Selective oestrogen receptor modulators (SERMs)

• Tamoxifen is a SERM that is used for the treatment of oestrogen receptor (ER) positive breast cancer.
  
• Tamoxifen binds to the oestrogen receptor of different tissues and exerts either agonistic or antagonistic effects, depending on the expression of either β-oestrogen or α-oestrogen receptors. It has an antagonistic effect on oestrogen receptors in mammary tissue, but an agonistic effect on the endometrium and therefore increases the risk of endometrial cancer.
  
• Other side effects include: increased risk of VTE, myalgia and hot flushes. Vaginal bleeding/discharge is also common and care should be taken to investigate this as appropriate, given the risk of endometrial malignancy.

Oestrogen receptor antagonists

Fulvestrant is a pure oestrogen antagonist, with no agonistic properties like the SERMs. It is given IM and the most frequent adverse events associated with its use are hot flushes, nausea, myalgia and arthralgia, increased risk of VTE and vaginal bleeding.

Aromatase inhibitors

• These are used in post-menopausal women with ER-positive breast cancer.
  
• They bind to and inhibit aromatase (the enzyme responsible for oestrogen synthesis). This is thought to have increased activity within breast tumours.
  
• They can be classified into first, second and third generation, as well as steroidal inhibitors (e.g. exemestane) and non-steroidal inhibitors (e.g. anastrozole and letrozole).
  
• Side effects include: hot flushes, headache, fatigue, arthralgia/myalgia, nausea, vomiting and diarrhoea. As they do not have an agonist effect on bone they can be associated with loss of bone density and osteoporotic fractures. However, the risk of secondary endometrial cancers is lower when compared to tamoxifen.

Gonadotrophin releasing hormone (GnRH) agonists

• Also known as lutenising-hormone-releasing hormone (LHRH) agonists, these cause so-called ‘medical castration’ via androgen suppression.
  
• These drugs (e.g. goserelin and leuprolide) mimic the naturally occurring hormone (GnRH) that is released from the hypothalamus, which stimulates the anterior pituitary to produce LH and FSH that stimulate the testes to produce androgens.
  
• Tumour flare:
  
  
  
  • When initially given, a GnRH agonist can cause overstimulation of the pituitary, causing a brief rise in androgen production. This is called ‘tumour flare’ and can lead to potentially harmful exacerbation of clinical symptoms, such as precipitation of spinal cord compression in patients with bone metastases.
    
  • This phenomenon can be counteracted by giving concurrent anti-androgen therapy (e.g. bicalutamide) for a short period of time.
    
  • After this initial flare the production of androgens slows as the pituitary becomes desensitised to GnRH stimulation and androgen levels fall significantly.
  
  
• Side effects include: decreased libido, low mood, hot flushes and erectile dysfunction.

Gonadotrophin releasing hormone (GnRH) antagonists

• The GnRH antagonist degarelix blocks the effect of GnRH on the pituitary directly.
  
• Unlike the GnRH agonists, there is no tumour/clinical flare syndrome associated with its use.
  
• Side effects include: gynaecomastia, erectile dysfunction, hot flushes and raised liver enzymes.

Anti-androgens

• Bicalutamide and nilutamide are examples of non-steroidal anti-androgens. They act by blocking androgen receptors, and thus the binding of testosterone.
  
• Side effects include: GI disturbance, gynaecomastia (especially if single agent therapy), hot flushes and hepatotoxicity.

Inhibitors of steroidogenesis

• Over time, androgen production, PSA and tumour growth can start to increase despite androgen blockade/inhibition. This is termed castration-resistant prostate cancer (CRPC).
  
• Abiraterone inhibits an enzyme (CYP17) involved in androgen synthesis in the testes and prostate (and therefore the tumour itself). This enzyme can be overexpressed in prostate cancer cells.
  
• Side effects include: fatigue, nausea, elevated hepatic transaminases and hypertension.
  
• Blockage of the CYP17 enzyme conversely leads to increased mineralocorticoid levels. This causes hypokalaemia, hypertension and peripheral oedema. This secondary hyperaldosteronism is prevented through the concomitant use of prednisolone, which should be continued throughout the duration of abiraterone treatment.