Ovarian responsiveness during random-start stimulation and DuoStim in women: comparative insights from domestic...

In women, recognition of sequential follicular waves throughout the menstrual cycle established the physiologic basis for random-start ovarian stimulation outside the conventional early follicular phase and for DuoStim within a single cycle. These approaches reduce treatment delays and, in the case of DuoStim, provide two oocyte-retrieval opportunities within a shortened interval, thereby benefiting fertility preservation and women with restricted reproductive windows. However, stimulation begins under ovarian physiologic and endocrine conditions that may differ even within the same menstrual-cycle phase according to follicular-wave stage, dominant follicle status, the recruitable follicular cohort, and corpus luteum maturity and function. Such heterogeneity at stimulation initiation may contribute to variability in ovarian responsiveness and limit the predictability of ovarian-response outcomes. This review integrates clinical evidence for random-start ovarian stimulation and DuoStim in women with basic and applied findings from cattle and mares, while recognizing the human protocols as related but physiologically distinct. In monovulatory domestic animal models, follicular-wave emergence, dominant follicle status, and luteal function can be characterized and experimentally manipulated before gonadotropin stimulation, permitting mechanistic relationships to be evaluated more directly than in women. Spontaneous-cycle random-start stimulation is also distinguished from the second stimulation of DuoStim, which begins in a treatment-modified, post-retrieval luteal environment following follicular-phase stimulation, final oocyte-maturation triggering, and oocyte retrieval. Comparative studies demonstrate similarities in follicular-wave dynamics among women, cattle, and mares. Experimental and production-management studies in cattle provide direct evidence that dominant follicle status and corpus luteum maturity and function influence follicular recruitment, endocrine conditions, and ovarian response to gonadotropin stimulation. Studies in mares provide complementary mechanistic evidence concerning control of wave emergence, follicle selection, and ovulation. Although they do not establish equivalent regulation in women, these comparative findings provide a mechanistic framework for identifying measurable follicular, luteal, and endocrine variables that may explain response variability, improve prediction, and inform optimization of stimulation strategies. Accordingly, the central hypothesis is that menstrual-cycle phase alone does not adequately characterize the heterogeneous ovarian environment at stimulation initiation. Evidence is strongest for ovarian-response and time-efficiency outcomes, whereas evidence for improved downstream reproductive outcomes, particularly pregnancy and live birth, remains limited and variable.