Understanding Hyperpigmentation: Unveiling the Science and Solutions

External and Internal Factors of Hyperpigmentation

UV-Radiation

Hyperpigmentation occurs in various different forms in skin of color. In many cases, hyperpigmentation is induced by UV radiation, hormonal changes, medication, or inflammatory responses in the skin.

There are two types of UV-R that reach the skin and influence skin pigmentation: UV-A (320-400 nm) and UV-B (280-320 nm). UV-A has the ability to reach deep into the dermis, and therefore, it has a higher capability to reach the depths of melanocytes and stimulate pigmentation than UV-B does. UV-B is majorly absorbed by the epidermis and upper dermis, resulting in the activation of melanin production. Additionally, it has a strong potential to induce erythema and to even cause cutaneous DNA damage. In terms of pigmentation, both the UV-R can activate the production of NO, ET-1, a-MSH (melanocyte stimulating hormone), ACTH, and PGE, which are signaling molecules that initiate the cellular signaling pathway responsible for the activation of melanogenesis.

Hormonal Impacts

Certain sex steroids have shown to increase the production of mRNA copies from the gene segments responsible for encoding melanogenic enzymes such as DCT and TYR (105 of human skin pig). Furthermore, estrogens have shown to increase keratinocyte proliferation (116 of human skin pig), and androgens, which are key sex hormones that contribute to reproductive health, modulate TYR activity by regulating cAMP (a second messenger involved in skin pigmentation) (126 of human skin pig). Progesterone, however, is a sex hormone that has shown to lower pigmentation; Weitnman et al showed that progesterone reduces the proliferation of melanocytes without having any impact on TYR.

Influence of Drugs

Certain drugs and chemicals have shown to have significant pigmentary side effects. Medications used in common treatments have the ability to stimulate pigment production in skin of color. Antibiotics such as sulfonamides and tetracyclines, diuretics, NSAIDs (non-steroidal anti-inflammatory drugs), and some pain relievers can activate hyperpigmentation in the skin. A study has shown that oral contraceptives were correlated with uneven pigmentation in the cheeks, forehead, and nose as it enlarged the melanocytes in the epidermis and enhanced the rate of melanogenesis (94 in human skin pig). Additionally, antiepileptic chemicals, primarily hydantoins, can lead to hyperpigmentation (95 in human skin pig). A study has shown that melanin concentration increases dramatically in females with caucasians being especially sensitive to hydantoins (96 human skin pig). Since DOPA is a key molecule in the process of melanin synthesis, Levodopa, which is used to treat Parkinson’s disease, has shown to induce discolored pigmentation in the skin since the DOPA therapy used with this drug might be responsible for enhancing melanin biosynthesis (97 human skin pig).

Heavy metals, such as arsenic, bismuth, gold or silver, contained in certain medications have also been associated with hyperpigmentation (98). These metals bind to and inactive sulfhydryl compounds in the skin, which are inhibitors of TYR. Inactivating the substrate that binds to the TYR enzyme results in a higher activity of TYR, which yields a higher rate of melanogenesis.

Common forms of Hyperpigmentation

Melasma

Most common causative factors of melasma are hormonal changes during pregnancy, oral contraceptives, sun exposure, and anti-epileptic drugs. Involving the epidermis and the dermis, the clinical features of melasma include symmetrical facial hyperpigmentation due to an increase in size of melanocytes and increased melanocyte production with the number of melanocytes remaining unchanged. Melasma is typically associated with high levels of estrogen and MSH (melanocyte stimulating hormone), which consequently increases the transcription of DNA segments that code for DCT and TYR enzymes.

Physiology pic of melasma (morphology image)

Solar Lentigines

This pigmentary condition involves dark spots or patches on the skin resulting from UV-R exposure. Brown or black macules, ranging from less than 1 mm to several cm, are found on areas that were exposed to UV-R, such as the face, dorsum of hand, forearm, etc. Radiation causes an increased rate of melanin synthesis through an increase in the number of functioning melanocytes in the skin. There is a higher number of TYR cells per unit of length of the dermal/epidermal layer compared to skin that is unaffected by UV-R. Keratinocytes also have a supplemental potential to produce ET-1 (key signaling molecule in the process of melanin production) compared with unaffected skin.

Postinflammatory

Hyperpigmentation due to inflammatory responses develops after acne or contact dermatitis. Features of post-inflammatory hyperpigmentation include dark macules with discrete margins, which occur due to increased melanin production even though the number of melanocytes remains identical to unaffected skin. The increased melanin production can be credited to the upregulation of PGE2 and PGF2a, which are paracrine factors that stimulate melanocyte dendricity.

Hyperpigmentation Treatment

Melanin synthesis involves an intricate cell signaling pathway that involves various oxidative reactions and several key enzymes to reach the stage of melanogenesis. Tyrosinase activity has repeatedly shown to have a significant impact on the rate of melanogenesis. Melanin is synthesized in special membrane bound organelles in melanocytes called melanosomes. In the process of pigment production in these melanosomes, tyrosinase enzymes are responsible for key reactions that initiate the production of eumelanin, the type of melanin that is responsible for dark hair and skin color. There are two primary oxidative reactions that are catalyzed by the tyrosinase enzyme: the hydroxylation of tyrosine (amino acid) to Dopa (3, 4-dihydroxyphenylanine) and the oxidation of Dopa to Dopaquinone, creating hydrogen peroxide. Furthermore, other various melanocyte specific enzymes such as TYRP1 (tyrosinase related protein 1) and DCT (DOPAchrome tautomerase) further metabolize DOPA-quinone and its derivatives (DOPA chrome and DHICA), resulting in the formation of eumelanin.

Due to the role tyrosinase plays in the process of melanin production, tyrosinase inhibitors have been a critical part of hyperpigmentation therapies patients use in order to lower the rate of eumelanin synthesis. Additionally, in hyperpigmentation, melanocytes create excessive ROS (reactive oxygen species) from the oxidative reactions required to activate melanogenesis in response to factors such as infection and UV radiation. Seçkin et al demonstrated that hyperpigmentation disorders show increased levels of these ROS, such as nitric oxide, in the pathogenesis of pigmentation. For this reason, antioxidants have also been a common component of therapies used to treat pigmentation disorders. Agents that can combat the effects of the excessive oxidative stress in melanocytes are often used to treat hyperpigmentation.