A lot has been commented and speculated on how Finasteride could cause neurological side-effects.
Impaired memory, slurred speech, depression, anxiety states, insomnia and many more.
For many of us PFS has been a devastating condition and I applaude everybody still fighting.
DISCLAIMER: I want to clarify that I’m not claiming to have found the cause or any cure for PFS.
I post this article to start a discussion about a submechanism that could be happening in PFS.
Many of this will sound familiar but bear with me.
My goal in this article is to elucidate a pattern that is often seen in patients who haven taken Finasteride: a disrupted GABA system.
We currently know of 3 types of 5α-reductase enzymes: type 1, 2 and 3.
In the figure below you can see which enzyme is responsible for which conversion.
For the sake of simplicity, I will only focus on type 1 and 2 here (eventhough in vitro studies show that type 3 is inhibited at a similar potency as type 2 but this has been discussed in other topics before).
In vitro binding studies show that Finasteride has a 100-fold selectivity for the human type 2 over the type 1 enzyme.
So when Merck claims that Finasteride is a potent competitive inhibitor of type 2 enzyme this is actually true. It’s just not the full story.
There are several studies steroids pre- and after Finasteride. Let’s take to one by Duskova et al. from 2009. 20 men with benign prostate hyperplasia received daily doses of 5mg/day for 4 months. Here’s the full panel before and after:
Specifically look at Allopregnanolone (subsequently shortened as ALLO). See the statistically significant steep decrease? This is a pattern that’s been reproduced in several studies and discussed on these forums multiple times.
So we may assume that Finasteride can influence neurosteroid homeostasis.
We know that Progesterone and related molecules like ALLO and Pregnenolone are active in the CNS and modify several membrane receptors (e.g. GABA, glutamate, dopamine).
Progesterone for example directly binds to the α1 subunit of the GABA-A receptor.
It’s becoming clearer that Progesterone has multiple influences in the brain in regulating cognition, mood, inflammation, neurogenesis and myelination. We have heard this before.
But it’s not only the direct effect on the α1 subunit. Through type 1 5α-reductase (and 3-α-HSD) Progesterone is converted to ALLO. And ALLO itself is one of the most potent positive allosteric modulators of GABA-A. The reasons for 5α-reductase modulation are thoroughly discussed in other threads and won’t be futher speculated upon here. Let’s hypothesize this as a given.
In normal levels, ALLO acts like a sedative and produces anxiolytic and antidepressant effects and reduces seizure activity.
So what do Traish et al. mean when the claim that “Finasteride treatment resulted in decreased levels of [ALLO] […]supporting the hypothesis that deleterious effects of finasteride may be persistent or irreversible. This may explain some of the noted symptoms such as anxiety, depression and suicide in patients who have been treated with finasteride”?
GABA-A α4-subunit upregulation as a homeostatic response to prolongued withdrawal. Reduced levels of ALLO enhance the transcription of the gene encoding the α4-subunit.
And the upregulation of this specific subunit is associated with behavioural changes like increased anxiety or excitability.
An inverse relationship between endogenous ALLO levels and symptoms of anxiety and depression was reported in males with depression or in the early phase of alcohol withdrawal.
Wait, alcohol withdrawal? An increase in expression of the GABA-A α4-subunit gene was also observed on withdrawal of benzodiazepines. And now a group of researchers claims that protracted benzodiazepine withdrawal causes a hyperexpression of the α4-subunit that usually is not present.
«Chronic exposure to or withdrawal from […] BZDs can result in α4 subunit upregulation and the typical withdrawal outcomes»
Gulinello/Gong/Smith (2001): Short-term exposure to a neuroactive steroid increases a4 GABAA receptor subunit levels in association with increased anxiety in the female rat
Have you guys ever compared protracted benzodiazepine withdrawal with PFS?
As the graph below shows, GABA-A α4 mediates tonic signalling. And this effect depends on the length of exposure:
[*] Short-term neurosteroid exposure (acute stress, menstrual cycle) leads to an increase in α4 subunit expression and an increase in tonic currents.
[*] Long-term neurosteroid exposure (chronic stress, pregnancy) on the other hand leads to downregulation of the α4 subunit and an increase in circulating neurosteroids as a compensatory mechanism.
[*] Neurosteroid withdrawal results in α4 subunit upregulation
So should we all just jump on Pregnenolone or Progesterone?
As always in life, it’s not that simple.
Challenge 1: Short-term exposure to Progesterone leads to a 2-3x increase in α4 protein levels. This (further) upregulation is associated with more anxiety. This could the underlying effect that people report when they first start taking PROG. In animal models, α4 protein levels fall after 5-6 days of hormone exposure back to baseline.
Challenge 2: ALLO has a biphasic effect: at tiny doses, allopregnanolone stimulates GABA-A (that’s what we want), at higher doses it inhibits it (that’s what we don’t want) and then at very high doses again it stimulates it. So trial & error to find the correct dose is crucial.
Challenge 3: Withdrawing from PROG/ALLO after chronic exposure can bring on withdrawal.
What alternatives are there?
ALLO is only commercially available for research purposes. Plus we have the following problems (among others):
Currently parenteral administration only as there are issues with aqueous formulations
Short half life
Potential back-conversion to PROG
Marinus Pharmaceuticals, the manufacturer of Ganaxolone, a synthetic form of ALLO with an added methyl group to prevent back-conversion to Progesterone, has recently finished phase 3 trials (for people with focal onset seizures).
Sage Therapeutics has successfully treated patients with super-refractory status epilepticus in phase 3 trials with SAGE-547, another neurosteroidal allosteric modulator of both synaptic and extra-synaptic GABA-A
dart