Correspondence
Spironolactone
To the Editor: Shaw's article on spironolactone (J AM
ACAD DERMATOL 1991;24:236-43) is thorough, timely,
and welcome. This medication is valuable but learning to
use it effectively takes time and patience. On the basis of
my experience with more than 400 patients taking
spironolactone, I offer two further suggestions:
I. If oral contraceptives are to be prescribed, allow the
patient two full cycles to adjust to the contraceptive be-
fore adding the spironolactone. This avoids the need for
stopping both and starting all over again in the event of
breakthrough bleeding (the most common cause of
patient refusal to continue this valuable drug).
2. To minimize breakthrough menstrual bleeding,
start with as low as 25 mgjday for the first month and in-
crease by 25 mg/day monthly until further increases are
limited by side effects, a 2 mg/kgjday maximum, or
achievement of the desired positive clinical effect.
F. W. Danby, MD
Chairman, Division of Dermatology
Queen's University
Kingston, Ontario, Canada
Spironolactone in dermatology
To the Editor: We read with interest the excellent article
on the use of spironolactone in dermatology (J AM ACAD
DERMATOL 1991;24:236-43). We prescribed spironolac-
tone regularly' for patients with acne and hirsutism
following the guidelines suggested by Shaw until 1989
when we were informed by the British government that
spironolactone should only be used in congestive cardiac
failure, edema of hepatic and malignant origin, primary
aldosteronism, and essential hypertension-and should
be used only after careful consideration in young women
because of the tumorigenic effect of potassium can-
renoate, a metabolite of spironolactone, which has been
shown to produce tumors in rats. ]
The article by Shaw, however, suggests that the poten-
tial tumorigenic effect of spironolactone itself is insignif-
icant. Because the British government inhibits our use of
spironolactone, we would appreciate information con-
cerning the views of the U.s. Food and Drug Adminis-
tration on the use of spironolactone in dermatology. Such
additional information may activate a reassessment by
our government advisors on the use of oral spironolactone
for patients with troublesome acne and hirsutism.
We also wish to draw your readership's attention to our
data on topical spironolactone. 2 We investigated three
formulations including, we believe, those reported, by
Shaw; all three had no effect whatsoever on acne or sebum
excr,etion rate. Thus we do not consider that there is yet
a successful topical formulation of spironolactone.
W. J. Cunliffe, and
S. Macdonald Hull,
Dermatology Department,
General Infirmary,
Great George Street, Leeds LSi 3EX England
REFERENCES
1. Wagner BM. Long-term toxicology studies ofspironolactone
in animals and comparison ofpotassium canrenonate. J Drug
Dev 1987;I(suppl 2):7-1 1.
2. Walton S, Cunliffe W J, Lookingbill P, et al. Lack of effect
of topical spironolactone on sebum excretion. B r J Dermatol
1986;114:261-3.
Reply
To the Editor: The comments of Drs, Cunliffe, Hull, and
Danby are appreciated and helpful. The concern about
possible tumorigenicity of potassium canrenoate stems
from a study by Wagner 1,* in which rats were given high
doses of potassium canrenoate (20 to 270 mg/kgjday)
and a dose-related increased incidence of myelocytic leu-
kemia was observed that reached statistical significance
at doses of 125 and 270 mg/kg/day. Several additional
observations help to clarify the significance of that study
and its relation to the use of oral spironolactone in
humans.
First, in Wagner's article a comparable study using
similar doses of spironolactone in rats demonstrated no
tumorigenic or carcinogenic effect from spironolactone.
Dogs and monkeys were also tested and demonstrated no
significant pathologic organ changes. In addition, admin-
istration of oral canrenoate to monkeys in doses up to 60
mgjkg/day have shown no evidence of tumors after 3
years.!
Second, the finding that leukemia can develop in rats
given canrenoate stimulated further studies of the me-
tabolism ofspironolactone. These have demonstrated that
the mutagenic metabolites formed from potassium can-
renoate are not formed from spironolactone. It has been
found that canrenone is actually a relatively minor
metabolite of spironolactone and that further metabolism
of canrenone to mutagenic compounds is inhibited by
spironolactone and/or its sulfur-containing metabolites?
Thus, on the basis of metabolic differences, concern a bout
tumorigenicity with potassium canrenoate in rats cannot
be extrapolated to the use of spironolactone in humans.
*References I, 2, and 3 are from the proceedings of a round-table dis-
cussion entitled "Spironolactone: A Review of Clinical Safety and
Efficacy," sponsored by G. D. Searle & Co., April 30, 1987.'
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