Managing Pigment for Generation X

Hyperpigmentation remains one of the top concerns among Generation X (Gen X) patients, many of whom are now seeing the long-term effects of decades of sun exposure, hormonal changes, and environmental stress.¹ As a field, dermatology has moved beyond relying solely on hydroquinone (HQ) as the gold standard for pigmentation, partly due to safety concerns but also hastened by the removal of hydroquinone from the over-the-counter market due to the CARES legislation and its banning in Europe. Clinicians now have a new toolbox with a range of products targeting melanogenesis at multiple levels, offering more flexibility and safety when creating individualized pigment plans.

 For Gen X and younger patients, newer ingredients and oral therapies offer improvement in pigmentation with fewer safety concerns and better tolerability.

HYDROQUINONE
HQ, a tyrosinase inhibitor, has long been the gold-standard topical treatment for hyperpigmentation. It can deliver quick results, but it is best used short-term. Prolonged use can lead to skin irritation, rebound hyperpigmentation, and rarely, exogenous ochronosis.² Recent case reviews suggest that HQ treatment with concentrations above 4% and lasting longer than 3 months were most often linked to new cases of ochronosis.³ Tyrosinase can also metabolize hydroquinone, which can form melanotoxic metabolites. While human data are limited, animal studies have raised concerns about potential carcinogenicity.²

NEXT-GENERATION ACTIVE INGREDIENTS

Cysteamine: Among newer actives, cysteamine stands out as an aminothiol and antioxidant that acts on more levels of melanogenesis than any other topical agent.⁴ When combined with salicylic acid peels or exfoliating products, cysteamine can help decrease existing pigment while preventing new pigment formation with a rapid onset of action. Another benefit is that specific application to dark spots is not necessary. Treating the entire field evens out the skin tone without risk of halo hypopigmentation and gives the skin a characteristic glow.

Topical Tranexamic Acid (TXA): Topical TXA is gaining attention for its ability to reduce UV-induced pigmentation and melasma by inhibiting plasmin activity and reducing inflammatory mediators. It is a great option for maintenance after short hydroquinone courses or in combination regimens. One limitation is its large molecular size and its inability to fully penetrate the epidermis to achieve optimal results.

Lotus Sprout Extract (LSE): LSE promotes melanosome degradation in melanocytes and keratinocytes, inducing autophagosomes that metabolize existing pigment granules.

Thiamidol: Thiamidol was isolated from a screening of more than 50,000 different compounds as the only one to inhibit human tyrosinase, distinct from other inhibitors based on mushroom tyrosinase.⁶ Thiamidol has emerged as a breakthrough treatment for pigmentation and is well tolerated in Fitzpatrick skin types V and VI, which is beneficial for post-inflammatory hyperpigmentation (PIH) from acne, procedures, or other causes.⁷ In split-face studies, thiamidol matched or exceeded 4% hydroquinone’s effect on melasma, with mean mMASI reductions of 43% compared with 33% for HQ after 12 weeks.⁸

2-Mercaptonicotinoyl Glycine (2-MNG): While still emerging cosmetically, 2-MNG (found in Melasyl™) is an active ingredient that inhibits melanin synthesis and UV-induced pigmentation by binding melanin precursors upstream of tyrosinase and inhibiting them. By blocking pigment precursors, 2-MNG shows promise in becoming a maintenance agent after HQ or thiamidol courses. It has shown similar efficacy and better tolerability compared to 4% HQ for the treatment of melasma.⁹

ORAL AND ADJUNCT APPROACHES BEYOND TOPICALS

Oral Tranexamic Acid (TXA): Oral tranexamic acid is an adjunct that results in significant improvements in melasma in as little as 8 weeks.¹⁰ For Gen X patients with melasma who have plateaued with topicals, oral TXA can be considered as a short course combined with a topical and sun protection. Originally found to lighten skin while treating menometrorrhagia, oral TXA has prothrombotic risk and should not be used in smokers, those with a history of blood clots, or patients undergoing hormone replacement therapy.

Melatonin: New research suggests that oral melatonin, better known for improving sleep, can improve facial melasma by decreasing oxidative stress and by inhibiting tyrosinase.¹¹ This could be a promising therapy for patients struggling with sleep difficulties and pigmentation.

Malassezin: Malassezin is an aryl hydrocarbon receptor (AhR) agonist with antioxidant effects and has shown promise in improving melasma and photodamage.¹²

Metformin: Metformin goes beyond regulating insulin. Its role in decreasing inflammation positions it as a potential adjunct in hormonally driven pigmentation.¹³ 

PIGMENT PROTOCOL PEARLS

1. Address any underlying inflammatory process that may be causing the discoloration.
2. Treat pigmentation as a journey, not a one-time quick fix.
3. Set expectations early: complete resolution is unlikely, but significant improvement is achievable.

Gen X patients often represent the “in-between” group: balancing active lifestyles, aging skin, and accumulated environmental exposure. They want results that are fast, visible, and sustainable, but not aggressive or high maintenance. It is important to emphasize to these patients that hyperpigmentation may never completely disappear, but with a consistent and science-backed routine, they can reduce it and find their way to bright, glowing skin. 

1. Swinyer Woseth Dermatology. Most common skin concerns by generation. [Swinyer Woseth Dermatology website.] Published August 16, 2024. Accessed October 15, 2025. https://www.dwoseth.com/blog/most-common-skin-concerns-by-generation/

2. Zolghadri S, Beygi M, Mohammad TF, et al. Targeting tyrosinase in hyperpigmentation: [current status, limitations and future promises.] Biochem Pharmacol. 2023;212:115574. doi:[https://doi.org/10.1016/j.bcp.2023.115574]

3. Ishack S, Lipner SR. Exogenous ochronosis associated with hydroquinone: a systematic review. Int J Dermatol. 2022;61(6):675-684. doi:[https://doi.org/10.1111/ijd.15878]

4. Desai S, Hartman C, Grimes P, Shah S. Topical [stabilized cysteamine as a new treatment for hyperpigmentation disorders: melasma, post-inflammatory hyperpigmentation, and lentigines.] J Drugs Dermatol. 2021;20(12):1276-1279. doi:[https://doi.org/10.36849/jdd.6367]

5. Geyfman M, Chung R, Boissy R, et al. Lotus sprout extract induces selective melanosomal autophagy and reduces pigmentation. J Cosmet Dermatol. 2025;24(1):e16587. doi:[https://doi.org/10.1111/jocd.16587]

6. Mann T, Gerwat W, Batzer J, et al. Inhibition of human tyrosinase requires molecular motifs distinctively different from mushroom tyrosinase. J Invest Dermatol. 2018;138(7):1601-1608. doi:[https://doi.org/10.1016/j.jid.2018.01.019]

7. Roggenkamp D, Dlova N, Mann T, et al. Effective reduction of post-inflammatory hyperpigmentation with the tyrosinase inhibitor isobutylamido-thiazolyl-resorcinol (Thiamidol). Int J Cosmet Sci. 2021;43(3):292-301. doi:[https://doi.org/10.1111/ics.12694]

8. Philipp-Dormston WG, Vila Echagüe A, Pérez Damonte SH, et al. Thiamidol containing treatment regimens in facial hyperpigmentation: [an international multi-centre approach consisting of a double-blind, controlled, split-face study and of an open-label, real-world study.] Int J Cosmet Sci. 2020;42(4):377-387. doi:[https://doi.org/10.1111/ics.12626]

9. Passeron T, Kerob D, Le Dantec G, et al. Efficacy and tolerability of a new facial 2-mercaptonicotinoyl glycine-containing depigmenting serum versus hydroquinone 4% over 3-month treatment of facial melasma. Dermatol Ther (Heidelb). 2025;15(9):2379-2390. doi:[https://doi.org/10.1007/s13555-025-01473-4]

10. Del Rosario E, Florez-Pollack S, Zapata L Jr, et al. Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol. 2018;78(2):363-369. doi:[https://doi.org/10.1016/j.jaad.2017.09.053]

11. Sarkar R, Verma B, Mendiratta V. Use of oral melatonin in recalcitrant melasma. Int J Dermatol. 2024;63(8):1111-1112. doi:[https://doi.org/10.1111/ijd.17201]

12. Grimes PE, Bhawan J, Howell MD, et al. A novel proof-of-concept study assessing the lightening effects and safety of malassezin for treatment of facial hyperpigmentation. J Am Acad Dermatol. 2022;87(2):456-458. doi:[https://doi.org/10.1016/j.jaad.2021.10.008]

13. Ismail SA, Mohamed GA, Mohamedeen KN, Sotohy RSA, Bakr RM. Does systemic metformin have a role in treating melasma?[?] Dermatol Surg. 2024;50(4):366-371. doi:[https://doi.org/10.1097/DSS.0000000000004092]