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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 600-603
Copyright © 1998 by The Endocrine Society

Original Studies

Determinants of Serum Leptin Levels in Cushing’s Syndrome

Adji Widjaja, Thomas H. Schürmeyer, Alexander Von Zur Mühlen and Georg Brabant

Department of Clinical Endocrinology, Medizinische Hochschule Hannover (A.W., T.H.S., A.V.Z.M., G.B.), Hannover; and the Department of Endocrinology and Metabolism, FPP, Trier University (T.H.S.), Trier, Germany

Address all correspondence and requests for reprints to: Dr. A. Widjaja, Department of Clinical Endocrinology, Medizinische Hochschule Hannover, D-30623 Hannover, Germany. E-mail: ndxdadji{at}rrzn-serv.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing’s syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 ± 2.7 yr; body mass index (BMI), 29.6 ± 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 ± 3.1 yr; BMI, 26.3 ± 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing’s syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing’s syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CLONING OF the ob gene (1) has provided new insights into the molecular mechanism underlying obesity (2, 3). Expression of the ob gene is subject to regulation of nutrition and energy balance, and hormones such as insulin, catecholamines, or sex steroids have been shown in animal studies and men to profoundly influence circulating serum leptin levels (4, 5, 6, 7, 8, 9, 10, 11). A direct impact of glucocorticoids on ob gene expression was anticipated because of their well described effects on feeding behavior and long term energy balance. Glucocorticosteroids stimulate feeding behavior and insulin secretion, partly through a central hypothalamic action on NPY expression in the arcuate nucleus (12). In addition, glucocorticoids may induce insulin resistance, and insulin by itself stimulates leptin production in vivo and in vitro (4, 8, 13, 14, 15). Glucocorticoids act directly on ob gene transcription, and this stimulatory effect on leptin transcription is potentiated by a costimulation with insulin, as shown in in vitro cultures of human and rat adipocytes (9, 10, 16). Conversely, chronic administration of leptin to ob/ob mice shows a negative feedback of leptin on plasma corticosterone levels (17). In humans, only few data with contradictory results are available regarding the influence of chronic glucocorticoid excess on serum leptin levels (18, 19, 20, 21). We, therefore, studied serum leptin concentrations in a large group of patients with Cushing’s syndrome during active disease and in a small subgroup of these patients after successful removal of the tumor.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Cushing’s syndrome was diagnosed in 50 patients by clinical stigmata along with elevated 24-h urinary excretion of cortisol and lack of cortisol suppression after dexamethasone administration. Table 1Go summarizes the clinical characteristics of patients with Cushing’s syndrome.


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  		Table 1. Demographic details of 50 subjects with Cushing’s syndrome according to gender with serum leptin, cortisol, and plasma insulin concentrations

 
Fasting serum leptin and insulin levels were measured in all patients by sampling blood at 0800 h after an overnight fast starting at 2200 h and compared to the levels of 50 healthy controls matched 1:1 by gender (34 females and 16 males), age (±5 yr; females: mean, 40.5 yr; range, 18–70 yr; males: mean, 39.2 yr; range, 19–58 yr), and body mass index (BMI; ±3 kg/m2; females: mean, 26.1 kg/m2; range, 18.0–49.1 kg/m2; males: mean, 25.8 kg/m2; range, 18.3–52.1 kg/m2). The normal reference range of fasting insulin in our laboratory is below 9 mU/L. In 17 patients, Cushing’s syndrome was accompanied by diabetes mellitus according to WHO criteria. Five patients (female) were treated with insulin, 5 (4 females and 1 male) were treated with oral hypoglycemic agents, and 7 (5 females and 2 males) were treated with diet alone. In addition, serum cortisol levels were measured in all patients as a 24-h mean of 144 samples taken in 10-min intervals from 2000–2000 h. The normal reference range for the 24-h mean of serum cortisol is less than 8 µg/dL. The thyrotropic axis was normal in all patients, and none of the subjects had symptoms of diabetes insipidus. Gonadal status was assessed in men by measurement of total serum testosterone at 0800 h. In women, 23 of 34 patients were amenorrheic, 1 woman received estrogen replacement therapy, and the remaining 11 women had regular menstrual cycles. Seven female patients had an adrenal tumor as a cause of Cushing’s syndrome. Serum leptin concentrations were compared between these patients and 7 matched female patients with pituitary tumor (BMI, ±1.5 kg/m2).

In nine patients with Cushing’s syndrome, we conducted a matched pairs study and compared BMI, fasting serum leptin, serum cortisol, and plasma insulin before and after successful surgical therapy. After surgery, all patients needed substitution with hydrocortisone for a duration of 2.6 ± 0.7 yr (mean ± SD) until recovery of the hypothalamic-pituitary-axis. BMI, fasting serum leptin, serum cortisol, and plasma insulin were determined 3 months after cessation of hydrocortisone substitution. Table 2Go shows the characteristics of this subgroup before and after successful surgical therapy.


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  		Table 2. Demographic details of nine subjects with Cushing’s syndrome before (pre op) and after successful transsphenoidal pituitary resection (post op) with serum leptin, cortisol, and plasma insulin concentrations

 
All clinical studies were performed according to the Declaration of Helsinki, with approval from the ethics committee, and all patients gave informed consent.

RIA for serum leptin and other hormone determinations

Serum leptin was measured by RIA, as previously described (22). Rabbit antihuman leptin peptide (amino acids 126–140) antibody and [125I]leptin-(126–140) were used to determine the serum leptin concentration. Sephadex chromatography revealed that the assay selectively detects free leptin levels (22), with a minimum detectable concentration of 6 pmol/L, an intraassay variation of 4.8% at 100 pmol/L, and an interassay variation of 8.3% at 100 pmol/L.

Serum cortisol concentrations were measured with a coated tube immunoassay kit (DPC, Hermann Biermann, Bad Nauheim, Germany) (23). Plasma insulin concentrations were measured using a double antibody RIA (Pharmacia, Freiburg, Germany) (24), and total serum testosterone levels were determined by immunoassay, as previously described (25).

Statistical analysis

Results are given as the mean ± SEM or the geometric mean and SEM range unless noted otherwise. Serum leptin, serum cortisol, and plasma insulin were analyzed after log transformation. Statistical analysis was performed with SPSS for Windows (26). Pearson’s product-moment correlation was used to estimate linear relationships between variables. Differences between groups before and after surgical therapy were tested with Student’s t test for paired samples. Stepwise multiple regression analysis was performed to evaluate the relation of insulin, cortisol, and BMI to the serum leptin concentration in patients with Cushing’s syndrome. Statistical significance was accepted as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum leptin levels and BMI were positively related in both patients with Cushing’s syndrome (r = 0.48; P < 0.05) and control subjects (r = 0.67; P < 0.01). The origin of Cushing’s syndrome (pituitary vs. adrenal) did not influence serum leptin levels when subjects were compared in a subgroup of female patients matched for BMI. Serum leptin concentrations were higher in female than in male patients both in patients with Cushing’s syndrome (P < 0.01) and in the control group (P < 0.001). In male subjects with Cushing’s syndrome, serum leptin levels were significantly higher than those in controls (P < 0.05; Table 1Go). Their mean total serum testosterone level (2.11 ± 0.34 ng/mL) was below the normal range (>3.0 ng/mL). In contrast, serum leptin concentrations in female Cushing patients were comparable to control values (P = 0.51). Female subjects with Cushing’s syndrome who were amenorrheic had serum leptin levels comparable to those in women with regular menstrual cycles (data not shown).

In a stepwise multiple regression analysis taking both genders together, plasma insulin was the best predictor of leptin concentrations among patients with Cushing’s syndrome who were not receiving insulin or oral hypoglycemic agents (r2 = 0.42; P < 0.0001), whereas BMI or 24-h mean serum cortisol did not significantly contribute to the variance in leptin concentrations. When only insulin-treated diabetic patients were removed from the analysis, plasma insulin remained the dominant factor for serum leptin levels (r2 = 0.34; P < 0.0001). The contribution of plasma insulin to the variance in serum leptin levels remained significant (r2 = 0.37; P < 0.0001) when all patients with Cushing’s syndrome were included. Again, BMI and serum cortisol did not contribute significantly in either model.

In the subgroup of patients studied before and after surgery (n = 9), there was a significant decrease in mean serum cortisol (P < 0.00001), leptin (P < 0.0001), and plasma insulin (P < 0.001) into the normal range, associated with a significant decline in BMI (P < 0.001; Table 2Go and Fig. 1Go).



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  		Figure 1. Effect of transsphenoidal surgery on serum cortisol, serum leptin, plasma insulin, and BMI in nine subjects with Cushing’s syndrome. Subjects 1–5 are females; subjects 6–9 are males.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The effect of chronic endogenous hypercortisolemia and hyperinsulinemia on serum leptin concentrations was studied in a large group of patients with Cushing’s syndrome. Surprisingly, after stepwise multiple regression analysis, chronic endogenous cortisol excess in Cushing patients seems to have no direct influence on leptin secretion. Such a direct stimulatory effect of glucocorticoids on ob gene expression and leptin levels was anticipated from in vitro studies of rat and human adipocytes (9, 16, 27) and from in vivo data in humans after short term glucocorticoid application (28, 29). Thus, this apparently glucocorticoid-independent alteration of circulating leptin levels was unexpected and may be explained by an adaptation of the system after long term glucocorticoid excess.

In vivo studies show that short term glucocorticoid application rapidly increases circulating insulin levels and induces insulin resistance in humans (28, 29, 30), which is maintained in long term glucocorticoid excess as in patients with Cushing’s syndrome (31). A large number of reports support a BMI/fat mass-independent regulatory influence of insulin on serum leptin levels with an association among circulating insulin levels, insulin sensitivity, and serum leptin levels in both healthy subjects and patients with diabetes mellitus (32, 33, 34). Moreover, studies using the hyperinsulinemic clamp technique have demonstrated that long term hyperinsulinemia increases circulating serum leptin levels after 4–48 h (14, 15, 28, 29). This insulin dependency fits the results of the multiple stepwise regression analysis in our patients with Cushing’s syndrome. The important role of insulin in leptin regulation was further supported by the fact that serum leptin levels decreased in parallel with plasma insulin concentrations and BMI after successful surgery. BMI in our study was no predictor of serum leptin levels. However, BMI may not be an accurate measurement for assessing body fat mass in patients with Cushing’s syndrome because these patients have a tendency toward centrally localized adipose tissue with decreased muscle mass (31). Although it is unclear whether the fall in serum leptin levels is caused by the coexisting obesity, it has been reported that the change in serum leptin was significantly correlated with the change in plasma insulin independent of changes in obesity in women studied after sustained weight loss (35). Thus, amelioration of hyperinsulinemia may represent the dominant force for the decrease in serum leptin levels following surgery and add credit to a predominantly insulin-dependent alteration of leptin in active Cushing’s syndrome. This result is in accordance with previous reports in patients with Cushing’s syndrome, who showed no change in leptin levels shortly after correction of hypercortisolism (19) but demonstrated a decrease in leptin levels 6–9 months after successful surgery (18).

Our results in patients with Cushing’s syndrome and controls confirm that serum leptin concentrations are higher in female than in male subjects. However, compared to age- and BMI-matched controls, only male, not female, patients with Cushing’s syndrome had significantly higher serum leptin levels. Only speculations can be offered to explain this gender-specific effect. Previous studies have shown that female patients with Cushing’s syndrome had similar total body fat (36) and abdominal sc fat cell size (31), but a greater intraabdominal fat area compared to obese female controls (36), which could explain why no difference in serum leptin levels was found in our female group. As recent evidence points to a predominant role of the sc over the omental fat compartment for the maintenance of circulating leptin levels (37), a predominantly omental fat accumulation in female patients with Cushing’s syndrome may explain why in the female group serum leptin levels remain unchanged compared to control values. In male patients with Cushing’s syndrome, the regulation of sc fat cell size and fat distribution is unknown. However, the observed decrease in serum testosterone levels in our male patients may contribute to the apparent relative increase in serum leptin levels over those in healthy controls. Convincing evidence has been recently accumulating that testosterone exerts a negative feedback on circulating leptin levels (38) and may contribute to the gender-specific differences in leptin levels observed in many studies (39, 40). Thus, hypogonadism observed in our male patients with active disease may release this negative feedback inhibition and result in an elevation of serum leptin levels only in the male group despite comparable insulin resistance in both sexes.

In conclusion, chronic hypercortisolemia in Cushing’s syndrome appears to be no major regulator of serum leptin concentrations. It may induce hyperinsulinemia and/or impaired insulin sensitivity, which appears to be the major determinant of serum leptin levels in these patients.

Received June 23, 1997.

Revised September 25, 1997.

Accepted November 4, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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