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Genetics of 5-alpha Reductase Inhibition & Hair Therapy

October 15, 2009

Currently one of the most widely prescribed hair loss medications, finasteride (Propecia and Proscar), works by blocking the production of the androgen dihydrotestosterone (DHT). This hormone is responsible for hair loss in androgenetic alopecia (AGA) or male pattern baldness. The enzyme 5-alpha reductase is responsible for converting testosterone into DHT; this enzyme is inhibited by finasteride. Finasteride therapy stabilizes hair loss in 85% of patients and can strengthen and re-grow lost hair in 66% of patients. This class of 5-alpha reductase inhibitors includes dutasteride, which is used off label as a hair loss treatment. While effective, the side effects of these drugs include various types of sexual dysfunction, though in only approximately 3% of finasteride patients. In addition, other side effects include breast tenderness or enlargement. Despite the small proportion of patients afflicted with adverse effects, the threat can nonetheless deter patients from initiating 5-alpha reductase inhibition therapy who are uncertain of the risk-reward benefit.

The androgen receptor gene, which encodes androgen receptor, has been identified as an important determinant of AGA. The DNA sequence of genes can vary either as single nucleotide or variable length polymorphisms. These differences in gene sequence or length often have effects on the activity or function of the gene products. For instance, the androgen receptor gene has a length polymorphism of the CAG nucleotide repeat. This polymorphism helps to determine the sensitivity of the androgen receptor in both men and women. The variation in androgen sensitivity affects how cells respond to androgens. For instance, lower numbers of CAG repeats have been associated with increased androgen sensitivity. Therefore, for those with short CAG repeats, even low levels of DHT can elicit a strong response such as hair loss. This sensitivity and associated genotype have been associated with a myriad of physiologic effects. In particular to hair loss, it has now been shown in 2 independent studies from 2 major research groups in Japan, that a lower number of CAG repeats impacts patient responsiveness to medication therapies for AGA.

Despite the high response rates to medication therapies, several months are often required before visible signs of hair restoration are observed. Therefore, an accurate method to predict the effectiveness of finasteride response could alleviate the frustration and anxiety of uncertain treatment outcome. In addition, those who are unlikely to respond to medical therapy can seek alternative treatment options to preempt hair loss. The connection between the androgen receptor gene CAG repeat length and patient response provides an avenue for determining one's likelihood of benefiting from finasteride treatment.