Antiandrogens

Mechanism of Action

Antiandrogens work by either reducing androgen production or preventing androgens from activating their receptors.

Around 90% of prostate cancers depend on testosterone for growth and survival. Suppressing androgen signalling therefore slows tumour growth, promotes apoptosis and may result in tumour regression.

Furthermore, oestrogen receptors are found in a substantial proportion of breast cancers and activation of these receptors leads to cell proliferation, therefore antagonism of oestrogen suppresses cell growth in ER positive breast cancers.

Gonadotrophin-releasing hormone (GnRH) analogues

Goserelin, triptorelin and leuprorelin are gonadotrophin-releasing hormone (GnRH) analogues. 

Following initiation of treatment, these medicines initially overstimulate GnRH receptors in the anterior pituitary, producing a transient increase in LH and FSH secretion. This results in a temporary rise in testosterone concentrations in men, known as the tumour flare phenomenon.

With continuous administration, persistent receptor stimulation causes desensitisation and downregulation of pituitary GnRH receptors. Consequently, LH and FSH secretion falls markedly, leading to reduced testosterone production by the Leydig cells in men and reduced ovarian oestrogen production in women.

Unlike physiological GnRH, which is released from the hypothalamus in a pulsatile manner, GnRH analogues are administered continuously. Their effects are reversible following discontinuation of treatment.

Androgen Receptor Inhibitors

Bicalutamide and enzalutamide are androgen receptor inhibitors.

These drugs work by competitively binding androgen receptors without activating gene expression. This decreases the growth of prostate cancer cells and can lead to cancer cell death and tumour regression. 

Created in BioRender. Boucher, M. (2026) https://BioRender.com/a21wys8

Fig 1
Mechanism of action of antiandrogen drugs

Pharmacokinetics

GnRH analogues

Androgen Receptor Inhibitors

Contraindications

GnRH analogues are contraindicated during pregnancy and breastfeeding and should not be used in patients with undiagnosed vaginal bleeding.

Bicalutamide is contraindicated in females and children.

Enzalutamide is contraindicated during pregnancy and in women of childbearing potential.

Cautions and Adverse Effects

GnRH analogues

Common adverse effects are largely related to androgen or oestrogen deprivation and include hot flushes, sweating, reduced libido, erectile dysfunction, gynaecomastia, mood disturbance, depression, weight gain and osteoporosis. Long-term therapy may also lead to hyperglycaemia and an increased risk of cardiovascular disease, including myocardial infarction and heart failure.

QT interval prolongation may occur and caution is required when co-prescribing other QT-prolonging medicines. Injection site injury has been reported and goserelin implants should only be administered by the subcutaneous route.

During the initial weeks of treatment, the transient testosterone surge may cause tumour flare, potentially leading to worsening bone pain, ureteric obstruction or spinal cord compression in patients with metastatic disease. Antiandrogen therapy is therefore commonly initiated before or alongside GnRH analogue treatment in men at risk of tumour flare.

Rare adverse effects include hypercalcaemia in women receiving treatment for breast cancer, convulsions (particularly in women and children), and vaginal bleeding during the first month of therapy due to hormonal withdrawal.

Androgen deprivation may also increase the risk of anaemia.

Leuprorelin has several additional important adverse effects. Rare cases of idiopathic intracranial hypertension have been reported, which can present with severe or recurrent headache, visual disturbances and tinnitus. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported.

Androgen Receptor Inhibitors

Bicalutamide may cause photosensitivity, and patients should be advised to minimise sun exposure and use appropriate sun protection. As it undergoes extensive hepatic metabolism, liver function tests should be monitored periodically during treatment.

Both bicalutamide and enzalutamide may prolong the QT interval and commonly cause adverse effects related to androgen deprivation, including reduced libido, hot flushes and fatigue. 

Enzalutamide is additionally associated with somnolence and an increased risk of seizures. Rare cases of posterior reversible encephalopathy syndrome (PRES) and severe cutaneous adverse reactions, including SJS, have also been reported.

Antiandrogen therapy may cause changes to spermatozoa. Men receiving bicalutamide should use condoms during treatment and for 130 days after discontinuation. Men receiving enzalutamide should use condoms during treatment and for 3 months after treatment cessation if their partner is pregnant or of childbearing potential. Where their partner is of childbearing potential, condoms should also be used in combination with another effective method of contraception.

Interactions

Both GnRH analogues and androgen receptor inhibitors can prolong the QT interval therefore caution should be undertaken if administered alongside other agents which also prolong the QT interval such as antipsychotics, SSRIs, macrolides and tricyclic antidepressants.

GnRH Analogues

Medicines that increase prolactin concentrations, including metoclopramide, domperidone and antipsychotics, reduce GnRH receptor expression within the pituitary gland and may reduce the effectiveness of GnRH analogues. 

Androgen Receptor Inhibitors

Bicalutamide inhibits CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19 and CYP2D6. Caution is required with ciclosporin and calcium channel blockers due to potential increases in exposure.

Bicalutamide undergoes extensive hepatic metabolism via oxidation. Strong enzyme inhibitors such as ketoconazole and cimetidine may increase plasma concentrations. Bicalutamide may also potentiate the anticoagulant effect of warfarin by displacing it from plasma protein binding sites, necessitating close INR monitoring.

Enzalutamide is a potent inducer of CYP3A4 and a moderate inducer of CYP2C9, CYP2C19 and uridine diphosphate-glucuronosyltransferases (UGTs). As maximal enzyme induction develops gradually, clinically significant interactions may not become apparent until approximately one month after treatment initiation. Patients receiving medicines metabolised by these enzymes should therefore be monitored closely for reduced therapeutic efficacy. As enzalutamide induces CYP2C9, concomitant use with warfarin should generally be avoided.

Enzalutamide may inhibit the efflux transporter P-glycoprotein (P-gp), requiring caution when used with narrow therapeutic index substrates for P-gp such as digoxin, dabigatran and colchicine.

Enzalutamide is primarily metabolised by CYP2C8, therefore the dose should be reduced when administered with strong CYP2C8 inhibitors such as gemfibrozil. Although CYP3A4 also contributes to its metabolism, dose adjustment is not generally recommended with CYP3A4 inhibitors.

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
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