Androgens and Sebum Production

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The majority of potent androgens are produced by peripheral target tissues. For example, in postmenopausal women, 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors while in adult men approximately 50% of androgens are locally made in intracrine target tissues [4]. The major androgens that interact with the androgen receptor are testosterone and dihydrotestosterone. Androgen receptors have been localized to the basal layer of the sebaceous gland and the outer root sheath keratinocytes of the hair follicle [5, 6]. Dihydrotestosterone is approximately 5-10 times more potent than testosterone in its interaction with the androgen receptor.

An essential role for androgens in stimulating sebum production is supported by the following clinical evidence: (1) androgen-insensitive subjects who lack functional androgen receptors do not produce sebum and do not develop acne [7], and (2) systemic administration of testosterone and dehydroepiandrosterone increases the size and secretion of sebaceous glands [8].

Several clinical observations point to the importance of androgens in acne. The development of early acne in the prepubertal period has been associated with elevated serum levels of dehydroepiandrosterone sulfate (DHEAS), a precursor of testosterone [9, 10]. For example, acne occurs near the time of puberty. In fact, investigators have demonstrated that acne begins to develop at the time of adrenarche when the adrenal gland begins to produce large quantities of DHEAS [9, 10]. This hormone can serve as a precursor to the production of more potent androgens within the sebaceous gland. The rise in serum DHEAS in prepubescent children is associated with an increase in sebum production and the development of comedonal acne.

Severe acne is often associated with elevated serum androgens [11]. Conditions of androgen excess or hyper-androgenism are associated with increased sebum production and the development of acne. Hyperplasia or carcinomas that produce excess androgens (e.g. of the ovary or the adrenal) are often associated with the development of acne. Sudden onset of acne or treatment-resistant acne may be associated with hyperandrogenism from causes such as an adrenal or ovarian tumor or from conditions such as congenital adrenal hyperplasia or polycystic ovary disease. Conversely, it has been observed that men with androgen insensitivity (nonfunctional androgen receptors) do not produce adult levels of sebum and they do not develop acne [7]. This clinical observation implies that a functional androgen receptor is required for sebum production. Since both testosterone and dihydrotestosterone act at this receptor, either one or both of these androgens is required to produce adult levels of sebum.

Several early experiments have demonstrated that androgens act to stimulate sebum secretion. For example, prepubertal boys given injections of testosterone were shown to have increased sebum production [12]. Histologically, increase in the size of their sebaceous glands was demonstrated. In addition, systemic administration of DHEAS, androstenedione and testosterone were shown to exert similar effects on the sebaceous gland [8]. It has been hypothesized that DHT is the effector androgen that mediates sebum production and the development of acne. Since testosterone also acts at the androgen receptor, a role for this androgen in mediating sebum production cannot be excluded [13].

Serum androgens are elevated in cases of acne associated with hyperandrogenism and in cases of severe cystic acne. Serum androgens are however within normal limits in the majority of females with acne. For this reason, it has been hypothesized that there may be increased local production of androgens within the sebaceous glands of subjects with acne [14, 15]. Alternatively, the sebaceous glands from subjects with acne may be more sensitive to the effects of androgens. It is unclear as to whether acne is mediated by serum androgens, locally-produced andro-gens or a combination of both. Recently, insights have been gained regarding the local metabolism of androgens within sebaceous glands. Such insights may be of benefit in the design of new acne therapies.

Androgen Metabolism within the Skin Dehydroepiandrosterone sulfate (DHEAS) is produced in large quantities by the zona reticularis of the adrenal gland. It circulates in the bloodstream in high levels in relatively high levels compared to other hormones with the exception of cortisol. The enzyme 3P-hydroxyste-roid dehydrogenase (3P-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 3P-HSD enzyme has been identified by several investigators [16-18]. There are two known forms or isozymes of 3P-HSD. The type I iso-zyme is active in skin, placenta and mammary tissue, whereas the type II isozyme is active in the adrenal gland and the gonads [19]. The major isozymes of steroid-metabolizing enzymes that are active in human sebaceous glands are listed in table 1.

Fig. 1. Biochemical pathway of sex steroid hormone metabolism. HSD = Hydroxyste-roid dehydrogenase; 5a-R = 5a-reductase.

Steroid sulfatase

Dehydroepiandrosterone (DHEA)

Estradiol

Aromatase

Androstenec

i

5a-Androstanedione type 2

type 2

Testosterone

SoReductase 1

5a -Dihydrotestosterone

type 2

5a -Dihydrotestosterone

3a-HSD

17ß-HSD types 3,5

3a-HSD

5a-Androstanediol

type 2

Androsterone

Cell

5<x-Androstanediol glucuronide

Androsterone glucuronide

5<x-Androstanediol glucuronide

Androsterone glucuronide

Another important enzyme that is found within the skin is 17P-hydroxysteroid dehydrogenase (17P-HSD). 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. Testosterone in turn can be produced from androstene-dione. To date, seven types of human 17P-HSDs have been cloned, sequenced, and characterized, designated types 1-7 in the chronological order of their isolation [2023]. Recently, the type 8 17P-HSD also known as Ke6 gene was shown to efficiently transform estradiol to estrogen in transfected HEK-293 cells [24]. The type 2 isozyme of 17P-HSD appears to be the most active within the sebaceous gland where it prefers to oxidize testosterone back to androstenedione [25-27]. In this regard, the 17P-HSD enzyme may play a protective role in the skin by metabolizing testosterone back to the less potent precursor, androstenedione. It may also represent a regulatory point in androgen and estrogen metabolism within the skin.

Dihydrotestosterone is produced from testosterone within peripheral tissues such as the skin by the action of the 5a-reductase enzyme. Recently, two isozymes of 5 a-reductase have been identified [28]. The type 1 isozyme is

Table 1. Predominant isozymes of steroid metabolizing enzymes expressed in sebaceous glands

3ß-Hydroxysteroid dehydrogenase type 1

17ß-Hydroxysteroid dehydrogenase type 2

5a-Reductase type 1

active within the sebaceous gland and in keratinocytes derived from the infrainfundibular region of piloseba-ceous follicle (from the base of the epidermis to the point of insertion of the sebaceous duct) [3, 29]. The type 2 iso-zyme is most active in the prostate gland where it can be inhibited by drugs such as finasteride. While the type 1 5a-reductase has a broad alkaline pH optima of 6.0-8.5 and demonstrates relatively moderate affinity for steroid substrates (Km = 1-5 ^M), the type 2 5a-reductase has a narrow acidic pH optimum of 5.0-6.0 and demonstrates high affinity for substrates (Km = 4-50 nM) [30, 31]

Activity of 5a-reductase and 17P-HSD exhibits regional differences depending upon the source of the sebaceous glands [25, 29] (fig. 2). 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

Update and Future of Hormonal Therapy Dermatology 2003;206:57-67 59

in Acne from nonacne-prone skin. This implies that more DHT is being produced in sebaceous glands from facial skin compared to other areas of the body that are not prone to develop acne. In contrast, the oxidative activity of the type 2 17P-HSD enzyme is greater in sebaceous glands from nonacne-prone areas compared to sebaceous glands obtained from facial skin. Since the predominant activity of this isozyme is to transform testosterone back to its less active precursor, it may be inferred that facial skin is less able to metabolize testosterone to its less potent precursor. The net effect of the activity of these two enzymes is the greater production of potent androgens such as T and DHT within sebaceous glands of facial areas that may in part account for the development of acne in these areas.

Site of Androgen Action in Acne

The sebaceous gland is known to be a site of androgen action within the pilosebaceous unit. It has also been hypothesized that androgens may play a role in follicular hyperkeratinization in acne in addition to their effects on stimulating sebum secretion [1, 2]. Indirect evidence in support of this hypothesis includes the finding of androgen receptors in the outer root sheath of sebaceous follicles, the clinical observation that antiandrogens may reduce follicular casts and the finding of activity of andro-gen-metabolizing enzymes such as 3P-HSD, 17P-HSD and 5a-reductase in follicles. Furthermore, the activity of 17P-HSD and 5a-reductase is significantly greater in infrainfundibular keratinocytes compared to keratino-cytes obtained from the interfollicular epidermis, suggesting that follicular keratinocytes have a greater propensity to produce potent androgens [32]. Direct evidence in support of the effects of androgens on follicular keratiniza-tion is needed.

Mechanism of Androgen Action in Acne

Androgens are thought to stimulate the growth and differentiation (sebum production) of sebaceous glands. The exact mechanism by which this is accomplished has not been defined. Androgens such as testosterone and DHT form complexes with nuclear androgen receptors. The androgen/receptor complex then interacts with DNA in the nuclei of sebaceous cells to regulate genes involved in cell growth and lipid production. The exact target genes have not been identified, but likely candidates would include genes for various growth factors or enzymes involved in lipid production (lipogenic enzymes) (table 2).

It is not known if androgens act directly, indirectly or both on epithelial cells within the pilosebaceous unit by

Table 2. Enzymes involved in lipogenesis in human sebaceous glands

Enzymes involved in

Enzymes involved in

cholesterol synthesis

fatty acid synthesis

Acetoacetyl CoA thiolase

Acetyl CoA carboxylase

HMG CoA synthetase

Fatty acid synthetase

HMG CoA reductase

Mevalonic acid kinase

Mevalonate decarboxylase

Isopentenyl pyrophosphate isomerase

Geranyl transferase

Squalene synthetase

Squalene oxidocyclase

regulating the production of growth factors by dermal fibroblasts. The stromal/epithelial interaction of sex steroid hormones and growth factors is an important phenomenon in the local regulation of other endocrine-responsive tissues such as the prostate, breast, endometri-um and ovary. Evidence exists for the importance of these autocrine and paracrine effects of androgens and growth factors in the regulation of sebaceous glands. In addition to androgen receptors, sebocytes also possess receptors for growth factors such as epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) [33]. Evidence exists for the role of EGF, IGF-I and keratinocyte growth factor (KGF) in modulating sebaceous gland growth. For example, growth of sebocytes is enhanced by supplementation of cell culture medium with EGF and insulin. Treatment of experimental animals with KGF stimulates growth of hair and sebaceous glands [34, 35]. The action of andro-gens in the sebaceous gland may thus be mediated by growth factors.

Several important enzymes involved in lipid metabolism have been identified in sebaceous glands. These include 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase which is the rate-limiting enzyme in the synthesis of cholesterol and acetyl CoA carboxylase which is the key in the synthesis of fatty acids [36]. Whether or not androgens act by stimulating these enzymes remains to be determined.

In summary, there is strong clinical and experimental evidence that androgens stimulate the proliferation of sebaceous glands and sebum secretion. Acne is associated with systemic circulating hyperandrogenism. In acne subjects with normal circulating levels of androgens there may be a local or in situ excess production of androgens or imbalance of androgen metabolism. Acne subjects with

Acne Vulgaris
Fig. 2. Acne secondary to an adrenal tumor. This 10-year-old female patient developed acne and hirsutism as a result of an androgen-producing tumor of the adrenal gland.

Fig. 3. Acne associated with polycystic ovarian disease. This 28-year-old patient had recalcitrant acne and an elevated serum testosterone level.

normal circulating or local levels of androgens may be 'hypersensitive' to androgens either due to an increased number of androgen receptors or abnormal postbinding response [37, 38].

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