Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, and anemia. However, most men have preserved sexual function with bicalutamide monotherapy. In females, due to the minimal biological importance of androgens in this sex, the side effects of pure antiandrogens or NSAAs are few, and bicalutamide has been found to be very well tolerated. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash. The drug is well-tolerated at higher dosages than 50 mg/day, with rare additional side effects.Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes. In the Early Prostate Cancer (EPC) clinical programme of bicalutamide for early prostate cancer, the rate of abnormal liver function tests with bicalutamide monotherapy was 3.4% relative to 1.9% for placebo. Hepatic changes that have necessitated discontinuation of bicalutamide, such as marked increases in liver enzymes or hepatitis, have occurred in approximately 0.3 to 1.4% of men in clinical trials. Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment. Monitoring of liver function during treatment is recommended, particularly in the first few months. In men of advanced age with prostate cancer, bicalutamide monotherapy has been associated with an increase in non-prostate cancer mortality, in part due to an increase in the rate of heart failure.
In addition to the classical nuclear AR, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (IC50 = 66.3 nM), whereas it does not appear to interact with GPRC6A.The affinity of bicalutamide for the AR is relatively low as it is approximately 30 to 100 times lower than that of DHT, which is 2.5- to 10-fold as potent as an AR agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland. However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and DHT, allowing it to powerfully prevent them from binding to and activating the receptor. This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and DHT levels in the prostate gland are about 50 to 60% reduced. In women, levels of testosterone are substantially lower (20- to 40-fold) than in men, so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.Blockade of the AR by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion. This, in turn, results in an increase in circulating LH levels and activation of the gonadal production of testosterone and by extension production of estradiol.