Androgens are required for sexual hair and sebaceous gland development. However, pilosebaceous unit (PSU) growth and differentiation require the interaction of androgen with numerous other biological factors. The pattern of PSU responsiveness to androgen is determined in the embryo. Hair follicle growth involves close reciprocal epithelial-stromal interactions that recapitulate ontogeny; these interactions are necessary for optimal hair growth in culture. Peroxisome proliferator-activated receptors (PPARs) and retinoids have recently been found to specifically affect sebaceous cell growth and differentiation. Many other hormones such as GH, insulin-like growth factors, insulin, glucocorticoids, estrogen, and thyroid hormone play important roles in PSU growth and development. The biological and endocrinological basis of PSU development and the hormonal treatment of the PSU disorders hirsutism, acne vulgaris, and pattern alopecia are reviewed. Improved understanding of the multiplicity of factors involved in normal PSU growth and differentiation will be necessary to provide optimal treatment approaches for these disorders.

The peroxisome proliferator-activated receptor ␥ (PPAR␥) is a central regulator of adipogenesis and recruits coactivator proteins in response to ligand. However, the role of another class of nuclear cofactors, the nuclear receptor corepressors, in modulating PPAR␥ transcriptional activity is less clear. Such corepressors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT). Our data suggest that PPAR␥ recruits SMRT and NCoR in the absence of ligand and that these corepressors are capable of down-regulating PPAR␥-mediated transcriptional activity. The addition of the PPAR␥ ligand pioglitazone results in dissociation of the PPAR␥-corepressor complex. To define the role of SMRT and NCoR in PPAR␥ action, 3T3-L1 cells deficient in SMRT or NCoR were generated by RNA interference. When these cells are exposed to differentiation media, they exhibit increased expression of adipocyte-specific genes and increased production of lipid droplets, as compared with control cells. These data suggest that the nuclear receptor corepressors decrease PPAR␥ transcriptional activity and repress the adipogenic program in 3T3-L1 cells. The thyroid hormone receptors (TRs)1 and retinoic acid receptors (RARs) are nuclear receptors that repress gene transcription in the absence of their respective ligands. This ligandindependent repression is mediated by nuclear receptor corepressors, such as the nuclear receptor corepressor protein (NCoR) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) (1, 2). NCoR and SMRT are recruited by TR and RAR isoforms in the absence of ligand and are released upon ligand binding. NCoR and SMRT, in turn, recruit a complex with histone deacetylase activity to repress transcription of target genes. More recently, NCoR and SMRT have been shown to be recruited by other nuclear receptors, some of which bind nuclear receptor corepressors in the presence of antagonists. However, it has been controversial whether NCoR and SMRT play a significant role in gene regulation by the peroxisome proliferator-activated receptor ␥ (PPAR␥) isoforms (3).Two types of PPAR␥ isoforms exist, PPAR␥1 and PPAR␥2. These receptors differ only in their amino-terminal A/B domain, such that PPAR␥2 contains an extra 30 amino acids (4). The function of PPAR␥2 has attracted considerable interest because it is specifically expressed in adipocytes and is an essential regulator of adipogenesis. In addition, many important adipocyte-specific genes contain response elements for PPAR␥ in their promoter regions. Although PPAR␥ clearly recruits coactivators in response to exogenous ligands, its ability to recruit corepressors is less certain. In contrast to the TR, PPAR␥ does not appear to be a strong repressor in the absence of its ligand. Such experiments, however, have been limited by the lack of information concerning physiologic endogenous ligands. Early work into PPAR␥ and corepressor recruitment suggested that PPAR␥ might not recruit NCoR or SMRT in the p...

It has been difficult to induce the expected sebocyte differentiation in vitro with dihydrotestosterone (DHT). We reasoned that our culture system lacks differentiating factors, and peroxisome proliferator-activated receptors (PPARs) were the prime candidates. We tested PPAR activators informative about diverse PPAR subtypes, with and without DHT (10^–6 M): BRL-49653 (10^–6 M, PPAR-γ), WY-14643 (10^–6 M, PPAR-α), and linoleic acid (LIN, 10^–4 M, PPAR-d). Treatments were added in serum-free medium to cultures of rat preputial sebocytes. Control, DHT, BRL and BRL + DHT treatments caused 11, 25, 66 and 80%, respectively, of preputial cell colonies to differentiate into lipid-forming colonies (LFCs) (p <0.001). WY induced 20% and LIN over 95% LFC formation. PPAR-γ mRNA was identified in preputial sebocytes by the RNase protection assay. These data suggest that differentiation of sebocytes is transduced by PPARs and have implications for the development of new treatments for acne.

Several observations suggest that GH stimulates sebaceous gland growth and development. Therefore, we studied the effects of GH and insulin-like growth factors (IGFs), alone and with androgen, on sebaceous epithelial cell (sebocyte) growth and differentiation in vitro. The rat preputial cell culture model system was used to judge differentiation (induction of lipid-forming colonies, LFCs) and DNA synthesis. GH increased sebocyte differentiation. At a dose of 10(-8) M in the presence of micromolar insulin, GH was 3.8 times more potent than IGF-I (38.1+/-4.2%, SEM, vs. 10+/-1.5% LFCs) and 6 times more potent than IGF-II (6+/-0.5% LFCs). IGF-I 10(-8) M alone stimulated a similar amount of differentiation as insulin 10(-6) M, although it was less effective than insulin in augmenting the effect of GH on differentiation. GH had no effect on sebocyte uptake of 3H-thymidine at doses up to 10(-6) M. On the other hand, IGF-I was the most potent stimulus of DNA synthesis (168% of control; P < 0.001 vs. all others). IGF-II 10(-8) M stimulated 3H-thymidine incorporation similarly to insulin 10(-6) M. In the presence of insulin, dihydrotestosterone (DHT) 10(-6) M induced 31.4+/-1.7% LFCs, and there was a tendency of DHT and GH to interact in promoting differentiation. When insulin was omitted from the system, differentiation was decreased overall, but GH +/- DHT slightly improved differentiation. The IGFs had no effect on the response to DHT. DHT decreased DNA synthesis by 40%, an effect unaltered by GH or IGFs. These results suggest that GH and IGFs have different functions in sebaceous cell growth and differentiation: GH stimulated differentiation beyond that found with IGFs or insulin, yet had no effect on DNA synthesis, a parameter stimulated most potently by IGF-I. While GH augmented the effect of DHT on differentiation, the IGFs had no effect on the response of DHT. These data indicate that GH may in part act directly on sebocytes rather than indirectly through IGF production. These data are consistent with the concept that increases in GH and IGF production contribute in complementary ways to the increase in sebum production during puberty and in acromegaly.

PPARs are nuclear hormone receptors. PPAR subtypes (α, γ, δ, the latter a xPPARβ homologue) were initially investigated in skin because of their known role in regulating lipid metabolism. Studies adding specific PPAR ligand activators to cultured skin or skin cells are compatible with the concepts that PPARα activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARγ activation plays a unique role in stimulating sebocyte lipogenesis, and PPARδ activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARα and PPARδ mRNA and a trace of PPARγ mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARγ gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARα, while sebocytes express more PPARγ than PPARα. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARα to skin barrier function, suggest that PPARγ is necessary for sebocyte differentiation, and indicate that PPARδ can ameliorate inflammatory responses in skin. PPARs appear to play a role in keratinocyte synthesis of the lipids that they export to the intercellular space to form the skin permeability barrier. They also appear to be important for sebocyte formation of the intracellular fused lipid droplets that constitute the holocrine secretion of the sebaceous gland. In addition, they may play roles in keratinocyte growth and differentiation and the inhibition of skin inflammation by diverse mechanisms not necessarily related to fat metabolism.