Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment

Abstract

Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication "ovarian hyperstimulation syndrome" (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.

Figure 1.

Site of action of inductors of oocyte maturation during IVF treatment. hCG and rLH act directly at LH receptors in the ovary. GnRHas act at GnRH receptors in the pituitary gland to stimulate the secretion of endogenous LH and FSH. Kisspeptin acts at the hypothalamus to stimulate kisspeptin receptors on GnRH neurons and the release of an endogenous pool of GnRH.

Figure 2.

Final oocyte maturation. The midcycle gonadotropin surge causes a decrease in intraoocyte cAMP. The oocyte is removed from meiotic arrest and undergoes a series of coordinated changes affecting both the nucleus and cytoplasm. During nuclear maturation, the haploid metaphase I oocyte extrudes half of its genetic material in a polar body and transitions toward a haploid metaphase II gamete. To achieve this, the germinal vesicle breaks down (GVBD) and chromosomes align along the spindle before separation of genetic material occurs and the polar body is extruded. During oocyte maturation, cytoplasmic and nuclear maturation both occur in related but independent processes. Cytoplasmic maturation prepares the oocyte to meet the metabolic demands of fertilization and embryo growth through changes in organelles. Prior to germinal vesicle breakdown, mitochondria surround the germinal vesicle (GV), and the Golgi apparatus remains intact. By the end of oocyte maturation, mitochondria are associated with smooth endoplasmic reticulum, the Golgi body has been fragmented, and the polar body is extruded. Adapted from Mao et al. 2014 (69).

Figure 3.

Serum profiles of inductors of oocyte maturation. hCG has a long duration of action with peak serum levels at ~18 hours following administration. GnRHa induces a peak serum LH at ~4 hours following administration (26). Kisspeptin-54 (KP54) also induces a rise in serum LH at 4 to 6 hours following administration but to a lower amplitude than GnRHa (16–18). The profile of rLH is less certain and may peak higher and sooner (15). Serum LH at 24 hours following rLH was 20 IU/L following 5000 IU, 60 IU/L following 15,000 IU, and 90 IU/L following 30,000 IU of rLH (15).