The episodicity of 24 h GH release was studied in 18 patients with active acromegaly, 12 patients 7-10 days after pituitary surgery, 14 patients long after operation (3-17 years), and 21 healthy gender-and age-matched control subjects, using a recently introduced scale-and model-independent regularity statistic, approximate entropy (ApEn). Blood samples were taken at 10-min intervals for 24 h, and plasma GH concentrations were measured by immunofluorometric assay (detection limit 11.5 ng/l). For this study we selected operated patients who were biochemically in remission, defined by normal circulating IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) concentrations, normal glucose-suppressed plasma GH concentration (<0.38 mg/l), and the normalization of the paradoxical rise of GH to TRH or GnRH. In patients with active acromegaly ApEn was 1.23 Ϯ 0.04, with no overlap with the control subjects (P ¼ 1.2 × 10 ¹16 ), who had an ApEn of 0.40 Ϯ 0.04. ApEn in patients shortly after surgery was 0.71 Ϯ 0.09 (P < 0.001 vs controls), and long after surgery 0.56 Ϯ 0.05 (P < 0.011 vs controls). ApEn values in treated and untreated patients correlated significantly with the plasma concentration of IGF-I (r ¼ 0.531) and IGFBP-3 (r ¼ 0.598), and the log-transformed 24 h GH secretion rate (r ¼ 0.749). Shortly after surgery only one-third of the patients had a normal ApEn value, whereas long after surgery about 70% of the patients had a normal ApEn value. Although ApEn eventually normalized in about 70% of the operated patients, the cause of the persistence of abnormal GH release in the remainder of the subjects is not known, and might reflect permanent hypothalamic-pituitary dysfunction or a very early recurrence of the somatotroph adenoma.

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 ACT...

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The present study probes putative disruption of hypothalamic control of multihormone outflow in polycystic ovarian syndrome by quantitating the joint synchrony of leptin and LH release in adolescents with this syndrome and eumenorrheic controls. To this end, hyperandrogenemic oligo- or anovulatory patients with polycystic ovarian syndrome (n = 11) and healthy girls (n = 9) underwent overnight blood sampling every 20 min for 12 h to monitor simultaneous secretion of leptin (immuno-radiometric assay), LH (immunofluorometry), and androstenedione and T (RIA). Synchronicity of paired leptin-LH, leptin-androstenedione, and leptin-T profiles was appraised by two independent bivariate statistics; viz., lag-specific cross-correlation analysis and pattern-sensitive cross-approximate entropy. The study groups were comparable in chronological and postmenarchal age, body mass index, fasting plasma insulin/glucose ratios, and serum E2 concentrations. Overnight mean (+/- SEM) serum leptin concentrations were not distinguishable in the two study groups at 30 +/- 4.8 (polycystic ovarian syndrome) and 32 +/- 7.4 microg/liter (control). Serum LH concentrations were elevated at 9.5 +/- 1.4 in girls with polycystic ovarian syndrome vs. 2.8 +/- 0.36 IU/liter in healthy subjects (P = 0.0015), androstenedione at 2.8 +/- 0.30 (polycystic ovarian syndrome) vs. 1.2 +/- 0.11 ng/ml (control) (P = 0.0002), and T at 1.56 +/- 0.29 (polycystic ovarian syndrome) vs. 0.42 +/- 0.06 ng/ml (P < 0.0001). Cross-correlation analysis shows that healthy adolescents maintained a positive relationship between leptin and LH release, wherein the latter lagged by 20 min (P < 0.01). No such association emerged in girls with polycystic ovarian syndrome. In eumenorrheic volunteers, leptin and androstenedione concentrations also covaried in a lag-specific manner (0.0001 < P < 0.01), but this linkage was disrupted in patients with polycystic ovarian syndrome. Anovulatory adolescents further failed to sustain normal time-lagged coupling between leptin and T (P < 0.01). Approximate entropy calculations revealed erosion of orderly patterns of leptin release in polycystic ovarian syndrome (P = 0.012 vs. control). Cross-entropy analysis of two-hormone pattern regularity disclosed marked disruption of leptin and LH (P = 0.0099), androstenedione and leptin (P = 0.0075) and T-leptin (P = 0.019) synchrony in girls with polycystic ovarian syndrome. In summary, hyperandrogenemic nonobese adolescents with oligo- or anovulatory polycystic ovarian syndrome manifest: 1) abrogation of the regularity of monohormonal leptin secretory patterns, despite normal mean serum leptin concentrations; 2) loss of the bihormonal synchrony between leptin and LH release; and 3) attenuation of coordinate leptin and androstenedione as well as leptin and T output. In ensemble, polycystic ovarian syndrome pathophysiology in lean adolescents is marked by vivid impairment of the synchronous outflow of leptin, LH and androgens. Whether analogous disruption of leptin-gonadal axis integration is ameliorat...