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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1874-1878
Copyright © 1997 by The Endocrine Society

Clinical Studies

Differences in Corticotropin-Releasing Hormone-Stimulated Adrenocorticotropin and Cortisol before and after Weight Loss

Jack A. Yanovski, Susan Zelitch Yanovski, Philip W. Gold and George P. Chrousos

Developmental Endocrinology Branch, National Institute of Child Health and Human Development (J.A.K., G.P.C.); Office of the Director, The Warren Grant Magnuson Clinical Center (J.A.Y.); the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (S.Z.Y.); and the Clinical Neuroendocrinology Branch, National Institute of Mental Health (P.W.G.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Jack A. Yanovski, M.D., Ph.D., National Institutes of Health, Building 10, Room 10N262–1862, 9000 Rockville Pike, Bethesda, Maryland 20892-1862. E-mail: YANOVSKJ{at}CC1.NICHD.NIH.GOV


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Little is known about the effects of intentional weight loss on the function of the hypothalamic-pituitary-adrenal (HPA) axis of obese individuals. We studied the HPA axis of 34 healthy obese women (body mass index, 40.2 ± 7.9 kg/m2) before and after a 21.0 ± 7.9-kg weight loss induced by a 26-week weight loss program that included 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet, 6 weeks of gradual refeeding, and 6 weeks of caloric stabilization at 5020–6280 kJ/day (1200–1500 Cal/day). Obese subjects were evaluated twice: before caloric restriction and during the last 3 weeks of caloric stabilization with a 3-h evening 1 µg/kg ovine CRH (oCRH) stimulation test. CRH-stimulated ACTH and cortisol values were compared to those of a control group of 12 normal weight women. Before caloric restriction, both ACTH and cortisol responses to oCRH were similar in obese women and normal weight controls. Weight loss did not significantly alter the ACTH response to oCRH; however, the total plasma cortisol response to oCRH decreased significantly with weight loss (area under the curve, 96,320 ± 21,040 nmol/L·min before weight loss; 82,450 ± 22,460 nmol/L·min after weight loss; P < 0.001). Cortisol-binding globulin also decreased significantly after weight loss (2,270 ± 1,050 nmol/L) compared either to values obtained before weight loss (3,590 ± 1,360 nmol/L; P < 0.001) or to those of normal weight controls (3,910 ± 1,400 nmol/L; P < 0.001). Assay for plasma free cortisol, either before or 180 min after oCRH treatment, showed no significant changes in cortisol responses resulting from weight loss. As plasma free cortisol was not altered by weight reduction, the decrease in the total cortisol response to oCRH after weight loss appears to be secondary to significant decreases in cortisol-binding globulin. We conclude that when obese women lose large amounts of weight with a 3350 kJ/day, very low energy diet, such weight reduction does not significantly affect the HPA axis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE IMPORTANCE of hypothalamic-pituitary-adrenal (HPA) axis hormones for the deposition and metabolism of fat is well established. Peripheral infusion of CRH transiently increases energy expenditure in lean and obese humans (1), whereas intracerebroventricular CRH injections stimulate the sympathetic system in rats and monkeys, decreases appetite, and increases thermogenesis in rats (2, 3). ACTH is lipolytic for human and animal adipocytes, through activation of hormone-sensitive lipase (4, 5, 6). Cortisol promotes differentiation of adipocyte precursors into adipocytes and stimulates lipogenesis in the presence of insulin (7, 8). The clinical signs of weight loss in adrenocortical deficiency states and obesity in Cushing’s syndrome underscore the role of glucocorticoids in human obesity (9). Although cortisol metabolism is somewhat enhanced in obesity (10), the HPA axis of obese individuals generally shows normal function, with a fairly normal circadian rhythm of plasma cortisol, normal suppression of cortisol by dexamethasone, and normal cortisol responsiveness to ACTH (11). However, there have been inconsistent reports of blunting of the ACTH and/or cortisol response to exogenous CRH in obese patients (12, 13, 14, 15). Some reports find that obese individuals with high waist to hip ratios (>0.85) have greater ACTH and cortisol levels than those with a more gynoid pattern of obesity (16, 17, 18).

Despite the potential role of the HPA axis in the development and maintenance of human obesity, alterations in the activity and regulation of this axis with weight loss have not been systematically evaluated in obese individuals. The neuroendocrine response to complete fasting is well established and includes failure to suppress serum cortisol after dexamethasone administration, increase in urinary free cortisol excretion, and disruption of the normal circadian variation of serum cortisol and ACTH (19, 20, 21, 22, 23, 24). Extremely underweight patients, such as those with anorexia nervosa, have elevated basal plasma cortisol levels and little further increase in either ACTH or cortisol after ovine CRH (oCRH) administration (25). However, there is little information regarding changes in the HPA axis of obese individuals undergoing weight loss. Some studies have confounded the effects of weight loss with those of a coadministered anorexigenic medication (14, 26). Others have studied only basal ACTH and cortisol (27). There has been only one study of five obese subjects in which the CRH test was examined after weight loss, but this sample size was too small to detect changes in CRH-stimulated ACTH or cortisol (28).

Very low energy diet regimens have changed greatly over the past decade. There have been improvements in the quality of the proteins employed and increases in both energy and carbohydrate content. Modern, very low energy diets containing 3350 kJ/day (800 Cal/day) enable patients to lose as much weight as was possible when patients used older formulations containing less than half the energy content (29, 30). These changes in diet regimen afford the opportunity to explore whether differences in the HPA axis previously observed with weight loss are related to metabolic alterations induced by some aspect of starvation or by rapid weight loss itself. Therefore, we studied CRH stimulation tests in obese women before and after very low energy diet-induced weight loss.


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

Forty-six volunteer women (aged 21–50 yr), 30 of whom were white and 16 of whom were black, were recruited through posted notices in the Bethesda, MD area (Table 1Go). Thirty-four of the volunteers had responded to an advertisement to participate in a weight loss study and had body mass index (BMI) greater than 30 kg/m2. Twelve subjects were recruited as a control group and were of normal weight (body mass index, 19–27 kg/m2). The study was approved by the NIH Intramural Clinical Research Subpanel, and each subject gave written consent for participation in the protocol.


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  		Table 1. Demographics and other characteristics of study participants

 
All subjects were medication free, with the exception of over the counter analgesics, for 2 weeks before each CRH test, and all were free of significant medical disease, with the exception of mild hypertension. All had normal physical examinations and normal hepatic, renal, and thyroid function. None had used any steroid preparations, including oral contraceptive pills, for a minimum of 3 months before the study. All underwent psychological testing, including the Structured Clinical Interview for the DSM-III-R, to rule out significant psychiatric disease that might affect HPA axis activity (31, 32). No patient had anorexia or bulimia nervosa; however, 20 of the obese subjects met proposed criteria for binge eating disorder (33). Because no significant differences were found between subjects with and without binge-eating disorder for any of the measured variables, the data are not presented separately by binge eating status.

Protocol

All subjects underwent anthropometric measurements at the NIH out-patient clinic (Table 1Go), collected urine for two consecutive 24-h periods for determination of free cortisol, and were admitted to the NIH Warren Grant Magnuson Clinical Center for a CRH stimulation test. Obese subjects were first studied between 1 and 4 weeks before the start of weight reduction and were subsequently admitted for a second CRH stimulation test during the weight stabilization period of the very low energy diet program (described below).

Antropometric measurements. Anthropometric measurements were obtained as recommended by the Airlie Consensus Conference (34). Height was measured using a stadiometer (Holtain, Crymmyck, Wales) calibrated before each measurement to the nearest 1 mm. Weight was obtained using a digital scale to the nearest 0.1 kg (Scale-Tronix, Wheaton, IL). Waist to hip ratios were obtained with a flexible, nonstretching, tape measure while the patient was standing. Waist circumference was measured at the smallest horizontal circumference between the 12th rib and the iliac crest. Hip circumference was measured around the buttocks at the point of maximum circumference. The waist to hip ratio was calculated by dividing the waist circumference by the hip circumference.

oCRH test. Each control subject underwent one evening oCRH stimulation test; obese subjects were studied twice with oCRH tests. Subjects were scheduled to be admitted during the midfollicular phase of their menstrual cycle and consumed a diet containing maintenance energy, as calculated by the Harris Benedict equation, for the 2 days preceding CRH tests. oCRH (Bachem, Torrance, CA; 1 µg/kg) was administered as an iv bolus injection at 1900 h, 2 h after iv placement. All plasma samples were assayed for ACTH and cortisol at two basal time points 15 min apart and then 5, 15, 30, 60, 90, 120, 150, and 180 min after CRH. Plasma free cortisol and cortisol-binding globulin (CBG) were measured in basal samples in 28 obese subjects and all controls, and plasma free cortisol was determined at the 180 min point in 27 of the obese subjects.

Very low energy weight reduction program. After a 1-week introduction, during which subjects were advised to consume a balanced diet of approximately 5020 kJ/day (1200 Cal/day), obese subjects began 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet. The diet consisted of a powdered supplement (Optifast 800) mixed with noncaloric liquids, which was taken five times daily. This supplement provided 70 g protein, 100 g carbohydrate, and 13 g fat daily as well as 100% of the recommended daily allowance of vitamins and minerals according to the manufacturer (Sandoz Nutrition, Minneapolis, MN). Subjects were permitted no other foods, with the exception of up to 80 kJ/day (20 Cal/day) sugar-free gum or mints. Subjects also used a psyllium fiber supplement as needed. All subjects were seen by a physician weekly and attended a weekly behaviorally oriented weight loss group. All started a low level exercise program during the fifth week of the diet. After the 12 weeks of the liquid formula diet, solid foods were reintroduced during 6 weeks of gradual refeeding, followed by 6 weeks of caloric stabilization at 5020–6280 kJ/day (1200–1500 Cal/day).

Hormone assays

Urinary free cortisol was measured by RIA as previously described (36). Sensitivity was 20 nmol/L, and the intra- and interassay variabilities were 4–11% and 6–18%, respectively. Plasma ACTH was measured by an extraction polyclonal RIA (37). The sensitivity for the extraction ACTH RIA ranged from 0.9–2.2 pmol/L, and that for the ACTH immunoradimetric assay ranged from 1–2 pmol/L. The intra- and interassay variabilities were 7–12% and 12–25%, respectively, for the ACTH extraction RIA and 7% and 16% for the ACTH IRMA. Plasma cortisol and plasma free cortisol were measured by direct RIA, the latter after ultrafiltration, as previously described (37, 38, 39). The sensitivity of the assay for plasma cortisol was 20 nmol/L, and that for plasma free cortisol was 0.1 nmol/L. The intra- and interassay variabilities were 6% and 13%, respectively, for cortisol and 20% and 29% for free cortisol. CBG was measured as previously described (40). The sensitivity of the CBG assay was 4 µg/dL; intra- and interassay variabilities were 1.6% and 3.4%, respectively.

Data analysis

A power calculation suggested that a peak ACTH difference of 3 pmol/L (15 pg/mL) and a peak cortisol difference of 80 nmol/L (3 µg/dL) could be detected with a power of 0.80 and a two-sided significance level of 0.05 with 33 subjects. Therefore, 34 subjects were enrolled. Data were analyzed on a Macintosh PowerPC with Superanova and StatView 4.5 (Abacus Concepts, Inc., Berkeley, CA). Two-way ANOVA with repeated measures was performed to detect between-group and time-related differences. Logarithmic data transformation was performed where appropriate, and post-hoc Fisher LSD tests were performed and interpreted with the Bonferroni adjustment for multiple comparisons. Categorical data were examined with contingency table analysis. The area under the curve (AUC) for plasma ACTH and cortisol responses to CRH was approximated with the trapezoidal rule. The mean ± SD are reported.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All 34 obese subjects lost weight during the supplemented fast. Weight decreased in obese subjects by 21.0 ± 7.9 kg during the period between the two oCRH tests, for an average 19 ± 6% decrease in body weight. All but two subjects lost at least 10% of their initial body weight. As anticipated, the waist to hip ratio decreased with weight loss (Table 2Go; P < 0.005).


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  		Table 2. Anthropometric and biochemical characteristics of study participants

 
Plasma ACTH concentrations were not altered by weight loss at any time either before or after the administration of oCRH (Fig. 1AGo). ACTH levels were not significantly different between normal weight control women and obese subjects examined before or after weight loss (data not shown). The time-integrated AUCs were also similar in obese women before and after weight loss and were not different from the AUCs of controls (Fig. 1BGo).



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  		Figure 1. Plasma ACTH response to oCRH (1 µg/kg) in obese subjects. A, Plasma ACTH before and after oCRH. B, Inset, ACTH AUC in obese subjects before and after weight loss and in normal weight controls. The shaded area indicates the mean ± 2 SEM in controls. There were no significant changes in ACTH levels after weight loss. C, Cortisol response to oCRH (1 µg/kg) in obese subjects. A, Total plasma cortisol before and after oCRH; D, Inset, Cortisol AUC in obese subjects before and after weight loss and in normal weight controls. The shaded area indicates the mean ± 2 SEM in controls. Total plasma cortisol decreased significantly after weight loss. *, P < 0.05; **, P < 0.005; ***, P < 0.001 (comparison of obese subjects before vs. after weight loss).

 
In contrast to ACTH, plasma cortisol decreased significantly with weight loss (Fig. 1CGo; P < 0.001, by ANOVA). Thus, at all time points between 30–180 min after the administration of oCRH, total plasma cortisol was significantly lower after weight loss. The plasma cortisol AUC (Fig. 1DGo and Table 2Go) was also significantly lower after weight loss. The plasma cortisol AUC in obese subjects before weight reduction (96,320 ± 21,040 nmol/L·min) was significantly greater than that after weight loss (82,450 ± 22,460 nmol/L·min; P < 0.001). Plasma cortisol levels or AUC of obese subjects did not differ significantly from those of controls either before or after weight loss.

Plasma free cortisol concentrations were not significantly altered by weight loss either before or 180 min after the administration of oCRH (Table 2Go). However, CBG decreased significantly after weight loss (2270 ± 1050 nmol/L) compared either to values obtained before weight loss (3590 ± 1360 nmol/L; P < 0.001) or to those of normal weight controls (3910 ± 1400 nmol/L; P < 0.001).

The effect of differences in waist to hip ratio were also examined in obese subjects before weight loss. No significant differences in plasma ACTH or cortisol were found, either before or after the administration of oCRH, for obese women with a waist to hip ratio of 0.85 or more (n = 12) vs. those with lower waist to hip ratios (P > 0.9; data not shown). Similarly, the urinary free cortisol measurements, corrected or uncorrected for body surface area or creatinine, were not different between the two groups (P > 0.47; data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, subjects lost an average of 21.0 kg (19% of total body weight) after 12 weeks of consuming a very low energy diet, without significant disruption of the HPA axis. We found no changes in plasma ACTH and modest decreases in total plasma cortisol during CRH tests after weight loss. The decrement in total plasma cortisol was accompanied by a significant decrease in plasma CBG. As plasma free cortisol levels, measured either before or after the administration of oCRH, were not changed by weight reduction, we believe that the HPA axis remained essentially unchanged despite the large amount of weight lost by participants in this study. These results contrast greatly with the disruptions reported during relatively short term fasting in normal weight subjects or in long term starvation accompanied by weight loss well below ideal body weight, and are in accord with previous findings of no changes in results of dexamethasone suppression tests with very low energy diet-induced weight loss in obese subjects (41).

The nutritional supplement provided by the very low energy diet used in this study contains more carbohydrate, fat, protein, and total energy than those ingested in other studies of weight loss in obese individuals (42, 43, 44), yet allowed equivalent weight loss. Thus, the higher rate of disruption of the HPA axis with weight loss seen by others may be due to the stress of starvation and/or specific metabolic alterations, such as increased reliance on ketones for cerebral metabolism, rather than weight loss per se. The larger amounts of carbohydrate in the very low energy diet of this study may be important, because increased carbohydrate intake has been suggested to attenuate the fall in serum T3 and resting metabolic rate that have been observed after the use of very low energy diets (45, 46, 47). Carbohydrate may also have a protein-sparing effect during caloric restriction (48) and help conserve calcium and zinc (49). The precise metabolic derangements responsible for producing HPA axis abnormalities during fasting and the potential ameliorating effects of carbohydrate remain to be elucidated.

We conclude that when obese women lose large amounts of weight with a 3350 kJ/day (800 Cal/day), very low energy diet, such weight reduction does not significantly affect the HPA axis. The alterations observed in the HPA axis that occur with very low energy-induced weight loss are primarily the result of decreases in CBG. We further hypothesize that one of the concomitants of restricted energy intake may be of greater importance in causing abnormalities of the HPA axis than rapid weight loss per se.

Received January 16, 1997.

Revised February 26, 1997.

Accepted February 28, 1997.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. A. Yanovski, K. D. Miller, T. Kino, T. C. Friedman, G. P. Chrousos, C. Tsigos, and J. Falloon
Endocrine and Metabolic Evaluation of Human Immunodeficiency Virus-Infected Patients with Evidence of Protease Inhibitor-Associated Lipodystrophy
J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1925 - 1931.
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