The standard definition of poor ovarian reserve (or, poor ovarian responder) remains uncertain, and consequently the proposed protocols adopted to manage poor responders are very difficult to compare. The Bologna criteria represent the first attempt to build an international consensus in the definition of poor ovarian reserve.
According to the Bologna criteria, at least two of the following features are required to define a poor ovarian reserve:
Advanced maternal age (≥40 years) or any other poor ovarian reserve risk factor (genetic or acquired conditions, pelvic infections, ovarian endometriomas, and patients who have undergone ovarian surgery for ovarian cyst, chemotherapy, shortening of the menstrual cycle),
A previous cycle with poor ovarian reserve (≤3 oocytes with a conventional stimulation protocol),
A low ovarian reserve test in terms of Anti-Müllerian hormone (AMH) (<0.5-1.1 ng/ml) (<3.6-7.8 pmol/l) and antral follicle count (AFC) (<5-7 follicles).
However, two cycles with three oocytes or less after maximal stimulation are enough to classify a patient as a poor responder even in the absence of the other two criteria.
Recently, the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) group suggested a more detailed novel stratification of women with low ovarian response to stimulation. Four groups of “low prognosis patients” in ART were identified on the basis of age and the expected aneuploidy rate, biomarkers of ovarian reserve (AFC and AMH), and ovarian response in previous stimulation cycle. The new classification introduces a new concept: the ability to achieve an adequate number of oocytes in order to give the patient the higher chance to obtain at least one euploid embryo.
The chance of pregnancy after IVF is highly dependent upon the number and quality of retrieved oocytes, as both factors determine the number of good-quality embryos.
Recently, the cumulative live birth rate (CLBR) has been suggested as indicator of quality and success in IVF. It incorporates the totality of live birth episodes following successive treatments of fresh as well as thawed frozen embryo transfer. CLBR per oocyte retrieval is a more meaningful indicator for both clinicians’ and patients’ perspective: the outcome of the whole IVF-ICSI cycle (including cryopreservation) allows better evaluations between different centers with different strategies for freezing and extended culture of embryos. Moreover, CLBR would be more appropriate for making economic and political decisions.
In the recent literature, some authors have tried to determine the ideal number of oocytes to optimize the performance of live birth in fresh embryos transfer cycles. Generally, a number of 10-15 oocytes has been considered adequate in order to give the patients the maximum chance of pregnancy after a fresh embryo transfer cycle.
Nevertheless, the prediction of a live birth cannot be based only on the oocyte yield. Indeed, the aneuploidy chromosomal constitution is strongly related to the woman’s age, ranging from 25% to 30% in women younger than 35 to over 90% in women older than 42, and represents a critical element affecting embryo reproductive competence. Thus, women with the same number of retrieved oocytes might have opposite clinical outcomes according to the age-dependent blastocyst aneuploidy rate. Though, implantation rate of a euploid blastocyst is independent from the woman’s age.
In this context, the number of oocytes retrieved after COS, greatly affects the clinical outcome. Thus, the optimization of the strategies of COS based on the ovarian reserve of each single patient is essential in order to maximize the age-related chances to obtain at least one euploid blastocyst.
Due to the lack of definition, it is difficult to determine the prevalence of poor ovarian reserve condition. Its reported frequency in IVF cycles varies from 9% to 30% in different studies.
The management of patients with low AFC and/or AMH is still a debated issue in reproductive medicine. Certainly IVF-ICSI compared with IUI showed superior pregnancy rates in the setting of patients with poor ovarian response after COS.
The obvious and most used approach for women with poor ovarian reserve is to increase the daily dose of gonadotropin. Actually, higher gonadotropin dosages can increase the number of transferable embryos and, therefore, cumulative pregnancy chances. The National Institute for Health and Care Excellence (NICE) guideline on fertility recommends not to use a dosage of FSH of more than 450 IU/day for COS in poor responder patients. A recent open-label, multicenter randomized controlled trial (RCT) recommended using a standard dose of 150 IU/day in women scheduled for IVF/ICSI with a predicted poor response.
Among the various protocols and strategies toward optimization of management for poor responders, there is no concrete evidence on the advantage of any stimulation protocol over another. Examples of recommended protocols for poor responder patients include:
Low-dose (or “mild”) protocol,
Low-dose clomiphene/gonadotropin protocol,
Augmented natural cycle protocol,
Delayed start antagonist protocol,
Flare-up agonist protocol,
Micro-dose flare GnRH agonist protocol.
Mild COS protocols using low doses of gonadotropins have been implemented in clinical practice, demonstrating significant advantages, including cost-effectiveness and patient-friendly regimens. This protocol optimizes the balance between outcomes and risks of treatment, although the expected number of retrieved oocytes is low, usually ranging from two to seven.
Mild stimulation is based on the following known evidences:
Because of low-dose stimulation, only the healthier follicles with more competent egg(s) are encouraged to develop,
The physiologic hormonal follicular milieu might be altered when the follicles are exposed to a high dose of gonadotropins,
It was demonstrated that follicular AMH significantly higher in natural cycles in comparison with the ovarian stimulation,
RCT found that the number of euploid embryos with conventional IVF was no higher than that with mild stimulation IVF,
Supraphysiologic levels of serum E2 could affect implantation.
The low-dose gonadotropin protocol involves initiating 150 IU of gonadotropins daily on day 2 for 9 days. GnRH antagonist is administered when the lead follicle reaches ≥12 mm in diameter, and the ovulation trigger is suggested when the lead follicle is 16-17 mm.
Despite convincing scientific evidence, moderate ovarian stimulation was lower than traditional regimens when applied to poor responders who underwent IVF/ICSI in terms of retrieved oocytes.
Low-dose clomiphene/gonadotropin protocols may be a good option for patients who have previously responded to clomiphene, but did not have a successful cycle. This protocol is characterized by the administration of clomiphene citrate 100 mg/day for 5 days beginning on day 2.
In augmented natural cycles, patients are monitored for estradiol production >20 pg/ml and/or the presence of 3-4 mm-sized basal antral follicles. Once these conditions are satisfied, ovarian stimulation is initiated with a low-dose combination of HP-hMG and rFSH (e.g., 75 IU/day of each) and continued for approximately 6 days. When the lead follicle reaches ≥12 mm, GnRH antagonist is added. Ovulation is triggered with hCG 10,000 IU or leuprolide.
The delayed-onset antagonist protocol is based on the observation that endogenous FSH can stimulate larger follicles in the previous luteal phase and subsequently lead to a divergence in the size of the cohort of developing follicles. According to this protocol, a GnRH antagonist is administered from day 2 and continued for 7 days, then ovarian stimulation is started with gonadotropins, and GnRH antagonist is added again if the ultrasound monitoring showed at least one follicle with diameter ≥ 14 mm and continued until the trigger day.
The flare-up protocols are based on the 24-h-long surge in endogenous FSH and LH released when administering GnRH agonists in the early follicular phase. GnRH agonists are initiated in the follicular phase of a stimulation cycle before commencing gonadotropin injections.
The very low-dose, “micro-dose” GnRH agonist flare protocol represents an attempt to decrease the suppressive effects of GnRH agonists during a flare protocol. Daily GnRH agonists are administered at the dose of 20-50 μg twice and continued until the day of hCG administration. After 2 days (on the fourth day of menstruation), the patients received rFSH 300 IU/day.
Synchronizing Early Follicle Development
Ovarian follicles mature over a period of approximately 2-4 months. COS can only support the cohort of follicle responsive to the stimulation without generating de novo follicles. The synchronization of earlier follicle wave with oral estrogens, contraceptive pill, or progestins, prior to traditional COS, has been suggested as a possible strategy to increase the number of responsive follicles, particularly for poor responders.
In some patients, a decrease in ovarian reserve was associated with androgen deficiency. In these women, taking androgens through testosterone or dehydroepiandrosterone (DHEA) can help stimulate early follicular development and improve ovarian functional reserve.
DHEA is produced in the zona reticularis of the adrenal cortex and by ovarian theca cells.
It promotes follicular development and granulosa cell proliferation and can also enhance the level of follicular insulin-like growth factor-1 (IGF-1), which promotes folliculogenesis by enhancing the effect of gonadotropin and reducing follicular arrest.
After the beginning of androgen supplementation, the follicles require 6-8 weeks to achieve synchronization and become mature enough to respond to COS. Among androgenic supplements, DHEA is the preferred method over testosterone as it is metabolized by organs as needed, whereas testosterone overflows the body with a fixed level. However, it is important to note that conclusive clinical evidence of the influence of DHEA or testosterone is limited and the use of androgen supplementation is still considered experimental. In addition, patients offering these supplements should be informed of potential side effects such as acne, oily skin, deepening of the voice, hirsutism, and hair loss.
Growth hormone (GH) co-treatment improved the ovarian response to COS in poor responders. This conclusion was supported by studies demonstrating that GH, either directly or indirectly via insulin-like growth factor 1 (IGF-1), regulates oocyte maturation by increasing the sensitivity of the ovaries to gonadotropins and promoting early follicle development. Clinical studies demonstrated contrasting effects of GH on oocyte and embryo-related outcomes. Moreover, studies are few in number and included small sample size.