Immunohistochemical Evaluation of Androgen Receptor and Nerve Structure Density in Human Prepuce from Patients with Persistent Sexual Side Effects after Finasteride Use for Androgenetic Alopecia
Carla Di Loreto, Francesco La Marra, Giorgio Mazzon, Emanuele Belgrano, Carlo Simone Trombetta, Sabina Cauci
PLoS ONE2014
In plain terms
Researchers in Italy took a small skin sample from the foreskin of 8 men who had lasting sexual problems, including loss of feeling in the penis, more than 6 months after stopping finasteride for hair loss. They compared it with foreskin removed during circumcision from 11 men who had never taken the drug. In two of the three tissue types checked, more cells in the finasteride group showed the androgen receptor, the part of a cell that male hormones such as testosterone act through. The number of nerves looked about the same in both groups.
What it doesn’t show: It can't show that finasteride caused the difference or what it means for how the tissue works, because the groups were very small, the tissue was collected in different ways, and there were no samples from before the men took the drug.
Summary (paraphrased)
In a retrospective case-control design, foreskin tissue from 8 men with persistent sexual side effects (including genital sensitivity loss) more than 6 months after stopping finasteride was compared with tissue from 11 healthy circumcision controls never exposed to the drug. Immunohistochemistry showed significantly higher nuclear androgen-receptor density in stromal and epithelial cells of cases versus controls, while nerve density and vessel smooth-muscle AR positivity did not differ. The authors interpret receptor upregulation as a possible compensatory response to prior androgen deprivation, offering one of the first tissue-level molecular correlates of persistent genital symptoms.
Evidence
Extracted from the full text; page numbers refer to the paper. The library’s own notes are labelled as such.
- Design
- Case–control studyRetrospective case-control study comparing immunohistochemistry of foreskin tissue from men with persistent sexual side effects after finasteride with finasteride-naive men undergoing circumcision
- Setting
- Urological Unit, University Hospital of Trieste (enrolment, visits) and University Hospital of Udine (laboratory analyses), Italy; study dates not stated
- Population
- Cases, 8 white men aged 29–43 who took finasteride for hair loss and had sexual side effects, including self-reported loss of genital sensitivity, lasting 6 months or more after stopping; 5 enrolled after a clinical consultation and 3 through the Propeciahelp.com forum. Controls, 11 otherwise healthy white men aged 23–49 with hair loss (Norwood grade 2 or more), never exposed to finasteride or other anti-androgenic drugs, undergoing circumcision for phimosis. Both groups excluded obesity (BMI over 30) and chronic disease.
- Size
- 19 · 8 cases and 11 controls
- Exposure
- Finasteride for hair loss, 4 men at 1 mg/day and 4 at 1.25 mg/day (quartered 5 mg tablets); mean duration 956 ± 1,130 days (range 49–3,100).
- Compared with
- Finasteride-naive men with hair loss, circumcised for phimosis
- Outcome
- Percentage of epithelial, stromal and vessel smooth-muscle cells with androgen receptor (AR) positive nuclei (semi-quantitative immunohistochemistry, AR441 antibody); nerve density on H&E slides (average of 25 fields); serum total and calculated free testosterone. In cases only, the ASEX sexual-function score now and as recalled for before finasteride. Assessors blinded to subject characteristics.
- Follow-up
- None (single visit and tissue sample), a mean 1,672 ± 862 days after stopping finasteride (range 240–3,010)
Key results
- Stromal cells with AR-positive nuclei 40.0 ± 15.1% in cases vs 23.4 ± 8.68% in controls (p = 0.023), about 1.7-fold by the paper's means (described as "almost 2-fold") · p. 4, Table 2
- Epithelial cells 80.6 ± 8.63% vs 65.0 ± 19.1% (p = 0.043); vessel smooth-muscle cells 3.13 ± 3.04% vs 3.41 ± 2.61% (p = 0.331); average of the three 41.2 ± 4.46% vs 30.6 ± 8.75% (p = 0.007) · p. 4, Table 2
- No difference in nerve density (2.22 ± 0.653 vs 1.91 ± 0.952, p = 0.215), total testosterone (11.6 ± 2.96 vs 13.6 ± 3.45 nmol/L, p = 0.290) or calculated free testosterone (218 ± 52.2 vs 270 ± 80.2 pmol/L, p = 0.413) · pp. 4–5, Table 2
- Ratio of AR-positive stromal cells (%) to total testosterone 3.47 ± 1.25 vs 1.86 ± 0.372 (p = 0.001), about 1.9-fold (described as 2-fold); to free testosterone 0.192 ± 0.095 vs 0.096 ± 0.027 (p = 0.005), 2.0-fold · p. 5, Table 2
- Within the 8 cases, worse current sexual function went with fewer AR-positive stromal cells (rho −0.722, p = 0.043), more strongly for the change from recalled pre-finasteride ASEX (rho −0.913, p = 0.002) · p. 5
- All 8 cases reported loss of penile sensitivity and of pleasurable response to touch; 7 of 8 loss of scrotal or testicular sensitivity, erectile dysfunction, hardened or rubbery tissue, and flaccidity or retraction into the scrotum. ASEX 22.5 ± 2.78 now vs 7.6 ± 1.92 recalled for before finasteride · pp. 3–4, Table 1
Limitations the authors note
- Small number of subjects, partly due to strict selection
- DHT, especially local tissue DHT, could not be measured
- No testing for androgen receptor gene polymorphisms, partly offset by hair-loss-matched controls
- Retrospective design, with no tissue from before or during finasteride use
- The design cannot show whether the nuclear AR in cases works normally as a transcription factor
- The apparent AR increase might reflect low local androgen levels
Also worth weighing (library’s note)
- Tissue was obtained differently (5 mm punch biopsy, 2–4 mm deep, in cases vs circumcision tissue in controls), and controls had phimosis, a foreskin condition; the paper does not discuss whether either affects AR staining or nerve counts
- Scoring was semi-quantitative by light microscopy; the number of assessors and their agreement are not reported
- Very small groups, several outcomes and no correction for multiple comparisons; the correlations are within 8 men
- Pre-finasteride ASEX scores were recalled at interview, and the before/after comparison used an unpaired test (Mann–Whitney) on the same men
- Among cases, 3 had used testosterone after finasteride (stopped over a year before entry) and 5 had used tadalafil
- The matching method is not described beyond age and hair-loss grade; no case was married or partnered vs 5 of 11 controls (p = 0.045)
Funding: University of Udine funds; the funders had no role in the study Interests: None declared
What it can support (library’s note): A difference in the proportion of androgen-receptor-positive cells in foreskin tissue between 8 men with persistent sexual symptoms after finasteride and 11 unexposed men, with no difference in nerve density. It cannot establish that finasteride caused the difference, or what it means for receptor function.
Why it’s in the corpus
Rare human tissue evidence in PFS: reports a higher percentage of stromal and epithelial cells with androgen-receptor-stained nuclei (semi-quantitative immunohistochemistry) in foreskin from 8 affected men than from 11 unexposed controls, relevant to the corpus's androgen-signaling mechanism thread. It did not measure AR gene expression or receptor function, which the authors say their design cannot determine.
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