Prolactin, human nutrition and evolution, and the relation to cystic fibrosis

Cystic fibrosis (CF) is a lethal, genetically transmitted disease of Caucasian populations. Its prevalence is highest (ca 1:2000 live births) among Western and Central Europeans and their descendants. Major clinical symptoms are chronic, obstructive, pulmonary disease, impaired intestinal digestion and absorption and elevated concentration of salt in sweat. The last is important, not only for diagnosis, but because it is an example of an electrolyte transport defect present in other epithelial tissues. Numerous other clinical manifestations are generally present. The history of prolactin (PRL), especially its role in osmoregulation, is outlined and related to the symptomatology and electrolyte defect of CF. Data are presented showing the relation of PRL to regulation of sweat electrolytes and its presence and probable synthesis in the coil of the human sweat gland. The basic biochemical defect of CF has not yet been elucidated, but recent research has shown that it is probably an abnormality of a regulatory factor. We propose that PRL is a likely candidate. The large variety of functions of PRL, in particular the regulation of the transport of sodium and chloride across epithelial membranes, and the regulation of mucus production, can be matched to the major disease symptomatology. Additionally, every other one of the multiple abnormalities of CF can be associated with described activities of PRL. In lower vertebrates epithelial tissues regulated by PRL are phylogenetic progenitors of affected tissues in CF. In the human, these tissues contain cells of the Diffuse Neuroendocrine System, or APUD cells, that show PRL-like immunoreactivity, or overt synthesis of the hormone. Thus, the regulatory activity of these tissues could be paracrine. The geographic distribution and the dietary habits of early Caucasians are examined. It appears that the Neolithic revolution, with the necessity of adapting to agriculturally produced foods, i.e. milk and wheat, could have brought about the genetic selection of post-translational variants of PRL. It is suggested that the combination of two or more of these mutations in the same individual may be responsible for CF. This is illustrated with proposed models of CF inheritance. We conclude by postulating that PRL acts at the level of the target cell by triggering (in conjunction with a steroid) the gene expression of unique proteins; these act as intermediaries of PRL activity; two or more abnormalities of these proteins when present in an individual produce CF; the protein abnormalities are the consequence of nutritional and ecological pressure.