Hormonal Influences in Acne"2"

ESTROGENS IN ACNE
Very little is known about the role of estrogens inmodulating sebumproduction.Any
estrogen given systemically in sufficient amounts will decrease sebum production.
The dose of estrogen required to suppress sebum production, however, is greater
than the dose required to suppress ovulation (27). The major active estrogen is estra-
diol, which is produced from testosterone by the action of the enzyme aromatase.
Aromatase is active in the ovary, adipose tissue, and other peripheral tissues.Estradiol
can be converted to the less potent estrogen, estrone, by the action of the 17b-HSD
enzyme. Both aromatase and 17b-HSD are present in the skin (17,28). Estrogens
may act by severalmechanisms; theymay: (i) directly oppose the effects of androgens
locallywithin the sebaceous gland, (ii) inhibit the production of androgens by gonadal
tissue via a negative feedback loop on pituitary gonadotrophin release, and (iii)
regulate genes that negatively influence sebaceous gland growth or lipid production.
GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTORS IN ACNE
Growth hormone is secreted by the pituitary gland. It acts on the liver and periph-
eral tissues to stimulate the production of IGFs, formerly known as somatomedians.
There are two forms of IGF, termed IGF-1 and IGF-2. IGF-1 is the more prevalent
growth factor. It has been hypothesized that growth hormone may be involved in
the development of acne (29). Acne is most prevalent in adolescents during a
time when growth hormone is maximally secreted and serum levels of IGF-1 are
highest. In addition, IGF-1 can be produced locally within the skin, where it can
interact with receptors on the sebaceous gland to stimulate its growth. Furthermore,
conditions of growth hormone excess such as acromegaly are associated with sebor-
rhea and the development of acne. In some tissues, the actions of IGF-1 can be
mediated by androgens. It is possible that androgens may influence IGF-1 action
in the sebaceous gland as well.
WHEN TO SUSPECT AN ENDOCRINE DISORDER IN ACNE PATIENTS
Although hormones influence acne, most acne patients do not have an endocrine
disorder. Hyperandrogenism should be considered in female patients whose acne
is severe, sudden in its onset, or is associated with hirsutism, or irregular menstrual
periods. Additional clinical signs of hyperandrogenisminclude Cushinoid features,
increased libido, clitoromegaly, deepening of the voice, acanthosis nigricans, or
androgenetic alopecia. Women with hyperandrogenism may also have insulin
resistance. They are at risk for the development of diabetes and cardiovascular
disease. It is therefore important for the long-term health of these patients to ident-
ify hyperandrogenism so that they can receive appropriate therapy from an endo-
crinologist or gynecologist.
SCREENING FOR AN ENDOCRINE DISORDER
A medical history and physical examination should be performed that is directed
toward eliciting any symptoms or signs of hyperandrogenism. Screening laboratory
tests for hyperandrogenism include a serum DHEAS, total testosterone, free testos-
terone, and luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio.
These tests should be obtained apart from the time of ovulation in order to avoid
the surge of hormones associated with ovulation. From a practical standpoint, it
may be easiest to suggest that women have these tests performed either just prior
to or during the menstrual period. It is important to note that if a patient is on
oral contraceptives at the time of hormonal testing, an underlying hyperandrogen-
emia may be masked. This does not occur with antiandrogens such as cyproterone
or spironolactone. Therefore, it is best that patients discontinue oral contraceptives
four to six weeks prior to the endocrine evaluation.
Excess androgens may be produced by either the adrenal gland or the ovary.
Serumlevels ofDHEAS can be used to screen for an adrenal source of excess androgen
production. Patientswith a serumDHEAS greater than 8000 ng/mL (unitsmay differ
depending upon the laboratory)may have an adrenal tumor and should be referred to
an endocrinologist for further evaluation. Some adrenal tumorsmay also produce tes-
tosterone.Values ofDHEAS in the range of 4000 ng/mL to 8000 ng/mLmay be associ-
ated with congenital adrenal hyperplasia, which is most commonly due to a partial
deficiency in the 21-hydroxylase or 11-hydroxylase enzyme in the adrenal gland.
Such an enzyme deficiency results in the shunting of steroids fromthe cortisol biosyn-
thetic pathway into the androgen biosynthetic pathway.
An ovarian source of excess androgens can be suspected in cases where the
serum total testosterone is elevated. Serum total testosterone in the range of
150 ng/dL to 200 ng/dL or an increased LH/FSH ratio (greater than 2 to 3) can
be found in cases of polycystic ovary disease. This condition is a spectrum and is
often, but not always, associated with irregularmenstrual periods, reduced fertility,
obesity, insulin resistance, or hirsutism. Greater elevations in serum testosterone
may indicate an ovarian tumor and appropriate referral should be made. In some
cases, there can be modest elevations in both DHEAS and testosterone. A serum
level of 17-hydroxypregneneolone can be obtained to discern between an ovarian
or adrenal source of androgens. If 17-hydroxypregneneolone is elevated, it indicates
an adrenal source of excess androgens, most often secondary to late onset congeni-
tal adrenal hyperplasia. Of note is that there is a significant amount of variation in
an individual’s serum androgen levels. In cases where abnormal results are
obtained, it is recommended to repeat the test before proceeding with therapy or
a more extensive work-up.
Questions arise as to the importance of a pelvic ultrasound in the diagnosis of
polycystic ovarian syndrome. This test can be nonspecific, in that women with
normal androgens may have ovarian cysts and conversely, women with hyperan-
drogenism and other findings associated with polycystic ovarian syndrome
may not have ovarian cysts at the time of pelvic ultrasound. For this reason, the
diagnosis of polycystic ovarian syndrome is more heavily based upon the serum
hormonal profile and associated clinical findings.
In the majority of women with acne, serum androgens are completely normal,
yet thesewomen will in fact respond if treated with hormonal therapy. Studies have
shown that, as a group,women with acnemay have higher levels of serumDHEAS,
testosterone, and DHT than those without acne (7,34). However, although higher,
these laboratory values may still be within the normal range. Serum levels of
DHEAS, DHT, and IGF-1 are reported to correlate positively with acne lesion
counts in women, whereas androstenedione and DHEAS correlate with lesion
counts in men (35). Reduction of serum androgens or inhibition of their action, as
obtained with oral contraceptives or antiandrogens, respectively, can lead to
improvement in acne in women with normal serum androgen levels.