PFS Investigator Roberto Melcangi suspects the post-treatment variety springs from neuroendocrine disorder, rather than genital pathology
Aug. 28, 2023
By this point in the epidemiology of PFS, few self-respecting doctors would argue with that statement. But the molecular mechanisms that cause ED in finasteride patients, and whether those mechanisms are also at work after quitting the drug, is another story—one that Roberto Cosimo Melcangi, PhD, knew was virtually non-existent in medical literature.
So the Head of the Neuroendocrinology Unit in the Department of Pharmacological and Biomolecular Sciences at the University of Milano (UniMi), and his colleague Silvia Diviccaro, PhD, conceived a study aimed at broaching those questions.
Titled Exploring Rat Corpus Cavernosum Alterations Induced by Finasteride Treatment and Withdrawal, and funded in part by the PFS Foundation, the study appears in the current issue of Andrology.
In all, Prof. Melcangi and his team of seven researchers treated 24 adult male rats each with 1 mg of finasteride for 20 days, then began investigating the effects of that treatment. Next, they suspended the drug for 30 days, then began investigating the effects of withdrawal.
“[Our] results…indicate that finasteride treatment, but not its withdrawal, affects [testosterone (T)] metabolism in the rat corpus cavernosum [aka the penile tissues facilitating erection], and this alteration was linked to mechanisms associated with erectile dysfunction,” writes Melcangi.
Separately, he tells us, “We suspect that post-finasteride ED may be related to alterations in neuroendocrine control of sexual desire, rather than physical damage to the genital area. That’s an important distinction when formulating strategies for attacking the problem of developing effective treatments for sexual dysfunction in PFS patients.”
Among Team Melcangi’s other notable findings:
• In addition to lowering T levels, finasteride “induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug.”
• T levels “in the corpus cavernosum, which we reported to be increased after subchronic [i.e., approximately one month] drug treatment, are negatively correlated with [nitric oxide synthase (NOS)] activity [i.e., neurotransmitters that affect memory, and the central nervous system, particularly in the regulation of blood pressure and muscle activity involved in penile erection], while tissue levels of DHT, which we demonstrated to be decreased, are positively correlated with [ornithine transcarbamylase (OTC)] activity [deficiencies of which can cause delirium, erratic behavior, reduced consciousness, headaches, and seizures]. This is particularly interesting because, even if previous observations already indicated the presence of the enzyme 5α-R type II in the corpus cavernosum, to our knowledge this is the first observation suggesting that a local change in T metabolism is linked to mechanisms associated with ED.”
• “[C]linical and experimental studies evaluating ED have analyzed only steroid changes in plasma, [so] it is interesting to note that the finasteride treatment did not increase T levels in plasma, suggesting that the T accumulation in corpus cavernosum could be involved in the dysfunction of the NOS activity.”
Along with Michael S. Irwig, MD, at Harvard Medical School, and Abdulmaged M. Traish, PhD, at Boston University, Melcangi is one of three pioneers who have been investigating PFS in excess of a decade.
His first such study, titled Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid and Plasma of Post‐Finasteride Patients Showing Persistent Sexual Side Effects and Anxious/Depressive Symptomatology, was published in 2013. It concluded, in part:
[T]hree post-finasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their neuroactive steroid levels with those of healthy controls…
The present observations confirm that an impairment of neuroactive steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment.
Most recently, prior to his corpus cavernosum alterations study, Melcangi published Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats in 2022, marking the first-ever demonstration that it’s possible to recover from a PFS symptom. He wrote:
[P]revious observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we…explored the effect of chronic treatment with finasteride…and its withdrawal…on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of [ALLO] decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1 and TNF-, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations.
[B]ecause (i) sexual dysfunction may be related to alterations in gut microbiota and (ii) the existence of the well-described gut-brain axis, observations here obtained may provide an important background to explore [the] protective effect of ALLO on psychiatric and andrological dysfunctions, laying the groundwork for possible therapy in PFS patients.
Following are all of Team Melcangi’s PFS studies to date:
Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid and Plasma of Post‐Finasteride Patients… The Journal of Sexual Medicine, 2013
Adverse effects of 5α-reductase inhibitors… Reviews in Endocrine and Metabolic Disorders, 2015
Patients treated for male pattern hair with finasteride show, after discontinuation… Journal of Steroid Biochemistry and Molecular Biology, 2015
Effects of subchronic finasteride treatment and withdrawal on neuroactive steroid levels…Neuroendocrinology, 2016
Neuroactive steroid levels and psychiatric and andrological features in PFS… Journal of Steroid Biochemistry and Molecular Biology, 2017
Treatment of male rats with finasteride, an inhibitor of 5alpha-reductase enzyme, induces…Psychoneuroendocrinology, 2019
Altered methylation pattern of the SRD5A2 gene in cerebrospinal fluid of PFS… Endocrine Connections, 2019
Alterations of gut microbiota composition in PFS… Journal of Endocrinological Investigation, 2020
Post-finasteride syndrome: An emerging clinical problem Neurobiology of Stress, 2020
Three-Dimensional Proteome-Wide Scale Screening for the 5‑Alpha Reductase… Journal of Medicinal Chemistry, 2021
Gut Inflammation Induced by Finasteride Withdrawal… Biomolecules, 2022
Anyone living in the US who suffers from PFS should report his or her symptoms to the US FDA. Anyone living outside the US who suffers from PFS should report his or her symptoms to the US FDA as well as to his or her local drug-regulatory authority (DRA), as directed on our Report Your Side Effects page.
Finally, if you or a loved one are suffering from PFS, and feeling depressed or unstable, please don’t hesitate to contact the PFS Foundation as soon as possible via our Patient Support hotline: firstname.lastname@example.org.