Gonadorelin and analogues

Comparative studies

In 67 premenopausal Japanese women randomized to 4-weekly, low-dose buserelin 1.8 mg or leuprorelin 1.88 mg, women given leuprorelin had a more rapid clinical response and a higher rate of hot flushes [ ].

Adverse reactions and quality of life have been compared in 431 men with prostate cancer treated with a gonadorelin agonist or orchidectomy [ ]. Of the men who reported normal sexual function before treatment, 51% had reduced libido and 69% became impotent. Of those given gonadorelin, 57% had hot flushes. Breast swelling was more common in those given gonadorelin (25% compared with 10% after orchidectomy).

Of 547 men randomized to leuprorelin plus flutamide for 3 or 8 months, those treated for 8 months had a higher overall rate of adverse events, and 87% had hot flushes, compared with 72% of those who were treated for 3 months [ ].

Placebo-controlled studies

In a randomized, placebo-controlled study in women who received leuprolide acetate depot 11.25 mg intramuscularly with tibolone 2.5 mg/day (n = 36), leuprolide acetate depot 11.25 mg with placebo (n = 37), or a placebo injection with placebo tablets (n = 39), irritable bowel syndrome related to the menstrual cycle improved in those who received leuprolide [ ]. There were hot flushes in those who took leuprolide compared with placebo; no data were given about the frequency of hot flushes, but there were no withdrawals because of this symptom. Amenorrhea also occurred. Both flushing and amenorrhea are expected adverse effects of leuprolide.

Cardiovascular

Gonadorelin inhibits nitric oxide-mediated arterial relaxation, which disappears within 3 months after stopping treatment. This effect was abolished with “add-back” hormone replacement in a prospective, randomized study of 50 women treated for 6 months [ ].

Respiratory

There have been reports of pneumonitis associated with gonadorelin agonists.

• A 75-year-old man developed a high fever and cough immediately after an injection of leuprorelin acetate 3.75 mg and 8 days after starting flutamide 375 mg/day [ ]. He died of respiratory failure after a month, and interstitial pneumonitis was confirmed postmortem.

Ear, nose, throat

Local irritation or rhinitis occurs uncommonly when gonadorelin agonists are taken intranasally.

• A 34-year-old woman had to stop using nafarelin nasal spray after 14 days because of exacerbation of maxillary sinusitis [ ].

Nervous system

Pituitary apoplexy (hemorrhagic infarction presenting with sudden severe headache, often followed by pituitary hormone deficiency) has been reported after intravenous gonadorelin testing to investigate a pituitary macroadenoma and in several patients with gonadotropin-secreting pituitary macroadenomas who were given gonadorelin to treat prostate cancer [ ]. It may be advisable to assess gonadotropin status prior to therapy in such patients.

• A 43-year-old woman with a pituitary macroadenoma, who took quinagolide 37.5 micrograms/day for 33 months, developed a severe headache, nausea and vomiting, and photophobia 30 minutes after diagnostic testing with gonadorelin 50 micrograms intravenously [ ]. Although a CT scan at the time showed no evidence of hemorrhage, an MRI scan 18 months later showed a partial empty sella.

• A 67-year-old man with prostate cancer and an unsuspected pituitary macroadenoma developed a severe frontal headache, nausea and vomiting, and blindness within 12 hours of insertion of a goserelin implant [ ].

Two further cases have been reported, in which gonadorelin was administered either alone [ ] or with insulin [ ]. The mechanism of pituitary apoplexy in these cases is unclear. Gonadorelin may have a direct effect on vascular tone or may increase tumor metabolic activity.

There has been one previous report of seizure exacerbation during leuprorelin treatment, in a girl with pre-existing brain damage [ ], and a case of de novo seizures has also been reported [ ].

• A 13-year-old girl, who had previously had surgery and radiotherapy for a medulloblastoma, developed atypical absence seizures for the first time after 3 months of therapy with leuprorelin. The seizures stopped 1 month after treatment was withdrawn and did not recur until 30 months later. The seizures were not related to estradiol concentrations or the menstrual cycle.

Neuromuscular function

Prolonged administration of gonadorelin is commonly associated with reduced muscle bulk and voluntary muscle function. In a prospective, uncontrolled study of 62 men with prostate cancer, treatment with cyproterone acetate and goserelin caused an increase in fatigue scores and increased muscle fatiguability on objective testing within 6 weeks, in 66% of subjects [ ]. Fatigue was unrelated to psychological complaints or to self-reported functional ability.