Gonadotropin-Releasing Hormone (GnRH)

GnRH is a ten-residue peptide with the sequence pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-amide. Both termini are blocked, the amino end by cyclisation to pyroglutamate and the carboxy end by amidation, which defeats exopeptidases; even so the plasma half-life is only a few minutes, because endopeptidases cleave it internally around residues 5 to 7. It is released into the hypophyseal portal vessels, a short circuit between hypothalamus and anterior pituitary, so it reaches gonadotropes at high concentration while remaining unmeasurable in peripheral blood.

Humans have only a few thousand GnRH neurons, born in the olfactory placode and migrating into the hypothalamus during fetal development. Failure of that migration produces Kallmann syndrome, in which absent sense of smell accompanies hypogonadotropic hypogonadism. Native GnRH, gonadorelin, has been used as a pituitary stimulation test. Substituting a D-amino acid for glycine at position 6 removes the principal cleavage site and yields far more potent, longer-lived analogues: leuprolide, goserelin, triptorelin.

The portal anatomy means peripheral GnRH cannot be measured usefully, so the axis is assessed from downstream LH and FSH, and the peptide's brevity is why no therapeutic product is native GnRH given as a simple injection. Everything in clinical use is either an analogue or a pump delivering the peptide on a schedule.

The misreading to guard against treats GnRH as a fertility hormone where more is better. Continuous or high-dose exposure shuts the axis down rather than driving it, which is exactly how prostate cancer therapy works. Gonadorelin sold in grey-market listings as a gentle testosterone stimulant inherits that problem: what the pituitary does depends on the pattern of delivery, and a pattern that never resembles hourly pulses is not reproducing the physiology invoked.