Management 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
Androgenic hair loss has been a field of study since ancient times
ICD-10 L64.1
ICD-9 704.0
DiseasesDB 7773
MedlinePlus 001177
eMedicine derm/21
MeSH D000505

Androgenic hair loss is due to the activity of androgens, predominantly DHT, at the dermal papillae of the individual follicles. In adult men, its incidence is roughly equivalent to chronologic age, and it has a strong genetic component.[1]

Female androgenic alopecia more often causes diffuse thinning without hairline recession, and like its male counterpart rarely leads to total hair loss.[2] Treatment options are similar to those for men, although topical or systemic estrogen is used more often.[2][3] Finasteride and minoxidil are usually first line therapy for its treatment, with other like topical or systemic spironolactone or flutamide more often used in female androgenic hair loss due to a higher incidence of feminizing side effects.

More advanced cases may be resistant or unresponsive to medical therapy, however, and require hair transplantation. Naturally occurring units of one to four hairs, called follicular units, are excised and moved to areas of hair restoration. These follicular units are surgically implanted in the scalp in close proximity and in large numbers. The grafts are obtained from either Follicular unit transplantation (FUT), colloquially referred to as 'strip harvesting,' or Follicular Unit Extraction (FUE). In the former, a strip of skin with follicular units is extracted and dissected into individual follicular unit grafts. The surgeon then implants the grafts into small incisions, called recipient sites.[4][5] Specialized scalp tattoos can also mimic the appearance of a short buzzed haircut.[6][7]

Conventional medication[edit]

The two first line medications in treatment of male pattern baldness are minoxidil (Rogaine)[8] and finasteride (Propecia).[9] They may also be used simultaneously when hair loss is progressive or further regrowth is desired after 12 months.[8] A number of other medications used commonly off-label are dutasteride and ketoconazole, and in female androgenic alopecia spironolactone and flutamide.[10] Combinations of finasteride, minoxidil and ketoconazole are more effective than individual use, suggesting synergistic effects of the medications.[11]

5 alpha reductase inhibitors[edit]

Finasteride[edit]

Propecia (finasteride) 1 mg tablets

Finasteride (marketed by Merck as Propecia and Proscar) is a type-2 isoenzyme 5 alpha-reductase inhibitor. It was originally FDA approved for treatment of benign prostatic hyperplasia (BPH), and binds 5-alpha-reductase, preventing conversion of testosterone to DHT. Its effects on androgenic alopecia were not unexpected due to observations of the pseudo-hemaphrodite population in Papua, New Guinea. Both systemic and topical formulations are effective in androgenic hair loss.[12]

Inhibition of 5α-reductase results in decreased conversion of testosterone to dihydrotestosterone (DHT) by reducing the Δ4,5 double-bond. This, also leads to increased levels of testosterone and estradiol. Gynecomastia, erectile dysfunction and depression, are some possible side-effects. Other locally expressed enzymes can compensate to a degree, including DHT conversion through reductive 17b-hydroxysteroid dehydrogenase, oxidative 3a-hydroxysteroid dehydrogenase, and 3b-hydroxysteroid dehydrogenase enzymes.[13]

In clinical studies, finasteride, like minoxidil, is effective at the crown and frontal hairline area, but more so at the former.[14] A study over 2 years with 1,553 men between ages 18 and 41 with mild to moderate hair thinning taking 1 mg/day showed 83% maintained or increased hair growth.[15] In 1997, the drug was FDA approved for male pattern baldness. A 5-year study revealed that 9 of 10 men taking finasteride at 1 mg/day experienced results. 42% had no further loss while 48% experienced regrowth.[16]

The drug is lipophilic,[17] and development of a liposomal system of finasteride for topical application has been a subject of recent study, with vehicles shown stable for up to two months in refrigerated preparation.[18] Topical formulations show some effect in reversal of androgenic effects on hair follicles,[19] as well as in hirsutism.[20] Studies of transgenic mice have shown hair regrowth with topical administration.[21] More recent studies have looked at microemulsions[17] and liquid crystalline nanoparticles for topical finasteride delivery. In the latter, addition of glycerol, propylene glycol, and polyethylene glycol 400, increased finasteride permeation, while addition of oleic acid made it decrease.[22] Topical 0.1% finasteride in combination with topical 3% minoxidil is more effective than topical minoxidil alone.[23] Small studies of topical finasteride formulations in combination with other drugs have also been found effective.[24] Surfactants have been shown to aid topical absorption.[25] Topical finasteride gel has been shown an effective route of administration.[26] Of note, the studies evaluating topical finasteride did not correlate with serum PSA in humans, or prostatic weight in animal studies to see if effects were related to systemic absorption. Other studies have shown lower doses of topical finasteride to be less effective.[27] Microparticulate vehicles, like liposomes and nanoparticles, are more effective at delivering drug molecules much deeper into hair follicles than conventional formulations like creams and ointments.[28]

The medication is not entirely benign. Some patients experience neurologic or psychiatric sequellae after discontinuation of the drug, a condition described in medical literature as 'post-finasteride syndrome'.[29]

Dutasteride[edit]

Avodart (dutasteride) 500 µg capsules

Dutasteride (trademark name Avodart, manufactured by GlaxoSmithKline) is approved for the treatment of benign prostatic hyperplasia (BPH), and used off label for androgenic alopecia.[30] It is a dual 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone (DHT). The drug inhibits all three isoforms of 5-alpha reductase, whereas finasteride only inhibits type II and III.

Phase I and II clinical trials for dutasteride as a hair loss drug were started, but discontinued in late 2002 for unknown reasons. Phase II studies showed that dutasteride, at both 0.5 mg and 2.5 mg per day, showed a superior hair count as compared to finasteride 5 mg at 3 and 6 months.[31]

Phase II results at 24 weeks showed placebo to decrease by 32 hairs, dutasteride 0.5 mg to increase an average of 95 hairs, while the dutasteride 2.5 mg group increasing by 110 hairs. GlaxoSmithKline ran a phase III, six month study in Korea to test the safety, tolerability and effectiveness of a once-daily dutasteride at 0.5 mg. They looked at male pattern baldness (MPB) at the vertex of the scalp, types III, IV and V on the Hamilton-Norwood scale. The study completed in January 2009.[32][33] Future intentions by GlaxoSmithKline for FDA approval of dutasteride in androgenic alopecia are unknown.

Alfatradiol[edit]

Alfatradiol is a topical 5α-reductase inhibitor that has been shown to slow progression of hair loss in women.[34] It is marketed as Avixis, ELL Cranell Alpha and Pantostin.[35]

Other topical treatments[edit]

Minoxidil and ketoconazole are two long standing topical treatments of androgenic alopecia, with only the former having FDA approval for androgenic alopecia in the United States. Ketoconazole is also used as an anti-fungal in the treatment of tinea capitis.

Minoxidil[edit]

Minoxidil (Rogaine) is a vasodilator. It was originally used as the oral drug Loniten to treat hypertension, and discovered to cause hair growth as a side effect. Upjohn received FDA approval to market a topical solution that contained 2% minoxidil as Rogaine, marketed outside the United States as Regaine.

It is effective at both the front and scalp vertex. In a 12 month study, vertex improvements were seen in 51% of men using 5% minoxidil, 42% using 2% minoxidil, and 13% of placebo users. Moderate to great increases in hair growth were seen in the frontal scalp regions of 19% of men using 5% minoxidil, 10% using 2% minoxidil, and 3% of placebo.[36]

Its mechanism is not fully understood. Studies have suggested three possible mechanisms:

  1. Activation of sulfonylurea receptors (SURs) to prolong anaphase by unduction of IGF-1, VEGF, HGF, and potentiates HGF and IGF-1 by activation of uncoupled SURs at the plasma membrane of dermal papillae cells;
  2. Inhibition of TGF beta induction of apoptosis, by opening the Kir 6.0 channel pore, coupled with the SUR on mitochondrial inner membranes;
  3. Direct vasodilation of hair follicle arteries and increasing blood flow to dermal papilla by opening Kir 6.0 potassium channel pores coupled with SURs on plasma membranes of smooth muscle cells,[37] mimicking nitric oxide.[38]

Although a mitogen for dormant telogen follicles, minoxidil can cause hairs in later phases of the cell cycle to shed early. This is often followed by growth of new, thicker hairs. The mitogenic effect is temporary and does not appear to change follicular structure, leading to indefinite minoxidil application to maintain growth.[39] Use of minoxidil without propylene glycol as a vehicle can reduce associated itching.[40] The drug can also be combined with other active ingredients such as tretinoin.[10]

Anti-androgens[edit]

Ketoconazole is a mild topical anti-androgen available over the counter and in prescription strength in the United States. It is established as treatment for tinea capitis, but also has anti-androgenic and microfloral benefit in androgenic hair loss. Spironolactone and flutamide are potent topical and systemic anti-androgens, typically not used in men as they have a high incidence of feminizing side effects.[41] They can be prescribed off-label as part of a more aggressive medical regimens, and are effective in female androgenic hair loss.[42] There is some association between androgen deprivation and precipitation of underlying heart disease, with complications including myocardial infarction and congestive heart failure.[43]

Ketoconazole[edit]

Ketoconazole is a topical anti-fungal agent. As an imidazole, ketoconazole is effective for the treatment of dermatitis and dandruff, and its action on scalp microflora may benefit those with AGA associated follicular inflammation.[10][44][45] It is also an anti-androgen, and may improve hair growth in AGA through androgen dependent pathways.[46]

Spironolactone[edit]

Spironolactone is a possible selective androgen receptor modulator,[47] and both reduces adrenal androgen production and exerts competitive blockade on androgen receptors in target tissues.[41] It can be administered topically or systemically. In addition to anti-androgenic activity, it increases estrogen production, which in turn increases production of SHBG. SHBG binds free DHT and decreases free androgen indices.[48] Due to its feminizing side effects and risk of infertility in men[49] It is used more often in female androgenic alopecia,[50] particularly PCOS.[51] As it is also an anti-hypertensive, patients need to be monitored for hyperkalemia and associated cardiac dysrhythmia. Also, women who are pregnant or trying to become pregnant generally cannot use the medication as it is a teratogen, and can cause ambiguous genitalia in newborns.[42]

Flutamide[edit]

Flutamide has more anti-androgenic activity than spironolactone, and is also referred to as chemical castration. It can cause marked reduction in libido and estrogenic side effects including gynecomastia, lipid profile changes, and emotional lability, although when used in women it can be associated with increased positive affect. There is a significant incidence of hepatic dysfunction with the medication in women.[52] Like spironolactone, it is more often used clinically in female androgenic alopecia.[53]

Hair transplantation[edit]

Main article: Hair transplantation
A man before and after a hair transplant.

Hair transplantation is a surgical technique that moves individual hair follicles from a part of the body called the 'donor site' to bald or balding part of the body known as the 'recipient site'. It is primarily used to treat male pattern baldness. In this condition, grafts containing hair follicles that are genetically resistant to balding are transplanted to bald scalp. It is also used to restore eyelashes, eyebrows, beard hair, chest hair, and pubic hair and to fill in scars caused by accidents or surgery such as face-lifts and previous hair transplants. Hair transplantation differs from skin grafting in that grafts contain almost all of the epidermis and dermis surrounding the hair follicle, and a single strip of skin is transplanted, rather than many tiny grafts.

Since hair naturally grows in follicles in groups of 1 to 4 hairs, transplantation takes advantage of these naturally occurring follicular units. This achieves a more natural appearance by matching hair for hair through Follicular unit transplantation (FUT).

Donor hair can be harvested two different ways. Small grafts of naturally occurring units of one to four hairs, called follicular units can be moved to balding areas of the hair restoration. These follicular units are surgically implanted in the scalp in very close proximity to one another and in large numbers. The grafts are obtained in one or both of the two primary methods of surgical extraction, Follicular unit transplantation (FUT), colloquially referred to as 'strip harvesting,' or Follicular Unit Extraction (FUE), in which follicles are transplanted individually.

In FUT, a strip of skin containing many follicular units is extracted from the patient and dissected under stereoscopic microscope. Once divided into follicular unit grafts, the surgeon implants each individually into small recipient sites made by incision at the bald scalp. In newer technique, roots are extracted from the donor area and divided into strips for transplantation. The strip, two to three millimeters thick, is isolated and transplanted to bald scalp.[54] After surgery, bandaging is worn for two days for healing.[55]

More recently, bioengineered hair follicles have been successfully transplanted to create histologically normal hair follicles. Specifically, bioengineered hair follicle germ, which was reconstituted with embryonic skin-derived epithelial and mesenchymal cells were ectopically transplanted. On histology, the bioengineered hair follicles also autonomously connected with nerves and the arrector pili muscle at the permanent recipient region.[56] Facial hair follicles have been successfully transplanted to disguise prior transplant scar.[57] Surgical technique has become sophisticated to the point that piloerection is preserved in follicles.[58]

Experimental[edit]

The field of research to prevent and treat 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 section discusses those with the greatest degree of peer reviewed research and recognition.

Cyproterone acetate[edit]

Cyproterone acetate is a topical agent in a lipid suspension that has anti-androgenic activity at the pilosebaceous unit.[59] 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.[60] 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.[61]

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.[62] 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.[10]

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.[63] 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.[64]

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.[65] Low energy radiofrequency irradiation induces IGF-1 in cultured human dermal papilla cells.[66] 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.[66] Dietary isoflavones increase IGF production in scalp dermal papillae in transgenic mice.[67] Topical capsaicin also stimulates IGF at hair follicles via release of vanilloid receptor-1, which in turn leads to more CGRP.[68][69] Ascorbic acid has led to increased IGF expression in vitro.[70]

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.[71][72][73] Ginger can affect PGD2 levels in serum.[citation needed]

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.[74][75] 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.[76] PRP is also available as a standalone treatment for AGA, though there is only one small study to date in its support.[77]

Other surgical methods[edit]

Guyuron et al article published on Dec 23rd found that a pre-trichial (hairline) surgery for forehead rejuvenation caused preservation of the hairline in women when compared to controls that did not have the surgery and also when compared to endoscopic surgery which makes smaller incisions. study

Impact of exercise[edit]

Although there are few studies directly comparing exercise and hair loss, several lines of evidence demonstrate the direct relationship between androgen indices and hair loss. The impact of exercise on testosterone and DHT has also been studied extensively. Quantification of androgen indices in response to exercise can be understood in four categories: short versus long term, and anaerobic versus aerobic. These are indirect assays of exercise impact on hair loss, although the ability of exogenous androgen to worsen or precipitate miniaturization in the genetically predisposed is well documented.[78] Investigations have been either self-report, or cross-sectional and cohort studies with exercise and serum hormonal indices, but no phase III clinical trials. In some studies, conflicting results are thought related to differences in exercise mode, volume, or physical condition of subjects.[79]

In cross-sectional analyses, aerobic exercisers have lower basal total and free testosterone compared to the sedentary.[80][81][82][83] Anaerobic exercisers also have lower testosterone compared to the sedentary[80] but a slight increase in basal testosterone with resistance training over time.[84] There is some correlation between testosterone and physical activity in the middle aged and elderly.[85] Acutely, testosterone briefly increases when comparing aerobic, anaerobic and mixed forms of exercise.[86] A study assessed men who were resistance trained, endurance trained, or sedentary in which they either rested, ran or did a resistance session. Androgens increased in response to exercise, particularly resistance, while cortisol only increased with resistance. DHEA increased with resistance exercise and remained elevated during recovery in resistance-trained subjects. After initial post-exercise increase, there was decline in free and total testosterone during resistance recovery, particularly in resistance-trained subjects. Endurance-trained subjects showed less change in hormone levels in response to exercise than resistance-trained subjects.[87] Another study found relative short term effects of aerobic, anaerobic and combined anaerobic-aerobic exercise protocols on hormone levels to not be different. It showed increases in testosterone and cortisol immediately after exercise that returned to baseline in 2 hours.[88]

Aerobic[edit]

In trained long term aerobic exercisers, basal levels are unchanged,[89] or decreased.[88][90] Acutely, endurance based aerobic efforts cause testosterone to rise.[91]

A year long, moderate-intensity aerobic exercise program increased DHT and SHBG in sedentary men age 40–75, but had no effect on other androgens. Both DHT and SHBG increased 14% in exercisers at 3 months, and at 12 months they remained 9% above baseline. SHBG is protective against DHT as it binds free androgen.[92] In acute assessment of hormone levels in soccer players before, during and after a game, DHT and testosterone increased during the match, but returned to baseline after 45 minutes rest.[93] Aerobic exercise in Japanese rats done on a rodent treadmill doubled local concentrations of DHT in calf muscles as assessed by protein assay.[94] After intense aerobic effort, high endurance athletes were also found to have lower free testosterone the next day.[95] In prolonged endurance exercise, such as a marathon, levels ultimately decrease.[96] Similarly, DHT drops, while adrenal androgen and cortisol will increase with the stress response.[97]

Anaerobic[edit]

Effects of anaerobic exercise also vary with length of time.

It is unknown if anaerobic training changes individual hormone profiles, or if conditioned athletes in studies self-selected because of physiologic predisposition to athletic conditioning.[98] There is variation of response to anaerobic stress depending on exercise intensity, age, gender, length of time studied, and time at which serum indices were drawn. Most studies report that testosterone increases or is unchanged acutely, though some even report it to decrease. Anaerobic exercisers have testosterone levels below sedentary controls in cross sectional analysis. Over months to years, levels are stable to slightly increased.

The ratio of testosterone to cortisol can both increase[99] and decrease[100] during resistance training, depending on intensity of exercise. A study comparing young and old subjects showed acute increases in GH and testosterone for both, although the latter increased less in older men.[101] Testosterone rises in late hours of sleep after anaerobic exercise.[102] Androgen receptor expression increases with acute exercise in correlation to free testosterone.[103] When comparing men and women in the 30, 50 and 70 year age groups, young and middle aged men showed increased testosterone after exercise, with the latter also having increased cortisol. Elderly men showed no change.[104] Other studies have also shown with age there is a downtrend of testosterone[105] and attenuated growth hormone response.[106] Young men have shown no acute change in testosterone with resistance training, with increase in cortisol and growth hormone depending on intensity.[107] One study in young men showed testosterone acutely stable, with increase in GH and IGF-1.[108] Similarly, a study showed testosterone did not increase in young men, women, and pubescent boys unaccustomed to weight training when corrected for plasma volume.[109] Extreme intensity of strength training may trigger the stress response, resulting in lower testosterone levels,[110] an effect accentuated by energy deprivation.[111] A separate study comparing different ages, however, found no difference in acute testosterone and cortisol levels between groups, but attenuated growth hormone response in the elderly.[106] Acutely, other studies have shown testosterone to increase.[112] In a small group of anaerobically trained athletes, stressful training acutely even decreased serum testosterone and its ratio to cortisol and SHBG, with an increase in LH. With subsequent decompensation, testosterone was stable, but cortisol and SHBG decreased.[100] Another case control showed with intense training followed by rest, testosterone dropped and LH increased initially.[113]

Interval and quality of exercise also affect hormonal response. Sessions of moderate to high intensity with multiple sets and short time intervals, during which energy is derived from glycolytic lactate metabolism, appear to be the greatest stimulus for steroid hormone response. Hormonal response in young men varies with the number of sets in the exercise session. However, when the number increased from 4 to 6, anabolic levels stabilized and cortisol continued to rise, suggesting that alterations in anaerobic volume could alter anabolic and catabolic hormonal balance.[114] When sets are performed at maximum repetitions, interval has no influence at a certain intensity range, with no acute hormone response difference between protocols at 10 maximum reps with 2- and 5-minute intervals.[115] There is a higher total testosterone response in hypertrophy protocols compared to those for strength and power, despite equalization of total work load (defined as load x sets x repetitions).[116] There is a 27% greater testosterone response using protocols with simultaneous use of all four limbs. Androgenic response was also noted in protocols using upper and lower limbs separately to a lesser degree.[117]

A number of studies have looked at effects of anaerobic exercise over months to years, showing it to be constant or slightly increased. A small case-control of anaerobic training in young untrained males over six weeks found decline in free testosterone of 17 percent.[118] With men in their 60s, resistive training over 16 weeks did not affect baseline anabolic hormone levels, although GH increased acutely with exercise.[119] A study over 21 weeks in male strength athletes showed basal hormone levels to be constant, despite strength increase.[120] A follow up study looked at a larger group of weight trainers over 24 weeks, with 12 week decompensation. Training caused no change in total testosterone, but there were decreases in free testosterone, progesterone, androstendione, DHEA, cortisol, transcortin, and in the cortisol:CBG ratio, suggesting androgen turnover increased with training intensity, without change in total testosterone.[99] A study looking at young men and resistance training over 48 weeks found increases in baseline serum testosterone from 20 ± 5 to 25 ± 5 nmol/l, and an increase in testosterone:SHBG ratio, LH and FSH.[84]

Combined training[edit]

One study showed GH increase with anaerobic effort to be blunted in those who performed aerobic training for 60 minutes prior to strength training. Testosterone levels remained high only at the end of the training session with aerobic training followed by strength training, a phenomenon not seen with weight training done before aerobics.[121] In an 11 week soccer training program focusing on combined vertical jumps, short sprints, and submaximal endurance running, total testosterone increased, but SHBG rose in parallel, maintaining a constant free androgen index.[122]

Laser therapy[edit]

There is some evidence that laser light can stimulate hair growth at some wavelengths.[123] With one exception,[124] however, there is limited clinical evidence of their benefit.[125]

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 (Pygeum africanum), turmeric (Curcubita pepo), and Urtica dioica.[126] 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.[62][127]

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.[128] Studies of Italian men have found it effective at 320 mg/day at improving symptoms of prostate enlargement.[129] 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.[130]

Nettle[edit]

Nettle (Urtica dioica) inhibits 5 alpha reductase in vitro when given in combination with Pygeum africanum.[131] It ameliorates symptoms of BPH in rats,[132] and has been found protective against reperfusion injury in organ ischemia.[133] In testosterone treated animal models when compared to finasteride, it has been found therapeutic for prostatic hyperplasia, although less efficate than the medication.[134] Nettle is approved for treatment of prostate disorders in Germany.[128]

Pygeum africanum[edit]

Pygeum africanum inhibits 5 alpha reductase in vitro when given with Nettle (Urtica dioica).[131] In vitro cultured prostate stromal cells from patients with BPH show the herb to induce apoptosis.[135] N-butylbenzene-sulfonamide (NBBS), isolated from Pygeum africanum bark, acts as an androgen antagonistic, inhibits AR nuclear translocation and prostate cancer cell growth.[136] Atraric acid, isolated from bark material of Pygeum africanum, has anti-androgenic activity, inhibiting transactivation mediated by ligand-activated human AR.[137] 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.[130]

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.[138] Deficiencies can also occur in patients on long term TPN[139] and after modified Whipple procedures.[140] In its fulminant form and more often in children, biotinidase deficiency is characterized skin rashes, developmental delay, seizures, seborrheic dermatitis, alopecia and acidosis.[141] In forme fruste it can present as hair loss occurring only during times of stress.[142] Treatment involves replacement of biotin, and treatment of underlying malabsorptive disorder if contributive.[143] Biotin supplementation was found beneficial in a case of familial unruly hair.[144] Deficiencies can be detected by urine assay.[145]

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.[146] An early study in animal models showed that substance P induced by capsaicin stimulated hair growth.[147] It also promotes neural innervation of hair follicles in neonatal animal studies.[148][149] 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.[68] Other studies on less nociceptive medications found topical raspberry extract to work through a similar mechanism as capsaicin.[150] 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.[151] 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[152] The same research group found that TRPV1 activation also inhibits sebum formation.[153] 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.[154]

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.[155][156] Specifically, curcumin has been reported to enhance androgen receptor (AR) degradation.[157] In vitro studies of keratinocytes showed it to oppose TGF-beta1 release, which DHT induces. TGF-beta1 induces anagen in hair follicles.[158] It also has weak affinity for the vitamin D receptor.[159] It has been shown to work via a glutathione (GSH)-linked detoxification mechanisms in rats and ex vivo human models.[160] Studies on prostate cancer with curcumin alone, or coupled to anti-androgens, suggest it prevents growth by inhibiting pseudopodia formation.[161] 3-dimensional imaging has shown curcumin to conform to the androgen receptor,[162] which other studies have confirmed.[163] In combination with soy, it is inhibitory for symptoms of BPH.[164] ASC-J9, a derivative of curcumin, has been used to target androgen receptors for degradation.[165] It also down regulates androgen receptor gene expression.[166] Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation.[167]

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.[163]

Stem cell therapy[edit]

Although follicles were previously thought gone in areas of complete baldness, they are more likely dormant, as recent studies have shown the scalp contains the stem cells from which the follicles arose.[168] Research on these follicular stem cells may lead to successes in treating baldness through hair multiplication (HM), also known as hair cloning.

One of the groups developing hair multiplication is Aderans Research Institute (ARI), a Japanese owned company in the United States.[169][170] In 2008, Intercytex announced results of a Phase II trial to clone hair follicles from the back of the neck, multiply them and then reimplant the cells into the scalp. Initial testing showed at least two thirds of male patients regrew hair. The company estimated treatment would take "a number of years to complete" Phase III trials.[171] After failing to achieve success in their trials, the company discontinued its hair multiplication project in 2010, with intention to sell off its assets and research.[172] Aderans Research Institute Inc. (ARI) then acquired technology from Regenerative Medicine Assets Limited (formerly Intercytex Group plc)[173] and is conducting Phase II clinical trials.[174]

Scientists grew the first artificial hair follicles from stem cells in 2010. Researchers in the study predicted that by 2015 people could grow new hair from their own stem cells, and have it surgically implanted at areas of hair loss. The lead investigator said preparations for clinical trials were "already in motion".[175] In their first human clinical trial, Replicel Life Sciences was able to regenerate 20% percent of hair on stem cell treated areas. Replicel is using dermal sheath cup cells instead of dermal papillae cells for multiplication, in distinction to Aderans. They will be conducting Phase II trials at the end of 2012.[176] In early 2012 a research group demonstrated "functional hair regeneration from adult stem cells" in mouse animal models with the potential for "organ replacement regenerative therapies".[177]

Genetics[edit]

Curis and Procter & Gamble spent $1,000,000 on development of a topical hedgehog agonist for hair loss. The agent did not meet safety standards, and the program was stopped in 2007.[178] In 2008 researchers at the University of Bonn announced they have found the genetic basis of two distinct forms of inherited hair loss. They found the gene P2RY5 causes a rare, inherited form of hair loss called hypotrichosis simplex. It is the first receptor in humans known to play a role in hair growth.[179][180][181] Researchers found that disruption of the gene SOX21 in mice caused cyclical hair loss. Research has suggested SOX21 as a master regulator of hair shaft cuticle differentiation, with its disruption causing cyclical alopecia in mice models.[182] Deletion of SOX21 dramatically affects hair lipids.[183]

See also[edit]

References[edit]

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