Linnaeus is focused on melanoma oncology. However, our technologies have the ability to be used in aesthetics for both skin darkening and skin lightening by increasing and decreasing melanin production. Safe and effective approaches for modulating skin melanocyte function (increasing and decreasing melanin production) for therapeutic benefit are lacking, largely because the factors normally regulating melanocyte homeostasis are complex and incompletely deciphered. Defining these mechanisms is important however, 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).

Skin Darkening

There is currently no available therapeutic that promotes protective eumelanin pigment production. The only method currently available to increase skin melanin is UV exposure. While effective at darkening skin, the requisite DNA damage promotes premature aging, wrinkles, and skin cancer. However, the specific activation of GPER alternatively activates cAMP signaling, bypassing MC1R, to stimulate melanin synthesis, and could therefore be especially useful in this sun-vulnerable population. Selective GPER activation in skin could potentially be a safe alternative to intentional UV radiation exposure (via natural sunlight or tanning beds) for individuals seeking what they perceive as an aesthetically desirable tan.

People with naturally light skin, especially those with red hair, who have a markedly decreased ability to synthesize UV-protective brown eumelanin as a result of inactivating mutations in MC1R (Valverde et al., 1995) could potentially benefit from increased pigmentation. This large population is especially susceptible to photodamage, sunburns, and has an increased lifetime risk of keratinocyte and melanocyte-derived skin cancers (Han et al., 2006).

Skin Lightening

Commonly utilized approaches for decreasing skin melanin are often unsafe, and involve application of toxic mercury or arsenic compounds, especially common in India, China, Japan, and Korea, but also encountered in the U.S., and recently highlighted in a report from the California Department of Public Health (Report #14–046, 2014), or hydroquinone, a tyrosinase inhibitor, which has been banned in Europe because of concerns regarding its possible association with cancer (McGregor, 2007).

Our findings describe small molecule sex steroid analogs, without these toxicities, that modulate pigment production.