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Objective: To assess the LH response of the pituitary gland to GnRH stimulation in healthy women with a mutant beta-subunit (Trp8 to Arg8 and Ile15 to Thr15)., Design: Clinical study., Patients: We studied 40 healthy non-pregnant Japanese women of known zygosity for the LH beta-subunit gene (3 homozygotes for the mutant gene, 17 heterozygotes, and 20 homozygotes for the wild type). All women had normal ovulatory cycles., Measurements: Serum LH status was determined by comparing LH immunoassays results using a monoclonal antibody recognizing only wild-type LH with those from a polyclonal antibody assay recognizing both variant and wild-type LH. The ratio of monoclonal to polyclonal immunoassay results determined the serum LH status. LH secretion in response to a GnRH stimulation test was measured., Results: All women with the wild-type LH showed a normal response of LH to GnRH according to both assays. Over the time course of the response, the ratios in women with wild-type LH showed no remarkable changes. The response curves in women heterozygous for the mutant peaked 15-30min after GnRH injection; their response patterns included a statistically significant decrease in the rates of response at 15min after injection., Conclusions: There are the differences in circulatory kinetics between the two LH forms and in regulation of the two types of LHbeta genes. The maximal response of the variant LH to pituitary stimulation with GnRH appears to be greater than that of wild-type LH.

With recent progress in endocrinology and in procreation physiology, the importance of kinetics of pituitary gonadotropin has been increasing, and the measurement method has been improved. In the present study, however, we found inconsistency in measured LH values between IRMA (SPAC-S LH) as the conventional method and CLEIA (IMMULYZE LH) as the newly developed method. The inconsistency between the SPAC-S LH value and the IMMULYZE LH value was observed in 10.0% of the healthy group and in 12.5% of the patient group. The cause of this discrepancy was due to a reaction of the SPAC-S LH of the intact LH monoclonal antibodies to the LH with the abnormal structure beta chain by two point mutation in the LH beta gene. The response of LH-RH test varied depending on the measurement reagent of LH in patients who had the LH with the abnormal structure beta chain, which made it difficult to determine the lesion and histological grading regarding the ovulation mechanism. Therefore, in patients with abnormal beta chain, an accurate treatment protocol was indeterminate. In this study, although a relationship between various gynecological diseases and the point mutation of LH was not clarified, we suggest that LH of the abnormal structure beta chain may cause excessive secretion in the early stage, and lead to some effect on physical activities.

To determine the frequency of a common luteinizing hormone variant in a Japanese population and to evaluate its significance in infertility, serum samples were collected from 169 healthy non-pregnant Japanese women, 105 healthy adult Japanese men and 97 female Japanese infertility patients. The luteinizing hormone variant includes two point mutations in the beta-subunit gene (Trp8 to Arg8 and Ile15 to Thr15). DNA from blood cells was studied in 10 healthy women, 10 men and five patients using polymerase chain reaction and direct sequencing. In immunoassays, results with a monoclonal antibody recognizing only the wild-type hormone and a polyclonal antibody recognizing the variant as well were compared as a ratio; ratios in heterozygotes and in individuals with only wild-type alleles ranged from 0.19 to 0.50 and from 0.56 to 1.21, respectively, and 0.50 was considered a 'cut-off' value for identifying individuals with the variant. For the larger subject groups, the frequency of the variant was 9.5% in normals. The mean ratio (0.80 +/- 0.35) in infertility patients was significantly lower (P < 0.01) than in healthy women (1.09 +/- 0.56), and the variant occurred more frequently in infertility patients (16.5%) than in healthy women (8.3%; P < 0.05). The variant was more frequent in patients with ovulatory disorders (43.8%) than other patients (16.0%; P < 0.05).