Objectives: As a second messanger, cAMP principally regulates granulosa steroidogenic gene expression, and partly its mitogenic and/or differentiative response to FSH. The contribution of these cellular, and molecular events to the heterogeneity of low ovarian response has not been characterized. Phosphodiesterase inhibitors could amplify cAMP signal, and possibly sensitize low responder granulosa cell to FSH.Design: Prospective.Materials and Methods: The study included 30 ICSI cycles in a special group of low respoders (number = 14 women) whose previous “52” attempts resulted in “poor” embryos despite frequent changes of stimulation protocol. All previous cycles invariably expressed low estradiol per follicle-oocyte, resistance to adjunctive growth hormone, and high preponderance of oocytes that resisted hyaluronidase dispersion. An oral phosphodiesterase inhibitor was administered one week before and during hMG stimulation. ICSI was performed for male factor indication. Outcome measures included some potential cellular responses to enhanced local cAMP. In part these included follicular growth parameters, estradiol response, premature progesterone rise, incidence of failure to extrude first polar body, and rate of embryo cleavage.Results: Although follicular number was similar, follicular growth duration, from a size of 10 mm, was significantly shorter (6.8 + 2.4 vs. 11 + 3 days). Total estradiol (629 + 187 pg/ml), and estradiol per follicle (144 + 70) were significantly higher compared to previous attempts (209 + 66 and 51 + 30). The use of the phosphodiesterase inhibitor did not change the rate of first polar body extrusion, although oocyte number (2.8 + 1.1) was significantly higher compared to previous attempts (0.9 + 0.6). Hyaluronidase resistance decreased significantly with phosphodiesterase inhibitor (22%) as compared to previous cycles (69%). As their previous attempts produced poor embryos, current development was compared to the contemporary program’s control. Significantly more embryos reached 6–8 cell stage (43%), 24 hours after fertilization, as compared to control (21%). Five pregnancies resulted, 3 ongoing, and 2 abortions after cardiac tube pulsation.Conclusion: Amplification of postreceptor signal transduction could be a potential therapeutic approach in some low responders characterized by oocyte dismorphy, and low estradiol. Objectives: As a second messanger, cAMP principally regulates granulosa steroidogenic gene expression, and partly its mitogenic and/or differentiative response to FSH. The contribution of these cellular, and molecular events to the heterogeneity of low ovarian response has not been characterized. Phosphodiesterase inhibitors could amplify cAMP signal, and possibly sensitize low responder granulosa cell to FSH. Design: Prospective. Materials and Methods: The study included 30 ICSI cycles in a special group of low respoders (number = 14 women) whose previous “52” attempts resulted in “poor” embryos despite frequent changes of stimulation protocol. All previous cycles invariably expressed low estradiol per follicle-oocyte, resistance to adjunctive growth hormone, and high preponderance of oocytes that resisted hyaluronidase dispersion. An oral phosphodiesterase inhibitor was administered one week before and during hMG stimulation. ICSI was performed for male factor indication. Outcome measures included some potential cellular responses to enhanced local cAMP. In part these included follicular growth parameters, estradiol response, premature progesterone rise, incidence of failure to extrude first polar body, and rate of embryo cleavage. Results: Although follicular number was similar, follicular growth duration, from a size of 10 mm, was significantly shorter (6.8 + 2.4 vs. 11 + 3 days). Total estradiol (629 + 187 pg/ml), and estradiol per follicle (144 + 70) were significantly higher compared to previous attempts (209 + 66 and 51 + 30). The use of the phosphodiesterase inhibitor did not change the rate of first polar body extrusion, although oocyte number (2.8 + 1.1) was significantly higher compared to previous attempts (0.9 + 0.6). Hyaluronidase resistance decreased significantly with phosphodiesterase inhibitor (22%) as compared to previous cycles (69%). As their previous attempts produced poor embryos, current development was compared to the contemporary program’s control. Significantly more embryos reached 6–8 cell stage (43%), 24 hours after fertilization, as compared to control (21%). Five pregnancies resulted, 3 ongoing, and 2 abortions after cardiac tube pulsation. Conclusion: Amplification of postreceptor signal transduction could be a potential therapeutic approach in some low responders characterized by oocyte dismorphy, and low estradiol.