METHOD FOR MONITORING AND ASSESSING PITUITARY FUNCTION
Methods for monitoring pituitary function and for distinguishing Cushing's disease from Cushing's syndrome. The methods includes (1) providing a subject, (2) administering to the subject a daily dosage of a glucocorticoid antagonist, (3) monitoring adrenocorticotropic hormone (“ACTH”) and/or cortisol levels in the subject. Subjects having normal pituitary function typically show an increase in ACTH and/or cortisol levels following glucocorticoid antagonist therapy, while subjects having abnormal pituitary function will typically show no significant change in ACTH or cortisol following glucocorticoid antagonist therapy. Similarly, subjects having Cushing's disease show a significant rise in ACTH and cortisol levels following glucocorticoid antagonist therapy, while, in contrast, subjects having Cushing's syndrome show no significant change in ACTH and/or cortisol following glucocorticoid antagonist therapy.
1 . A method for assessing pituitary function, comprising:
providing a subject;
administering to the subject a dosage of a glucocorticoid antagonist; and
monitoring adrenocorticotropic hormone (“ACTH”) and/or cortisol levels in the subject,
wherein subjects having normal pituitary function show an increase in ACTH and/or cortisol levels following glucocorticoid antagonist therapy, and wherein subjects having abnormal pituitary function show substantially no significant change in ACTH and/or cortisol following glucocorticoid antagonist therapy.
2 . The method of claim 1 , wherein changes in ACTH and/or cortisol levels can be observed in the subject within one (1) day following glucocorticoid antagonist therapy.
3 . The method of claim 1 , wherein changes in ACTH and/or cortisol levels can be observed in the subject within 1-14 days following glucocorticoid antagonist therapy.
4 . The method of claim 1 , wherein the glucocorticoid antagonist comprises a steroidal glucocorticoid receptor antagonist selected from the group consisting of mifepristone, monodemethylated mifepristone, didemethylated mifepristone, 17-α-[3′-hydroxy-propynyl]mifepristone, ulipristal (CDB-2914), CDB-3877, CDB-3963, CDB-3236, CDB-4183, cortexolone, dexamethasone-oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone, cortisol-21-mesylate, dexamethasone-21-mesylate, 11(-(4-dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,9-estradien—3one, and 17(-hydroxy-17(-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one, and combinations thereof.
5 . The method of claim 1 , wherein the glucocorticoid antagonist comprises a non-steroidal glucocorticoid receptor antagonist selected from the group consisting of N-(2-[4,4′,441-trichlorotrityl]oxyethyl)morpholine; 1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazine dimaleate; N-([4,4′,4″]-trichlorotrityl)imidazole; 9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone; 1-(2-chlorotrityl)-3,5-dimethylpyrazole; 4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol; 5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol; N-(2-chlorotrityl)-L-prolinol acetate; 1-(2-chlorotrityl)-1,2,4-triazole; 1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol; 4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha., 9,10,10.alpha.(R)—octahydro-phenanthrene-2,7-diol (“CP 394531”), 4.alpha.(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha., 9,10,10.alpha.(R)-oc-tahydro-phenanthrene-2,7-diol (“CP-409069”), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-1 pyrrolidinyl)cyclohexyl]benzeneacetamide, bremazocine, ethylketocyclazocine, naloxone compounds of Formula I
wherein R1 is H and R2 is H or Cl, or R1 is o-chloro or m-chloro and R2 is H, or compounds of Formula II
wherein R1 is F and R2 is pyrrolidine, or R1 is t-butyl and R2 is selected from the group consisting of H, a phenyl group, and —CH 2 —O—CH 3 .
6 . The method of claim 1 , wherein the glucocorticoid antagonist comprises at least one of mifepristone, onapristone, or Cissus quadrangularis.
7 . The method of claim 6 , wherein the Cissus quadrangularis comprises a chemical extract of Cissus quadrangularis plant material.
8 . The method of claim 1 , wherein the glucocorticoid antagonist comprises a daily dose mifepristone administered for at least 1 day.
9 . The method of claim 1 , wherein the monitoring includes monitoring in an outpatient setting.
10 . A method for distinguishing Cushing's Disease from Cushing's Syndrome, comprising:
providing a subject having one of Cushing's Disease or Cushing's Syndrome;
administering to the subject a daily dosage of a glucocorticoid antagonist; and
monitoring adrenocorticotropic hormone (“ACTH”) and/or cortisol levels in the subject,
wherein subjects having Cushing's disease show a significant rise in ACTH and/or cortisol levels following glucocorticoid antagonist therapy and wherein subjects having Cushing's syndrome show no significant change in ACTH or cortisol following glucocorticoid antagonist therapy.
11 . The method of claim 10 , wherein changes in ACTH and/or cortisol levels can be observed in a subject having Cushing's disease within one (1) day following glucocorticoid antagonist therapy.
12 . The method of claim 10 , wherein changes in ACTH and/or cortisol levels can be observed in a subject having Cushing's disease within 1-14 days following glucocorticoid antagonist therapy.
13 . The method of claim 1 , wherein the glucocorticoid antagonist comprises a steroidal glucocorticoid receptor antagonist selected from the group consisting of mifepristone, monodemethylated mifepristone, didemethylated mifepristone, 17-α-[3′-hydroxy-propynyl]mifepristone, ulipristal (CDB-2914), CDB-3877, CDB-3963, CDB-3236, CDB-4183, cortexolone, dexamethasone-oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone, cortisol-21-mesylate, dexamethasone-21-mesylate, 11 (-(4-dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,9-estradien—3one, and 17(-hydroxy-17(-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one, and combinations thereof.
14 . The method of claim 1 , wherein the glucocorticoid antagonist comprises a non-steroidal glucocorticoid receptor antagonist selected from the group consisting of N-(2-[4,4′,441-trichlorotrityl]oxyethyl)morpholine; 1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazine dimaleate; N-([4,4′,4″]-trichlorotrityl)imidazole; 9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone; 1-(2-chlorotrityl)-3,5-dimethylpyrazole; 4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol; 5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol; N-(2-chlorotrityl)-L-prolinol acetate; 1-(2-chlorotrityl)-1,2,4-triazole; 1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol; 4.alpha.(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4.alpha., 9,10,10.alpha.(R)—octahydro-phenanthrene-2,7-diol (“CP 394531”), 4.alpha.(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4.alpha.,9,10,10.alpha.(R)-oc-tahydro-phenanthrene-2,7-diol (“CP-409069”), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-1 pyrrolidinyl)cyclohexyl]benzeneacetamide, bremazocine, ethylketocyclazocine, naloxone compounds of formula I
wherein R1 is H and R2 is H or Cl, or R1 is o-chloro or m-chloro and R2 is H, or compounds of formula II
wherein R1 is F and R2 is pyrrolidine, or R1 is t-butyl and R2 is selected from the group consisting of H, a phenyl group, and —CH 2 —O—CH 3 .
15 . The method of claim 10 , wherein the glucocorticoid antagonist comprises at least one of mifepristone, onapristone, or Cissus quadrangularis.
16 . The method of claim 15 , wherein the Cissus quadrangularis comprises a chemical extract of Cissus quadrangularis plant material.
17 . The method of claim 10 , wherein the glucocorticoid antagonist comprises a daily dose mifepristone administered for at least 1 day.
18 . The method of claim 17 , wherein the daily dose mifepristone ranges from about 100 mg/day to about 2000 mg/day, or about 300 mg/day.
19 . The method of claim 10 , wherein the monitoring includes monitoring in an outpatient setting.