Consequences of targeted inactivation of LH receptors

The inactivation of luteinizing hormone (LH) receptors was neither lethal nor it had any effect on sex differentiation. However, it dramatically reduced the growth and development of gonads and the reproductive tract. As a result, both female and male animals were infertile. Serum LH levels were dramatically elevated, follicle stimulating hormone (FSH) levels moderately elevated in both sexes, estradiol and progesterone levels partially decreased in females, testosterone levels dramatically decreased and estradiol levels moderately increased in males. The knockout of LH receptors had no effect on gonadal FSH receptors in both sexes, progesterone receptors in females and androgen receptors in males. However, estrogen receptor ERalpha and steroidogenic acute regulatory protein decreased and ERbeta increased in both sexes. cDNA expression array analyses revealed that testes were affected more than ovaries and more genes showed an increase rather than a decrease in testes. The affected genes came from many unexpected families. Both null females and males had a decreased density of femur and became obese with age. The ovarian failure in knockout animals could not be reversed by estradiol/progesterone replacement therapy or by PMSG and human chorionic gonadotropin (hCG) injections. Although, testosterone replacement therapy of 30-60-day old null males partially improved spermatogenesis, the animals still remained infertile. A single testosterone injection on postnatal day 1 followed by 21-45-day testosterone replacement therapy beginning at 30 days of age, however, restored fertility. Studies showed that uterus of null animals could not initiate pregnancy even though the size and morphology were greatly improved by estradiol and progesterone replacement therapy. In general, non-gonadal phenotypes in null females and males were not completely reversed by hormone replacement therapy, suggesting that LH signaling could be important for their function. Heterozygous animals were indistinguishable from wild-type animals at 60 days of age. However, as they grew to about 1 year of age, they began to stop cycling, some became extremely obese, showed a decreased density of femur and all animals developed endometrial tumors with a cancer histology. LH receptor-knockout animals will be useful in advancing our present understanding on the importance of classical as well as non-classical actions of LH in the body, in advancing novel therapeutic uses of hCG, and in better understanding and rationalizing the consequences of inactivating type human LH receptor mutations.