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30 ASCP Skin Deep Winter 2023 and other biochemical stressors. Melanin also protects against heat and elevated temperature and contributes antimicrobial benefits. There are certainly specific systemic illnesses, including liver and adrenal disease, pituitary tumors, and hemochromatosis (excessive iron accumulation and deposition in organs and tissues), linked to inappropriate pigmentation. But the most important point to recognize from a therapeutic perspective is that melasma is a sign of a biological stress—associated with aging, pregnancy, perimenopause, menopause, malnourishment, and nutritional deficiencies—as well as physiological/ mechanical stress, such as the inflammation that occurs after skin wounding, trauma, or lesions (post- inflammatory hyperpigmentation). Regardless of the initial trigger of an inappropriate or excessive pigmentation response, like all biochemical processes in the body, skin darkening is mediated by hormones. It's important to note that most melasma patients are women. The culprit here is the quintessential female hormone estrogen, which is also associated with the stress response. Melasma appears at the time in a woman's life when estrogen levels are most unstable, either because of aging, ingestion of pharmaceutical estrogen (birth control pills, hormone replacement therapy), or biochemical imbalances associated with excess body fat, liver dysfunction, or intestinal pathology. It's well known that fluctuations in the production of this hormone are linked to the appearance of the dark, splotchy signs of melasma. Cortisol, recognized as a prime modulator of the stress response, also plays a role in skin darkening. Under conditions of chronic stress, changes in levels of this hormone can be a cause of inflammation. It's known that long-term stressful circumstances can worsen melasma and it's likely that the same biochemical factors linked to the secretion of cortisol and subsequent inflammation are also involved in hyperpigmentation. Additionally, adrenocorticotropic hormone, which triggers the release of cortisol, can cause an increase in the production of melanin and lead to hyperpigmentation. The third hormonal horseman is insulin. While most people think of this molecule in terms of reducing blood glucose levels, insulin is much more than a sugar hormone. In fact, it's a growth- enhancing substance that increases the rate of cell division and has an overall activating effect on all cells, including melanocytes. Over time, if insulin levels remain elevated, cells reduce their responsiveness to the hormone and lead to a condition called insulin resistance. Insulin resistance is linked to many skin conditions, including hirsutism, acne, and skin darkening. An unhealthy thyroid may also play a role in skin darkening. Although the exact mechanism is unclear, it is known that there is a connection between low thyroid function (hypothyroidism) and hyperpigmentation. And the molecules associated with hypothyroidism, including autoimmune antibodies and thyroid stimulating hormone, have been shown to be elevated in melasma patients. Additionally, the symptoms of hyperthyroidism, caused by an overactive thyroid, have also been reported to include hyperpigmentation. TREATMENT STRATEGIES To best treat melasma, you need to address the biochemical causes associated with the condition. Because of the relationship of melasma to estrogen, strategies that balance out excesses in this powerful biomolecule should be considered. Progesterone has an antagonizing effect on estrogen, so systemic, prescription versions of this hormone taken orally can be helpful. Because elevated estrogen (and its breakdown metabolites) can be caused by digestive and liver issues, using probiotics, fiber, and other digestive support supplements is advisable. Using liver-strengthening nutrients like alpha lipoic acid and vitamins C and E may also provide anti-hyperpigmentation benefits. There are also cortisol-reducing nutrients that may help melasma clients. Melatonin, widely recognized as a sleep aid, also has anti-inflammatory effects that can protect against stress hormone (cortisol)-induced hyperpigmentation. And, as its name implies, melatonin (mela meaning "black" and tonin referring to "control" or "regulation") plays an important role in the skin- coloration process. It's also a general antiaging and antioxidant molecule, and some literature suggests melatonin deficits exist in melasma patients. 2 In addition to being anticortisol, melatonin has an inhibitory effect on chemicals that activate the production of melanin. Certain adaptogenic and calming botanicals, including ashwagandha, lemon balm, and rhodiola, may also balance or suppress cortisol secretion. Vitamins E and C have cortisol-lowering properties, as well as the ability to reduce the darkening (oxidation) of skin pigment. Prescription-Strength Treatments From a topical perspective, melasma clients can choose from a variety of skin-lightening ingredients. The gold standard of depigmenting agents is hydroquinone