Adenylate cyclase in the primate corpus luteum during chorionic gonadotropin treatment simulating early pregnancy: homologous versus heterologous desensitization.

Stimulation of the primate corpus luteum by endogenous CG in early pregnancy or by exogenous CG in simulated conditions is transient despite continued exposure to this luteotropic hormone. The transitory response to CG is not due to the down-regulation of gonadotropin receptors. The current studies were designed to determine if the transient response involves a postreceptor lesion at the membrane level, i.e. the loss of CG receptor activation of adenylate cyclase. Nonpregnant female rhesus monkeys received increasing doses of hCG for up to 10 days beginning near the typical time of implantation (9 days post-LH surge) to simulate early pregnancy. Corpora lutea were removed at specific intervals after the onset of hCG treatment, luteal homogenates were prepared, and adenylate cyclase activity was assessed by the conversion of [alpha-32P]ATP to [32P] cAMP. Basal activity of adenylate cyclase was unchanged throughout the in vivo hCG treatment interval. Nonhormonal activators, such as forskolin (100 microM) and 5'-guanylylimidodiphosphate (50 microM) stimulated (P less than 0.05) adenylate cyclase to a similar extent (greater than 10-fold the control level) throughout hCG treatment. On day 0, both gonadotropins (hCG and human LH; 250 nM) and prostaglandins (PGE2 and PGI2; 500 nM) stimulated cAMP production (approximately 3-fold the control level; P less than 0.05). The responses of adenylate cyclase to PGE2 and PGI2 did not diminish throughout the in vivo hCG treatment. In contrast, exposure to hCG for 3 days reduced the sensitivity of adenylate cyclase to gonadotropin. Moreover, adenylate cyclase in luteal tissue after 6-10 days of treatment was insensitive to hCG. The loss of gonadotropin sensitivity of adenylate cyclase by 6 days of hCG treatment correlated with the decline in circulating progesterone levels. These results demonstrate that 1) the gonadotropin-responsive adenylate cyclase of the macaque corpus luteum is also stimulated by paracrine factors, notably PGs of the E and I series; and 2) CG exposure stimulating early pregnancy conditions leads to homologous, not heterologous, desensitization of the adenylate cyclase system. We hypothesize that homologous desensitization of the adenylate cyclase system is an important mechanism leading to the transient response of the primate corpus luteum to CG in early pregnancy.