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Effect of Pioglitazone on Adrenocorticotropic Hormone and Cortisol Secretion in Cushing’s Disease

Department of Medicine (D.S.) and Committees on Molecular Medicine and Nutritional Biology and General Clinical Research Center (R.E.W.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., Thyroid Study Unit, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Mail Code 3090, Chicago, Illinois 60645. E-mail: rweiss{at}medicine.bsd.uchicago.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The lack of an effective medical therapy for patients with Cushing’s disease (CD) requires the search for new modalities of treatment. Peroxisomal proliferator-activated receptors (PPAR)- are abundantly expressed in ACTH-secreting pituitary tumors. Treatment with PPAR agonists inhibits ACTH-secreting pituitary tumor growth, proliferation, and ACTH secretion in vitro in human and murine models and in vivo in murine corticotroph tumors. It was hypothesized that treatment with the PPAR agonist pioglitazone would normalize the hypothalamic-pituitary-adrenal axis of patients with CD.

We evaluated the hypothalamic pituitary adrenal axis in five patients with CD in whom we measured: 1) the 24-h urine concentration of free cortisol; 2) the 24-h profile of serum cortisol and plasma ACTH; and 3) the ACTH and cortisol response to CRH stimulation. All measurements were taken at baseline and after low-dose dexamethasone treatment (0.5 mg dexamethasone every 6 h). The entire protocol was done before and after 30 d of treatment with 45 mg of daily oral pioglitazone.

At baseline, before low-dose dexamethasone, all five patients had elevated 24-h urine free cortisol, elevated 24-h serum cortisol and plasma ACTH levels, and robust responses to CRH, consistent with their diagnosis of CD. There was no significant change in any of the above variables after 30 d of treatment with pioglitazone. Furthermore, there was no significant difference in the number of cortisol or ACTH spikes or in their diurnal rhythms. In summary, pioglitazone treatment (45 mg daily for 30 d) of patients with CD was not found to be effective at attenuating either ACTH or cortisol levels and does not appear to be an alternative to surgical therapy.

	Introduction

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THE MOST COMMON etiology of endogenous Cushing’s syndrome, accounting for over 70% of cases, is an ACTH-secreting pituitary adenoma, termed Cushing’s disease (1). Untreated hypercortisolism resulting from persistent adrenal stimulation by ACTH can lead to impaired glucose metabolism, hypertension, osteoporosis, visceral obesity, immune suppression, and psychiatric disturbances (2), with an 8-yr mortality of 11% (3). The treatment of choice for patients with Cushing’s disease is the selective microsurgical removal of the ACTH-secreting pituitary adenoma. Ideally, the removal of the adenoma should cure the Cushing’s disease, whereas leaving no other pituitary dysfunction. However, the reported success rates vary from 50% to 80%, depending on a variety of factors including initial size of the tumor, preoperative ACTH levels, and skill and experience of the neurosurgeon (4, 5). Primary radiotherapy is effective in only 50–60% of adults with Cushing’s disease (6, 7, 8, 9). Adjunct radiotherapy for unsuccessful pituitary surgery may be more useful, but it may take years to see a maximal effect and the risk of hypopituitarism approaches 80% (10). Currently the medical therapy of Cushing’s disease is less than optimal and is limited to the inhibition of steroidogenesis, which is only moderately successful. Mitotane and ketoconazole are the most potent agents available, but they effectively reduce cortisol levels over the short term in only three quarters of patients studied, and less than one third of this group will have a sustained remission after discontinuation of the medication (11). Additionally, the significant untoward effects of these medications limit their usage.

The lack of a curative, affordable, and easily tolerated medical therapy for Cushing’s disease has therefore led to the search for new modalities of treatment. It was recently reported that peroxisomal proliferator-activated receptor (PPAR)- is abundantly expressed in human pituitary tumors (12). Furthermore, it was demonstrated that human and murine ACTH-secreting pituitary tumors incubated in vitro with PPAR activators induced cell cycle arrest and apoptosis and inhibited tumor proliferation and proopiomelanocortin expression (ACTH precursor). In vivo administration of PPAR activators prevented AtT20 murine tumor growth and suppressed ACTH and corticosterone secretion in mice (12, 13). The presence of a PPAR response element in the proopiomelanocortin promoter was recently described, making corticotroph hyperactivity potentially more amenable to PPAR treatment than other pituitary tumors (14). The PPAR activators are commercially available as the oral thiazolidinediones, pioglitazone, and rosiglitazone. PPAR is a member of the nuclear receptor superfamily, and PPAR activation leads to gene transcription events involved in glucose metabolism, adipocyte differentiation, and impairment of angiogenesis and inflammation (15). Additionally, PPAR ligands have been demonstrated to have tumor-suppressive effects on breast, prostate, colon, renal cell, and non-small-cell lung cancers through their effect on cell apoptosis and proliferation (16, 17, 18, 19).

Given the above, we sought to determine whether patients with documented ACTH-secreting pituitary adenomas leading to Cushing’s disease would respond with attenuation of ACTH and cortisol secretion after treatment with a PPAR agonist. We report here the results obtained in five consecutive patients with Cushing’s disease, who were treated with the PPAR activator pioglitazone in an attempt to normalize their hypothalamic-pituitary-adrenal axis.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Experimental subjects

The five patients studied (Table 1) were referred for further diagnosis and management of their documented hypercortisolism.

Patient 2, a 48-yr-old Caucasian male, reported daily headaches, fatigue, weakness, and worsening libido for 2 yr. He was found to have an elevated outpatient 24-hr UFC of 240 µg. A MRI of the pituitary revealed a normal pituitary gland. Inpatient testing in the GCRC demonstrated persistent elevations of 24-h UFC, suppression of urine and serum cortisols with HDD but not LDD, and a robust response of ACTH to CRH stimulation. IPSS demonstrated a central/peripheral ACTH gradient of 16:1. The patient refused surgery.

Patient 3, a 40-yr-old Caucasian male, was initially diagnosed with Cushing’s disease in 1987 when he presented with recurrent nephrolithiasis, rib fractures, weakness, weight gain, and abdominal striae. At that time, he had documented hypercortisolism with a likely pituitary etiology, a normal pituitary MRI, normal computed tomography scans of the chest and abdomen, and IPSS with an increased central/peripheral gradient, localizing to the right IPSS. In 1987 he underwent a right transphenoidal hypophysectomy at another institution. His operative report states that no tumor was visualized, nor did surgical pathology ascertain any definitive tumor in the pituitary tissue submitted for evaluation. Nonetheless, he had a postoperative plasma ACTH less than 1.0 µg/dl, normal circadian rhythm of cortisol secretion, and a 24-h UFC that normalized to 17 µg. He also experienced rapid resolution of his symptoms and weight loss. Recently he began complaining of daily headaches, weight gain, and decreased libido. An outpatient 24-h UFC was elevated at 275 µg, and a MRI of the pituitary demonstrated a small residual pituitary gland demonstrating normal enhancement with postsurgical changes in the sella but no evidence of a tumor. Inpatient testing in the GCRC, as described below, demonstrated recurrent pituitary-dependent Cushing’s.

Patient 4, a 33-yr-old Caucasian female, initially presented in 1997 with a 5-yr history of oligomenorrhea, recurrent infections, and easy bruisability. She had an elevated 24-UFC of 500 µg, a pituitary MRI demonstrated an 8-mm pineal cyst but no evidence of a pituitary lesion, and IPSS demonstrated a central/peripheral ACTH gradient of 16:1, with a left/right gradient of 4:1. In May 1997 she underwent a partial transphenoidal hypophysectomy, with evidence of an ACTH-staining adenoma on pathology. She had complete resolution of her symptoms and normalization of her 24-h UFC. Her menses returned and she was able to become pregnant, delivering a healthy baby girl in March 1999. She was able to breast-feed for 9–12 months but did not resume menstruation after childbirth. In November 1999, a 24-h UFC was 142 µg, and in March 2000 a 24-h UFC continued to be elevated at 169.8 µg. A MRI of the pituitary revealed residual pituitary tissue. In June 2000 she underwent repeat transphenoidal hypophysectomy. Her postoperative plasma ACTH level dropped from 53 to 18 pg/ml, suggesting a residual tumor. In August 2000 her 24-h UFC was also slightly elevated at 95.2 µg. She was treated with radiation therapy and mitotane but had to discontinue the mitotane secondary to lipid abnormalities. For the past year, she was maintained on ketoconazole 400 mg PO twice daily but continued to have persistent hypercortisolism, with a recent outpatient 24-h UFC of 154 µg and a serum ACTH of 66 pg/ml. Inpatient testing in the GCRC, described below, demonstrated findings consistent with recurrent pituitary-dependent Cushing’s.

Patient 5, a 58-yr-old Hispanic female, initially presented in 1989 with a 2-yr history of oligomenorrhea, hirsutism, proximal muscle weakness, and a 25-lb weight gain. She had an elevated 24-h UFC of 735 µg, inpatient testing in the GCRC demonstrated pituitary-dependent cortisol excess, and a pituitary MRI demonstrated 3 x 3 mm right pituitary microadenoma. In November 1989 she underwent a transphenoidal hypophysectomy, which demonstrated an ACTH-staining adenoma on pathology. She reported resolution of her symptoms and weight loss, but she was lost to follow-up, and no subsequent urine or serum cortisols were obtained. In the last year, she has been diagnosed with hypertension, type 2 diabetes mellitus, obstructive sleep apnea, and a weight gain of 30 lb. An outpatient 24-h UFC cortisol was elevated at 320 µg. In April 2004 a MRI demonstrated pituitary scarring but no evidence of residual tumor. Inpatient testing in the GCRC, described below, yielded results consistent with recurrent Cushing’s disease.

Study design

Between 2003 and 2004, five consecutive patients with suspected Cushing’s disease were recruited to participate in this study. The diagnosis of Cushing’s disease (new or recurrent) was based on endocrine testing that included: 1) elevated 24-h UFC on at least two occasions; 2) failure to suppress 24-h UFC less than 20 µg/24-h after 2 d of LDD (0.5 mg PO every 6 h); 3) stimulation of serum cortisol 2 µg/dl or more and plasma ACTH to 16 pg/ml or more with CRH (ACTHREL, corticorelin ovine triflutate for injection; Ferring Pharmaceuticals, Tarrytown, NY) on dexamethasone suppression; 4) failure to suppress 24-h UFC by at least 50% after 2 d of HDD (2.0 mg PO every 6 h) (20); and 5) a demonstrable pituitary adenoma on pituitary MRI or a normal MRI examination but positive IPSS. Positive IPSS was defined as a central to peripheral ACTH gradient greater than 3, after ovine CRH injection (21).

Each subject participated in two admissions to the GCRC: before and after 30 d of daily treatment with 45 mg of oral pioglitazone. We chose to use pioglitazone because its in vivo antidiabetic effectiveness is equal to rosiglitazone and the medication was made available without charge to our research subjects. The dose of 45 mg was chosen because it is the maximum approved dose for the treatment of diabetes. The time period of 30 d was chosen because the medication’s antidiabetic effects are seen within this period of time. For each patient during both admissions, an indwelling catheter was inserted into a forearm vein, and blood samples were drawn at 30-min intervals for 25 h, starting 1 h after catheter insertion. Data obtained during the first hour of sampling were discarded to avoid the artifactual products of a secretory peak associated with venipuncture. At each admission we measured: 1) the 24-h UFC; 2) the 24-h profile of cortisol and ACTH measured every 30 min; and 3) the response to CRH stimulation, defined as the peak increase above baseline plasma ACTH after the iv injection of 100 µg of ovine CRH. Plasma ACTH levels are measured 15 min before and immediately before CRH administration as well as 15, 30, 60, 90, 120, 150, and 180 min after CRH administration. Recent studies reported that a peak incremental increase of ACTH greater than 50% has an 86% diagnostic accuracy for Cushing’s disease (22). All of the above measurements were taken at baseline and after LDD. Serum dexamethasone levels were measured four times over 24 h in all patients beginning on the second day of LDD, both before and after pioglitazone. Patients remained on 45 mg PO daily pioglitazone during their second GCRC admission. Patients were contacted by phone during the month of participation to determine whether there were any adverse effects of the pioglitazone and confirm medication compliance.

The institutional review board approved this study, and written informed consent was obtained from all subjects. Patients did not receive monetary compensation for participation in this study.

Assays

Serum cortisol was measured by RIA (Coat-A-Count; Diagnostic Products Corp., Los Angeles, CA), with a lower limit of detection of 0.2 µg/dl, an intraassay coefficient of variation (CV) of 3.0–5.1% and an interassay CV of 4–6.4%. All samples from the same 24-h sampling period for each subject were measured in the same assay. UFC was measured using the same RIA after extraction with methylene chloride. The upper limit of normal for this assay is 100 µg per 24 h.

Plasma ACTH was measured by immunochemiluminometric assay (Quest Diagnostics, Terterboro, NJ), with a lower limit of detection of 0.5 pg/ml and an intraassay CV of 4.6%.

Serum dexamethasone level was measured by RIA after chromatography (Esoterix Laboratory Services, Calabasas Hills, CA), with a lower limit of detection of 30 ng/dl and an intraassay CV of 15.1%.

Pulsatility analysis

Pulsatility analyses were performed for all 24-h profiles. The mean, SD, and CV (SD divided by the mean) of cortisol and ACTH levels were calculated for each subject. The pulsatility pattern of each profile was described by quantifying the number of significant secretory pulses and their absolute and relative increments. All pulsatility analyses were performed using a computer program (ULTRA) specifically designed for that purpose (23). A pulse was defined as significant if the increment and decrement in concentration exceeded both the lower limit of sensitivity of the assay and twice the average intraassay CV. The absolute increment of each pulse was defined as the difference between the level at the peak and the level at the preceding trough.

Diurnal rhythm analysis

Diurnal rhythm analysis was performed on all subjects’ 24-h cortisol and ACTH profiles. The diurnal variations were quantified using a best-fit curve generated by repeated periodogram calculations, using a confidence interval of 95% (24). Acrophase was defined as the time of the best-fit curve maximum. Nadir was defined as the time of the best-fit curve minimum. The amplitude of the diurnal rhythm was defined as 50% of the difference between the acrophase and nadir values.

Statistical analysis

For each 24-h profile, the mean, SD, and CV of cortisol and ACTH were calculated. Each profile actually had 51 data measurements (every 30-min measurements for 26 h), but the first three were not included in the analysis to exclude the issue of continued elevation of cortisol and ACTH after the recent admission and iv catheter placement. The analysis was therefore done for 24-h profiles.

Comparisons between individuals before and after pioglitazone treatment were analyzed using paired t tests, using Minitab (version 13.0; Minitab, Inc., State College, PA). We applied the Bonferroni correction for multiple comparisons. Confidence intervals were derived using exact probabilities calculated from the binomial distribution. All values are mean ± SD unless otherwise stated.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Initial endocrine evaluations

Testing of all five patients, before treatment with pioglitazone, demonstrated persistent elevations of 24-h UFC, elevated mean serum cortisol and plasma ACTH, and incomplete suppression of urine and serum cortisol with LDD suppression (Tables 2 and 3). All five patients also had brisk responses of serum cortisol and ACTH to stimulation with CRH after dexamethasone suppression. The above evidence convincingly demonstrated hypercortisolism in all five patients.

Cortisol and ACTH response to pioglitazone treatment

Twenty-four-hour UFC. There were no statistically significant changes seen in any of the variables studied before and after pioglitazone administration (Table 2). Patients 1–4 had a nonsignificant trend toward increased 24-UFC measurements after pioglitazone treatment. Patient 5 had a 52% decrease in her 24-h UFC after 1 month of pioglitazone therapy. However, overall in all five patients’ combined data, there was no significant difference between pre- and postpioglitazone treatment values of 24-h UFC (228 ± 97 vs. 214 ± 32 µg per 24 h; P = 0.8).

Twenty-four-hour profile of cortisol and ACTH secretion. There was no significant difference in mean serum cortisol levels (20.8 ± 6.3 vs. 21.8 ± 6.2 µg/dl P = 0.45) and mean plasma ACTH levels (57 ± 43 vs. 52 ± 33 pg/ml; P = 0.52) between pre- and posttreatment values.

Analysis of the 24-h cortisol and ACTH profiles pre- and postpioglitazone treatment demonstrated no significant differences in the number of pulses per 24 h in ACTH (10.6 ± 2.1 vs. 9.8 ± 3.1; P = 0.3) or cortisol (8.6 ± 1.3 vs. 8.8 ± 2.4; P = 0.8) with pioglitazone treatment (Fig. 1). Additionally, there was no significant difference in ACTH and cortisol pulse sizes (expressed as the mean relative or absolute increment) with pioglitazone treatment (data not shown). Before treatment with pioglitazone, a significant diurnal rhythmicity of cortisol and ACTH secretion was detected in four subjects. Subject 2 did not demonstrate a significant diurnal component in his ACTH or cortisol profile. After treatment with pioglitazone, a significant diurnal rhythmicity of cortisol and ACTH secretion was detected in three subjects. Subject four no longer demonstrated a significant diurnal component in her 24-h ACTH or cortisol profile. In the three patients who maintained their diurnal rhythmicity, there were no significant differences in the amplitudes of the cortisol and ACTH diurnal rhythms or the relative acrophase and nadir values before and after pioglitazone (data not shown).

View larger version (49K): [in this window] [in a new window]   FIG. 1. In the upper left, the prepioglitazone treatment basal 24-h plasma ACTH rhythms for the five patients studied are shown. In the upper right, the postpioglitazone treatment basal 24-h plasma ACTH rhythms are shown. There were no significant differences in the number of ACTH pulses per 24 h (P = 0.3), ACTH pulse size (P = 0.3), or mean plasma ACTH levels (P = 0.5) before and after pioglitazone treatment. In the lower left, the prepioglitazone treatment basal 24-h plasma cortisol rhythms for the five patients studied are shown. In the lower right, the postpioglitazone treatment basal 24-h plasma cortisol rhythms are shown. There were no significant differences in the number of cortisol pulses per 24 h (P = 0.8), cortisol pulse size (P = 0.6), or mean plasma cortisol levels (P = 0.5) before and after pioglitazone treatment.

The ACTH response to CRH was studied before and after pioglitazone therapy. The response to CRH is defined as the peak ACTH increase over baseline after the injection of 100 µg ovine CRH. We found no significant change in ACTH response to ovine CRH (178 ± 156.1 vs. 218 ± 219%; P = 0.33) in either the magnitude or pattern of ACTH response (Fig. 2). There was no normalization of the ACTH and cortisol responses to CRH, as is seen after a successful cure with transphenoidal adenomectomy (25).

View larger version (16K): [in this window] [in a new window]   FIG. 2. Peak ACTH response (percent increase above baseline levels) to 100 µg ovine CRH. There was no significant difference in the mean peak ACTH response to CRH before and after pioglitazone (PIO) treatment (P = 0.3).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Our present study did not demonstrate a response to pioglitazone treatment in any of the parameters examined. In particular, we did not observe a reduction in hypercortisolism or a significant reduction in serum ACTH levels. There was no change in any of the other components of the HPA axis, as measured by circadian rhythm profile, response to CRH, or LDD suppression. However, we did observe two interesting points.

Three of four patients studied achieved lower concentrations of serum dexamethasone with LDD after pioglitazone than before pioglitazone. We hypothesize that this was due to increased metabolism of dexamethasone in the liver by pioglitazone because both drugs are metabolized via the cytochrome P450 liver microsomal enzyme complex. Accelerated hepatic inactivation of dexamethasone, with resultant rapid clearance from the circulation, may explain the lower serum dexamethasone levels seen after treatment with pioglitazone. Further research is warranted to determine whether patients being treated with PPAR agonists for the management of diabetes require discontinuation of this medication before undergoing LDD suppression to achieve adequate dexamethasone levels.

We additionally noted that subject 5, the only patient to experience a clinically notable reduction in 24-h UFC levels after 30 d of treatment with pioglitazone, was the only patient who had a pituitary adenoma visualized on MRI at the time of initial presentation with Cushing’s disease. We hypothesize that a possible mechanism is that PPAR receptors may be differentially expressed in distinct adenomas vs. corticotroph hyperplasia. In the normal human pituitary gland, PPAR expression in restricted to corticotrophs. However, in human pituitary tumors PPAR is abundantly expressed in somatotrophs, lactotrophs, gonadotrophs, and corticotrophs. Treatment of all the subtypes of pituitary tumors with PPAR ligands resulted in decreased in vitro tumor growth and proliferation and suppressed in vitro hormone secretion (13). Therefore, it is conceivable that the attenuation of excess hormone secretion in pituitary tumors treated with PPAR activators is at least partially mediated by the decrease in tumor size seen with these agents due to the induction of cell-cycle arrest and apoptosis by PPAR ligands.

Our results are in concordance with a recently published study by Cannavo et al. (26) that demonstrated that acute treatment with the PPAR activator rosiglitazone did not decrease ACTH or cortisol levels or blunt their response to CRH injection. Our results, however, are not synonymous with two recent studies investigating the chronic effects of the PPAR ligand rosiglitazone in Cushing’s disease (27, 28). The first study, conducted in Greece, studied five patients with residual or recurrent Cushing’s disease who were treated with 8 mg of daily oral rosiglitazone for 30 wk. They demonstrated a statistically significant decrease in early-morning serum ACTH and cortisol beginning at 4 wk of treatment, with a continued decline in early-morning serum cortisol values with prolonged duration of treatment. In four of the five patients studied, the mean morning serum cortisol at 16 wk was significantly lower than the mean morning serum cortisol at baseline. No 24-h UFC was reported. The authors concluded that treatment with the PPAR agonist rosiglitazone had a sustained, progressive effect in four of five patients treated for residual or recurrent Cushing’s disease for 16 wk. The second study, conducted in Italy, studied 14 patients with new or recurrent Cushing’s disease who were treated with 8 mg of daily oral rosiglitazone for 30–210 wk. Approximately 40% of the patients (six of 14) experienced significant normalization of their 24-h UFC within 30–60 d of starting rosiglitazone, without any statistically significant reduction in their serum ACTH and cortisol levels. Two of these six responders have been treated with 8 mg daily rosiglitazone for 7 months, with continued suppression of their 24-h UFC and clinical improvement. The remaining eight patients experienced no significant decrease in their 24-h UFC, serum cortisol, and serum ACTH treatment in response to 30–60 d of rosiglitazone therapy. We are not aware of any clinical differences between the responders and nonresponders to PPAR agonist therapy.

The primary differences between our study and the two described above are the choice of PPAR agonist used and the duration of treatment. We treated patients with 45 mg pioglitazone daily, the maximum approved dosage of pioglitazone and theoretically equivalent in dosage to the 8 mg rosiglitazone, the maximum approved dosage of rosiglitazone, used in the above studies. However, it is known that rosiglitazone has a higher in vitro binding affinity for the PPAR receptor and may be the more potent of the commercially available thiazolidinediones. There is no evidence that either drug is more effective biologically or clinically (29). Variable potency of the PPAR agonist used may explain why our study did not demonstrate a significant response to treatment. Additionally, we studied patients after only 30 d of treatment with pioglitazone. The reported results of other investigators suggest that this may be the earliest time period at which one can reliably see an effect of treatment, and we may have observed some reduction in hypercortisolism if we had implemented a longer duration of treatment. Nevertheless the use of thiazolidinediones, if effective, in mitigating the elevated cortisol levels would require a therapeutic lag time that may be unacceptably long.

We conclude that short-term therapy with pioglitazone therapy is unlikely to modulate the HPA axis in subjects with Cushing’s disease. However, further studies with more potent PPAR agonists for longer durations of treatment may be warranted.

	Acknowledgments

 
The authors thank Drs. David Ehrmann and Plamen Penev for reviewing the manuscript; Dr. Rachel Leproult for her assistance with the rhythm analysis; the nurses, dietitian, and core laboratory personnel of the University of Chicago Clinical Research Center for their devotion to the patients and this protocol; and the patients and referring physicians.

	Footnotes

 
This work was supported by National Institutes of Health Grants RR18372, DK17050, DK 58258, RR00055, DK07011, and DK58258.

First Published Online December 7, 2004

Abbreviations: CV, Coefficient of variation; HDD, high-dose dexamethasone; HPA, hypothalamic-pituitary-adrenal; IPSS, inferior petrosal sinus sampling; LDD, low-dose dexamethasone; MRI, magnetic resonance imaging; PO, by mouth; PPAR, peroxisomal proliferator-activated receptor; UFC, urine free cortisol.

Received September 7, 2004.

Accepted November 23, 2004.

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