Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, U.S.A.
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). DHT is approximately five to 10 times more potent than testosterone in its interaction with the androgen receptor.
An essential role for androgens in stimulating sebum production is supported by several lines of evidence. For example, the development of acne in the prepuber- tal period has been associated with elevated serum levels 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
Acne may be mediated by serum androgens, locally produced androgens, or a com- bination of both. Insights have been gained regarding the local metabolism of 83
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.
FIGURE 1 The steroidogenic pathway. Abbreviations: HSD, hydroxysteroid dehydrogenase; P450scc, P450 side chain cleavage enzyme; StAR, steroidogenic acute regulatory protein.
The Sebaceous Gland Is a Steroidogenic Tissue
The skin and sebaceous glands are capable of synthesizing cholesterol de novo from acetate (22 – 24). Although this cholesterol is utilized in cell membranes, in the for- mation of the epidermal barrier, and is secreted in sebum, its use as a substrate for steroid hormone synthesis had not been established until recently. In order for steroid synthesis to occur, cholesterol needs to be translocated from the outer to the inner mitochondrial membrane. This process is regulated by the steroidogenic acute regulatory protein (25). Additional enzymes and cofactors needed to convert cholesterol into a steroid include P450 cholesterol side chain cleavage, adrenodoxin reductase, cytochrome P450c17, and steroidogenic factor-1. Expression of each of these proteins was found in human facial skin, sebocytes, and in a recently devel- oped simian virus (SV) 40-immortalized human sebocyte cell line (SEB-1) (26). These data demonstrate that the skin is in fact a steroidogenic tissue. The clinical significance of this finding in mediating androgenic skin disorders such as acne, hirsutism, or androgenetic alopecia remains to be established.
m and in the estrogen-related fluid retention associated with some oral contraceptives (43).