Increased episodic release and disorderliness of prolactin secretion in both micro- and macroprolactinomas

Abstract

To quantify prolactin (PRL) secretion patterns, ten untreated (female) microprolactinoma patients and six (male) macroprolactinoma patients underwent repetitive blood sampling every 10 min over 24 h. PRL release activity was analyzed from plasma PRL concentration (immunofluorimetric assay) profiles via a model-independent discrete peak detection program (Cluster) and a waveform-independent deconvolution technique (Pulse). Diurnal variations were analyzed by cosinor analysis. The number of distinct PRL pulses (mean +/- S.E.M.) was increased in patients: microprolactinoma 18.6 +/- 0.6/24 h versus female controls 12.4 +/- 0.6 (P = 6.7 x 10-s), and macroprolactinoma 18.0 +/- 0.9 versus male controls 13.5 +/- 0.8/24 h (P = 0.003). In patients, PRL pulse height, amplitude, pulse area and interpeak nadir concentrations were each greatly elevated compared with gender-matched controls. By 2-component deconvolution analysis, the mean nadir PRL secretion rate in microprolactinoma patients was augmented 20-fold at 0.408 +/- 0.089 microgram/l per min versus in female controls 0.019 +/- 0.009 microgram/l per min (P < 0.001); and in macroprolactinoma by 130-fold at 2.067 +/- 0.693 micrograms/l per min versus male controls 0.016 +/- 0.001 microgram/l per min (P = 0.001). Corresponding 24 h mean PRL secretion rates were in women, 0.658 +/- 0.147 and 0.044 +/- 0.018 (P < 0.001), and in men, 3.309 +/- 1.156 and 0.035 +/- 0.010 micrograms/l per min (P = 0.001), being respectively 15- and 94-fold increased in tumors. The estimated PRL production per day was 160 +/- 15 and 187 +/- 20 micrograms in male and female controls respectively. PRL production was 2860 +/- 640 micrograms in female patients with microadenomas (P < 0.001), and 37,800 +/- 5900 micrograms in male macroadenoma patients (P = 0.001). Cosinor analysis of the plasma concentrations revealed a significant rhythm in nine of ten, patients with a microadenoma, and in five of six with a macroadenoma. The same method applied to pulse height and amplitude disclosed a significant rhythm for PRL pulse height, but not for pulse amplitude, suggesting preserved rhythmicity of baseline interpulse nadir PRL concentrations. Approximate entropy (ApEn), a scale- and model-independent regularity statistic, averaged 1.6559 +/- 0.028 in microprolactinoma patients versus 0.8128 +/- 0.079 in female controls (P = 1.7 x 10(-8)); ApEn in macroadenomas was 1.5674 +/- 0.054 versus male controls 0.8773 +/- 0.076 (P = 1.7 x 10(-5), signifying greater secretory irregularity in the patients. Compared with microadenomas, macroadenomas exhibited a higher mean plasma concentration, overall mean PRL secretion rate, nadir secretion rate and pulse area, but similar peak frequency. We conclude that PRL secretion by prolactinomas is characterized by increased plasma PRL episodicity of release, increased total (15- to 100-fold) and basal (20- to 130-fold) secretion rates, and increased disorderlines of minute-to-minute secretion. These abnormalities of secretory control are very similar to those for GH and ACTH identified earlier in acromegaly and Cushing's disease respectively, thus suggesting mechanistic generality of pituitary tumor secretory derangements, independent of the particular hormone.