Since one inception, development in the field of reproductive medicine is constantly growing. Successful oocyte cryopreservation was one such breakthrough that expanded the scope of assisted reproductive technology (ART).
Initially, oocyte cryopreservation was limited to use in the cancer patients undergoing gonadotoxic treatments to preserve their fertility. However, during the recent years, oocyte freezing has also been widely applied for non-medical reasons, wherein women are offered the opportunity to freeze their own oocytes, in anticipation of age-related fertility decline for use later. Thus, the scope of IVF is expanding from medical to social practice. The use of ART in normal healthy women further emphasizes the need for simpler and more patient-friendly ovarian stimulation protocols.
Ovarian Stimulation Protocols
Ovarian stimulation protocols are aimed at achieving multi-follicular growth without causing premature growth in luteinizing hormone (LH). Exogenous gonadotropins, administered during folliculogenesis, maintain levels of follicle-stimulating hormone (FSH) above the threshold, prolonging the duration of the opening of FSH window. This prevents the natural process of follicle dominance, and leads to a simultaneous increase in the cohort of follicles.
The supraphysiological increase in serum estradiol levels associated with multi-follicular development may cause a premature surge in LH, and thus cause premature luteinisation in the mature follicles or atresia in the immature ones, voiding IVF cycles. The use of GnRH analogues (e.g., the GnRH agonist) in ovarian stimulation protocols to prevent pituitary LH surge significantly improved the outcomes of IVF.
Due to unpredictability of LH rise during ovarian stimulation, hCG was uniformly used as the final oocyte maturation trigger in IVF cycles. hCG binds to the LH/hCG receptor and, in the presence of pre-ovulatory follicles, causes granulosa cell luteinisation, followed by progesterone production, resumption of meiosis, and oocytes maturation followed by follicle puncture after 36-40 h.
However, hCG differs from a physiological spike, since it does not cause an increase in FSH. In addition, it has a longer serum half-life compared to LH. Consequently, its administration is associated with a stable luteotropic effect with multiple corpora lutea development and supraphysiological steroid levels, which increases the risk of the ovarian hyperstimulation syndrome (OHSS) developing.
OHSS is a serious, potentially fatal complication of IVF. It is characterized by bilateral expansion of the ovaries with an extravascular fluid shift, secondary to increased vascular permeability. hCG is known to play an important role in its development, and therefore the latest trends in ART practice shift to the use of the GnRH agonist as the final maturation trigger.
Adnexal torsion is a well-recognized emergency of hyper-stimulated ovary, more common in the first and second trimesters of pregnancy. A rapid diagnosis is the key to saving the ovaries. More than often, it may be delayed due to the similarity to OHSS symptoms, such as abdominal distension and abdominal tenderness. The simple untwisting (de-torsion) of the adnexa for the restoration of blood supply is associated with a good prognosis if the accident is raised earlier.
Color Doppler can help in early diagnosis too with the detection of a decrease in diastolic blood flow. Reduction of OHSS and a high degree of suspicion in women who develop ovarian hyper-response are needed to reduce the incidence of adnexal accidents, and for conservative treatment of adnexal torsion.
The issue associated with the use of the GnRH agonist as ovulation trigger is the suboptimal response observed in a subgroup of patients who do not respond with an adequate endogenous LH release. This can be expected from women with hypothalamic-hypogonadic amenorrhea. However, women with regular menstrual cycles, but having a reduced hypothalamic-pituitary axis, have a greater risk of suboptimal response. These patients are characterized by the presence of rarely low LH and FSH at the beginning of the menstrual cycle, requiring more exogenous gonadotropins and having a longer duration of stimulation.
Ideal Timing of Triggering Final Oocyte Maturation
In regular IVF patients, the ideal timing of triggering is quite important in a GnRH antagonist protocol cycle, since the delay in the triggering after three follicles of >17 mm diameter is associated with a decrease in pregnancy rates. This is due to an increase in the level of progesterone, which affects the endometrium that leads to a decrease in the implantation rates. The prolongation of the follicular phase apparently does not have any negative effect on the quality of the oocyte and cleavage rate in the embryo. Thus, delay in triggering during segmentation IVF cycles can be beneficial by improving the number of mature oocytes retrieved.
Breast cancer, uterine cancer or ovarian cancer have a common multifactorial etiology with hormonal factors that play a significant role in the development of most of these cancers. Thus, it is necessary to ensure the safety of short duration of supraphysiological hormone levels during IVF taking into account potential cancer risks development.
Effects on Ovarian Reserve and Future Fertility
ART stimulation is an elective procedure for apparently healthy women, and it is therefore vital that the stimulation be simplified by eliminating risks as much as possible. Despite advances in IVF practice, OHSS remains the most iatrogenic complication after stimulation and, therefore, is a cause of concern for most clinicians. Efforts are being made to improve outcomes and reduce risks, and one such modification is the introduction of the GnRH antagonist protocols during the stimulation cycle.
Their use is associated with simpler stimulation cycles and reduced side effects with a similar result in terms of live birth rates compared to the GnRH agonist. They also allow the use of the GnRH agonist to trigger the final oocyte maturation, which significantly reduces the risk of OHSS developing. However, OHSS is not completely eliminated with their use. In addition, there is a small subset of patients, who develop an inadequate response to the GnRH agonist trigger. Therefore, an important question remains, “Is the GnRH agonist trigger really the Holy Grail?”