Obstetrics & Gynecology:
Leptin as an Acute Stress‐Related Hormone in the Fetoplacental Circulation
Takahashi, Yuichiro MD, PhD; Yokoyama, Yasuhiro MD, PhD; Kawabata, Ichiro MD, PhD; Iwasa, Shinichi MD, PhD; Tamaya, Teruhiko MD, PhD
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, Japan; and Department of Obstetrics and Gynecology, Iwasa Hospital, Gifu City, Japan.
Address reprint requests to: Yuichiro Takahashi, MD, PhD, Gifu University School of Medicine, Department of Obstetrics and Gynecology, Tsukasamachi‐40, Gifu City, 500–8705, Japan; E‐mail: y‐firstname.lastname@example.org‐u.ac.jp.
The authors express their gratitude to Mr. John Cole for reading our draft and giving us suggestions on language and style.
Received September 10, 2001. Received in revised form March 29, 2002. Accepted April 18, 2002.
OBJECTIVE: To investigate the relationship between fetoplacental leptin secretion and blood gases.
METHODS: We measured the levels of umbilical arterial and venous leptin, umbilical cord gas, umbilical venous blood glucose, and estradiol‐17β (E2) in 89 pregnant women. Correlation between the leptin levels and other variables (gestational age, birth weight, maternal body weight, height, body mass index, maternal body weight gain, placental weight, umbilical cord gas data, and levels of umbilical venous blood glucose and E2) were examined statistically.
RESULTS: Umbilical arterial and venous leptin levels were 7.64 ± 12.76 and 7.76 ± 13.17 (ng/mL), respectively, correlating positively with carbon dioxide pressure levels (r = 0.446, P < .001; r = 0.406, P < .001, respectively) and correlating inversely with pH (r = −0.337, P = .001; r = −0.247, P = .019, respectively). Umbilical venous glucose, E2, and other factors did not correlate with leptin levels.
CONCLUSION: Leptin secretion into the fetoplacental circulation may be associated with fetal hypercapnia, suggesting two important roles for leptin: one for basal control of fetal fat tissue and one as an acute stress‐related hormone.
Leptin is a 16‐kD protein encoded by the ob gene. It is a hormone secreted by adipocytes1 and acts on the hypothalamic centers to regulate body weight,2 causing a decrease in food intake and an increase in body temperature and energy expenditure.3,4 In 1997, Masuzaki et al demonstrated leptin production in nonadipose tissues such as human placental trophoblastic and amniotic cells and in gestational trophoblastic neoplasms.5 The biological implication of circulated fetoplacental leptin is still controversial. Birth weight and placental weight positively correlated with umbilical cord blood leptin level,6–9 which has an independent association with intrauterine growth restriction10,11 and macrosomia.12 Maternal serum leptin was drastically reduced after placenta delivery,5 yet there was no correlation between maternal and cord leptin levels.13 This evidence shows that leptin's fetoplacental circulation is independent of its maternal circulation. The release of leptin from placenta into the fetal circulation was very low, compared with the release into the maternal circulation.14 Fetoplacental circulation of leptin may be influenced not only by fetal growth and fat tissue, but also by other related systems.
In adult humans, leptin is discussed as a stress‐related hormone.15–18 Chronic or repeated stress results in reduction of food intake and body weight in rats,19 suggesting that leptin plays a bridging role between stress and body fat control for maintaining homeostasis and energy supply. The aim of the present study is to clarify a plausible relationship between fetal distress and leptin secretion in fetoplacental circulation. Our hypothesis was that leptin may be not only a growth‐related hormone but also a bridging hormone between fetal stress and fetal energy control (fetal fat tissue decrease and fetal growth restriction).
MATERIALS AND METHODS
Eighty‐nine randomly selected pregnant women (Table 1) were enrolled in the study at the Department of Obstetrics and Gynecology, Gifu University School of Medicine, between January 1999 and June 2000. Prior informed, written consent for the following study was obtained from the women and the Research Committee for Human Subjects. Gestational age was 34–41 weeks. There were four fetuses with growth restriction and two with macrosomia, along with four women with preeclampsia and three women with diabetes mellitus.
Umbilical arterial (UA) and venous (UV) blood was collected at birth. All serum samples were stored at −20C until assayed. Serum leptin levels were measured by radioimmunoassay (Linco Research, St. Charles, MO) as previously described.20 Blood gas analysis was performed using a RADIOMETER analyzer (RADIOMETER, Copenhagen, Denmark). The UV blood glucose and estradiol‐17β (E2) levels were measured by routine methods for evaluation of maternal hyperglycemia21 and hormonal factors,22 respectively.
The paired Student t test for analysis of UA and UV leptin level differences was performed, and multivariate analysis between leptin levels and other variables—gestational age, birth weight, maternal body weight, maternal body weight gain, maternal height, maternal body mass index, placental weight, UV blood glucose, UV E2, UA and UV pH, oxygen pressure, carbon dioxide pressure, and base excess (Tables 1 and 2) was performed. A P value of < .05 was considered significant. We evaluated the fetal stress using the umbilical cord gas analysis after birth.
The UA and UV leptin levels were 7.64 ± 12.76 and 7.76 ± 13.17 (ng/mL), respectively (Table 2), and there was no significant difference between them by the paired Student t test. The UA and UV levels positively correlated with carbon dioxide pressure (r = 0.446, P < .001; r = 0.406, P < .001, respectively) (Figure 1) and inversely correlated with pH (r = −0.337, P = .001; r = −0.247, P = .019, respectively) (Table 3). There was no correlation between leptin levels and oxygen pressure, nor between leptin levels and base excess of UA and UV.
All maternal factors, UV blood glucose, and E2 failed to correlate with UA and UV leptin levels. Though the number of data is small, umbilical cord leptin has no tendency in each high‐risk groups (growth‐restricted fetus, macrosomia, maternal preeclampsia, maternal diabetes mellitus) (Figure 2).
Hypercapnia of the umbilical cord, monitored as fetal distress, is induced by acute placental dysfunction and umbilical cord occlusion. In this study, hypercapnia, but not base excess, correlated with leptin level, suggesting that leptin may be associated with acute stress. In adult humans, a significant correlation was reported between baseline levels of leptin and body mass index 3 days before cholecystectomy, but on the third postoperative day, there were significant increases in the serum levels of cortisol, free fatty acids, leptin, and C‐reactive protein,18 suggesting that there may be two biological implications of leptin secretion in body mass index and surgical stress. In the fetoplacental circulation, respiratory acidosis, which is one stress‐related factor, may induce leptin secretion. Umbilical cord erythropoietin as an adaptation factor for hypoxia is also associated with cord blood leptin in mothers with insulin‐dependent diabetes mellitus.21 Intrauterine growth restriction infants show an increased leptin level in the umbilical cord,11 whereas there is a positive correlation between fetal leptin levels and fetal fat mass in severe intrauterine growth restriction,23 demonstrating conflicting roles for leptin secretion from fetal fat mass. Intrauterine growth restriction induces chronic and acute asphyxic conditions via the stress of labor (contraction stress), causing an alteration in umbilical cord leptin levels.
Leptin secretion is increased in a human trophoblastic carcinoma cell line (BeWo cells) under hypoxic conditions, compared with those under normal conditions.24 The experiment may indicate that additional leptin secretion in the fetoplacental circulation has some relation with fetal asphyxia, but the evidence supported by that report is at present insufficient.
Cord blood hypertriglyceridemia is important for fetal energy supply when the fetus becomes asphyxic.25 Fetal hypoxia induces hypersecretion of catecholamines from fetal adrenal glands and accelerates the energy production of blood glucose from glycogen. When a fetus undergoes stress, free fatty acid may be secreted as a second energy source to compensate for increased glucose consumption, and leptin may have some relation with this mechanism. These metabolic features may have some connection to fetoplacental leptin secretion.
In conclusion, although the pathophysiology of leptin secretion in the fetoplacental circulation is complicated and leptin secretion seemingly has contradictory functions, it seems likely that leptin may have two important roles: one as an acute stress‐related hormone, and the other for fetal fat mass control. Further investigation into these theories could possibly clarify some mechanisms of fetal growth restriction and fetal asphyxia.
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© 2002 The American College of Obstetricians and Gynecologists