Inappropriately low serum GH in an acromegalic: lysosomal involvement in intracellular hormone degradation

A patient with galactorrhea, amenorrhae and severe acromegaly was found to have a large pituitary adenoma. In view of the severity of the disease the serum growth hormone (GH) level (22.5 mlU/liter) was considered inappropriately low. Tissue from the adenoma was obtained during successful treatment with interstitial irradiation. (90Yttrium). Trypsin-dispersed biopsy cells in culture for 12 days secreted low amounts of GH compared to the same number of adenoma cells from 5 other unselected acromegalics or a normal pituitary. No other hormones were secreted in culture. Immunocytochemical staining was positive only with GH antisera but showed low intracellular content. This was confirmed by direct analysis of the tumor tissue which showed the GH content to be only 20% of that found in 5 normal pituitaries and 4% of that found in 8 other adenomas from acromegalics. Electron microscopy showed a striking appearance, with GH secretory granules that were sparse in number, smaller than usual, and in the main arranged around numerous intracellular profiles with double membranes and low electron density that were tentatively identified as autophagic vacuoles (secondary lysosomes). Subcellular fractionation showed the distribution of the radioimmunoassayable GH in the gradient to be coincident with the peak of the lysosomes whereas in 2 other acromegalics the GH peak was clearly separated from the lysosomes. We conclude that the simultaneous appearance in our patient of the relatively low serum GH together with a large tumor and severe acromegaly can be explained biochemically by the striking finding of crinophagy - disposal of hormone secretory granules within the somatotroph cells themselves.