Side Effects of GnRH Antagonists
GnRH antagonists cause menopausal symptoms (hot flushes, sweating, headaches) and bone loss with prolonged use, but these effects are generally reversible and less severe than with GnRH agonists. 1, 2
Common Side Effects
Menopausal Symptoms
- Hot flushes and sweating are the most frequent side effects, occurring in the majority of patients but typically of low severity grade 1
- Headaches are commonly reported 3
- Vaginal dryness may occur due to the hypo-estrogenic state 4
- These symptoms are reversible upon discontinuation of therapy 1, 3
Bone Health Effects
- Accelerated bone loss occurs with prolonged use due to the induced hypo-estrogenic state 2
- Standard GnRH treatment regimens of 6 months cause significant bone loss in both trabecular and cortical bone 1
- After treatment discontinuation, bone loss recovers slowly but may not be completely recovered in all women 1
- Baseline bone density assessment is recommended for patients at risk of osteoporosis (age >65, family history, chronic steroid use) 1
Psychiatric and Mood Effects
Mood Disorders
- Anxiety and mood disorders can occur, including panic disorder and major depression with or without psychotic features 4
- Emotional lability has been reported as an adverse effect 4
- These psychiatric consequences may be underappreciated in clinical practice 4
- Women with no prior psychiatric history can develop severe psychiatric symptoms during GnRH therapy 4
Management of Psychiatric Symptoms
- Sertraline has been shown to improve mood and anxiety symptoms in patients experiencing psychiatric side effects while on GnRH therapy 4
Key Differences from GnRH Agonists
Absence of Flare-Up Effect
- GnRH antagonists lack the initial flare-up effect seen with GnRH agonists because they have no intrinsic activity 3
- GnRH antagonists rapidly suppress gonadotropin release within 4-8 hours, while agonists require 2-3 weeks for clinical effects 3
- This rapid suppression eliminates the risk of symptom exacerbation during treatment initiation 3
Timing of Ovarian Suppression
- Complete ovarian suppression is not achieved for several weeks after administration, which is important for treatment timing 2, 5
Reproductive and Sexual Function Effects
Fertility and Ovarian Function
- GnRH antagonists induce reversible azoospermia in men without loss of libido when combined with low-dose testosterone 6
- In women, the induced hypo-estrogenic state is consistent with castrate levels of estrogen 4
- Ovarian function and menstruation typically resume after discontinuation of therapy 3
Sexual Function
- In male studies, no decrease in libido or potency was reported despite hypogonadal testosterone levels when GnRH antagonists were combined with testosterone supplementation 6
Injection Site Reactions
- Minimal local reactions at the injection site may occur 6
- No significant systemic side effects beyond those related to hormonal suppression have been documented 6
Cardiovascular and Metabolic Considerations
While the evidence primarily addresses GnRH agonists, the induced hypo-estrogenic state with antagonists warrants similar monitoring:
- Risk of metabolic syndrome with prolonged use 1
- Potential cardiovascular effects should be considered, particularly in patients with pre-existing cardiac risk factors 1
Clinical Monitoring Recommendations
During Treatment
- Monitor for menopausal symptoms and provide symptomatic management 1
- Assess bone density at 3-6 month intervals for patients on prolonged therapy 1
- Screen for mood changes and psychiatric symptoms, particularly in patients with no prior psychiatric history 4