Keratinocyte growth inhibition through the modification of Wnt signaling by androgen in balding dermal papilla cells

J Clin Endocrinol Metab. 2009 Jan 13.

Keratinocyte growth inhibition through the modification of Wnt signaling by androgen in balding dermal papilla cells.
Kitagawa T, Matsuda KI, Inui S, Takenaka H, Katoh N, Itami S, Kishimoto S, Kawata M.

Department of Dermatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan; Department of Anatomy and Neurobiology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan; Department of Regenerative Dermatology, Graduate School of Medicine Osaka University, Osaka, Japan.

Context/Objective: Androgen induces androgenetic alopecia (AGA) which has a regressive effect on hair growth from the frontal region of the scalp. Conversely, Wnt proteins are known to positively affect mammalian hair growth. We hypothesized that androgen reduces hair growth via an interaction with the Wnt signaling system. The objective of this study was to investigate the effect of androgen on Wnt signaling in dermal papilla (DP) cells. Design: The effect of androgen and Wnt3a on keratinocyte (KC) proliferation was measured by use of a co-culture system consisting of DP cells and KCs. The molecular mechanisms of androgen and Wnt pathway interactions in DP cells were examined by analyzing the expression, intracellular localization and activity of the androgen receptor (AR) and also down-stream Wnt signaling molecules. Results: Wnt3a-dependent keratinocyte growth was suppressed by the addition of dihydrotestosterone (DHT) in coculture with DP cells that were derived from AGA patients, but growth was not suppressed in coculture with DP cells from non-AGA males. While DP cells from both scalp regions expressed AR protein, the expression levels of AR and co-translocation with beta-catenin, a down stream Wnt signaling molecule, were higher in DP cells of AGA patients than in DP cells from non-AGA males. In addition, significant suppression of Wnt signal-mediated transcription in response to DHT treatment was observed only in DP cells from AGA patients. Conclusion: These results suggest that Wnt signaling in DP cells is regulated by androgen and this regulation plays a pivotal role in androgen's action on hair growth.

This is hardly a surprise, here is a related study.

Note: I have a hypothesis of my own, which is modest doses of Lithium Aspartate or Lithium Orotate 5 to 10 milligrams (elemental) per day can significantly block DKK-1, the protein that suppresses Wnt signaling in AGA Androgen receptor.

Topical Lithium will also reduce DKK-1, while DMSO will help increase Wnt signaling. However, there is 10 to 15% of that have higher inflammation with topical Lithium.

J Invest Dermatol. 2008 Feb;128(2):262-9.
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.

Department of Immunology, School of Medicine, Kyungpook National University, Daegu, Korea.

Recent studies suggest that androgen-driven alteration to the autocrine and paracrine factors produced by scalp dermal papilla (DP) cells may be a key to androgen-potentiated balding. Here, we screened dihydrotestosterone (DHT)-regulated genes in balding DP cells and found that dickkopf 1 (DKK-1) is one of the most upregulated genes. DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT. A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells. Analysis of co-cultured ORS cells showed a significant increment of sub-G1 apoptotic cells in response to DHT. Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death. In addition, DHT-induced epithelial cell death in cultured hair follicles was reversed by neutralizing DKK-1 antibody. Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia. Altogether, our data strongly suggest that DHT-inducible DKK-1 is involved in DHT-driven balding.

IH, these studies indicated that ORAL lithium could benefit hair? Is it true that lithium interupts the methylation cycle?

Joejoebaggins - I wasn't sure, so I checked into it.

Here's a study about it here:

Nutr Health. 1984;3(3):153-62.
Membranes, methylation and lithium responsive psychoses.
Hitzemann R, Hirschowitz J, Panini A, Mark C, Garver D.

Data are presented showing that the erythrocyte ghost membranes of lithium-responsive and non-responsive schizophrenic-like patients are different from control membranes. In both groups of patients there was a significant decrement of phosphatidylcholine (PC) which was largely compensated for by an increase in sphingomyelin. The decrement in PC may in part be associated with a decrease in phospholipid methylation which converts phosphatidylethanolmine (PE) to PC. Interestingly, in the lithium-responsive but not the non-responsive patients, lithium stimulates methylation activity. This stimulation may affect a variety of membrane functions, e.g. adenyl cyclase activity, which would be involved in lithium's therapeutic actions.

Finding studies on how low-dose Lithium is very difficult, since almost all the research uses Lithium Carbonate (the toxic form) at high doses. Toxic doses are needed for the Carbonate version.

There's no question that high dose lithium will interfere with the thyroid, but I have noticed that low-dose Lithium Orotate or Aspartate reduces sebum.

Of course topically it does this.

Oral Lithium in the typically prescribed toxic form (Carbonate) usually causes loss of hair. I have always suspected this is because Lithium suppresses thyroid function with usually high dose used in psychiatry.

Here's a reference:

Ann Clin Psychiatry. 2000 Mar;12(1):35-42.
Hair loss in psychopharmacology.
Mercke Y, Sheng H, Khan T, Lippmann S.

Department of Psychiatry and Behavioral Science, University of Louisville School of Medicine, Kentucky, USA.

Medication-induced alopecia is an occasional side effect of many psychopharmaceuticals. Most of the mood stabilizer and antidepressant drugs can lead to this condition. Some antipsychotic and antianxiety agents induce alopecia. Hair loss is also related to hypothyroidism, which can be induced by lithium and other agents. Alopecia might not be reported by some people, but physicians should be aware of this potential problem which may contribute to noncompliance. Lithium causes hair loss in 12-19% of long-term users. Valproic acid and/ or divalproex precipitates alopecia in up to 12% of patients in a dose-dependent relationship. Incidences up to 28% are observed with high valproate concentration exposures. These pharmaceuticals also can change hair color and structure. The occurrence of carbamazepine-induced alopecia is at or below 6%. Hair loss is less common with other mood stabilizers. Tricyclic antidepressants, maprotilene, trazodone, and virtually all the new generation of antidepressants may on rare occasions lead to alopecia. The same applies to haloperidol, olanzepine, risperidone, clonazepam, and buspirone, but not to other neuroleptics, benzodiazepines, or barbiturates, selected antihistamines, and antiparkinsonians. Discontinuation of the medication or dose reduction almost always leads to complete hair regrowth. The therapeutic value of mineral supplements remains unclear.

Wow nice find. A doc told me that info...he was way wrong.

Been taking a Lithium Oratate tab in the AM and PM for at least 6 months now, I doubt that it's done much for my hair though. I just take it largely for my brain.

Am I reading this correctly? Is topical Lithium in some cases not good for hair loss?

hadrion - Usually topical lithium has an anti-inflammatory effect. There is a small number of users who may have adverse effects, which often result in a rash. I read somewhere it's about a 13% occurrence.

Usually however, prescription lithium (carbonate) which is toxic at the doses needed for internal effects impair thyroid function and result in hair loss.

Topically lithium should not be a problem.

Internal natural lithium, such as aspartate or orotate will reduce sebum. The mechanisms of action are described below:


Arch Dermatol Res. 2008 Jun;300(5):215-23.
Anti-inflammatory effects of lithium gluconate on keratinocytes: a possible explanation for efficiency in seborrhoeic dermatitis.
Ballanger F, Tenaud I, Volteau C, Khammari A, Dréno B.

Department of Dermatology, CHU Hôtel Dieu, Nantes Cedex 01, France.

Topical lithium (Li) gluconate has a beneficial effect on seborrhoeic dermatitis (SD), unlike oral lithium (Li) used in psychiatry. SD is an inflammatory dermatitis associated, in most of cases, with colonization by lipophilic yeasts of the genus Malassezia. However, the exact mechanism of action of Li gluconate in SD still remains unknown. The aim of our study was to investigate the effect of topical Li on cytokine secretion and innate immunity. For this purpose, we investigated first the modulatory effect of Li on two pro-inflammatory and two anti-inflammatory cytokine secretion and second, the modulatory effect of Li on Toll-like receptor (TLR) 2 and 4 expression by unstimulated and stimulated keratinocytes. Two different skin models were used: keratinocytes in monolayer and skin explants. In some of them, inflammation was induced with LPS (1 mug/ml) or zymosan (2 mg/ml). Then the skin models were incubated with Li gluconate (Labcatal*, Montrouge, France) at three different concentrations (1.6, 3, 5 mM) determined according to viability MTT test. Expression of TNFalpha, IL6, IL10, TGFbeta1, TLR2 and TLR4 was detected by immunohistochemistry (IHC). Cytokines were quantified by ELISA methods. Our results showed that the effect of Li on keratinocytes is dose-dependent. At low concentration (1.6 mM), Li enhanced TNFalpha secretion, whereas, at higher concentration (5 mM), Li significantly enhanced IL10 expression and secretion. However, there was no significant modulation of Li on IL6 and TGFbeta1 secretion. Moreover, Li at 5 mM significantly decreased TLR2 and TLR4 expressions by differentiated keratinocytes. As Li concentration during topical treatment is probably closer to 5 mM than to 1 mM, the therapeutic effect of Li gluconate in DS may be explained by two anti-inflammatory actions: an increased expression and secretion of IL10 and a decreased expression of TLR2 and TLR4 by keratinocytes. The diminution of TLR2 expression by Li may not allow MF to trigger inflammation response in lesional skin.

Ann Dermatol Venereol. 2007 Apr;134(4 Pt 1):347-51.
[Lithium gluconate 8% in the treatment of seborrheic dermatitis]
[Article in French]

Dréno B, Blouin E, Moyse D.

Département de Dermatologie, CHU de Nantes, 44035 Nantes Cedex. bdreno@wanadoo.fr

Seborrheic dermatitis is a chronic from of inflammatory dermatitis characterized by erythema and desquamation with predominant localization on the face (nasolabial folds, eyebrows, hair-line and ears). It appears to be caused by proliferation of Malassezia yeasts. Lithium gluconate 8% gel (Lithioderm 8% gel) is the only drug containing topical lithium salt commercially available in France for the treatment of seborrheic dermatitis. The mechanism of action of topical lithium is not well known; it may act through anti-inflammatory and antifungal action. Efficacy and safety were assessed in 2 clinical studies, one versus placebo and the other versus ketoconazole 2% foaming gel using the same principal criterion defined as the rate of patients showing complete remission after 2 months of treatment (complete disappearance of both erythema and desquamation). Lithium gluconate 8% was significantly more effective than placebo and than ketoconazole 2% foaming gel and was well tolerated. Adverse events observed were cutaneous (burning sensation, erythema and pruritus), for the most part of mild severity. No cutaneous side effects contributed to those reported with the use of systemic lithium in psychiatric disorders were noted. Pharmacokinetic studies have shown that systemic absorption after topical application is low. Lithioderm 8% gel is applied twice daily over a recommended period of 2 months. It constitutes a new alternative in the treatment of facial seborrheic dermatitis, regardless of severity.

Thanks IH. I think I fall into the category of people who topical lithium works as an anti-inflammatory since my inflammation and itching has been nil since I've used your topical.

CS, I see you removed the lithium topical from your immortalhair.org page, do you still recommend using lithium as a topical? And what are your thoughts on oral supplementation with lithium these days?

It works good as a way to stop the sebum. The only problem is, it wasn't really effective to boosting hair growth. And it can feel quite dry on the scalp. So, it's more of a treatment than something that works something providing multiple benefit.

Vitamin A (with Vitamin D3) will keep a better handle in the long run on sebum, so that's primarily why I took the lithium topical off the page.

Lithium as orotate (not the prescription form) at 5 to 10 milligram elemental doses is quite helpful for neurological conditions.

CausticSymmetry wrote:

Vitamin A (with Vitamin D3) will keep a better handle in the long run on sebum, so that's primarily why I took the lithium topical off the page.

Lithium as orotate (not the prescription form) at 5 to 10 milligram elemental doses is quite helpful for neurological conditions.

CS, do you mean topical Vit. A and D3 or internal for sebum reduction?

Also, when you say Lithium Orotate 5 to 10mg being helpful for neurological conditions, does it increase Nerve Growth Factor?