Antiandrogen Monotherapy May Increase Dementia Risk in Prostate Cancer Patients

A study compared dementia risk among prostate cancer patients receiving different types of androgen deprivation therapy and observed a correlation between antiandrogen monotherapy, but not gonadotropin-releasing hormone (GnRH) agonists or orchiectomy, and dementia and Alzheimer’s disease.

Previous studies on the topic yielded inconsistent results, according to the authors of the present report. Further, different androgen deprivation therapy types impact follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels differently: “For example, gonadotropin-releasing hormone (GnRH) antagonists decrease serum FSH and LH levels, while orchiectomy and antiandrogens increase their levels. Sustained use of GnRH agonist suppresses LH; however, FSH gradually increases over time. Furthermore, increased FSH and LH levels have been reported in men with dementia or [Alzheimer’s disease],” the researchers explained. Therefore, dementia and Alzheimer’s disease risks may be different based on androgen deprivation therapy type.

Data were obtained and linked from the Taiwan National Cancer Registry, National Health Insurance Research Database, and Taiwan National Death Registry on patients newly diagnosed with prostate cancer between Jan. 1, 2008, and Dec. 31, 2015. Patients were followed for one year following diagnosis. The main outcomes were all-cause dementia or Alzheimer’s.

Final analysis included 23,651 men with prostate cancer (median [interquartile range (IQR)] age, 73 [66–79] years). Just under a third of patients (n=6,904; 29.2%) received no androgen deprivation therapy; half of patients (n=11,817; 50.0%) received GnRH agonists, 876 (3.7%) received orchiectomy, and 4,054 (17.1%) received antiandrogen monotherapy. Over a median (IQR) follow-up of 3.46 (1.92–5.51) years, 1,525 patients received a dementia diagnosis (1.72 per 100 person-years). Patients who received antiandrogen monotherapy, compared to patients who did not receive androgen deprivation therapy, had a greater risk of dementia (weighted hazard ratio [HR]=1.34; 95% confidence interval [CI], 1.16 to 1.55) and Alzheimer’s (weighted HR=1.52; 95% CI, 1.13 to 2.04). When compared with patients not receiving androgen deprivation therapy, dementia risk did not largely differ for patients receiving GnRH agonists weighted HR=1.13; 95% CI, 1.00 to 1.28) or orchiectomy (weighted HR=1.00; 95% CI, 0.74 to 1.37).

The study was published in JAMA Network Open.

In their conclusion the researchers called for “future prospective studies to confirm these results.”

“The mechanism underlying the ADT causes of dementia remains unclear and could be multifactorial,” they said. “We did not identify a clinically meaningful hazard on GnRH agonist treatment compared with patients who did not receive [androgen deprivation therapy]. GnRH agonist usage reduces testosterone and LH levels. Future studies should assess whether the suppressed LH counteracts the biological effect of low testosterone on cognitive decline. We speculated that increased LH level on treatment using antiandrogen monotherapy could partly explain the association of antiandrogen monotherapy with dementia and [Alzheimer’s]. There is a need for further studies to elucidate the underlying mechanisms of the association between antiandrogen and dementia.”