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New discoveries in regulating pigmentation


Researchers have uncovered new pathways that control skin lightening and tanning, which could lead to a novel class of therapeutics for treating pigmentation disorders.

University of Pennsylvania researchers have uncovered new pathways that control skin lightening and tanning. The knowledge could lead to a novel class of therapeutics, which is especially important given the limited options for safe and effective treatment of pigmentation disorders, according to a new study.1

“Although we have always assumed that there was some connection between pregnancy ‘hormones’ and pigmentation, the specific hormones and mechanism through which they regulate pigment has never been defined,” says the study’s senior author Todd W. Ridky, M.D., Ph.D., assistant professor of dermatology at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Ridky and colleagues exposed human melanocytes to estrogen levels generally seen during pregnancy. The cells responded by increasing melanin production. Ethinyl estradiol, which is commonly used in birth control pills, had a similar effect, as did tamoxifen, which usually blocks estrogen’s effects.

The melanin content of the cells increased 200% to 300% after four days.

When melanocytes were exposed to progesterone, melanin production decreased.

With further testing, the researchers found that melanocytes express receptors not previously studied: a separate, non-classical, estrogen receptor, GPER, as well as a non-classical progesterone receptor, PAQR7. They confirmed those receptors are responsible for the skin pigment effects.

In the lab, they tested new compounds that alter skin pigmentation based on the finding that the receptors’ activity was activated or inhibited by synthetic estrogen or progesterone analogs, which do not bind to estrogen or progestin receptors.

The researchers purified the selective GPER-activating compound, creating a cream, and applied it to mice’s ears. The treatment increased melanin levels by about 60% during three weeks, according to a press release.

These compounds will have to go through the FDA and clinical trials before they’re made available to dermatologists, according to Dr. Ridky.

“There is a potential role for these agents in post-inflammatory hyper and hypo-pigmentation, melasma, and possibly vitiligo. These new agents also will also likely fill a cosmetic need. The new potential tanning agents darken skin without UV damage — a major improvement over tanning beds and sitting out in the sun,” he says.

NEXT: A win for melasma patients, but not for those with vitiligo?


A win for melasma patients, but not for vitiligo?

lltefat Hamzavi, M.D., senior staff physician, department of dermatology-multicultural center at Henry Ford Hospital, and co-chair of the Vitiligo Working Group, says this study follows previous clinical findings that women suffer from melasma to a much greater degree.

“The vast majority patients (almost 90%) are female. The condition does seem to worsen with pregnancy and birth control pills. However, melasma and other pigmentary problems can last a lifetime. So the hormone-melasma link makes sense with this pathway,” Dr. Hamzavi, who is not a study author, tells Dermatology Times.

“This pathway could help patients with too much pigment but those who have lost pigment have a different pathway. Conditions like vitiligo involve an immune process, which is not likely involved in this mechanism discovered at Penn. However, a combination of the two pathways may lead to better treatments. In this scenario, the immune system would be managed with one agent and these new estrogen pathways may help bring color back with another method.”

Mehdi Rashighi, M.D., research fellow, department of medicine, division of dermatology,

University of Massachusetts Medical School, agrees that it’s unlikely that the results of the current study would apply to vitiligo.

“In vitiligo, as opposed to melasma, the melanocytes are destroyed and, therefore, absent, so increasing pigment production would most likely not help in the absence of the pigment-producing cells,” says Dr. Rashighi, who reviewed the University of Pennsylvania study.


1 Natale CA, Duperret EK, Zhang J, et al. Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. Elife. 2016;5



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