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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2075-2079
Copyright © 1999 by The Endocrine Society

Original Studies

Leptin Secretion in Cushing’s Syndrome: Preservation of Diurnal Rhythm and Absent Response to Corticotropin-Releasing Hormone

Martina Weise, Veronica Abad, Robert V. Considine, Lynnette Nieman and Kristina I. Rother

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (M.W., V.A., L.N., K.I.R.), Bethesda, Maryland 20892; and the Division of Endocrinology, University of Indianapolis School of Medicine (R.V.C.), Indianapolis, Indiana 00000

Address all correspondence and requests for reprints to: Kristina I. Rother, M.D., Building 10, Room 10N262, National Institutes of Health, Bethesda, Maryland 20892. E-mail: rotherk{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The normal inverse relationship between leptin and cortisol is lost in chronic hypercortisolism. We studied this apparent dysregulation in patients with Cushing’s syndrome to investigate 1) the effect of chronic hypercortisolemia on the circadian rhythm of leptin secretion, 2) the response of leptin after administration of CRH, and 3) the short term effect of curative surgery on leptin.

The preoperative morning leptin concentration was 54.2 ± 8.1 ng/mL, and the nighttime value was 68.6 ± 9.8 ng/mL, reflecting a mean rise of 32.8 ± 7.6%, similar to the nocturnal increase observed in normal subjects. By contrast, cortisol’s diurnal variation (21.8 ± 1.7 vs. 16.9 ± 1.1 mg/dL) was blunted. In women, but not men, body mass index correlated with leptin (P = 0.001).

Preoperative ACTH and cortisol (both P < 0.0001), but not leptin levels increased after CRH. Ten days after surgery, basal cortisol values were subnormal (1.1 ± 0.6 mg/dL), but leptin levels remained unchanged and did not increase after CRH. Body mass index and insulin also remained unchanged. Insulin, but not age, urinary free cortisol, or plasma cortisol correlated with leptin (P < 0.05).

In summary, patients with Cushing’s syndrome have moderately elevated leptin levels that maintain an intact circadian rhythm but do not respond to acute or subacute alterations of cortisol.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADIPOCYTES secrete leptin in a circadian and pulsatile fashion (1, 2, 3). Maximum leptin secretion is observed shortly after midnight, whereas the lowest levels are found around noon (3, 4, 5, 6). Although multiple factors influence leptin expression and secretion, including insulin, glucocorticoids, catecholamines, and cytokines, the pulse generator of its highly organized secretion remains unknown. Absent or blunted excursions of diurnal leptin secretion have been described in nutritional extremes, such as anorexia nervosa (7) and obesity (3, 4), respectively. The existence of a feedback mechanism has been suggested involving a central suppressive effect of leptin on the hypothalamic-pituitary-adrenal axis (2) and a stimulatory effect of glucocorticoids on leptin in the periphery (5, 8, 9, 10, 11, 12, 13, 14, 15, 16). However, not all reports show consistent results (17, 18, 19).

This study was designed to investigate further the loss of the normal inverse relationship between leptin and cortisol in chronic hypercortisolism. We studied patients with ACTH-dependent Cushing’s syndrome and examined whether 1) their abnormal diurnal cortisol secretion was associated with a disturbed circadian rhythm of leptin; 2) acutely elevated cortisol concentrations after administration of CRH affected leptin; and 3) leptin concentrations decreased shortly after curative surgery. As previous studies in patients with Cushing’s syndrome showed no change in leptin over the short term (20), but a decrease during the long term follow-up period (8, 15), we attempted to identify other factors besides cortisol that affect leptin secretion and speculated that insulin may play an important role.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

We studied 30 patients who were referred to the NIH for evaluation and treatment of Cushing’s syndrome. The diagnosis of Cushing’s syndrome was made unequivocally in all patients and was based on history, physical examination, elevated 24-h urinary free cortisol (UFC) excretion, abnormal circadian cortisol secretion, ovine CRH test, positive imaging studies, and/or inferior petrosal sinus sampling. Written informed consent was obtained for the research studies. In 18 patients (group A) we studied diurnal leptin secretion, and in 12 patients (group B) we investigated the acute effects of CRH administration on leptin as well as leptin levels before and 10 days after surgical cure of Cushing’s syndrome.

In group A (14 females and 4 males; age range, 11–57 yr; 15 pituitary adenomas and 3 ectopic ACTH-producing tumors) we determined diurnal cortisol and leptin concentrations in the morning (0730 and 0800 h) and at night (2330 and 2400 h). Twenty-four-hour urine samples for UFC measurement were obtained on the same day.

In group B (7 females and 5 males; age range, 13–62 yr; all pituitary adenomas) CRH tests (1 mg ovine CRH/kg BW, iv) were performed before and 10 days after transsphenoidal surgery. ACTH, cortisol, and leptin concentrations were measured at -5 to 45 min during the preoperative and at -5 to 180 min during the postoperative CRH test. Fasting insulin levels were determined at time zero before injection of CRH. Preoperatively, urine samples were collected for UFC measurements during the 24 h before the CRH test. After transsphenoidal surgery, replacement therapy with hydrocortisone (12–15 mg/m2/day) was initiated in patients with evidence of adrenal insufficiency. However, glucocorticoids were withheld on the morning of the CRH test.

Hypogonadism was assessed by serum testosterone measurements in male patients and by a history of oligo/amenorrhea or menopause in female patients.

Assays

Serum leptin levels were determined by RIA (Human Leptin RIA kit, Linco Research, Inc., St. Charles, MO; normal range, 7.3 ± 9.3 ng/mL) (31). Cortisol was measured by fluorescence polarization immunoassay [TDxFLx kit for serum cortisol, Abbott Laboratories, North Chicago, IL (normal range: morning, 7–25 µg/dL; midnight, <7.5); Abbott TDx kit for urine (normal range, 24–108 µg/24 h)]. ACTH was determined by RIA after extraction [normal range supine (0800 h), <26.0 pg/mL] (21), insulin was determined by microparticle enzyme immunoassay (Abbott IMx kit; normal range, 11–18 µU/mL), and testosterone was determined by extraction chromatography followed by RIA (22) (normal range in men, 200-1000 ng/dL; in women, 20–60 ng/dL).

Statistical analyses

Body mass index (BMI) was calculated as weight (kilograms)/height2 (meters). Obesity was defined as a BMI greater than 27.3 for men and greater than 27.8 for women according to the criteria developed by the NIH Technology Assessment Conference Panel (23).

We determined the total area under the curve by the trapezoidal method for leptin, ACTH, and cortisol at -5, 0, 15, 30, and 45 min of the CRH test. As the postoperative CRH test did not include a 45 min value, we interpolated it from the 30 and 60 min concentrations, which were similar in all cases. For analysis of the diurnal variation of leptin and cortisol secretion, mean morning values were compared with mean nighttime values. Data are reported as the mean ± SE. Comparisons were made by Mann-Whitney test or Student’s t test as appropriate. The effect of CRH administration was analyzed by repeated measures ANOVA. Relationships among serum leptin, BMI, age, cortisol, insulin, and testosterone were assessed by linear correlation. Leptin and BMI were log transformed for correlation analysis. Adjustment for multiple comparisons was performed according to the Bonferroni method. Significance was accepted at P < 0.05, by two-tailed test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Entire group

Results for the entire group of 30 patients are summarized in Table 1Go. Obese patients (6 males and 13 females) had significantly (P < 0.01) higher leptin levels than patients with normal BMI (3 males and 8 females). Leptin correlated with BMI in women (r = 0.679; P = 0.001), but not in men or in the entire group (Fig. 1Go). Fasting leptin was significantly (P < 0.01) higher in women than in men despite similar age and BMI. Leptin levels were not correlated with serum cortisol or UFC values in the 30 patients. Hypogonadism was present in all male patients (testosterone range, 17.1–124.0 ng/dL) and in 17 of the 21 female patients (testosterone range, 10.3–96.8 ng/dL). In neither men nor women was leptin correlated with testosterone.


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  		Table 1. Fasting leptin and cortisol values in 30 patients (groups A and B) with Cushing’s syndrome before surgery

 


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  		Figure 1. Relationship between basal leptin levels and body mass index in 30 patients with Cushing’s syndrome (groups A and B) preoperatively. A significant correlation was observed for female (r = 0.679; P = 0.001), but not for male (r = -0.061; P < 0.5), patients.

 
Diurnal leptin secretion (group A)

Patient characteristics and results are shown in Table 2Go. Sixteen of 18 patients had a nocturnal rise in leptin (Fig. 2Go). The mean morning concentration was 54.2 ± 8.1 ng/mL (range, 11.8–158.3), and the mean nighttime value was 68.6 ± 9.8 ng/mL (range, 17.2–192.2). This reflects a mean rise of 32.8 ± 7.6% (range, -36.0 to 95.8). Obese (n = 10) and nonobese patients (n = 8) had very similar nocturnal leptin increases (32.9 ± 5.7 vs. 32.7 ± 16.3, respectively). The mean morning cortisol level was 21.8 ± 1.7 µg/dL (range, 14.2–45.6), and the mean nighttime value was 16.9 ± 1.1 µg/dL (range, 6.2–26.5). No correlation was observed between absolute leptin and cortisol concentrations or between {Delta} (difference between mean morning and nighttime values) leptin and {Delta} cortisol. In addition, the {Delta} leptin was independent of age and gender.


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  		Table 2. Diurnal variation in leptin and cortisol in 18 patients with Cushing’s syndrome (group A)

 


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  		Figure 2. Diurnal variation in leptin in 18 patients with Cushing’s syndrome (group A). Dots indicate individual morning (mean of 0730 and 0800 h values) and nighttime (mean of 2300 and 2400 h values) leptin concentrations.

 
Pre- and postoperative leptin levels and effect of CRH administration (group B)

Leptin, ACTH, and cortisol values during the pre- and postoperative CRH test are presented in Table 3Go. Preoperative CRH administration caused a marked rise in ACTH and cortisol (both P < 0.0001) as determined by ANOVA. However, leptin concentrations did not change.


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  		Table 3. Leptin, ACTH and cortisol levels during the pre- and postoperative CRH test in 12 patients with Cushing’s syndrome (group B)

 
Compared to preoperative values, postoperative basal ACTH and cortisol values were drastically decreased, and the response to CRH was significantly blunted. In contrast, leptin levels were similar before and 10 days after surgery both at baseline and after CRH administration. In addition, the magnitude of the postoperative ACTH and cortisol decline did not affect leptin.

Similarly, preoperative and postoperative BMI (32.9 ± 1.8 and 32.5 ± 1.8) and fasting insulin (19.3 ± 3.7 and 22.0 ± 6.7 mU/mL) did not change. Insulin and leptin concentrations correlated significantly both before (r = 0.714; P < 0.05) and after surgery (r = 0.683; P < 0.05).

Mean testosterone concentrations in the male patients increased from 81.6 ± 15.9 to 256.0 ± 61.6 ng/dL (P < 0.05) by the 10th postoperative day. However, this pronounced rise in testosterone was not associated with a decrease in leptin.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data provide evidence that cortisol feedback does not play a primary role in the control of circadian leptin secretion. We confirm that the abnormal secretion pattern of ACTH and cortisol in Cushing’s syndrome does not affect the diurnal rhythm of leptin (5) and show that the nocturnal rise in leptin in Cushing’s patients is similar to that reported in healthy subjects (4, 6, 24). In agreement with our results are studies reporting that factors such as day/night reversal and shift of meal times alter leptin rhythm, leading to a dissociation of the circadian secretion of leptin and cortisol (6, 25). Furthermore, the diurnal variation of leptin secretion was completely absent in patients with anorexia nervosa despite preserved cortisol rhythm (7).

Our finding that patients with chronic hypercortisolemia have moderately elevated leptin concentrations compared to previously published values in healthy subjects with similar BMI (1, 4, 26, 27) suggests that long term exposure to excess glucocorticoids may increase leptin secretion. These results contrast with other publications reporting leptin levels to be appropriately elevated for BMI in patients with Cushing’s syndrome both in men and women (20) or only in women (15). It is not evident that our patient population is different from these previously reported cases with Cushing’s syndrome. However, this inconsistency may be resolved by focusing on patients with a normal BMI. The mean leptin level in our nonobese patients was 33.5 ± 5.3 ng/mL, which is more than twice the reported concentration found in healthy subjects [12.0 ± 4.4 ng/mL (4) and 14.2 ± 2.2 ng/mL (26)]. In contrast, a smaller difference in leptin concentrations was observed between our obese patients (55.0 ± 7.1 ng/mL) and healthy subjects of comparable BMI (41.7 ± 9.0 ng/mL) (4). In addition, patients with Cushing’s syndrome have a predominantly visceral body fat distribution (28). Yet, the most important determinant of leptin concentrations in healthy subjects is subcutaneous fat (24, 29, 30). This also supports the concept that chronic hypercortisolemia directly or indirectly causes elevated leptin concentrations beyond simple obesity (8). Therefore, hypercortisolemia might interfere with the well established (3, 31, 32) correlation between BMI and leptin. In addition to our patients, this has recently been shown in depressed subjects with elevated cortisol levels (33).

In contrast, an acute increase in cortisol after the administration of CRH did not alter leptin in our patients with Cushing’s syndrome. Others have reported a similar lack of effect in healthy individuals (18, 19, 20) and in Cushing’s patients (20) after acute stimulation of the hypothalamic-pituitary-adrenal axis.

We also found that during the immediate postoperative period after cure of Cushing’s syndrome, leptin levels remained stable despite a dramatic decrease in cortisol and ACTH concentrations. Others also failed to find a decrease in leptin shortly after curative surgery (20), but described a decline later in the postoperative period (8, 15).

Taken together, data from this study and others suggest that factors other than glucocorticoids alone determine leptin secretion in patients with Cushing’s syndrome. Among these, body fat and chronic hyperinsulinemia may play the most important roles. In support of this premise, fasting leptin and insulin levels in our patients with Cushing’s syndrome were significantly correlated before and after surgery. Previously, insulin and leptin had been shown to closely correlate in lean and obese healthy subjects (27, 34, 35) as well as in patients with diabetes mellitus (36), insulin resistance (37), and insulinoma (38). Therefore, we speculate that chronic hypercortisolemia increases serum leptin indirectly via the associated chronic hyperinsulinemia and/or impaired insulin sensitivity.

It is well established that leptin is higher in females than in males (3, 39), which might be explained in part by a potent suppressive effect of androgens and a less pronounced stimulatory effect of estrogens on leptin (32, 39). In a state of chronic hypercortisolemia, we also observed this gender difference, although all male patients and the majority of our female patients were hypogonadal. However, testosterone levels were still significantly higher in the male patients. Yet, the marked increase in testosterone in our male patients in the postoperative period did not lead to a decrease in leptin. Therefore, like cortisol, testosterone does not appear to be involved in the acute regulation of leptin.

In summary, chronic hypercortisolism with abnormal ACTH and cortisol secretion does not abolish the diurnal rhythm of leptin. In this setting, acute changes in plasma cortisol concentrations do not affect leptin levels, whereas long term effects appear to be mediated by changes in the amount of body fat and possibly by serum insulin.


   Acknowledgments
 
We thank the nurses and staff of the NIH Clinical Center for invaluable help in clinical care and blood sampling, and Kevin Barnes for excellent technical support.

Received November 11, 1998.

Revised March 9, 1999.

Accepted March 10, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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