Gonadotropin-Releasing Hormone Analogues for Prostate Cancer: Untoward Side Effects of High-Dose Regimens Acquire a Therapeutical Dimension

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Abstract
Gonadotropin-releasing hormone (Gn-RH), a hypothalamic decapeptide, mediates the synthesis and release of pituitary luteinizing hormone (LH). Synthetic Gn-RH analogues with prolonged duration of action are therapeutically administered with ‘pro-fertility’ intention to overcome endogenous Gn-RH deficiency, i.e. hypogonadotropic hypogonadism and related disorders. When Gn-RH analogues are chronically administered in high supraphysiological dosages, however, a paradoxical effect of pituitary overstimulation becomes evident: gonadotropin release is reduced, Leydig cell responsiveness is impaired, and testosterone secretion is blocked to castrate levels. Metabolic mechanisms involved include desensitization of the pituitary to Gn-RH, down-regulation of Gn-RH receptors, the depletion of the releasable LH pool, the breakdown of physiological feedback mechanisms, as well as direct interactions of the Gn-RH analogue with the Leydig cell. It is tempting to assume that, on the basis of this untoward side effect, high dose Gn-RH analogues will acquire a therapeutical dimension in the palliative treatment of prostate cancer. The therapeutical effect of castrate levels of testosterone is achieved without orchiectomy, cardiovascular side effects of estrogens are avoided, and the drug is conveniently applicable via the pemasal route. From the data available today Gn-RH analogues in overstimulatory dosage can be expected to be safe and effective in the palliative treatment of prostate cancer and would thus prove a true alternative to conventional contrasexual measures.

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