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.
Highlights
Cutaneous pigmentary changes have been long recognized as common side effects of pregnancy
The magnitude of this change was similar to that observed with alpha-melanocyte stimulating hormone (aMSH) (Figure 1—figure supplement 1D), and is consistent with prior in vitro studies implicating estrogen in melanin synthesis (McLeod et al, 1994; Ranson et al, 1988)
Safe and effective approaches for modulating skin melanocyte function for therapeutic benefit are lacking, largely because the factors normally regulating melanocyte homeostasis are complex and incompletely deciphered. Defining these mechanisms is important as myriad genetic and acquired conditions including common afflictions such as acne, eczema, vitiligo, ultraviolet (UV) radiation exposure, traumatic injury, and pregnancy are associated with alterations in skin pigmentation that can be extensive and long-lasting (James et al, 2011)
Summary
Cutaneous pigmentary changes have been long recognized as common side effects of pregnancy. . .more peculiar, according to our great master Hippoc., to Big Belly’d women, and recon’d as one of the Signs of Conception.”. Modern physicians recognize this common pregnancy-associated hyperpigmentation as melasma (Sheth and Pandya, 2011; Nicolaidou and Katsambas, 2014). While Turner noted this association with fetal sex to be ’fallible’, Hippocrates was remarkably astute in linking the pigment increases to the tanning response to DNA-damaging solar ultraviolet (UV) radiation. While early physicians attributed the pigment changes to “Retention of the menstrual Flux” (Turner and Cutaneis, 1726), the molecular mechanisms through which pregnancy-associated hormonal changes modulate skin color have remained elusive for over 2,000 years
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