Effects of the mutations (Trp(8)->Arg and Ile(15)->Thr) in human luteinizing hormone (LH) beta-subunit on LH bioactivity in vitro and in vivo

The mutations (Trp(8)-->Arg and Ile(15)-->Thr) in the human LH beta-subunit caused by nucleotide point mutations in the LH beta gene were reported in women with immunologically anomalous LH and menstrual disorders. To estimate the effects of the mutations on LH bioactivity in vitro and in vivo, we constructed a LH beta gene containing this nucleotide mutation in each site or in both sites by site-directed mutagenesis and analyzed the bioactivities of the mutant LH expressed in Chinese hamster ovary cells. Although no alterations were noted in the receptor-binding activity of LH due to the mutations, the LHs containing the mutations at Trp(8)-->Arg and at both sites in the beta-subunit showed a higher biopotency of progesterone production in vitro. The clearance rate from the circulation was faster in vivo in all mutant LHs, which were induced primarily by the mutation at Trp(8)-->Arg. However, the mutations did not affect the ability of LH to induce ovulation in vivo. These results indicate that LH consisting of the mutant beta-subunit exhibits hyperbioactivity on steroidogenesis and has a short turnover rate. This may affect the endocrine pathway among women with the mutant LH and lead to menstrual disorders.