Experimental treatment of androgenic alopecia

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Management of androgenic alopecia
Classification and external resources
1583 - Archaeological Museum, Athens - Herm of the kosmetes Heliodoros - Photo by Giovanni Dall'Orto, Nov 11 2009.jpg
Experimental treatment of androgenic hair loss is a vast and expanding industry.
ICD-10 L64.1
ICD-9 704.0
DiseasesDB 7773
MedlinePlus 001177
eMedicine derm/21
MeSH D000505

The experimental treatment of androgenic hair loss is vast, with systemic and topical therapies with varying degrees of efficacy. In the United States alone, it is a multi-billion dollar industry. The entire field of research cannot be appropriately addressed in a single article, but the following discusses those with the greatest amount of peer reviewed research and recognition.

Experimental medical treatment[edit]

Bimatoprost and latanoprost[edit]

Prostaglandin F2α (PGF2a) analogues induces hair regrowth in animal models of androgenic alopecia with transgenic mice,[1] and stump-tailed macaques,[2] and initially generated 'great expectations' in pharmaceutical research for potential effectiveness in alopecia.[3] Latanoprost and bimatoprost are specific PGF2a analogues applied topically, and have been found to lengthen eyelashes,[4][5] darken hair pigmentation[6] and elongate hair.[7] Bimatoprost (Latisse®) is available as treatment for eyelash growth.[8] Latanoprost (Xalatan®) has shown ability to promote scalp hair density and pigmentation,[9] and is theorized to function at the dermal papilla.[10] A study found latanoprost ineffective on eyelashes in a patient with alopecia areata.[11] It has also been found ineffective in treatment of eyebrow hair loss.[12]

Caffeine[edit]

Caffeine has been identified as a stimulator of human hair growth in vitro, and reduced testosterone-induced follicle growth suppression.[13] It has been demonstrated that the addition of caffeine to a shampoo-formulation is effective in administering caffeine to the hair follicles in the scalp.[14] Further research must be done to evaluate the efficacy and adequate dosage of caffeine in the treatment of androgenetic alopecia. A spray made with coffee beans is claimed by the UK pharmacy chain Boots to prevent age-related hair loss in women.[15]

Copper complexes[edit]

Topical copper complexes such as Tricomin have been reported[where?] successful in preventing hair follicle death.[citation needed]

Cyproterone acetate[edit]

Cyproterone acetate is a topical agent in a lipid suspension that has anti-androgenic activity at the pilosebaceous unit.[16] It has shown similar efficacy to 2% minoxidil in treatment of female androgenic hair loss, with cyproterone acetate being more effective when women had high body mass indices, and minoxidil more effective when they weighed less.[17] It has also been shown effective in acne and hirsutism, but no longer marketed due to theoretical risks of venous thromboembolism. More recent studies have shown that this risk is no greater than that seen with oral contraceptives.[18]

Estrogen[edit]

Estrogens are indirect anti-androgens, and can be used to treat androgenetic hair loss in females with oral contraceptives. Systemic estrogen increases SHBG, which binds androgens, including testosterone and DHT, in turn reducing their bioavailability. Topical formulations are available in Europe.[19] Hair follicles have estrogen receptors and it is theorized topical compounds act on them directly to promote hair growth and antagonize androgen action. Large clinical studies showing effectiveness are absent. Topical treatment is also usually unavailable in North America.[7]

HIF-1[edit]

HIF-1 help prevents apoptosis, or cell death, in hypoxic conditions. In vitro, when supernatant from HIF-1 transfected fibroblast cells was administered to hair follicle cells, it induced VEGF, which had stimulatory effects on hair follicle cells. VEGF promotes growth of blood vessels, which would be an appropriate response to low oxygen conditions.[20] Other studies have suggested hypoxia initiates a potentially self-perpetuating cycle involving HIF, VEGF, and AKT activation. Ciclopirox, otherwise known as ciclopiroxolamine, is used as a topical shampoo, has anti-fungal properties, and may induce HIF-1.[21]

IGF-1[edit]

In December 2012, topical application of IGF-1 in a liposomal vehicle led to thicker and more rapid hair growth in transgenic mice with androgenic alopecia. The study did not show measurable systemic levels or hematopoietic side effects, suggesting potential for use in humans.[22] Low energy radiofrequency irradiation induces IGF-1 in cultured human dermal papilla cells.[23] Adenosine stimulates dermal papillae in vitro to induce IGF-1, along with fibroblast growth factors FGF7, FGF-2 and VEGF. β-catenin transcription increased, which promotes dermal papillae as well.[23] Dietary isoflavones increase IGF production in scalp dermal papillae in transgenic mice.[24] Topical capsaicin also stimulates IGF at hair follicles via release of vanilloid receptor-1, which in turn leads to more CGRP.[25][26] Ascorbic acid has led to increased IGF expression in vitro.[27]

Piroctone Olamine[edit]

Piroctone olamine is a topical agent that has similar efficacy to 1% ketoconazole in small controlled trials.

Prostaglandin D2[edit]

In 2012, scientists found the lipid prostaglandin D2 (PGD2) in balding male scalps at levels higher than controls, and theorized it prevented hair follicles maturation. The lead investigator said treatment could be possible within two years.[28][29][30]

Valproic acid[edit]

Mouse models have found valproic acid activates alkaline phosphatase in human dermal papilla cells and induces hair regeneration in transgenic mice.[31] Systemic valproic acid can cause alopecia,[32] although this may be related to deficiencies of biotin and zinc.[33][34]

Wnt protein introduction[edit]

Androgens interact with the Wnt signalling pathway to cause hair loss; researchers are also affecting the pathway in animal models.

In May 2007, U.S. company Follica Inc licensed technology from the University of Pennsylvania to regenerate hair follicles by reawakening genes from embryonic development. Studies began with the study of hair regrowth in wound healing in mice when Wnt proteins were introduced. Time till development of pharmaceutical treatment is expected to take several years.[35][36]

In other methods, cells are cultured and the supernatant is processed to produce a compound rich in hair growth promoting factors, like Wnt proteins. This approach is still in Phase I or II trials. Platelet rich plasma (PRP) isolated from whole blood can be used for its growth factors and stimulatory mediators. Some hair transplant surgeons use this product to encourage transplanted graft growth.[37] PRP is also available as a standalone treatment for AGA, though there is only one small study to date in its support.[38]

Dietary and health supplements[edit]

The dietary supplement industry is distinct from the pharmaceutical industry, and is more loosely regulated than FDA approved medications. The most commonly used and well researched plants are saw palmetto (Serenoa repens), stinging nettle (Urtica dioica), turmeric (Curcubita pepo), and pygeum africanum (Prunus africana).[39] Other herbs include black cohosh (Actaea racemosa), dong quai (Angelica sinensis), false unicorn (Chamaelirium luteum), chasteberry (Vitex agnus-castus), and red clover (Trifolium pratense). Each of them purport hair promoting effects by various mechanisms. Common nutritional supplements include biotin, caffeine and melatonin.[19][40]

5 alpha reductase inhibitors[edit]

A number of herbal substances have been reported to inhibit 5 alpha reductase, the enzyme which catalyzes conversion of testosterone to DHT to cause androgenic miniaturization at the hair follicle dermal papilla. Examples of inhibitors include certain unsaturated aliphatic fatty acids, such as gamma-linolenic acid and myristoleic acid, as well as other natural compounds, including alizarin and curcumin, and green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG).[41] Zinc,[42] azelaic acid,[42] β-sitosterol,[43] certain unsaturated aliphatic fatty acids such as gamma-linolenic acid, alpha-linolenic acid, linoleic acid, myristoleic acid, and oleic acid,[44] and a variety of polyphenols[45] have been found to inhibit 5α-reductase activity to varying degrees. Other inhibitors include alizarin, curcumin, and green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG).[41]

Among polyphenols, valoneic acid dilactone and gallagyldilactone, two hydrolysable tannins isolated from the heartwood of Shorea laeviforia[46] and in oaks species like the North American white oak (Quercus alba) and European red oak (Quercus robur),[47] shows an inhibitory effect on 5α-reductase. Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens.[48]

Compounds in nature are able to inhibit 5α-reductase, such as the chemical found in the Reishi mushroom Ganoderma lucidum.[49] [50][51] Ganoderic acid[52] or organoderol B are thought to be the compounds in the mushroom that are specifically active.[53]

Medium chain fatty acids such as those found in coconut and the kernel of many palm fruits also inhibit 5α-reductase.[54]

Other herbs include:

These supplements have limited testing in human clinical trials, and their complete potential for treatment of androgenic hair loss.

Saw palmetto[edit]

Saw palmetto (Sabal serrulatum or Serenao repens) may inhibit 5 alpha reductase and is approved for treatment of prostate disorders in Germany as well.[74] Studies of Italian men have found it effective at 320 mg/day at improving symptoms of prostate enlargement.[75] A meta-analysis looking at effects of Serenao in BPH and prostate adenocarcinoma was unable to make conclusions regarding its effects in BPH due to limitations of studies in the literature.[76]

Nettle[edit]

Nettle (Urtica dioica) inhibits 5 alpha reductase in vitro when given in combination with Pygeum africanum.[77] It ameliorates symptoms of BPH in rats,[78] and has been found protective against reperfusion injury in organ ischemia.[79] In testosterone treated animal models when compared to finasteride, it has been found therapeutic for prostatic hyperplasia, although less efficate than the medication.[80] It has also shown to impair inflammation by inhibiting platelet aggregation.[81] Patients treated with the plant have also shown reduced need for anti-inflammatory medication.[82] Nettle is approved for treatment of prostate disorders in Germany.[74]

Pygeum africanum[edit]

Pygeum africanum inhibits 5 alpha reductase in vitro when given with Nettle (Urtica dioica).[77] In vitro cultured prostate stromal cells from patients with BPH show the herb to induce apoptosis.[83] N-butylbenzene-sulfonamide (NBBS), isolated from Pygeum africanum bark, acts as an androgen antagonistic, inhibits AR nuclear translocation and prostate cancer cell growth.[84] Atraric acid, isolated from bark material of Pygeum africanum, has anti-androgenic activity, inhibiting transactivation mediated by ligand-activated human AR.[85] A meta-analysis looking at effects of Pygeum africanum in BPH and prostate adenocarcinoma was unable to make conclusions regarding its effects in BPH due to limitations of studies in the literature.[76]

L-Arginine[edit]

L-Arginine is the amino acid precursor to nitric oxide. Nitric oxide itself is a free radical with an unpaired electron, and has a role in host immune defense against pathogens. Citrulline is produced as a side product by nitric oxide synthase. Consumption of 5 to 9 grams of arginine leads to growth hormone release.[86] The enzyme trichohyalin specifically converts arginine to citrulline at the inner root sheath and medulla of hair follicles.[87] Administration of arginine prior to resistance exercise attenuates the growth hormone response.[88] In vitro studies have shown dermal papilla cells derived from human hair follicles spontaneously produce nitric oxide. Basal nitric oxide levels are enhanced threefold by stimulating dermal papilla cells with 5alpha-dihydrotestosterone (DHT) but not with testosterone. Addition of N-[3-(aminomethyl)benzyl]acetamidine (1400W), a highly selective inhibitor of inducible nitric oxide synthase, restrained DHT induced elevation in nitric oxide.[89] Androgens enhance inducible nitric oxide synthase from occipital dermal papillae cells.[90]

Boswellia serrata[edit]

Boswellia serrata is an herb that has been used in Ayurvedic medicine, and has recently come to the mainstream for its effects on the hormone cascade.[citation needed]

Biotin and MSM[edit]

Biotin is taken as a health supplement, although it is not usually recommended by nutritionists, as it is already produced as a byproduct of gut bacteria. Patients with biotinidase deficiency have been reported.[91] Deficiencies can also occur in patients on long term TPN[92] and after modified Whipple procedures.[93] In its fulminant form and more often in children, biotinidase deficiency is characterized skin rashes, developmental delay, seizures, seborrheic dermatitis, alopecia and acidosis.[94] In forme fruste it can present as hair loss occurring only during times of stress.[95] Treatment involves replacement of biotin, and treatment of underlying malabsorptive disorder if contributive.[96] Biotin supplementation was found beneficial in a case of familial unruly hair.[97] Deficiencies can be detected by urine assay.[98]

Black tea[edit]

Theaflavins in black tea are supposed to inhibit formation of DHT to a degree similar to finasteride.

Capsaicin[edit]

Capsaicin is the active ingredient in chili pepper and works through TRPV receptor. Animal and human studies showing it affects hair regrowth.

The transient receptor potential vanilloid type 1 ion channel (TRPV1) mediates the intense burning sensation after exposure to heat greater than approximately 43°C, or capsaicin, the pungent ingredient of hot chilli peppers. This receptor may play an important role in regulation of the hair follicle cycle.[99] An early study in animal models showed that substance P induced by capsaicin stimulated hair growth.[100] It also promotes neural innervation of hair follicles in neonatal animal studies.[101][102] A study in which a combination of subcutaneous capsaicin and isoflavone was administered to bald (CGRP knockout) mice dermal IGF-1 at hair follicles and hair regrowth. The mechanism was thought to be through activation of vanilloid receptor-1 causing release of CGRP from neurons, in turn causing release of IGF-1. Human volunteers administered oral isoflavone and capsaicin also showed hair regrowth.[25] Other studies on less nociceptive medications found topical raspberry extract to work through a similar mechanism as capsaicin.[103] However, recent studies on rats in which skin was denervated by capsaicin showed slower egress of stem cells after wounding, suggesting a mechanism for slower healing with dennervation.[104] In vitro studies have not been consistent. Vanilloid receptor-1 (VR1, or transient receptor potential vanilloid-1 receptor, TRPV1) is activated by capsaicin, the key ingredient of hot peppers. In organ culture, capsaicin activation of TRPV1 caused dose-dependent inhibition of hair elongation, suppressed proliferation, induced apoptosis, caused premature regression (catagen), and up-regulated TGF-β2[105] The same research group found that TRPV1 activation also inhibits sebum formation.[106] Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel activated by capsaicin, is also activated by 4 essential oil — rose, thyme geraniol, palmarosa, and tolu balsam.[107]

L-Carnitine[edit]

In vitro studies suggest L-carnitine induces hair growth, and it is a component of some dietary supplements.[108][109][110]

Curcumin[edit]

Curcumin, from Curcuma longa, is the yellow curry pigment in turmeric, an herb used in traditional Indian and east Asian cuisine. It has been reported modulate several pathways including cellular proliferation, apoptosis, inflammation, and androgen receptor signaling.[111][112] Specifically, curcumin has been reported to enhance androgen receptor (AR) degradation.[113] In vitro studies of keratinocytes showed it to oppose TGF-beta1 release, which DHT induces. TGF-beta1 induces anagen in hair follicles.[114] It also has weak affinity for the vitamin D receptor.[115] It has been shown to work via a glutathione (GSH)-linked detoxification mechanisms in rats and ex vivo human models.[116] Studies on prostate cancer with curcumin alone, or coupled to anti-androgens, suggest it prevents growth by inhibiting pseudopodia formation.[117] 3-dimensional imaging has shown curcumin to conform to the androgen receptor,[118] which other studies have confirmed.[119] In combination with soy, it is inhibitory for symptoms of BPH.[120] ASC-J9, a derivative of curry, has been used to target androgen receptors for degradation.[121] It also down regulates androgen receptor gene expression.[122] Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation.[123]

3,3′-Diindolylmethane[edit]

3,3'-Diindolylmethane (DIM) is a compound derived from the digestion of indole-3-carbinol, found in cruciferous vegetables such as broccoli, brussels sprouts, cabbage and kale.[124] The reputation of Brassica vegetables as healthy foods rests in part on the activities of diindolylmethane.[125][126] Controlled studies have shown activity in the Wnt signalling pathway in prostate cancer.[127] In androgen receptor sensitive disease, it specifically acts through the Wingless pathway.[128]

Emu oil[edit]

The emu, or Dromaius novaehollandiae, is a large flightless bird native to Australia. Its oil extract increases levels of prostaglandin E, and reduces transdermal inflammation when applied topically.[129] Quality of bird diet affects the amount of polyunsaturated fat in the oil extract, which could limit standardization of effect.[130] The oil is high in nonpolar monounsaturated fatty acids, which may explain its ability to easily pass through the stratum corneum of the skin. It also reduces levels of TGF-alpha, which plays a part in the inflammatory response.[131] The oil has been used therapeutically in traditional Aboriginal medicine for centuries, and is preferred to mineral oil in cosmetic studies.[132]

Ginger[edit]

Ginger may decrease levels of Prostaglandin F2 (PGF2). Older studies on Zingiber officinale roscoe does not affect platelet activity ex vivo.[133] More recent work on Zingiber cassumunar showed two of its specific phenylbutenoid monomers to have moderate inhibitory activity.[134] Ginger inhibits eicosanoid formation in phase II studies of people at risk for colon cancer, suggesting anti-inflammatory properties.[135] It also suppresses production of free radicals, proinflammatory proteins, and cancer cells in ex vivo and in vitro conditions.[136] When applied topically, ginger extracts protect against inflammation in UV damaged skin in animal models.[137]

Grape seed extract[edit]

Proanythocyanidin oligomers, extracted from grape seeds and applied topically, promote hair growth in vitro, and induce anagen in vivo. Procyanidin C2 was the subtype of extract most effective.[138] Another study found grape seed extract to promote over twice as much hair follicle proflieration than controls.[139] Grape seed also contains resveratrol, a plant compound also found in red wine and Japanese knotweed, and which some experiments have shown to slow aging.[140]

Grateloupia elliptica[edit]

In 2012, a Korean scientific study showed that Grateloupia elliptica, a red seaweed native to Jeju Island, South Korea, has the potential to treat androgenic alopecia and alopecia areata.[141][142]

Green tea[edit]

Green tea research has been mixed, although it generally supports that it prevents hair loss. Green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG) are non-steroidal 5 alpha-reductase inhibitors, similar to the steroidal inhibitor finasteride, although non-covalent in bonding and reversible. Topically, it inhibits growth of DHT sensitive tissue with in vivo animal models.[41] It may increase testosterone levels. It does enhance the activity of chemotherapy on androgen sensitive prostate cancer,[143] Dihydrotestosterone sensitises LNCaP cells to death induced by epigallocatechin-3-Gallate (EGCG) or an IGF-I receptor inhibitor.[144] One study in mice showed it to increase DHT.[145]

Lycopene[edit]

Lycopene may inhibit 5 alpha reductase[citation needed]

Pumpkin seed oil[edit]

Pumpkin seed oil (Curcurbitae pepo) may inhibit 5 alpha reductase and is approved for treatment of prostate disorders in Germany.[74]

Resveratrol[edit]

Resveratrol is a polyphenol found in red wine and grape seed, and thought to mimic calorie restriction through SIRT1 activation. It lengthens telomeres on DNA, and theoretically slows ageing.

Soy[edit]

There has been a great deal of research on the plant ligands in equol, a component of soy protein. Studies suggest it has effect against prostate cancer, although this also applies in androgen receptor negative variants.[119]

Quercetin[edit]

Quercetin has an anti-inflammatory effect on prostaglandins. It prevents alopecia areata in animal models, although studies have not been done in the setting of androgenic hair loss.[146]

See also[edit]

References[edit]

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