Leuprorelin

Leuprorelin, also known as leuprolide, is a synthetic derivative of the hormone GnRH (gonadotropin-releasing hormone) used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, pubertas praecox, and as part of transgender hormone therapy. It is administered by injection into a muscle or under the skin.

Leuprorelin was first approved as a daily subcutaneous injection in 1985 under the brand name Lupron™ by Abbvie Endocrine Inc. Delayed-action intramuscular and subcutaneous variants have since been developed, which only need to be given 2 times per year. Leuprorelin remains the first-line agent for all conditions for which it is approved.

Pharmacodynamics

Gonadotropin-releasing hormone (GnRH) is a naturally occurring decapeptide that modulates the so-called hypothalamic-pituitary-gonadal (HPG) axis. GnRH binds to corresponding receptors on the anterior pituitary gland in the brain, which in turn release luteinizing hormone (LH) and follicle-stimulating hormone (FSH); these in turn influence the downstream synthesis and release of the sex hormones testosterone, dihydrotestosterone, estrone, and estradiol.

Despite the variety of conditions indicated for treatment with leuprolide, the underlying mechanism of action is the same in all cases. As a GnRHR agonist, leuprorelin binds to the GnRH receptor and initially stimulates downstream LH and FSH release. This initial increase in hormone levels is responsible for some of the adverse side effects associated with treatment. After 2-4 weeks of treatment, the continuous stimulation of GnRH receptors leads to what is known as negative feedback. In this process, due to the permanently elevated hormone levels, the release of hormones is throttled, ultimately leading to low hormone levels and therapeutic effect. These effects are reversible when treatment is discontinued.

Pharmacokinetics

Leuprolide is usually administered as a long-acting single-dose formulation using either microspheres or biodegradable solid depots. Regardless of the exact formulation and the strength of the initial dose, Cmax is usually reached 4-5 hours after injection. Leuprorelin has an apparent volume of distribution of 27 L after intravenous bolus administration. Plasma protein binding is 43% and 49%. Leuprolide has a terminal elimination half-life of approximately three hours.

Side effects

Leuprorelin is considered extremely safe, with low dose-related toxicity and comparatively few adverse effects.

Contraindications

Women being treated for endometriosis or uterine leiomyoma must be evaluated for pregnancy prior to use.

Toxicological data

LD50, mouse, i.v.: 137 mg/kg