Ovarian stimulation modalities in poor responders

In a group of IVF/ICSI cycles, despite the appropriate ovarian stimulation, the number of oocytes collected is below the expected value. This condition is defined as poor ovarian response (POR) to stimulation. POR brings the risk of cycle cancellation with an estimated rate of 20%. Infertility experts are trying to improve cycle outcomes of POR cases with multiple modifications. This review article will present the latest modifications on the management of POR. The studies performed for improving cycle outcome in POR cases were evaluated and their notable results were presented. The first intervention among infertility specialists is to make a standard definition for POR. The BOLOGNA criteria and the subsequent POSEIDON group definitions are the latest updates in POR management. GnRH antagonists, estradiol priming, double stimulation, letrozole administration, DHEA, and herbal therapy supplementations are the recent modifications done to improve oocyte retrieval and subsequent embryo transfer for POR cases. This review article presents the encouraging methods applied for POR cases to improve cycle outcome.


Recently the POSEIDON (Patient-Oriented Strategies Encompassing
Individualized Oocyte Number) group reported a new approach for the definition and management of patients suffering from POR [13]. Their final aim was to determine the ideal stimulation for obtaining a euploid embryo for a successful transfer. This new approach classified the low responder women into four groups according to age, ovarian reserve, and stimulation response with the aim of determining the prognosis.
With this concept, low responders were defined as having poor prognosis. Age is the main predictor for IVF/ ICSI cycle outcome because the older age brings DOR with decreased oocyte quality. Researchers observed lower pregnancy rates in older POR patients compared to that in younger POR patients [4].

Treatment modalities
Increasing gonadotropin doses in stimulation protocols is the first step used by all clinicians for poor responders. It was reported that there was no difference among 300-450 and 600 units of gonadotropins for IVF/ICSI cycle outcomes in poor responders [14]. It was accepted that long pituitary suppression with a GnRH agonist is detrimental for the oocyte pools of DOR cases. Due to this condition, microdose flare-up and short-flare protocols were developed for women suffering from POR [15].
Pituitary downregulation with GnRH antagonists is the second step to improve the cycle outcome in POR [16][17][18], but studies indicate that there is not a significant improvement in cycle outcomes with GnRH antagonists compared to agonist cycles [19][20][21].
The addition of growth hormones, transdermal testosterone, L-arginine, and pyridostigmine are experimental modifications that have been shown to not improve cycle outcomes in POR [22][23][24][25].

Stimulation modifications
Luteal estradiol (LE) priming is one of the other experimental modifications applied for POR to improve hypothalamic-pituitary-ovarian axis function [26]. Generally, LE priming is initiated on the 20th day of the previous cycle by daily administration of 4 mg of oral estradiol supplement or 0.1 mg of estradiol patch every other day, and is continued until day 2 of the following menstruation [27]. Supplementation of 4 mg of oral estradiol during the luteal phase combined with a short GnRH agonist protocol did not improve pregnancy rates compared to a long agonist protocol primed with oral contraceptive pills [28]. Metaanalysis showed that LE primed cycles had lower cancellation risk with improved clinical pregnancy rates compared to non-LE primed cycles despite no improvement on collected mature oocyte numbers and number of embryos per cycle [27].
Midfollicular recombinant luteinizing hormone (rLH) or urinary human chorionic gonadotrophin (HCG) supplementation is another experimental modification applied to improve retrieved oocytes in POR cases during antagonist cycles [29].

Double stimulation/Shanghai protocol
Researchers modify ovarian stimulation with a GnRH antagonist in different steps for POR. The first step is to combine gonadotropins with antiestrogenic agents such as clomiphene or letrozole. The second step is a GnRH agonist trigger combined with ibuprofen for final maturation before oocyte retrieval. For follicles with a diameter greater than 17 mm, oocytes are retrieved and embryo freezing is performed. The third step is luteal gonadotropin stimulation with an antiestrogenic agent with GnRH antagonist for follicles smaller than 13 mm in diameter. The fourth step is agonist trigger with ibuprofen again. The fifth step is endometrial preparation for frozenthawed embryo transfer. This stimulation type gives the opportunity of more oocyte retrieval without improvement in live birth rate in POR [30,31].

Aromatase inhibitors
Letrozole is an aromatase inhibitor first applied for breast cancer for the decrement of estrogen levels. Decrement of estrogen levels results in increment of androgen levels. This microenvironment induces endogenous gonadotropin secretion and, according to this result, letrozole is being used for ovulation induction especially in POR [32]. Researchers reported improved cycle outcomes in gonadotropin dose decrement with letrozole combination compared to high-dose gonadotropin administration for POR [33].

Supplemental therapies
Dehydroepiandrosterone (DHEA) is a steroid prohormone originating from ovarian theca cells and the adrenal cortex [34]. DHEA is an androgenic supplement given to improve the number of oocytes collected in POR [35]. While some researchers reported improvement with DHEA supplementation on clinical pregnancy rates, live birth rate, endometrial thickness, and retrieved oocyte number [36], other researchers did not report improvement in cycle outcomes with DHEA supplementation [37].
The Kuntai capsule is one of the recent herbal therapy components of Chinese medicine applied for premature menopause. A Kuntai capsule consists of six traditional Chinese herbs, including Radix Rehmanniae Preparata, Rhizoma Coptidis, Radix Paeoniae Alba, Donkey Hide Gelatin, Radix Scutellariae, and Poria. In an experimental premature menopause model, researchers showed improvement in number of antral follicles with Kuntai capsule treatment [38]. Lian and Jing observed increment of retrieved oocyte numbers and high-quality embryos in POR cases after Kuntai capsule treatment [39].

Conclusion
Despite the multiple modifications of stimulation protocols and dietary intake presented here, POR remains a hard problem for infertility experts to solve.