Laser-Assisted Prostaglandin Analogs in the Treatment of Hypopigmented Scars: A Systematic Review

J Clin Aesthet Dermatol. 2023;16(9):28–32.

by Pooja H. Rambhia, MD; Angel D. Pagan, BS; Karan Lal, DO, MS; and David Goldberg, MD, JD

Dr. Rambhia is with the Department of Dermatology at Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New Hyde Park, New York. Mr. Pagan is with Ponce Health Sciences University School of Medicine in Ponce, Puerto Rico. Drs. Lal and Goldberg are with the Skin Laser and Surgery Specialists Division of Schweiger Dermatology in New York, New York. Addtionally, Dr. Goldenberg is with the Department of Dermatology at Icahn School of Medicine at Mount Sinai in New York, New York.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no relevant conflicts of interest for this study.

ABSTRACT: Background. Hypopigmented scars are challenging to treat due to a lack of effective treatments and often transient results. Recent reports suggest that prostaglandin analog-induced hyperpigmentation may have favorable dermatological applications.

Objective. Analyze previous studies involving the use of prostaglandin analogs in the treatment of hypopigmented scars.

Methods. PubMed/Medline was queried through 10/01/2022 with the following search terms: (bimatoprost AND scar), (latanoprost AND scar), (travoprost AND scar), (prostaglandin analogs AND hypopigmented scars), (PGF2alpha AND hyperpigmentation), (prostaglandin analogs AND hyperpigmentation).

Results. In total, 88 unique studies were reviewed for eligibility. Five studies met inclusion criteria including two prospective, double-blinded, randomized (only one was placebo-controlled), one prospective case series, one retrospective chart review, and one case report; comprising a total of 87 patients. All five studies utilized topical prostaglandin analogs as an adjunctive treatment via laser-assisted delivery. While both, the placebo-controlled and non-placebo-controlled, trials reported more than 75 percent of patients experienced at least 50 percent or more (Grade 3 or higher) improvement, the retrospective study reported 100 percent of patients experienced at least 75 percent or more (Grade 4 or higher) improvement, measured as scar repigmentation. The prospective case series and the reported single case showed overall qualitative improvement in all patients measured as repigmentation of hypopigmented and depigmented scars.

Limitations: Different laser devices, parameters, treatment frequency, and follow-up timepoints.

Conclusion. All studies evaluated demonstrated favorable treatment outcomes with no reported adverse events. Additional, large randomized controlled trials are needed to fully assess the effectiveness and long-term safety of PGF2α agonists for hypopigmented scars.

Keywords. hypopigmented scars; prostaglandin analogs; skin of color; lasers; hyperpigmentation; systematic review; bimatoprost 

Hypopigmented scarring can be challenging to treat, largely due to a lack of current efficacious treatments and often transient results.¹ Notably, prostaglandin F2α agonists (PGF2α) are FDA-approved as topical ophthalmic solutions for treatment of open-angle glaucoma. More recently, they have been used for desired cosmetic side effects like hypertrichosis and have been shown to induce cutaneous side effects including hyperpigmentation. This effect of PGF2α analog-induced hyperpigmentation has previously provided efficacy in treating vitiligo, and may also provide therapeutic benefit in management of hypopigmented scars.^2,3 Thus, we aimed to systematically review the literature to assess the use of prostaglandin analogs in the treatment of hypopigmented scars.

Methods

PubMed/Medline was queried through 10/01/2022 with the following search terms: (bimatoprost AND scar), (latanoprost AND scar), (travoprost AND scar), (prostaglandin analogs AND hypopigmented scars), (PGF2alpha AND hyperpigmentation), (prostaglandin analogs AND hyperpigmentation).  Studies met inclusion criteria if they used prostaglandin analogs specifically for the treatment of hypopigmented scars and reported on scar cosmesis. Clinical trials, original interventional studies, case series, and case reports were included. Citations of studies that met inclusion criteria were reviewed to identify additional studies not captured by the database search.  Publication duplicates, abstracts, review articles, animal studies, and human studies that did not use PGF2α agonists for the treatment of hypopigmented scars, specifically, were excluded. 

Results

In total, 88 unique studies were reviewed for study eligibility (Figure 1). Five studies met inclusion criteria including two prospective, double-blinded, randomized (one was placebo-controlled), one prospective case series, one retrospective chart review, and one case report; comprising a total of 87 patients (Table 1). Data extracted included patient demographics, Fitzpatrick Skin Type (FST), PGF2α analog used, adjunctive treatments, and patient outcomes. 

Siadat et al⁴ evaluated 28 FST II to IV patients with hypopigmented scars who were treated with six sessions of 10,600nm fractional ablative CO₂ laser (FAL) + application of latanoprost 0.005% for 24 weeks versus 10,600nm fractional CO₂ laser + distilled water placebo. Eleven of 14 patients demonstrated more than 50 percent improvement in hypopigmentation (p=0.027), correlating with higher patient satisfaction scores compared to CO₂ laser + placebo, (p=0.003). Notably, the FAL + bimatoprost group on average had a higher FST compared to other groups, suggesting darker phototypes may respond better.⁴  Waibel et al. also evaluated treatment of hypopigmented scars in 40 subjects receiving 1,550nm non-ablative fractional erbium-doped laser (NAFL) (n=10), 10,600nm FAL-CO₂ (n=10), FAL-CO₂ + bimatoprost 0.03% solution, and epidermal harvesting + FAL-CO₂. Interestingly, the group treated with FAL-CO₂ + bimatoprost had the highest improvement compared to all groups, with 76 percent of these patients exhibiting more than 50 percent improvement in pigmentation (p<0.001).⁵ Massaki et al,⁶ similarly demonstrated 50 to 75 percent improvement in the hypopigmented scars of 14 patients treated with a mean of 4.5, 1,550nm NAFL-Erbium treatments, followed by bimatoprost 0.03% solution twice daily for three or more months. Da Silva et al⁷ treated four patients with four sessions of 2,940nm FAL-CO₂ followed by bimatoprost 0.03% solution massage, and noted clinical improvement of hypopigmentation, affirmed by patient satisfaction four weeks posttreatment. Most recently, Wilson et al¹ reported a patient with FST V, who developed COVID-19 prone-positioning-induced facial atrophy and hypopigmentation. The patient experienced marked repigmentation of scars five months after initiating bimatoprost 0.03% solution delivered with FAL-CO₂ and microneedling.

Discussion

PGF2α agonists are FDA-approved as topical ophthalmic solutions for treating open-angle glaucoma and ocular hypertension, including bimatoprost, latanoprost, and tafluprost, travoprost, and unoprostone.⁸ Their proposed mechanism of action is the induction of metalloproteinase activity in the ciliary body, which increases aqueous humor outflow and decreases intraocular pressure.⁹ All five ophthalmic prostaglandin F2α agonists have label warnings for iris and periorbital skin hyperpigmentation. The prostaglandin agonist-induced eyelash changes include increase in length and thickness and has propelled research in dermatology as a potential therapy for alopecia areata of the eyebrows and eyelashes, androgenetic alopecia of the scalp, and chemotherapy-induced eyelash hypotrichosis.^10–12 While the efficacy of latanoprost as a hair regrowth therapy is still controversial, bimatoprost (Latisse, Allergan Inc.) has been FDA-approved as 0.03% solution for eyelash hypotrichosis since 2010.^13–15 Carboprost, on the other hand, is an FDA-approved PGF2α agonist for the treatment of postpartum hemorrhage administered intramuscularly.¹⁶ Since no cases of carboprost-induced hyperpigmentation of skin, hair, or nails have been identified, it may be possible that route of administration plays a role in inducing pigment production and warrants further study. Moreover, studies suggest that excessive periorbital hyperpigmentation induced by PGF2α agonist applied to treat eyelash hypotrichosis is reversible upon treatment discontinuation.^17–20

Overall, we have presented recent studies analyzing the efficacy and safety of PGF2α agonists in treating hypopigmented scars, especially by way of laser-assisted delivery, and found that there is substantial preliminary evidence to support their use (Table 1). Although the exact mechanism of action remains unknown, a study by Kapur et al²¹ analyzing the histopathological findings of bimatoprost-induced periocular skin hyperpigmentation found that increased melanogenesis and increased melanosome transfer to basal keratinocytes, but not melanocyte proliferation or atypia, are the potential underlying mechanisms.²¹ Similarly, human keratinocytes have been shown to secrete PGE2 and PGF2α in-vitro and stimulate increased melanocyte dendricity via paracrine receptors.²² 

Studies in mice treated with PGF2α analogs, latanoprost, and isopropyl unoprostone, demonstrated hair follicle conversion from the telogen to the anagen phase 12 days after treatment initiation with cutaneous darkening and pigmentation. Interestingly, each PGF2α showed a distinct pigmentation pattern in all treated mice, but not controls, while treatment with PGE2 agonist demonstrated increased pigmentation in only two out of five mice.²³ Similarly, a study in guinea pigs comparing NB-UVB alone, PGF2α analogs alone, and the combination of both found the highest rate of cutaneous pigmentation in combination therapy. All three PGF2α analogs studied (latanoprost, bimatoprost, travoprost) showed equivalent results clinically and histologically.²⁴ Most recently, trans-epidermal delivery of PGF2α agonists has been facilitated by laser adjuncts such as FAL and NAFL resurfacing, further enhancing their role as an adjunctive agent to treat hypopigmented scars in humans.^4,5 Taken together, these studies highlight the potential of prostaglandin agonist-induced skin pigmentation and advocate for studies in humans.

Studies in patients with vitiligo place prostaglandin-analogs as a promising therapeutic option for patients with disorders of skin pigmentation. A randomized, double-blind clinical trial with over 31 patients showed significant repigmentation of eyelid vitiligo patches with topical latanoprost gel, but not placebo, twice daily for 12 weeks.²⁵ In addition, a randomized, double-blind, controlled clinical trial with 32 patients showed that bimatoprost 0.03% solution alone, or in combination with mometasone, provided greater repigmentation of nonfacial vitiligo than treatment with mometasone alone.²⁶ Even studies with smaller samples (n=8) have demonstrated at least 50 percent of patients achieve “excellent repigmentation,” and another 25 percent experience “partial repigmentation.”²⁷ Furthermore, a prospective right-left comparative study of 25 patients with vitiligo vulgaris showed more than 50 percent repigmentation was achieved in 13 (52%) patients with combination NB-UVB and topical bimatoprost 0.03% eyedrops versus 10 (40%) patients with NB-UVB alone.²⁸ Although these results seem promising, further molecular and clinical studies are needed to elucidate the exact mechanisms by which immune responses affect skin pigmentation and the long-term safety of these therapies, respectively.³  

In conclusion, further studies are needed to elucidate the mechanistic pathways, tissue specificity, and patient demographics that may impact topical prostaglandin analog therapy. Additional, large randomized controlled trials are needed to further evaluate the efficacy and long-term utility of PGF2α agonists in treatment of hypopigmented scars.

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