Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
Paroxetine and finasteride both act on the epinephrine enzyme PNMT.
This may have something to do with erectile dysfunction (after discontinuation who knows?)
- Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug.
https://www.sciencedirect.com/science/a ... 602201345X
- Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
https://www.endocrine-abstracts.org/ea/0081/ea0081p448
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Journal of Molecular Structure
Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug.
Paroxetine is a widely used antidepressant drug, usually prescribed to treat major depression disorder, anxiety, but is also common in managing chronic pain, eating disorders, some forms of headache and sleep disturbances. Antidepressants, and paroxetine in particular, are linked to side effects, and sexual dysfunction is one of the most prevalent. To explore possible mechanisms leading to this symptomatology, an unbiased approach was applied to retrieve potential paroxetine off-target proteins. A 3D proteome-wide scale in silico screening of a human and murine protein database using SPILLO-PBSS software indicated that the enzyme phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in the formation of epinephrine, also potentially interacts with paroxetine. Then, a multidisciplinary approach was applied to confirm this finding. Indeed, docking and molecular dynamics analysis and an in vitro assay indicated that paroxetine is able to inhibit PNMT, a result also confirmed in an animal model. The catecholamines norepinephrine and epinephrine are involved in sexual function, and their altered levels have been associated with erectile dysfunction. Thus, based on the fact that the PNMT enzyme is involved in epinephrine production, and that the data here reported indicate that paroxetine inhibits PNMT, a possible role of this enzyme in the sexual dysfunction reported by antidepressant users can be suggested.
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Reproductive and Developmental Endocrinology
Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
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.
This may have something to do with erectile dysfunction (after discontinuation who knows?)
- Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug.
https://www.sciencedirect.com/science/a ... 602201345X
- Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
https://www.endocrine-abstracts.org/ea/0081/ea0081p448
------
Journal of Molecular Structure
Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug.
Paroxetine is a widely used antidepressant drug, usually prescribed to treat major depression disorder, anxiety, but is also common in managing chronic pain, eating disorders, some forms of headache and sleep disturbances. Antidepressants, and paroxetine in particular, are linked to side effects, and sexual dysfunction is one of the most prevalent. To explore possible mechanisms leading to this symptomatology, an unbiased approach was applied to retrieve potential paroxetine off-target proteins. A 3D proteome-wide scale in silico screening of a human and murine protein database using SPILLO-PBSS software indicated that the enzyme phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in the formation of epinephrine, also potentially interacts with paroxetine. Then, a multidisciplinary approach was applied to confirm this finding. Indeed, docking and molecular dynamics analysis and an in vitro assay indicated that paroxetine is able to inhibit PNMT, a result also confirmed in an animal model. The catecholamines norepinephrine and epinephrine are involved in sexual function, and their altered levels have been associated with erectile dysfunction. Thus, based on the fact that the PNMT enzyme is involved in epinephrine production, and that the data here reported indicate that paroxetine inhibits PNMT, a possible role of this enzyme in the sexual dysfunction reported by antidepressant users can be suggested.
----
Reproductive and Developmental Endocrinology
Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
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.
Last edited by anacleta on Sat Jul 09, 2022 9:49 am, edited 1 time in total.
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Re: Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction. Melcangi et al. 2022
What about those who have normal corpora cavernosa function but instead have corpus spongiosum dysfunction (aka flaccid glans and urethra) ? This seem pretty common with PSSD and other psychotropic drug withdrawals but doesn't have an explanation other than assumed nervous pathways hinted by the fact a lot of suffers also have numbness specific to the glans.
Interestingly my med that caused me all the issues is a strong norepinephrine blocker.
Interestingly my med that caused me all the issues is a strong norepinephrine blocker.
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Re: Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
this: Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug
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Re: Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
anacleta wrote: ↑Sat Jul 09, 2022 2:32 pmthis: Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug
Oh yes. It says available on July 9th. Thank you for staying on top of this.
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Re: Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
Phenylethanolamine N-methyltransferase (PNMT) also a got brief mention in this Japanese study published a month ago.
Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics
Glucocorticoids are well-known to induce phenylethanolamine N-methyltransferase (PNMT), an adrenaline synthetic enzyme(25), which results in increased CA levels. Meanwhile, CA may also induce pituitary ACTH secretion(26). Increased cortisol levels in patients with pheochromocytomas but not those with paragangliomas has been reported(11), suggesting that paracrine, rather than endocrine CA action, plays a more essential role in inducing cortisol secretion(27). This indicates that there should be cortical and medullary interactions, but their physiological and pathological roles remain unclear.
CA in this case stands for catecholamine.
https://www.nature.com/articles/s41598-022-13132-1
Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics
Glucocorticoids are well-known to induce phenylethanolamine N-methyltransferase (PNMT), an adrenaline synthetic enzyme(25), which results in increased CA levels. Meanwhile, CA may also induce pituitary ACTH secretion(26). Increased cortisol levels in patients with pheochromocytomas but not those with paragangliomas has been reported(11), suggesting that paracrine, rather than endocrine CA action, plays a more essential role in inducing cortisol secretion(27). This indicates that there should be cortical and medullary interactions, but their physiological and pathological roles remain unclear.
CA in this case stands for catecholamine.
https://www.nature.com/articles/s41598-022-13132-1
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Re: Paroxetine and finasteride both act on the epinephrine enzyme PNMT. Melcangi et al. 2022
https://zenodo.org/record/1230661#.YuEujBYpCaM
This could explain why some individuals describe a reduced response to alcohol during PSSD.
The only substances I’ve found that increase the PMNT enzyme are glucocorticoids.
This could explain why some individuals describe a reduced response to alcohol during PSSD.
The only substances I’ve found that increase the PMNT enzyme are glucocorticoids.
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