Downregulation
A decrease in the number or sensitivity of receptors on a cell surface in response to sustained stimulation. Downregulation is the therapeutic mechanism behind GnRH agonist therapy — continuous administration causes pituitary GnRH receptor downregulation, ultimately suppressing sex hormone production.
Technical Context
Receptor downregulation involves multiple processes: agonist-induced receptor internalisation via clathrin-coated pits and endosomes, increased lysosomal degradation of internalised receptors, and decreased receptor gene transcription. The time course of downregulation (hours to days) is slower than desensitisation (minutes). In GnRH agonist therapy, continuous exposure causes GnRH receptor downregulation from approximately 15,000-20,000 receptors per gonadotroph cell to much lower levels over 1-2 weeks. This reduces pituitary responsiveness to GnRH, suppressing LH/FSH secretion and downstream sex steroid production. The degree and reversibility of downregulation depends on agonist concentration, exposure duration, and receptor reserve.