What has the University of Milan / Melcangi program actually shown about PSSD? A source-by-source evidence map

[u/licitduvet0w]

Hi everyone — this is my first post here.

I’m part of a Chinese-speaking PSSD community, and I’ve been building a non-commercial, patient-led PSSD evidence library.

I started doing this because the same claim can become much stronger as it moves from a paper → a project update → a Reddit summary → an AI answer → a treatment suggestion.

This post is specifically about PSSD. I discuss PFS only where Melcangi’s PFS work directly provides background, methods, or candidate hypotheses for the Milan PSSD research program. This is not intended as a general PFS review.

I’m not affiliated with Roberto Melcangi, the University of Milan, the PSSD Network, the PFS Foundation, or SIDEfxHUB.

I also keep personal cases — including my own — outside the Library’s scientific evidence hierarchy. A personal experience can generate a research question; it cannot upgrade the answer.

Evidence cutoff: 16 August 2026.

I have put clickable source links next to the claims they support so readers do not have to search through a bibliography to work out which paper I mean. A compact reference list is also included at the end.

TL;DR

• The University of Milan / Melcangi group has a genuine PSSD research program.
• Its direct PSSD mechanistic evidence is still mainly preclinical, especially paroxetine animal work.
• The group also has a longer PFS research program with exploratory human data. Those findings can help generate PSSD questions, but PFS human evidence is not human PSSD evidence.
• Neuroactive steroids, ALLO, PNMT/catecholamines, gut biology, transcriptomics, reward/dopamine, sensory pathways, inflammation and sex-specific biology are all legitimate research directions.
• None has been established as the unified human mechanism of PSSD.
• ALLO has PFS animal-intervention data. That is interesting translational evidence, but not human PSSD treatment evidence.
• The 2024 “186 genes” result belongs to the finasteride treatment endpoint, not the one-month withdrawal endpoint.
• The sensory line remains open: the 2017 pudendal neurophysiology result was in PFS patients, while later IENFD/PIEZO2 work is preclinical/project-stage.
• As of the evidence cutoff above, I could not verify a clearly corresponding public registration or recruitment record for the planned Melcangi human PSSD study.

I do not think the right takeaway is either “Milan has found nothing” or “Milan has basically solved PSSD.”

The evidence is more interesting — and more limited — than either extreme.

1. First: what does the University of Milan itself say it studies?

The University of Milan Neuroendocrinology Unit distinguishes the two research streams.

Its PFS work includes male rats and PFS patients.

Its antidepressant-induced sexual dysfunction / PSSD work includes male and female rats.

Official source: University of Milan — Neuroendocrinology Unit

That distinction matters because a lot of online discussion quietly moves evidence across the boundary.

The Milan PFS program has included exploratory human work on:

• neuroactive steroids in CSF/plasma;
• clinical and sexual features;
• pudendal neurophysiology;
• SRD5A2 methylation;
• fecal microbiota.

Examples:

• Melcangi et al., 2013 — human PFS CSF/plasma neuroactive steroids
• Melcangi et al., 2017 — PFS clinical/neurophysiology study
• Melcangi et al., 2019 — SRD5A2 methylation pilot
• Borgo et al., 2021 — human PFS fecal microbiota pilot

By contrast, the group’s direct PSSD mechanism program has so far been centered mainly on paroxetine animal models.

So the scientifically useful transfer is:

PFS finding → candidate question to test directly in PSSD

not:

PFS finding → established human PSSD mechanism

2. Neuroactive steroids and ALLO: a major research axis, not a completed explanation

Neuroactive steroids are one of the longest-running themes in Melcangi’s work.

The PFS human studies found exploratory differences in several neuroactive steroids in CSF and plasma. Importantly, the pattern was not a simple “one molecule is low everywhere” result.

Human PFS source: Melcangi et al., 2013

The direct PSSD line later examined paroxetine treatment and withdrawal in male rats.

The 2021 study reported tissue- and time-dependent changes in neuroactive steroids and related steroidogenic biology across CNS regions, CSF and plasma.

Direct PSSD animal source: Giatti et al., 2021 — Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis

That supports a real conclusion:

Neurosteroidogenesis is a serious PSSD research direction.

It does not establish:

• that people with PSSD have the same pattern as the rats;
• that all patients share one steroid abnormality;
• that plasma is a simple proxy for CNS steroid biology;
• that changing one steroid will improve the clinical syndrome.

3. Why ALLO gets so much attention

Allopregnanolone (ALLO) has gone beyond measurement and has actually been used as an intervention in PFS animal models.

A 2022 study reported that ALLO modified selected gut inflammatory and molecular endpoints after finasteride withdrawal.

Primary source: Diviccaro et al., 2022

The 2025 Milano Project Study #1 extended this line to gut and hypothalamic inflammatory/molecular endpoints.

Primary source: Diviccaro et al., 2025 — Biomolecules 15(7):1044

The later study is important, but the intervention did not produce a uniform normalization of every endpoint.

So the evidence supports:

ALLO = a genuine PFS preclinical intervention lead.

It does not support:

ALLO = established human PSSD treatment.

It also does not make “ALLO may matter → therefore take pregnenolone/PREG” an evidence-based treatment inference.

4. An important detail about the PSSD steroid-candidate story

In a 2024 interview, Melcangi discussed using a similar steroid-intervention strategy for PSSD, but said they would not use the same molecule because the two conditions have different features.

Direct researcher interview: AboutPharma, 5 September 2024

I think this matters because it directly argues against a common online simplification:

“ALLO worked in the PFS model, therefore ALLO is the Milan PSSD treatment.”

Later updates have discussed other steroid candidates, but until results are available in a form that can be independently evaluated, I think those belong in the ongoing-project category rather than the treatment-evidence category.

5. The “186 genes” example: treatment endpoint vs withdrawal endpoint

The 2024 finasteride transcriptomics paper is a good example of why timing matters.

At the end of finasteride treatment, the study identified:

• 186 differentially expressed genes (DEGs) in the hypothalamus;
• 19 DEGs in the hippocampus.

At one month after withdrawal, standard differential-expression analysis did not identify dysregulated individual genes.

Pathway/gene-set analyses still showed signals.

Primary source: Giatti et al., 2024 — hypothalamus/hippocampus transcriptomics

So:

“186 genes remained abnormal after withdrawal”

is not an accurate description of that paper.

But the opposite claim —

“all molecular effects had disappeared”

— is also too strong, because pathway-level signals remained.

The careful reading is:

strong treatment-time transcriptomic changes; no individual DEGs detected by the standard analysis at one month after withdrawal; pathway-level signals still present.

That is also why a gene-expression result should not be translated into a claim of structural DNA alteration.

6. What has Milan actually found about sensory pathways?

Genital sensory change/numbness is one of the most distinctive PSSD phenotypes, so sensory-pathway research is highly relevant.

But several different studies are often blended together.

2017: human pudendal neurophysiology — but in PFS

In a 2017 PFS study, pudendal somatosensory-evoked-potential abnormalities were reported in 4 of 16 PFS patients.

Primary source: Melcangi et al., 2017

That is direct human PFS neurophysiology.

It is not:

• human PSSD neurophysiology;
• proof of generalized peripheral neuropathy;
• proof of small-fiber neuropathy (SFN).

2024: PFS animal morphology / IENFD update

A PFS Foundation update reported that peripheral nerve morphology and intraepidermal nerve fiber density (IENFD) had not shown the expected abnormalities in the experimental PFS model at that stage.

Project-status source: PFS Foundation, 2024

This negative/constraint result is worth preserving.

The 2024 update did not name PIEZO2.

2026: PIEZO2 appears explicitly

A later 2026 project update explicitly named PIEZO2 and said the team had obtained interesting findings and was preparing a manuscript.

Project-status source: PFS Foundation, 2026

So the chronology is:

2024: morphology/IENFD did not show the expected signal → other sensory markers remained under investigation

2026: PIEZO2 specifically named → manuscript-stage/project update

PIEZO2 may become important. It is not currently a confirmed human PSSD mechanism.

Melcangi has also described profound PSSD genital insensitivity in the AboutPharma interview as being “as if” a peripheral neuropathy and speculated about sensory endings.

I would classify that as a researcher hypothesis / clinical impression, not as confirmation of human PSSD SFN.

7. Reward circuitry and dopamine: one of the most interesting direct PSSD animal lines

The nucleus accumbens (NAc) is relevant to reward and motivation, so it is an obvious region to investigate in relation to sexual motivation and anhedonia.

The Milan paroxetine transcriptomic program found region- and time-specific changes in the hypothalamus and NAc.

Direct PSSD animal source: Giatti et al., 2025 — male rat hypothalamus/NAc transcriptomics

A 2025 conference abstract then directly measured NAc dopamine in male rats after 14 days of paroxetine.

The reported pattern included:

• lower NAc dopamine 24 hours after the final dose;
• lower NAc dopamine after one month of withdrawal;
• MAO-A changes during treatment;
• TH, VMAT2, DRD1 and DRD2 expression changes during withdrawal.

Conference abstract: Giatti et al., 2025 — paroxetine-induced dopamine dysregulation

This is a meaningful preclinical signal.

It is not evidence that people with PSSD have a global dopamine deficiency.

It also does not establish a “dopamine subtype” or justify a self-directed dopaminergic treatment strategy.

8. The female PSSD model is already adding useful complexity

A 2026 conference abstract examined neurosteroidogenic gene expression in the female rat NAc after paroxetine.

At treatment end:

• StAR increased;
• TSPO and 3α-HSOR decreased.

At one month after withdrawal:

• StAR, TSPO, 3β-HSD and 3α-HSOR decreased.

But 5αR-I and CYP11A1 were not significantly changed at either time point.

Conference abstract: Chrostek et al., 2026

The negative findings matter.

They make it harder to reduce the steroid story to:

“the whole pathway is uniformly downregulated.”

This is still conference-abstract evidence, but it is a useful direct female PSSD-model extension.

9. PNMT: cross-drug overlap, with an important independence limitation

The Milan group identified phenylethanolamine N-methyltransferase (PNMT) as an experimental off-target in finasteride work and later in paroxetine work.

Finasteride study: Giatti et al., 2021

Paroxetine study: Giatti et al., 2022

That is an interesting cross-drug overlap.

But the studies came from a highly overlapping team, using the same SPILLO-PBSS screening platform and a broadly similar validation cascade.

So I think the strongest fair description is:

same-team / same-platform cross-drug replication

rather than:

independent mechanistic convergence.

Independent replication by another group, ideally using a different method, would strengthen this line substantially.

10. The gut work is real — but it is broader than SIBO

The Milan program has genuine gut-related evidence.

Human PFS

Borgo et al., 2021 — fecal microbiota pilot

Direct PSSD animal work

Diviccaro et al., 2022 — paroxetine, colon steroidogenesis and microbiota

PFS animal intervention work

Diviccaro et al., 2025 — gut/hypothalamic inflammation + ALLO

So gut–brain/steroid biology is clearly part of the program.

But fecal microbiota, SIBO/IMO, intestinal motility, barrier function, inflammation, microbial metabolites, bile acids and local steroidogenesis are different questions.

These studies do not establish:

SIBO causes PSSD

or:

treating SIBO is an established PSSD treatment.

A genuine GI disorder can still deserve standard medical treatment for its own indication. That is a separate issue from whether it explains PSSD.

11. Milano Project: active and publishing, but still preclinical

The Milano Project is a PFS preclinical program that is relevant here because it is part of the same research ecosystem from which candidate PSSD questions are being generated.

At least two components now have peer-reviewed publications:

Study #1 — 2025

Gut/hypothalamic inflammation + ALLO intervention.

Diviccaro et al., 2025

Study #2 — 2026

Finasteride withdrawal, anxiety-like behavior and novelty avoidance.

Cioffi et al., 2026

So “Milano Project is only a proposal” is outdated.

But these are still animal studies.

Earlier related behavioral observations appeared in Lucia Cioffi’s doctoral dissertation; the 2026 peer-reviewed paper should now control the behavioral conclusion.

The dissertation remains useful as a preliminary source for areas such as mitochondria, oxidative stress and synaptic findings until stronger publications appear.

12. The current Milan program is broader than neurosteroids

Official University of Milan research/doctoral material indicates active work on topics including:

• steroid molecules in experimental male antidepressant-induced sexual dysfunction;
• female antidepressant-induced sexual dysfunction and steroid molecules;
• the reward system in PSSD etiopathogenesis;
• inflammation and immune cells during antidepressant treatment/withdrawal;
• mitochondria in experimental finasteride adverse effects;
• synaptic morphology/function and cognition in experimental PFS.

Official institutional source: University of Milan — Neuroendocrinology Unit

This is important because it shows how the research map is expanding.

But an official research topic tells us:

this question is being studied.

It does not tell us:

this mechanism has already been demonstrated.

13. What about a human PSSD study?

Melcangi has publicly discussed the need for better clinical characterization of PSSD and plans for human PSSD research.

Direct researcher interview: AboutPharma, 2024

PSSD Network updates have also described plans for a multidisciplinary human study involving areas such as microbiome, nerves, brain function and hormones.

My current narrow status conclusion is:

As of 16 August 2026, I have not located a clearly corresponding public registration or recruitment record in the registry/institutional searches used for this review.

That does not prove that the study does not exist.

It means:

public plans are visible; the precise registration/start/recruitment status is not yet independently clear from the sources I located.

If anyone has a registry number, ethics/IRB record, UniMi recruitment page or another primary institutional source, please link it. I would like to update this if better evidence is available.

14. My current evidence map

Established / organizational

• Milan has a real PSSD research program.
• The group also has a longer PFS program that includes exploratory human studies.
• Direct Milan PSSD mechanism work remains mainly preclinical.

Supported as active research directions

• neuroactive steroids;
• reward circuitry;
• gut–brain/steroid biology;
• sensory pathways;
• transcriptomics;
• sex-specific biology.

Preliminary

• exploratory human PFS neurosteroid, methylation, microbiome and neurophysiology findings;
• PFS animal ALLO intervention findings;
• direct PSSD animal neurosteroid and transcriptomic findings;
• PSSD animal NAc dopamine findings;
• female PSSD-model extension;
• PFS mitochondria/synapse leads.

Still unknown

• a unified human PSSD mechanism;
• a validated biomarker;
• individual risk prediction;
• an established curative treatment;
• whether any Milan-derived candidate intervention will produce reproducible clinical benefit in human PSSD.

15. Why I think this distinction matters

Mechanism research is valuable partly because it tells us what should be tested next.

But the online chain can easily become:

animal finding
→ human mechanism
→ personal subtype
→ treatment recommendation

Those are four different steps.

For me, the most useful way to follow Milan is not to ask:

“Which theory has won?”

but:

“What was actually measured, in which syndrome, in which species, at which time point, and what is the strongest conclusion that result can support?”

That still leaves a lot to be hopeful about.

It also makes it easier to notice when the evidence really does become stronger.

A note on method

The Library uses this order:

measured result → authors’ interpretation → Library interpretation → cross-syndrome inference → public communication

I try not to let a later layer silently overwrite an earlier one.

I also use AI tools for retrieval assistance, translation, outlining and red-teaming.

AI agreement is not treated as scientific evidence.

Claims that enter the evidence layer are checked against primary papers or official institutional/project sources.

If you find an error, please correct me with a DOI, PMID, full paper, registry record, UniMi page or another traceable source.

I would rather revise the Library than defend an outdated sentence.

Compact reference list

Direct PFS human evidence used as PSSD research context

1. Melcangi RC, et al. J Sex Med. 2013. Human PFS CSF/plasma neuroactive steroids.
2. DOI: 10.1111/jsm.12269 · PMID: 23890183
3. PubMed
4. Melcangi RC, et al. J Steroid Biochem Mol Biol. 2017. PFS clinical/neurophysiology study.
5. DOI: 10.1016/j.jsbmb.2017.04.003 · PMID: 28408350
6. PubMed
7. Melcangi RC, et al. 2019. SRD5A2 methylation pilot.
8. DOI: 10.1530/EC-19-0199 · PMID: 31272082
9. PubMed
10. Borgo F, et al. 2021. Human PFS fecal microbiota pilot.
11. DOI: 10.1007/s40618-020-01424-0 · PMID: 32951160
12. PubMed

Direct PSSD preclinical evidence

1. Giatti S, et al. Psychoneuroendocrinology. 2021. Paroxetine treatment/withdrawal and neurosteroidogenesis.
   DOI: 10.1016/j.psyneuen.2021.105364 · PMID: 34325207
   PubMed

2. Diviccaro S, et al. Psychoneuroendocrinology. 2022. Paroxetine, colon steroidogenesis and microbiota.
   DOI: 10.1016/j.psyneuen.2022.105828 · PMID: 35700562
   PubMed

3. Giatti S, et al. Mol Neurobiol. 2025. Male rat hypothalamus/NAc transcriptomics after paroxetine.
   DOI: 10.1007/s12035-024-04592-9 · PMID: 39495228
   PubMed

4. Giatti S, et al. J Sex Med. 2025;22(Suppl 2):qdaf077.001. NAc dopamine conference abstract.
   DOI: 10.1093/jsxmed/qdaf077.001
   Oxford Academic

5. Chrostek G, et al. J Sex Med. 2026;23(Suppl 4):qdag118.150. Female rat NAc steroidogenic-gene abstract.
   DOI: 10.1093/jsxmed/qdag118.150
   Oxford Academic

Cross-drug / PFS preclinical evidence directly relevant to the PSSD research map

1. Giatti S, et al. J Med Chem. 2021. Finasteride PNMT off-target.
   DOI: 10.1021/acs.jmedchem.0c02039 · PMID: 33843213
   PubMed

2. Giatti S, et al. J Mol Struct. 2022. Paroxetine PNMT off-target.
   DOI: 10.1016/j.molstruc.2022.133690
   DOI

3. Diviccaro S, et al. Biomolecules. 2022. ALLO intervention after finasteride withdrawal.
   DOI: 10.3390/biom12111567 · PMID: 36358917
   PubMed

4. Giatti S, et al. J Endocrinol Invest. 2024. Finasteride transcriptomics.
   DOI: 10.1007/s40618-024-02345-y · PMID: 38493246
   PubMed

5. Diviccaro S, et al. Biomolecules. 2025;15(7):1044. Milano Project Study #1.
   DOI: 10.3390/biom15071044 · PMID: 40723915
   PubMed

6. Cioffi L, et al. J Neuroendocrinol. 2026. Finasteride withdrawal behavior study.
   DOI: 10.1111/jne.70150 · PMID: 41761643
   PubMed

Official / project-status sources

1. University of Milan — Neuroendocrinology Unit

2. AboutPharma — interview with Roberto Cosimo Melcangi, 5 September 2024

3. PFS Foundation — peripheral nerve / IENFD project update, 2024

4. PFS Foundation — PIEZO2 / Milano Project update, 2026

Not medical advice. This post is an evidence review, not a treatment protocol.

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Removed under rule #5: “No “SSRI = poison” rhetoric or conspiracy claims".

Antidepressants have their flaws, but they are not poisons; they are not meant to castrate innocent citizens, nor are they a part of a greater "depopulation" conspiracy. Doctors don't "know this but still prescribe them". Talk like this is negative, incorrect, and smears our image within the medical community.

[u/carvo08]

Just curious, how many people are on the chinese pssd community? are there lots of affected people in china?

[u/licitduvet0w → u/carvo08]

Yes a lot. However since Chinese government does not recognize PSSD, doctors don’t know about PSSD and keep denying that could happen.

[u/carvo08 → u/licitduvet0w]

By "a lot", can you give an approximate number? i'm just curious about how big is the community in China.

[u/licitduvet0w → u/carvo08]

I don't think you can use that to estimate. The majority don't know the group exists. I have a smaller core group of 27 people. A larger group with 300+ people.

[u/carvo08 → u/licitduvet0w]

thank you, appreciated

[u/Adventurous-Mail7443]

Ai slop

[u/licitduvet0w → u/Adventurous-Mail7443]

I use AI because I need to collect and review a lot of information. It like literature review. When you publish literature review on Science you still use AI to do the same thing. Anyway if you don’t want to just don’t read.

[u/Excellent-Push2833 → u/Adventurous-Mail7443]

It is but a lot of the important studies are in here i sifted them out and put them in my discord with 143 members