New Melcangi paper: "Post-Finasteride Syndrome: An Emerging Clinical Problem"

The latest (December 2019) review paper by Melcangi et al.

Abstract

The presence of side effects during pharmacological treatment is unfortunately a quite common problem. In this review, we focused our attention on adverse events related to 5 alpha-reductase (5α-R) inhibitors (i.e., finasteride and dutasteride), approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia (AGA).

Although these drugs are generally well tolerated, many reports described adverse effects in men during treatment, such as sexual dysfunction and mood alteration. In addition, it has been also reported that persistent side effects may occur in some AGA patients. This condition, termed post-finasteride syndrome (PFS) is characterized by sexual side effects (i.e., low libido, erectile dysfunction, decreased arousal and difficulty in achieving orgasm), depression, anxiety and cognitive complaints that are still present despite drug withdrawal. Indeed, some national agencies (e.g., Swedish Medical Products Agency, the Medicines and Healthcare Products Regulatory Agency of UK and the U.S. Food and Drug Administration) required to include multiple persistent side effects within the finasteride labels.

As here reported, these observations are mainly based on self-reporting of the symptomatology by the patients and few clinical studies have been performed so far. In addition, molecular mechanisms and/or genetic determinants behind such adverse effects have been poorly explored both in patients and animal models. Therefore, results here discussed indicate that PFS is an emerging clinical problem that needs to be further elucidated.

Full text:

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Found this part interesting, seems only one promoter gene for Type2 5AR shows signs of methylation and that occurs in tissue only and not in blood of CSF fluid. Also there is no signs of methylation for Type1 promoter.

Epigenetic modifications seem to be also involved (Melcangi et al., 2019). Indeed, as recently demonstrated, methylation analysis of the promoter genes coding for type 1 (i.e., SRD5A1 ) and type 2 (i.e., SRD5A2 ) 5α-R performed in plasma and CSF of 16 PFS patients, indicated that SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to healthy controls (56.3% versus 7.7%). **Importantly, this is a tissue-specific methylation. Indeed, SRD5A2 promoter methylation has not been observed in plasma. Interestingly, both in plasma and CSF, SRD5A1 promoter was not methylated ([Melcangi et al., 2019]**(https://www.sciencedirect.com/science/article/pii/S235228951930061X#bib69)).

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I’m starting to doubt the methylation hypothesis, when taking methylation inhibiting supplements I get bad brain fog and anxiety and no benefits

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I’m only starting to research genes but I don’t think you can SELECTIVELY un-methylate or reactivate genes. That task is for mother nature to perform.

Overall, these data indicate the urgent need to high quality clinical trials, with long-term follow up, specifically addressing sexual function and mood disorders.

You dont fucking say…

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I just finished reading the paper. I am sorry to say it, but I am extremely disappointed…

I think the confirmation that both type1 and type 2 genes are not methylated in plasma/blood is positive. It’s like we still have a “good” copy of our DNA

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Why are you disappointed? I think it’s very well written, easy to interpret and will likely open up new avenues.

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I was scared to read the part about our brain.

Who the f… is going to treat our brain is the most complicated organ!!!

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There are users around who know way more about the science than I do, but the clear thing is what @Papasmurf says - this is more news about the condition and about opening new research. 2020 may yet be our most important year.

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There are a lot of very serious problems with this paper.

One of them, and not even the biggest one, is the uncritical citation of the methodologically flawed study of Haber et al., 2019 to legitimize the denial of the damages done by finsteride. This study is so flawed that no self-respecting scientist would ever cite it, at least not without a long disclaimer.

Why is the study flawed? Imagine finasteride instantly killed 99% of its users. If you did a survey similar to the one cited, you would conclude that finasteride is 100% safe. If anyone with knowledge of statistics cares to elaborate more on this, please do.

There was also no mention in the paper of the fraud perpetrated by Merck in the original clinical trials of Finasteride.

On the basis of all this, the authors conclude that “Overall, these results indicate no consensus with respect to the presence of sexual side effects during treatment with 5α-R inhibitors.”

Great job, Diviccaro et al!

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how do you know you are taking the ones that inhibit the methylation at the genes we got methylated?

no one knows which substance or if more complex, which combination of substances would produce results for us, yet anyways

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Very nice study. I wonder if Baylor will show more than this

They better do with all the hype :joy:

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PFS
“an alternative possibility is a direct action of finasteride on gut microbiota.”

In the future, more knowledge of this will probably lead to more sophisticated drug treatment across all fields of medicine.

The Haber study doesn’t look at people who discontinue finasteride. It also doesn’t look into how long people have been taking finasteride, which Kiguradze et al (2017) found was the primary predictor.

Finally, can we rely on written self-reports of sexual dysfunction? Have there been any general studies on the validity? Moore (2015) points out that SSRI sexual side effects were underreported because trials relied on spontaneous self-reports. The Haber study uses questionnaires to score on the ASEX scale.

I just found this interesting article:
Gordijn et al, March 2019
Adverse drug reactions on sexual functioning: a systematic overview


They write:

However, the awareness of sexual ADRs [adverse drug reactions] is still low under healthcare professionals and underreported during clinical trials.

P.S. References are here:
http://bit.ly/finasteride-research

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I think you are getting at the concept of a survivorship bias. The study looks at a pool of patients who have been taking the drug for a period of time and had the opportunity to drop out if they wanted to but didn’t. The people who had adverse events from finasteride would have stopped taking it, so you are weeding out those guys and the ones who remain don’t have them. You simply can’t determine the frequency of side effects for a drug from that kind of study because it’s hugely biased. I don’t know how that paper was peer-reviewed, but it was published somehow. To be honest though, I don’t know how you deal with that in a literature review that is going to be peer reviewed since it’s hard to say here is the literature but this one paper is total garbage. A lot of the anti-PFS authors have done stuff like that though.

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P.S. I found two studies that found the ASEX score valid and acceptable for research on sexual dysfunction.

A responsible literature review should evaluate the methodology of the papers it reviews. Meta-analyses typically set criteria for quality and methodology of the research under review, and eliminate studies that don’t meet the criteria.

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I took a look at this article again today to revisit the full context. I do wish the authors took a stronger stance in support of the existence of PFS but it isn’t all that bad. There was a paragraph where Melcangi explains how PFS cannot be adequately studied in larger cohorts, as it is a rare condition. That would apply to the Haber study and the others he mentioned.

I definitely do agree that the Haber study was terribly intellectually dishonest or moronic and should never have been published but the authors chose to be more diplomatic.

In terms of including the admission of fraud, I do hope that gets into the medical literature at some point. I don’t know if this article was submitted for review before the evidence of fraud became public.

We have Belknap’s controlled epidemiological study showing PFS exists, we have strong arguments that the other controlled studies are too low powered or inadequately designed to detect PFS, we have a Merck exec admitting they withheld information from the product label, and we’ve identified a couple biomarkers that are different in PFS versus healthy controls. What we lack is a very clear mechanism that is showing how taking finasteride causes PFS and why it happens in some people but not others. That’s a very ambitious goal to accomplish. People with vested interests will still fight this but we have more than enough evidence to show a more disinterested party that PFS is real. The biological mechanism may be the missing piece needed to convince some of the more stubborn-minded people that PFS is real.

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