Gonadorelin (GnRH)

Also known as: GnRH, LHRH, Luteinizing hormone-releasing hormone, Factrel, Lutrepulse, Gonadorelin acetate, Gonadorelin hydrochloride, Cystorelin (veterinary), Fertagyl (veterinary)

Evidence: Clinical

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Overview

Synthetic GnRH decapeptide; pulsatile doses raise LH and FSH, continuous exposure suppresses them. US human products Factrel (1982) and Lutrepulse (1989) are discontinued.

Gonadorelin is synthetic gonadotropin-releasing hormone, identical to the hypothalamic decapeptide. The FDA approved it as Factrel (NDA 018123, 1982) for testing pituitary gonadotropin reserve and as Lutrepulse (NDA 019687, 1989) for pulsatile pump induction of ovulation; both are discontinued. Every current gonadorelin label on DailyMed is veterinary (Factrel by Zoetis, Cystorelin, Fertagyl, used in cattle). Human trials used an infusion pump giving a pulse every 1 to 2 hours, which induced puberty in men and ovulation in women with hypogonadotropic hypogonadism (Hoffman 1982; Martin 1993). The once-daily subcutaneous use alongside TRT sold by vendors has no published trial.

Benefits

LH and FSH release test of pituitary reserve (approved diagnostic, US product discontinued), puberty and ovulation induction by pulsatile pump in hypogonadotropic hypogonadism (human trials), testicular support during TRT (community use, no trial)

Dosing reference

Research dose: Community range 200 to 300 mcg subcutaneous (off-label; no current US human label).
Range: 200 to 300 mcg, 1x daily (before bed)
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 2 mg, 5 mg

Community protocols use 200 to 300 mcg subcutaneously to stimulate LH and FSH alongside TRT (off-label). The US human products Factrel and Lutrepulse are discontinued, so no current label gives a dose. Sustained exposure suppresses the gonadal axis rather than stimulating it.

Mechanism

Gonadorelin binds the GnRH receptor on pituitary gonadotrophs and releases LH and FSH (Conn 1991). The response depends on the pattern of exposure: in rhesus monkeys with hypothalamic lesions, hourly pulses restored LH and FSH secretion while a continuous infusion of the same hormone suppressed it (Belchetz 1978). That finding is the basis both for pulsatile pump therapy and for long-acting GnRH agonists used to shut the axis down. Native GnRH is cleared within minutes, which is why therapeutic use needed a pump rather than daily injections (Handelsman 1986).

Evidence

Clinical: at least one published human trial or an approved drug

Hourly GnRH pulses restored LH and FSH in rhesus monkeys with hypothalamic lesions, while continuous infusion suppressed them (Belchetz et al., 1978)
Long-term low-dose pulsatile GnRH induced puberty in men with hypogonadotropic hypogonadism (Hoffman and Crowley, 1982)
Pulsatile GnRH was compared with exogenous gonadotropins for ovulation induction in women with hypogonadotropic amenorrhea (Martin et al., 1993)
Review of GnRH and its analogue pharmacology in reproductive medicine (Conn and Crowley, 1991)
Human-trial status: approved by the FDA as Factrel (1982, diagnostic) and Lutrepulse (1989, ovulation induction), both discontinued; current US labels are veterinary only, and no trial has tested daily subcutaneous gonadorelin during TRT

References

Side effects

Injection-site reactions, headache, nausea, and flushing are the most common effects. Continuous rather than pulsatile administration downregulates the pituitary and suppresses the gonadal axis, the opposite of the intended effect. Rare hypersensitivity reactions have been reported.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: ~2-4 minutes (very short)
Bioavailability: Subcutaneous: Rapid absorption; requires frequent pulsatile dosing for physiologic effect
Molecular weight: 1182.29 Da
Sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2