Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study
Roberto Cosimo Melcangi, Livio Casarini, Marco Marino, Daniele Santi, Samantha Sperduti, Silvia Giatti, Silvia Diviccaro, Maria Grimoldi, Donatella Caruso, Guido Cavaletti, Manuela Simoni
Endocrine Connections2019
In plain terms
Researchers looked for a chemical tag on DNA (called methylation) that can turn down the gene for the enzyme finasteride blocks. They tested DNA from the spinal fluid (the fluid around the brain and spinal cord) and blood of 16 men with lasting symptoms after finasteride, and of people who had never taken it. In spinal fluid the tag was found in 9 of the 16 men and in 1 of 13 comparison people; it was not found in anyone's blood. Men with and without the tag had similar scores for erection problems, depression and anxiety.
What it doesn’t show: It can't tell whether the tag was caused by finasteride or was there from birth, as the authors say themselves; the groups were very small, and no one who took finasteride without problems was tested.
Summary (paraphrased)
In this pilot case-control study, 16 PFS patients were compared with 36 controls who had never used finasteride: 18 surgical patients giving cerebrospinal fluid (2 of whom also gave blood) and 18 blood-only donors; controls' mean age was 40.8 years vs 34.5 in patients. The SRD5A2 gene promoter was methylated in cerebrospinal fluid-derived DNA of 56.3% of PFS patients (9 of 16) versus 7.7% of the 13 controls with enough CSF DNA (1 of 13), while no methylation appeared in blood samples of either group (16 patients, 20 controls) and the SRD5A1 promoter was unmethylated everywhere. The authors proposed this tissue-specific epigenetic silencing of the 5α-reductase type 2 gene as a candidate mechanism for the neuroactive-steroid disturbances and behavioral symptoms previously documented in PFS. They cautioned it is unknown whether the methylation pattern is pre-existing or induced by finasteride treatment.
Evidence
Extracted from the full text; page numbers refer to the paper. The library’s own notes are labelled as such.
- Design
- Case–control studySecondary analysis of the DISC-013 case-control study: methylation of the SRD5A1 and SRD5A2 gene promoters in DNA from CSF and blood, men with PFS vs controls, with CSF steroid levels and clinical scores compared by methylation status (pilot)
- Setting
- Patients from the Italian network of finasteride side effects; controls at San Gerardo Hospital, Monza, plus blood donors; laboratory work in Modena, Italy; dates not stated
- Population
- 16 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; the same patients as DISC-013. Controls had never used finasteride: 18 otherwise healthy people having spinal anaesthesia for planned lower-limb orthopaedic surgery (CSF; 2 also gave blood) and 18 healthy blood donors. Mean age 40.8 ± 17.9 in controls vs 34.5 ± 8.8 in patients (P = 0.192).
- Size
- 29 · 29 in the main CSF comparison (16 patients, 13 controls; CSF DNA was insufficient in 5 of 18 control samples). Blood DNA from 16 patients and 20 controls. 36 controls recruited in all; the overlap between CSF and blood controls is not fully stated, so the total analysed across both tissues is 47–49
- Exposure
- Finasteride 1–1.25 mg/day for hair loss, stopped at least 3 months earlier; duration not reported in this paper
- Compared with
- Controls who never used finasteride; within patients, methylated vs unmethylated
- Outcome
- Promoter methylation of SRD5A1 and SRD5A2 by quantitative methylation-specific PCR, "methylated" meaning 10% or more methylated DNA. Secondary: CSF levels of 11 neuroactive steroids (taken from DISC-013), and erectile function, depression and anxiety scores, by methylation status.
- Follow-up
- None; a single sample per person
Key results
- SRD5A2 promoter methylated in CSF DNA of 9 of 16 patients (56.3%) vs 1 of 13 controls (7.7%); P = 0.006 by Pearson's chi-square, which recomputes correctly (chi-square 7.49). Two expected cell counts are below 5; Fisher's exact test gives P = 0.008 · p. 1121, Table 1
- In the 9 methylated patients, methylation ranged from 15.4% to 100% (mean 40.3%, median 31.8%); the one methylated control (58.0%) was a man with normotensive hydrocephalus · p. 1121
- SRD5A2 unmethylated in every blood sample (16 patients, 20 controls); SRD5A1 unmethylated in every sample, blood or CSF · p. 1121
- CSF steroids (pg/µL, mean) in 12 unmethylated controls, 7 unmethylated and 9 methylated patients: unmethylated patients had lower pregnenolone (0.09 vs 0.39), DHT (0.05 vs 0.15) and dihydroprogesterone (0.25, the detection limit, vs 3.07) and higher testosterone (2.53 vs 0.23) than controls; methylated patients differed from controls only in dihydroprogesterone (1.00 vs 3.07). Steroid levels did not correlate with the percentage of methylation (P > 0.05) · pp. 1121–1122, Table 2
- Methylated and unmethylated patients did not differ in degree of ED (P = 0.362), any IIEF-15 domain (P = 0.456 to 0.805), K-10 (P = 0.890), Beck Depression (P = 0.475) or Beck Anxiety (P = 0.485) scores · p. 1121
Limitations the authors note
- The low number of subjects; the steroid results "must be interpreted with extreme caution"
- It cannot be established whether the methylation was set before birth or caused by finasteride
- Whether the sexual and psychiatric symptoms relate to methylation cannot be concluded
- DNA extraction was insufficient in five CSF samples
- The LC-MS/MS method's sensitivity was limited for some steroids
- The proposed mechanism (finasteride altering DNA methylation in the nervous system) is "highly speculative"
Also worth weighing (library’s note)
- No finasteride users without symptoms were tested, so the study cannot separate an association with PFS from one with finasteride exposure itself
- The method assumes the few cells in CSF are nervous-system (ependymal) cells representative of the brain; which cells the DNA came from was not checked
- Controls were different people for each tissue: CSF from surgical patients, blood mostly from separate donors. The abstract's "20 age-matched healthy men" are the blood controls; the 13 CSF controls' age is not given separately
- Inconsistent with the source study: DISC-013 says 2 of these 16 men declined CSF sampling and reports CSF steroids for 14, whereas this paper gives CSF DNA and CSF steroid results for all 16 (7 + 9); mean patient age is 34.5 here vs 32 in DISC-013
- Some Table 2 entries look inconsistent: controls' 17β-estradiol is 0.4 ± 0.06 pg/µL against 0.02 in unmethylated patients, yet P = 0.676; controls' testosterone is 0.23 ± 0.85. DISC-013 gave control CSF values of 0.07 ± 0.05 and 0.13 ± 0.11. These may be typographical; the paper does not allow a check
- Three-way comparisons of 11 steroids in groups of 7 to 12, with no correction for multiple testing stated
Funding: Post-Finasteride Foundation Interests: None declared
What it can support (library’s note): A difference, in a pilot study, in a DNA tag on the SRD5A2 gene in spinal-fluid cells between 16 men with PFS and 13 controls. It cannot show whether finasteride caused the tag, whether it explains symptoms (it did not track them here), or that it is specific to PFS.
Why it’s in the corpus
Pilot evidence (16 vs 13) of SRD5A2 promoter methylation in CSF-derived DNA, but not blood, of men with PFS, relevant to epigenetic hypotheses of persistent post-drug syndromes. The degree of methylation did not correlate with CSF steroid levels and methylation status was unrelated to clinical scores; specificity to PFS is untested without asymptomatic finasteride-exposed controls, and any relevance to PSSD is by analogy, as only PFS was studied.
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