Understanding Ovarian Hypo-Response to Exogenous Gonadotropin in Ovarian Stimulation and Its New Proposed Marker-The Follicle-To-Oocyte (FOI) Index

Abstract

Hypo-responsiveness to controlled ovarian stimulation is an undervalued topic in reproductive medicine. This phenomenon manifests as a low follicles output rate (FORT) with a discrepancy between the relatively low number of pre-ovulatory follicles which develop following ovarian stimulation as compared to the number of antral follicles available at the start of stimulation. The pathophysiology mechanisms explaining the ovarian resistance to gonadotropin stimulation are not fully understood, but the fact that both hypo-responders and normal responders share similar phenotypic characteristics suggests a genotype-based mechanism. Indeed, existing evidence supports the association between specific gonadotropin and their receptor polymorphisms and ovarian hypo-response. Apart from genotypic trait, environmental contaminants and oxidative stress might also be involved in the hypo-response pathogenesis. The ratio between the number of oocytes collected at the ovum pick up and the number of antral follicles at the beginning of OS [Follicle to oocyte index (FOI)] is proposed as a novel parameter to assess the hypo-response. Compared with traditional ovarian reserve markers, FOI might reflect most optimally the dynamic nature of follicular growth in response to exogenous gonadotropin. In this review, we contextualize the role of FOI as a parameter to identify this condition, discuss the underlying mechanisms potentially implicated in the pathogenesis of hypo-response, and appraise possible the treatment strategies to overcome hyper-responsiveness to gonadotropin stimulation.

Keywords: POSEIDON criteria; assisted reproductive technology; follicle output rate; follicle to oocyte index; hypo-response; in vitro fertilization; ovarian stimulation; ovulation induction.

Figure 1

Ovarian sensitivity using FORT [adapted from (12)].

Figure 2

Ovarian sensitivity using the Follicle-to-Oocyte Index (FOI). Case number 1 depicts a patient with normal FOI, in whom the number of oocytes retrieved was consistent with the AFC at the start of stimulation. Case number 2 illustrates a patient with suboptimal number of oocytes retrieved (between 4 and 9), but with a normal Follicle-to-Oocyte index (FOI >50%). Case number 3 shows a patient with both hypo-response and suboptimal oocyte number. This patient had only 7 oocytes collected despite an AFC of 15 at the beginning of stimulation (FOI ≤ 50%). Case number 4 depicts a patient with both hypo-response and poor response.

Figure 3

Possible causes of low Follicle-to-Oocyte Indeces.

Figure 4

Number of oocytes collected form patients with low (Group A) vs. high intrafollicular benzene levels [adapted from (36)]. *stand for statistically significant.