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Naoki Hattori, Takashi Ishihara and Akira Shimatsu

Design

Macro TSH is a large molecular-sized TSH that is mostly a complex of TSH and IgG. Patients with macro TSH have elevated serum TSH and normal free thyroxine levels, mimicking subclinical hypothyroidism. The aim of this study was to clarify the degree of cross-reactivity of macro TSH to different commercial immunoassay systems.

Methods

Screening for macro TSH was done using a polyethylene glycol (PEG) method and confirmed with gel filtration chromatography in serum samples from 1901 patients with subclinical hypothyroidism. Interference due to human anti-mouse antibodies (HAMA) was examined using HAMA blockers. TSH was measured with an enzyme immunoassay for the analysis of macro TSH. Serum TSH values in patients with macro TSH were also determined with the widely used commercial immunoassay platforms Elecsys, Centaur and Architect, and the detectability of macro TSH was compared among them.

Results

Gel filtration chromatography was performed with 174 serum samples with PEG-precipitable TSH ratios >75%. Twenty serum samples were found to contain large molecular-sized TSH, five of which were due to interference by HAMA. The prevalence of macro TSH was eventually 0.79% (15/1901). Commercial immunoassay systems variably recognized macro TSH. The Architect TSH immunoassay platform was the least reactive to macro TSH, but still recognized it in 60% of macro TSH-containing serum samples.

Conclusions

There were no commercial TSH immunoassay platforms that did not cross-react with macro TSH. Screening for macro TSH should be performed before hormone replacement therapy is initiated for subclinical hypothyroidism.

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Naoki Hattori, Akira Shimatsu, Chutaro Yamanaka, Toru Momoi and Hiroo Imura

Abstract. Nocturnal urinary growth hormone levels in children with short and normal stature were measured by a sensitive enzyme immunoassay. Urinary GH excretion during sleep correlated positively with peak plasma GH values during pharmacological (r = 0.74, P < 0.001) and sleep (r = 0.85, P < 0.001) tests. The amounts of urinary GH excretion during sleep differed significantly from each other in the following groups: complete GH deficiency (mean ± sem: 0.1 ± 0.1 ng/m2 of body surface area; range: < 0.1–0.4), partial GH deficiency (1.6 ± 0.3 ng/m2; 0.2–3.1), and short stature without GH deficiency (3.7 ± 0.6 ng/m2; 0.7–11.5). No significant difference was found between short stature without GH deficiency and normal stature (5.0 ± 0.5 ng/m2; 2.1 – 10.5). Measurement of nocturnal urinary GH excretion is a simple method for screening of GH excretion and may be helpful in the differentiation of the various etiologies of short stature in children.

Free access

Naoki Hattori, Takashi Adachi, Takashi Ishihara and Akira Shimatsu

Objective

Macroprolactinaemia is a condition in which serum prolactin (PRL) consists mainly of large molecular weight PRL (macroPRL). The aim of this study was to examine the natural history of macroprolactinaemia.

Design and participants

Six hundred and fifty-four hospital workers participated in this study, including 27 subjects with macroprolactinaemia and 627 controls. MacroPRL and serum PRL concentrations were evaluated over a 4-year period. The ratio of macroPRL was examined by the polyethylene glycol (PEG) method and gel filtration chromatography. IgG-bound PRL and anti-PRL autoantibodies were examined by protein G and 125I-PRL binding studies respectively.

Results

Over the 4 years of the study, all 27 macroprolactinaemic subjects had persistent macroprolactinaemia without the development of raised free PRL, while none of the 627 controls developed macroprolactinaemia. The ratios of PEG–precipitable PRL and IgG-bound PRL did not significantly change, but 125I-PRL binding ratios significantly increased. As a whole, total and free serum PRL concentrations did not significantly change in subjects with macroprolactinaemia over the 4-year period. However, hyperprolactinaemia developed in five of the 18 macroprolactinaemic subjects who were initially normoprolactinaemic along with an increase in anti-PRL autoantibody titres. One of the remaining nine macroprolactinaemic subjects who were initially hyperprolactinaemic showed a decrease in serum PRL concentrations, which occurred concomitantly with a decrease in the anti-PRL autoantibody titre.

Conclusions

Macroprolactinaemia may develop before middle age and is likely a chronic condition leading to hyperprolactinaemia.

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Hossein Assadian, Akira Shimatsu, Hiroyuki Koshiyama, Naoki Hattori, Yasuhiro Ishikawa, Tsutomu Tanoh and Hiroo Imura

Abstract.

Plasma alpha and TSH-beta subunit responses to iv administration of GHRH were examined in 19 patients with active acromegaly. In 4 patients (21%), plasma alpha subunit levels were increased over 50% of basal levels after administration of GHRH, whereas plasma TSH-beta subunit levels were increased in response to GHRH in another 5 patients (26%). No patient showed simultaneous increases of alpha and beta subunits. After successful surgery, alpha and TSH-beta subunits did not respond to GHRH. These findings support the idea that some pituitary adenomas in acromegaly co-secrete GH and either alpha subunit or TSH-beta subunit.

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Naoki Hattori, Akira Shimatsu, Yuzuru Kato, Hiroyuki Koshiyama, Yasuhiro Ishikawa, Tsutomu Tanoh, Hossein Assadian and Hiroo Imura

Abstract.

Urinary excretion of growth hormone during night-time was measured by a highly sensitive enzyme immunoassay in 6 normal men for 18–24 days. Urinary GH excretion distributed widely from 0.12 to 4.7 pg/μmol creatinine and the coefficient of variation in each subject ranged from 37 to 57% (mean 49%). Urinary excretion of albumin and α1-microglobulin also showed moderate day-to-day variations (mean coefficients of variation: 37 and 42%, respectively). No correlation was found among urinary excretion of GH, albumin and α1-microglobulin. Plasma and urinary GH levels were determined every 5 min and 2 h, respectively, from 09.00 h to 17.00 h in 4 normal men. Urinary GH excretion every 2 h during daytime closely reflected the change of plasma GH levels in each subject, suggesting that physiological GH secretory dynamics are reflected on the urinary GH excretion. Repeated measurements of urinary GH excretion are required to evaluate GH secretory capacity.

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Naoki Hattori, Katsuji Ikekubo, Takashi Ishihara, Kunisaburo Moridera, Megumu Hino and Hiroyuki Kurahachi

We present the case of a normal ovulatory woman with marked hyperprolactinemia and no evidence of a pituitary adenoma on CT and MRI. Gel filtration studies showed that most immunoreactive PRL was eluted as 150K–170K macroprolactin. Anti-PRL autoantibody was detected and Scatchard analysis revealed a low-affinity (the association constant: 1.29×107 l/mol), high-capacity (the maximal binding capacity: 1174 μg/l) antibody. Dopamine had little suppressive effect on PRL levels and an anti-dopaminergic agent elicited an augmented response of PRL secretion. These results suggest that the presence of anti-PRL autoantibody may delay the clearance of PRL and/or may alter the central regulation of PRL secretion.

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Naoki Hattori, Katsuji Ikekubo, Takashi Ishihara, Kunisaburo Moridera, Megumu Hino and Hiroyuki Kurahachi

Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M, Kurahachi H. Correlation of the antibody titers with serum prolactin levels and their clinical course in patients with anti-prolactin autoantibody. Eur J Endocrinol 1994;130:438–45. ISSN 0804–4643

Patients with anti-prolactin (PRL) autoantibody were surveyed among 208 patients with hyperprolactinemia (PRL ≥ 30 μg/l) and 228 subjects with normal PRL levels, and the relationship of the antibody titers with serum PRL levels and their clinical course were studied. Diagnosis of possessing the anti-PRL autoantibody was based on the polyethylene glycol method, displacement of the binding of [125I]PRL with the serum by unlabeled PRL and the binding of PRL to protein G, the affinity gel for immunoglobulin G. Prolactin was measured by an immunoradiometric assay that we found was not affected by the anti-PRL autoantibody. A significantly high frequency of anti-PRL autoantibody in patients with idiopathic hyperprolactinemia (16%) and a positive correlation between titers of the autoantibody and serum PRL levels (r = 0.74, p < 0.01) may indicate that the anti-PRL autoantibody itself is another cause of hyperprolactinemia, probably owing to the delayed clearance of PRL. Most patients with anti-PRL autoantibody lacked the clinical symptoms of hyperprolactinemia, such as amenorrhea and galactorrhea, and spontaneous pregnancy occurred despite the marked hyperprolactinemic state, indicating that the biological activity of PRL was attenuated by the autoantibody. In addition, PRL levels and the titers of anti-PRL autoantibody were not changed significantly during the observation period of up to 5 years without any medical intervention. These results suggest that the anti-PRL autoantibody itself is one of the causes of hyperprolactinemia and that medical intervention is unnecessary for this type of hyperprolactinemia.

Naoki Hattori, Department of Endocrinology, Kobe City General Hospital, 4–6 Minatojima Nakamachi, Chuo-ku, Kobe 650, Japan

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Naoki Hattori, Katsuji Ikekubo, Takashi Ishihara, Kunisaburo Moridera, Megumu Hino and Hiroyuki Kurahachi

Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M, Kurahachi H. Effects of anti-prolactin autoantibodies on serum prolactin measurements. Eur J Endocrinol 1994:130:434–7. ISSN 0804–4643

The influence of anti-PRL autoantibodies on PRL measurements determined by immunoassays was investigated in 10 patients with anti-PRL autoantibodies. Four different immunoassay systems (two double-antibody radioimmunoassays (RIAs), a single-antibody RIA and an immunoradiometric assay (IRMA)) were examined. Total and free PRL were extracted from sera by precipitating γ-globulin with polyethylene glycol with and without acidification, respectively. PRL values determined by direct measurement were compared with total PRL values. The proportion of free to total PRL levels determined by each immunoassay in sera with anti-PRL autoantibodies was significantly lower than in control sera. Values obtained by direct measurement of PRL (a routine assay procedure) in control sera were similar to total PRL values, whereas in sera with anti-PRL autoantibodies the values varied from one immunoassay to the other. In sera with anti-PRL autoantibodies, double-antibody RIA I, RIA 2 and single-antibody RIA 3 yielded values lower for PRL than for total PRL (52 ±15% in RIA 1, 40±8.8% in RIA 2.40±14% in RIA 3), while PRL levels determined by IRMA were not significantly different (112 ±14%). Immunoglobulin G purified from serum with anti-PRL autoantibodies dosedependently decreased the recovery of PRL assayed by the double-antibody technique, while it did not affect that by IRMA. These data suggest that the presence of anti-PRL autoantibodies gives variable results depending on the immunoassays used. It is noteworthy that anti-PRL autoantibodies do not cause falsely high PRL values, as in the case of antithyroid hormone autoantibodies, rather they cause an underestimate, when a double-antibody RIA, a routine method for PRL measurement, is used.

Naoki Hattori, Department of Endocrinology. Kobe City General Hospital, 4-6 Minatojima Nakamachi, Chuoku, Kobe 650, Japan

Free access

Takashi Adachi, Naoki Hattori, Takashi Ishihara, Hirokazu Iida, Takanori Saito, Shigeo Miyashima and Akira Shimatsu

Objective

Macroprolactin primarily comprises a complex of prolactin (PRL) and IgG molecules, particularly anti-PRL autoantibodies. However, it is unknown why autoantibodies against PRL develop in certain subjects. This study aimed to elucidate post-translational modifications in the PRL molecule that may be involved in the pathogenesis of macroprolactinaemia.

Methods

Macroprolactinaemia was screened with a polyethylene glycol method in 238 patients with rheumatoid arthritis (RA) and 302 control subjects and confirmed by gel chromatography. We examined the relationship between macroprolactinaemia and several RA-related laboratory tests including matrix metalloproteinase-3 (MMP-3) and anti-cyclic citrullinated peptide (CCP) antibody titres. The effect of MMP-3 on the PRL molecule was examined by western blotting.

Results

Patients with RA exhibited a significantly higher prevalence of macroprolactinaemia (15/238; 6.3%) than the young control subjects (5/219 subjects; 2.3%), but the prevalence was not different from that observed in the elderly control subjects (5/83 subjects; 6.0%). The prevalence of macroprolactinaemia in patients with elevated MMP-3 levels (9.68%) was significantly higher than that in those with normal MMP-3 levels (2.63%). Digestion of PRL with MMP-3 produced vasoinhibins with several molecular species. Serum total and free PRL levels in RA patients were higher than those in the age- and gender-matched control subjects. The levels of macroprolactin were not significantly correlated with those of RA-specific anti-CCP antibody.

Conclusions

We speculate that elevated MMP-3 levels may lead to the formation of new epitopes on the PRL molecule that might trigger an immune response to produce anti-PRL autoantibodies in some patients with RA. Such post-translational modifications may possibly contribute to the increased prevalence of macroprolactinaemia in elderly subjects.