0021-972X/92/7403-0608$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society

Cortisol Resistance Syndrome G. NORBIATO, M. MORONI,

Vol. 74, No. 3 Printed in U.S.A.

in Acquired

Immunodeficiency

M. BEVILACQUA, T. VAGO, G. BALDI, M. GALLI, AND N. OLDENBURG

Servizio di Endocrinologia, Ospedale L. Sacco (Vialba), Studi di Milan0 (M.M., M.G., N.O.), Milan, Italy

E. CHEBAT,

and Clinica di Ma&tie

ABSTRACT. This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H] thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 f 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 + 2.6 fmol/million cells; P < 0.01) and sex- and age-matched controls

P. BERTORA,

Znfettive, UniversitZl

degli

(3.15 + 2.3 fmol/million cells; P < 0.01). The affinity of glucocorticoid receptors (KJ was strikingly decreased (9.36 + 3.44 nM in group 1; 3.2 + 1.5 nM in group 2; 2.0 + 0.8 nM in controls; P < 0.01). (3H]Thymidine incorporation was decreased dosedependently by dexamethasone in controls and patients; the effect was significantly blunted (P c 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implys a complex change in immune-endocrine function, which may be important in the course of immunodeticiency syndrome. (J Clin Endocrirwl Metab 74: 608-613,1992)

B

ASED on symptoms such as weight loss, general weakness, anorexia, and diarrhea, adrenal insufficiency has been suspected in a number of patients infected with the human immunodeficiency virus (HIV) (l-5). Although some of these patients had the expected low plasma cortisol levels and blunted plasma cortisol response to ACTH stimulation, others had high plasma cortisol values (6-8). This has created a controversy about the mechanisms leading to hypercortisolism in such patients. The finding has been interpreted as a stress pattern of response to illness (9) or a result of ectopic production by lymphocytes or monocytes of factors that stimulate the adrenal cortex (10, 11). Owing to the lack of signs of hypercortisolism, it can be hypothesized that such patients have an acquired form of peripheral resistance to glucocorticoid. We, therefore, examined the characteristics of the glucocorticoid receptor in nine acquired immunodeficiency syndrome (AIDS) patients displaying an Addisonian picture in the presence of elevated values of serum and urinary free cortisol. The

study was performed on lymphocytes, since they possess glucocorticoid receptors (12, 13) and are target cells for HIV infection. To evaluate one of the effects consequent to glucocorticoid receptor activation, we measured the effect of dexamethasone on [3H]thymidine incorporation in the same cells (14). Subjects

and Methods

Patients

The study included 9 patients with AIDS and a history of iv drug addiction. Of these patients, 1 was asymptomatic, and 8 had 1 or more opportunistic infections. None of the patients had known bacterial infections. No patient was receiving immunomodulatory or antiviral therapy at the time of study. All patients exhibited Addisonian features (weakness,weight loss,mucocutaneousmelanosis,and hyponatremia) in the presenceof elevated levelsof serumand urinary free cortisol (Table 1; group 1). Studies were also performed in 12 patients with AIDS (all had beendrugabusers)but without clinical symptoms of adrenal disfunction (group 2); of these patients, 3 were asymptomatic, and 9 had 1 or more opportunistic infections. Control subjectswere 12 age- and sex-matched healthy seronegative heterosexualadults.

Received October 29, 1990. Address all correspondence and requests for reprints to: Prof. Guido Norbiato, Servizio di Endocrinologia, Ospedale L. Sacco (Vialba), Via GB Grassi 74, 20157 Milan, Italy. 608

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CORTISOL

RESISTANCE

IN AIDS

TABLE 1. Biochemical characteristics of nine AIDS patients with addisonian picture (group l), AIDS patients without addisonian picture (group 2), and normal subjects (controls) (PC, plasma cortisol; ACTH, adrenocorticotropic hormone; m, morning at 0800 h; e, evening at 2000 h; Aldo, aldosterone; UFC, urinary free cortisol; Na, serum sodium; K, serum potassium; BG, blood glucose; MBP, mean blood pressure; Dex, after dexamethasone treatment); nd, not determinable

Age (yrs) Group 1 1

24 Dex 26 Dex

3

22 Dex

4

21 Dex

5

31 Dex

6

29 Dex

7

21 Dex

8

34 Dex

9

42 Dex

PC (nmol/L) m e

ACTH (pmol/U m e

UFC

Aldo

(nmol/day) (pmol/L)

679 521 745 510 1642 1371 723 408 1161 1192 863 554 800 513 1068 902 703 575

698 483 706 469 1344 1241 786 428 1090 1068 841 516 875 861 967 470 762 603

11.4 10.5 2.8 3.9 13 13.6 11 10.7 12 10.3 14.5 14 15.8 12.7 9.2 10.5 3.9 3.3

10.7 1.7 3.3 4.6 14.3 13 12 10 10.5 11.6 13.2 11.2 17 14.3 10 8 4.4 3.5

400 419 1247 830 1517 1344 897 593 1600 1586 861 546 1117 665 897 510 281 403

516 14 14 4 A 408 39 nd

262 110 nd

5.5 2.2 1 1 B 3.7 1 1 1

2 2.4 nd 0.6 0.6 nd

Renin

MBP

(rig/L)

Na

K

BG

(mmHg) (mmol/L) (mmol/L) (mmol/L)

380

15

82

131

3.1

3.9

58

20

78

128

3.2

3.6

286

17

78

136

3.9

4.1

319

21

73

126

3.5

3.7

305

16

73

131

3.7

3.6

233

18

75

129

4.1

3.8

208

15

86

130

3.6

3.4

299

20

81

132

3.9

3.6

208

13

90

127

3.9

4

433 157 14 8

241 97

18 5

95 7

139 4

4.2 0.3

4.3 0.2

229 39 28 6

363 33

20 6

96 2

145 1

4.6 0.1

4.7 0.1

Group 2 Dex

:D m SD

Controls :D Dex :D

Endocrine

176 14 nd

testing

Baselinestudieswereperformed on 2 consecutivedays. During the first day, blood waswithdrawn with the patients supine at 0800 and 2000 h for measurementof plasma ACTH and serumcortisol and at 0800 h for measurementof aldosterone and renin. On the secondday, blood was withdrawn to obtain lymphocytes. Twenty-four-hour urine sampleswere collected on both days for measurementof urinary free cortisol. A dexamethasonesuppressiontest was performed a week later. The dexamethasonedosewas given for 2 consecutive days in equal dosesevery 6 h for a total daily doseof 2 mg. Measurements of serumcortisol and ACTH were made while the patients were supineat 0800 h and 2000h during dexamethasone administration. Twenty-four-hour urine sampleswere collected daily throughout the dexamethasonestudy. The dexamethasonestudy wasperformed in all patients from group 1 and in six patients from group 2. Mononuclear

leukocyte (MNL)

suspensions

MNL isolated from heparinized peripheral blood of patients and controls subjectsby Ficoll-Paque sedimentation (15) were washedand suspendedin Dulbecco’sModified Eagle’sMedium

(Gibco, Grand Island, NY) containing 50 pg/mL gentamicin and 2 mM glutamine. More than 95% of the MNL were viable, as determined by the trypan blue exclusion test and counting on a hemocytometer. Biochemical

assay

Serum electrolytes were measuredby flame photometry. Serum cortisol, urinary free cortisol, and aldosterone were measuredaspreviously reported (16, 17). Renin was measured by an immunoradiometric assay (IRMA) for renin (Pasteur, Paris, France) with a 12% intraassay coefficient of variation and an 18% interassay coefficient of variation. ACTH was measuredby an IRMA kit (Allegro, Nichols Institute, San Juan Capistrano,CA) with a 10% intraassay coefficient of variation and a 14%interassaycoefficient of variation. All analyseswere performed in duplicate. PHlDexamethasone

binding

The binding capacity of MNL wasdeterminedby incubating the cells in 0.5 mL Dulbecco’sModified Eagle’sMedium and adding various concentrations of [3H]dexamethasone(SA, 45

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610

NORBIATO

ET AL.

JCE & M. 1992 Vol74.No3

Ci/mmol; New England Nuclear, Boston, MA) with or without a 200-fold molar excess of cold dexamethasone (Sigma, St. Louis, MO). Each tube contained 1 million cells/O.4 mL medium, and incubation was performed at 4 C overnight. The cells were harvested on glass-fiber filters (Whatman GF/C, Clifton, NJ), washed twice with 10 mL cold phosphate-buffered saline, and analyzed for radioactivity in a Packard Tri-Carb scintillation spectrometer (Downers Grove, IL). Binding capacity, expressed as femtomoles of receptors per million cells, and the apparent dissociation constant were calculated according to the method of Scatchard (18) by means of a Ligand program running on an IBM-PC (19).

0 CONTROL

8,,,=6.5 =2.4

KD

o AIDS

fmol/lO%ells nM

B max= 15.5 fmol/106cells

Thymidine incorporation In vitro sensitivity to glucocorticoids was measured by studying the effects of dexamethasone on incorporation of radiolabeled thymidine (14). MNL (1 million cells/ml) were incubated in RPMI-1640 with 10% fetal calf serum at 37 C for 18 h. Then, different doses of dexamethasone (0.1-100 nM) were added, and the incubation was continued for 24 h at 37 C. Radiolabeled thymidine ( [methyl-3H]thymidine; SA, 85 Ci/mmol; Amersham, Aylesbury, Buckinghamshire, United Kingdom] was then added (2 &i/mL), and the incubation was continued for 6 h. The cells were harvested on glass-fiber filters, and thymidine incorporation was determined by liquid scintillation counting. Results from in uitro sensitivity studies were expressed as the percent change in cellular isotope incorporation after dexamethasone treatment. Statistical analysis The data in text and figures are presented as the mean + SD. Analysis of variance was used for statistical evaluation among the three groups of subjects. Results Endocrine

testing

Mean serum cortisol, which was measured on 3 days, showed elevated levels and a blunted circadian rhythm in all group 1 patients (Table 1). Plasma ACTH levels analyzed contemporaneously with serum cortisol showed normal to elevated levels (Table 1). Urinary free cortisol was strikingly elevated in these patients (Table 1). Individual data for the suppression test showed decreased cortisol and ACTH suppression in response to exogenous dexamethasone in group 1 patients. Plasma aldosterone was normal or low, and plasma renin in the recumbent position was normal. Serum sodium and potassium levels were low to normal (Table 1). In group 2 patients, serum cortisol, plasma ACTH, and urinary free cortisol were normal and normally inhibited by dexamethasone.

2

4

6

8 10 8 (fmol/l06cells)

12

14

16

FIG. 1. Representative Scatchard analysis of glucocorticoid receptors in MNL from control subjects (0) and patients with AIDS and clinical features of peripheral glucocorticoid resistance (0). B, Bound; B/F, bound/free ratio; B,.., number of binding sites; Kd, affinity of the binding sites for [3H]dexamethasone. [3H]dexamethasone binding to MNL demonstrated a single class of binding sites with a Kd of 9.36 f 3.44 nM, which was significantly lower than in group 2 patients (Kd, 2.0 f 0.8 nM; P < 0.01) and controls (Kd, 2.04 f 0.82 nM; P < 0.01). The number of receptors was higher in group 1 patients (16.21 + 9.41 fmol/million cells us. 6.05 f 2.6 in group 2 patients and 3.15 & 2.33 in controls; P < 0.01). Individual data for binding capacity and Kd from group 1 patients and control subjects are reported

in Fig. 2. Thymidine

incorporation

As shown in Fig. 3, dexamethasone dose-dependently inhibited the accumulation of [3H]thymidine in lymphocytes from controls and group 1 patients. The effect was more evident

in controls;

in fact, dexamethasone

at 10

inhibited [3H]thymidine incorporation by about 32% in controls and by 12% in group 1 patients (P < 0.01). Dexamethasone inhibited [3H]thymidine incorporation by about 29% in group 2 patients. At 100 nM, dexamethasone inhibited thymidine incorporation by about 45% in controls and by 23% in group 1 AIDS patients (P < 0.01). At 100 nM, dexamethasone inhibited thymidine incorporation by about 41% in group 2 patients. nM

Receptor studies A representative Scatchard plot of one group 1 patient and one control subject, is depicted in Fig. 1. Analysis of

Our study describes primary abnormalities

cortisol resistance due to

of the glucocorticoid

receptor

in some pa-

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CORTISOL

45-

. CONTROL

42-

0 AIDS

RESISTANCE

0

3936332 30= $ 27“0 y 24B E a-

z a

18-

0

0

:15-

0

0

0

12 -

0

9-

0

0

6-

0

l

3-

.$‘.

0.

0, 2

I 6

4

I 8

I 10

I 12

I 14

I 16

,

Ko(nM)

FIG. 2. Number of binding sites for [3H]dexamethasone (B,..) and their affinity (Kd) in control subjects (0) and nine patients with AIDS and clinical features of peripheral resistance to glucocorticoids (0).

0 CONTROL

F z 60f z s

50I 10

I 9 -109

IDEXAMETHAS~NEI

I 8

I 7 (M)

FIG. 3. Dose-related inhibition of [3H]thymidine incorporation in lymphocytes by dexamethasone. Cells were obtained from control subjects (0) and nine patients with AIDS and clinical features of peripheral resistance to glucocorticoids (0). Counts per minute in the absence of dexamethasone were 6125 + 857 in controls (O), 3957 f 640 in group 1 patients (O), and 4141 + 750 in group 2 patients.

tients with AIDS. In spite of high serum and urinary cortisol levels, the patients had a number of signs and symptoms, including mucocutaneous pigmentation, weakness, weight loss, hypotension, and tendency to hyponatremia, that recalled adrenal insufficiency. This

IN AIDS

611

clinical picture is consistent with the diagnosis of peripheral resistance to cortisol (14, 20-26). In these patients, ACTH levels were normal to high. Interestingly, normal to slightly elevated levels of ACTH have been found in other patients with peripheral resistance to glucocorticoids (14, 20-26); the reason why ACTH is only marginally elevated in such patients is unknown. We measured ACTH by an IRMA that recognizes ACTH-(1-39); it is, therefore, possible that glucocorticoid overproduction in our patients may be due to other forms of ACTH. Pituitary resistance to glucocorticoids was demonstrated by the lack of inhibition of ACTH and plasma and urinary cortisol by administration of dexamethasone. The affinity of the MNL glucocorticoid receptors for [3H]dexamethasone was reduced, and the number of receptors increased in these patients, suggesting that a receptor abnormality was responsible for glucocorticoid resistance. Many researchers (14, 20-26) have identified abnormalities of the glucocorticoid receptor in MNL from patients with peripheral resistance to cortisol; these include 1) decreased number of glucocorticoid receptors (23), 2) decreased affinity of glucocorticoid receptors (22), 3) decreased stability of glucocorticoid receptors at 42 C (14), and 4) decreased induction of glucocorticoid receptors by in vitro infection of lymphocytes with Epstein-Barr virus (27). A major difference from previously described syndromes of cortisol resistance and our patients was that MNL from HIV-infected patients showed an increase in glucocorticoid receptor density and a decrease in affinity for [3H]dexamethasone. Such a glucocorticoid receptor abnormality has never been described before. The inhibitory effect of dexamethasone on [3H] thymidine incorporation in MNL, a well recognized effect of glucocorticoids (14, 28, 29), was also impaired in these patients. The cause of the glucocorticoid receptor abnormality in these HIV-infected patients is unknown; it is unlikely that this abnormality is secondary to cortisol excess. In fact, high concentrations of glucocorticoids decrease receptor density in vitro and in vivo without affecting receptor affinity (30, 31). Viral infection is known to cause glucocorticoid receptor induction (32); the high incidence of Epstein-Barr viral infection in HIV-infected patients may be a factor in the increase in glucocorticoid receptor number. Mutagens such as Concanavalin-A and phytohemagglutinin were also found to increase glucocorticoid receptor density in T-lymphocyte cultures (30, 33). By analogy, endogenous mitogens such as interleukins may be potentially responsible for such a receptor change. Interestingly, Nunez and co-workers (7, 34-36) have recently shown that a lipid perturbation found in AIDS patients’ serum and blood cells is associated with a decrease in the affinity of dexamethasone for glucocor-

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612

NORBIATO

ticoid receptors and a decreased ability of dexamethasone to inhibit [3H]thymidine incorporation in thymocytes. The cause of the lipid perturbation in AIDS patients is unknown. The alteration of glucocorticoid receptors in HIV patients may have important consequences. It is well known that glucocorticoid hormones exert an antiproliferative and cytolytic action on lymphoid tissue, mainly on T-lymphocytes (28, 29). The mechanism of the cellular events responsible for T-lymphocyte cytolysis remains uncertain, but the pivotal role played by glucocorticoid receptors is well documented (28). Studies in animals and humans have identified many receptor gene mutations that affect receptor function and convey steroid resistance (37, 38). HIV infection or viral complications of the immunodeficiency syndrome may have induced mutations of the lymphocyte gene loci that alter the steroid receptor response. Thus, as exemplified by [3H]thymidine incorporation data, the defect in the glucocorticoid receptor in AIDS patients is associated in vitro with a reduced cytolytic effect of glucocorticoids on lymphocytes (28, 29). The effects of glucocorticoid resistance on the immune system should also be considered. Glucocorticoids are not only able to alter the circulating populations of white cells, but can inhibit the production of interleukin-2 (review in Ref. 39), which is an important T-cell growth factor and influences mitogen-induced immunoglobulin synthesis in human lymphocytes in uiuo and in uitro. These and other possible actions of glucocorticoids on antibody-secreting cells may be altered in HIV patients due to receptor abnormality and glucocorticoid resistance. In summary, patients with the immunodeficiency syndrome may develop hypercortisolism without clinical manifestation of glucocorticoid excess as a result of a functionally abnormal glucocorticoid receptor responsible for peripheral resistance. The receptor abnormality consists of a lower receptor affinity for glucocorticoids and a higher receptor density; it is detected in lymphocytes, which are an important component of the immune system. The receptor abnormality in lymphocytes from AIDS patients might be responsible for an alteration in the immune-endocrine interaction (40), which, in turn, may influence the course of the disease. References 1. Glasgow DJ, Steinsapir KD, Anders K, Layfield W. Adrenal pathology in the acquired immune deficiency syndrome. Am J Clin Pathol. 1985;84:594-7. 2. Greene LW, Cole W, Greene JB, et al. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med. 1984;101:497-3. 3. Dobs AS, Dempesey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 1987;84:611-6.

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4. Membreno L, Irony I, Dere W, Klein R, Biglieri EG, Cobb E. Adrenocortical function in acquired immunodeficiency syndrone. J Clin Endocrinol Metab. 1987;65:482-7. DN, Friedland GH, Surks MI. Adrenocortical 5. Klein RS, Mann function in acquired immunodeficiency syndrome. Ann Intern Med. 1983;99:566. 6. Dluhy RG. The growing spectrum of HIV-related endocrine abnormalities. J Clin Endocrinol Metab. 1990;70:563-5. 7. Christeff N, Michon C, Goertz G, et al. Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients. Eur J Cancer Clin Oncol. 1988;17:1814. 8. Villette JM, Bourin P, Doinel C, et al. Circadian variations in plasma levels of hypophyseal, adrenocortical and testicular hormones in men infected with human immunodeficiency virus. J Clin Endocrinol Metab. 1990;70:572-7. 9. Parker LN, Levin ER, Lifrac ET. Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab. 1985;60:94752. 10. Whitcomb RW, Marston Linehan W, Wahl LM, Kuazeh RA. Monocytes stimulate cortisol production bv cultured human adrenocortical cells. J Clin Endocrinol Metab. i988;66:33-8. 11. Smith EM. Blalock HE. Human lvmnhocvte nroduction of corticotropin and endorphin-like substances: association with leukocyte interferon. Proc Nat1 Acad Sci USA. 1981;75:7530-4. 12. Gustafsson J-A, Carlstedt-Duke J, Poellinger L, et al. Biochemistry, molecular biology and physiology of the glucocorticoid receptor. Endocr Rev. 1987;8:185-234. 13. Delarche-Homo F. Glucocorticoid receptors and steroid sensitivity in normal and neoplastic human lymphoid tissues: a review. Cancer Res. 1984;44:431-7. 14. Bronnegard M, Werner S, Gustafsson J-A. Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom. J Clin Invest. 1986;78:1270-8. 15. Boyum A. Isolation of mononuclear cell and granulocyte from human blood. Stand J Clin Lab Invest. 1968;21(Suppl97):77-89. 16. Norbiato G, Bevilacqua M, Raggi U, Micossi P, Moroni C. Metoclopramide increases plasma aldosterone concentration in man. J Clin Endocrinol Metab. 1977;45:1313-7. 17. Norbiato G, Bevilacqua M, Chebat E, et al. Metoclopramide increases vasopressin secretion. J Clin Endocrinol Metab. 1986;63:747-52. 18. Scatchard G. The attraction of proteins for small molecules and ions. Ann NY Acad Sci. 1949;51:660-72. 19. Munson PJ. Rodbard D. LIGAND: a versatile comnuterized anpreach for characterization of ligand-binding systems. Anal Biochem. 1980;107:220-39. 20. Vingerhoeds ACM, Thijssen JHH, Schwarz F. Spontaneous hypercortisolism without Cushing’s- syndrome. J Clin Endocrinol Metab. _ 1976;43:1128-33. 21. Chrousos GP, Vingerhoeds ACM, Loriaux DL, Lipsett MB. Primarv cortisol resistance: familv ” studv. ” J Clin Endocrinol Metab. 1983;56:1243-5. 22. Chrousos GP, Vingerhoeds ACM, Brandon D, et al. Primary cortisol resistance in man: a glucocorticoid receptor-mediated disease. J Clin Invest. 1982;69:1261-9. 23. Ida S, Gomi M, Moriwaki K, et al. Primary cortisol resistance accompanied by a reduction in glucocorticoid receptors in two members of the same family. J Clin Endocrinol Metab. 1985;60:967-71. 24. Nawata H, Sekiva K, Higuchi K, Kato K, Ibayashi H. Decreased deoxyribonucleic acid binding of glucocorticoid-receptor complex in cultured skin fibrohlasts from a patient with glucocorticoid resistance syndrome. J Clin Endocrinol Metah. 1987;65:219-26. 25. Lamberts SWJ, Polderman D, Zweens M, de Jong FH. Familial cortisol resistance: differential diagnostic and therapeutic aspects. J Clin Endocrinol Metab. 1986;63:1328-33. 26. Malchoff CD, Javier EC, Malchoff DM, et al. Primary cortisol resistance presenting as isosexual precocity. J Clin Endocrinol Metab. 1990;70:503-7. 27. Tomita M, Brandon DD, Chrousos GP, et al. Glucocorticoid receptors in Epstein-Barr virus transformed lymphocytes from patients “.



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CORTISOL

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RESISTANCE

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-*

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Cortisol resistance in acquired immunodeficiency syndrome.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or meta...
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