Peptide Histidine Methionine May Be a Prolactin-Releasing Hormone in Humans*

Abstract

Peptide histidine isoleucine (PHI) was initially isolated from the porcine gastrointestinal tract and may be present in the brain. It has been suggested that PHI may be PRL-releasing hormone (PRH) because of its potent PRL-releasing activity and its existence in hypophysial portal plasma in rats. Vasoactive intestinal peptide and PHI are coded by the same gene, and human PHI has a C-terminal methionine instead of isoleucine [peptide histidine methionine (PHM)]. To investigate the possibility that PHM is a physiological PRH in humans, we measured the immunoreactive PHM concentration in human hypothalamic tissue and cerebrospinal fluid (CSF) using a specific RIA. We also examined in vivo the PRH activity of synthetic PHM. The human hypothalamus contained 19.3 +/- 6.2 (+/- SD; n = 5) pmol/hypothalamus, very similar to the content of GHRH or CRH. Immunoreactive PHM was also present in CSF; its levels in CSF were significantly lower in patients with prolactinomas than in control subjects. The CSF PHM levels in such patients increased after correction of hyperprolactinemia by long term bromocriptine therapy. The CSF PHM levels also were low in pregnant women. There was a significant negative correlation between plasma PRL and CSF PHM levels in all of these subjects. Gel filtration profiles of CSF extracts from normal subjects revealed two peaks of immunoreactive PHM: a high mol wt peak and one at the elution position of synthetic PHM. This profile resembled that of hyppothalamic extract. In contrast, only high mol wt material was detected in CSF from hyperprolactinemic subjects. Intravenous administration of synthetic PHM elicited a significant increase in plasma PRL in normal subjects; the responses to PHM were higher in women than in men. The presence of large amounts of immunoreactive PHM in the human hypothalamus suggests that PHM may participate in the regulation of anterior pituitary hormone secretion. Its specific PRL-releasing activity in vivo and the low CSF PHM levels of hyperprolactinemic subjects suggest that PHM may be a physiological PRH in humans.