Recent evidence has illustrated a role for prostaglandins in regulating hair growth. For example, the PGF2α
analog latanoprost is Food and Drug Administration (FDA)–approved and routinely used clinically to enhance hair growth of human eyelashes (15
has been proposed to protect from radiation-induced hair loss in mice (29
), and both PGE2
have been shown to enhance hair growth in mice (20
). Our studies show that prostaglandins are dysregulated in AGA, the most common type of hair loss in men. Specifically, PGD2
inhibits hair growth and thus represents a negative counterbalance to the positive effects on hair growth shown for PGE2
There is precedence for the opposing functions of individual prostaglandins that are downstream from the PTGS enzymes. For example, in the lung, PGE2
causes relaxation, whereas PGD2
causes contraction of bronchial muscle tone (16
). Our results suggest that in mouse and human skin, a balance between PGE2
controls hair growth. This model predicts then that efforts to reverse alopecia should optimally focus on both enhancing PGE2
and inhibiting PGD2
signaling. This model also explains why agents such as aspirin, which inhibit upstream prostaglandin synthesis enzymes (PTGS1 and PTGS2), have minimal effects on hair growth because of likely equally decreased production of PGE2
Given our current report that PGD2
inhibits hair growth, prostaglandins represent an underappreciated network for controlling the rate of hair lengthening. Evidence to support the PGD2
pathway’s direct induction of the apoptotic catagen stage includes the temporal expression of Ptgds
with catagen onset, in vitro studies of 15-dPGJ2
showing inhibition of hair growth, and the Ptgs2
-overexpressing mouse model, which develops alopecia (23
). These results are consistent with the notion that PTGDS elevation in balding scalp leads to increased levels of PGD2
, which then promote the onset of catagen and decrease hair lengthening, leading to the increase in telogen follicles and miniaturization of the hair follicle characteristic of AGA. PGD2
may also cause sebaceous hyperplasia seen in AGA.
Although we did not elicit premature catagen in mice treated topically with PGD2
, we observed a negative effect on hair growth (). This could be explained because of inappropriate prostaglandin delivery, frequency, or concentration. Other explanations include potential cofactors that are required with PGD2
to more directly affect hair cycling. Nevertheless, our results do suggest that prostaglandins directly modulate speed of hair growth during anagen. Current explanations of the differences in hair length by species focus mostly on duration of hair follicle cycling rather than accompanying potential differences in hair-lengthening rates during anagen (4
). Our results suggest that greater attention should be paid to the possibility that prostaglandins modulate hair growth speed and that compounds increasing hair growth speed may benefit patients with AGA.
is a highly testosterone-responsive transcript (30
), which further suggests its importance in AGA. PGD2
is thought to play a central role in male gonadal sex determination (32
) and is highly expressed in male genitalia (32
). Similarly, Ptgds
expression in the heart is regulated by estrogen (34
). Estrogen leads to increases in 15-dPGJ2
levels in the uropygial gland (35
). Recent evidence also suggests that prostaglandins induce virilization of the mouse brain through estrogen (36
). Given the androgens are aromatized into estrogens, these results may be relevant to hair growth and alopecia in both men and women. Thus, these or similar pathways might be conserved in the skin and suggest that sex hormone regulation of Ptgds
may contribute to the pathogenesis of AGA.
Additional evidence that prostaglandins control hair follicle cycling and can be used therapeutically to treat AGA arises from findings on the possible mechanism of the AGA drug minoxidil. Although minoxidil alters potassium channel kinetics (7
), it is also known to increase production of PGE2
). Given the decreased amount of PGE2
present in bald scalp versus haired scalp (), minoxidil may normalize PGE2
levels. Future studies should address whether minoxidil can concomitantly decrease PGD2
levels and thus normalize multiple prostaglandin species as a mechanism to improve AGA.
The lower absolute amount of 15-dPGJ2
compared to PGE2
is particularly relevant; although this eicosanoid has been hypothesized to be a natural ligand for the nuclear hormone transcription factor peroxisome proliferators–activated receptor γ (PPARγ), the measured concentration of 15-dPGJ2
is often lower than the binding constant for PPARγ (17
). Thus, although it is attractive to speculate that the sebaceous gland hypertrophy and elevated levels of 15-dPGJ2
observed in both human AGA and mouse K14-Ptgds
model might be related, the causal connection is unclear. Despite this, a growing literature correlates elevated 15-dPGJ2
levels with sebaceous hyperplasia, such as in acne (38
). Given the common requirement of circulating sex hormones and common histology of sebaceous hyperplasia, acne and AGA may have overlapping pathogeneses.
Another report has linked altered lipid metabolism and alopecia (39
). In a distinct type of human alopecia called lichen planopilaris, expression of PPARγ is decreased with accompanying altered lipid metabolism. These were discovered through an approach similar to ours using micro-array analysis of affected and unaffected scalp. The most up-regulated transcript from affected subjects, cytochrome P450 family 1 member A1 (CYP1A1), was up-regulated 1020-fold. The authors hypothesized that a xenobiotic, such as dioxin, might up-regulate CYP1A1 expression and trigger lichen planopilaris. However, cytochrome P450s also have roles in eicosanoid biology, and they may alter prostaglandin metabolism (40
). Thus, altered prostaglandin metabolism might contribute to more than one type of human alopecia, although additional studies are needed.
Our findings should lead directly to new treatments for the most common cause of hair loss in men, AGA. Given its suspected role in allergic diseases, at least 10 antagonists of the GPR44 (DP-2) receptor have been identified (41
) and several are in clinical trials (42
). The potential for developing these compounds into topical formulations for treating AGA should elicit great interest moving forward. The question of whether similar changes in PGD2
levels are found in the affected scalp of women with AGA also needs to be addressed. AGA in women may not be androgen-mediated, but if prostaglandins represent a final common pathway, targeting prostaglandins should benefit women with AGA as well.
Our findings also suggest that supplemental PGE2 could be therapeutic. By correcting its deficiency and increasing its level in bald scalp, the inhibitory effects of PGD2 may be overcome. Analogs of PGF2α, which are already FDA-approved to promote eyelash growth, should also have similar effects on the scalp and are currently in clinical trials for this indication. Once issues of delivery, dosing, and safety are addressed, additional agonists and antagonists of prostaglandin pathways should become available. The K14-Ptgs2 transgenic mouse model, which phenocopies AGA, may assist in screening novel therapeutic agents. Ultimately, multiple mechanisms may be responsible for hair loss in AGA. Inhibiting PGD2 may prevent miniaturization and provide benefit to those in the process of balding; however, it is unclear whether men who are already bald will regrow hair.