Researchers from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia have found that estrogen and progesterone reciprocally regulate melanin synthesis in epidermal melanocytes, according to a paper published in eLife (Apr. 26, 2016; 10.7544/eLife.15104). The findings potentially explain skin colour changes observed in pregnant women and may open avenues of research into methods of altering skin colour without exposure to ultraviolet (UV) light or bleaching agents, the authors note. “Correcting disorders of human skin pigmentation is difficult, as safe and effective medications that alter melanin pigment production are lacking. But, the information uncovered in this study suggests that by using derivatives of sex hormones to selectively influence the natural melanin production machinery, we may be able to develop treatments to correct such disorders,” senior author Dr. Todd W. Ridky, an assistant professor of dermatology at the Perelman School of Medicine said in a press release. The investigators treated human melanocytes with estrogen in culture and as part of a three-dimensional organotypic skin model. Estrogen exposure levels in the in vitro samples were comparable to what would occur during pregnancy. After four days of this exposure, melanin was markedly increased (208% +/- 27%) in three individual isolations of primary human melanocytes. After one week, the estrogen-treated model skin displayed a three-fold increase in melanin, while melanocyte count and density did not change. When they then examined the impact of progesterone—known to counteract the effects of estrogen in other bodily systems—at a concentration comparable to that seen in the third trimester of pregnancy, investigators observed progesterone halved melanin production (58% +/- 11.4%) both in vitro and in the model tissue without altering the number of melanocytes. Further investigation revealed the two hormones were upregulating and downregulating, respectively, the same molecular cascade normally triggered by Melanocyte Stimulating Hormone (MSH), the production of which is usually triggered by UV exposure. Melanocytes do not have traditional estrogen or progesterone receptors, and those receptors had not been linked to the signalling molecules triggered by MSH, so the researchers looked for another connection. They found two non-traditional receptors, GPER and PAQR7, and confirmed these were the vector for the two hormones’ effects on melanocytes. They exposed cells where genes that had these two receptors were deleted to estrogen and progesterone, which produced no change in pigmentation. The authors also developed synthetic estrogen and progesterone analogues that would bind to GPER and PAQR7, but not traditional estrogen and progesterone receptors. Testing in the in vitro and tissue models, as well as a mouse model, demonstrated the ability to alter melanin production. “The development of drugs that specifically target the natural pigment production pathway in skin cells could be a safer and more effective alternative to the tanning beds and bleaching creams frequently used today,” said Dr. Ridky.