Giatti et al (2020): Physiopathological Role of the Enzymatic Complex 5α-reductase and 3α/β- Hydroxysteroid Oxidoreductase in the Generation of Progesterone and Testosterone Neuroactive Metabolites

From researchers in Italy and Spain including Roberto Melcangi.
View on PubMed

Highlights

  • Progesterone and testosterone reduced metabolites are physiological neuromediators.

  • Progesterone and testosterone reduced metabolites are neuroprotective agents.

  • Neuropathological events affect progesterone and testosterone reduced metabolite levels.

Abstract

The enzymatic complex 5α-reductase (5α-R) and 3α/3β-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors.

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whats the point

Yeah this one is a bit cryptic. First, background on what scientific field this is. It’s called neuroendocrinology, which is the study of how hormones get converted (metabolized) into other chemicals that help regulate the nervous system, brain and sexual function.

Melcangi’s group has been focused on metabolism downstream from T and DHT. Metabolism leads to intermediate substances which they call neuroactive metabolites, which help regulate and maintain things like nerve transmisson, brain development, sexual functioning and stress response.

In a previous study (Melcangi et al, 2017) they found altered levels of neuroactive steroids in cerebrospinal fluid (CSF) of post-finasteride patients.

Here they are not looking at post-finasteride patients, but thinking more generally about how the system works, and what happens when levels get out of whack.

They look at how the disruption of two enzymes leads to lower or higher levels of these neuroactive metabolites. One of the enzymes is 5-alpha reductase (5-AR). (This is relevant because finasteride can disrupt 5-AR function after discontinuing the drug.) When this happens, patients may be less able to adapt to stress and maintain reproductive/sexual function.

Then they suggest this:

…the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies.

These are interesting suggestions. The first one: rather than use T or DHT, they are exploring using some of these downstream metabolites as therapy to restore them to normal levels. The second one, “5α-R modulation” means trying to restore proper functioning of 5α-reductase. I haven’t looked into what they mean by that.

My sense is that in post-finasteride symptoms, the whole system is out of equilibrium and can’t get back to equilibrium (“in a rut” you might say). The ideal treatment would knock the system back into equilibrium, but there’s no known way to do that today. It’s a delicate and complex system that we do not understand.

If we can’t restore the original equilibrium, the next best thing would be to provide hormones or metabolites to restore the balance at least temporarily. In this scenario – if it pans out – one would have to keep taking these metabolites because the system cannot recover its own equilibrium.

cc: @simonsayss

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I also think now, that hormone replacement could be an important step in reducing the long-term risk of cardiovascular disease and Alzheimer’s in PFS.
There are studies where giving & withdrawing Finasteride induces neuroinflammation in a rat model, as well as reducing neurosteroids that are protective against Alzheimer’s. I stronly believe that the “brain fog” that many describe is actully neuroinflammation and a process that in the long run increases our risk of developing Alzheimer’s diseases in PFS.

I was wondering why women tend to get more Alzheimer’s than men. Then I found these studies: that the sex hormones actually are protective against Alzheimer’s. Women seem to have a higher righ as men because they get “menopause”. Men don’t really get menopause, their hormones slowly decrease but at a later stage of age. Therefore they seem to be more protected against AD.
There are studies that hormone replacement in post-menopausal women decreases the Alzheimer’s risk. https://www.intechopen.com/books/sex-hormones-in-neurodegenerative-processes-and-diseases/sex-hormones-and-alzheimer-s-disease

Everything is pointing towards that the longterm consequeces of PFS may be increased AD risk (depending on how strong and long the cognitive symptoms had been). Therefore probably the low dose substitution of sex hormones could reduce the AD risk for us. I think same is true for the cardiovascular risk.

" These data demonstrate that androgen depletion accelerates the development of AD-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, our finding that DHT protects against acceleration of AD-like neuropathology predicts that androgen-based hormone therapy may be a useful strategy for the prevention and treatment of AD in aging men."

https://www.ncbi.nlm.nih.gov/pubmed/17182789

“Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer’s disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer’s dementia**. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men.”**
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997989/

"Researchers have found an association between androgen deprivation therapy (ADT) for prostate cancer and increased risk for Alzheimer’s disease, according to a recent study in the Journal of Clinical Oncology. …The researchers looked at electronic medical data from 16,888 men with prostate cancer. The data came from the Stanford health system and Mt. Sinai Hospital in New York City. Overall, 14% of the men underwent ADT and were followed for a median of 2.7 years.

The team found that the men on ADT had higher rates of Alzheimer’s diagnoses during the follow-up period, compared to men who did not receive ADT**. In fact, men on ADT were about 88% more likely to develop Alzheimer’s.**"

@anon22245532 @Sibelio

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