Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction, Melcangi et al. 2022

Science PFS Research
#1

Reproductive and Developmental Endocrinology

Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction

Silvia Giatti1, Silvia Diviccaro1, Alessandro Di Domizio2, Lucia Cioffi1, Eva Falvo1, Donatella Caruso1, Alessandro Contini3 & Roberto Cosimo Melcangi1

Finasteride is a 5alpha-reductase (5α-R) inhibitor used in clinics to treat androgen-dependent conditions, such as benign prostate hyperplasia and androgenetic alopecia (AGA). Its use has been associated with several adverse effects, including sexual complaints. However, to date, no hypothesis to explain such adverse effects has been proposed. This is a consequence of the still incomplete knowledge of the intricate network of motivational, psychological, and molecular inputs that are involved in sexual behavior. In this work, a multidisciplinary approach has been used to evaluate whether finasteride may interact with targets different from 5α-R (i.e., off-target proteins − OTPs). In silico analysis (SPILLO-PBBS software and docking/molecular dynamics) indicated that the enzyme phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in epinephrine production, might be a finasteride OTP. This is interesting, since epinephrine and norepinephrine are involved in erection (Becker et al ., 2000, J Urol), and alterations in their levels has been observed in patient with erectile dysfunction (Becker et al ., 2002, Urology). An inhibitory assay developed in vitro confirmed that finasteride blocks the human PNMT. Finally, to verify the in vivo interaction, adult male rats were treated with finasteride (1 mg/rat/day s.c. daily for 20 days). Ex vivo analysis indicated that epinephrine levels were decreased by finasteride treatment in adrenal glands, while those of norepinephrine were increased. This, together with no variation in PNMT protein levels, confirmed the hypothesis of a block in epinephrine synthesis. Therefore, we explored if corpora cavernosa (CC) of finasteride-treated rats presented molecular alterations. A decreased protein level of estrogen receptor beta was observed in CC of finasteride-treated rats, in line with evidence in aging and diabetic rats with erectile dysfunction (Shirai et al ., 2004, Urology). Moreover, the levels of dopamine, which improve the penis relaxation, were significant decreased in CC tissue after finasteride administration. Overall, the data here presented indicate that finasteride affects epinephrine synthesis by blocking PNMT enzymatic activity in humans. This block can have an impact in sexual behavior, as suggested in an animal model treated with finasteride. In addition, the alterations observed in CC indicate possible impairment of erectile function. Our results suggest possible mechanisms for the sexual dysfunction observed after finasteride treatment in humans and add a piece of knowledge on the mechanisms controlling sexual function in mammals.

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#2

Interesting, this could explain a lot of our issues in theory.

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#3

This motherfucking drug

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#4

I wonder if this can go some way to explaining anhedonic symptoms and those of emotional blunting too…

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#5

How nauseating! Like an onion, the more you peel/cut it, the more it stinks, and the more you cry, except the stink vanishes and the tears dry up then you enjoy a good meal. Heck, you eventually go nose blind and your eyes stop watering if done regularly enough.

It’s like the body says: “Hi, self! I feel like hyper-methylating today, even though I don’t know what that means yet, because I can, because why not?” Yeah, it’s like the body goes into “friendly fire” mode. Don’t mind me; I’m just making a rant while trying to make sense of it all.

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#6

I wonder if this shines a light on a possible treatment?

I wonder if the study looked at what happened after Finasteride treatment ceased? For all we know the levels returned back to normal in time.

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#7

exactly, i wonder what our body molecules thought about us when we took the poison, probably they went like: he wants to kill himself but he doesn’t know what poison to take specifically. my heart goes out for myself indeed, how dumb was i to think that i could trust the FDA, it is like a dark comedy.

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#12

I can see it explaining much of the stuff that AR can’t explain.

Like the lack of feeling in the skin.

Thus, Merkel cells release noradrenaline across synapses to activate sensory neurons.

Also the ERb downregulation that they saw, have also been noted in the brain of rats after fin exposure. Even after a washout period.

Same thing happens after TBI and with aging IIRC.

#13

I wonder if anything can be done about it or if there’s a meaningful and low risk way to upregulate it.

1 Like