Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors

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Abstract

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.

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Christopher A Natale

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
Christopher A Natale, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.
Elizabeth K Duperret

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Junqian Zhang

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Rochelle Sadeghi

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Ankit Dahal

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Kevin Tyler O'Brien

Department of Chemistry, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Rosa Cookson

Department of Chemistry, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Jeffrey D Winkler

Department of Chemistry, University of Pennsylvania, Philadelphia, United States

Competing interests
Jeffrey D Winkler, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.
Todd W Ridky

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

For correspondence
ridky@mail.med.upenn.edu

Competing interests
Todd W Ridky, Listed as an inventor on patent applications held by the University of Pennsylvania for the use of topical estrogen and progesterone derivatives for modulating skin pigmentation.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#803381) of the University of Pennsylvania.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.