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Introduction
The luteal phase begins after ovulation, when the corpus luteum secretes progesterone which is the crucial hormone for preparing the endometrium for embryo’s implantation. High levels of progesterone reduce GnRH from hypothalamus, thereby they inhibit the luteinizing hormone (LH) peak induced by high levels of estradiol, so analogs of GnRH are not necessary, and this method could be cost-effective. Luteal phase stimulation (LPS) represents the methods of manipulation of the luteal phase, used in assisted reproductive technologies (ART), such as in vitro fertilization (IVF), oocyte donation and fertility treatments. LPS has the objective to improve the number of oocytes for poor responder patients using ovarian stimulation after ovulation, on a new follicular wave.
Poor response to ovarian stimulation is one of the biggest challenges of assisted reproduction technology and is reported in 10.3% of cases(1). The European Society for Human Reproduction and Embryology (ESHRE) defined poor ovarian response depending of the presence of at least two features from: 1) history of previous poor ovarian response; 2) an abnormal ovarian reserve test; and 3) advanced maternal age or any others risk factors. Initially, LPS was used for women with cancer, but recently it has been proven an efficient method for obtaining competent oocytes.
Materials and method
This review aims to synthesize information and studies about the results of luteal phase stimulation. We used keywords such as “luteal phase”, “ovarian stimulation” and “follicular phase”, and we have identified over 20 articles describing luteal phase stimulation and its benefits.
Luteal phase stimulation protocol
The typical protocol of luteal phase stimulation starts 2-7 days before oocyte retrieval during the same menstrual cycle. A second ovarian stimulation is started with low-dose gonadotropins (75-150 IU/day) and clomiphene citrate (25-100 mg/day) or letrozole (2.5-5 mg/day) when the lead follicle is below 13 mm(2). Blood hormone levels and ultrasound are used after five days of stimulation. When the lead follicle becomes above 18 mm, human chorionic gonadotropins (5000 IU) or GnRH agonist (0.1 mg) is used for oocyte maturation(3). Embryo freezing is usually recommended because clomiphene citrate could cause a thin endometrial lining(4,5). Studies revealed that a later frozen-thawed embryo transfer (FET) has similar treatment results compared to a fresh embryo transfer(6).
Luteal phase stimulation versus follicular phase stimulation
The luteal phase stimulation was initially used in fertility preservation for oncology patients or couples with time constraints to prevent delay, and is used now on a large group of patients. Luteal phase stimulation is based on a “wave-like” model of foliculogenesis, where multiple follicular recruitment occurs during the same menstrual cycle, despite the old theory based on single antral follicular recruitment(7) (Figure 1). It can be used isolated or after a follicular phase stimulation in the same menstrual cycle (DuoStim) to increase the number of oocytes and embryos in women with poor ovarian reserve and to improve the chances of a pregnancy. Poor ovarian response after ovarian stimulation can be a challenge for women and doctors, especially for women with reduced ovarian reserve, who require and could benefit of individualized treatment thanks to the development of multiple protocols to improve the outcome of poor responders.
Studies have shown that patients who are poor responders to treatment and have a poor prognosis tend to abandon the procedure and have lower pregnancy rates(3). In a retrospective cohort study including 118 women undergoing DuoStim, luteal phase stimulation rescued approximately 70% of the cycles with no embryos after the follicular phase. This strategy is useful for patients who are prone to giving up after the first failed attempt(8). The conclusion of the study was that using the luteal phase stimulation increases the chances of a pregnancy compared to follicular stimulation alone. High levels of estradiol and GnRH antagonist administration at the beginning of luteal phase stimulation could recruit a cohort of antral follicles and could have as result a higher number of oocytes(9,10). In addition to that, exposure to progesterone and high levels of follicular estradiol could lead to a better response by sensitizing FSH receptors in the granulosa cells of the new follicles(11).
The first review on luteal phase stimulation in 2016 showed a longer duration of this procedure and a higher use of gonadotrophin consumption compared to follicular phase stimulation, but the differences between peak estradiol levels or the number of oocytes retrieved were not clinically significant(12). Those results were confirmed by two others systematic reviews. The higher number of studies was in Sönmezer and colleagues’ review – 11 studies, including 1764 patients with cancer before gonadotoxic treatment(13). The standardized mean difference according to Sönmezer and colleagues’ review was 0.35 days(13), a standardized mean difference (SMD) of 0.3 day longer stimulation period calculated by Alexander and colleagues(14), while Boots and coworkers calculated an SMD of 1.1 days in the stimulation period(15). As a result of extending the stimulation phase, the need for gonadotropins and the cost of the treatment increase. The stimulation duration can be reduced by using letrozole which is known for increasing the intraovarian androgen levels and follicular sensitivity of FSH receptors, but the clinical benefits in poor responders need to be more explored(2).
The number of oocytes retrieved is an important indicator for the success of ovarian stimulation. Some studies report a higher number of mature oocytes and fertilization rates during luteal phase stimulation(16), while others did not find a significant difference, but it has the advantage of being an effective stimulation method for fertility preservation in oncological patients or poor responders, because they do not have sufficient time to undergo the standard stimulation procedure in the early follicular phase(13,14).
In a retrospective study including 446 patients selected based on the Bologna criteria for poor ovarian responders, 154 patients underwent luteal phase stimulation, 231 patients underwent follicular phase stimulation and 61 were submitted to double ovarian stimulation. This study showed a longer stimulation, the use of higher doses of HMG and higher MII oocyte rates for LPS (p<0.001), with no differences in clinical pregnancy rate and live birth rate, therefore this protocol could be worthwhile for women with poor ovarian response(17).
In the future, luteal phase stimulation should be analyzed from a financial perspective to decide whether the higher cost of the medication and the longer duration of the treatment are clinically justified by the increased number of retrieved oocytes.
Conclusions
Luteal phase stimulation has emerged as a valuable strategy in assisted reproductive technologies and has an important role in improving reproductive outcomes. Due to its controversies regarding protocols, indications and results, future research such as large cohort studies or randomized clinical trials are necessary to optimize the management of luteal phase stimulation and focus on refining protocols, long-term outcomes, and balancing the cost-effectiveness of LPS for various patient groups. The higher costs and extended treatment duration need further evaluation to determine its clinical and financial justification. Ultimately, luteal phase stimulation represents a promising approach in ART, offering hope to women with challenging fertility conditions.
Autor corespondent: Amina Al Battah E-mail: amina.albattah@yahoo.ro
CONFLICT OF INTEREST: none declared.
FINANCIAL SUPPORT: none declared.
This work is permanently accessible online free of charge and published under the CC-BY.
