The link between prostaglandin D2, mast cells, and male pattern baldness

There is a significant link between prostaglandin D2 (PGD2), mast cells, and male pattern baldness (androgenetic alopecia). This connection involves multiple pathways and mechanisms that are now increasingly well-characterised in the scientific literature, though some aspects remain incompletely understood.

Five key takeaways

1. PGD2 is consistently elevated in balding scalp and is implicated as an inhibitory mediator in AGA pathophysiology [1].
2. PGD2 signalling is primarily mediated through DP2 and can intersect with androgen biology by enhancing AR signalling in human dermal papilla cells [2].
3. DP2 antagonism shows functional benefit in preclinical human models, including improved dermal papilla cell recovery after DHT injury and enhanced hair growth in organ culture [3].
4. Mast cells are a plausible upstream driver of local PGD2 excess, given their H-PGDS expression and coordinated release of PGD2 with other pro-inflammatory mediators  [4], [5].
5. AGA may involve a broader immune and prostaglandin imbalance, where type 2 immune circuits (including ILC2 activation) and reduced growth-promoting prostaglandins (PGE2/PGF2?) may compound PGD2-driven follicular miniaturisation [8], [10].

The role of Prostaglandin D2 in hair loss

Prostaglandin D2 has emerged as a critical player in the pathophysiology of androgenetic alopecia (AGA). One of the most compelling lines of evidence comes from the observation that PGD2 levels are significantly elevated in bald scalp areas compared to non-bald areas [1]. The mechanism by which PGD2 contributes to hair loss appears to involve direct effects on hair follicle epithelial stem cells and dermal papilla cells. Research suggests that PGD2-dependent reduction in hair follicle epithelial stem cell progenitor generation may be one of the pathways through which hair miniaturisation occurs [1], indicating that PGD2 specifically impairs the proliferation and function of the critical stem cell populations necessary for hair growth.

Molecular mechanisms of PGD2-mediated hair loss

The effects of PGD2 on hair follicles are primarily mediated through its receptor, DP2 (prostaglandin D2 receptor 2). PGD2 stimulates androgen receptor (AR) signalling in human dermal papilla cells through DP2-dependent mechanisms, which subsequently activates downstream factors including transforming growth factor-?1 (TGF-?1), cyclic AMP response element binding protein (Creb), and lymphoid enhancer binding factor 1 (LEF1) [2]. This PGD2-DP2 axis is particularly significant because it appears to interact with the androgen-dependent mechanisms that drive AGA pathogenesis. When DP2 antagonists are applied to human follicle dermal papilla cells damaged by dihydrotestosterone (DHT), they promote wound healing efficiency, increase alkaline phosphatase levels (a marker of dermal papilla inductivity), and reduce reactive oxygen species (ROS) levels [3]. Additionally, DP2 antagonists recover the membrane potential of mitochondria and enhance the phosphorylation levels of both Akt and ERK in DHT-damaged cells, while also improving hair growth in organ culture of human hair follicles [3].

Mast cells as producers of prostaglandin D2

Mast cells are one of the major cellular sources of PGD2 in human tissues. They are primarily express hematopoietic prostaglandin D synthase (H-PGDS), which catalyses the conversion of prostaglandin H2 to PGD2 [4]. Upon activation, mast cells release PGD2 as a de novo synthesised mediator, along with other inflammatory molecules including histamine, tryptase, and various cytokines [5]. The production of PGD2 by mast cells is not merely constitutive but varies depending on the activation stimulus and microenvironmental context, making mast cell behaviour a critical determinant of local PGD2 levels.

Immune microenvironment and hair follicle immune privilege

An important aspect of the PGD2-mast cell connection to male pattern baldness relates to the immune microenvironment of the hair follicle. Anagen stage hair follicles normally exhibit immune privilege through multiple mechanisms, including absence of MHC class I and II molecule presentation and expression of immunoinhibitory signals [6]. In healthy hair follicles, perifollicular mast cells contribute to the maintenance of this immune privilege [6]. However, in AGA, spatial transcriptomic analyses have revealed that there is a significant disturbance of the immune microenvironment within hair follicles, with evidence of increased CD4+ helper T cells and a pronounced shift toward Th2 (T helper 2) responses [7]. This Th2-biased immune response is particularly relevant because Th2 cells are also known producers of PGD2, creating a potential amplification loop where immune activation drives increased PGD2 production.

The PGD2-ILC2 pathway and inflammatory responses

Prostaglandin D2 activates group 2 innate lymphoid cells (ILC2s) through the DP2 receptor pathway [8], which can drive type 2 immune responses and allergic inflammation. In the context of hair follicles, this represents another mechanism through which mast cell-derived PGD2 could contribute to the microinflammatory state observed in AGA. ILC2s are activated by mast cell lipid inflammatory mediators, including PGD2 [8], suggesting that mast cell activation in the hair follicle environment could create a self-amplifying cycle of type 2 immune activation and PGD2 production.

Therapeutic implications

Understanding the PGD2-mast cell-hair loss connection has led to the development of novel therapeutic approaches. In addition to traditional DP2 antagonists, newer strategies include the use of agents that inhibit mast cell activation or reduce PGD2 production. For example, cetirizine, a histamine H1-receptor antagonist that also inhibits PGD2 release from mast cells while simultaneously stimulating prostaglandin E2 (PGE2) production, has been shown to be effective in treating male androgenetic alopecia, with significant improvements in hair density observed after 16 weeks of treatment [9]. This dual mechanism—suppressing inhibitory PGD2 while promoting growth-promoting PGE2—highlights the importance of the prostaglandin balance in hair cycle regulation.

Prostaglandin imbalance in AGA

The broader context of PGD2’s role in male pattern baldness involves a fundamental dysregulation of prostaglandin signalling. Multiple prostaglandins play spatiotemporally distinct roles in hair follicle biology, with prostaglandin F2? (PGF2?) and prostaglandin E2 (PGE2) generally promoting hair growth and anagen maintenance, while PGD2 inhibits hair follicle growth [10]. A comprehensive review of the physiological and pharmacological roles of prostaglandins in hair growth emphasises that the pathogenesis of AGA involves a prostaglandin imbalance, where elevated PGD2 production and impaired PGE2/PGF2? signalling work together to promote hair miniaturisation and shortened anagen phases [10].

Unresolved questions and future directions

Despite the substantial evidence for a PGD2-mast cell connection in male pattern baldness, important questions remain unresolved. The upstream triggers for mast cell activation in AGA scalp tissue are not fully characterised, nor is the relative contribution of mast cell-derived versus other cellular sources of PGD2 completely defined. The interplay between PGD2 signalling and androgen-dependent mechanisms in AGA pathogenesis, while increasingly understood, still requires further investigation. Additionally, whether approaches that specifically target mast cell-derived PGD2 production might yield superior therapeutic outcomes compared to global DP2 antagonism remains to be determined through properly designed clinical trials [1].

In summary, there is compelling evidence that prostaglandin D2 produced by mast cells represents a significant pathogenic factor in male pattern baldness, operating through multiple mechanisms including direct effects on hair follicle stem cells and dermal papilla cells, modulation of the hair follicle immune microenvironment, and interaction with androgen-dependent pathways that characterise AGA.

Disclaimer: This article is for informational purposes only and is not a substitute for professional medical advice.

References:

[1] S. Altendorf, M. Bertolini, A. L. Riche, A. Tosti, and R. Paus, “Frontiers in the physiology of male pattern androgenetic alopecia: Beyond the androgen horizon.,” Physiological Reviews, Jul. 2025, doi: 10.1152/physrev.00005.2024.

[2] K. H. Jeong, J. Y. Jung, J. H. Kim, and H. Kang, “Prostaglandin D2-Mediated DP2 and AKT Signal Regulate the Activation of Androgen Receptors in Human Dermal Papilla Cells,” Multidisciplinary Digital Publishing Institute, Feb. 2018, doi: https://doi.org/10.3390/ijms19020556.

[3] H. W. Lim et al., “Anti-Hair Loss Effects of the DP2 Antagonist in Human Follicle Dermal Papilla Cells,” Cosmetics, Oct. 2024, doi: 10.3390/cosmetics11050177.

[4] Q. Liu et al., “Biological and prognostic insights into the prostaglandin D2 signaling axis in lung adenocarcinoma,” Frontiers in Pharmacology, May 2025, doi: 10.3389/fphar.2025.1562261.

[5] I. Halova, L. Draberova, and P. Drber, “Mast Cell Chemotaxis  Chemoattractants and Signaling Pathways,” Front. Immun., May 2012, doi: 10.3389/fimmu.2012.00119.

[6] M. Bertolini, K. McElwee, A. Gilhar, S. Bulfone-Paus, and R. Paus, “Hair follicle immune privilege and its collapse in alopecia areata,” Experimental Dermatology, Jul. 2020, doi: 10.1111/exd.14155.

[7] S. Charoensuksira et al., “Disturbance of Immune Microenvironment in Androgenetic Alopecia through Spatial Transcriptomics,” Multidisciplinary Digital Publishing Institute, Aug. 2024, doi: https://doi.org/10.3390/ijms25169031.

[8] J. Jin, S. Sunusi, and H. Lu, “Group 2 innate lymphoid cells (ILC2s) are important in typical type 2 immune-mediated diseases and an essential therapeutic target,” Journal of International Medical Research, Jan. 2022, doi: 10.1177/03000605211053156.

[9] D. H. Mostafa, A. Samadi, S. Niknam, S. A. Nasrollahi, A. Guishard, and A. Firooz, “Efficacy of Cetirizine 1% Versus Minoxidil 5% Topical Solution in the Treatment of Male Alopecia: A Randomized, Single-blind Controlled Study,” Canadian Society for Pharmaceutical Sciences, Apr. 2021, https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31456

[10] D. Shin, “The physiological and pharmacological roles of prostaglandins in hair growth,” Korean Journal of Physiology and Pharmacology, Nov. 2022, doi: 10.4196/kjpp.2022.26.6.405.