Targeted Disruption of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Gene

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Abstract
LH/hCG receptors were disrupted by gene tar- geting in embryonic stem cells. The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testos- terone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdomi- nal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round sperma- tid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in tes- tes. However, it caused a dramatic decrease in StAR and estrogen receptor-a (ERa) mRNA lev- els and an increase in ERb mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phe- notype and biochemical changes were a conse- quence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained in- fertile. It is anticipated that the LH receptor knockout animals will increase our current un- derstanding of gonadal and nongonadal actions of LH and hCG. (Molecular Endocrinology 15: 184-200, 2001)

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