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Leptin and the Perioperative Neuroendocrinological Stress Response¹

Departments of Anesthesiology (Z.N.K.), Pediatrics (Z.N.K.), and Psychiatry (Z.Z., G.H.), Yale University School of Medicine, New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Zeev N. Kain, M.D., Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510. E-mail: zeev.kain{at}yale.edu

	Abstract

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The human response to surgical stress is characterized by massive release of neuroendocrine hormones, provoking catabolism, thermogenesis, and hyperglycemia. Considering the possible adverse outcomes of excessive stress hormones, understanding various components of the stress response may improve management of postoperative morbidity. Leptin, initially described as an adipocyte-derived signaling factor, may also play an important role in regulating the hypothalamo-pituitary-adrenocortical axis.

In phase I, plasma leptin and cortisol were measured in women before, during, and after total abdominal hysterectomy. The anesthetic technique was strictly controlled, balanced anesthesia. In phase II, plasma leptin and cortisol levels were measured in cardiac surgery patients. These subjects were anesthetized with a high dose opioid technique that blunts the intraoperative surgical stress response. In phase 1, mean leptin levels did not change over the week before surgery, had a maximal decrease to 49% of baseline 2 h after surgery, and increased to just above baseline 24 h postoperatively. Cortisol was 176% of the baseline just before surgery, peaked at 2 h after surgery (383%), and remained elevated 24 h (200%) and 48 h (165%) after surgery. During the first 2 h of surgery, the decrease in leptin parallels the increase in cortisol. In phase II, high dose fentanyl limited both the cortisol increase and the leptin decrease; thus, the ratio of cortisol increase to leptin decrease was similar for the cardiac patients and the hysterectomy patients.

These data indicate that leptin has a role in the surgically induced acute stress response in humans. Early in surgery the decrease in leptin parallels the increase in cortisol. This suggests a possible relationship between the neurobiology of these two systems, which could have important implications for regulation of the neuroendocrine response to surgical stress.

	Introduction

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THE HUMAN response to surgical stress is characterized by a series of inflammatory, hormonal, and metabolic changes that together constitute the global stress response (1, 2, 3, 4). Although it is clear that activation of the hypothalamo-pituitary-adrenocortical (HPA) axis is essential for the response for surgery, excessive activity may be detrimental. The stress-induced release of neuroendocrine hormones (e.g. ACTH, cortisol, GH, PRL, and antidiuretic hormone) and cytokines [e.g. interleukin-6 (IL-6)] provokes thermogenesis, hyperglycemia, loss of muscle protein, acute phase protein synthesis, and a decrease in the plasma divalent cations iron and zinc (2, 3, 5, 6).

Cortisol is of particular interest given that patients receiving inadequate replacement therapy have increased surgical morbidity and mortality, but the excessive cortisol levels seen in surgical patients may delay wound healing by promoting catabolism and inhibiting the immune system leading to postoperative immunosuppression and infection (3, 4, 7, 8, 9, 10, 11). Considering the numerous possible adverse outcomes associated with an excessive global surgical stress response, it is important to understand the various components of this response to improve postoperative morbidity and mortality (12).

Leptin, which was discovered 3 yr ago, was initially described as an adipocyte-derived signaling factor that, after interaction with its receptors, induced a complex response, including control of body weight and energy expenditure (13). Leptin’s receptors are abundant in brain areas such as the hypothalamus, cortex, dorsal Raphe nucleus, and cerebellum. Evidence supporting the claim that leptin was an adipostat was provided by the decrease in body weight and the improvement in metabolic control in rodents with genetic or diet-induced obesity that were injected with leptin (13). More recently, however, it was reported that leptin seems, in addition to its role in metabolic control, to have important roles in regulating the HPA axis, angiogensis, and the immune response (13, 14, 15, 16, 17, 18). The leptin-HPA axis interaction may be of clinical importance, and recent findings have led to the suggestion that leptin is an acute phase stress hormone (16). The data supporting this idea are mostly limited to studies involving animal models and human volunteers, and little previous work has been published about the relation of leptin and the HPA axis during acute stress in humans (14, 15, 19).

The purpose of this study was to characterize the dynamics of circulating leptin in relation to the acute activation of the HPA axis in women undergoing major elective abdominal surgery. We also studied a group of patients who underwent coronary artery bypass graft surgery and who received for their anesthetic very high doses of opioids. These high doses of opioids have been shown to blunt the cortisol surge that is typically associated with surgery (20).

	Materials and methods

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Experimental subjects and study design

In this observational cohort report, the patients included 21 women, aged 32–59 yr, with American Society of Anesthesiology physical status 1 or 2 (i.e. healthy or with a mild systemic illness) who were undergoing total abdominal hysterectomy secondary to bleeding fibroids. To avoid potential confounding variables, patients suspected as having a malignant process were not recruited for this study. In the second phase of this investigation, we studied 9 patients undergoing coronary artery bypass surgery secondary to ischemic heart disease. The studies were approved by the institutional review board, and written informed consent was obtained from all patients.

Study protocol (hysterectomy patients)

Patients were recruited 1 week before surgery while undergoing preoperative evaluation and testing in the hospital. The evaluation consisted of nursing and anesthesia functional health evaluation, provision of information regarding the surgery, and obtaining appropriate laboratory testing. After recruitment into the study, informed written consent and demographic data were obtained, and blood was drawn for later measurement of plasma cortisol and leptin. All baseline samples were obtained between 1000–1200 h.

On the morning of surgery at the admission area, an iv cannula was inserted into each patient, and blood was drawn before the patient received any drugs (0730–1030 h). The patients were next brought to the operating room where they underwent anesthesia and surgery. The anesthetic protocol was strictly controlled in all patients and consisted of an iv induction using 3–5 mg/kg thiopental, 0.1 mg/kg vecuronium, and 1–2 µg/kg fentanyl. Once intubated with an endotracheal tube, anesthesia was maintained with inhaled O₂/N₂O (1:2), isoflurane (0.5–1.5%), and iv fentanyl (1–2 µg/kg·h). Vecuronium was titrated to keep TOF (train of four) at less than 2 (0.05 mg/kg·dose). Upon the conclusion of the case, reversal of the muscle paralysis with neostigmine (3–5 mg) and glycopyrrolate (0.8–1 mg) was performed, and the patient’s trachea was extubated. Blood was obtained from all patients at 2 h intraoperatively and upon closure of the muscle layer.

Next, the patients were admitted to the postanesthesia care unit for a period of 1 h and then transferred to a surgical ward. Blood was obtained from all patients at 1, 2, 4, 24, and 48 h postoperatively. The patients’ postoperative pain was managed using patient-controlled analgesia with morphine sulfate. Typically, patients were discharged on postoperative day 3 unless a major complication occurred.

Study protocol (cardiac patients)

These subjects were recruited 1 day before surgery, after being admitted to the hospital. After recruitment to the study, informed written consent and demographic data were obtained. On the morning of surgery at the admission area, an iv cannula was inserted into each patient, and blood was drawn before the patients received any drugs. The subjects were next brought to the operating room where they underwent anesthesia and surgery. The anesthetic protocol was controlled strictly in all patients and consisted of an iv induction using 0.1 mg/kg vecuronium and 75–100 µg/kg fentanyl. Previous research has demonstrated that these high doses of fentanyl are capable of blunting the cortisol surge that typically is associated with intraoperative stress (20). Once intubated with an endotracheal tube, anesthesia was maintained with inhaled O₂ and iv fentanyl. Vecuronium was titrated to keep TOF (train of four) at less than 2 (0.05 mg/kg/dose). Blood samples were obtained on the morning of surgery (0730 h) and at 2 h into the surgical procedure (0930 h). The study was terminated at 2 h before the cardiopulmonary bypass was initiated, as large amounts of iv fluids and blood are typically given and hormonal concentrations are no longer accurate.

Measurements

Cortisol and leptin analyses were performed as follows. After obtaining blood from the subjects, each sample was transferred immediately into a precooled tube. After gentle mixing, the blood was centrifuged at 4000 rpm for 2 min, and the plasma was stored at -70 C. Samples were assayed in a single large batch, duplicates agreed within 15%, and quality assessment samples were well within the manufacturer’s defined range. Leptin was measured with a commercial enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN) that uses monoclonal antibodies. Cortisol was measured with a commercial RIA kit (INCSTAR Corp., Stillwater, MN).

Statistics

Data are expressed as the mean ± SD, and statistical significance was accepted at P < 0.05. Data were analyzed with the use of SPSS version 6.1.1 (SPSS, Inc., Evanston, IL). Change in hormone levels are displayed as the change from the baseline value that was obtained 1 week before surgery. This was calculated using the formula: displayed value = hormone levels at time t - baseline hormone level. Statistical differences over time were calculated by ANOVA for repeated measures with post-hoc testing with Dunnett’s test where appropriate. Correlations between leptin and body mass index (BMI) were determined by Pearson’s correlation coefficient.

	Results

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From Table 1, the mean age of the 21 women undergoing hysterectomy was 45 ± 9 yr, with an average BMI of 23 ± 6. Seventy-seven percent of the subjects had no other illness, and 23% had other illness, including migraine headaches and asthma. None of the patients in the study was routinely treated with any medication such as steroids or ergots. One patient had borderline hypertension.

View larger version (16K): [in this window] [in a new window]   Figure 1. a–c, Leptin and cortisol concentrations as a function of perioperative time. Zero on the time line indicates the morning of the day of surgery. The first data point (-168) represents when the baseline blood sample was obtained approximately 1 week before the day of surgery. Values are normalized to the baseline.

As shown in Fig. 1c, during the early onset of surgery the decrease in leptin parallels the increase in cortisol, and the correlation between the decrease in leptin levels and the increase in cortisol levels during that time period was moderate (r = 0.40). The correlation coefficient between BMI and percent change in leptin intraoperatively was nonsignificant (r = 0.12).

In Table 1, the ages and sexes of the nine patients recruited for the cardiac surgery study are given. They had a mean age of 69 ± 10 yr and consisted of six men and three women. None of the patients had diabetes or was taking any steroidal preparation. As shown in Table 2, high dose fentanyl limited the cortisol increase during open heart surgery to only 4.8 ± 0.3 µg/dL at 2 h intraoperatively. Interestingly, leptin levels decreased intraoperatively by only 3.5 ± 1.3 µg/mL; thus, the ratio of cortisol increase to leptin decrease was similar in the cardiac patients and the hysterectomy patients.

	Discussion

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These observations are consistent with the hypothesis that leptin has a biphasic response to acute stress. Acute perioperative stress results in an initial decrease in leptin levels, and as leptin has inhibitory effects on cortisol secretion, lower leptin levels may permit higher cortisol levels, which, in turn, trigger higher leptin levels 24 h later, possibly the result of increased leptin expression (21). This hypothesis is supported by previous reports that indicate that high levels of leptin inhibit the response of the HPA axis to acute stress in both animal models and humans (14, 19, 22). Further, Korbonits et al. previously reported an inverse relationship between cortisol and leptin in an investigation exploring the circadian rhythm in fasting subjects (23). Data reported by Bornstein et al. (24) and Pralong et al. (25) demonstrate that leptin also acts directly in the adrenal gland to suppress cortisol production. This inhibition was observed at concentrations of leptin occurring in humans in vivo, suggesting its physiological relevance (26). Because of the slower time course of the adrenal-suppressive effect, however, it may be that leptin has a long term regulatory effect in the adrenal, in contrast to its effects on the hypothalamus, which occur more rapidly. Leptin in concentrations that occur in vivo led to a dose-dependent reduction of basal cortisol release from adrenocortical cells in bovine primary cultures (24). Thus, we suggest that a decrease in leptin levels will result in higher cortisol levels. Although some studies suggest that at the hypothalamic level leptin may, in fact, stimulate CRH release, this phenomenon may relate more to the central control of appetite rather than to the activity of the peripheral adrenal axis (27, 28). The initial inverse relationship between leptin and cortisol also raises an alternative hypothesis that actually an initial cortisol surge triggered an initial decrease in leptin concentrations and not vice versa. To our knowledge, there are no published data to support this alternative hypothesis. Also, we cannot exclude the existence of another process, such as a third hormone that triggers both the decrease in leptin levels and the increase in cortisol levels.

There is evidence to support phase II of the biphasic response, where increased cortisol levels produce an increase in leptin levels. Previously, it has been shown that exogenous ACTH and cortisol can stimulate leptin expression and secretion from the adipocyte in animal models and human subjects (21, 29, 30, 31, 32, 33). These reports generally indicate that women and individuals with higher BMI have more robust increases in leptin response to glucocorticoid treatment. It should be noted, however, that other investigations suggest that the effects of glucocorticoids on leptin levels may be restricted to pharmacological dosing (34) and that endogenous ACTH and glucocorticoids do not significantly affect leptin concentrations (15, 22). Also, the study by Licinio et al. involved patients with Cushing’s disease who underwent curative surgery. Thus, the results of the study may not be applicable to patients with no known endocrinological disease who undergo elective surgery. Finally, cytokineses such as IL-1 and IL-6, which are elevated during the perioperative period, are also reported to stimulate leptin expression in rodents and humans (35, 36). These studies may explain our observations at 24 h postoperatively at which both cortisol and leptin levels were increased in our patients.

To our knowledge, only three previous investigations have reported about the relationship between leptin and the HPA axis in human subjects undergoing acute stress such as surgery or critical illness (37, 38, 39). Bornstein et al. followed a group of 16 critically ill patients diagnosed with sepsis. The investigators demonstrated that plasma levels were significantly increased in survivors of acute sepsis, whereas its circadian rhythmicity was significantly altered (38). Further, no inverse relationship between leptin and cortisol was reported in this study. We should note, however, that patients were recruited to the study after clinical evidence of sepsis have been established. Thus, the initial decrease in leptin levels may have not been observed in this study as it occurred before the onset of systemic symptoms. Further, the neuroendocrinological profile of patients with a life-threatening illness such as sepsis may be significantly different from that of relatively healthy women undergoing elective abdominal surgery. In a similar investigation, Torpy et al. measured plasma IL-6, leptin, and cortisol levels in patients with sepsis on their first day of intensive care unit admission and repeated their measurements on days 3 and 5 (37). The investigators reported that leptin levels were markedly elevated and showed little variation over a 24-h period. A significant negative correlation between leptin and cortisol and IL-6 levels was also reported (37). The researchers suggest, however, that the findings with respect to cortisol should be interpreted with caution, as reduced corticosteroid-binding globulin levels occur in septic shock, so free cortisol concentrations may be higher than implied by total cortisol levels. Stratton and colleagues followed six patients undergoing total hip replacement (39). The investigators report that leptin concentrations were significantly increased (56%) 24 h after surgery compared with the baseline value. There are no data, however, in Stratton’s study regarding leptin’s concentrations intraoperatively or over the first 24 h postoperatively. Thus, we suggest that the acute drop in leptin concentrations was missed in Stratton’s study because of the lack of frequent measurements.

The changes observed in leptin concentrations in our study could also be affected by the reduced food intake in our population. All patients were fasting for the first 24 h after surgery, and most patients were started on clear liquids on the second postoperative day. In rodents, leptin levels are greatly decreased after fasting (40). Similarly, in humans, a study reported a 64% decline in leptin levels in normal weight subjects after 24 h of fasting (41). Thus, as our subjects were all fasting during the first 24 h after surgery, they could have been expected to reduce their leptin concentrations at the 24-h sampling point. Therefore, the significant increase observed in our population at that sampling point underestimates the effect of surgery on the circulating leptin concentration.

It should be noted that the plasma creatinine levels of our patients did not suggest any impairment of the excretory function of the kidney, a major site for leptin removal (42). Thus, the initial decrease in leptin cannot be explained by a kidney problem.

Finally, phase II in our experiment demonstrates that this inverse relationship between leptin and cortisol is not related to the anesthetic technique. That is, even if the cortisol surge is blocked by pharmacological agents, the inverse relationship between cortisol and leptin persists, as evidenced by ratio of cortisol increase to leptin decrease that was similar for the cardiac patients and the hysterectomy patients.

In conclusion, it is clear that the connection between the function of the HPA axis and leptin is complex, with both positive and negative relationships being demonstrated. Thus, acute stress in humans is associated with an initial decrease in leptin levels. As in rats, leptin inhibits HPA function, the observed decreased plasma leptin during surgery may contribute to the stress-induced increased HPA function in humans.

	Footnotes

 
¹ This work was supported in part by the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

Received February 18, 1999.

Revised April 1, 1999.

Accepted April 7, 1999.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kain, Z. N. Articles by Heninger, G. Search for Related Content PubMed PubMed Citation Articles by Kain, Z. N. Articles by Heninger, G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Coronary Artery Bypass Surgery Hysterectomy Hazardous Substances DB FENTANYL HYDROCORTISONE