to play a pivotal role in hair loss pathology.37 Ashwaghanda contains biochemical constituents including steroidal lactones(withanolides), sitoindosides, and other alkaloids.48 Withanolides interact with various signaling pathways, transcription factors such as NFK-b, and heat shock proteins that interact with steroid receptors. Withanolides anti-stress properties are attributed to their ability to mimic certain corticosteroids, interact with steroid receptors and modulate and reduce cortisol levels, thereby modulating the stress response.49-51 In a doubleblind placebo-controlled study, daily supplementation with standardized 10% withanolide ashwaghanda in patients with a history of chronic stress resulted in a significant reduction in stress scales and lowering of elevated serum cortisol levels as compared to controls.49Withanolides also increase endogenous antioxidants, decrease inflammation, modulate immune response, and prevent carcinogenesis.52 Ashwaghandha increases cell mediated immunity by increasing nitric oxide levels in macrophages, thereby enhancing phagocytic capability.53 The effects of standardized withanolides on inducing endothelial nitric oxide synthase also help improve blood flow, which may increase oxygenation and nutrient delivery to the follicle.54Saw Palmetto: Serona repensSaw palmetto extract (SPE) is a botanical that has been evaluated for treating benign prostate hyperplasia (BPH) and associated erectile dysfunction.55 Saw palmetto extract is a natural inhibitor of both isoforms of 5-alpha reductase, preventing conversion of testosterone to the active form DHT.56 Although there is conflicting data surrounding the use of SPE for treating symptoms of BPH, it remains of interest as a natural active for treating androgenetic alopecia.57 In a 2014 comparative study, 100 men with mild to moderate AGA were treated with 320mg of saw palmetto or 1mg finasteride daily for two years.58 Global photographs before and after two years showed significant improvement in 38% of patients taking saw palmetto and 68% of patients taking finasteride. Although saw palmetto was more effective in the vertex area, a significant percentage in this group had stabilization or improvement in non-vertex areas as well. As expected, patients with more severe AGA responded more favorably to the pharmaceutical preparation. While finasteride’s efficacy is confirmed by these studies, adverse events including erectile dysfunction are of concern. The use of saw palmetto to inhibit DHT may offer significant advantages in this regard. Animal studies suggest that saw palmetto may have potential for treating erectile dysfunction by increasing inducible nitric oxide synthase (iNOS) and acting as an inhibitor of phosphodiesterase 5 activity.59 Further studies are warranted to determine the significance of these findings in the clinical setting. Additionally, saw palmetto has no effect of prostate specific antigen (PSA) levels, while they are significantly reduced in patients taking finasteride.60Tocotrienols/TocopherolsThe vitamin E family consists of four tocopherols and four tocotrienols.61 These eight lipid soluble vitamins are natural antioxidant compounds that are extracted from vegetable oils such as palm oil, rice bran oil, and oils derived from nuts, seeds, and grains. Vitamin E isoforms scavenge lipid peroxyl radicals preventing lipid peroxidation of cell walls.62 Tocotrienols have superior lipid solubility comparedto tocopherols and are far superior at preventing lipid peroxidation.63 Patients with alopecia have been shown to have lower levels of antioxidants such as GSH and GSH-Px and an increase in thiobarbituric acid reactive substances (TBARS) that are indicative of lipid peroxidation64. Thus oral administration of antioxidants such as tocopherols and tocotrienols may be of value for mitigating oxidative stress and lipid peroxidation.In a randomized, placebo-controlled study, supplementation with a standardized tocotrienol-rich tocotrienol-tocopherol complex was evaluated on 38 patients with hair loss ages 18-59. Patients in the tocotrienol group showed a gradual mean increase in hair counts from a pre-determined scalp area from baseline with a mean increase of more than 34% by the end of the study. The placebo group showed no appreciable increase in hair counts. Cumulative weight of 20 strands of hair was not different between baseline and 8 months in eitherthe supplement and placebo group after 8 months.65 The authors suggest that the observed effect was most likely due to the antioxidant activity of tocotrienols, inhibition of lipid peroxidation, and oxidative stress in the scalp.65,66Black Pepper Fruit: PiperineThe concept of enhancing bioavailability using natural compounds is gaining favor as method of drug delivery.67 Referred to as natural bioenchancers, these compounds may act by decreasing hydrochloric acid excretion, increasing gastrointestinal blood supply, lengthening GI transit time, gastric emptying time, and gastrointestinal motility.67 Additionally, natural bioenchancers can suppress first pass metabolisms and enzymatic breakdown. The first natural bioenhancer to be identified and studied extensively is piperine. As previously discussed, piperine inhibits glucuronidation of curcumin increasing bioavailablity.44 Piperine also binds to vanilloid receptors in the gastrointestinal tract68 activating membrane-bound adenyl cyclase, which catalyzes the synthesis of the second messenger molecule cAMP. cAMP activates protein kinase A (PKA) that inhibits intestinal motility and dilates blood vessels in the intestine.69 This physiologic action of piperine results in better digestion and absorption of a variety of nutrients including herbal extracts, water and fat-soluble vitamins, antioxidants, and amino acids like lysine and methionine. Minerals such as zinc and selenium are also better absorbed when administered with piperine.70
