Deglycosylated LH ( DGLH ) abolished the stimulatory effect of LH on cAMP production by mature granulosa cells. DGLH , however, had no such inhibitory effect on the stimulatory activity of FSH, prostaglandin E2, isoproterenol, or choleragen. We have examined whether DGLH could prevent the desensitization of the cAMP response induced by continuous exposure to LH, or if it would induce receptor down-regulation. Cells were cultured with DGLH and LH concomitantly for a period of 3 h or 20 h and afterwards washed in acidic medium to dissociate bound ligands from their receptors. The cells were then challenged with fresh LH or with labeled 125I-human CG. At 20 h of culture with LH the cAMP response to the LH challenge was only 10% of the control, whereas after a 20-h culture with DGLH there was a 55% response to challenge with LH. DGLH , however, prevented LH from inducing desensitization in a dose-dependent manner (0.2-1.0 microgram/ml). Both LH and DGLH (1.0 microgram/ml each) markedly reduced (85%) the extent of binding of 125I-human CG to membrane receptors. At 3 h of culture, the cAMP response to challenge with LH was 25% of the control, whereas after 3-h culture with DGLH there was a 65% response to challenge with LH. DGLH (1.0 micrograms/ml) again prevented LH-induced desensitization, although only a moderate reduction in receptor-binding capacity (33%) by LH or DGLH was noted. The results suggest that occupancy of LH receptors alone for a long period is essential, but not sufficient to induce hormone desensitization. DGLH on its own is as active as LH in inducing a loss of membrane receptors, but causes only a moderate desensitization. The data support previous evidence that desensitization may result from postreceptor events, such as uncoupling of the receptors from the adenylate cyclase moiety, rather than receptor disappearance.