How Dihydrotestosterone Causes Cell Death in Hair Follicles: DKK-1 Upregulation

Androgenetic alopecia is a complicated condition involving hormones (particularly dihydrotestosterone) and genetics. So it's not really surprising that the underlying mechanism that causes hair follicle miniaturisation has eluded scientists for years. And, as a result of this complexity, many areas of research have been pursued.

This article brings together two studies and reveals that DNA damage may result from excess dihydrotestosterone levels in the hair follicle, and the subsequent response of one gene that can cause follicle cell death.

The first study involved the human dickkopf 1 (hDkk-1) gene and reported a number of interesting observations and findings:

hDkk-1 is secreted from dermal papilla cells in response to dihydrotestosterone (DHT).

2. hDKK-1 levels are higher in the male pattern baldness (MPB) region of the scalp in those with androgenetic alopecia.

3. hDKK-1 inhibits the growth of outer root sheath (ORS) cells and triggers apoptosis (cell death) in them.

4. Measurement of DNA in ORS cells showed that they undergo apoptosis in the presence of DHT.

Hair follicle.

The dermal papilla and outer root sheath are shown in the picture opposite. The dermal papilla is a cluster of specialized cells which play a key role in the regulation of hair cycling and growth.

The outer root sheath encloses the inner root sheath and hair shaft. (The inner root sheath is the white thickening at the end of a hair shaft if it is pulled out).

All these findings suggest that hDKK-1 is involved in the hair loss process.

In the second study it was reported that the hDkk-1 gene (and the hDkk-1 protein it forms) respond to DNA damage by sensitizing tumour cells to apoptosis.

It also states that:

"The damage-induced increase in hDkk-1 mRNA levels occurred in many human tumour cell lines"

What I find most interesting about this study is the link between hDkk-1 and cancer.

Here's the reason why...

DHT and androgen receptors have both been linked to prostate cancer. And, given that DHT levels and androgen receptor expression are greatly elevated in hair follicles within the MPB region (i.e., for those with androgenic alopecia) it seems likely to me that the high DHT concentrations in ORS cells (reported in the first study) causes DNA damage. That's because steroid hormones like DHT promote rapid cell division* and proliferation.

* For further information about how dihydrotestosterone increases cell division read this article: How Finasteride Treats the Secondary Effects of DHT.

DKK-1 levels then increase and causes cell death (i.e., the same response the body gives to prevent tumour development).

So, essentially, the increased expression (upregulation) of the hDkk-1 gene is a response by the body to excessive DHT levels. Very high concentrations of DHT can cause DNA damage and the body will automatically react to this by causing ORS cell apoptosis via DKK-1 upregulation.

The discussion section of the first study ends with:

"However, it still remains to be investigated whether our observations translate into a significant role for DKK-1 in the decreased growth of the hair follicle and ultimately in androgenetic alopecia."

I think DKK-1 probably does further decrease the growth of the hair follicle, but I also think it's important to look at the bigger picture...

Why are DHT levels so high in the first place?

It simply doesn't make sense that hair follicles should first increase DHT levels and then produce DKK-1 which ultimately causes ORS cell death. Surely an external influence beyond the follicle must also be involved in this accumulation of DHT.

For those with androgenetic alopecia, DHT levels in the MPB region are much higher than in the rest of the scalp.

The current theory simply states that MPB region follicles have higher androgen receptor gene expression and 5 alpha reductase levels than in the non-MPB region.

But the skull expansion theory states that androgen receptor gene expression and higher levels of 5 alpha reductase and DHT in MPB follicles all result from the response to frontal and parietal bone growth.

The body tries to restore hair growth back to normal by upregulating DHT to the MPB region.

The high levels of DHT produced should assist hair growth. But, since the miniaturised hair follicles have an inadequate blood supply, and skull expansion is progressive, DHT upregulation does not work. The body continues to increase DHT levels but this only makes things worse (as pointed out in the first article).

It's very straightforward for scientists today to isolate individual genes, molecules, etc, and point the finger of blame at them as the root cause of various conditions and diseases. But, it's also very easy to become so focused on such minute details that it's easy to lose sight of the bigger picture.

Dihydrotestosterone has been given the main blame for androgenetic alopecia, and it's true that this steroid hormone is intrinsic to the development of this type of hair loss. But skull expansion can explain how dihydrotestosterone gets involved with the hair loss process in the first place, and why not all men with high dihydrotestosterone levels are affected by hair loss.

References used:

First study: J Invest Dermatol. (2008) 128, 262-9; doi:10.1038/sj.jid.5700999. Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, Kim JC.

Second study: Oncogene (2002) 21, 878 889 DOI: 10.1038/sj/onc/1205138. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Shou J, Ali-Osman F, Multani AS, et al.

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