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Feldman RJ, Maibach HIRegional variation in percutaneous penetration of 14C cortisol in man. J Invest Dermatol 48:181-183

Copyright 1967 by The Williams & Wilkins Co. Vol. 46, No. S
Printed in U.S.A.
Previously we reported hydroeortisone per-
cutaneous penetration rates as estimated by
amounts of radioactivity recovered in the
urine under several experimental circum-
stances but always employing the ventral as-
pect of the human forearm (1). This study
quantitates the effect of regional variation
on percutaneous penetration of hydrocorti-
All subjects were normal male volunteers.
0.06 mg of hydrocortisone with 5 microcuries of
14C activity was dissolved in each 0.1 ml dose,
using acetone as a solvent. The quantity of hy-
drocortisone applied is similar to the application
of a 025 per cent topical preparation. A circular
13 sq cm area was delineated with petrolatum.
The test material was applied with a micropipcttc
and the acetone evaporated by gentle flowing.
The subjects were requested not to wash the area
for one day; the site was not protected. All urine
was collected for 5 days and analyzed for "C by
a method previously described (2). Results are
expressed in per cent of the dose applied. Since
about 75 per cent of an intravenous control-dose
of hydrocortisone appears in urine in man, the
actual penetration of the compound is somewhat
larger than reported here (1).
Measurable absorption occurred through all
regions except the heel.
Table I gives the mean values in each ex-
periment for the total five day excretion and
the rates of excretion in each collection period.
We chose to compare absorption in each anatomic
region with absorption through the ventral as-
pect of forearm (the area most commonly used
and with which we have had the most ex-
perience). Variation between subjects was oh-
This study was supported in part by U.S.P.H.S.
2tTT-AM-5372-01A1, and the Skin Disease Re-
search Foundation. Mr. John Beal of Dome
Chemicals provided the AC hydrocortisone.
Presented at the Twenty-seventh Annual Meet-
ing of The Society for Investigative Dermatology,
Inc., Chicago, Illinois, June 27, 1966.
* From the Division of Dermatology, Depart-
ment of Medicine, University of California School
of Medicine, San Francisco, California 94122.
served; the absorption ratios between ana-
tomic sites in each subject showed a smaller
variation. Subjects served as their own con-
trols for the several areas examined.
Great differences were observed in absorp-
tion through various sites. Fig. 1 illustrates
the ratio of the total excretion for each ana-
tomic site to that of the ventral forearm. This
varied from a trace for the heel (not illus-
trated) to a forty-two fold increase for the
The figures demonstrate the excretion rates
in each time period. The great differences in
penetration required presenting this data in
three graphs with different scales. Fig. 2 shows
the excretion pattern for sites having an ab-
sorption less than that of the ventral aspect of
the forearm: palm, ankle, foot. Fig. 3 shows
this pattern for sites somewhat greater than
that of the ventral aspect of the forearm: dorsal
aspect of the forearm, back, axilla, scalp; Fig.
4 shows this pattern for sites showing a great
increase over the ventral aspect of the fore-
arm: forehead, angle of the jaw and scrotum.
The '4C excretion rate was maximal in the
second twelve hour period except for the foot
and back. The maximum rate for the foot oc-
curred during the third and fourth day. The
highest rate for the back occurred in the sec-
ond day. After the maximum, the excretion
rates in general declined gradually, with meas-
urable excretion in the fifth day.
Several generalizations can be made. Ap-
parent absorption (estimated by amounts in
the urine) is increased in areas where folli-
cles are larger or more numerous (such as the
forehead and scalp) and decreased where the
stratum corneum is thicker (the foot). Our
data suggest, but do not prove, that absorp-
tion takes place transepidermally and through
hair follicles. The increased absorption in
hairy areas may be due partly to structural
differences in the stratum corneum, but the
data suggest that much of the increase is due
Effect of anatomic region on absorption of topical 14 hydrocortisone (Urinary 14C excretion expressed
as % applied dose)
Anatomic region No.
Excretion rate per 24-hours Total exrretion
Collrctino period (days) .
ment Forearm
control .ain
0—1/2 1/2—1 2345
Forearm (ventral)
Forearm (dorsal)
Foot arch (plantar)
Ankle (lateral)
Jaw angle
* Samples missing: control corrected to 4 day period.
cogati(vEHTRAQ l.Ox
FQRE&R11 (DORSAl.) l.lx
M4KLE (ijstERM..) 0.42's
PMJI O.83x
SCAAP ________
AXItA.A ____________
hz',%4%i%%V,V///////////½i%i7/,l 13.0 a.
V//SS/SSt//4 42x
Ftc. 1. Hydrocortisone absorption total-effect of anatomic region
to the presence of hair follicles, and probably
occurs through them. In hairy areas, follicular
absorption may be greater than transepider-
mal absorption.
These generalizations are not consistent with
onr observations of the palm and scrotnm.
Significant absorption occurred through the
palm, which has a fairly thick stratum cor-
ncum and no hair follicles. The scrotum pro-
vides almost no barrier to hydrocortisone,
quantitating the observation of Smith, Fischer
and Blank (5). Other determining factors
may be present in these regions of obvious
specialization in structure and function.
Tragear (3) concluded that hair follicles do
not increase skin penetration. His experiment
compares disappearance of surface radioactiv-
ity of "P tributyl phosphate when applied
around hair follicles and between hair folli-
cles in the pig. His data show that tributyl
phosphate is absorbed at a rate of 7 per cent
per hour in hairless pig skin areas, while we
find hydrocortisone is absorbed from hairless
human skin areas at a rate of .02 per cent
pcr hour. A compound absorbed this rapidly
(300 times faster than hydrocortisone) may
not show a prominent follicular component.
Others have noted penetration differences in
different body areas. Cronin and Stoughton
(4) have reviewed this data.
55 I23
TitlE (DAYS)
Fio. 2. Hydrocortisone absorption rates—effect
of anatomic regions.
FIG. 4. Hydrocortisone absorption rates—effect
of anatomic regions.
1. Absorption of bydrocortisone occurs
through all skin regions tested.
2. Absorption is increased in regions with
large or numerous hair follicles. The scalp
absorbed 3.5 times and the forehead 6 times
the quantity of hydroeortisone as the ventral
aspect of the forearm.
3. Absorption is decreased in some regions
of skin having thickened stratum corneum,
e.g. the foot.
4. In seeming contradiction, the palm is far
from impenetrable to hydrocortisone.
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in the present study.
'a,& 5.50C
C't05F-UI3IaU102. 5 4
TIME (c'Axo)
Fm. 3. Hydrocortisone absorption rates—effect
of anatomic regions.
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Objective: Topical steroid use is common, but its association with Cushing’s syndrome is rare. We report the rapid development of iatrogenic Cushing’s syndrome in a patient on ritonavir who applied a moderate-potency topical steroid cream, triamcinolone, on his genital mucosa for treatment of phimosis. Methods: Clinical and diagnostic challenges associated with topical steroid use are presented and discussed. Results: A 41-year-old man with human immunodeficiency virus infection on stable antiretroviral therapy that included ritonavir, a cytochrome P450 3A4 inhibitor, presented with new onset diabetes and development of overt cushingnoid features over a four-week period. He reported no known history of steroid use. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported at >15.0 μg/dL (normal <0.112 μg/dL). However, free cortisol in a 24-hour urine collection was undetectable by high-performance liquid chromatography and morning plasma cortisol was also unexpectedly low at 1.1 μg/dL (reference: 4.5 - 23.0 μg/dL). Further investigation revealed that the patient had been applying a topical cream with triamcinolone acetonide (0.1%) on the glans penis for treatment of phimosis. The salivary enzyme immunoassay for cortisol appears to have detected the absorbed triamcinolone, a compound known to cross-react with cortisol in this assay. Conclusion: This case raises awareness on the severe metabolic consequence resulting from the seemingly benign use of a topical steroid medication when applied to the genital mucosa in the setting of stable therapy with ritonavir and illustrates the limitations of salivary cortisol enzyme immunoassays for the evaluation of Cushing’s syndrome in this setting.
Lysosomes, as demonstrated biochemically in the liver, are subcellular particles con-taining a group of hydrolytic enzymes enclosed by a membrane-like barrier. They are apparently inactive in the normal state, but when subjected to various forms of injurious treatments the enzymes associated with them are released. The existence of lysosomes in skin is demonstrated in the present communication. The resistance of this tissue to homogenization makes the biochemical study of lysosomes very difficult. Yet, by the application of histochemical methods to sections of skin, it has been possible to use the same criteria as would be employed in the biochemical character-ization of these organelles. By using the controlled-temperature freezing-sectioning method it has been possible to obtain frozen sections in which cytoplasmic particles could be demonstrated which were enzymically inactive for acid phosphatase until the sections were subjected to such injurious treatments as heat, repeated freezing and thawing, hypotonic solutions, distilled water, and 'triton-X-100'. Since the sub-cellular particles demonstrated behaved in the same manner as lysosomes prepared biochemically from liver, it is concluded that the cytoplasmic organelles staining for acid phosphatase in mouse skin are lysosomes as biochemically defined.
Summary Lysosomes, as isolated and defined by biochemists, are particles in which acid lytic enzymes are contained by a lipoprotein membrane; they are inert until the membrane has been rendered permeable. Previously it has not been possible to demonstrate cyto- chemically organelles which meet all these criteria, since all the preparatory procedures have affected the membrane permeability. The controlled temperature freezing- sectioning method has permitted the demonstration of granules which are inactive for acid phosphatase until subjected to agents that will disrupt lipid-protein structures, such as heat, formalin, and 'triton X-ioo'. Hence such organelles may be identified with the biochemists' lysosomes.
Between 0.2 and 1.0 per cent of hydrocortisone, applied to normal skin appears in the urine over a period of ten days. Stripping the skin doubles this amount and significantly alters the absorption rate curve. An occlusive dressing increases absorption ten-fold but does not basically alter the absorption rate curve. Evidence is presented suggesting that both the stratum corneum and the Malpighian/basal layers serve as skin barriers.
Aqueous extracts of the epidermis of adult mice, rats, guinea pigs and rabbits contain some substance capable of depressing mitotic activity in adult mouse epidermis, both in vivo and in vitro. Such extracts also depress mitotic activity in cornea, sebaceous glands and the oesophageal lining epithelium, but not in the other tissues tested. Extracts of tissues other than epidermis do not have the same power to depress epidermal mitotic activity. It has previously been proposed that a tissue-specific mitotic inhibitor with the characteristics of that obtained from the epidermis should be called a chalone.The epidermal chalone has been shown to be without effect in the absence of sufficient adrenalin and it appears that the actual mitotic inhibitor is an unstable chalone-adrenalin complex. Adrenalin alone, like chalone alone, evidently has no power to reduce epidermal mitotic activity.These results provide an explanation for the main mitotic phenomena seen in adult mouse epidermis. The diurnal mitotic cycle is evidently the outcome of fluctuations in the adrenalin content of the blood; with reduced adrenalin secretion in sleeping mice the chalone-adrenalin complex breaks down and the epidermal mitotic rate rises. The high epidermal mitotic activity alongside a wound is evidently the outcome of a reduced intracellular concentration of epidermal chalone; with the lack of chalone the diurnal fluctuations in the adrenalin content of the blood are without any effect and even injections of adrenalin do not easily depress the mitotic rate. The possible situation in tissues other than epidermis is discussed.