Purpose: The purpose of the present study is to describe the possible mechanisms which may explain the apparent paradox of "less is more." Mild ovarian stimulation for in vitro fertilization (IVF) minimizes ovarian hyperstimulation syndrome (OHSS) and multiple gestations without compromising the pregnancy rate (PR).
Methods: The pertinent English literature (PubMed) addressing mild stimulation for IVF/assisted reproductive technology (ART) and publications addressing "mild" or "soft" controlled ovarian stimulation (COS) vs conventional COS for IVF, OHSS, natural cycle IVF, and IVF outcome in association with COS was searched.
Results: Four possible mechanisms can be put forward to explain the apparent paradox of "less is more." (1) In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of "quality for quantity"; (2) high estradiol (E2) in the late follicular phase significantly correlated with higher rates of small for gestational age (SGA) and low-birth-weight (LBW) neonates; (3) anti-Mullerian hormone (AMH), LH, testosterone, and E(2) are significantly higher in natural cycle (NC)-IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles; and (4) supraphysiological E(2) may increase the growth hormone-binding protein (GH-BP) bio-neutralizing GH and diminishing the resultant insulin-like growth factor (IGF) levels, necessary for optimal synergism with follicle-stimulating hormone (FSH).
Conclusions: It is suggested to aim at the retrieval of around eight to ten eggs. Mild stimulation should be the common practice for IVF. In cases where more than ten ova are retrieved or high E(2) levels are reached, either intentionally or unintentionally, "freeze-all policy" should be considered and embryo transfer (ET) done in a subsequent natural cycle.
Keywords: Growth hormone-binding protein (GH-BP); In vitro fertilization (IVF); Mild controlled ovarian stimulation (COS); Minimal ovarian stimulation; Ovarian hyperstimulation syndrome (OHSS).