Ketoconazole (Brand name Nizoral) is actually a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immuno-compromised patients. This drug, an Imidazole (an organic crystalline base that is an inhibitor of histamine) derivative, is an effective oral agent that has broad-spectrum antifungal activity and is also a steroid biosynthesis inhibitor. The androgen lowering potential of high doses of Ketoconazole has led to its use in the treatment of advanced prostate cancer.
Formulated as a topical treatment, oral tablet and as a shampoo, the drug Ketoconazole is available by prescription. Branded Nizoral shampoo contains 2 percent Ketoconazole and is prescribed not only for the treatment of infectious fungal scalp conditions, but also in combination with other treatments for androgenetic alopecia. Ketoconazole can cause a reduction in the production of testosterone and other androgens in the skin. A 1 percent version is available over-the-counter, but it may not be as effective as the 2 percent prescription strength.
How does ketoconazole work
Research studies show that Ketoconazole can interfere with steroidogenesis in patients and rat in vitro systems by inhibiting Cytochrome P450 dependant enzymes. The interaction of Ketoconazole with Cytochrome P450 at the heme iron site in several organs, including gonads and adrenals, may result in destruction of the heme portion (molecule containing iron) of Cytochrome P450, thereby inhibiting Cytochrome P-450 and effectively suppresses testicular and adrenal androgen production.
Therefore in the adrenal gland and gonads, Ketoconazole inhibits synthesis of adrenal corticosteroids. However, much higher concentrations are necessary to affect Cytochrome P450-dependent enzymes in mammals compared with those in fungi. Extensive clinical trials to prove the efficacy of Ketoconazole have not been carried out. In fact, there are only anecdotal reports of Ketoconazole use in hirsutism, but none in women with pattern hair loss. In one particular study, 27 subjects used 2% Ketoconazole shampoo exclusively 2–4 times a week for 21 weeks. The remaining 12 in the control group used an un-medicated shampoo. The group using the Ketoconazole shampoo showed results of an increase in hair density, size and proportion of anagen hair follicles post treatment.
Although the effects of Ketoconazole on 5 alpha – reductase had been documented earlier, the authors of the study asserted that androgenetic alopecia has a multi-factorial pathogenesis with an inflammatory reaction caused by a Malassezia fungal infection, and claimed that the Ketoconazole shampoo was probably effective due to its beneficial effect on fungal scalp infections in genetically predisposed individuals. It was concluded that Ketoconazole was therapeutic by reducing inflammation through its anti-inflammatory properties and by clearing the adjacent fungal infection.
Exploration of the inflammatory aspect of androgenetic alopecia was largely based on the results of a biopsy study by Jaworsky et al., showing that androgenetic alopecia patients had signs of T-cell infiltration of follicular stem cell epithelium. However, the veracity of the conclusions drawn from the Jaworsky study is uncertain as the study included 4 subjects and only 3 of them were men.
However, another school of thought believes that the clinical efficacy of Ketoconazole shampoo in the treatment of androgenetic alopecia is primarily a function of dihydrotestosterone (DHT) pathway disruption rather than an anti-inflammatory effect. The development of androgenetic alopecia in genetically susceptible individuals has been linked to an overproduction of 5 -reductase and an over expression of androgen receptor, and in rat studies, Ketoconazole has been seen to cause 5 -reductase inhibition. Additionally, in humans Ketoconazole has also been shown to inhibit the binding of 5 -reductase to sex hormone globulins. All these clinical studies therefore suggest that Ketoconazole may inhibit the production of DHT just like Finasteride. In fact, the effect of Ketoconazole may be two fold, as it has been shown additionally to bind to human androgen receptor, having a distinct advantage over Finasteride. Therefore these authors believe that Ketoconazole inhibits the pathway that leads to the characteristic miniaturization of hair follicles in androgenetic alopecia by inhibiting DHT and/or inhibiting the binding of DHT to AR.
Ketoconazole usage
Ketoconazole is not advised as an oral drug for treating androgenetic alopecia, as the high concentrations required for the drug to affect steroidal hormone binding are higher than the safety limit. In the case of androgenetic alopecia treatment, the only tissue that requires a relative high concentration of Ketoconazole is the hair follicles, and a local application of Ketoconazole in the form of a shampoo is the best way to administer treatment. This helps to avoid systemic toxicity and the agent can be directly delivered to the affected area. So far there has been no analysis of the systemic absorption / concentration of Ketoconazole when using Ketoconazole 2% shampoo.
Further clinical trials are needed to evaluate the effectiveness of Ketoconazole shampoo in the treatment of androgenetic alopecia. These trials should also endeavor to determine whether the mechanism of action of Ketoconazole in androgenetic alopecia is by its anti-inflammatory effect or by inhibition of the DHT pathway.