New review focusing on gut steroids, meanwhile, hints at possible PFS biomarker
Dec. 13, 2024
Dear Friends:
Is Roberto Cosimo Melcangi, PhD, now taking a page out of Enzo Ferrari’s playbook?
Judging by the speed at which he’s been completing research projects, the answer is a resounding “sì.”
New Year’s conclusions
Since his April launch of the Milano Project, a three-year effort to map the basic science of PFS, the Head of the Neuroendocrinology Unit in the Department of Pharmacological and Biomolecular Sciences at the University of Milano and his team have wrapped three investigations:
▪ How don’t you feel? Possible mechanisms involved in genital numbness and paresthesia (aka “pins and needles”), symptoms common among PFS patients, have been identified in an animal model. These observations may represent a possible target for future therapeutic strategies.
▪ Does loss of libido originate in the brain? Many behavioral parameters have been analyzed in a PFS animal model, confirming alterations in motivational behavior and anxiety-like behaviors. The resultant data will help identify areas of the brain involved in various PFS symptoms, thus providing a roadmap of which tissues to focus on in subsequent analyses.
▪ Does the mind mind being fixed? As a follow-up to its 2022 study Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats, Team Melcangi has explored how an animal brain reacts after gut inflammation is alleviated by ALLO. Is the improvement durable? Or is it transitory?
Papers on each study are being drafted as we speak, and are on track for submission to peer-reviewed journals during the first half of 2025. While there’s never any guarantee that any research will be accepted by any medical journal, Prof. Melcangi—whose previous 14 PFS investigations have appeared in the likes of Frontiers in Neuroendocrinology, Neurobiology of Stress and the Journal of Medicinal Chemistry—is confident that these new investigations will be published during the second half of 2025.
“We’ve been very fortunate so far in our Milano Project research,” he says. “Not only has it progressed at a rapid pace, it’s yielding much of the data we’ll likely need in the coming years to move from testing target therapies on animals to testing them on humans.”
Gut reaction
In addition to the planned studies that comprise the Milano Project, Team Melcangi last month published a review article in the Journal of Neuroendocrinology presenting new points of view on steroids as a potential therapy for gastrointestinal disorders and brain comorbidities, including depression, anxiety and insomnia.Among the concepts raised is that PPAR-α, a nuclear receptor protein that regulates energy combustion, inflammation and lipid metabolism, could serve as a biomarker for PFS.
“A clinical study reported that in PFS patients, persistent alterations of steroid levels both in plasma and in cerebral spinal fluid were associated with andrological and psychiatric features,” Prof. Melcangi writes in the paper, titled The gut-microbiota-brain axis: Focus on gut steroids.
He further notes that, while taking finasteride and after quitting, patients’ steroid levels were altered, not only in plasma and cerebrospinal fluid, but—as observed an animal model as well—in the brain. Additionally:
The effect of finasteride treatment and its withdrawal were also evaluated on the gut steroid levels. As previously reported, finasteride treatment not only decreased DHT levels as expected but also the levels of its active androgen metabolite 3α-diol with a significant increase in T levels.
Of note, a significant reduction in ALLO was observed in the colon of PFS rats, which persisted even after 1 month of withdrawal. In addition, the persistent decrease in ALLO levels was instead associated with an increase in [pregnenolone] (PREG) levels, suggesting a local relationship between these two steroid molecules…
Considering the important evidence suggesting the interaction of PPAR-α and ALLO in the [gut-microbiome-brain axis] (GMBA), it will be crucial to investigate whether this interaction is altered in the PFS animal model… PPAR-α was proposed as a potential biomarker in [inflammatory bowel disease] (IBD). Therefore, the potential significance of ALLO-based intervention in shaping future treatment options could be definitely a new approach for PFS.
Funding progress
Hand in hand with such scientific enlightenment, of course, comes the economic reality of keeping the Milano Project on track for completion by the end of 2026. To that end, we raised an additional $22,000 during Phase I of our funding drive, bringing the current total to $52,000, or 17% of our $300,000 target.
Thanks goes to the increasing number of PFS patients and their loved ones who’ve donated to the project in recent months. And an equal dose of gratitude goes to SIDEfxHUB, a new UK-based charity catering to sufferers of PFS and Post-SSRI Sexual Dysfunction.
Among the services SIDEfxHUB offers is an ever-expanding network of WhatsApp Peer Support Groups, where patients can freely, yet politely, discuss all things related to their condition, in hopes of advancing recovery.
More than 50% of the funds raised to date for the Milano Project have come from SIDEfxHUB, whose board of directors is made up of four PFS patients—Morten Skov, Robert Dixon, Bernard Morlet and Ryan Clarke—and one parent of a PFS patient, Gary Shields.
Donate now
Phase II of our fundraising drive for the Milano Project gets under way immediately, and has a target of $50,000.
“Please don’t sit back and assume others will make that goal a reality,” says PFS Foundation President Philip Recchia.
“If you’ve ever contacted us directly, you can attest to the fact that we work day and night, 365 days a year, helping PFS patients and their families cope with this devastating condition. And if you’re wondering how you can return the favor this holiday season, we’re not shy about asking you to do so by donating any amount, be it $5,000 or $5.”Throughout the Milano Project, and beyond, SIDEfxHUB plans to continue working in association with the PFS Foundation to raise funding for PFS research.
Finasteride was originally developed by Merck & Co., Inc., and first approved by the US Food and Drug Administration in 1993 as Proscar (5 mg, for enlarged prostate), and again in 1997, as Propecia (1 mg, for hair loss).
In June 2021, Merck spun off its Organon subsidiary as an independent public company (NYSE: OGN). Founded in the Netherlands in 1923, Organon bills itself as a “global health care company dedicated to making a world of difference for women, their families and the communities they care for.”
Among the Merck products Organon acquired in the deal were Proscar and Propecia. To report adverse events for either finasteride product, call the Organon Service Center at (844)674-3200, or email Service_Center@Organon.com.
Anyone living in the US who suffers from PFS should also 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 DRA, as directed on our Report Your Side Effects page.
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: social@pfsfoundation.org
Thank you.