Biochemistry of baldness #1: Prostaglandin D2

This is the first post in a series on the biochemical mechanisms behind pattern baldness. I’m an independent researcher, so I’m mostly self-funded—if you want to support my work, buy me a coffee!

Disclaimer: I am not a doctor and nothing I write constitutes medical advice. This article is for informational purposes only, might contain inaccuracies, and should not be used as a substitute for professional medical advice.

A few weeks ago, I came across a thread on Twitter suggesting a connection between male-pattern baldness (androgenetic alopecia, AGA) and seed oils. This was hard for me to believe, so I decided to read the literature and come to my own conclusions. This series of posts is intended to be an accessible overview of what I learn.

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We begin with this molecule, prostaglandin D2 (PGD2).

Prostaglandin D2 (Gareth Chebi, via Wikipedia)

Here are three observations about PGD2, from a 2012 study

¹

:

1. Bald scalp contains much higher PGD2 concentrations compared to haired scalp.

2. PGD2, and its metabolic product 15-dPGJ2, inhibit hair growth in mice when applied to the skin.

3. Mice genetically altered to produce more PGD2 and 15-dPGJ2 have a phenotype that mimics AGA: miniaturization of the follicles, enlarged sebaceous glands, and hair loss.

The authors draw the conclusion that PGD2 synthesis is dysregulated in AGA, resulting in hair loss. However, both the cause of elevated PGD2 and the exact mechanism of hair loss remain unclear.

The enzyme directly responsible for producing PGD2 is PGD synthase. In fact, another study finds that the distribution of PGD synthase over the scalp directly correlates with the characteristic pattern of AGA

²

. In all people studied (men and women, with and without hair loss), PGD synthase concentrations form a gradient that is maximized on the vertex of the scalp and minimized on the lateral edges. This suggests that certain regions of the scalp are predisposed to increased PGD2 production. Furthermore, PGD synthase concentrations are approximately 50% higher in men than in women for each scalp region, which may explain the difference in propensity for hair loss between the sexes.

However, surprisingly, there is no significant difference in PGD synthase concentrations between people with and without hair loss for any given scalp region. PGD synthase cannot be the sole determining factor in whether hair loss occurs. Instead, something upstream must be involved.

Let’s zoom out.

PGD2 is part of a family of lipid compounds known as eicosanoids, which are derived enzymatically from arachidonic acid (AA). Here’s a simplified diagram:

Eicosanoid synthesis (Jfdwolff, via Wikipedia)

This pathway is primarily executed within the mast cell, a type of white blood cell usually located in tissues that interface with the environment

³

. When activated by an external stimulus, mast cells synthesize and release a wide variety of physiologically active compounds in a process known as degranulation. These compounds serve as signals that coordinate tissue repair, the immune response, and inflammation, among other things.

When a mast cell activates, phospholipase A2 extracts arachidonic acid from the cell’s phospholipid membrane. A series of enzymes rapidly converts AA into PGD2, which is then released from the mast cell.

With this in mind, I see four possible explanations for elevated PGD2 production.

1. Something is up-regulating the PGD2 synthesis pathway. When mast cells degranulate normally and activate the pathway, too much PGD2 is released.

2. The mast cells are being triggered due to some pathology, either internally or caused by environmental factors. There is plenty of evidence that this is possible; pathological mast cell activation is implicated in allergic reactions and asthma.

3. The body is intentionally triggering the mast cells, possibly even for the purpose of shedding hair.

4. The PGD2 pathway is being activated by some factor that is independent of mast cell degranulation.

The second explanation is currently my focus, but all require further investigation, and more than one may be correct.

Thanks for reading! The next post will delve further into the arachidonic acid pathway, examining how it’s regulated and localized within the cell. Subscribe to be notified when it’s published.

You can find me on twitter @ftlsid.

1. Garza LA, Liu Y, Yang Z, et al. Prostaglandin D2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia. Sci Transl Med. 2012;4(126). doi:10.1126/scitranslmed.3003122

2. Larson AR, Zhan Q, Johnson E, Fragoso AC, Wan M, Murphy GF. A prostaglandin d-synthase-positive mast cell gradient characterizes scalp patterning: Prostaglandin d-synthase in alopecia. J Cutan Pathol. 2014;41(4):364-369. doi:10.1111/cup.12286

3. da Silva EZM, Jamur MC, Oliver C. Mast Cell Function: A New Vision of an Old Cell. J Histochem Cytochem. 2014;62(10):698-738. doi:10.1369/0022155414545334