What are Gonadotropin-Releasing Hormone (GnRH) analogues?

From the Guidelines

GnRH analogues should not be considered a proven fertility preservation method and should not be used in place of proven fertility preservation methods. The use of GnRH analogues for fertility preservation is still a topic of controversy and uncertainty, with conflicting results from various studies 1. While some studies have reported higher rates of pregnancy in patients receiving chemotherapy plus GnRHa versus chemotherapy alone, these findings are weakened by limitations such as missing data and lack of adjustment for pregnancy intent 1.

Key Points to Consider

• The POEMS trial reported significantly higher rates of pregnancy in women with hormone receptor–negative breast cancer receiving chemotherapy plus goserelin versus chemotherapy alone, but the findings are not definitive due to methodological limitations 1.
• Systematic reviews have also reported mixed results, with some finding higher rates of pregnancy in patients receiving GnRHa, while others have found no significant difference between treatment groups 1.
• The current evidence base is limited by the reliance on surrogate markers and the lack of uniform criteria for defining ovarian insufficiency, making it challenging to draw definitive conclusions about the effectiveness of GnRHa in preserving ovarian function 1.
• The American Society of Clinical Oncology clinical practice guideline update suggests that GnRHa may be considered an unproven option in emergency or extreme circumstances where proven options are not available, but this should be done with caution and careful consideration of the patient's specific cancer and needs 1.

Clinical Implications

• Patients should be counseled to rely on methods with proven effectiveness in fertility preservation, rather than GnRHa, which has uncertain benefits and potential adverse effects such as hot flashes and bone loss 1.
• Providers should carefully discuss the controversy and uncertainty surrounding the use of GnRHa for fertility preservation with their patients, and consider the individual patient's needs and circumstances when making treatment decisions 1.

From the FDA Drug Label

ZOLADEX is a synthetic decapeptide analogue of GnRH. ZOLADEX acts as an inhibitor of pituitary gonadotropin secretion when administered in the biodegradable formulation Nafarelin acetate is a synthetic analog of the naturally occurring gonadotropin-releasing hormone (GnRH)

GnRH analogues, such as goserelin and nafarelin, are synthetic decapeptide analogues of GnRH that act as inhibitors of pituitary gonadotropin secretion. They are used to treat various conditions, including prostate cancer and precocious puberty. The mechanism of action of these analogues involves the initial stimulation of gonadotropin release, followed by sustained suppression of pituitary gonadotropins, leading to a decrease in serum levels of testosterone and estrogen. Key points about GnRH analogues include:

• Mechanism of action: inhibition of pituitary gonadotropin secretion
• Uses: treatment of prostate cancer, precocious puberty, and other conditions
• Examples: goserelin, nafarelin
• Administration: subcutaneous implantation (goserelin), nasal spray (nafarelin) 2 3

From the Research

GnRH Analogues

• GnRH analogues are a class of drugs that, when chronically administered, result in marked reductions in blood levels of testosterone and estrogen 4.
• These drugs include leuprolide acetate, nafarelin acetate, and goserelin acetate, which have approved indications for advanced prostate cancer, endometriosis, and precocious puberty 4.
• GnRH analogues are also being evaluated in many other diseases, including uterine fibroids, polycystic ovarian disease, breast cancer, fibrocystic breast disease, benign prostatic hypertrophy, and irritable bowel syndrome 4.

Clinical Use

• GnRH analogues are long-term known to be safe and effective in the clinical management of hormone-dependent advanced prostate cancer 5.
• However, their unusual mechanism of action of de-sensitizing pituitary receptors makes generic market entry challenging 5.
• GnRH antagonists, such as degarelix, are also available and make promising treatments that avoid the transient surge in testosterone that occurs with the use of GnRH agonists 6.

Efficacy and Safety

• All GnRH agonists have comparable potential to suppress testosterone levels, but goserelin has shown better efficacy in maintaining testosterone levels ≤50 ng/dL compared with leuprolide 7.
• The incidences of testosterone escape are lower with goserelin and leuprolide than buserelin 7.
• The frequency and severity of adverse events, such as hot flushes, fatigue, and sexual dysfunction, are comparable among the GnRH agonists 7.

Advantages and Limitations

• GnRH analogs are potent therapeutic agents that are considerably useful in a variety of clinical indications, including management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumours 8.
• However, GnRH analogs have limitations, such as the need for continuous administration and the potential for adverse events 8.