Hormonal Influences in Acne"1"

INTRODUCTION
The effects of hormones in acne are most notable in women. Androgens such as
dihydrotestosterone (DHT) and testosterone, the adrenal precursor dehydroepian-
drosterone sulfate (DHEAS), estrogen, and other hormones, including growth
hormone or insulin-like growth factors (IGFs), may each be important. It is likely
that the hormones affecting the sebaceous gland are both taken up from the
serum in addition to being made locally within the gland.
Hormonal therapy is an option in women whose acne is not responding to
conventional treatment or if signs of endocrine abnormalities are present. The great-
est therapeutic benefit from hormonal therapy is achieved in combination with
other effective anti-acne medications. This chapter focuses on the role of hormones
in acne, the clinical presentation of adult female acne, the work-up of a suspected
endocrine abnormality, and the available options for hormonal therapy.
ANDROGENS IN ACNE
Both clinical observation and experimental evidence confirm the importance of
androgens in the pathophysiology of acne. The majority of circulating androgens
are produced by the gonads and the adrenal gland.Androgens can also be produced
locally within the sebaceous gland from the adrenal precursor hormone, DHEAS.
The main androgens that interact with the androgen receptor are testosterone
and DHT. Androgen receptors are found in the basal layer of the sebaceous gland
and the outer root sheath keratinocytes of the hair follicle (1,2).DHTis approximately
five to 10 times more potent than testosterone in its interaction with the androgen
receptor.
An essential role for androgens in stimulating sebumproduction is supported
by several lines of evidence. For example, the development of acne in the prepuber-
tal period has been associatedwith elevated serumlevels of DHEAS, a precursor for
testosterone (3,4). Androgen-insensitive subjects who lack functional androgen
receptors do not produce sebum and do not develop acne (5). Tumors of the
ovary or the adrenal that produce androgens are often associated with the
development of acne. Systemic administration of testosterone and dehydroepian-
drosterone increases the size and secretion of sebaceous glands (6), and we know
that severe acne is often associated with elevated serum androgens (7,8).
Androgen Metabolism Within the Skin
Acnemay bemediated by serumandrogens, locally produced androgens, or a com-
bination of both. Insights have been gained regarding the local metabolism of
androgens within sebaceous glands (9). Such insights may be of benefit in the
design of new acne therapies. The skin and sebaceous gland are capable of
producing and metabolizing androgens (9). DHEAS is the major adrenal androgen
precursor. It circulates in the blood stream in relatively high levels compared with
other hormones with the exception of cortisol. In fact, in for review, see
Ref. postmenopausal women, all sex steroids made in the skin are from adrenal
steroid precursors, especially DHEA. Secretion of this precursor steroid by the
adrenals decreases progressively from age 30 to less than 50% of its maximal
value at age 60 (10). The enzyme 3b-hydroxysteroid dehydrogenase (3b-HSD)
acts on DHEA to convert it to androstenedione (Fig. 1). This conversion may take
place in the adrenal gland and tissues such as the sebaceous gland, where activity
of the 3b-HSD enzyme has been identified by several investigators (11–13). The
reversible conversion of androstenedione into testosterone is then catalyzed in
the human skin by 17b-HSD, a member of the short chain alcohol dehydrogenases
that are related to retinol metabolizing enzymes (14–18). This is a reversible
enzyme that can oxidize and reduce both androgens and estrogens. It is responsible
for converting the weak androgen androstenedione into the more potent androgen
testosterone. It can also interconvert weak and potent estrogens such as estrone
and estradiol. The 17b-HSD enzyme may represent a regulatory point in andro-
gen and estrogen metabolism within the skin.
DHT is produced from testosterone within peripheral tissues such as the skin
by the action of the 5a-reductase enzyme. Two isozymes of 5a-reductase have been
identified (19). The type 1 isozyme is active within the sebaceous gland (20,21). The
type 2 isozyme is most active in the prostate gland, where it can be inhibited by
drugs such as finasteride. Activity of 5a-reductase and 17b -HSD exhibits regional
differences depending upon the source of the sebaceous glands (9). In skin that is
prone to acne, such as facial skin, activity of the type 1 5a-reductase in sebaceous
glands is greater than in sebaceous glands obtained from nonacne-prone skin
(20). This implies that more DHT is being produced in sebaceous glands from
facial skin compared with other areas of the body that are not prone to develop
acne. The net effect of the activity of these two enzymes is the greater production
of potent androgens such as testosterone and DHT within sebaceous glands of
facial areas, which may in part account for the development of acne in these areas.