Dihydrotestosterone in Amyotrophic lateral sclerosis—The missing link?

OBJECTIVE: Testosterone has been postulated to be involved in ALS causation. MATERIALS AND METHODS: CSF levels of free testosterone and dihydrotestosterone were measured in 13 ALS patients [7 males, 6 females] and 22 controls [12 males, 10 females]. RESULTS: CSF free testosterone levels did not show any significant differences but CSF dihydrotestosterone levels were significantly decreased in all male and female ALS patients. CONCLUSIONS: DHT is probably integral to survival of motor neurons. In patients predisposed to develop ALS, there is possibly a sort of “testosterone resistance” at level of blood–brain barrier [BBB] existing right from birth and is likely the result of dysfunctional transport protein involved in testosterone transfer across the BBB. In these patients, lesser amount of testosterone is able to breach the BBB and enter the central neural axis. Lesser amount of testosterone is available to 5 α reductase in the anterior pituitary to be converted to DHT and lesser amount of DHT is generated. There is inadequate negative feedback suppression of LH at the level of anterior pituitary by DHT. As a result of higher LH levels, testosterone levels rise in the peripheral testosterone fraction [the fraction outside the BBB] and this explains the various physical attributes of ALS patients like lower Ratio of the index and ring finger lengths (2D:4D ratio), increased incidence of early onset alopecia etc. This deficiency of DHT leads to motor neuron death causing ALS.