“Extended ovarian stimulation”: a prolonged ovarian exposure to gonadotrophins leads to an increase in the oocyte yield—evidence from the DuoStim experience

The recent better understanding of folliculogenesis throughout the ovarian cycle (the “continuous/waves” theory), as well as the improvement of embryo survival rates after vitrification (which permits untangling the timing of embryo transfer from ovarian stimulation and oocyte yield) has permitted to elevate ovarian stimulation from the old classic single stimulation starting in the early follicular phase to novel strategies of ovarian stimulation, such as random start, luteal phase, and double ovarian stimulation. The role of FSH in follicular recruitment and growth is well known and is the cornerstone of ovarian stimulation. Prolonged exposure to FSH, as it happens in the double stimulation protocol, may lead to a potential increase in the number of oocytes obtainable after the second stimulation. A very high number of studies on DuoStim showed a greater number of oocytes retrieved, expressed as cumulus-oocyte complexes (COCs) or mature oocytes (MIIs), in the second ovarian stimulation rather than the first ovarian stimulation. This was particularly significant when a GnRH agonist was used to trigger the ovulation. Different hypotheses can be formulated to explain this eventuality including increased synchronization of antral follicles at the time of the second stimulation, enhanced granulosa cell sensitivity to FSH, the flare-up effect of the GnRH agonist at the time of the first triggering, and an increased rate of progression of small follicles to the antral recruitable stage as a consequence of the prolonged exposure to gonadotropins. The evidence that repeated back-to-back ovarian stimulations could lead to a progressive increase in the number of oocytes retrieved reported in our review opens the way to the consideration of innovative stimulation protocols based on this new concept of “Extended ovarian stimulation.” If future prospective studies designed on purpose will confirm our thesis that the prolonged FSH stimulation would involve a clear gain in the number of oocytes retrieved, this strategy could become the first therapeutic choice when the goal is to maximize the oocyte yield.

Abstract representation of a back-to-back multicycle approach. The incremental number of oocytes retrieved after consecutive ovarian stimulations is well depicted. Created in BioRender (2025).