Gonadorelin Analogues

Analogues of gonadotrophin releasing hormone (GnRH) have been developed and tested over the last 30 years. They are now widely used to treat hormone dependent diseases and more research on analogues and the receptors may open up other applications (such as contraception).^1,2

GnRH is an important hypothalamic hormone regulating reproduction, and GnRH agonist and antagonist analogues have now been developed. They are decapeptides sharing terminal NH₂ and COOH groups important in receptor binding and activation.

• GnRH agonists initially stimulate release of gonadotrophins (follicle stimulating hormone or FSH, and luteinising hormone or LH) but then down regulation of receptors and inhibition of FSH and LH release occurs (a paradoxical response).
• GnRH antagonists block the receptors for GnRH producing a more immediate blocking of the release of gonadotrophins (LH and FSH). Antagonist development lags behind that of agonists. The antagonists are particularly expensive to produce and their use was initially inhibited by histamine release. Newer agents avoid this.²
• Reduction of FSH and LH then leads to reduction of androgen and oestrogen production.

Indications and side effects derive from the mode of action.

• Endometriosis^3,4,5,6,7
• Precocious puberty^8,9
• Infertility¹⁰
• Anaemia from menorrhagia¹¹
• Breast cancer^12,13
• Prostate cancer^14,15
• Before uterine surgery^16,17

• To protect ovarian function during chemotherapy¹⁸
• Benign prostatic hyperplasia-further trials needed, but suggested as an adjunct with other treatments¹⁹
• Pelvic pain after appropriate investigation²⁰
• Treatment of obsessive-compulsive disorder²¹

• Initiation of treatment with gonadorelin analogues will usually follow specialist work up and investigations.¹¹
• Different formulations are available including implants, nasal preparations and subcutaneous preparations.
• Gonadorelin analogues will usually form one part of a range or combination of treatments under specialist review.
• Exclude pregnancy before starting (start during menstruation or use barrier contraception for one month beforehand). Use barrier contraception during treatment period.
• The initial stimulation produced by agonist gonadorelin analogues can produce, in the first 2 weeks, an increase in testosterone production and so called 'tumour flare'. This can cause complications from progression of disease (for example cord compression or increased bone pain in secondary prostatic cancer) so the concomitant use of anti-androgens (e.g. cyproterone acetate or flutamide) 3 days before starting the gonadorelin and for 3 weeks after is recommended.

These are mostly consistent with the mode of action and use is limited to 6 months for benign indications. For example:

• Caution in metabolic bone disease (because of the propensity to reduce bone mineral density).
• Contraindications where hormone changes are or could be harmful (e.g. pregnancy, breast feeding).
• Side effects resulting from reduced oestrogen production (menopausal symptoms) and the metabolic effects (reduction in bone mineral density).

Although use is limited to 6 months for benign conditions, the effect on bone mineral density and bone metabolism do resolve after 1 to 2 years.^22,23 Nevertheless repeat treatments are not recommended.

Endometriosis

• This is one of the most common conditions which might be treated with gonadorelin analogues, affecting 7-10% of women²⁴ and 20-50% of infertile women.²⁵
• Goserelin and leuprorelin are the most commonly used gonadorelin analogues.
• Treatment is indicated for pain (dyspareunia and dysmenorrhoea) and impaired fertility.
• Efficacy for pain is broadly similar between the medical treatments.³ A RCT with nafarelin and danazol shows similar efficacy but better tolerability with the GnRH analogue.⁴ So called "add back" therapy may help with oestrogen deficiency symptoms.^3,26
• Improvement of fertility in endometriosis with GnRH analogue treatment is not consistently reported. Some have shown improvement²⁷ and other trials have not.^28,16

Breast cancer

• Goserelin is licensed for treatment of advanced breast cancer in premenopausal women.
• GnRH analogues can be used in early and advanced breast cancer.¹² Breast cancer is often oestrogen dependent (ER-positive).
• In early ER-positive disease GnRH analogues are well tolerated and appear to improve clinical outcome. ^12,13
• In advanced breast cancer combination with tamoxifen improves response rates and disease progression relative to GnRH alone.¹²
• The value of combinations is not yet clear. Combination with aromatase inhibitors is of interest.¹²

Prostate cancer

• Buserelin, goserelin, leuprorelin and triptorelin have all been used in metastatic carcinoma of the prostate. A 12-18 month response is common, but hormone refractory prostate cancer is difficult to treat, some patients responding to anti-androgens.¹⁵
• GnRH analogues are being investigated in early localised disease. The rationale for so called neoadjuvant androgen deprivation (NAD) is that 50% of radical prostatectomy specimens actually have tumour outside the capsule and a high proportion of these patients will relapse. It is hoped that NAD before radical prostatectomy might eradicate malignant androgen dependent cells and improve outcome.¹⁴

Preoperative treatment for menorrhagia

• Endometrial thinning prior to hysteroscopic surgery for menorrhagia improves operating conditions and affords higher rates of post-operative amenorrhoea. Post-operative pain is also reduced.¹⁷
• GnRH analogues produce slightly more consistent endometrial thinning than danazol.¹⁷
• Use preoperatively with large fibroids can reduce the size of fibroids and may enable a vaginal rather than abdominal hysterectomy to be performed.
• Interestingly there is no effect on patient satisfaction with the surgery.

Precocious puberty

GnRH analogues are used in the treatment of central precocious puberty and are often combined with growth hormone.^8,26

Infertility

GnRH antagonists can shorten the treatment when compared with GnRH agonists in the regimens used to induce ovulation.¹⁰However pregnancy rates were lower and the ovarian hyperstimulation syndrome still occurs.¹⁰ A recent review and meta-analysis concluded that the probability of live birth after ovarian stimulation for IVF does not depend on the type of analogue used for pituitary suppression.²⁹