How ZOLADEX works to reduce testosterone production

It’s all in the hormones [1, 2] ZOLADEX reduces the production of testosterone in the body by mimicking the action of a natural hormone known as luteinizing hormone releasing hormone (LHRH). As its name suggests, this hormone acts by stimulating the release of another hormone, namely luteinizing hormone (LH).

In both men and women, LHRH is produced about every 90 minutes in the hypothalamus region of the brain and is then transported to another part of the brain, the pituitary, where it stimulates the release of LH. (In fact, this is how the majority of hormones work; they are produced in one part of the body but exert their effects in another part of the body.) In men, LH is then transported to the testes where it stimulates the production of testosterone.

So where does ZOLADEX fit in?
The shape and size of the natural LHRH molecule means that when it arrives at the pituitary, LHRH slots into specific receptors on the pituitary surface. In the same way that other receptor systems work in the body, once LHRH is locked into place, a sequence of biochemical events is triggered that leads to the release of LH.

When a patient receives a depot (bolus) injection of ZOLADEX, small amounts of the active ingredient – goserelin – are gradually released into the body such that a steady supply of goserelin reaches the pituitary. ZOLADEX is a synthetic ‘analogue’ of naturally occurring LHRH and so has been designed to perfectly fit the LHRH receptors on the surface of the pituitary.

When ZOLADEX reaches the pituitary, LHRH receptors act as if they are occupied by natural LHRH, causing an initial surge in hormone levels. However, the sustained presence of ZOLADEX means sustained LHRH receptor occupation and this causes the receptors to disappear. As the receptors disappear so does the biochemical response that receptor occupation had previously caused.

As a result, the production of LH and testosterone is reduced. As testosterone is the hormone that enables prostate cancer to grow and thrive, this sequence of events is responsible for the therapeutic action of ZOLADEX in prostate cancer.

Sequence of events following a ZOLADEX injection

ZOLADEX administration is by subcutaneous injection into the anterior abdominal wall (ZOLADEX cannot be taken orally as it would be degraded by digestive enzymes) The ZOLADEX formulation material dissolves slowly and goserelin is released gradually over time as the depot material comes into contact with body fluids ZOLADEX reaches the pituitary: ZOLADEX mimics naturally occurring LHRH and occupies LHRH receptors on the pituitary [1] 1 – 4 days after administration: the initial pituitary response to ZOLADEX results in a short-lived increase in testosterone levels. This is called ‘flare’ – on some occasions the effects of the excess testosterone can be blocked by adding in an antiandrogen, such as bicalutamide 50mg 5 – 21 days after administration: as LHRH receptors disappear, testosterone concentrations fall. By the end of the third week, testosterone levels are the same as if the patient had been surgically castrated Continued ZOLADEX administration: The initial testosterone surge does not occur with subsequent injections of ZOLADEX due to the fact that LHRH receptors disappear with continued treatment. ZOLADEX 3.6mg should be given every 28 days – if a patient does not receive their next injection on time, the previous injection remains effective for an additional four days [3] ZOLADEX 10.8mg should be given every three months – if a patient does not receive their next ZOLADEX injection on time, the previous injection remains effective for an additional four weeks [4] Depriving prostatic tumours of testosterone means that the tumour shrinks in size, and further growth stimulation is reduced bringing symptomatic relief and proven survival benefits for the majority of patients

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Further information:

• ZOLADEX Monograph
• Prescribing Information
  
• ZOLADEX Mode of Action
  

1. Clayton RN, Catt KJ. Gonadotropin-releasing hormone receptors: characterization, physiological regulation, and relationship to reproductive function. Endoc Rev 1981;2:186-209
2. Walker KJ, Turkes AO, Turkes A et al. Treatment of patients with advanced cancer of the prostate using a slow-release (depot) formulation of the LHRH agonist ICI 118630 (ZOLADEX®). J Endocrinol 1984;103:R1-4
3. Donelly RJ, Milstead RAV. ZOLADEX studies in prostatic and breast cancer. In: Vickery BH, Nestor JJ, eds. LHRH and its analogues: contraception and therapeutic applications, Part 2. Lancaster: MTP Press, 1987;397-407
4. Prescribing Information for ZOLADEX 10.8mg