Gonadorelin

Gonadorelin is synthetic gonadotropin-releasing hormone (GnRH), a decapeptide identical in sequence to native hypothalamic GnRH. It was previously FDA-approved as Factrel (gonadorelin hydrochloride) for injection and Lutrepulse (gonadorelin acetate) for pulsatile intravenous use; both are discontinued in the United States. Compounded gonadorelin preparations include subcutaneous injections, sublingual rapid dissolve tablets, buccal troches and nasal sprays.

• Former FDA labeling: Factrel was indicated for diagnostic evaluation of hypothalamic-pituitary gonadotropic function, as a single 100 mcg subcutaneous or intravenous dose. Lutrepulse was indicated for induction of ovulation in women with primary hypothalamic amenorrhea, given by pulsatile intravenous pump.
• Prescribers use compounded gonadorelin in men's health, including in men receiving testosterone therapy, and in fertility care. No FDA-labeled dose exists for these uses or for sublingual, buccal or nasal routes.

Gonadorelin binds GnRH receptors on anterior pituitary gonadotropes and stimulates synthesis and release of luteinizing hormone (LH) and, to a lesser extent, follicle-stimulating hormone (FSH). LH and FSH drive gonadal steroid production and gametogenesis. Pulsatile exposure maintains pituitary responsiveness; continuous or excessive exposure down-regulates GnRH receptors and suppresses gonadotropin secretion.

After intravenous administration, gonadorelin has an initial plasma half-life of about 2 to 10 minutes and a terminal half-life of about 10 to 40 minutes. It is hydrolyzed in plasma and tissues to inactive peptide fragments, which are excreted in the urine. Subcutaneous injection is absorbed rapidly. Oral bioavailability is negligible, and bioavailability by sublingual, buccal or nasal routes is low and has not been established for compounded preparations.

• Known hypersensitivity to gonadorelin or any ingredient of the preparation.
• Former ovulation-induction labeling (Lutrepulse) contraindicated use in women with conditions that could be worsened by pregnancy, such as pituitary prolactinoma, and in women with ovarian cysts or anovulation not of hypothalamic origin.
• Because gonadorelin raises gonadotropin and sex-steroid levels, it is generally avoided in patients with hormone-dependent cancers such as prostate or breast cancer.

• Hypersensitivity and anaphylaxis have been reported, mainly after repeated doses. Antibody formation has been reported rarely with prolonged use and may reduce response.
• In women, ovarian hyperstimulation and multiple pregnancy have been reported with ovulation induction; monitor ovarian response.
• Continuous or excessive dosing can desensitize the pituitary and suppress the pituitary-gonadal axis. With intravenous pump use, catheter-site inflammation, infection and phlebitis were reported.

• Drugs that directly affect pituitary gonadotropin secretion, including androgens, estrogens, progestins and glucocorticoids, can alter the response. Spironolactone may transiently raise and levodopa may minimally raise gonadotropin levels; oral contraceptives and digoxin may suppress them; phenothiazines and other dopamine antagonists that raise prolactin may blunt the response. Use with GnRH agonists or antagonists only under prescriber direction.

Reported effects include headache, flushing, lightheadedness, nausea and abdominal discomfort. Injection can cause local pain, redness, swelling, itching or induration. With repeated doses, rash, urticaria, bronchospasm, tachycardia and anaphylaxis have been reported rarely. Nasal use may cause nasal irritation, and sublingual or buccal use mild oral irritation.

Human data are limited. Gonadorelin was used for ovulation induction under specialist supervision, and treatment was generally stopped once pregnancy was confirmed. Do not use in known or suspected pregnancy unless under specialist fertility supervision. It is not known whether gonadorelin passes into breast milk; avoid during breastfeeding unless the prescriber directs.

Monitor LH, FSH and sex-steroid levels as clinically indicated, along with symptoms and, in men, semen parameters when fertility is the goal. In women undergoing ovulation induction, monitor ovarian response by ultrasound and hormone levels. Watch for hypersensitivity reactions and local reactions.

• Factrel (gonadorelin hydrochloride) Prescribing Information (archived, discontinued).
• Lutrepulse (gonadorelin acetate) Prescribing Information (archived, discontinued).