Therefore, although leptin concentrations in cycling versus postpartum nonpregnant animals were similar (P > 0.05), concentrations in pregnant animals were dramatically higher (P < 0.01) than in either cycling or postpartum baboons. Concentrations in maternal serum increased significantly (P < 0.005) between Day 60 (63.6 ± 10.4 ng/ml) and Day 160 (157.8 ± 16.1 ng/ml) of gestation. Following both early pregnancy delivery (Days 58 and 64, n = 2) and near term delivery (Days 162 and 165, n = 2) maternal leptin levels plummeted (P < 0.005), within 15 days, to levels comparable to those of nonpregnant females. Additionally, specific mRNA transcripts for leptin were determined in placental villous tissue collected at early (Days 60–62, n = 5), mid (Days 98–102, n = 5), and late (Days 159–167, n = 5) pregnancy. As assessed by quantitative competitive RT-PCR (Fig. 3A), leptin transcripts in placental villous tissue declined approximately eightfold between early and late gestation (P < 0.02). Commensurately, maternal serum leptin levels (Fig. 3B) increased almost threefold between early and late gestation, and in late pregnancy therefore were greater (P < 0.005) than at either early or midgestation. Maternal leptin concentrations, throughout gestation, were positively correlated (r = 0.66, P < 0.001), and placental leptin mRNA levels were negatively correlated (r = -0.64, P < 0.01) with advancing gestational age. Maternal leptin concentrations were also correlated (r = 0.76, P < 0.01) with maternal body weight, although not with fetal weight, in late gestation.



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  		FIG. 3. Placental leptin mRNA levels (mean ± SEM) determined by quantitative competitive RT-PCR (A) and maternal serum leptin concentrations determined by RIA (B) in early (n = 5), mid (n = 5), and late (n = 5) baboon pregnancy. Different lowercase letters indicate significant differences between means (ab, P < 0.01; cd, P < 0.05). (Reprinted with permission from Henson et al. [71] © the Endocrine Society.)

As discussed previously, the leptin receptor exists as alternatively spliced isoforms that differ in the length of their intracellular domains. They include a long form, OB-RL, that has JAK/Stat signaling capabilities and a short form, OB-RS, that has distinct signaling capabilities involving mitogen activating protein kinase [72]. As depicted in Figure 4, expression of transcripts for both OB-RL and OB-RS was detected by RT-PCR in placental villous tissue, corpus luteum (CL), decidua, and amniochorion, as well as in maternal omental and subcutaneous adipose tissues collected from baboons [73]. Both OB-Rs and OB-RL mRNAs were present in adipose tissues and placenta at early, mid, and late pregnancy; and in CL, decidua, and amniochorion near term. The OB-RL and OB-RS isoform transcripts appeared to be expressed constitutively throughout gestation in both placenta and adipose tissue, with the short form expressed in greater (P < 0.02) abundance than the long form. Specific in situ hybridization determined transcript expression for both isoforms of the leptin receptor, mainly in syncytiotrophoblast. In the same manner, leptin transcript expression in placenta was localized predominantly in trophoblast cells, almost exclusively to that layer of syncytiotrophoblast encasing placental villi. Subjectively, expression intensity was greatest in early pregnancy, which was in keeping with the enhanced abundance of leptin transcripts at that time, as indicated by competitive RT-PCR [71].



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  		FIG. 4. Expression of mRNA transcripts for OB-RL (439 bp) and OB-RS (573 bp) was demonstrated by RT-PCR in baboon placental villous tissue (P), amniochorion (AC), decidua (D), corpus luteum (CL), omental adipose tissue (OAT), and subcutaneous adipose tissue (SAT). The first lane contains a 1-kilobase ladder. (Reprinted by permission of Blackwell Science, Inc. [73].)

In Rodent Pregnancy

In the pregnant mouse, serum leptin levels peak on Day 17 and are many fold higher than nonpregnant levels. Leptin was found in the placenta, decidua, uterus, and adipose tissue. Leptin mRNA in adipose tissue increased several fold over that in nonpregnant mice [74, 75]. Transcripts encoding leptin, as well as the leptin receptor, were identified in the mouse fetus and placenta in late pregnancy using RT-PCR and in situ hybridization. There were significant levels of gene expression for leptin and the long splice variant of the leptin receptor in the placenta, fetal cartilage, bone, and hair follicle. Receptor expression was also detected in lungs, as well as leptomeninges and choroid plexus of the fetal brain. These studies suggest that leptin may play a role in fetal development, either as a paracrine or endocrine regulator [75, 76]. Leptin receptor has been detected in placenta but not in decidua in vivo, and because it was unaffected by addition of leptin to placental cells in culture, this suggests that leptin does not regulate receptor concentrations. Addition of 8-bromo-cAMP to placental cultures inhibited both steady-state levels of leptin receptor mRNA and secretion of soluble leptin receptor into the media, suggesting that cAMP may be a natural regulator of soluble leptin receptor secretion by the mouse placenta [77]. Although these studies demonstrate that leptin is indeed produced during mouse pregnancy, expressed by the placenta, and that the receptor may be an important component of the system, the importance of leptin to pregnancy maintenance is not clear. The ob/ob mouse is infertile, but leptin administration will restore normal body weight, as well as fertility. When these animals were allowed to mate, withdrawal of leptin as early as 0.5 days postconception did not interfere with gestation, suggesting that leptin is not essential to the maintenance of mouse pregnancy [78]. Clearly, other studies are needed to determine the pregnancy-specific role(s) of leptin, if any, in this species.

In the pregnant rat, serum leptin increases during pregnancy [79], perhaps declining before parturition [80]. Leptin mRNA transcripts are expressed in various tissues [79–81], including the uterus, placenta, and maternal adipose tissue. Terada et al. [82], demonstrated that serum leptin levels in lactating rats were lower than in nonlactating rats, but only limited samples were obtained during the period of lactation. No increase in serum leptin levels was noted with advancing pregnancy, but a decline did occur by Day 20. This remains the only study in the pregnant rat that does not report an increase in maternal serum leptin with advancing gestation. In an earlier study [83], investigators were not able to demonstrate leptin mRNA in either the placenta or decidua. However, these results have been superceded with the advent of more sensitive methodologies, as subsequent studies have demonstrated an increase in serum leptin that declined before parturition, as well as leptin mRNA increasing in maternal adipose tissue as pregnancy advanced, but then decreasing by the third day of lactation. These authors have also suggested that insulin, placental lactogen, and steroids may be involved in the regulation of leptin production, although more studies are needed to confirm this. In a more recent study, Kawai et al. [84] colocalized a variety of splice variants of the leptin receptor, as well as placental lactogen-II, in the labyrinth zone of the placenta on Days 19–21. These results suggest a physiological, probably paracrine, role in the placenta.

During mouse pregnancy, OB-Re, a soluble form of the leptin receptor, is reported as being secreted into the peripheral circulation, where it has been suggested to bind leptin and prevent it from being bound by a signaling form of the receptor, thereby potentiating leptin resistance [78, 85]. Thus, observation of a 40-fold increase in this protein has been proposed to explain the counterintuitive enhancement in leptin concentration, an appetite suppressant, during pregnancy, a period of enhanced nutritional requirement [86]. Although prior studies have detected a similar protein in the human [87], a similarly dramatic rise in leptin-binding proteins has not been reported to occur with pregnancy [88], which may more closely resemble pregnancy in the rat, a species that exhibits only a 1.8-fold increase in binding protein during gestation [85]. We have observed that the elevated maternal serum levels in the pregnant rat peak around Day 18 and then decline by Day 21. Removal of the conceptuses via hysterectomy results in a premature decline in serum leptin, indicating the important role of the fetal-placental unit in maintaining elevated maternal serum leptin levels. In pregnant rats who nurse their young, there is a dramatic decline in serum leptin [89]. However, when pups were removed at the time of delivery, serum leptin levels increased above pregnant levels (Butterstein and Castracane, unpublished observations). In a similar manner to the decreased leptin levels reported in food-deprived lactating rats [90], this mechanism may allow the postpartum rat to meet the metabolic demands of lactation, because low leptin levels would be less likely to induce satiety.


   PROSPECTIVE ROLES FOR LEPTIN IN PREGNANCY
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 
Those physiological roles most commonly postulated for leptin during human pregnancy involve the regulation of fetal growth and conceptus development [91, 92]. Thus, Harigaya et al. [93] reported that leptin levels in infants whose birth weights were classed as large for gestational age were threefold higher than those for whom body weights were considered appropriate for gestational age and 12-fold greater than for those infants classed as small for gestational age. It has been proposed, therefore, that leptin in umbilical cord blood originates exclusively from fetal and/or placental sources and, in light of correlations with birth weight and/or ponderal index, may play a role in conceptus growth and development [94]. Others have reported similar results [52, 54, 95] and added that leptin concentrations in cord blood were also correlated with placental weights [53, 94–96], while others detected no correlation with placental weight [40, 49, 55, 93]. In addition to an association with birth weight, Ong et al. [97] noted that cord leptin levels were also correlated with infant length and head circumference. In this capacity, leptin in cord blood, originating in the placenta [59] and/or fetus [44, 48], may potentiate growth by modulating growth hormone (GH) secretion [98], as proposed in the rat [99], via regulation of GH-releasing hormone at the level of the hypothalamus [100, 101]. Indeed, leptin receptor mRNA has been identified in human fetal anterior pituitary, and leptin administration specifically stimulated GH secretion from primary human fetal pituitary cultures without affecting ACTH, prolactin, or gonadotropin secretion [102]. Although placental GH, originating in the syncytiotrophoblast, might also affect both placental development and overall conceptus growth by autocrine or paracrine mechanisms [103], a direct effect of leptin on placental GH production has yet to be reported.

Speculative functions for leptin during pregnancy are not limited to the regulation of conceptus growth [104], as it has also been proposed as a regulator of both hematopoiesis [105] and angiogenesis in various developmental models. Therefore, Cioffi et al. [106] reported that at least one isoform of the leptin receptor is expressed in murine fetal liver, the YS4 yolk sac-derived cell line, enriched hematopoietic stem cells, and in a variety of lymphohematopoietic cell lines. These findings support those of Hirose et al. [107] who reported a correlation between serum leptin levels and red blood cell counts in male adolescents. Similarly, transcripts for ObR/B219.1, a proposed hematological subtype of the leptin receptor, are detectable in blood cells within fetal vessels but not in placental cells [108]. Leptin receptor has also been shown to be expressed in human vasculature and in primary cultures of human endothelial cells. Both in vitro and in vivo assays have revealed that leptin possesses angiogenic activity via induction of neovascularization in normal rat corneas but not in corneas from genetically obese rats that lack functional leptin receptors [109]. Similarly, leptin may promote angiogenic processes in both cultured porcine aortic endothelial cells and human umbilical venous endothelial cells by activation of leptin receptors [110]. These observations fuel speculation that leptin may stimulate blood vessel formation in other tissues, as well.

Localization of leptin, OB-RL and OB-RS transcripts to the trophoblast may also relate to the placenta's function as an endocrine organ [62]. Thus, a delicate regulatory interplay of steroid and polypeptide hormones produced by the syncytiotrophoblast is basic to the maintenance of primate pregnancy [66, 67]. In this milieu, peripheral leptin levels increase with advancing gestation in both human and nonhuman primates. Indeed, leptin concentrations are correlated with progesterone levels during the luteal phase of the menstrual cycle and with hCG concentrations during human pregnancy [42], demonstrating the potential for regulatory associations with placental steroid and polypeptide hormones necessary for pregnancy maintenance. The potential for an association between leptin and hCG is supported further by the report of Yura et al. [64], that leptin secretion by first trimester placental villous tissue is approximately 50-fold greater than that by tissue collected at term. This period of peak leptin production corresponds closely with that of hCG. Because leptin receptors reside in the syncytiotrophoblast, a leptin-producing tissue, one may suggest the potential for autocrine and paracrine mechanisms in an organ that is responsible for the production of a wide range of hormones vital to conceptus maintenance. This potential may lend further significance to the report that leptin levels in women suffering spontaneous abortions in the first trimester were 38% lower (P < 0.001) than in women who successfully maintained their pregnancies [111]. In this regard, it has recently been determined that cultured first trimester cytotrophoblast cells produce leptin in considerable amounts and that secretion is potentiated by interleukin (IL)-1{alpha}, estradiol [112], and IL-6 [113]. Although earlier in vivo observations had implied a correlation between maternal hCG and leptin in early pregnancy [42], addition of recombinant leptin enhanced hCG release by trophoblast cells in this in vitro system and provided the first evidence for a role for leptin in placental endocrine function [112]. Similarly, as reviewed by Rosenbaum and Leibel [114], a great body of recent work indicates that leptin secretion is regulated by the steroid hormones. Although effects differ in regard to the tissue, species, and experimental paradigm employed, consensus opinion supports a role for estrogens in enhancing transcription/production in leptin-producing tissues and a role for androgens in inhibiting the synthesis of the polypeptide. This information, further implicating leptin with other hormones of trophoblastic origin, could link the polypeptide with mechanisms supporting pregnancy maintenance.

In addition to its projected roles as a regulator of fetal and placental development, leptin may be associated with mechanisms mediating lactation and neonatal growth, as well. Thus, leptin, which declines rapidly in maternal serum postpartum, is negatively correlated with serum prolactin levels in early lactation [44]. However, leptin concentrations were shown by Mukherjea et al. [115] to be dramatically higher in lactating women than in nonlactating controls, leading the authors to suggest a role for leptin in mobilizing needed energy reserves. Additionally, leptin receptor mRNA transcripts have been determined to be specifically expressed in ovine mammary epithelial cells, strongly suggesting a role in mammary gland growth and development [116]. Leptin levels in neonates decrease rapidly following birth. It has been proposed that this rapid decline might be important to the stimulation of feeding behavior and the maintenance of energy homeostasis in early life [46]. Perhaps relatedly, growth-retarded babies exhibiting low leptin levels at birth may indeed exhibit increased growth rates in early neonatal life, an effect still evident at 24 mo of age [97].


   PUTATIVE REGULATORY MECHANISMS FOR LEPTIN IN PREGNANCY
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 
It is evident that increases in maternal leptin levels throughout human [61] and baboon [71] pregnancy do not directly reflect concomitant decreases in placental leptin mRNA. Generally supportive of these findings, Ranganathan and coworkers [117] reported that serum leptin levels in humans are not directly related to adipose ob mRNA concentrations and that changes in leptin levels, while independent of fluctuations in mRNA abundance, are finely regulated by post-transcriptional mechanisms at the level of the adipocyte or by alteration of peripheral leptin degradation or clearance. Similarly, Kirchgessner et al. [118] found that plasma leptin was decreased in tumor necrosis factor (TNF) knockout mice, with no commensurate decline in mRNA, and that 3T3-L1 cells evidenced a similar disparity between transcript abundance and leptin secretion. Although one might postulate that a decline in placental leptin transcript abundance is simply not predictive of the amount of leptin protein secreted by the primate placenta or that the increasing mass of the syncytiotrophoblast, which increases with advancing gestation along with placental size, may be solely responsible for increases in maternal peripheral leptin concentrations, we might also hypothesize that 1) other pregnancy-specific tissues (decidua and amniochorion) may also produce leptin and, with increasing gestational age, contribute progressively greater amounts to the peripheral circulation; 2) an alteration in the placenta's contribution and/or that of maternal adipose stores, prompted by the elevated levels of hormones (most specifically, estrogen) typical of advancing primate pregnancy, might be at least partially responsible for increased serum leptin concentrations; or 3) the increase in maternal leptin concentrations with advancing gestational age might be attributed to the action of a leptin-binding protein or soluble leptin receptor expressed in greater abundance, or perhaps exclusively, during pregnancy. Interaction with such a circulating receptor may be responsible, at least in part, for the hyperleptinemia typical of pregnancy and may serve to inhibit optimal interaction with hypothalamic receptors during pregnancy, promoting a state of leptin resistance, similar in effect to that conferred by the suppressors of cytokine signaling (SOCS-3) in the hypothalamus [119].

In women of reproductive age, leptin and estradiol have been reported by some to have similar profiles throughout the menstrual cycle [120–122], further suggesting a role for estrogen in the stimulation of leptin secretion. However, results of studies have not been unanimous in establishing a link between estrogens and leptin, as Lin [123] reported that no change in circulating leptin concentrations occurred during normal menstrual cycles, and others have added that significant correlations between leptin and estrogen were only apparent following ovulation induction for in vitro fertilization [124–126]. Serum leptin levels have been reported to be dramatically higher in cycling women than in postmenopausal women [36], ostensibly in response to available estrogen, although recent work in our laboratory indicated no significant differences [34]. Estrogen replacement in postmenopausal women has also resulted in disparate conclusions. Thus, although investigations in North America [127] and the Netherlands [128] both concluded that short-term estrogen replacement increases leptin levels in postmenopausal women, the results of an Italian study suggested that serum leptin levels were depressed in women receiving estrogen replacement therapy over several months [129]. Disparities in results might possibly be due to differences in sampling techniques, to the diurnal cyclicity exhibited by leptin secretion [130], or to relative differences in adipose mass [131]. In rats, ovariectomy diminished leptin gene expression in subcutaneous and retroperitoneal white adipose tissue and caused a peripheral decline in serum leptin levels but enhanced expression in mesenteric white adipose tissue [36]. Administration of estradiol reversed all the effects of ovariectomy. Reports of the effects of estrogen in rodents are also not unanimous, however, as Brann et al. [132] noted that 5 µg estradiol administered to ovariectomized rats for 2 days significantly enhanced both leptin mRNA levels in adipose tissues and circulating leptin levels over that of untreated controls. Divergently, Wu-Peng et al. [133] reported no changes in transcription or leptin concentration in ovariectomized rats receiving 2.5 µg estradiol for 1–2 wk, although in fully differentiated 3T3-L1 mouse adipocytes, leptin release increased 120% when cultured with estradiol [47]. Similarly, estrogen, that rises in the human maternal circulation with advancing gestation [65–67] has been reported to enhance leptin secretion by cultured human placental cytotrophoblast cells in a dose-responsive manner [112]. Maternal serum leptin levels, however, are not directly correlated with peripheral estrogens [46, 47], perhaps as a result of increased leptin clearance and/or degradation in late pregnancy. Certainly, the effects of estrogen on leptin transcription and synthesis may be tissue specific. Evidence of tissue-specific rates of leptin gene transcription is plentiful, as rates of transcription in subcutaneous fat are significantly higher than in omental adipose depots in humans [134–136], and identification of a novel placenta-specific transcription factor [137] implies that placental leptin might be expected to be regulated differentially from leptin of adipose origin. Finally, the potential significance of a putative leptin-binding protein/soluble receptor to the maintenance of enhanced leptin levels in pregnancy should also be considered. Evidence has been found of a protein with definite leptin-binding capacity in human serum [85, 138]. As proposed by Heaney and Golde [139], these binding proteins may take the form of soluble hormone receptors, available in the peripheral serum. In a similar finding, a small increase in bound leptin is known to occur during human pregnancy [140]. It is unknown if leptin-binding capacity is affected by estrogen.


   LEPTIN AND PERINATAL MORBIDITY
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
SUMMARY
 REFERENCES
 
Possible interactions of leptin with mechanisms regulating pre-eclampsia and pregnancy-associated diabetes have been proposed. Thus, in pre-eclamptics, hypertension contributes to placental hypoxia, and plasma leptin levels are dramatically enhanced [141, 142], a situation that might be related to degree of adiposity, as women with prepregnancy body mass indices of >25 kg/m2 exhibited lower peripheral leptin levels compared to normotensives of similar adiposity [143]. In this capacity, leptin mRNA/ß-actin mRNA ratios were significantly higher in placental villous tissue from pre-eclamptics than in those of controls matched for gestational age. In pregnancies complicated by pre-eclampsia, certain angiogenic factors (vascular endothelial and placental growth factors) are depressed in maternal serum [144], potentially explaining the shallow placentation characteristic of this condition. Perhaps leptin, a proposed angiogenic regulator [110], may act to support some degree of placentation in such patients.

With respect to significant interactions of leptin with diabetes in pregnancy, placental leptin mRNA transcripts are enhanced in diabetics receiving insulin [145], as are maternal leptin concentrations [140, 145, 146]. Because this increase in leptin mRNA resulted in a three- to fivefold increase in placental leptin protein, it was proposed that insulin might regulate fetal weight gain via an upregulation of leptin secretion. Divergently, in mild gestational diabetes, maternal leptin levels are significantly lower than in nonaffected controls, who exhibit similar adiposity and fasting insulin levels [147]. Elevated leptin concentrations in cord blood are associated with macrosomia [148], although it was noted by Persson et al. [146] that among insulin-treated diabetic mothers, cord blood leptin levels were not correlated with birth weight or altered significantly with respect to gender, as is typical in normal pregnancy.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
REFERENCES
 
Investigations employing a variety of paradigms have strongly suggested that leptin may serve a number of important regulatory roles throughout gestation. Therefore, ongoing work in a number of laboratories is dedicated to answering the most important questions about leptin in pregnancy, which concern 1) the mechanisms by which leptin may affect conceptus growth and development, 2) the possible interaction of leptin with steroid and polypeptide hormone production in the placental syncytiotrophoblast, and 3) the potentially tissue-specific manner in which leptin biosynthesis and serum levels are regulated throughout pregnancy. Because leptin has only recently been recognized as a hormone important to pregnancy, it is difficult to envisage accurately all of its potential physiological functions or predict definitively the range of endocrine mechanisms regulating its secretion. However, apart from its postnatal role as a satiety factor, it appears that leptin may function in a variety of roles. With respect to the regulation of leptin production throughout gestation, significant cross-talk may occur between the placenta, fetus, and maternal adipose stores, with evidence implying that fetal and placental steroids that are present in increasing concentrations with advancing gestational age influence leptin synthesis/action in a tissue-specific manner. Mechanisms mediating leptin/leptin receptor synthesis may thus be sensitive to the changing endocrine milieu of gestation, changes that may actively alter leptin's role(s) with advancing pregnancy.


   FOOTNOTES
 
First decision: 3 April 2000.

1 Correspondence: Michael C. Henson, Department of Obstetrics and Gynecology (SL-11), Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699. FAX: 504 584 1846; michael.henson{at}tulane.edu Back

Accepted: May 17, 2000.

Received: March 13, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 LEPTIN AS A GESTATIONAL...
 PROSPECTIVE ROLES FOR LEPTIN...
 PUTATIVE REGULATORY MECHANISMS...
 LEPTIN AND PERINATAL MORBIDITY
 SUMMARY
 REFERENCES
 

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