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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 379-384
Copyright © 2003 by The Endocrine Society

Original Article

11ß-Hydroxysteroid Dehydrogenase Activity in Hypothalamic Obesity

Dov Tiosano, Israel Eisentein, Daniela Militianu, George P. Chrousos and Ze’ev Hochberg

Departments of Pediatrics (D.T., I.E., Z.H.) and Radiology (D.M.), Meyer Children’s Hospital, Haifa 31096, Israel; and National Institute of Child Health and Human Development, Pediatric and Reproductive Endocrinology Branch (G.P.C., Z.H.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ze’ev Hochberg, M.D., D.Sc., Meyer Children’s Hospital, P.O. Box 9602, Haifa 31096, Israel. E-mail: z_hochberg{at}rambam.health.gov.il.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
After extensive suprasellar operations for hypothalamic tumor removal, some patients develop Cushing-like morbid obesity while they receive replacement doses of glucocorticoids. In this study, we examined the hypothesis that target tissue conversion of inactive 11-ketosteroids to active 11ß-OH glucocorticoids might explain the obesity of some patients with hypothalamic lesions. Toward this aim, we studied 10 patients with hypothalamic obesity and secondary adrenal insufficiency and 6 control Addisonian patients while they were on glucocorticoid replacement therapy. Pituitary hormone deficiencies were replaced when medically indicated. Twenty-four-hour urine was collected after a single oral dose of 12 mg/m2 hydrocortisone acetate. The ratios of free and conjugated cortisol (F) to cortisone (E) and their metabolites, [tetrahydrocortisol (THF)+5{alpha}THF]/tetrahyrdocortisone (THE), dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5{alpha}THF), were considered to represent 11ß-hydroxysteroid dehydrogenase (HSD) activity. The 11-OH/11-oxo ratios were significantly higher in the urine of patients with hypothalamic obesity. The 11-OH/11-oxo ratios, however, did not correlate with the degree of obesity, yet a significant correlation was found between conjugated F/E and the ratio of visceral fat to sc fat measured by computerized tomography at the umbilical level. The consequence of increased 11ß-HSD1 activity and the shift of the interconversion toward cortisol may contribute to the effects of the latter in adipose tissue. We propose that deficiency of hypothalamic messengers after surgical injury induces a paracrine/autocrine effect of enhanced glucocorticoid activity due to up-regulated 11ß-HSD1 activity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HYPOTHALAMUS BALANCES the intake of food, energy expenditure, and body fat tissue in an intricate equilibrium. As the unwinding story of leptin and its hypothalamic messengers is being unraveled (1), we learn more about the message that fat tissue delivers to the hypothalamus. We still, however, know very little about the return pathway of how the hypothalamus regulates body fat. The impact of hypothalamic damage on body fat has been extensively documented in animals and man, and it is believed that human obesity after craniopharyngioma surgery is related to hyperphagia as a result of hypothalamic injury at operation (2, 3). Indeed, an anecdotal report described patients in whom surgical removal of a craniopharyngioma was followed by abnormal food-seeking behavior, including foraging for food, stealing food, or stealing money for food (4). Classic neurophysiology explains the hyperphagia in animals or humans with hypothalamic injury on the basis of unopposed activity of a hypothalamic-feeding center. Yet, our own clinical impression has been that weight gain in such patients is often disproportionate to food intake. We thought it likely that the hypothalamus may send to the adipose tissue messengers disproportionate to or independent of food intake.

A further clinical impression we had was that the obesity, which developed in several of our patients after extensive surgery for craniopharyngioma, resembled the obesity of Cushing syndrome. Facial and upper body obesity, as well as a buffalo hump, was often so obvious that postulating a relation to glucocorticoid excess was inevitable. Yet, many of these patients, including all those who underwent operations for craniopharyngioma, depend solely on exogenous supplementation to provide for their glucocorticoid needs, and the dose currently in use for such patients is as little as possible. We hypothesized that abnormal metabolism of the exogenously delivered glucocorticoid might be involved in the development of hypothalamic obesity.

The implications of 11ß-hydroxysteroid dehydrogenase (HSD) in the pathogenesis of disease are numerous (5). Two isoenzymes of 11ß-HSD catalyze the interconversion of the inactive cortisone to the active cortisol. The type 1 isoenzyme acts as a reductase (cortisone to cortisol) and is expressed in several organs, including liver and adipose tissue (6). Although earlier reports assumed enhanced 11ß-HSD1 activity in patients with obesity (7), clinical studies in obese patients demonstrated global inhibition of enzymatic activity, as measured by urinary cortisol/cortisone metabolites in relation to body fat distribution of android or central obesity, but not in gynoid obesity (8). On the other hand, an 11ß-HSD1 null mouse did not reveal a unique adipose tissue phenotype. A recent report may reconcile these apparent contradictory results, and tissue-specific changes were suggested (9). Although hepatic 11ß-HSD1 conversion of oral cortisone to cortisol was impaired in obese women, enzyme activity in adipose tissue was positively correlated with body mass index (BMI).

The aim of the present study was to evaluate 11ß-HSD activity in patients with hypothalamic obesity. This was performed in postoperative patients with craniopharyngioma who had hypothalamic obesity and hypopituitarism, including ACTH deficiency, and who required glucocorticoid replacement therapy. A group of patients with glucocorticoid deficiency resulting from other reasons served as controls for the metabolism of exogenously delivered glucocorticoids.


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

Patients with hypothalamic obesity. Ten patients with hypothalamic obesity were the subjects of this study (Table 1Go). The protocol required that they all be ACTH-deficient and receiving glucocorticoid replacement therapy. There were 5 females and 5 males, and the age range was 9–22 yr. Hypothalamic obesity was diagnosed when we observed an abrupt weight increase in BMI (> +2 SD, or increased by >1 SD after surgery) following surgery to the hypothalamic-pituitary region. Pituitary hormones were replaced whenever required, L-T4 according to T4 levels, hydrocortisone at 8–10 mg/m2·d, and DDAVP. GH therapy was given to 6 children who had deceleration of their growth rate, and sex-steroid replacement was given when required to 2 boys older than 13 yr and 3 girls older than 11 yr.


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  		Table 1. Clinical characteristics of the study groups

 
Patients with glucocorticoid deficiency. Three patients with ACTH unresponsiveness and two patients with congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency were included in this control group. The patients with ACTH unresponsiveness had isolated glucocorticoid deficiency and increased plasma ACTH levels. Involvement of the ACTH receptor was excluded by linkage analysis (10), and Allgrove‘s syndrome was excluded by sequencing the AAAS gene (11). Patients of this group were 4 males and 2 females, aged 8–19 yr, who had received glucocorticoid replacement therapy for several years. Their BMI was less than +1 SD value for age.

Experimental design The Internal Review Board and the Israel Ministry of Health approved the protocol, and patients and parents of minors signed informed consent forms.

Each patient was admitted to the Pediatric Ward the day before sampling, and his or her regular glucocorticoid replacement was discontinued. The following morning, a 24-h urine collection was begun, and a single dose of 12 mg/m2 hydrocortisone acetate was administered orally.

Laboratory methods The urinary steroid metabolites profile was analyzed using gas chromatography/mass spectrometry for A-ring reduced cortisol and cortisone metabolites, i.e. tetrahydrocortisols (THF and allo-THF) and tetrahydrocortisone (THE). In addition, urinary free cortisol and free cortisone were quantified using 3H-labeled internal standards, as previously reported (12), measuring free and conjugated F and E metabolites. The ratios of free and conjugated F/E, (THF+5{alpha}THF)/THE, dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5{alpha}THF) were considered to represent 11ß-HSD activity (13). Serum cortisol was measured by an Immulite cortisol-PDC (Diagnostic Products Corp., Los Angeles, CA).

Computerized tomography (CT) fat measurements It was previously reported that the visceral fat area from a single scan is highly correlated with overall visceral volume. Visceral fat measurement was obtained by a single CT slice at the level of the umbilicus with a Picker CT Twin RTS. The technical parameters were 120 kVp, 275 mAs, and 1-mm slice thickness. The image was analyzed on a Marconi MX view computer workstation. Total adipose tissue area and visceral adipose tissue area were obtained by tracing the respective areas through the skin and through the abdominal wall muscles and vertebral body. The cross-section of adipose tissue was determined in square centimeters by using an automatic computerized fat tissue highlighting technique.

The sc fat was obtained by subtracting visceral fat area from the total fat area.

Statistics A nonparametric statistical test, the Mann-Whitney U Test, was used to compare concentrations of the hormones and their metabolites; the significance level was set at P value less than 0.05. Subsequently, we used the two-way ANOVA to explore the extended role of GH and sex steroids on 11ß-HSD activity as expressed by the metabolite ratios. Statistical significance was defined as P value less than 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After withdrawal of glucocorticoid replacement for 24 h and before any drugs were administered, basal 0800 h serum cortisol levels were below 22–68 nmol/liter (normal, 190–690 nmol/liter) in the patients with hypothalamic obesity and in the glucocorticoid-deficient control group. After a single dose of 12 mg/m2 hydrocortisone acetate (Rekah, Holon, Israel), urine was collected for the next 24 h. Urinary free cortisol in the patients with hypothalamic obesity was 34.7 ± 52.0 µg/24 h, and in the glucocorticoid deficient patients it was 11.7 ± 9.1 µg/24 h. At the same time, urinary free cortisone levels were 31.6 ± 27.0 µg/24 h and 24.5 ± 19.6 µg/24 h, respectively. The ratios of urinary free and conjugate cortisol/cortisone and their metabolites (11-OH/11-oxo) in the glucocorticoid-deficient control group were similar to reference data obtained from healthy male and female subjects, measured in the same laboratory (Refs. 12 and 13 ; Table 2Go and Fig. 1Go).


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  		Table 2. Urinary metabolites in 11 patients with hypothalamic obesity after a single dose of 12 mg/m2 hydrocortisone acetate

 


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  		Figure 1. 11-OH/11-oxo ratios in hypothalamic obesity (HyOB), in control patients with hypoadrenalism (Ctr), in 24-h urine collections after administration of 12 mg/m2 hydrocortisone, and reference levels. Mean ± SD. *, P < 0.05; **, P < 0.001.

 
The 11-OH/11-oxo ratios were significantly higher in the urine of patients with hypothalamic obesity (Fig. 1Go). Urinary free cortisol/cortisone ratio was also significantly different in patients with hypothalamic obesity (1.1 ± 0.64) and patients with hypoadrenalism (0.49 ± 0.07; P < 0.05). Conjugated cortisol/cortisone ratio was also significantly higher in patients with hypothalamic obesity (1.74 ± 1.16) than patients with hypoadrenalism (0.55 ± 0.21; P < 0.001). Furthermore, the THF/THE ratio was significantly higher in patients with hypothalamic obesity (2.67 ± 1.1) than patients with hypoadrenalism (0.95 ± 0.58; P < 0.001), and the same was true for the cortols/cortolones ratio that was significantly higher in patients with hypothalamic obesity (0.53 ± 0.33) than patients with hypoadrenalism (0.21 ± 0.08; P < 0.001).

Using a similar approach, we also measured urinary 5{alpha}-reduced and -unreduced metabolites and calculated the ratios of etiocholanolone (ET)/androsterone (AN), 11ß-ET/11ß-AN, tetrahydrocorticosterone (THB)/5{alpha}-THB, and THF/5{alpha}-THF. 5{alpha}-Reductase activity in patients with hypothalamic obesity was similar to that of healthy and glucocorticoid-deficient controls (data not shown).

The 11-OH/11-oxo ratios did not correlate with the degree of obesity, as represented by BMI or BMI SD values. However, a significant correlation was found between conjugated F/E and the ratio of visceral fat/sc fat measured by CT at the umbilical level (P < 0.05; Fig. 2Go).



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  		Figure 2. Correlations between 11-OH/11-oxo ratios and visceral fat/sc fat tissue. Visceral fat and sc fat tissue were measured by a CT slice at the umbilical level.

 
In an attempt to verify the role of GH and sex hormones in the abnormal 11ß-HSD activity, hypothalamic obese patients were divided on the basis of hormonal replacement therapy into four groups: GH and sex hormones, GH alone, sex hormones alone, and neither type of hormone. A two-way ANOVA test was performed (Fig. 3Go). The ratio of urinary free cortisol/cortisone was influenced by neither GH treatment nor sex hormone therapy. However, the other three metabolites that express 11ß-HSD1 reductase activity, THF/THE, conjugated F/E, and cortols/cortolones, were significantly influenced by GH but not by sex hormones. Multiple regression analysis revealed that 31% of the abnormal conjugated F/E ratio in hypothalamic obesity, 46% of free F/E, 10% of THF/THE, 62% of cortols/cortolones, and 33% of F+E/THF+THE+5{alpha}THF were generated by GH deficiency.



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  		Figure 3. Two-way ANOVA of 11-OH/11-oxo metabolites in patients that were stratified into those who received and those who did not receive sex steroids and GH replacement. GH+/Sx+, Patients with intact GH and sex steroids (n = 6). GH+/SxH-, Patients who received hGH and did not receive sex hormones (n = 4). GH-/SxH+, Patients who received only sex hormones and did not receive hGH (n = 4). GH-/SxH-, Patients with hypopituitarism who did not receive either hormone (n = 2). Mean ± SD. Asterisks indicate statistical comparisons to the GH+/SxH+ group.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results presented here demonstrate a striking change in 11ß-HSD activity, in which cortisone to cortisol conversion is enhanced in patients with hypothalamic obesity. The inclusion criteria in this study provided a unique human model to investigate the potential impact of hypothalamic injury on glucocorticoid metabolism. Deprived of their endogenous glucocorticoid source, urinary metabolites in these patients reflect solely the peripheral pharmacokinetics of the administered compound (14). This approach also required a unique control group of patients with glucocorticoid deficiency due to adrenal etiologies. These control patients had 11-OH/11-oxo ratios compatible with reference values obtained from healthy controls in the same laboratory.

Abnormal metabolism of glucocorticoids has been implicated in the mechanism of obesity for over 30 yr (15). However, urinary cortisol/cortisone metabolite ratios are very variable in idiopathic obesity, having been reported as increased (16), decreased (8, 17, 18), or unchanged (19). The explanation probably relates to tissue-specific differences in 11ß-HSD1 activity in obesity, which is down-regulated in liver (17) but up-regulated in adipose tissue (18) and probably skeletal muscle (20). The overall ratio reflects the balance between these tissue-specific differences. Recently, it was shown that in undifferentiated omental adipose stromal cells, 11ß-HSD1 acts primarily as a dehydrogenase, whereas in mature adipocytes, oxoreductase activity predominates. It was postulated that because glucocorticoids inhibit cell proliferation, 11ß-HSD1 dehydrogenase activity in the undifferentiated omental adipose stromal cells promotes cell proliferation, whereas once differentiation starts, the oxoreductase activity promotes adipogenesis (21).

We now show that in our patients with hypothalamic obesity, 11ß-HSD1 activity was enhanced. All five ratios of 11-OH/11-oxo metabolites were higher than control values, ranging from a 2-fold increase of cortols/cortolones, (F+E)/(THF+THE+5{alpha}THF) to a 3-fold increase in conjugated compounds, both indicating enhanced 11ß-HSD1 activity. It is not clear whether the main factor that influences 11ß-HSD1 activity is the extreme obesity due to hypothalamic damage or the hypothalamic damage itself. To understand this point further, investigations are needed to evaluate the role of the hypothalamic and pituitary hormones on 11ß-HSD1 activity in the adipose tissue. This is addressed in the accompanying paper (22).

11ß-HSD2 converts cortisol to cortisone in the kidney; urinary free F/E ratio reflects its activity, with a high ratio indicating inhibition of 11ß-HSD2 activity in patients with hypothalamic obesity, or conversely, higher levels of the substrate cortisol as a result of enhanced 11ß-HSD1 activity. Increasing the dose of hydrocortisone from 20 to 60 mg/d resulted in an increased ratio of urinary free cortisol/cortisone (23), emphasizing the fact that a high level of the substrate cortisol may result in an increased ratio of urinary free cortisol/cortisone.

These results imply that the hypothalamus conveys a message to the periphery, which modulates its 11ß-HSD1 activity. This is also suggested by a report that patients with hypothalamic obesity have elevated adipose tissue lipoprotein lipase activity, compared with subjects with simple obesity of similar magnitude (24). A prime candidate to convey this message from the hypothalamus is GH. GH was shown to decrease extra-renal 11ß-HSD1 activity in hypopituitary adults (23). The present results support this contention. In patients who received GH therapy for their GH deficiency, the 11-OH/11-oxo ratio tended toward normal values, although they did not fully normalize. We estimated that GH deficiency accounts for 10–46% of the change in 11ß-HSD1 activity. Another candidate that may convey the hypothalamic message is sex steroids. Sexual dimorphism in 11ß-HSD1 activity was reported in hypopituitary subjects, with 11-OH/11-oxo ratios being lower in females than males (14, 25). Replacement therapy with sex steroids in a subgroup of our patients did not influence 11-OH/11-oxo ratios. It is possible that the lack of difference between the two groups resulted from the extreme obesity in these hypothalamic patients.

Thyroid hormones regulate 11ß-HSD activity (26), but T4 levels were normal and comparable in both study groups (data not shown). Insulin was suggested to inhibit 11ß-HSD1 activity (27). The hyperinsulinemia of hypothalamic obesity would then induce an opposite change in 11-OH/11-oxo ratios. It is presently unknown whether the autonomic nervous system, regulated by the hypothalamus, CRH, ACTH, and norepinephrine/epinephrine, or cytokines may regulate 11ß-HSD1 activity (28).

The consequence of increased 11ß-HSD1 activity and the shift of the interconversion toward cortisol may contribute to availability of this compound to the glucocorticoid receptors of adipose tissue, either from the liver or through a para-autocrine effect within the adipose tissue itself. 11ß-HSD1 expression facilitates glucocorticoid action in both the liver (29) and adipose tissue (30). Another report addressed the issue of whether android obesity reflected Cushing’s disease of the omentum (21). The body habitus typical of hypothalamic obesity is also android, and the concept we propose is that deficiency of hypothalamic messengers after surgical injury induces a para-autocrine effect of enhanced glucocorticoid activity due to a change in 11ß-HSD1 activity.

Recently, transgenic mice overexpressing 11ß-HSD1 selectively in adipose tissue were created, and it is striking how similar these animals are to our patients with hypothalamic obesity (30). The transgenic mouse started to gain weight after 9 wk, even on a low-fat diet. With a modest overexpression of adipose tissue 11ß-HSD1, the mouse had a disproportionate accumulation of visceral fat depots. Indeed, in our patients with enhanced 11ß-HSD1 oxo activity, the ratio of visceral fat/sc fat was significantly higher than in the healthy fat control subjects.

Whatever the mechanism may be, a possible inference from these results is that patients with hypothalamic obesity may require a smaller dose of glucocorticoid replacement than other patients with hypoadrenalism. When hypothalamic obesity is associated with ACTH deficiency and a need for glucocorticoid replacement therapy, the dose should be as low as possible.


   Acknowledgments
 


   Footnotes
 
Abbreviations: BMI, Body mass index; CT, computerized tomography; E, cortisone; F, cortisol; HSD, hydroxysteroid dehydrogenase; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

Received March 31, 2002.

Accepted July 30, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response
Endocr. Rev., October 1, 2004; 25(5): 831 - 866.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. W. Tomlinson, J. S. Moore, P. M. S. Clark, G. Holder, L. Shakespeare, and P. M. Stewart
Weight Loss Increases 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Human Adipose Tissue
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2711 - 2716.
[Abstract] [Full Text] [PDF]

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 Recent Prog Horm ResHome page
J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker
Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue
Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
H. Mersebach, O. L. Svendsen, A. Astrup, and U. Feldt-Rasmussen
Abnormal Sympathoadrenal Activity, but Normal Energy Expenditure in Hypopituitarism
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5689 - 5695.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Westerbacka, H. Yki-Jarvinen, S. Vehkavaara, A.-M. Hakkinen, R. Andrew, D. J. Wake, J. R. Seckl, and B. R. Walker
Body Fat Distribution and Cortisol Metabolism in Healthy Men: Enhanced 5{beta}-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men with Fatty Liver
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4924 - 4931.
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 J. Clin. Endocrinol. Metab.Home page
D. J. Wake, E. Rask, D. E. W. Livingstone, S. Soderberg, T. Olsson, and B. R. Walker
Local and Systemic Impact of Transcriptional Up-Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3983 - 3988.
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 J. Clin. Endocrinol. Metab.Home page
R. S. Lindsay, D. J. Wake, S. Nair, J. Bunt, D. E. W. Livingstone, P. A. Permana, P. A. Tataranni, and B. R. Walker
Subcutaneous Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity and Messenger Ribonucleic Acid Levels Are Associated with Adiposity and Insulinemia in Pima Indians and Caucasians
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2738 - 2744.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
B. R. Walker and R. Andrew
Cortisol Metabolism in Type 2 Diabetes
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2951 - 2952.
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 J. Clin. Endocrinol. Metab.Home page
M. Friedberg, E. Zoumakis, N. Hiroi, T. Bader, G. P. Chrousos, and Z.'e. Hochberg
Modulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers
J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 385 - 393.
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