What are the potential adverse effects of Cetrorelix (GnRH antagonist) in patients of reproductive age undergoing assisted reproduction, particularly those with a history of allergic reactions or impaired liver and kidney function?

Cetrorelix Adverse Effects

Cetrorelix is generally well-tolerated with primarily mild injection site reactions, but carries important risks including hypersensitivity reactions (including rare anaphylaxis), menopausal symptoms, and is absolutely contraindicated in pregnancy and severe renal impairment. 1

Hypersensitivity and Allergic Reactions

• Anaphylactoid reactions can occur even with the first dose, as documented during post-marketing surveillance 1
• One severe anaphylactic reaction (cough, rash, hypotension) was reported after prolonged treatment (7 months at 10 mg/day) in a non-infertility indication 1
• Cetrorelix should not be used in women with severe allergic conditions or active allergic symptoms 1
• Special caution is required in patients with known history of allergic predisposition 1
• Hypersensitivity to cetrorelix, other GnRH analogs, extrinsic peptide hormones, or mannitol is an absolute contraindication 1

Injection Site Reactions

• Very slight and transient erythema and pruritus at the injection site are the most commonly reported adverse effects 2
• These reactions are generally mild and self-limiting 3, 2
• No severe local reactions have been documented in clinical trials 3, 2

Hormonal and Menopausal Symptoms

• GnRH antagonists cause menopausal symptoms including hot flushes, headaches, sweating, and vaginal dryness, though these are generally reversible and of low severity 4
• Hormonal suppression occurs rapidly: LH and estradiol fall to subnormal ranges within 24 hours of administration and remain suppressed during treatment 5
• LH decreases by 56-66% and FSH by 29-32% within 24 hours of a single dose 2
• Estradiol decreases by 81-85%, reaching nadir at 24-48 hours after injection 2

Bone Health Concerns

• Prolonged use causes accelerated bone loss due to the induced hypo-estrogenic state, with slow and potentially incomplete recovery after discontinuation 4
• Baseline bone density assessment and regular monitoring are necessary with extended use 4
• This is particularly relevant if cetrorelix is used beyond standard assisted reproduction protocols 4

Hepatic Effects

• Enzyme elevations (ALT, AST, GGT, alkaline phosphatase) occur in 1-2% of patients during controlled ovarian stimulation 1
• Elevations range up to three times the upper limit of normal 1
• The clinical significance of these findings remains undetermined 1
• One case of severe worsening of graft function occurred in a liver transplant recipient during hormonal treatment for assisted reproduction, which improved with steroid administration 6

Pregnancy and Reproductive Risks

• Cetrorelix is absolutely contraindicated in pregnancy due to complete fetal resorption observed in animal studies 1
• In rats, doses as low as 4.6 mcg/kg (0.2 times the human dose) caused early resorptions and total implantation losses 1
• Treatment with 0.46 mg/kg for 4 weeks resulted in complete but reversible infertility in female rats 1
• The drug should not be used by nursing mothers as excretion in human milk is unknown 1

Renal Considerations

• Severe renal impairment is an absolute contraindication to cetrorelix use 1
• No dose adjustments are specified for mild to moderate renal impairment, but caution is warranted 1

Safety Profile in Assisted Reproduction

• No allergic or hyperergic reactions have been reported in standard assisted reproduction protocols 3
• Patient compliance is excellent due to the short treatment duration 3
• The procedure appears safer than long GnRH agonist protocols, with reduced risk of severe ovarian hyperstimulation syndrome (OHSS) 3
• Pregnancies and offspring health appear comparable to other protocols 3
• No flare-up effects occur, eliminating risk of cyst formation seen with GnRH agonists 3

Important Clinical Caveats

• Unlike GnRH agonists, mistaken administration during early pregnancy is less likely since cetrorelix is only used during active ovarian stimulation 3
• Pregnancy should be ruled out by testing for hCG before starting gonadotropin stimulation on cycle day 2-3 3
• No formal drug interaction studies have been performed, so potential interactions remain unknown 1
• Long-term carcinogenicity studies have not been conducted 1