PSA

**Biology** - PSA = kallikrein-related peptidase 3 (KLK3), a serine protease made by prostatic glandular epithelium. - Normal function: cleaves semenogelin in the seminal coagulum, liquefying semen and allowing sperm motility. - Circulates in serum both bound to protease inhibitors (e.g., alpha-1-antichymotrypsin; complexed PSA) and unbound (free PSA).

**Causes of elevated PSA** - Prostate adenocarcinoma - Benign prostatic hyperplasia (BPH) - Acute prostatitis (markedly elevated) - Prostate infarction, urinary retention, recent catheterization/cystoscopy/prostate biopsy - Ejaculation within about 24-48 hours; vigorous prostate massage. Routine DRE has minimal effect. - Age (levels rise physiologically)

**Medications lowering PSA** - 5-alpha-reductase inhibitors (finasteride, dutasteride) reduce PSA by about 50% after 6-12 months. Double the measured value to interpret it.

**Refinements to improve specificity** - Free PSA percentage: low free PSA (<10%) favors cancer; high free PSA (>25%) favors BPH. Cancer-associated PSA is mostly bound. - PSA velocity (rapid rise, e.g., >0.75 ng/mL/year) - PSA density (PSA divided by prostate volume) - Age-specific reference ranges - Traditional cutoff is about 4 ng/mL, but there is no true "normal." Cancer can occur at lower levels.

**Screening** - USPSTF (2018): Grade C for ages 55-69, meaning individual decision after discussing benefits and harms. Grade D for age 70 and older. - Harms: overdiagnosis, overtreatment (incontinence, erectile dysfunction), false positives, and biopsy complications. - Abnormal PSA or DRE leads to MRI and/or transrectal ultrasound-guided biopsy. Diagnosis is by biopsy and Gleason score/Grade Group.

**Clinical use in known prostate cancer** - Monitoring after radical prostatectomy: PSA should become undetectable. Detectable or rising PSA indicates biochemical recurrence. - Monitoring response to radiation or androgen deprivation therapy. - Very high PSA (>100 ng/mL) suggests metastatic disease. Prostate cancer commonly spreads to bone as osteoblastic lesions (also elevated alkaline phosphatase) via the Batson venous plexus.

**High-yield associations** - Prostate cancer: usually adenocarcinoma in the peripheral zone (posterior lobe, palpable on DRE). BPH arises in the transitional/periurethral zone. - Treatment: active surveillance, prostatectomy, radiation, and ADT (GnRH agonists such as leuprolide, GnRH antagonists such as degarelix, antiandrogens such as flutamide, bicalutamide, enzalutamide). - Other meaning of PSA in medicine (context-dependent): pulmonary stenosis/Pulse-synchronous... and "Pressure Support Assist"—but on boards PSA nearly always means prostate-specific antigen.

**Test-taking pearls** - PSA is a tumor marker for monitoring and not a diagnostic test. - Prostatitis and BPH are classic causes of falsely elevated PSA. - Finasteride lowers PSA, so correct the value before interpreting it.