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Hypothalamus-pituitary-adrenal axis suppression by superpotent topical steroids
Journal of the American Academy of Dermatology Volume 29, Number 3
Briefcommunications
501
Hypothalamus-pituitary-adrenal axis suppression by superpotent topical steroids Patrick Walsh, MD, John L. Aeling, MD, Lois Huff, RN, and William L. Weston, MD Denver, Colorado Since "superpotent" topical steroids became available, their efficacy has resulted in their increasing use and reports of more numerous side effects, including suppression of the hypothalamus-pituitary-adrenal (HPA) axis. I We report a new study and reviewour published study designed to compare directly the safety and efficacy of the "superpotent" topical steroids.? METHODS This study was designed to parallel the previously reported study- that compared HPA axis suppression in patients with psoriasis treated with topical augmented betamethasone dipropionate (ABD) or clobetasol-17propionate ointment (CP). The present study compared ABD with halobetasol propionate (HP). Forty men with moderate to severe psoriasis were enrolled in this doubleblind, parallel group study. Twenty patients were randomly placed in the ABD group and 20 received HP. One patient in the HP group withdrew from the study on the third day and was excluded from all efficacy and safety analyses. Men who entered this study were not taking medications that might affect psoriasis. Each subject was instructed to measure the amount of ointment (3.5 gm) used with a paper pad with a measured line and then transfer this amount of ointment to their skin lesions. Patients were instructed to treat affected areas twice daily and to continue the treatment for the entire 2-week period. Each patient received 49 gm/wk of "superpotent" topical steroid ointment for 2 weeks. Serum cortisol levels were measured by radioimmunoassay from blood samples obtained at 8:00 AM on two
From the Department of Dermatology, University of Colorado School of Medicine. Supported by a grant from the Schering Corporation. Presented in part in poster format at the Fifty-first Annual Meeting of the American Academy of Dermatology, San Francisco, Calif.. Dec. 5-10,1992. Reprint requests: Patrick Walsh, MD, Department of Dermatology, University of Colorado School of Medicine, 4200 E. Ninth Ave., Box B-153, Denver, CO 80262.
JArvi ACAll DERMATOl. 1993;29:501-3. Copyright @ 1993 by thc American Acadcmy of Dermatology, Inc, 0190.9622/93/$1.00+ .10
16/54/46107
consecutive days and the results paired. Twenty-fourhour urinary samples were started at the time of the blood sampling for the first serum cortisol level and completed just before the second sample. Two pretreatment serum cortisol levels were obtained and additional levels were obtained on days 4 and 5, 7 and 8, 15 and 16 during therapyand 1 week after stopping therapy (days 2] and 22). Twenty-four-hour urine samples were collected on days 2, 5,8, and 16, and urine cortisols were measured. Because of technical errors, gas chromatograph-mass spectrometry data were uninterpretable. Patients were examined by the investigator for signs and symptoms of psoriasis on days 2, 8, and 16, and global efficacy evaluation was done on days 8 and 16. Each clinical sign or symptom (erythema, induration, scaling, and pruritus) was assessed and assigned a score of 1 to 6: I == complete absence of tha t particular sign or symptom; 2 == 75% clearing; 3 = 50% improvement; 4:= 25% improvement; 5 == no change; 6 == deterioration or exacerbation in that category. The total score for efficacy was obtained by summing the individual score for each clinical category assessed. Efficacy in each treatment group was compared and evaluated by the two-tailed Fisher exact test.
RESULTS
The serum cortisol levels were evaluated by an analysis of a covariance model with adjustment for the observed baseline difference between the two groups. Analysis of treatment-by-covariate interactions failed to show statistical significance, but a trend with lower mean cortisol levels at day 4 was seen in patients treated with HP (Fig. 1). There was also no statistically significant difference in the number of patients with suppressed HP A axis in the two groups. There was a statistically significant difference in urine cortisol levels at day <5 and 16 in the two groups, with HP more likely to suppress (Fig. 2). With only one exception, patients with a urinary cortisol levelbelow normal also had a serum cortisol level below normal at day 4. No patient had a suppressed urinary free cortisol value without concomitant suppression of plasma cortisol. Unfortunately, analysis of urinary steroid metabolites by gas chro-
Journal of the American Academy of Dermatology
502
Brie! communications
September 1993
4 -r-- - - -.--- - - -r--- - ---.- - - --, 2 -+-- -- -+-- - -+0 - + - - - -+
- 2 -+-- - --+- 4 -t-- - - -t-- 6 -+----+--
- 8 -t--- - -t--1 0 - + - - --
- - t-
-
-1 2 -+--
- t-
- - - + - - - - - - t --
-
baseline day 4
day 8
-
-i
day 16
Fig. 1. Serum cortisol levels: Change from baseline. Each bar represents average change from baseline of serum cortisol levels (i.e., mean serum cortisol level on indicated day subtracted from mean serum cortisol level at baseline) in patients treated with augmented betamethasone dipropionate (ABD) or halobetasol propionate (HP). Analysis of treatmentby-covariate interactions failed to show statistical significance between treatment groups, but a trend with lower mean cortisol levels at day 4 was seen in the HP group. Solid bar, ABD; shaded bar, HP.
O- . - - - --r-1 0 - t --
-
-+_
- 20 - t -- --
__+_
- 3 0 - t -- --
-;---
- 4 0 - + - - - --
-+---
- 5 0 - t --
-
--;---
- 6 0 - t -- -- -;--- - - 1 f - - -- - - t -- - - ---j Baseline Day 4 Day 8 Day 16 Fig. 2. Urine cortisol levels: Change from baseline. Each bar represents average change from baseline of urine cortisol levels (mean urine cortisol level at indicated time subtracted from mean urine cortisol level at baseline). There is a statistically significant difference in urine cortisol levels at days 5 and 16 between the two groups, with HP more likely to suppress (p = 0.01). Solid bar, ABO; shaded bar, HP.
matograph-mass spectrometry did not yield interpretable data most likely because of improper storage of the samples. There were no statistically significant differences in treatment efficacy between the two treatment
groups after 2 weeks (Table O. Eighty percent of patients in the ABO group and 68% of patients in the HP group had either cleared or had only slight signs and symptoms of psoriasis. Ninety percent of patients in the ABD group and 89% of patients in the
Journal of the American Academy of Dermatology Volume 29, Number 3
Brief communications 503
Table I. Summary of efficacy (total score*)
------------Day 2 (Baseline) Day 8 Actual Change from baseline Day 16 Actual Change from baseline
I--------ABD (n =20) 8.9 (1.7) 4.4 (I.4) -4.5 (1.5) 2.7 (1.6) -6.1 (1.6)
HP (n=
]9)
9.1 (1.7) 4.5 (1.5) -4.6 (1.7) 2.8 (1.6)
-6.2 (2.4)
p VaJuet
0.71 0.87 0.81 0.86 0.86
Data expressed as mean ± stand ard deviation . ABD, Augmented beta rnethasone dipropionate; HP, halobetasol propionate. "Total score = sum of erythema, induration, scaling, pruritus. tBased on two-sample l test (two-t ailed).
HP group had at least 50% improvement by global evaluation. DISCUSSION
This report confirms and extends the findings of our previous similarly designed study. The previous study demonstrated that the two "superpotent" topical steroids tested produced significant HPA axis suppression. This suppression was greatest during the first 7 days before healing of the skin lesions and recovery from HP A axis suppression was rapid despite continued application of the superpotent steroids. The present report demonstrates similar HP A axis suppression, as assessed by serum cortisol levels, at day 4 in both treatment groups and significant, albeit somewhat less, decrease in serum cortisol levels on days 8 and 16 for the HP group. Urinary cortisol levels also demonstrated significant decreases from baseline levels in both groups, with the most dramatic decrease within the first 5 days of treatment. Levels appeared to be returning toward normal as the study progressed.
In our previous study we demonstrated significantly less suppression of the HPA axis by betamethasone dipropionate than clobetasol propionate, despite equal efficacy. In this present study the same trend was observed; ABD showed less suppression than HP . However, because the baseline controls were different between the two groups, statistical significance could not be demonstrated. Do all "superpotent" steroids show the same safety profile? Although all three "superpotent" steroids suppress the HPA axis, ABD exhibits less suppression than CP or HP despite equal efficacy. However, all three "superpotent" topical steroids have a high likelihood of HP A axis suppression. REFERENCES
I. Yohn 11, Weston W L. Topical glucorticosteroids. Cure Prob Dermatol 1990;II(2):31-63. 2. Weston WL, Fennessey PV , Morelli 1. et al. Comparison of hypothalamus-pituitary-adrenal axis suppression from superpotent topical steroids by standard endocrine function testing and gas chromatographic mass spectrometry. 1 Invest Dermatol 1988;90:532-5.
Briefcommunications
501
Hypothalamus-pituitary-adrenal axis suppression by superpotent topical steroids Patrick Walsh, MD, John L. Aeling, MD, Lois Huff, RN, and William L. Weston, MD Denver, Colorado Since "superpotent" topical steroids became available, their efficacy has resulted in their increasing use and reports of more numerous side effects, including suppression of the hypothalamus-pituitary-adrenal (HPA) axis. I We report a new study and reviewour published study designed to compare directly the safety and efficacy of the "superpotent" topical steroids.? METHODS This study was designed to parallel the previously reported study- that compared HPA axis suppression in patients with psoriasis treated with topical augmented betamethasone dipropionate (ABD) or clobetasol-17propionate ointment (CP). The present study compared ABD with halobetasol propionate (HP). Forty men with moderate to severe psoriasis were enrolled in this doubleblind, parallel group study. Twenty patients were randomly placed in the ABD group and 20 received HP. One patient in the HP group withdrew from the study on the third day and was excluded from all efficacy and safety analyses. Men who entered this study were not taking medications that might affect psoriasis. Each subject was instructed to measure the amount of ointment (3.5 gm) used with a paper pad with a measured line and then transfer this amount of ointment to their skin lesions. Patients were instructed to treat affected areas twice daily and to continue the treatment for the entire 2-week period. Each patient received 49 gm/wk of "superpotent" topical steroid ointment for 2 weeks. Serum cortisol levels were measured by radioimmunoassay from blood samples obtained at 8:00 AM on two
From the Department of Dermatology, University of Colorado School of Medicine. Supported by a grant from the Schering Corporation. Presented in part in poster format at the Fifty-first Annual Meeting of the American Academy of Dermatology, San Francisco, Calif.. Dec. 5-10,1992. Reprint requests: Patrick Walsh, MD, Department of Dermatology, University of Colorado School of Medicine, 4200 E. Ninth Ave., Box B-153, Denver, CO 80262.
JArvi ACAll DERMATOl. 1993;29:501-3. Copyright @ 1993 by thc American Acadcmy of Dermatology, Inc, 0190.9622/93/$1.00+ .10
16/54/46107
consecutive days and the results paired. Twenty-fourhour urinary samples were started at the time of the blood sampling for the first serum cortisol level and completed just before the second sample. Two pretreatment serum cortisol levels were obtained and additional levels were obtained on days 4 and 5, 7 and 8, 15 and 16 during therapyand 1 week after stopping therapy (days 2] and 22). Twenty-four-hour urine samples were collected on days 2, 5,8, and 16, and urine cortisols were measured. Because of technical errors, gas chromatograph-mass spectrometry data were uninterpretable. Patients were examined by the investigator for signs and symptoms of psoriasis on days 2, 8, and 16, and global efficacy evaluation was done on days 8 and 16. Each clinical sign or symptom (erythema, induration, scaling, and pruritus) was assessed and assigned a score of 1 to 6: I == complete absence of tha t particular sign or symptom; 2 == 75% clearing; 3 = 50% improvement; 4:= 25% improvement; 5 == no change; 6 == deterioration or exacerbation in that category. The total score for efficacy was obtained by summing the individual score for each clinical category assessed. Efficacy in each treatment group was compared and evaluated by the two-tailed Fisher exact test.
RESULTS
The serum cortisol levels were evaluated by an analysis of a covariance model with adjustment for the observed baseline difference between the two groups. Analysis of treatment-by-covariate interactions failed to show statistical significance, but a trend with lower mean cortisol levels at day 4 was seen in patients treated with HP (Fig. 1). There was also no statistically significant difference in the number of patients with suppressed HP A axis in the two groups. There was a statistically significant difference in urine cortisol levels at day <5 and 16 in the two groups, with HP more likely to suppress (Fig. 2). With only one exception, patients with a urinary cortisol levelbelow normal also had a serum cortisol level below normal at day 4. No patient had a suppressed urinary free cortisol value without concomitant suppression of plasma cortisol. Unfortunately, analysis of urinary steroid metabolites by gas chro-
Journal of the American Academy of Dermatology
502
Brie! communications
September 1993
4 -r-- - - -.--- - - -r--- - ---.- - - --, 2 -+-- -- -+-- - -+0 - + - - - -+
- 2 -+-- - --+- 4 -t-- - - -t-- 6 -+----+--
- 8 -t--- - -t--1 0 - + - - --
- - t-
-
-1 2 -+--
- t-
- - - + - - - - - - t --
-
baseline day 4
day 8
-
-i
day 16
Fig. 1. Serum cortisol levels: Change from baseline. Each bar represents average change from baseline of serum cortisol levels (i.e., mean serum cortisol level on indicated day subtracted from mean serum cortisol level at baseline) in patients treated with augmented betamethasone dipropionate (ABD) or halobetasol propionate (HP). Analysis of treatmentby-covariate interactions failed to show statistical significance between treatment groups, but a trend with lower mean cortisol levels at day 4 was seen in the HP group. Solid bar, ABD; shaded bar, HP.
O- . - - - --r-1 0 - t --
-
-+_
- 20 - t -- --
__+_
- 3 0 - t -- --
-;---
- 4 0 - + - - - --
-+---
- 5 0 - t --
-
--;---
- 6 0 - t -- -- -;--- - - 1 f - - -- - - t -- - - ---j Baseline Day 4 Day 8 Day 16 Fig. 2. Urine cortisol levels: Change from baseline. Each bar represents average change from baseline of urine cortisol levels (mean urine cortisol level at indicated time subtracted from mean urine cortisol level at baseline). There is a statistically significant difference in urine cortisol levels at days 5 and 16 between the two groups, with HP more likely to suppress (p = 0.01). Solid bar, ABO; shaded bar, HP.
matograph-mass spectrometry did not yield interpretable data most likely because of improper storage of the samples. There were no statistically significant differences in treatment efficacy between the two treatment
groups after 2 weeks (Table O. Eighty percent of patients in the ABO group and 68% of patients in the HP group had either cleared or had only slight signs and symptoms of psoriasis. Ninety percent of patients in the ABD group and 89% of patients in the
Journal of the American Academy of Dermatology Volume 29, Number 3
Brief communications 503
Table I. Summary of efficacy (total score*)
------------Day 2 (Baseline) Day 8 Actual Change from baseline Day 16 Actual Change from baseline
I--------ABD (n =20) 8.9 (1.7) 4.4 (I.4) -4.5 (1.5) 2.7 (1.6) -6.1 (1.6)
HP (n=
]9)
9.1 (1.7) 4.5 (1.5) -4.6 (1.7) 2.8 (1.6)
-6.2 (2.4)
p VaJuet
0.71 0.87 0.81 0.86 0.86
Data expressed as mean ± stand ard deviation . ABD, Augmented beta rnethasone dipropionate; HP, halobetasol propionate. "Total score = sum of erythema, induration, scaling, pruritus. tBased on two-sample l test (two-t ailed).
HP group had at least 50% improvement by global evaluation. DISCUSSION
This report confirms and extends the findings of our previous similarly designed study. The previous study demonstrated that the two "superpotent" topical steroids tested produced significant HPA axis suppression. This suppression was greatest during the first 7 days before healing of the skin lesions and recovery from HP A axis suppression was rapid despite continued application of the superpotent steroids. The present report demonstrates similar HP A axis suppression, as assessed by serum cortisol levels, at day 4 in both treatment groups and significant, albeit somewhat less, decrease in serum cortisol levels on days 8 and 16 for the HP group. Urinary cortisol levels also demonstrated significant decreases from baseline levels in both groups, with the most dramatic decrease within the first 5 days of treatment. Levels appeared to be returning toward normal as the study progressed.
In our previous study we demonstrated significantly less suppression of the HPA axis by betamethasone dipropionate than clobetasol propionate, despite equal efficacy. In this present study the same trend was observed; ABD showed less suppression than HP . However, because the baseline controls were different between the two groups, statistical significance could not be demonstrated. Do all "superpotent" steroids show the same safety profile? Although all three "superpotent" steroids suppress the HPA axis, ABD exhibits less suppression than CP or HP despite equal efficacy. However, all three "superpotent" topical steroids have a high likelihood of HP A axis suppression. REFERENCES
I. Yohn 11, Weston W L. Topical glucorticosteroids. Cure Prob Dermatol 1990;II(2):31-63. 2. Weston WL, Fennessey PV , Morelli 1. et al. Comparison of hypothalamus-pituitary-adrenal axis suppression from superpotent topical steroids by standard endocrine function testing and gas chromatographic mass spectrometry. 1 Invest Dermatol 1988;90:532-5.