Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients
Roberto Cosimo Melcangi, Daniele Santi, Roberto Spezzano, Maria Grimoldi, Tommaso Tabacchi, Maria Letizia Fusco, Silvia Diviccaro, Silvia Giatti, Giuseppe Carrà, Donatella Caruso, Manuela Simoni, Guido Cavaletti
The Journal of Steroid Biochemistry and Molecular Biology2017
In plain terms
Researchers in Italy examined 16 men, aged 22 to 44, who still had sexual and mental-health symptoms at least three months after stopping finasteride for hair loss. All 16 had some degree of erection problems (10 of them severe), half met the criteria for major depression, and a test of the nerve that carries feeling from the penis was abnormal in 4 of them. In the 14 who gave a sample of spinal fluid (the fluid around the brain and spinal cord), levels of several steroid hormones that act on the brain differed from those of 25 people having planned leg surgery. Some were lower, including DHT (a stronger form of testosterone), and some were higher, including testosterone itself.
What it doesn’t show: It can't show that finasteride caused any of this: the study was small, there were no measurements from before treatment, the mood, sexual and nerve tests had no comparison group at all, and the paper doesn't say whether the surgery patients had ever taken finasteride.
Summary (paraphrased)
Multicenter case-control study of 16 men with post-finasteride syndrome, combining psychiatric/andrological phenotyping with cerebrospinal fluid and plasma neuroactive-steroid measurements in 14 of them (2 declined CSF sampling), compared against 25 surgical controls. Eight of sixteen patients met criteria for major depressive disorder and all showed erectile dysfunction; pudendal-nerve somatosensory evoked potentials were abnormal in 4 of 16 (25%), which the authors linked to severe erectile dysfunction and took to suggest peripheral neuropathy. CSF showed decreased pregnenolone, progesterone/DHP, DHT, and 17beta-estradiol with increased DHEA, testosterone, and 5alpha-androstane-3alpha,17beta-diol relative to controls. The authors interpreted this as finasteride broadly perturbing neuroactive-steroid pathways beyond simple 5alpha-reduction blockade, but there were no before-treatment measurements or finasteride-exposed controls, and they called for asymptomatic former users as comparators in future studies.
Evidence
Extracted from the full text; page numbers refer to the paper. The library’s own notes are labelled as such.
- Design
- Case–control studyCase-control study at a single time point: clinical assessment of men with post-finasteride syndrome (no comparison group), plus cerebrospinal fluid (CSF) and plasma neuroactive steroid levels compared with surgical controls
- Setting
- Patients recruited through the Italian network on finasteride side effects; controls at San Gerardo Hospital, Monza, Italy; study dates not stated
- Population
- Men aged 22–44 with persistent sexual and mental-health symptoms after finasteride 1–1.25 mg/day for hair loss, stopped at least 3 months earlier, with no reported depression or sexual dysfunction before finasteride and no drugs known to affect neuroactive steroids. Controls: 25 otherwise healthy people having spinal anaesthesia for planned lower-limb orthopaedic surgery, screened for neurological and psychiatric disorders; mean age 33, not significantly different from patients (p = 0.791).
- Size
- 41 · 16 men with PFS assessed clinically (mean age 32), of whom 14 gave paired CSF and plasma (2 declined CSF sampling); 25 controls for steroid levels only
- Exposure
- Finasteride 1–1.25 mg/day for hair loss; mean treatment 1,037 days; 451–4,697 days since stopping (median 1,970)
- Compared with
- Steroid levels only, against 25 surgical controls whose sex and finasteride history are not stated; no comparison group for the psychiatric, sexual-function, testicular or nerve tests
- Outcome
- Major depressive disorder (K-10 screen, then the MINI diagnostic interview for those screening positive); Beck Depression and Anxiety Inventories; erectile dysfunction by IIEF-15 (erectile function score of 25 or less); testicular ultrasound; pudendal nerve somatosensory evoked potentials (PN-SEPs); 11 neuroactive steroids in CSF and plasma by LC-MS/MS.
- Follow-up
- None; a single assessment, a median of 1,970 days after stopping finasteride
Key results
- Major depressive disorder in 8 of 16 (50%); 9 of 16 screened positive on the K-10. Men with MDD vs without had higher Beck Depression (20.87 ± 11.62 vs 7.62 ± 6.48) and Beck Anxiety (21.50 ± 10.76 vs 7.50 ± 5.55) scores · p. 16; Table 2, p. 34
- All 16 had erectile dysfunction (mean erectile function score 10.31 ± 9.48): 10 severe (62.5%), 6 mild-moderate (37.5%). MDD and ED were not associated (p = 0.296). Testicular volume was normal (right 17.77 ± 5.06 mL, left 17.13 ± 4.69 mL) · p. 16; Table 3, p. 35
- PN-SEPs abnormal in 4 of 16 (25%): no reproducible response in 3, delayed P1 wave in 1. The paper reports abnormal results were linked to severe ED (p = 0.032) but does not give the split; even if all 4 were among the 10 men with severe ED, Fisher's exact test (the paper's stated test for categorical data, p. 15) gives p = 0.23 two-sided (0.12 one-sided), so the reported p-value cannot be reproduced from the counts given · p. 17
- CSF, 14 patients vs 25 controls (pg/µL, mean): lower pregnenolone (0.12 vs 0.31), progesterone (undetectable vs 0.19), dihydroprogesterone (0.56 vs 2.83), DHT (0.06 vs 0.25, about a quarter) and 17β-estradiol (undetectable vs 0.07); higher DHEA (0.33 vs 0.20), testosterone (1.97 vs 0.13, about 15-fold) and 3α-diol (0.20 vs undetectable) · p. 17; Table 4, p. 36
- Plasma: higher pregnenolone (2.48 vs 0.96), DHEA (8.79 vs 1.86, about 4.7-fold) and testosterone (12.3 vs 5.70, about 2.2-fold); lower dihydroprogesterone (0.26 vs 0.73) and tetrahydroprogesterone (undetectable vs 0.29); DHT not different (0.49 vs 0.42). The plasma pattern did not mirror CSF · pp. 17–18; Table 4, p. 36
- At assessment, all 16 reported loss of libido, difficulty getting an erection and a felt loss of connection between brain and penis at least sometimes (10, 9 and 10 "always"); 14 reported genital numbness, 13 depression or hopelessness and 9 suicidal thoughts at least sometimes · Table 1, p. 33
Limitations the authors note
- The symptom questionnaire is not validated
- Nerve testing was limited to PN-SEPs, to limit patient discomfort
- A link between neuroactive steroids and ED has not been demonstrated
- Larger studies are needed on CSF progesterone and depression
- Steroid changes differ from the group's earlier, smaller studies and remain heterogeneous; future studies need more patients, an age-matched control group and asymptomatic former users of similar doses
- The mechanism of PFS is still not demonstrated
Also worth weighing (library’s note)
- Described as prospective and longitudinal, but results come from one assessment, with no measurements from before or during finasteride
- The diagnostic interview for depression was given only to the 9 men who screened positive on the K-10, so MDD could only be found among those 9
- Table 1 records symptoms before finasteride, recalled at assessment, despite the entry criteria: 6 of 16 reported depression or hopelessness and 2 of 16 erection difficulty at least sometimes, and 11 of 16 anxiety
- Table 3 lists left varicocele in 8 of 16 (50%) and right in 1; the text does not discuss it
- Sampling conditions (such as time of day or fasting) are not described for either group, which matters for hormones such as testosterone
- Eleven steroids in two fluids were compared, with no correction for multiple testing stated
- The same 16 patients were re-analysed in DISC-025 (2019), which reports CSF results for all 16 and a patient mean age of 34.5; this paper says 2 declined CSF sampling and gives a mean age of 32
- Accepted manuscript; the published version may differ in detail
Funding: Post-Finasteride Foundation, financial support to R.C. Melcangi; the funder's role is not stated Interests: Not stated (no declaration in the accepted manuscript)
What it can support (library’s note): That some men with persistent symptoms after finasteride have erection problems, depression in about half, abnormal penile nerve tests in a quarter, and spinal-fluid steroid levels that differ from those of surgical controls. It does not establish that finasteride caused these differences, nor how common they are among former users.
Why it’s in the corpus
Foundational clinical PFS paper pairing psychiatric/andrological phenotyping with CSF neurosteroid profiling; anchors the neurosteroid-dysregulation hypothesis of PFS. NOTE: discord label 'CYP2D pharmacogenomics' is incorrect; PMID 28408350 is this Melcangi neuroactive-steroid study.
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