Dihydrotestosterone in Amyotrophic lateral sclerosis, the missing link?

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Leslie P. Weiner, MD proposed in 1980 that the mechanism of motor neuron death is sometimes related to the loss of androgen receptors.

(doi:10.1001/archneur.1980.00500520027002)

A recently published article brings some substance to his hypothesis.

Weiner based his hypothesis on characteristic of ALS.

  1. Male-to-female ratio. There have been frequent reports of preponderance of male to female patients with ALS. The ratio of 1.5 to 2.5 has been reported. A 1:1 ratio has been calculated for patients over the age of 65.

  2. Age. The average age of ALS patients is 55 to 60 years.

  3. Sparing of neuronal populations. In almost all cases of ALS, the extraocular muscles are not involved. The urinary and anal sphincters are also spared. The neurons of cranial nerves III, IV, and VI and sacral spinal cord motor neurons (S-2) are left intact even in far advanced cases of ALS.

  4. Axonal changes. There are changes in ALS that suggest axonal involvement.

  5. Certain types of axonal injury and axonal repair.

Leslie P. Weiner hypothesis:

  1. Could androgen receptors, and hence, androgens themselves, be important in motor neuron function?
  2. Could the sparing of cranial nerves in ALS be due to the lack of dependence of these neurons on androgens?
  3. Could the role of androgens be important in repair processes following axonal injury?

One could postulate that normal people have insults to their nerves and muscles hundreds of times in a life time. The neuron, with the "anabolic" help of androgen, can repair its axon. In ALS, whether due to toxins, viruses, trauma, or an accelerating "aging" process, androgen receptors are lost and axonal changes result in the death of the motor neuron.

What about dihydrotestosterone in ALS?

Fast forward in 2020, dr Nishit Sawal and colleagues aimed at testing Cerebrospinal fluid (CSF) levels of free testosterone and dihydrotestosterone in 13 ALS patients [7 males, 6 females] and 22 controls [12 males, 10 females].

While testosterone is well known for its role in sexual development, it does not stop here. Androgen including testosterone enhances muscle growth. Testosterone also regulates platelet aggregation in humans. It has been correlated with health deterioration in several neurodegenerative diseases, including Alzheimer.

Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels might decrease in the later decades of adult life.

Androgens affect the cerebral vasculature and may contribute to sex differences in cerebrovascular diseases. Men are at a greater risk for stroke and vascular contributions to cognitive impairment and dementia (VCID) compared to women throughout much of the lifespan. In men, low androgen levels have been linked to metabolic and cardiovascular diseases including hypertension, diabetes, hyperlipidemia, and obesity, which greatly increase the risk of stroke and VCID.

Dihydrotestosterone (DHT) is the most potent natural androgen in humans. There has been an increasing interest in this androgen and its role in the development of primary and secondary sexual characteristics as well as its potential roles in diseases ranging from prostate and breast cancer to Alzheimer's disease. Dihydrotestosterone is created when testosterone is converted into a new form, dihydrotestosterone. About 10% of the testosterone in the bodies of both men and women is converted into dihydrotestosterone in adults, with a much higher amount in puberty. This may be why it is so closely related to the triggering of puberty. The dihydrotestosterone hormone is much more powerful than testosterone.

What the scientists found

What they found was that CSF free testosterone levels did not show any significant differences but CSF dihydrotestosterone levels were significantly decreased in all male and female ALS patients.

What did the scientists conclude?

They concluded that dihydrotestosterone 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 dihydrotestosterone and so fewer dihydrotestosterone is generated. There is inadequate negative feedback suppression of Luteinizing hormone at the level of anterior pituitary by dihydrotestosterone. As a result of higher Luteinizing hormone 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 dihydrotestosterone leads to motor neuron death causing ALS.

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