POR patients undergoing IVF/intracytoplasmic sperm injection (ICSI) usually suffer from a limited number of oocytes, poor embryo quality, and a low pregnancy rate per cycle. Considerable attention has been paid to developing strategies to improve oocyte quality and quantity. Clinicians were the first to perform modifications to the ovarian stimulation protocol. Multiple stimulation protocols were reported, including GnRH antagonist protocol, luteal phase ovarian stimulation, mild/minimal stimulation, progestin-primed ovarian stimulation, and modified natural cycles [19-22]. Various Gn and/or starting doses have also been administered [23, 24]. Although there is insufficient evidence to support their administration, supplements such as growth hormone, dehydroepiandrosterone, coenzyme Q10, and multi-nutrients have all been used in an attempt to improve oocyte quality [25-29]. To date, the most effective protocol for POR patients remains controversial, and the management of these patients is still a challenge for clinicians.
An increasing number of researchers believe that an efficient, patient-friendly regimen that can improve ovarian response and decrease the costs involved is needed for POR patients. Oral ovulation induction medications such as CC fulfill the concept of patient-friendly IVF. CC is a selective estrogen receptor modulator that binds competitively to estrogen receptors. By the negative feedback of estrogen, secretion of gonadotropin hormones increases, and follicular growth is induced. The present study aimed to compare ovarian response and clinical outcomes in POR patients treated by a CC priming protocol vs. a flexible GnRH antagonist protocol.
Previous studies suggested that FORT could act as an efficient quantitative and qualitative marker and be used to evaluate the ovarian sensitivity to gonadotropins and predict IVF/ICSI outcomes [30]. In the present study, patients in the study group presented a higher FORT, although the difference was statistically insignificant. It might be partially due to the limited sample size of this study. Furthermore, patients in the study group had fewer antral follicles and a higher basal FSH level, suggesting a lower ovarian reserve. FOI also reflects the ovarian sensitivity to Gn [17, 31]. The present study demonstrated a much higher FOI in the study group, even though they had a lower AFC than the control group. We also evaluated ovarian sensitivity to stimulation by Gn dosage per follicle, which showed promising results in our unpublished data. The results indicated that the Gn dosage required to obtain a pre-ovulatory follicle was considerably lower in the study group. Growing evidence suggests that increased Gn stimulation cannot improve clinical outcomes, but it increases the treatment costs for poor ovarian responders [32]. Therefore, the lower Gn dosage per pre-ovulatory follicle in the study group suggested a better ovarian sensitivity to Gn than in the control group. We conclude that patients stimulated by the CC priming antagonist protocol achieved a better ovarian response or sensitivity.
Such an improved ovarian response could have several causes. First, through a negative feedback mechanism. CC may have occupied the hypothalamic estrogen receptors for a longer time than estrogen [33], increasing GnRH release, and thus the endogenous gonadotropin levels in the patients, including FSH and LH. FSH could stimulate follicular development and synthesis of estrogen. As a result, the administration of CC improved follicular growth and reduced the exogenous FSH dose needed. Second, CC increased the release of endogenous LH through the feedback increase of GnRH. POR patients, in whom LH activity is usually insufficient, may have benefited from the additional LH. Many researchers commented that adding LH to hypo-responders could increase the number of mature oocytes and improve implantation rate while significantly reducing the total FSH dosage administered [4, 34-37]. Moreover, CC has a relatively long half-life of 5 to 7 days, going through liver metabolization and stool excretion. This suggests that residual CC continues to work for some time after terminating its administration. In this case, CC increased the endogenous FSH and LH content for a long time, improving the ovarian response to the stimulation process.
CC is a selective estrogen modulator that can negatively impact endometrial development, resulting in a thinner endometrium. Previous studies reported that a negative effect of CC on the endometrium was behind the inferior fertility outcomes [38, 39]. In the present study, endometrial thickness in the study group on the ovulation triggering day was significantly lower than in the control group. Recent studies suggested that under CC treatment, an endometrial thickness cut-off value of ≥8 mm at midcycle was associated with a better outcome [40]. It is well known that time-to-pregnancy should be considered when making decisions related to infertility treatment, especially for POR patients whose ovarian reserve suffers from a considerable decline. Therefore, we propose that when sufficient endometrial thickness is observed on ovulation triggering day in the study group, the negative effect of CC during ovarian stimulation will be avoided, and a good pregnancy outcome could be achieved by fresh embryo transfer, resulting in a shorter time-to-pregnancy.
The study group had a significantly lower total Gn dosage and shorted Gn administration time than the control group. Such results imply lower costs and more convenient and patient-friendly treatment when using the CC priming protocol. These aspects are important, considering that POR patients often suffer from economic and time stresses due to the need for repeated ovarian stimulation.
There were no differences in the rates of cumulative clinical pregnancy, cumulative ongoing pregnancy, or live birth per cycle between the two groups. The cumulative ongoing pregnancy rate was comparable between treatment groups even after adjusting for possible confounders. Age, BMI, Gn dosage per follicle, and FOI were all directly associated with reproductive outcomes (Table 4). Considering the limited size of the present study and limited number of available embryos for transfer per cycle in POR patients, the comparison of reproductive outcomes between the two protocols needs further research.
POR patients often suffer from repeated, unsuccessful ovarian stimulation cycles. We performed a sensitivity analysis of 55 patients stimulated by both protocols in separate cycles as a comparative self-control study. Most stimulation parameters and laboratory outcomes were in line with the data on the entire POR patient group. FORT, FOI, and the number of available embryos were higher in the study group, although the differences were statistically insignificant. This insignificant outcome could, at least partially, be because of the limited sample size available for the comparison. Although there were no statistically significant differences, reproductive outcomes in the self-control study appeared to have improved following CC priming stimulation.
Guidance on how to most optimally manage POR patients is still lacking till now. Many clinicians may be keener on developing new ovarian stimulation protocols, but the old things, including drugs, may still have new uses, such as CC priming protocol in the present study for POR patients. CC has been used for ovarian stimulation since decades. However, the application of CC in this study still achieved very inspiring results. For clinicians, the results could inspire them raising concerns regarding the use of this convenient and patient-friendly protocol during ovarian stimulation in POR patients to increase ovarian sensitivity. For POR patients, it is helpful to enhance the treatment confidence of them, better cooperate with doctors and shorten time-to-pregnancy.
In conclusion, the current study suggests that the CC priming protocol offers a convenient and patient-friendly way to reduce the costs and increase ovarian sensitivity to stimulation in POR patients. The study has some limitations arising from its retrospective nature and small sample size. Secondly, the patients are from a single center with similar ethnicities. Thirdly, the Bologna criteria is used for definition of POR in the present study. Further large scale multicenter randomized clinical trials are warranted to verify the utility of this CC priming antagonist protocol and should be based on the POSEIDON criteria.