Sexual hormones utilize complex mechanisms to modulate sebocyte differentiation

Abstract

Sexual hormones are important in the maintenance of human skin. Being the endocrine “brain” of the skin, the sebaceous gland is a major target of sexual hormones. While androgens stimulate sebocyte proliferation, estrogens do not to affect sebaceous gland growth. Regarding differentiation, androgens are expected to stimulate and estrogens to suppress sebaceous lipid synthesis, while estrogens, in vivo, enhance sebaceous lipogenesis in aged skin. The latter results have been disputed by current in vitro data indicating no direct effect of sexual hormones on sebocyte differentiation. To elucidate these contradictions we have investigated possible pathways which may be used by sexual hormones to modulate sebocyte differentiation in vitro. It has been postulated that androgen induction of lipogenesis requires the concomitant presence of peroxisome proliferator‐activated receptor (PPAR) ligands. We found that arachidonic acid (AA), the direct precursor of leukotriene B4, a natural PPARα ligand, and linoleic acid (LA), a natural PPARδ ligand, induce sebocyte enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation. The combined administration of testosterone and AA or LA slightly increased sebaceous lipogenesis. In contrast, synthetic PPAR ligands were unable to enhance sebaceous lipogenesis. Interestingly, AA synthesis in human sebocytes was significantly stimulated by the prostaglandins (PG) E2 and Δ15‐J2. On the other hand, PPARγ expression was downregulated by the phytoestrogen genistein. Interestingly, 17β‐estradiol has previously been shown to induce the metabolism of PGD2 to Δ12‐PGJ2, a natural PPARγ ligand. In addition, we found that 17β‐estradiol increases IGF‐I synthesis (+28%) and down‐regulates IGF‐IR expression (−37 to −48%), whereas IGF‐I significantly induces sebaceous lipogenesis. In conclusion, sexual hormones are not directly active but are likely to utilize complex mechanisms, including modified known pro‐inflammatory pathways, to modulate sebocyte differentiation.