Regulation of Pilosebaceous Unit Activity

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There are many controlling influences on the pilosebaceous unit (Fig. 3). The development of model systems for the sebaceous gland and duct has made it easier to study these pathways in vitro.


Perhaps the most profound and well-known effect of hormones on the pilosebaceous unit is the one caused by androgens, more specifically in causing sebaceous gland enlargement, sebocyte proliferation, and lipid metabolism (91,92). It is well established that the increase in lipid production and enlargement of the sebaceous glands at puberty is attributable to an increase in circulating androgens from the testes in males, the ovaries in females, and the adrenal glands of both sexes. Androgen-insensitive subjects do not produce sebum (93). Furthermore, the local application of testosterone to skin resulted in a 15-fold increase in sebum excretion rate, although admittedly this was a small study in which 2% testosterone cream was applied to the foreheads of prepubertal boys. In fact, three subjects failed to respond, but this study does demonstrate that skin can respond to local androgens (94).

Androgen sensitivity of pilosebaceous units has been confirmed by the positive detection of androgen receptors in pilosebaceous units by immunohistochem-istry (Fig. 4) (95-97) and by their isolation from sebaceous gland cells (98). However, it has not been possible to demonstrate differences in receptor levels that explain androgen dependent dermatoses, such as acne or the different rates of sebum production in different individuals. There is a strong correlation between sebum excretion rate and acne grade (99,100), but it has not been possible

tgf-s hTOF KGF

tgf-s hTOF KGF

Pilosebaceous Unit

FIGURE 3 A schematic representation of potential pathways in sebocytes that can regulate lipogenesis. Abbreviations: CAMP, cyclic adenosine monophosphate; CRH, corticotrophic releasing hormone; EGF, epidermal growth factor; FGF, fibroblast growth factor; GH, growth hormone; IGF, insulin-like growth factors; KGF, keratinocyte growth factor; MSH, melanocyte stimulating hormone; PPARs, peroxisome proliferator-activated receptors; TGF, transforming growth factor.

FIGURE 3 A schematic representation of potential pathways in sebocytes that can regulate lipogenesis. Abbreviations: CAMP, cyclic adenosine monophosphate; CRH, corticotrophic releasing hormone; EGF, epidermal growth factor; FGF, fibroblast growth factor; GH, growth hormone; IGF, insulin-like growth factors; KGF, keratinocyte growth factor; MSH, melanocyte stimulating hormone; PPARs, peroxisome proliferator-activated receptors; TGF, transforming growth factor.

Sebocytes Stain
FIGURE 4 Immunohistochemical labeling of a cross-section through the infundibulum of a sebaceous follicle stained with a monoclonal antibody for androgen receptors. Positively stained nuclei are dark gray.

to relate the rate of sebum production to differences in androgen receptor levels in different acne patients.

Androgen receptor antagonists, such as oral cyproterone acetate and spironolactone compete with androgens for the androgen receptor-binding site (101), and while both compounds effectively decrease sebum production, they also have feminizing side-effects. Since their effect is not specific for skin, their use is restricted to women. Antiandrogens also decrease follicular impactions (see later) (102), but this may be secondary to a reduction in sebum flow or a change in sebaceous lipid composition.

An important feature of the effect of androgens on pilosebaceous unit metabolism is the metabolic conversion of the androgens themselves, and much work has been done in the last decade to define the pathways of androgen metabolism. It is now clear that pilosebaceous units possess all the steroid metabolizing enzymes needed to convert dehydroepiandrosterone to the most potent androgen, dihydro-testosterone (DHT), including 3-^-hydroxsteroid dehydrogenase (103-105), and 5-a-reductase (5-a-R) (106). These latter two enzymes exist in several isoforms: type 2 isozyme of 17 ^-hydroxy steroid dehydrogenase (^-HSD) is predominant in sebaceous glands and type 1 5a-R is highest in sebaceous glands (107,108), isolated and cultured infundibular keratinocytes, and in epidermis (109). This would explain why 5a-R II inhibitors such as finasteride, do not produce a significant reduction in sebum output (93).

Furthermore, sebocytes have the biosynthetic capacity to produce their own androgens from cholesterol through the cytochrome P450 side-chain cleavage system (P450scc) (110). Along with its cofactors, adrenodoxin, adrenodoxin reductase, and the transcription factor, steroidogenic factor 1, P450scc converts cholesterol to pregnenolone, which is also the precursor for estrogen synthesis. Positive staining using antibodies to these proteins was demonstrated in hair follicles in human facial skin, and biochemical activity was demonstrated in vitro confirming that sebaceous glands are locally steroidogenic with the capacity to produce the highly potent DHT from cholesterol. The conclusion from this body of work is that the skin has its own capacity to metabolize androgens suggesting that the skin exercises local control over the ultimate effects of circulating androgens on the target tissue.

Genes for lipid biosynthesis are regulated in sebaceous glands by androgen-dependent transcription (111). Topical application of 0.005% DHT to hamster ear activated the steroid regulating element (SRE) binding proteins in sebaceous glands, with an upregulation of the mRNA expression for enzymes involved in lipid production, including HMG CoA reductase and synthase, glycerol 3-phosphate acyltransferase, and stearoyl CoA desaturase. SREs are present in the promoter regions of the genes for these enzymes (112).


In contrast to the stimulatory effect of androgens on the sebaceous glands, estrogens and compounds that have estrogenic activity, such as phenol red (113), reduce lipo-genesis in vitro. In vivo, the effect of estrogens is contradictory, although at pharmacological doses estrogens are sebosuppressive in rat preputial gland (114) and in humans also producing feminizing side effects (115). This action of estrogens is indirect and occurs by inhibiting the adrenals and gonads via the pituitary, thereby reducing the production of androgens. During hormonal treatments, such as hormone replacement therapy (HRT), the effect on skin surface lipids depends on the predominant hormone given. Skin surface lipids are increased during combined HRT, possibly reflecting stimulatory effects of the progestogen component on sebaceous gland activity, while estrogen alone has a sebum-suppressive action (116).

Local effects of estrogens have been demonstrated (115). Thus, ethinyl estra-diol is capable of reducing sebum secretion when applied to the forehead. In addition, sebum secretion was reduced at sites on the forehead distal to the site of application. In agreement with a local effect, both a and b receptor subtypes for estrogens are detected in sebaceous glands of human terminal follicles in both basal and partially differentiated sebocytes (117). There was also widespread expression of estrogen receptor b in the terminal hair follicle, where it was localized to the nuclei of the outer root sheath, epithelial matrix, dermal papilla cells, and in the cells of the bulge (118).


Retinoids exert dramatic, dose-dependent effects on sebocytes in vitro and in vivo. The effect of retinoids is mediated through nuclear receptors [retinoic acid receptor (RAR), retinoid X receptor (RXR)] expressed in sebocytes (119), and in vitro, sebocytes respond differently to retinoids depending upon whether RAR or RXR agonists are given. Activation of RAR by all-trans-retinoic acid (all-trans-RA) mediated the antiproliferative and antidifferentiation effects, while RXR agonists caused differentiation and only weak proliferation in rat preputial cells (120).

Vitamin A was essential for the proliferation, lipogenesis, and differentiation of immortalized human sebocytes in vitro (121), but these cells showed different responses to other retinoids and the effects were dose dependent. In delipidized serum (i.e., in the absence of vitamin A), isotretinoin [13-cis-retinoic acid (13-cis-RA)] and acitretin at concentrations <10~7M enhanced sebocyte proliferation and lipid synthesis, whereas at concentrations > 10~7M-sebocyte proliferation was inhibited (121). In contrast, with cells cultured in media containing vitamin A, further addition of either isotretinoin or to a lesser extent, all-trans-RA at concentrations ranging from 10~8M to 10~5M inhibited cell proliferation and lipid synthesis, and altered keratin expression (122). For 13-cis-RA to affect sebocyte proliferation, differentiation, and lipogenesis, it must apparently be first isomerized to all-trans-RA (123), so it is perhaps not surprising that these retinoids show similar effects.

Other culture systems support the inhibitory role for retinoids in sebaceous glands. Retinoids significantly inhibited proliferation in the rank order 13-cis-RA > all-trans-RA ^ acitretin in immortalized sebocytes (124) and in sebaceous gland organ culture, 13-cis-RA caused a significant decrease in lipogenesis over seven days (113,125), and reduced thymidine uptake in pilosebaceous duct organ culture (126).

Clinically, 13-cis-RA is given orally for severe acne at doses of 1 mg/kg/day for four months and produces a rapid reduction in sebum excretion, for example, down to 20% of its former level within four weeks (127). This is due to sebaceous gland atrophy as demonstrated by histological methods (128) but the mechanism involved is unknown. 13-cis-RA and the derivatives, 3,4-didehydroretinoic acid, and 3,4-didehydroretinol are potent competitive inhibitors of the oxidative 3 a-HSD, potentially downregulating the production of potent androgens, DHT, and androstandione, in vitro (129). 13-cis-RA does not however have any effect on 5-a-R responsible for the production of DHT (107). There is also a strong increase in cellular retinoic acid binding protein II expression in the sebaceous gland, and to some extent, in the infundibular structures compared with the level of expression in the epidermis in biopsies obtained from patients treated with 13-cis-RA. Strongest staining was always found in layers of suprabasal sebocytes lacking lipid droplets, and staining was absent in the basal layers (130).

Vitamin D

The effect of topical vitamin D on human sebocytes and sebum secretion has not been documented, although receptors for vitamin D have been demonstrated in the nuclei of basal sebocytes (131,132). In a culture system of hamster auricular sebocytes, 1-a,25-dihydroxyvitamin D3, decreased the triglyceride level by 34.3%, but augmented the accumulation of wax esters by 30%, with no difference in the level of cholesterol produced (133).

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  • Pasqualina
    Does vitamin D lower sebaceous activity?
    11 months ago

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