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Hyperpigmentation

Hyperpigmentation is a common dermatological condition characterized by localized or diffuse darkening of the skin due to excessive melanin production and deposition by melanocytes.^[1]^[2] It arises from an imbalance in melanin synthesis, often triggered by external factors like ultraviolet radiation or internal processes such as inflammation, resulting in benign but cosmetically distressing patches that vary in color from brown to black.^[1]^[3] The most prevalent form, postinflammatory hyperpigmentation (PIH), develops as a reactive response following skin injury, acne, or dermatitis, where inflammatory mediators stimulate melanogenesis and irregular melanin distribution within the epidermis or dermis.^[2]^[4] Other notable types include melasma, often linked to hormonal fluctuations in women during pregnancy or with oral contraceptives, and solar lentigines from chronic sun exposure, which accelerate melanin accumulation as a protective mechanism against UV damage.^[1]^[5] While generally harmless and more pronounced in individuals with darker skin tones due to inherently higher melanocyte activity, hyperpigmentation can persist for months to years, significantly impairing quality of life through psychosocial effects like reduced self-esteem.^[6]^[7] Causal factors extend beyond UV light—empirically the primary driver—to include drug-induced reactions (e.g., from antimalarials or chemotherapy) and endocrine disorders like Addison's disease, underscoring melanocyte hyperactivity as the core physiological pathway rather than mere cosmetic variance.^[1]^[8] Management typically involves topical agents inhibiting tyrosinase (e.g., hydroquinone or retinoids) or procedural interventions like chemical peels, though efficacy varies by depth of pigment involvement and requires sun protection to prevent recurrence, as UV exposure exacerbates all forms.^[9]^[6] Despite advances, no universal cure exists, highlighting the condition's multifactorial etiology rooted in evolutionary adaptations for photoprotection.^[10]

Pathophysiology

Melanin Production and Regulation

Melanocytes, specialized pigment-producing cells derived from neural crest cells and residing primarily in the basal layer of the epidermis, synthesize melanin within membrane-bound organelles known as melanosomes.^[11] The process begins with the oxidation of tyrosine by the copper-containing enzyme tyrosinase, which acts as the rate-limiting catalyst in the melanogenesis pathway, converting tyrosine to dopaquinone and subsequently to melanin polymers.^[12]^[13] Mature melanosomes are then transferred via dendritic processes from melanocytes to surrounding keratinocytes, where they distribute throughout the epidermis to confer pigmentation and photoprotection.^[11] Two main types of melanin are produced: eumelanin, a dark, insoluble polymer with high UV absorption capacity that dissipates over 99.9% of absorbed ultraviolet radiation as heat, thereby shielding DNA from photochemical damage; and pheomelanin, a lighter, sulfur-containing variant predominant in fair-skinned individuals, which absorbs UV less efficiently and can generate reactive oxygen species upon irradiation, potentially exacerbating oxidative stress.^[14]^[15] The ratio of eumelanin to pheomelanin is genetically influenced, particularly by variants in the melanocortin-1 receptor (MC1R) gene, with higher eumelanin levels correlating with darker skin tones and greater resistance to UV-induced damage.^[14] Ultraviolet radiation serves as a key extrinsic regulator of melanogenesis, triggering a cascade that enhances melanin production as an adaptive response. UV exposure activates DNA damage sensors, leading to upregulation of tyrosinase transcription and increased α-melanocyte-stimulating hormone (α-MSH) release, which binds MC1R to elevate cyclic AMP levels and stimulate melanogenic enzymes.^[16]^[17] Empirical studies demonstrate that acute UVB doses (e.g., 100-200 mJ/cm²) induce a 2- to 5-fold increase in tyrosinase mRNA within hours in human melanocytes, culminating in delayed tanning via eumelanin accumulation over days.^[16] This mechanism underscores melanin's role in limiting UV penetration, with constitutive pigmentation reducing erythema risk by up to 50% per skin type increment on the Fitzpatrick scale.^[17]

Mechanisms of Excess Pigmentation

Excess pigmentation in hyperpigmentation disorders results from dysregulated melanin synthesis, primarily through hyperactivity of melanocytes or impaired degradation of melanosomes, leading to accumulation in the epidermis or dermis. The melanogenesis pathway begins with tyrosinase catalyzing the oxidation of tyrosine to dopaquinone, the rate-limiting step in producing eumelanin or pheomelanin; upregulation of tyrosinase expression or activity, often via transcription factors like MITF, drives overproduction.^[18] Inflammatory stimuli, such as tissue injury or infection, provoke post-inflammatory hyperpigmentation by releasing cytokines and mediators that stimulate melanocytes. Prostaglandin E2 (PGE2) and endothelin-1 from inflamed keratinocytes bind receptors on melanocytes, activating protein kinase C (PKC) and phospholipase C pathways to enhance tyrosinase transcription. Alpha-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), cleaved from pro-opiomelanocortin during stress or inflammation, bind the melanocortin-1 receptor (MC1R) to elevate intracellular cAMP via adenylate cyclase, phosphorylating CREB and inducing MITF-mediated gene expression for melanogenic enzymes. Molecular studies of post-inflammatory hyperpigmentation in darker skin tones confirm elevated α-MSH and inflammatory cytokines correlate with increased melanocyte dendricity and melanosome transfer.^[19]^[20] Ultraviolet (UV) radiation induces excess pigmentation via oxidative stress, generating reactive oxygen species (ROS) like superoxide and hydrogen peroxide that overwhelm cellular antioxidants. ROS directly activate tyrosinase by oxidizing its sulfhydryl groups or indirectly via signaling through MAPK/AP-1 pathways, upregulating tyrosinase and TRP-1/2 expression; this delayed tanning response peaks 72 hours post-exposure. UV also stimulates keratinocyte-derived α-MSH and ACTH, amplifying cAMP signaling, while ROS-induced inflammation sustains cytokine loops (e.g., IL-1, TNF-α) that prolong melanogenesis. In vitro and ex vivo models show ROS scavengers like N-acetylcysteine reduce tyrosinase activity and melanin output, establishing causality.^[21]^[22] Genetic polymorphisms modulate susceptibility to these pathways by altering receptor sensitivity or enzyme efficiency. Variants in MC1R, such as R151C or R160W, impair α-MSH signaling, typically reducing eumelanin and increasing pheomelanin, but in inflammatory or UV contexts, they heighten ROS vulnerability and compensatory melanocyte activation, elevating hyperpigmentation risk in cohort analyses of UV-exposed populations. Other loci, including those in OCA2 or SLC24A5, influence baseline tyrosinase regulation, with minor alleles linked to exaggerated responses in pigmentation challenge studies. Empirical data from genomic cohorts underscore these variants' role in variable melanogenic output without implying uniform hyperpigmentation causation.^[23]^[24]

Epidemiology

Global Prevalence

Hyperpigmentation manifests in various forms, with global prevalence estimates varying by subtype and population demographics. A comprehensive survey of 48,000 individuals across 34 countries conducted between December 2022 and February 2023 revealed that approximately 50% of respondents reported at least one pigmentary disorder, predominantly hyperpigmentary conditions such as solar lentigines (27%), post-inflammatory hyperpigmentation (PIH, 15%), and melasma (11%).^[25] Melasma alone exhibits prevalence rates ranging from 1% in general populations to 9-50% in high-risk groups, particularly those in tropical or sun-exposed regions.^[26] These figures underscore the condition's ubiquity, though comprehensive global data remain limited due to diagnostic variations and self-reporting biases. Prevalence disproportionately affects individuals with Fitzpatrick skin types IV-VI, who demonstrate heightened vulnerability to PIH following trauma, inflammation, or procedures, with acne-related PIH documented in up to 65.3% of African Americans (type V-VI), 52.7% of Hispanics (type IV-V), and 47.4% of Asians (type III-V).^[4] In contrast, lighter phototypes (I-III) exhibit lower rates, such as 2.7% for current or prior hyperpigmentation in type I, though subtle presentations in these groups may contribute to underreporting owing to reduced visibility against baseline tone.^[27] This disparity reflects melanocyte hyperactivity in darker skin, amplifying post-injury pigmentation responses. Incidence trends indicate escalation in aging populations attributable to lifelong ultraviolet exposure, with senescent melanocytes under daytime UV promoting aberrant pigmentation even at lower doses.^[28] Dermatology surveys from the early 2020s highlight rising consultations in tropical latitudes, where chronic high-UV environments compound photoaging effects, manifesting as lentigines and irregular hyperpigmentation in up to 27% of surveyed adults globally.^[29] Such patterns emphasize environmental causality over genetic predisposition alone in prevalence shifts.

Risk Factors and Demographics

Individuals with darker skin phototypes, classified as Fitzpatrick types III to VI, exhibit higher susceptibility to hyperpigmentation due to elevated baseline melanin production, resulting in more pronounced post-inflammatory and UV-induced changes compared to lighter skin types.^[30] Women comprise the majority of cases, particularly for melasma, representing up to 90% of diagnosed instances in clinical cohorts from diverse populations.^[30] This gender disparity reflects both higher treatment-seeking behavior among women for visible facial pigmentation and physiological vulnerabilities, such as hormonal influences, though men experience similar conditions at lower reported rates.^[31] Chronic ultraviolet radiation exposure ranks as the primary modifiable risk factor, promoting excess melanin synthesis via melanocyte stimulation and inflammation, with epidemiological data linking it to exacerbated post-acne and other post-inflammatory hyperpigmentation.^[32] Hormonal shifts, especially elevated estrogen and progesterone during pregnancy, drive melasma onset in 15% to 50% of cases, varying by ethnicity and region, with persistence post-partum in many instances.^[33] Genetic predisposition modulates individual risk, evidenced by familial aggregation in melasma and inherited hyperpigmentation syndromes, where variants in pigmentation regulatory genes influence melanocyte activity and response to triggers.^[34] Darker-skinned demographics show increased clinic attendance for hyperpigmentation management, attributable to cosmetic visibility rather than incidence alone, per dermatology registries.^[35]

Etiology

Environmental Triggers

Ultraviolet (UV) radiation from solar exposure represents a principal environmental trigger for hyperpigmentation, primarily through induction of DNA damage in epidermal cells, which activates repair mechanisms involving p53 and other transcription factors that stimulate melanocyte proliferation and melanin synthesis.^[36] This response manifests as immediate pigment darkening followed by delayed tanning, with chronic exposure leading to cumulative effects like solar lentigines—discrete hyperpigmented macules predominantly on sun-exposed sites such as the face, dorsal hands, and forearms, corroborated by histopathological evidence of melanocyte hyperplasia and elongated rete ridges in affected areas.^[37] Experimental data from repetitive UV irradiation studies demonstrate up to a 75% reduction in erythema sensitivity alongside increased pigmentation and epidermal thickening, underscoring a dose-dependent adaptive yet pathological process.^[37] Trauma and inflammation from cutaneous injuries, including acne vulgaris eruptions, mechanical abrasions, or dermatologic procedures like laser therapy, precipitate post-inflammatory hyperpigmentation (PIH) via release of proinflammatory mediators such as prostaglandins (e.g., PGE2), leukotrienes, and cytokines (e.g., IL-1, TNF-α), which enhance melanocyte tyrosinase activity and melanosome transfer to keratinocytes.^[4] ^[38] In acne, even subclinical inflammation correlates with PIH development, with lesion resolution yielding macular hyperpigmentation that persists for months to years, particularly in Fitzpatrick skin types III–VI, as evidenced by clinical grading scales showing higher severity post-inflammatory flares.^[39] This pathway highlights inflammation's causal role independent of initial injury depth, with histological confirmation of increased epidermal melanin without significant melanocyte numbers in early PIH.^[4] Chemical exposures, though less common, include contact with phenolic compounds in certain cosmetics, adhesives, or industrial settings, which can trigger localized hyperpigmentation through irritant or allergic dermatitis leading to secondary inflammatory melanosis, or direct effects on melanogenesis.^[40] Documented cases involve substituted phenols inducing melanocyte stimulation via oxidative stress or haptenization, with occupational reports linking prolonged contact to flagellate-like or diffuse patterns, albeit rare compared to hypopigmentation from similar agents.^[41] Empirical evidence remains limited to case series, emphasizing exposure-response correlations in susceptible individuals rather than universal causality.^[40]

Hormonal and Genetic Factors

Hormonal influences on hyperpigmentation primarily manifest through sex steroids that modulate melanocyte function and melanin synthesis. In melasma, a common facial hyperpigmentation disorder, elevated serum progesterone levels have been observed in affected patients, with one study reporting a statistically significant increase (p=0.001) relative to controls.^[42] Similarly, raised estradiol concentrations correlate with melasma development in females, acting via estrogen receptors to enhance pro-pigmentary signaling in melanocytes and keratinocytes.^[43] ^[44] These surges, often linked to physiological states like pregnancy or exogenous hormone exposure, stimulate tyrosinase activity and melanosome transfer, though direct causation remains modulated by individual susceptibility.^[45] Genetic predispositions underpin familial patterns and variability in hyperpigmentation susceptibility. Polymorphisms in the TYR gene, encoding tyrosinase—the enzyme catalyzing the initial steps of melanin production—are associated with altered pigmentation phenotypes, including increased risk and severity of melasma.^[46] ^[47] Other loci, such as SLC45A2 and HERC2, interact epistatically to influence melanin levels and spot formation. Twin studies reveal high heritability for skin pigmentation traits, with estimates nearing 100% in some populations, indicating dominant genetic control over baseline tone and response to stimuli, though environmental interactions complicate expression.^[48] Familial clustering in disorders like melasma further supports polygenic inheritance, where rare variants amplify risk in pedigrees.^[49] Age-related hyperpigmentation, such as solar lentigines, arises partly from diminished melanosome degradation in keratinocytes, driven by declining autophagic efficiency. With advancing age, lysosomal processing falters, leading to melanin accumulation and visible spots on sun-exposed areas.^[29] This mechanism reflects genetically programmed senescence in melanocytes and keratinocytes, where reduced turnover exacerbates pigment retention independently of ongoing UV exposure.^[50] Hormonal shifts in menopause, including estrogen decline, may indirectly contribute by altering receptor-mediated degradation pathways.^[51]

Medical and Iatrogenic Causes

Primary adrenal insufficiency, or Addison's disease, represents a key endocrine cause of hyperpigmentation, where cortisol deficiency elevates adrenocorticotropic hormone (ACTH) levels via disrupted hypothalamic-pituitary-adrenal feedback; ACTH, derived from pro-opiomelanocortin (POMC), shares structural homology with melanocyte-stimulating hormone (MSH), thereby stimulating melanocyte tyrosinase and causing diffuse brownish hyperpigmentation of sun-exposed skin, creases, and mucous membranes in up to 90% of cases.^[52] ^[53] Other endocrine conditions, such as Nelson's syndrome following bilateral adrenalectomy for Cushing's disease, similarly produce ACTH-driven hyperpigmentation through MSH excess.^[54] Drug-induced hyperpigmentation arises from pharmacological agents that deposit pigmented metabolites or induce melanocyte hyperactivity via oxidative pathways. Minocycline, used long-term for acne or rheumatoid arthritis, leads to blue-gray dermal pigmentation in 2.4% to 41% of patients, primarily through chelation of iron by drug metabolites forming insoluble complexes in macrophages and collagen, as evidenced by electron microscopy in affected tissues.^[55] ^[56] Chemotherapeutic drugs like cyclophosphamide and busulfan cause linear or generalized hyperpigmentation, often via increased melanin synthesis or direct toxicity to basal cells, with case series documenting onset within months of initiation and resolution post-discontinuation in some instances.^[57] Systemic diseases involving metal overload, such as hereditary hemochromatosis, manifest with slate-gray or bronze hyperpigmentation from iron deposition in the dermis stimulating melanogenesis, corroborated by skin biopsies revealing hemosiderin-laden macrophages and elevated hepatic iron indices in affected patients.^[58] Iatrogenic hyperpigmentation occurs as a complication of dermatologic interventions, including ablative lasers (e.g., CO2) and medium-depth chemical peels (e.g., trichloroacetic acid), where thermal or chemical injury provokes post-inflammatory melanocyte activation; controlled studies report hyperpigmentation rates below 5% for superficial peels in Fitzpatrick skin types III-VI when pre-treated with hydroquinone, though risks escalate to 20-30% in deeper procedures without photoprotection.^[59]^[60]

Classification

Types Based on Depth and Distribution

Hyperpigmentation is categorized by the anatomical depth of melanin deposition, which influences histological appearance, diagnostic differentiation, and therapeutic responsiveness. Epidermal hyperpigmentation features melanin accumulation primarily within keratinocytes of the basal layer and stratum corneum, often resulting from increased melanogenesis or impaired desquamation.^[19] Dermal hyperpigmentation, conversely, involves melanin transferred to dermal macrophages (melanophages) or fibroblasts, typically following inflammation or incontinence of pigment from the epidermis.^[61] Mixed types exhibit melanin in both compartments, common in protracted conditions where initial epidermal overload progresses to deeper leakage.^[62] Diagnostic tools like Wood's lamp exploit ultraviolet light absorption differences: epidermal melanin accentuates sharply due to superficial location, appearing homogeneously darker, while dermal melanin shows minimal enhancement as it lies beyond the light's effective penetration.^[63] Histological confirmation via biopsy reveals epidermal types with hyperactive melanocytes and perikaryal melanin in keratinocytes, dermal types with perivascular melanophages lacking nuclear detail, and mixed patterns combining both.^[64] Empirical studies correlate epidermal depth with favorable outcomes from topical agents targeting tyrosinase inhibition, as melanin remains accessible to superficial penetration, whereas dermal forms resist topicals and necessitate deeper interventions like lasers, though with higher recurrence risks due to persistent macrophage-bound pigment.^[61] Distribution patterns further refine classification: focal hyperpigmentation manifests as discrete macules or patches, such as localized lentigines driven by clustered melanocytic hyperplasia, while diffuse forms involve broad melanosis from systemic factors altering global tyrosinase activity.^[1] Reticulated or blotchy distributions may indicate mixed depths, observable via dermoscopy showing uniform epidermal globules or hazy dermal veils.^[65] Chronic cases often evolve to mixed distributions, with histology demonstrating progressive melanin incontinence into papillary dermis, supported by confocal microscopy data quantifying pigment depth gradients.^[66]

Specific Clinical Variants

Melasma represents a distinct subtype of facial hyperpigmentation characterized by irregular brown or gray-brown macules, predominantly in a centrofacial distribution affecting the forehead, cheeks, upper lip, nose, and chin; it exhibits a strong hormonal etiology, with estrogen and progesterone implicated via increased prevalence during pregnancy (up to 70% of cases) and use of oral contraceptives. Approximately 90% of affected individuals are women of reproductive age, particularly those with Fitzpatrick skin types III-V, and genetic predisposition is evident in up to 33% with family history. Longitudinal observations indicate recurrence rates exceeding 50% within one year post-treatment if hormonal triggers persist, underscoring its chronic, relapsing nature tied to sustained melanocyte stimulation.^[67]^[68]^[69] Post-inflammatory hyperpigmentation (PIH) emerges as a reactive macular darkening at sites of prior dermal inflammation or trauma, such as acne vulgaris, eczematous eruptions, or procedural injuries, driven by transient upregulation of melanogenesis in keratinocytes and melanocytes. It predominates in darker skin phototypes (Fitzpatrick IV-VI), where lesions are more pronounced and persistent, lasting 6-12 months or longer compared to lighter skins; in acne-prone individuals, PIH affects up to 65% of darker-skinned patients post-lesion resolution. Unlike other variants, PIH lacks a primary epidermal proliferation but reflects exaggerated repair responses, with resolution often spontaneous yet prone to exacerbation by secondary irritation.^[19]^[70]^[71] Solar lentigines, or actinic lentigines, manifest as multiple discrete, sharply demarcated brown macules on chronically sun-exposed surfaces like the dorsum of hands, forearms, face, and shoulders, arising from cumulative ultraviolet-induced melanocyte hypertrophy and rete ridge elongation. They typically onset after age 50, with prevalence reaching 90% in fair-skinned Caucasians by that decade, directly correlating with lifetime UV dose rather than acute burns. Recurrence is near-universal upon re-exposure without photoprotection, as evidenced by repigmentation in 20-50% of treated sites within 1-2 years in sun-continuing cohorts.^[72]^[73]^[74] Acanthosis nigricans presents with symmetric, velvety hyperpigmented plaques in intertriginous areas including the neck, axillae, and inguinal folds, causally linked to hyperinsulinemia in insulin-resistant states like type 2 diabetes or obesity (prevalence up to 74% in obese youth), or paraneoplastically in 20-30% of malignancy-associated cases, particularly gastrointestinal adenocarcinomas. The hyperpigmentation stems from epidermal hyperplasia and dermal melanin deposition, distinguishing it from purely melanotic variants; familial forms exhibit autosomal dominant inheritance with onset in childhood, independent of metabolic factors.^[75]^[76]^[77] Periorbital hyperpigmentation, often termed allergic shiners, features bilateral bluish-gray shadowing beneath the eyes due to venous stasis and periorbital edema from chronic allergic rhinitis or sinusitis, with pigment intensification from repeated rubbing-induced melanosis. It affects up to 20% of atopic individuals, more prominently in children and those with perennial allergies, and contrasts with other facial variants by its vascular and inflammatory underpinnings rather than primary UV or hormonal drivers.^[78]^[79]^[80]

Clinical Presentation

Symptoms and Signs

Hyperpigmentation presents as localized or diffuse areas of skin darkening due to excess melanin deposition, typically manifesting as flat, well-defined brown, black, or grayish macules less than 1 cm in diameter or larger patches exceeding 1 cm.^[81]^[82] These lesions are generally asymptomatic, lacking associated pain, tenderness, or pruritus unless linked to concurrent inflammatory processes.^[83]^[84] The coloration varies by depth of melanin accumulation: epidermal hyperpigmentation appears light to dark brown, while dermal involvement often yields a blue-gray hue attributable to the Tyndall effect, where deeper pigments scatter shorter light wavelengths.^[85] Lesions may exhibit sharp or irregular borders, with the latter more common in postinflammatory variants following prior skin trauma or eruption.^[5] Distribution frequently favors sun-exposed sites such as the face, neck, dorsal hands, and forearms, though patterns can extend to flexural or truncal areas depending on the underlying mechanism.^[86]^[87] Clinically, hyperpigmentation evolves from acute onset in reactive forms, resolving over months if the trigger subsides, to chronic persistence in cases like solar lentigines, where patches remain stable without spontaneous regression.^[5] Atypical features, including asymmetry, irregular borders, color variegation, or rapid growth exceeding 6 mm, warrant heightened scrutiny for potential malignant transformation, as observed in entities like lentigo maligna.^[3] No textural changes such as scaling, induration, or velvety thickening are inherent to uncomplicated hyperpigmentation, distinguishing it from associated conditions.^[1]

Differential Diagnosis

Hyperpigmentation must be differentiated from conditions presenting with similar macular or patchy darkening to rule out malignancy, iatrogenic effects, or systemic disorders. Key mimics include melanocytic lesions evaluated using the ABCDE criteria—asymmetry, irregular borders, color variation, diameter greater than 6 mm, and evolving changes—which raise suspicion for melanoma, particularly in asymmetrically enlarging pigmented spots on sun-exposed areas.^[5] Clinical history of rapid change or personal/family history of melanoma further distinguishes these from benign hyperpigmentation.^[88] Acanthosis nigricans features velvety, hyperkeratotic plaques typically in flexural areas like axillae and neck, often linked to insulin resistance or endocrine disorders, contrasting with the smoother texture of most hyperpigmentations; its familial form presents similarly but without systemic associations.^[89] Drug-induced pigmentation, from agents such as minocycline or amiodarone, manifests as slate-gray or blue-black discoloration in sun-exposed sites, identified through medication history and resolution upon discontinuation.^[89] Exogenous ochronosis, a rare iatrogenic mimic arising from prolonged hydroquinone use, appears as blue-black hyperpigmented papules on the face with collagen degeneration, differentiated by patient-reported topical bleaching agent exposure and absence of melanin overproduction.^[90] Postinflammatory changes from resolved acne or trauma may simulate reactive hyperpigmentation but follow known inflammatory events, while solar lentigines present as discrete, UV-induced macules on chronically exposed skin, lacking the diffuse or patterned distribution of melasma-like hyperpigmentation.^[91] Vitiligo edges can show perilesional hyperpigmentation, but the central depigmentation and autoimmune context aid distinction.^[91]

Diagnosis

Clinical Evaluation

Clinical evaluation of hyperpigmentation begins with a detailed patient history to identify potential etiologies and risk factors. Key elements include the onset of pigmentation changes, which may be acute following trauma or inflammation or gradual with chronic sun exposure; precipitating triggers such as ultraviolet radiation, hormonal fluctuations (e.g., pregnancy or oral contraceptives), medications, or inflammatory skin conditions; and family history, which is particularly relevant for melasma where up to 60% of cases report a genetic predisposition.^[92]^[93] Assessment of sun exposure habits and personal history of skin trauma or diseases aids in distinguishing exogenous from endogenous causes.^[8] Physical examination emphasizes empirical observation of lesion characteristics, including distribution (e.g., sun-exposed areas versus generalized), color (brown for epidermal versus blue-gray for dermal involvement due to the Tyndall effect), and borders. Fitzpatrick skin phototyping is employed to stratify risk, as types IV-VI exhibit greater propensity for postinflammatory hyperpigmentation due to enhanced melanocyte activity and poorer barrier function following UV insult.^[8]^[85] Ultraviolet photography reveals subclinical pigmentation by highlighting melanin absorption, which attenuates UV light and unmasks mottled patterns not visible under standard illumination, facilitating extent assessment beyond overt lesions.^[94] For specific variants like melasma, standardized scoring such as the Melasma Area and Severity Index (MASI) quantifies involvement across facial regions by integrating area affected, darkness, and homogeneity, yielding scores from 0 to 48 to gauge baseline severity and guide monitoring.^[95] This index, though primarily validated for melasma, supports objective evaluation in hyperpigmentation protocols by correlating clinical features with measurable outcomes.^[96]

Diagnostic Tools and Tests

Dermoscopy, also known as dermatoscopy, provides magnified visualization of subsurface skin structures, aiding in the assessment of pigment networks and patterns in hyperpigmentation disorders, particularly useful in distinguishing epidermal from dermal involvement and evaluating post-inflammatory changes in darker skin types.^[97] It reveals features such as perifollicular repigmentation or edge reservoirs in conditions like melasma, correlating pigmentation observed with melanin location in keratinocytes or melanocytes, though its utility is limited for deeply dermal or nodular lesions where subsurface details are obscured.^[98]^[99] Wood's lamp examination employs long-wave ultraviolet light (approximately 365 nm) to evaluate melanin depth, with epidermal hyperpigmentation typically appearing accentuated or dark due to UV absorption, while dermal pigmentation may show less contrast or subtle fluorescence, facilitating classification in disorders like melasma.^[100]^[101] This tool delineates lesion borders more clearly in pigmented skin but has limitations in accuracy for precise depth determination, as histopathological studies indicate inconsistencies between Wood's lamp findings and actual pigment localization.^[102]^[103] Skin biopsy is infrequently required for uncomplicated hyperpigmentation but is indicated when malignancy such as melanoma must be excluded, particularly in lesions exhibiting rapid growth, asymmetry, irregular borders, color variation, or symptoms like itching or bleeding; punch or excisional biopsy provides histological confirmation as the gold standard, revealing melanocyte distribution, nesting, or atypia absent in benign hyperpigmentation.^[8]^[104] Laboratory investigations target underlying systemic causes, such as endocrine disorders; for suspected adrenal insufficiency (e.g., Addison's disease), serum cortisol, adrenocorticotropic hormone (ACTH), and electrolytes are assessed, as elevated ACTH drives melanocyte stimulation leading to diffuse hyperpigmentation, while thyroid function tests (TSH, free T4) evaluate hyperthyroidism-associated changes, and hormone panels including melanocyte-stimulating hormone proxies may be considered in refractory cases.^[105]^[106]^[107] These tests lack specificity for hyperpigmentation alone and should correlate with clinical suspicion to avoid overinvestigation.^[108]

Management

Prevention Strategies

Daily application of broad-spectrum sunscreen with SPF 50 or higher is a cornerstone of hyperpigmentation prevention, as ultraviolet radiation is a primary trigger for melanin overproduction. Clinical studies demonstrate that consistent sunscreen use can achieve 98% to 100% success in preventing post-inflammatory hyperpigmentation in patients with skin of color when applied for two months post-injury or procedure.^[109] Tinted sunscreens offer superior protection against visible light-induced pigmentation compared to non-tinted formulations, reducing relapse rates in conditions like melasma.^[110] ^[111] Complementary physical barriers enhance efficacy by minimizing UV exposure. Wearing wide-brimmed hats, long-sleeved clothing, and seeking shade during peak ultraviolet hours (10 a.m. to 4 p.m.) reduces cumulative solar damage that exacerbates hyperpigmentation.^[112] Antioxidant-rich topicals, such as niacinamide, inhibit melanosome transfer and mitigate pigmentation progression when applied daily, supported by randomized trials showing reduced hyperpigmentation scores.^[113] Oral antioxidants like vitamin C may offer adjunctive photoprotection by countering oxidative stress from UV exposure, though evidence is stronger for topical formulations in preventing melanin synthesis.^[114] Post-procedural sun avoidance protocols are critical to avert iatrogenic hyperpigmentation following laser or chemical treatments. Strict avoidance of direct sunlight for at least two weeks, combined with rigorous sunscreen adherence, minimizes post-inflammatory hyperpigmentation risk, which typically emerges 7-14 days after intervention and can persist for six weeks.^[115] ^[116] Patients should prioritize indoor recovery or fully covered outdoor exposure during this period to preserve treatment outcomes.^[117]

Topical Treatments

Hydroquinone, applied topically at 2-4% concentrations, serves as the benchmark agent for treating hyperpigmentation by competitively inhibiting tyrosinase, the rate-limiting enzyme in melanogenesis, with randomized controlled trials (RCTs) reporting substantial reductions in pigmentation scores, often exceeding 50% improvement after 8-12 weeks of use.^[118]^[119] Higher concentrations yield greater efficacy but increase risks, including exogenous ochronosis—a paradoxical bluish-black discoloration from prolonged application, observed primarily after months to years of unsupervised use in higher doses or on extensive areas.^[90]^[120] Topical retinoids, notably tretinoin at 0.1%, promote epidermal turnover and melanosome dispersion, demonstrating in RCTs a significant lightening of solar lentigines and other hyperpigmented lesions, with histological evidence of reduced melanin content after 10-24 weeks.^[121]^[122] Azelaic acid, typically at 20%, exerts antimelanogenic effects via tyrosinase inhibition and selective cytotoxicity to abnormal melanocytes, with RCTs affirming its efficacy for post-inflammatory hyperpigmentation and melasma, achieving comparable lesion clearance to 4% hydroquinone in darker skin phototypes while exhibiting lower irritation potential.^[123]^[124] Combination formulations, such as the triple cream integrating 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide, synergistically target multiple pathways—melanin inhibition, keratolysis, and inflammation reduction—yielding superior outcomes in melasma RCTs, with Melasma Area and Severity Index reductions of 60-80% by week 8, though steroid-related atrophy limits duration to short courses.^[125]^[126] Kojic acid and ascorbic acid (vitamin C) derivatives function as tyrosinase chelators, with in vitro and small clinical studies supporting modest pigmentation fading, but RCTs indicate inferior efficacy to hydroquinone monotherapy, particularly for stubborn lesions, due to instability and variable penetration.^[127]^[128] Common adverse effects across these agents include erythema, desquamation, and stinging, disproportionately affecting sensitive or inflamed skin and often necessitating dose adjustments or adjunctive moisturizers; long-term safety data underscore hydroquinone's reversible irritancy versus rarer ochronotic risks.^[129]^[130]

Systemic Therapies

Oral tranexamic acid, an antifibrinolytic agent that inhibits plasminogen activation and thereby reduces vascular endothelial growth factor-mediated melanogenesis, is employed for refractory melasma, a common form of facial hyperpigmentation. Doses typically range from 250 mg twice daily, administered for 8-12 weeks, with clinical trials demonstrating response rates of approximately 50% in improving Melasma Area and Severity Index scores compared to controls. A 2025 randomized controlled trial involving 50 patients confirmed superior efficacy of oral tranexamic acid over topical formulations, with significant lightening observed in treated groups alongside minimal adverse events such as mild gastrointestinal discomfort. Meta-analyses up to 2024 affirm its safety profile, though monitoring for rare risks like thromboembolism is advised, particularly in patients with predisposing factors.^[131]^[132]^[133] Oral antioxidants, such as extracts from Polypodium leucotomos, serve as adjunctive therapies by providing photoprotection against ultraviolet and visible light-induced pigmentation through antioxidant and anti-inflammatory mechanisms. A double-blind, placebo-controlled trial in Asian patients with melasma showed that 240-480 mg daily doses, combined with topical hydroquinone and sunscreen, yielded significant reductions in pigmentation versus placebo alone. However, these agents are not first-line due to limited standalone efficacy and potential gastrointestinal side effects like nausea in up to 10% of users; their role remains supportive in refractory cases exacerbated by photoexposure.^[134]^[135] Hormonal modulators are reserved for hyperpigmentation linked to identifiable endocrine disorders, such as polycystic ovary syndrome or thyroid dysfunction, where addressing the underlying hormonal imbalance—via agents like oral contraceptives or anti-androgens—may indirectly alleviate pigmentation. For instance, in melasma associated with oligomenorrhea, systemic anti-estrogenic therapies have improved symptoms by modulating estrogen-driven melanogenesis, though evidence is anecdotal and not broadly applicable without confirmed endocrine etiology. Routine hormonal intervention lacks robust support for idiopathic hyperpigmentation and requires endocrinologic evaluation to avoid unwarranted risks.^[136]^[137]

Procedural and Device-Based Treatments

Chemical peels utilizing glycolic acid (GA) or trichloroacetic acid (TCA) represent a common procedural approach for hyperpigmentation, particularly melasma and post-inflammatory variants, by inducing controlled epidermal injury to promote turnover and pigment reduction. A randomized trial comparing 15% TCA peels to 35% GA peels in melasma patients demonstrated superior efficacy for TCA, with greater lesion lightening after three sessions, though both yielded moderate improvements without significant differences in side effects like erythema.^[138] Sequential protocols combining high-concentration GA (e.g., 70%) followed by TCA (e.g., 15-20%) have shown effective reduction in melasma severity scores, with clinical improvements of approximately 20-30% in pigmentation indices across multiple sessions, supported by histopathological evidence of decreased melanin.^[139]^[140] TCA peels are notably safe in Fitzpatrick skin types III-IV, augmenting pigment clearance when combined with topicals, though risks include transient irritation and potential rebound hyperpigmentation if sessions are inadequately spaced.^[141] Device-based laser therapies target hyperpigmentation via selective photothermolysis, with intense pulsed light (IPL) suited for superficial epidermal lesions like solar lentigines by coagulating melanin-laden keratinocytes. Clinical studies confirm IPL's efficacy in reducing pigmentation by 50-75% in lighter skin types after 3-5 sessions, with visible darkening as an endpoint indicating treatment response.^[142]^[143] However, in darker skin (Fitzpatrick IV-VI), IPL elevates risks of post-inflammatory hyperpigmentation (PIH) rebound due to non-selective heating of surrounding melanocytes, occurring in up to 20% of cases per trial data, necessitating lower fluences and pre-treatment priming.^[144] Q-switched Nd:YAG lasers, operating at 1064 nm, penetrate deeper for dermal hyperpigmentation such as nevus of Ota, fragmenting melanosomes for macrophage clearance and yielding 40-60% improvement in dermal melanin density per comparative trials against peels.^[145] Microneedling, often paired with topical depigmenting agents like tranexamic acid, enhances transdermal delivery through microchannels, improving hyperpigmentation outcomes beyond monotherapy. A 2023 meta-analysis of randomized trials for melasma reported significant reductions in modified Melasma Area and Severity Index (mMASI) scores with microneedling combinations, achieving 30-50% greater efficacy than topicals alone, with high patient satisfaction and minimal downtime.^[146] Adverse events were limited to mild erythema resolving within 48 hours, positioning it as a low-risk adjunct for recalcitrant cases, though optimal needle depths (0.5-1.5 mm) vary by skin type to avoid excessive trauma-induced PIH.^[147] Comparative data from network meta-analyses favor microneedling over standalone peels for sustained results in combination regimens, emphasizing its role in procedural algorithms.^[148]

Emerging and Experimental Approaches

Topical cysteamine, a cysteine derivative acting as a tyrosinase inhibitor, has emerged as a promising agent for hyperpigmentation disorders including melasma and post-inflammatory hyperpigmentation, with stabilized formulations demonstrating efficacy in randomized controlled trials conducted since 2023.^[149] In a 2024 randomized trial, 5% cysteamine cream achieved comparable reductions in melasma severity scores to 4% hydroquinone combined with ascorbic acid after four months of use, with improved tolerability and fewer reports of irritation.^[150] Case series from 2025 further indicate visible improvements in skin luminosity and evenness when combined with isobionicamide, though long-term data beyond 16 weeks remains preliminary, and phase III-scale trials are ongoing to confirm sustained depigmentation without rebound effects.^[151] Advancements in picosecond-domain lasers, delivering ultra-short pulses to shatter melanin granules with minimal thermal damage, represent an experimental refinement over nanosecond lasers, potentially reducing post-treatment downtime and risks like erythema in diverse skin types.^[152] A 2025 retrospective analysis of 730-nm picosecond titanium-sapphire laser treatments reported an 88% efficacy rate for acquired dermal melanocytosis, surpassing 1064-nm alternatives in patient satisfaction and pigmentation clearance after multiple sessions spaced 4-6 weeks apart.^[153] Fractional picosecond protocols, explored in 2024-2025 studies, target dermal hyperpigmentation with reduced side effects compared to ablative methods, but randomized comparisons against topical benchmarks are limited, underscoring the need for controlled trials to validate claims of superior precision.^[154] Hypotheses linking skin microbiome dysbiosis to hyperpigmentation persistence have spurred early investigations into modulation via prebiotics or probiotics, positing that microbial metabolites influence melanocyte activity and inflammation.^[155] A 2025 clinical study of 38 women with facial hyperpigmentation identified microbiome signatures correlating with dark spot severity, suggesting targeted interventions could enhance treatment outcomes, yet human trials remain exploratory with no peer-reviewed evidence of clinical efficacy as of October 2025.^[155] Gene therapy approaches, confined to preclinical models, aim to edit genes regulating tyrosinase or melanin synthesis pathways, but lack translational data for hyperpigmentation, with ethical and delivery challenges tempering optimism for near-term application.^[156]

Prognosis and Complications

Long-Term Outcomes

Long-term outcomes for hyperpigmentation depend on the underlying type, treatment modality, and maintenance strategies, with recurrence rates varying widely across studies. In post-inflammatory hyperpigmentation (PIH), superficial epidermal lesions often achieve higher resolution rates than deeper dermal variants, as melanin deposition in the epidermis responds more readily to topical agents and superficial lasers, whereas dermal pigmentation persists longer due to its location in the dermis, which limits treatment penetration and efficacy.^[2]^[157] Follow-up data indicate that without ongoing maintenance, recurrence occurs in 40-50% of cases treated with intense pulsed light (IPL) within 6-12 months, attributed to re-exposure to triggers like inflammation or UV radiation.^[158] Melasma, a common form of acquired hyperpigmentation, demonstrates particularly chronic behavior, with high relapse rates even after initial improvement, often necessitating indefinite management. Clinical trials report recurrence in most patients discontinuing oral tranexamic acid within 6 weeks, compared to lower rates with sustained topical triple combinations like hydroquinone, tretinoin, and steroids.^[159] Long-term studies highlight melasma's resistance, with relapse common post-treatment due to persistent melanocyte hyperactivity and vascular factors, underscoring the need for lifelong photoprotection and therapy adjustments.^[160]^[161] Adherence to rigorous sun protection emerges as a critical factor influencing sustained clearance across hyperpigmentation subtypes. Consistent broad-spectrum sunscreen use (SPF >30) has been linked to reduced relapse by mitigating UV-induced melanogenesis, with observational data showing better pigmentation stability in compliant patients over months of follow-up.^[115] In contrast, non-adherence correlates with rapid repigmentation, as intermittent UV exposure reactivates dormant melanocytes, emphasizing photoprotection's causal role in long-term prognosis.^[162]

Associated Risks and Side Effects

Hyperpigmentation, particularly when visible on the face or other exposed areas, can lead to psychological distress, including reduced self-esteem and social withdrawal, as reported in patient surveys where 43% anticipated significant improvements in self-esteem following successful treatment.^[163] However, empirical quality-of-life studies indicate a relatively mild overall impact compared to conditions like vitiligo, with Dermatology Life Quality Index scores showing moderate impairment primarily in patients with postinflammatory hyperpigmentation alongside acne, though not severe enough to dominate daily functioning in most cases.^[164]^[165] For postinflammatory hyperpigmentation (PIH), untreated epidermal cases often resolve within months, but dermal or scarred variants can persist for years or become permanent in a subset of patients, especially in darker skin types where melanin deposition is deeper and slower to fade.^[4]^[166] While certain hyperpigmentation patterns, such as acanthosis nigricans, may rarely signal underlying internal malignancies as paraneoplastic phenomena, the overall endogenous link to cancer risk remains negligible for most acquired hyperpigmentations, which are typically benign and driven by inflammation, hormones, or sun exposure rather than oncologic processes.^[167]^[168] Treatment-associated risks include hypopigmentation from laser therapies, occurring in approximately 10% of Asian patients undergoing laser toning for melasma or PIH, with incidence varying from 0% to 16.8% depending on fluence and sessions; this risk is higher in darker phototypes due to melanocyte disruption.^[169]^[170] Topical agents like hydroquinone carry risks of irritant dermatitis, redness, and rare exogenous ochronosis with prolonged use exceeding recommended durations.^[118] Systemic therapies, such as oral tranexamic acid for refractory melasma, may induce gastrointestinal upset or transient hypopigmentation but lack widespread severe adverse events in dermatologic dosing.^[6] Procedural interventions also heighten postinflammatory hyperpigmentation rebound in 5-62% of cases without adjunctive cooling, underscoring the need for phototype-adjusted protocols.^[171]

Controversies

Safety of Lightening Agents

Hydroquinone, a common skin lightening agent, faces regulatory restrictions due to potential risks including carcinogenicity and ochronosis. The U.S. Food and Drug Administration (FDA) has banned over-the-counter (OTC) sales of hydroquinone-containing products following animal studies indicating carcinogenic effects, though human data remain equivocal and the International Agency for Research on Cancer classifies it as Group 3 (not classifiable as to its carcinogenicity to humans).^[172] It is similarly prohibited for cosmetic use in the European Union, Australia, and Japan owing to an uncertain long-term safety profile.^[173] Exogenous ochronosis, characterized by paradoxical skin darkening and bluish-black discoloration, emerges as a rare but disfiguring complication from prolonged hydroquinone application, typically after years of use at concentrations of 2% or higher, though cases occur with lower potencies.^[174]^[175] Incidence is higher among individuals with darker skin types and correlates with extended exposure averaging 9 years, affecting areas like cheeks and forehead; while exact prevalence is low (estimated under 2% in susceptible long-term users), it underscores risks of unsupervised, chronic cosmetic application beyond medical oversight for conditions like melasma.^[174]^[176] Unregulated skin lightening products, often imported and containing mercury, pose acute systemic toxicities including nephrotoxicity. Case reports document nephrotic syndrome, frequently minimal change disease, following 2–9 months of topical mercury exposure via such creams, with elevated blood and urinary mercury levels confirming causation; renal biopsies reveal podocyte injury leading to proteinuria and potential progression to renal failure if exposure persists.^[177]^[178]^[179] These products evade U.S. bans on OTC mercury, highlighting dangers of non-medical, cosmetic overuse where lightening intent deviates from targeted hyperpigmentation treatment. Safer alternatives, such as certain tyrosinase inhibitors, exhibit lower toxicity profiles but require comparative risk assessment in clinical contexts.^[180]

Socio-Cultural Dimensions

In regions with prevalent colorism—preferential treatment of lighter skin tones within ethnic groups—demand for hyperpigmentation treatments often stems from desires for even skin uniformity rather than drastic lightening, influenced by media portrayals of idealized complexions. Surveys indicate high usage rates; for instance, 52% of dermatology patients in East African clinics reported employing skin lightening products, frequently to address uneven pigmentation amid cultural preferences for homogeneity. Similarly, among South Asian Americans, colorism attitudes correlate with product adoption, with users perceiving stronger societal biases toward lighter tones. In Asia and Africa, prevalence among women ranges from 30% to over 70% in urban areas, driven by advertising equating uniform skin with success and attractiveness, though empirical data emphasize corrective intent for conditions like post-inflammatory hyperpigmentation over wholesale bleaching.^[181]^[182]^[183] Media amplification exacerbates these dynamics, as digital platforms and advertisements perpetuate colorism by featuring predominantly lighter-skinned models, fostering internalized preferences that boost market demand. A systematic review links such exposure to heightened cosmetic whitening interest globally, particularly in non-Western contexts where historical colonial legacies and modern globalization reinforce shade-based hierarchies. However, this demand empowers individuals with genuine hyperpigmentation from acne scarring or sun damage, enabling restored baseline pigmentation and enhanced self-confidence, independent of broader societal ideals.^[184]^[185]^[186] Critics highlight exploitation in unregulated markets, where vendors prioritize profit over safety, leading to widespread use of adulterated products containing undeclared mercury or corticosteroids, which cause exogenous ochronosis and nephrotoxicity. U.S. FDA actions underscore risks, including 2022 warnings against unapproved distributors of bleaching agents like hydroquinone formulations, and ongoing alerts on OTC imports evading bans on toxic ingredients. In developing regions, lax oversight results in higher morbidity, with case reports of mercury poisoning from smuggled creams; yet, legitimate interventions for pathological unevenness remain distinct from pressure-driven misuse, warranting targeted education over blanket condemnation.^[187]^[172]^[188]

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Jan 1, 2016 · 14,15 Periorbital hyperpigmentation can be caused by rubbing and scratching of skin around the eyes and by accumulation of fluid due to allergy ...
[80]
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May 4, 2017 · Allergic shiners are dark circles under the eyes caused by congestion of the nose and sinuses. They're usually described as dark, shadowy pigments that ...
[81]
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Nov 26, 2019 · A macule is a flat, distinct, discolored area of skin less than 1 centimeter (cm) wide. It doesn't involve any change in the thickness or texture of the skin.
[82]
Hyperpigmentation: What it is, Causes, & Treatment - Cleveland Clinic
Hormone changes, such as during puberty or pregnancy. Injury to the skin (for example, acne, cuts or burns), which is sometimes called postinflammatory ...Melasma · Azelaic Acid Cream · Tretinoin LotionMissing: empirical evidence
[83]
Idiopathic eruptive macular hyperpigmentation - DermNet
Idiopathic eruptive macular hyperpigmentation is characterised by multiple discrete asymptomatic brown-grey-black small macules or larger patches. Pigmentation ...
[84]
Hyperpigmentation - of the face and neck
Feb 15, 2023 · Group 2: Postinflammatory hyperpigmentation (PIH). PIH refers ... Acanthosis nigricans (AN). Characterised by darkening, thickening and ...
[85]
Disorders of hyperpigmentation. Part I. Pathogenesis and clinical ...
Key points · Epidermal hyperpigmentation appears light to dark brown, whereas dermal hyperpigmentation may have a blue-gray coloration due to the Tyndall effect.
[86]
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Jul 17, 2024 · Hyperpigmentation can look like freckles, spots, blotches, and patches, and often appears on sun-exposed areas of skin like the face, neck, and ...Missing: clinical | Show results with:clinical<|separator|>
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d) Hyperpigmentation is probably caused by increased melanogenesis and abnormal distribution of melanin, due to the action of inflammatory mediators.
[88]
Differential diagnosis of heavily pigmented melanocytic lesions
The differential diagnosis of heavily pigmented melanocytic neoplasms includes melanoma (especially animal type), melanosis of partially or completely ...
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Postinflammatory Hyperpigmentation Differential Diagnoses
Jun 13, 2023 · Differential Diagnoses · Acanthosis Nigricans · Achalasia · Achlorhydria · Dermatologic Aspects of Addison Disease · Ephelides · Erythema Dyschromicum ...<|separator|>
[90]
Exogenous Ochronosis - PMC - NIH
Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin- ...
[91]
Differential diagnosis of melasma and hyperpigmentation - Honigman
Aug 3, 2022 · Epidermal melasma tends to accentuate under Wood's lamp examination, which may help distinguish epidermal and dermal subtypes. In epidermal ...
[92]
Melasma - RACGP
The global prevalence of melasma is approximately 1%, although higher prevalence rates have been reported in people with darker Fitzpatrick skin types (III ...
[93]
Hyperpigmentation in a middle aged woman: a common yet ... - NIH
Jul 6, 2016 · Melasma affects approximately 5 million people in the United States (1) with a prevalence rate up to 40% in certain populations (2).
[94]
Sun damage in ultraviolet photographs correlates with phenotypic ...
UV photographs are an excellent means to display sun damage in the form of mottled pigmentation because UV light is attenuated by melanin. Recently, a computer ...
[95]
The Melasma Area and Severity Index (MASI ... - ScienceDirect.com
The total score range is 0 to 48. The MASI is the most commonly used outcome measure for melasma trials but has never been validated. The purpose of this ...
[96]
Interpretability of the Modified Melasma Area and Severity Index
May 4, 2016 · The Melasma Area and Severity Index (MASI) is the most common outcome measure used for melasma studies, and was validated 20 years after it was first reported.
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Dermoscopy Overview and Extradiagnostic Applications - NCBI - NIH
Brown pigmented structures are often seen on dermoscopy of various disorders in ethnic skin due to the propensity of post-inflammatory hyperpigmentation, and ...Continuing Education Activity · Equipment · Complications · Clinical Significance
[98]
Utility of dermoscopy for evaluating the therapeutic efficacy of ...
Feb 28, 2018 · In the present study, dermoscopy revealed perifollicular repigmentation in several patients and early reservoirs of pigmentation on the edge of ...
[99]
Dermoscopy: Overview, Technical Procedures and Equipment, Color
Jan 25, 2023 · Dermoscopy is a noninvasive method that allows the in vivo evaluation of colors and microstructures of the epidermis, the dermoepidermal junction, and the ...Guide Criteria · Overview Of Different... · Pattern Analysis
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Localization of malanin pigmentation in the skin with Wood's lamp
A new observation reported here illustrates that Wood's light can be used to determine the depth of melanin pigmentation in the skin.
[101]
Localization of melanin pigmentation in the skin with Wood's lamp
A new observation reported here illustrates that Wood's light can be used to determine the depth of melanin pigmentation in the skin: contrast in epidermal ...
[102]
Diagnosis of Melasma in Brown Skin: Wood's Lamp, Dermoscopy ...
Aug 20, 2017 · It is the most widely used method of melasma classification by highlighting the difference in pigmentation of the affected skin into four subtypes.
[103]
Wood lamp skin examination - DermNet
Aug 8, 2014 · Pigmented lesions have a clear border under Wood light because the light is absorbed by increased melanin; Loss of pigmentation (eg, vitiligo) ...
[104]
Skin biopsy in the diagnosis of neoplastic skin disease - RACGP
In the setting of an atypical pigmented lesion, a biopsy is usually required to distinguish between a cutaneous melanoma and benign mimics, such as atypical ...Actinic Keratosis · Non-Melanoma Skin Cancer · Pigmented LesionsMissing: hyperpigmentation | Show results with:hyperpigmentation
[105]
Dermatologic manifestations of endocrine disorders - PMC
In these patients, the concurrent presence of Addison's disease and vitiligo may give patients a striking mixture of pigment loss and hyperpigmentation.
[106]
Hyperpigmentation as a clue to Addison disease
Sep 1, 2022 · However, hyperpigmentation, caused by excess binding of ACTH and alpha-melanocyte stimulating hormone to the melanocortin 1 receptor, is a ...Missing: underlying | Show results with:underlying
[107]
Addison Disease - Endocrine and Metabolic Disorders
Beta-lipotropin has melanocyte-stimulating activity and, together with ACTH, causes the hyperpigmentation of skin and mucous membranes characteristic of Addison ...
[108]
Common Hyperpigmentation Disorders in Adults - AAFP
Nov 15, 2003 · Diffuse hyperpigmentation may have a sys- temic cause, such as Addison's disease, hyper- thyroidism, or hemochromatosis. It also may occur ...
[109]
Sunscreen is the Best Way to Prevent Post-Inflammatory ...
Feb 24, 2025 · In two studies, a 98% and 100% success rate in preventing post-inflammatory hyperpigmentation occurred after applying sunscreen for 2 months.
[110]
Visible Light Protection: An Updated Review of Tinted Sunscreens
Jun 24, 2025 · Multiple studies have demonstrated the superior efficacy of tinted sunscreens in preventing VL-induced pigmentation, compared to non-tinted ...
[111]
Prevention of melasma relapses with sunscreen combining ... - JAAD
Oct 22, 2014 · Our aim was to evaluate the protective properties against melasma relapses of a sunscreen protecting against UVA/UVB and the shorter wavelengths ...
[112]
Sun-Protective Behaviors in Patients with Melasma - ScienceDirect
Sun exposure is considered the greatest triggering and exacerbating factor in melasma. Melasma is a significant problem for patients and is associated with a ...<|separator|>
[113]
Mechanistic Basis and Clinical Evidence for the Applications of ... - NIH
Aug 21, 2021 · Topical treatment of nicotinamide, alone or in combination with other active ingredients, reduces the progression of skin aging and hyperpigmentation in ...
[114]
Vitamin C and Skin Health | Linus Pauling Institute
Dietary and topical ascorbic acid have beneficial effects on skin cells, and some studies have shown that vitamin C may help prevent and treat ultraviolet (UV) ...
[115]
The Role of Sunscreen in Melasma and Postinflammatory ... - NIH
[16] This study found that UV-only sunscreen played a role in improving melasma, but combination treatment was more efficacious.
[116]
The Importance of Sun Protection After Aesthetic Treatments
Dec 13, 2024 · Avoid sun exposure for at least two weeks after the procedure. · Apply a broad-spectrum sunscreen daily. · Wear protective hats and clothing if ...
[117]
How We Minimize Skin Discoloration After Laser Treatments
Jun 13, 2023 · Sun protection following laser treatments is the number one way to reduce the risk of post-inflammatory hyperpigmentation.
[118]
Topical Hydroquinone for Hyperpigmentation: A Narrative Review
Nov 15, 2023 · Studies have demonstrated that hyperpigmentation conditions respond very well to 2% HQ, and while higher concentrations are effective, they may ...Missing: RCTs | Show results with:RCTs
[119]
A randomized, controlled, split-face, double-blind comparison of a ...
Our hydroquinone-free, multimodal pigment-correcting topical serum, was effective and well tolerated in treating facial hyperpigmentation, including melasma.
[120]
Exogenous ochronosis by hydroquinone is not caused by inhibition ...
Jul 15, 2025 · The findings suggest that tyrosinase helps form dark spots when people use hydroquinone. True tyrosinase blockers are safe for treating ...
[121]
Topical Tretinoin (Retinoic Acid) Therapy for Hyperpigmented ...
May 20, 1993 · We investigated the treatment of this hyperpigmentation with topical tretinoin (0.1 percent retinoic acid cream). Fifty-four subjects completed ...
[122]
Topical Tretinoin (Retinoic Acid) Treatment for Liver Spots ...
Feb 6, 1992 · Topical 0.1 percent tretinoin significantly improves both clinical and microscopical manifestations of liver spots.<|separator|>
[123]
Azelaic acid 20% cream in the treatment of facial hyperpigmentation ...
Azelaic acid is an effective and well-tolerated treatment for hyperpigmentation in darker-skinned patients.
[124]
A comparative study of 20% azelaic acid cream versus 5 ... - NIH
A comparative study of 20% azelaic acid cream versus 5% tranexamic acid solution for the treatment of postinflammatory hyperpigmentation in patients with acne ...
[125]
TRIPLE COMBINATION OF HYDROQUINONE, TRETINOIN ... - NIH
The results were noted after four peels, in the form of more than 50% improvement in pigmentation in five out of 10 patients. Two patients showed more than 75% ...
[126]
Evaluation of the safety and efficacy of a triple combination cream ...
The triple combination formula was reasonably safe and effective for treatment of melasma in Middle Eastern patients.
[127]
Evaluation of the Reduction of Skin Hyperpigmentation Changes ...
Apr 4, 2023 · The aim of this study was to demonstrate the effects of using a preparation containing kojic acid on skin hyperpigmentation using hyperspectral imaging.
[128]
Kojic acid applications in cosmetic and pharmaceutical preparations
Evidence suggest that most skin-lightening compounds reduce the synthesis of melanin by inhibiting tyrosinase enzyme activity with low toxicity on melanocytes.
[129]
What are the side effects of Hydroquinone? - Patsnap Synapse
Jul 12, 2024 · One of the most common side effects of hydroquinone is skin irritation. This can manifest as redness, dryness, and a mild burning sensation.
[130]
A case of exogenous ochronosis caused by a triple combination ...
While it is well known that this triple combination cream may cause more irritation than hydroquinone alone, the more serious side effect of exogenous ...
[131]
Randomized Clinical Trial on the Efficacy of Oral Tranexamic Acid ...
Sep 9, 2025 · In this single‐center randomized trial, 50 melasma patients received oral TXA (250 mg twice daily) or topical TXA (a 5% cream applied twice ...
[132]
Randomized Clinical Trial on the Efficacy of Oral Tranexamic Acid ...
Patients/methods: In this single-center randomized trial, 50 melasma patients received oral TXA (250 mg twice daily) or topical TXA (a 5% cream applied twice ...Missing: 2020-2025 | Show results with:2020-2025
[133]
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Jun 6, 2024 · This study aimed to evaluate the efficacy of tranexamic acid (TXA) in treating melasma through a meta-analysis and systematic review of randomized controlled ...
[134]
Double-blind, Placebo-controlled Trial to Evaluate the Effectiveness ...
The oral PLE aqueous extract product appears to be a safe and effective adjunctive treatment for melasma in combination with topical hydroquinone and sunscreen.
[135]
Polypodium Leucotomos: 21st Century Evidence for an Ancient ...
Jun 15, 2021 · Double-blind, placebo-controlled trial to evaluate the effectiveness of Polypodium leucotomos extract in the treatment of Melasma in Asian Skin: ...<|separator|>
[136]
The role of oligomenorrhea in melasma - ScienceDirect.com
The results of this study showed that if melasma is due to oligomenorrhea, the use of systemic anti-estrogenic therapies can improve melasma by reducing of ...<|control11|><|separator|>
[137]
[PDF] The Role of Endocrine in Melasma
Aug 3, 2018 · Melanogesis Thyroid hormone works on melanogenesis because thyroid hormones stimulate epidermal oxygen consumption in the process of oxidation ...
[138]
Efficacy of 15% trichloroacetic acid peel versus 35% glycolic ... - NIH
Conclusion: In our research, 15% TCA has a better efficacy when compared with 35% GA peel after three sessions of chemical peeling. We therefore recommend ...
[139]
The effects and safety of sequential high concentration glycolic acid ...
This study found that a sequential chemical peel protocol using glycolic acid and trichloroacetic acid was effective in reducing melasma severity without ...
[140]
Comparative study of trichloroacetic acid versus glycolic acid ...
This study was designed to compare the therapeutic response of melasma in Indian women to glycolic acid (GA 20-35%) versus trichloroacetic acid (TCA 10-20%) ...
[141]
Safety and Efficacy of Trichloroacetic Acid Peels in the Treatment of ...
In this study, we showed that TCA chemical peels not only augment the response to melasma treatment, but are also safe in skin types III and IV. Despite the ...
[142]
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Mar 1, 2024 · IPL is safe and effective in treating benign pigmented and vascular disorders as well as performing hair removal and reducing signs of photoaging.
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Apr 8, 2024 · The results of the study indicate that the IPL module is both safe and effective in treating pigmented lesions and may have the potential to ...
[144]
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In darker skin types, there is a risk of inducing hyperpigmentation. The immediate endpoint from IPL treatment of dyschromia should be visible darkening of the ...
[145]
Comparative efficacy of chemical peels and laser treatments in ...
Dec 31, 2024 · Deeper peels offer more pronounced results but also carry a higher risk of complications such as scarring or prolonged erythema [8]. Laser ...Missing: iatrogenic | Show results with:iatrogenic
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The efficacy and safety of microneedling with topical tranexamic acid ...
Aug 16, 2023 · A large number of studies have shown that oral and local administration of TXA in the treatment of melasma has good efficacy and tolerance, our ...2 Methods · 3 Results · 3.3 Meta-Analysis Of...
[147]
Evaluation of the effectiveness of microneedling with tranexamic ...
Oct 20, 2023 · Microneedling with vitamin C and TXA is a safe and effective treatment option without side effects for treating melasma.
[148]
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Oct 16, 2024 · Microneedle is a valuable adjunctive therapy for melasma treatment. It enhances long-term clinical outcomes compared to monotherapy and is associated with high ...
[149]
Topical Stabilized Cysteamine as a New Treatment for ...
Aug 10, 2025 · Stabilized cysteamine has demonstrated significant effectiveness for the treatment of melasma by two double-blind randomized and vehicle control trials.
[150]
An Update on New and Existing Treatments for the Management of ...
Jun 19, 2024 · A randomised controlled trial of 4% hydroquinone + 3% ascorbic acid demonstrated equal effectiveness after 4 months to 5% cysteamine cream in ...<|separator|>
[151]
A Case Series With Cysteamine–Isobionicamide Complex - NIH
Jan 16, 2025 · Results. Clinical photos showed improvement in skin luminosity, increased evenness of skin tone, and reduction of fine wrinkles as well as ...
[152]
Laser and Light-Based Therapies for Treating Melasma - PubMed
Sep 29, 2025 · Emerging treatments such as picosecond lasers show promise in reducing melanin index and improving skin texture with fewer adverse effects ...
[153]
730-nm Picosecond Laser Is More Effective Than 1064-nm for ...
Mar 21, 2025 · The 730-nm picosecond laser had an efficacy rate of 88% with higher patient satisfaction compared to the 1604-nm wavelength.<|separator|>
[154]
Anti-Pigmentation Treatments In 2025: What's New & Trending?
Feb 19, 2025 · Clinics now use fractional lasers and picosecond lasers, which target only the pigmented cells, leaving the surrounding skin untouched. This ...
[155]
Rethinking Dark Spots Through the Microbiome - Sequential Bio
Sep 3, 2025 · This clinical study, conducted on 38 European women grouped by facial hyperpigmentation level, aimed to directly characterise the role of the ...
[156]
Newly Discovered Genes Could Change Vitiligo Treatment
Aug 28, 2023 · Scientists say the new findings could lead to new drugs for vitiligo and other pigmentation diseases.
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Skin Pigmentation and Pigmentary Disorders: Focus on Epidermal ...
May 25, 2016 · The colour of human skin is determined by the amount and type of melanin pigment produced by melanocytes and transferred to keratinocytes.
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IPL & Alex 755 Laser Treatment: Related Efficacy Rates for Pigment ...
Sep 1, 2025 · Nonetheless, darker skin types are more susceptible to adverse effects like post-inflammatory hyperpigmentation, requiring cautious application.<|separator|>
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Clinico‐epidemiological profile and long term follow up in Melasma
Sep 21, 2021 · Most patients on oral tranexamic acid group developed recurrence by 6 weeks post discontinuation, compared to triple combination therapy group ...Missing: outcomes | Show results with:outcomes
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Mar 22, 2024 · Melasma is often resistant to conventional treatments and often recurs even after successful treatment. To understand the challenges of treating ...Missing: cohort | Show results with:cohort
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Melasma management: Unveiling recent breakthroughs through ...
A rise in the general blood levels of progesterone, estrogen, or melanocyte-stimulating hormone, especially during pregnancy, was thought to be the causal ...
[162]
Prevention of Post‐Inflammatory Hyperpigmentation in Skin of Colour
Feb 14, 2025 · The most successful preventative measure was sunscreen alone or combined with other ingredients. Less successful outcomes were seen with topical ...
[163]
The Impact of Hyperpigmentation on the Lives of Patients - PubMed
Jul 1, 2025 · If their hyperpigmentation was successfully treated, 43.33% of respondents anticipated a very positive impact on their self-esteem. The current ...
[164]
Psychosocial Impact of Postinflammatory Hyperpigmentation in ...
May 1, 2017 · Conclusion: Patients with acne and postinflammatory hyperpigmentation had poorer quality-of-life scores compared to patients with only acne.Missing: psychological | Show results with:psychological
[165]
Quality of life in patients with acquired dermal macular ... - PubMed
Nov 22, 2024 · ADMH has a significant adverse impact on QoL, likely to a greater degree than melasma, and to a similar or lesser degree than vitiligo.
[166]
Postinflammatory Hyperpigmentation - an overview
Postinflammatory hyperpigmentation tends to fade over time, resolving completely in many cases within 6 months, although in darker-pigmented individuals the ...
[167]
Skin: A mirror of internal malignancy - PMC - PubMed Central
Peutz–Jeghers syndrome manifests as mucocutaneous pigmentation in peri- and intra-oral regions with risk of gastrointestinal malignancy.[16] Howel–Evans ...
[168]
Cutaneous manifestations of internal malignancy - UpToDate
Feb 8, 2023 · The cutaneous manifestations of internal malignancy include a wide variety of nonmalignant skin disorders that occur in association with ...
[169]
Mottled Hypopigmentation from Laser Toning in the Treatment of ...
7–11 Because they claimed that the incidence of hypopigmentation caused by laser toning was found to be about 10% in Asians, there was a growing concern ...
[170]
Evaluating the Risk Factors of Post Inflammatory Hyperpigmentation ...
The incidence of rebound hyperpigmentation or hypopigmentation associated with laser toning was reported to range from 0% to 16.8% [2,3,5,21]. For the PIHCP ...<|separator|>
[171]
Effect of Cold Air Cooling on the Incidence of Postinflammatory ...
Postinflammatory hyperpigmentation is probably the most common adverse effect of laser treatments in dark-skinned individuals.
[172]
FDA works to protect consumers from potentially harmful OTC skin ...
Apr 19, 2022 · FDA has received reports of serious side effects including skin rashes, facial swelling, and ochronosis (discoloration of skin) from the use of ...Missing: carcinogen | Show results with:carcinogen
[173]
Hydroquinone - StatPearls - NCBI Bookshelf
Hydroquinone is not FDA-approved due to its unknown safety profile. It is banned in the EU, Australia, and Japan.
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Exogenous Ochronosis: Characterizing a Rare Disorder in Skin of ...
Jun 28, 2023 · Exogenous ochronosis is a rare dyschromia that primarily impacts those with skin of color. It is characterized by blue–black pigmentation.
[175]
Exogenous Ochronosis with Use of Low Potency Hydroquinone in A ...
Incidence has been highest in patients with darker skin types, prolonged use, and higher concentration treatment, but has been reported with low dose (2%) as ...
[176]
The safety of hydroquinone: A dermatologist's response to the 2006 ...
“Hydroquinone has been shown to cause disfiguring effects (ochronosis) after use of concentrations as low as 1 to 2 percent… . Exogenous ochronosis was not ...<|separator|>
[177]
Nephrotic syndrome of minimal change disease following exposure ...
A 28-year-old female suffered from nephrotic syndrome after a long-term use of mercury-containing, skin-lightening cream. The blood and urinary mercury ...
[178]
Minimal change disease caused by exposure to mercury-containing ...
We describe here 4 cases of minimal change disease following exposure to mercury-containing skin lightening cream for 2 - 6 months.
[179]
Diverse clinical manifestations and prognosis in a couple's mercury ...
Jan 21, 2025 · Case 1 is a 33-year-old man who developed nephrotic syndrome after using skin-lightening creams containing mercury over 9 months. Renal puncture ...Abstract · Introduction · Case presentation · Discussion
[180]
Skin Product Safety - FDA
May 22, 2024 · Skin lightening products containing the ingredients hydroquinone or mercury may cause harm. The over-the-counter sale of these products is illegal in the US.Missing: carcinogen | Show results with:carcinogen
[181]
The dark side of skin lightening: An international collaboration and ...
Similarly, in regions of East Africa, 52% of patients use SL products ... After slavery was abolished, the discriminatory stratification by skin tone (or colorism) ...
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Skin-Lightening Product Use Among South Asian Americans: Cross ...
Nov 2, 2023 · Colorism attitudes and use of skin lightening agents in the United States. Int J Womens Dermatol. 2023;9(3):e092. [FREE Full text] [CrossRef] ...
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Colorism attitudes and use of skin lightening agents in the United ...
Jul 13, 2023 · The objective of this study is to examine SL habits among skin of color (SOC) individuals in the US and the role of colorism in motivating these behaviors.
[184]
Why are people cosmetic skin whitening? A systematic review
Jun 12, 2025 · A survey evaluating knowledge, perception, and use of skin lightening products among South African students. ... Colorism attitudes and use of ...
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[PDF] The Influence of Media Exposure and Colorism on the African ...
Oct 19, 2022 · Colorism has influenced a systematic inequality of income and social status between members of the same race based on skin color. Skin color ...
[186]
Knowledge, Perceptions, and Practices of Skin‐Lightening Products ...
Aug 4, 2025 · ... colorism. Digital media has a crucial role in changing beauty standards by encouraging unrealistic ideals through filtered and edited images.Missing: aspects | Show results with:aspects
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Skin PS Brands - 628396 - 04/13/2022 - FDA
Apr 19, 2022 · This letter concerns your firm's distribution of a drug product to bleach and/or lighten the skin. Dark Spot Fix drug product is an unapproved ...Missing: 2022-2024 | Show results with:2022-2024
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Skin lightening products can be dangerous, but users don't know risks
80% women — who used skin lighteners perceived stronger colorism in their lives than those who did not use the products, ...