Pituitary hormones circulate as immunoglobulin-associated macro-complexes in mammals

Abstract Pituitary hormones are generally assumed to circulate as single proteins that interact directly with cognate receptors. Clinical endocrinology has recognized rare high–molecular weight “macro-hormones,” but these are usually regarded as assay interference or pathological anomalies with limited physiological significance. Because circulating pituitary hormones are measured almost exclusively by immunometric assays, their molecular forms have rarely been examined directly, leaving a gap in understanding their circulating forms and whether macro-hormone formation is rare or conserved. Here we show that multiple pituitary hormones circulate as stable immunoglobulin-associated complexes conserved across mammals. Non-reducing immunoblot analyses revealed that thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, and prolactin occur as high–molecular weight complexes in rodents, livestock, and humans. Macro-hormone formation was markedly reduced in immunoglobulin-deficient conditions, including SCID mice and fetal bovine serum, demonstrating dependence on circulating immunoglobulins. These complexes resisted acidic and high-salt dissociation but were partially converted to ~50 kDa intermediates upon reduction. Immunoprecipitation identified immunoglobulin κ light chains as components of these complexes in mice. Our findings challenge the prevailing view that pituitary hormones circulate predominantly as free forms and suggest that immunoglobulin-associated macro-hormones represent a conserved molecular state in vertebrate endocrine systems.