Leuprolide (Leuprorelin)

Overview

Native GnRH is released in pulses to stimulate pituitary secretion of LH and FSH. Leuprolide, with a substitution at position 6 and an ethylamide C-terminus, resists enzymatic degradation and binds the GnRH receptor with high affinity. When given continuously (as a depot rather than in pulses), it first triggers a transient surge in LH, FSH and testosterone (the 'flare'), then downregulates and desensitises pituitary receptors, producing a profound, reversible fall in sex-hormone levels comparable to surgical castration.

In prostate cancer, depot leuprorelin achieves castrate testosterone (≤50 ng/dL) within about a month and maintains it throughout each dosing interval, forming the backbone of androgen-deprivation therapy. The same principle underlies its use to shrink endometriotic lesions and fibroids and to halt premature puberty in children.

Because of the initial flare, an anti-androgen is often co-administered at the start of prostate-cancer treatment to prevent transient symptom worsening. Depot formulations are available for 1-, 3-, 4- and 6-month dosing. Common effects reflect hypogonadism: hot flushes, reduced libido, fatigue and, with long-term use, bone-mineral-density loss.

Mechanism of Action

Sustained, non-pulsatile occupancy of the pituitary GnRH receptor causes receptor internalisation and uncoupling after an initial gonadotropin surge. LH and FSH fall, removing the stimulus for testicular or ovarian steroidogenesis. The effect is reversible on discontinuation. The early 'flare' surge is clinically relevant in metastatic prostate cancer, prompting temporary anti-androgen cover.