The Role of Adrenocortical Steroids in the Control of Human Sebaceous Gland Activity

THE ROLE OF ADRENOCORTICAL STEROIDS IN THE CONTROL OF HUMAN SEBACEOUS GLAND ACTIVITY* PETER E. POCHI, M.D., JOHN S. STRAUSS, M.D. AND HERBERT MESCON, M.D.

While testicular androgen has been unequiv- terone, and prednisonc was assayed by a proocally implicated in the direct stimulation of cedure previously reported (4) . The assay is sebaccous gland activity (1), the role of the dependent upon the finding that androgens and adrenal gland has remained an unsettled issue. estrogens do not exhibit mutual inhibition at the In a recent study of male castrates, we reported end-organ level of the sebaccous gland (1). evidence which suggested that sebaceous gland function is additionally mediated by steroids of

Thus, exogenously administered androgen will maintain sebaceous function despite the simuladrenal origin (2). Therefore, the present taneous administration of estrogen in amounts investigation was undertaken in an attempt to which would, of themselves, suppress sebaceous delineate further the precise nature of the control gland activity. exerted by the adrenal cortex upon the sebaccous In the assay procedure, one milligram of

ethynyl estradiol is administered to a normal adult male subject until sebam production is

glands. METHODS

markedly suppressed. ** The steroid to be assayed

I. Sebum production in disorders of the adrenal cortex

is then administered while the estrogen is continued. If the compound possesses androgcnic

activity for human sebaceous glands, the supeffect of estrogen will be overcome, as tory evidence of Cushing's syndrome were pressive evidenced by a rise in sebum production. The studied. All underwent partial or total adrenalecThree female patients with clinical and labora-

tomy and in each instance were found to have bilateral adrenal hyperplasia. A fourth patient, a male with Addison's disease, was similarly studied before and after adrenocortical replace-

reason for the administration of estrogen initially is that the glands of the adult male are normally

maximally stimulated and will not show a detectable response to stimulation unless

glandular activity is first suppressed. In these studies the same method for measuring In all four cases sebum production was sebum production was employed (3). Tests were measured prior to definitive therapy and at performed at approximately weekly intervals. varying intervals thereafter for periods ranging from seven to nineteen months. A quantitative EXPERIMENTAL gravimetric procedure, reported elsewhere in ment therapy.

detail (3), was used to measure sebum production.

I. Sebum production in disorders of the adrenal cortex

II. Seburn-stimulating potency of androgens and of prednisone

A. Cushing's syndrome. As previously mentioned, three adult females The sebum-stimulating potency of testosterone with Cushing's syndrome were studied. A brief propionate, dehydroepiandrosterone, andros- summary of each case is presented below: Case 1: a 20 year-old white female complained * From the Department of Dermatology and of fatigue and easy bruisability, Physical examiEvans Memorial Department of Clinical Research, nation revealed a moonlike facies, plethora, Massachusetts Memorial Hospitals, and Depart- buffalo-hump obesity, violaeeous striae and ment of Dermatology, Boston University School of

Medicine, Boston University Medical Center, Boston, Massachusetts.

This investigation was supported in part by

research grant AJVI 07084, special research fellow-

ship ASP-13,004 (Dr. Pochi), and graduate training grant 2A-5295, National Institutes of Health,

United States Public Health Service. Presented at the Twenty-fourth Annual Meeting of The Society for Investigative Dermatology, Inc., Atlantic City, N. J., June 18, 1963.

391

* Testosterone

propionate (Oreton®) and pred-

nisone (Meticorten®) supplied by Roger W.

Cooper, M.D., Schering Corporation, Bloomfield, New Jersey. Dehydroepiandrosterone and andros-

terone supplied by J. William Crosson, M.D., G. D. Searle & Co., Chicago, Illinois. ** Ethynyl estradiol (Estinyl®) supplied by Roger W. Cooper, M.D., Schering Corporation, Bloomfield, New Jersey.

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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 1 S'ebum production (mg lipid/JO sq cm/S hours) before and after adrenalectomy in 3 premenopausal females with Gushing's syndrome Case

1

2 3

Months, postoperative

Pre-

treatment Mean5

2

6

7

9

12

15

17

0.93 2.59 3.88

0.46 3.37 3.29

0.58

0.41 0.39 2.75

— 0.93

— 3.22

— 3.41

3.62

4.36

3.58

— 3.44 —

0.87 2.85

19

— 2.07 —

* Sebum output (mean and standard deviation) for normal adult premenopausal females (2): 1.98± 0.99.

hypertension. There was no evident hirsutism, acneform eruption or clitoral enlargement. The urinary excretion of 17-hydroxycorticosteroids

slightly lower than normal. Nonetheless, a significant fall in sebum production occurred fol-

was markedly elevated, but the output of 17-keto-

lowing surgery, and this reduction was

were performed periodically for 19 months. Case 3: a 41 year-old white female complained of fatigue, weakness and menstrual irregularities.

levels even higher than those found pre-

steroids was only slightly above the upper limit maintained for the follow-up period of 7 months. of normal. Treatment consisted of total adrenal- This patient's disorder was characterized by ectomy followed by daily replacement therapy excessive cortisol production without evidence with 37.5 mg of cortisone acetate and 0.1 milligram of 9-cs -fluorohydrocortisone acetate. Measure- of significantly increased androgen production, ments of sebum production were carried out for a as judged by clinical manifestations and urinary period of seven months post-operatively. 17-ketostcroid excretion. Case 2: a 32 year-old white female presented In case 2, pre-operativc mean sebum producwith symptoms of fatigue, menstrual irregularities tion, although somewhat elevated, was within and infertility. Physical examination disclosed the range of normal. Following a bilateral submarked obesity with buffalo-hump accentuation, acne, hirsutism and hypertension. The urinary total adrenalectomy, a marked fall in sebum excretion of both 17-ketosteroids and 17-hydroxy- production occurred by the sixth month (Figure corticosteroids was elevated above the normal. 1). Sebum levels remained low until the tenth The patient underwent a bilateral subtotal adrenalectomy. Post-operative steroid replace- month, some time after which they began to rise. ment therapy was discontinued four aod one-half When next tested, at the twelfth month, scbum months after surgery. Follow-up sebum studies production had increased markedly, reaching

On physical examination there was obvious

obesity, facial rounding and plethora, moderately severe acne and hypertension. There was a marked increased excretion of urinary 17-hydroxycorticosteroids, with a mild elevation of 17-ketosteroid output. The patient underwent a bilateral subtotal

operatively. Urinary steroid excretion studies at this time revealed a rise in 17-ketosteroids and 17-hydroxycorticosteroids from previously low

levels observed in the early months after adrenalectomy. An ACTH stimulation test performed at a later time (fourteen months

adrenalectomy. Post-operative steroid replace- postoperatively) did not result in any significant ment therapy was gradually reduced, but at the increase in adrenal steroid output. It is notepresent time (15 months postoperatively) the worthy that the rise in scbum production patient is still receiving 25 mg of cortisone acetate observed in the twelfth month followed by four orally daily. weeks the sudden death of the patient's mother. Results. Table 1 gives in detail the results of When the patient was last tested, sebum output

sebum production measurements performed appeared to be decreasing once again. In the third case, scbaccous gland activity before and after adrenalectomy in these three patients. There was a significant fall in sebum decreased initially following adrenalcctomy, secretion in all three subjects following although less than a 30 per cent reduction was adrenalectomy, although the magnitude of the observed, and by the ninth month sebum levels has returned to pro-operative levels. As menreduction varied from case to case. In case 1, the pre-operative scbum values were

tioned above, this patient had a subtotal

CONTROL OF SEBACEOTJS GLANDS BY ADRENAL CORTEX

393

5.'

SILATERAL ADEENAL HYPEEPLASIA

32 years old

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nestle nnca operation 0

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Fm. 1. (Case 2). Sebum production measurements before and after bilateral subtotal adrcnalectomy in a patient with bilateral adrenal hyperplasia.

adrenalectomy and to date has continued to would seem that this was an instance in which receive 25 mg. of cortisone acetate daily. sebaceous gland activity was stimulated by Comment. In case 1, it is quite significant that emotional stress, although in this particular the pre-operative sebum levels were quantitatively subnormal despite the excessive production of cortisol. Thus, it appears unlikely that hydrocortisone could be responsible for direct sebaceous gland stimulation. Yet, following total adrenalec-

patient, adrenal responsiveness cannot properly be considered normal. Even with such a qualification, this is the first reported instance in which emotional stimulation was followed by a truly

quantitative increase in sebum production. A

tomy and cortisone replacement therapy a previously reported study in this connection did definite reduction in sebaceous secretion occurred,

not employ adequate collection methods (5).

indicating a removal from the circulation of a The response in case 3 is more difficult to substance or substances with direct or indirect interpret. Preoperative sebum levels were absebum-stimulating capacity. Our interpretation normally high, and a much greater reduction in of this response will be presented in the general sebum secretion following subtotal adrenalectomy In case 2, the rise in sebum secretion noted in

had been anticipated than actually occurred. The fact that it has not been possible to discontinue

the twelfth postoperative month was accom-

cortisone therapy postoperatively has com-

discussion.

panied by an increase in urinary 17-ketosteroid

pounded the difficulty in assessing the results in this particular patient. Thus, further follow-up clearly the rise in sebum secretion was secondary studies will be necessary to appraise adequately to this renewed adrenal activity. As noted previ- the observed sebaceous gland response. ously, these changes followed a death in the B. Addison's disease. patient's family, which resulted in the patient's One male patient with previously untreated, developing an acute depressive reaction. Thus, it idiopathic Addison's disease was similarly studied.

and 17-hydroxycorticosteroid excretion, and

394

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

on the face. History revealed the previous occur-

ence of acne between the ages of sixteen and

4.0

twenty-two. Comment. The rise in sebum production in this

patient was marked and unequivocal. Interestingly, in a recent report, the development of nodular sebaccous gland hypcrtrophy was ob-

3.0

served following cortisone therapy for Addison's disease in a 51 year-old male (6). At first glance it might appear that the schaceous gland response and the subsequent development of acne were due to a direct stimulating effect of the glucocorticoids. However, this is probably not the mechanism involved for several reasons. First, it should be recalled that one of the patients with Gushing's syndrome (ease 1) showed subnormal levels of schum secretion despite high cortisol production.

0 c2 2.0

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&

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a. 2

ADDISONS DISEASE

&

6' DSy.osoI4

L oo'ks of Ik.,op' i CORTISONE

II I 2

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Second, it would be quite unlikely that such

I 10

12

20—27.2 g./4y%

HYDROCORTISONE

FIG. 2. Measurements of sebum secretion before

and after glucocorticoid replacement therapy in a patient with Addison's disease. This patient was a 25 year-old male who presented

relatively small doses of glucocorticoids as received by the patient with adrenocortical insufficiency could have such a potent androgcn-likc action on the sebaecous glands. And third, as will

be demonstrated subsequently, glucocorticoid administration does not stimulate schum output in experimental subjects. An alternate hypothesis,

which will be discussed later, to explain the response observed in this patient is that hydro-

with fatigue, weight loss, anorexia and pro- cortisone functions in a permissive capacity. gressively increasing pigmentation of the face, arms, genitalia and oral cavity. The urinary excretion of 17-hydroxycorticosteroids and 17ketosteroids was abnormally low, and no increase

II. Sebum-stimulating potency of androgens and of prednisone

cotropin administration. Adrenocortical replacement therapy was begun with cortisone acetate

A. Androgens. Nine young adult males comprised the subject panel for this study. All initially received ethynyl

in their output was observed following cortiin dosages of 25 to 37.5 mg daily. After five montbs,

the cortisone acetate was replaced by hydrocortisone acetate in dosages of 20 to 30 mg daily. This patient also received 0.1 mg of 9-a-fiuorohydrocortisone acetate daily throughout the treatment period.

Results. The data on sebum production in this patient arc illustrated in Figure 2. The prc-treat-

mcnt mean sebum production value was 1.33 mg/1O sq cm/3 hours, compared to a mean and standard deviation for similarly aged normal males of 2.55 1.05 mg. Following replacement therapeutic doses of cortisone and hydrocortisone,

cstradiol orally in a dosage of 1 milligram daily for a period of 6—b weeks in order to suppress scbum

production. While the estrogen was continued, three subjects received 100 mg of testosterone propionate in oil intramuscularly three times weekly for six to nine weeks. Another group of three subjects received 100 mg of dehydrocpiandrostcrone intramuscularly three times a week for six to twelve weeks, while the final group of three subjects received 100 mg of androstcrone intramuscularly three times weekly for six to nine weeks.

Results. Table 2 presents in detail the results sebum production began to rise, the increase obtained in this study. At the end of three weeks being already evident after four weeks of treatment. Scbum output continued to increase further

in subsequent months, such that by the ninth month it was three times that of the pre-trcat-

ment mean level. In the fourth month, the patient developed typical lesions of acne vulgaris

of androgen administration, the average per cent risc in sebum output with testosterone propionate was 74 per cent, which was approximately three t Subjects from the Massachusetts Correctional

Institution, Walpole, Massachusetts, John E. Gavin, Superintcndeot.

395

CONTROL OF SEBACEOIJS GLANDS BY ADRENAL CORTEX

TABLE 2 Sebaceous gland response following administration of testosterone pro pionate, dehydroepiandrosterone, and androsterone; 100 milligrams intramuscularly, 3 times weekly

Mean sebum production (mg lipid/b sq cm/3 hours) ..U Jec

Before Estrogen

Effect of androgen ainistration after:

After Estrogen 1—3 wks

7-9 wks

4—6 wks

10—12 wks

Testosterone propionate 1

2 3

3.25* 3.11

2.32

0.99** 0.98 1.08

— —

1.73t (75%) 2.89 (192%) 1.75 (79%) 1.80 (67%)

2.98 (204%) 1.99 (84%)

74%

160%

Mean % increase

2.08 (93%)

— — —

Dehydroepiandrosterone

4 5 6

4.89 3.51 2.63

1.15 1.57 0.62

1.65 (43%) 1.93 (23%)

0.66 (6%)

Mean % increase

24%

—

2.76 (140%) 2.32 (48%) 1.36 (119%)

2.08 (32%)

— —

1.29 (108%)

1.62 (161%)

102%

70% Androsterone

7

4.01

2.62

8

2.76

9

2.01

1.28 0.71

2.82 (8%) 1.87 (46%) 0.43

2.36

1.67 (30%) 0.48

— 1.30 (2%) 1.35 (90%)

— — —

* Mean sebum output of 4—5 separate control measurements.

** Mean

of 3 weekly tests preceding androgen administration. t Mean of 2—3 individual tests performed in period indicated. Per cent increase from estrogen-suppressed level.

times the average per cent rise for dehydroepian- vein blood, or they have been shown to be syndrosterone (24 per cent). Comparison of the mean thesized by normal human adrenal tissue in vitro.

per cent increase in sebum production from estrogen-suppressed levels after six weeks of androgen administration reveals testosterone propionate to have been the most efficient in stimulating sebum output, a mean increase of

Among these are dehydroepiandrosterone, zr.. androstenedione, 11 -f3-hydroxy-4-androstenedi-

sebum secretion by the ninth week. Subject S

one, and testosterone. The last three substances serve principally as intermediary compounds in steroid synthesis and are secreted in very small amounts, their actual physiologic significance being unknown. Dehydroepiandrosterone, on the other hand, is secreted by the adrenal cortex in relatively large amounts, the estimated rate for adult males averaging nearly 30 mg a day (7). Thus, dehydroepiandrosterone is probably the adrenal androgen of greatest physiologic import.

initially showed a rise in sebum production which,

Androsterone is a catabolite principally of

160 per cent being observed, as compared to 102 per cent for dehydroepiandrosterone and only 10 per cent for androsterone. It should be noted that the response to androsterone was variable. Subjects 7 and 9 showed-no-response at six weeks, but subject 9 demonstrated a90 per cent increase in

however, subsequently fell to the estrogen-sup- dehydroepiandrosterone and testosterone, but its biologic significance in man has not been clarified. pressed level by the ninth week. Comment. Numerous androgens have been The relative androgenic potency of these variisolated either from adrenal tissue or adrenal ous steroids have been extensively studied in

396

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 3

gland response to administration of prednisone, O milligrams orally daily

Sebaceous

Mean sebum production (mg lipid/b sq cm/3 hours) Subject

Before

Estrogen

After Estcogen

Effect of prednisone administration after: 1—3 wks

4-6 wks

7—9 wks

much variation in the "androgenicity" of a given substance, depending upon the species studied, the end-organ assayed, the route of administration, the nature of the vehicle, etc. In our sebaceous gland assay, dehydroepiandrosterone, administered in a dose of 100 mg intramuscularly three times weekly to three male subjects, produced in six weeks a rise in sebum secretion which

was approximately 60 per cent that of testosterone propionate. With androsterone, on the other 2.70* 1.27** 1.04t 0.76 0.69 1 2 2.29 0.82 0.77 0.81 0.81 hand, one subject failed to be stimulated, and in the other two the response was variable and in3.21 1.09 1.03 0.69 0.91 3 consistent. Certainly the response to androsterone * Mean sebum output of 4—5 separate control was in no way comparable to that following the measurements. administration of either dehydroepiandrosterone ** Mean of 3 weekly tests preceding prednisone or testosterone. Yet, in chick comb assays anadministration. drosterone is found to be more potent than f Mean of 2—3 individual tests performed in per-

iod indicated. animals in bio-assays utilizing androgen-sensitive

testosterone (11, 12), thus indicating the problem of species differences already alluded to in this section. One is not justified, then, in extrapolating

tissues such as the ventral prostate, seminal animal data to, for example, the expected revesicle, chick comb, etc. (8—12). However, it sponse of the human sebaceous gland to these should at once be appreciated that there exists agents.

3.0

I 0

(-)

& (I)

0 10

0.

-J

& 0WEEKS

ETHYNVI ESIRADIOL

PREDN SON!

METHYL TESTOSTERONE

FIG. 3.

Effect of prednisone administration on sebum production in an adult male (subject 1, Table 3)

sebum suppression by estrogen. Prednisone is unable to overcome the suppression induced by the estrogen.

following

CONTROL OF SEBACEOTJS GLANDS BY ADRENAL CORTEX

B. Prednisone

397

ascribe the lowering of sebum production as being

In a similar experiment, three adult male due to any one particular agent. Nonetheless, the suhj eets were administered 1.0 milligram of ethynyl estradiol daily until significant suppression of sehum secretion had occurred (6—9 weeks). Then,

while estrogen administration was continued, prednisone was administered in a daily dose of 20 mg for a period of eight to nine weeks. Again,

data obtained in these subjects, in conjunction with studies presented elsewhere, permit a reason-

able interpretation of the role of the adrentil cortex in the control of sebum production. It was shown previously that sebaceous gland

sebum secretion was measured approximately weekly throughout the period of steroid administration.

activity in adult male castrafpprhile lower than that of either intact males or females, was higher than that of prcpuberal individuals and that it Results. As shown in Table 3, there was no rise decreased gradually with aging (2). Furthermore, in sebum secretion during the administration of a direct correlation was observed in castrates prednisone. In subject 1, methyl testosterone in between scbum production and the urinary exan oral dose of 10 mg per day was administered cretion of 17-kctostcroids and 17-hydroxycortifollowing discontinuance of the prednisone, with costeroids. The results of the present study afford continuing estrogen administration (Figure 3). further evidence of the participation of the The resultant rise in sebum secretion indicated adrenal gland in the control of human sebaccous that the subject was capable of responding to gland activity. First of all, in the three patients androgenic stimulation. with Cushing's syndrome, adrenalcctomy was Comment. The failure of prednisone in a 20 mg

followed in each instance by a significant decrease

daily dose to stimulate sebum production in the in sebum output, although in two instances, estrogen-suppressed male supports animal experi- cases 2 and 3, sebum output returned to preoperments in which neither the local application nor ative levels, twelve and nine months, respectively, the parenteral administration of glucocorticoids followinadrcnalcctomy. In case 2 the marked induce any increase in sebaceous gland size (13— rise in sebum secretion observed in the twelfth 15). However, it should be stressed that neither postoperative month followed a death in the hydrocortisone nor cortisone have been tested as patient's family, suggesting a possible influence yet in our androgen assay procedure. Thus, it is of emotional stimulation upon sebum secretion. not absolutely certain that hydrocortisone would In case 3 the patient was still receiving replacenot have some sebum-stimulating action, par'ticu- ment therapy. larly in view of the report of an increase in It is most interesting to compare the results in sebaceous gland size following the daily adminis- case 1 in which the pre-operativc sebum levels tration of 80 mg. of hydrocortisonc to prepuberal were actually subnormal in the face of excessive subjects (16). In addition, a ' steroid configura- cortisol production with the result of glucocortition, as occurs in prednisone, is reported to coid administration in the patient with Addison's decrease the androgenic activity of certain &-3- disease. As previously mentioned, the data obketone steroids (17), and it is, therefore, remotely tained in this patient with Cusbing's syndrome possible that the failure of prcdnisone to stimu- militate against a direct stimulating effect of late sebum production is that it could be less hydrocortisonc. An alternate and more probable "androgenic" than hydrocortisone. Any possible explanation for the remarkable rise in sebum difference in this regard remains to be determined. production in the patient treated for Addison's

disease is that hydrocortisone functions in a permissive capacity, its presence in normal, It should be stressed that finite interpretations physiologic amounts being necessary for the DIscussIoN AND CONCLUSION5

as to the effect of adrenalectomy on sebum pro- sebaceous gland to respond to endogcnous circuduction in patients such as those we have studied lating androgens. Such a permissive action of

are necessarily limited by two considerations. hydrocortisone is known to occur for certain First, it is not at all certain that removal of normal metabolic processes (18). More pertinently, the adrenal glands would effect similar responses. sebaccous glands of adrenalectomizcd rats arc Second, adrenalectomy, as mentioned before, much less responsive to testosterone administraresults in removal from the circulation of nu- tion than arc those of rats with intact adrenals merous substances, and it would be hazardous to (19). Furthermore, the failure of prcdnisone in

398

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

a 20 mg daily dose to stimulate sebum production in the estrogen-suppressed male subjects (Table

3) lends further support to the contention that

in adult males whose sebum output had been suppressed by estrogen. 5. On the basis of these studies, it is proposed

that a) dehydroepiandrosterone is the adrenal tion of the sebaceous glands. It appears, then, steroid hormone principally responsible for direct that hydrocortisone, in physiologic amounts, sebaceous gland stimulation; and b) glucocortithe glucocorticoids do not directly cause stimula-

influences sebaceous gland activity principally, if eoids act in a permissive capacity with physiologic not solely, by allowing the sebaceous glands to amounts being necessary for the sebaceous glands to respond to stimulation by endogenous circulatrespond optimally to endogenous androgen. However, this proposed effect of hydrocortisone ing androgens. probably does not represent the only action of the REFERENCES

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terone, while certainly less potent than testosterone, is the androgen of adrenal origin directly mediating sebaceous gland activity. The dose of

dehydroepiandrosterone used in the present study, namely 100 mg three times weekly, is somewhat in excess of its endogenous production,

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