Concomitant Administration of FSH With HCG Improves Oocyte Maturation and Quality Double -Blinded Randomized Trial

We observe during (In vitro fertilization) IVF, there are deviations in oocyte morphology
and maturity within an individual cohort and that oocyte degeneration, and failed
fertilization exist. Regardless, even if fertilization occurs, a large proportion of
embryos fail to progress through the pre-implantation stages of development. In order for
fertilization and embryo development to occur, the oocyte must mature or develop
"competence". FSH may be a fundamental component to the final stages of oocyte maturation.
Evidence suggests that with exogenous ovarian stimulation not all follicles achieve equal
vascularity, and hence they are exposed to different amounts of FSH. We hypothesize FSH is
required, within each follicle, at the time of ovulation trigger for oocyte maturation and
prevention of atresia.

The ovarian stimulation prior to IVF attempts to mimic, and yet augment, normal physiology.
The stimulation begins with gonadotropins to rescue antral follicles and stimulate growth.
Subsequently hCG, which shares 80% homology with LH, is administered to facilitate
maturation of the oocyte. However, the ovulatory phase in the normal menstrual cycle
encompasses a concomitant LH and FSH prior to ovulation (see figure).

Maturation is a process whereby the oocyte undergoes changes in preparation for
fertilization and embryo development. This entails both nuclear and cytoplasmic
transformation. Nuclear maturation pertains to the resumption of meiosis to metaphase II. It
is well established that the LH surge is intimately involved in this process. Although the
mechanism is not completely known, there are several steps. It is thought germinal vesicle
breakdown requires a burst of calcium oscillations. During folliculogenesis, nuclear
maturation of the oocyte is normally under tonic inhibition by a putative factor,
oocyte-meiotic inhibitor (OMI). Some evidence suggests, prior to ovulation, LH inhibits the
release of OMI from either the granulosa or theca cells. OMI likely acts as a paracrine
factor and increases cAMP production in the granulosa cells (cumulus), which then acts as a
messenger to the oocyte to maintain minimal calcium levels. In addition, LH is thought to
decrease the gap junction communication between the cumulus and granulosa. Other evidence
points to a putative signal that is synthesized by the granulosa cells, called follicular
fluid meiotic activating substance. Both elements involved in nuclear maturation involve LH
activity. The induction of LH receptors is via FSH. Under physiologic conditions there is a
co-existent FSH surge with the LH surge. LH usually rises about 10 fold from baseline and
FSH rises roughly 4 fold from baseline. It is possible that the surge of FSH ensures the
required amount of LH receptors to complete nuclear maturation.

Cytoplasmic maturation is more difficult to identify. The process entails the synthesis of
new proteins and post-translational modifications of existing proteins to allow for calcium
activated pathways facilitating fertilization and embryo development. It is known that there
is extensive cross-talk between the oocyte and granulosa cells. Few morphogenetic
determinants of cytoplasmic maturation have been identified, but this remains an area of
intense investigation From a clinical perspective, it is possible that FSH is required in
this process of nuclear and/or cytoplasmic maturation, and that a minimal threshold of FSH
may be required to maintain the gap junctions for completion of oocyte development. This
evidence may be further supported by in-vitro maturation studies that show that FSH has a
stimulatory effect on cytoplasmic and nuclear maturation.

Oocyte degeneration (atresia) is observed in 5-15% of the oocytes at the time of, or after,
intracytoplasmic sperm injection. The etiology of degeneration has not been determined. The
fate of the oocyte is likely determined prior to oocyte retrieval. At the time of retrieval,
the apoptotic process in oocytes destined to undergo atresia has probably already been
initiated. Under physiologic conditions, the granulosa cells die prior to the oocyte. There
is evidence that atretic follicles have a high androgen to estrogen ratio. It is likely an
indication of the deteriorating health of the granulosa cells. It is known that FSH has
potent anti-apoptotic activity (inhibition of atresia), and the mechanism may be indirect
via estradiol production. There is evidence that FSH primed follicles can grow with LH
administration, in spite of low FSH levels. However, observations have shown that this
process favors large follicles and that in the smaller follicles a critical ratio of FSH
activity to LH activity is needed for survival. In support of this theory, others have
suggested there is a narrow therapeutic window for LH. If E2 production is not adequate, LH
may be detrimental to the follicle. The LH surge might hasten this process, in those
follicles with a relative lack of vascularity (and/or lack of maturity), by a massive
development of androgens and a relative lack of aromatase activity.