© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_2424. Prediction of Poor Responders and Current Concepts in Management
(1)
IVF and Reproductive Medicine, Rotunda – The Center for Human Reproduction, 36 Turner Road, B Wing, #101, 1st floor, Bandra West, Mumbai, 400 050, Maharashtra, India
Abstract
Ovarian stimulation is one of the most promising advances in the field of assisted reproduction that has successfully improved pregnancy rates by inducing multifollicular development. The response to ovarian stimulation is a significant predictor of a successful clinical outcome. The ability to predict a poor response to ovarian stimulation equips the clinician with the knowledge to plan and tailor the stimulation protocol to achieve the desired result cost-effectively while avoiding disappointing consequences like cycle cancelation or a failed assisted reproductive technique (ART) cycle. Several markers, such as age, basal (day 3) follicle-stimulating hormone (FSH), inhibin B levels, anti-Müllerian hormone (AMH) levels, and baseline antral follicle counts (AFCs), have been proposed as predictors of an ovarian response; however, no single marker is documented to accurately predict the ovarian response. Several treatment protocols have been formulated to achieve an optimal outcome in poor responders. However, the search for the ideal protocol still eludes clinicians owing to the difficulty in making meaningful comparisons in treatment strategies that stem from wide variations in the definition of a “poor ovarian response” and need for a thorough understanding of the etiologies of a poor response.
Keywords
Poor ovarian responsePoor responderManagementOvarian reservePredictors of poor ovarian response24.1 Introduction: Poor Ovarian Response (POR)
Poor ovarian response (POR) to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes [1]. There have been several definitions and several criteria to define a poor responder to ovarian stimulation. Small numbers of follicles developed or oocytes retrieved, and low estradiol (E2) levels after the use of a standard stimulation protocols have been considered as the most dominant criteria for poor ovarian response [2]. Significantly higher FSH, age, human chorionic gonadotropin (hCG) day luteinizing hormone (LH) level, cycle cancelation rate, total gonadotropin dose but significantly lower AFC, AMH, hCG day E2 level, and number of MII oocytes have been reported in the poor responder group [3].
A poor ovarian response to stimulation creates a significant problem and challenge for the health-care provider, and identification of the etiologies of poor ovarian response constitutes a formidable challenge [4, 5]. Cycle cancelation rates ranging from 9 to 24 % of all stimulated cycles have been reported in poor responders [4]. Low peak estradiol concentrations (<500 ng/L), few dominant follicles on the day of hCG administration (<5 to <2), and therefore, few retrieved mature oocytes (≤4 to ≤6) with resultant lower pregnancy rates have often been reported following stimulation with standard in vitro fertilization (IVF) therapy [6]. Lamazou et al. [7] reported significantly higher cancelation rates (37.8 % vs. 13.3 %, P < 0.004) and lower pregnancy (22.2 % vs. 35.0 %, P < 0.05) and live birth rates (11.1 % vs. 26.1 %, P < 0.05, respectively) following controlled ovarian stimulation (COS) in poor prognosis patients (age >38 years, AFC ≤ 3, and day 3 serum AMH and FSH levels less than 1 ng/mL and more than 10 IU/mL, respectively) compared to good prognosis women [7].
Though several ovarian reserve markers have been used to predict a poor response, there is no ideal predictive test as the poor responder is revealed only during ovulation induction [8].
The “Bologna criteria,” presented by the ESHRE working group, is the first realistic attempt by the scientific community to standardize the definition of POR in a simple and reproducible manner that. According to the “Bologna criteria,” for a patient to be defined as a poor responder to IVF, at least two of the following three features must be present: advanced maternal age (≥40 years) or any other risk factor for POR (i.e., genetic or acquired conditions, possibly linked to reduced amount of resting follicles), (ii) a previous POR (≤3 oocytes with a conventional stimulation protocol), and (iii) an abnormal ovarian reserve test (ORT) (i.e., AFC <5–7 or AMH <0.5–1.1 ng/mL). One stimulated cycle is considered essential for the diagnosis of POR [1] as a poor ovarian response following maximal stimulation in the first cycle of IVF without any prior testing, provides some information on OR status, and seems to be the preferable strategy [9]. Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT [1]. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as “expected poor responder” [1].
According to the authors, this definition of POR, if uniformly adapted as the “minimal” criteria needed to select patients for future clinical trials, could enable more homogenous populations to be tested for new protocols, reduce bias caused by spurious POR definitions, and also enable comparison of results and reliable conclusions to be drawn. However, the aim of the criteria is not to exclude patients with poor prognosis from IVF programs [1].
According to Polyzos and Devroey [10], although the Bologna criteria aim to define a consistent group of patients, their applicability needs to be tested through clinical trials [10]. Meanwhile, meta-analyses of the currently available trials should be strongly discouraged because they may lead to the adoption of interventions of ambiguous value owing to large variations in the definitions of poor responders within and across trials, adoption of the criteria in less than 50 % of the trials, and consistently different threshold values [10].
24.2 Predictors of Poor Ovarian Response
The success rates of any assisted reproductive technique (ART) depend on an optimum protocol for ovarian stimulation that must be decided upon by a proper assessment of the ovarian reserve before commencing ovarian stimulation [3]. Over the past two decades, a number of so-called ovarian reserve tests (ORTs), designed to determine the oocyte reserve, have been evaluated for their ability to predict the ovarian response to stimulation and the IVF outcome and have become part of the routine diagnostic procedure for infertility patients undergoing ART [9]. Some of these ORTs include the early follicular-phase FSH, estradiol, inhibin B, AMH levels, AFC, ovarian volume (OVVOL) and ovarian blood flow, clomiphene citrate challenge test (CCCT), exogenous FSH ORT (EFORT), and gonadotropin agonist stimulation test (GAST). Ovarian reserve markers can potentially provide an indirect measure of the cohort of recruitable antral follicles present in the FSH window at the beginning of each menstrual cycle [1]. However, evidence regarding the clinical application of these markers in predicting the outcome of stimulation in poor responders is conflicting.
In this chapter, we aim to assess the clinical accuracy of each of these markers in predicting a poor response and current treatment protocols for poor responders.
24.2.1 Age
Age is one of the most significant markers of the response to ovarian stimulation, an advanced maternal age being proportional to a poor response. Leridon [11] documented that under natural conditions, 75 % of women starting to try to conceive at age 30 years will have a conception ending in a live birth within 1 year, 66 % at age 35 years, and 44 % at age 40 years [11]. The age of patients undergoing assisted reproduction with IVF/GIFT has been inversely related to the pregnancy rate and directly related to the miscarriage rate. In women of 40 years or over, the overall pregnancy and live birth rates were significantly higher, and the miscarriage rate was significantly lower in the group receiving donated oocytes compared to the group using their own oocytes suggesting that the age-related decline in fecundity is associated with the age of the oocytes rather than the age of the uterus [12]. Studies on the ovarian sensitivity to gonadotropin stimulation suggest that the biological age is not equivocal to chronological age and is of greater importance in predicting the outcomes of assisted reproduction [13]. Serum and urinary markers of ovarian reserve, follicular-phase inhibin B, FSH, and AMH levels, have physiologically been associated with ovarian aging and can be used to predict low oocyte yield and treatment failure in infertile women undergoing IVF [14].
Female age and the number of oocytes retrieved have been shown to modulate the chances for pregnancy in current and subsequent cycles, the application which will allow the identification of couples with a reasonable prognosis and balanced decision-making on the management of poor responders. A systematic review of ten studies indicated that older poor responders had a lower range of pregnancy rates compared with younger poor responders (1.5–12.7 vs. 13.0–35 %, respectively) [15]. Though higher gonadotropin doses (225 IU rFSH) have proven more efficacious than 150 IU in younger women despite the higher total dose requirement, they failed to give a higher oocyte yield in older women, suggesting that a higher gonadotropin dose does not compensate for the age-related decline in the number of follicles available for stimulation [16]. Significantly fewer follicles (p < 0.05) have been reported in women >42 years, while those >39 years had significantly fewer oocytes (p < 0.01) compared to those <35 years. Live births declined with increasing age, when age was assessed as a continuous variable (p = 0.023) [17]. Age has been demonstrated as the only independent predictor of pregnancy in IVF as compared to hormonal and ultrasound indices of ovarian reserve [18]. Though it is a significant predictor of non-conception, it has a low predictive accuracy [19].
24.2.2 Number of Oocytes Received
Patients have been categorized into three groups according to the number of oocytes retrieved: 0–3 oocytes (poor responders), 4–15 oocytes (normo-responders), and >16 oocytes (hyper-responders). AMH and AFC were the best markers for the prediction of total oocyte count, independent of age, FSH, and LH levels and without any significant effects on pregnancy rates [3]. A systematic review of four studies on poor responders undergoing IVF showed that pregnancy prospects are reduced when fewer oocytes are retrieved (0–7 % with 1 oocyte vs. 11.5–18.6 % with 4 oocytes), while five studies concerning pregnancy rates in subsequent cycles suggested a more favorable outcome in unexpected poor responders and if ≥2 oocytes were retrieved [15].
24.2.3 Endocrine Markers
24.2.3.1 Anti-Müllerian Hormone (AMH)
The anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells of ovarian follicles during the early stages of follicle development [20]. Plasma levels of AMH reflect the continuous noncyclic growth of small follicles, thereby mirroring the size of the resting primordial follicle pool and, thus, acting as a useful marker of ovarian reserve [21]. The clinical applications of the measurement of circulating AMH are mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. It has also been proposed as a surrogate for AFC in the diagnosis of polycystic ovary syndrome (PCOS) and to indicate iatrogenic damage to the ovarian follicle reserve [22]. Women with low AMH levels have a high probability of treatment cancelation and failure to proceed to embryo transfer and a low chance of achieving a viable pregnancy [17].
Advantages of the use of AMH levels as a marker ovarian reserve are as follows: (i) they are among the best endocrine markers for assessing the age-related decline of the ovarian pool in healthy women; (ii) they are a reliable predictor of ovarian reserve, especially when combined with age with a sensitivity and specificity of 72–97 % and 41–93 %, respectively, positive predictive values between 30 and 79 % but higher negative predictive values, cycle stability, and operator independency; (iii) they are predictive of both poor and hyper ovarian responses prior to an in vitro fertilization (IVF) cycle, in a variety of ovarian pathological conditions, including PCOS, premature ovarian failure (POF) [21], and endometriosis [23]; (v) they can predict the number of oocytes retrieved [10]; (vi) they may help to individualize dosing for ovarian stimulation, thereby improving the efficiency and safety of IVF [20]; and (vii) they exhibit no intracycle fluctuations and are negligibly affected by hormonal changes, such as those that occur during pregnancy or under oral contraceptives. Patients with AMH levels ≤0.5 and ≤1 ng/mL have a poor response to ovarian stimulation, a significantly higher total dosage of gonadotropins used and day 3 FSH levels, and lower maximum E2 levels and clinical pregnancy rates suggesting that AMH could be an acceptable screening test in prediction of ovarian reserve [24]. Moreover, day 5 follicular-phase AMH concentrations have been reported as better predictors of the ovarian response following FSH stimulation under pituitary desensitization compared to basal (day 3) AMH levels, but the predictive capacity of day 5 AMH was not better than that provided by day 5 estradiol levels [25].
However, AMH levels have limited value in the prediction of ongoing pregnancies following IVF as a number of poor responders and older patients (>40 years) have been reported to achieve pregnancy in spite of very low AMH levels, with a better prognosis for young poor responders [21, 26]. An AMH cutoff value ≤1 ng/ml may predict poor ovarian reserve, poor ovarian response to stimulation [24], and whether patients could have an embryo transfer but had no power to predict the achievement of pregnancy [26]. Though some authors have suggested an influence of AMH in predicting live birth after assisted conception independently of age and its use in counseling couples before undergoing fertility treatment, its predictive accuracy is poor [27].
Despite its limitations, AMH, however, is the best current available measure of ovarian reserve for different clinical conditions [20]. The widespread clinical application of AMH levels as an ORT emphasizes the need for an international standard for AMH and improved assay validity, so that results using future assays can be reliably compared [20–22]. Prospective well-powered studies comparing different infertility treatment strategies, based on initial AMH levels using appropriate end points (live birth and cost-effectiveness), and that could represent a true step forward in rendering counseling and infertility care more patient tailored are urgently awaited [20].
24.2.3.2 FSH Levels
Significantly higher FSH levels but significantly lower AFC, AMH, hCG day E2 level, and number of MII oocytes have been reported in poor responders [3]. Studies have reported significantly higher cancelation rates (37.8 % vs. 13.3 %, P < 0.004), lower pregnancy (22.2 % vs. 35.0 %, P < 0.05), and live birth rates (11.1 % vs. 26.1 %, P < 0.05, respectively) following controlled ovarian stimulation (COS) in poor prognosis patients (>38 years ) with day 3 FSH levels >10 IU/mL, AFC ≤ 3, and day 3 serum AMH levels <1 ng/mL compared to good prognosis women [6]. Increased levels of day 3 FSH and decreased levels of inhibin B can be used to assess ovarian reserve [8].
Basal and clomiphene citrate (CC)-induced FSH and inhibin B levels have also been correlated with mean ovarian volume (MOV) and mean antral follicle counts (MFC). Erdem et al. [17] reported significantly higher basal FSH (p < 0.05), lower basal and induced inhibin B levels (p < 0.05), and lower MOV and MFC (p < 0.01) following IVF/ICSI in poor responders compared to normal responders [18]. Maman et al. [28], however, failed to show an association between patients with a history of high basal FSH (15.0 ± 3.6 IU/l) or those with low basal FSH (9.0 ± 3.0 IU/l) and a reduced ovarian reserve with the IVF outcome and further suggested that ovarian stimulation need not be delayed until FSH declines [28].
24.2.3.3 Inhibin Levels
Early follicular-phase inhibin B concentrations, obtained following ovarian stimulation under pituitary suppression for assisted reproductive treatment, have been reported to be highly predictive of the ovarian response [29]. Significantly lower day 3 and day 10 inhibin B levels (p < 0.001) have been demonstrated in women with diminished ovarian reserve. Peñarrubia et al. [29] demonstrated significantly lower day 5 inhibin A and inhibin B levels following gonadotropin therapy in patients with a canceled cycle compared to the control group. They demonstrated a significant association between day 5 inhibin B levels and the cancelation rate (with a predictive value of ovarian response of 91.03 %) that was independent of and stronger than the effects of any other hormone variable investigated. However, day 5 inhibin B was not a better predictor of pregnancy than the other hormone variables studied on this day [29].
24.2.4 Clomiphene Citrate Challenge Test (CCCT)
An abnormal CCC test has been identified as a better predictor of diminished ovarian reserve than basal (day 3) FSH concentrations or other hormonal and sonographic tests and the only independent significant factor in predicting ovarian response to stimulation in IVF cycles [16, 17] that provides valuable information for both patients as to their chances of achieving a pregnancy and also for the medical team deciding on options for stimulation protocols [16]. Yong et al. [16] reported significantly lower estradiol values on hCG day, number of retrieved and metaphase II oocytes, and rate of transfer cycles in women with an abnormal CCC test, while cycle cancelation rates (36.8 % vs. 19.8 %; P < 0.05) were significantly higher, and pregnancy rates per embryo transfer (13.3 vs. 21.5 %, respectively) were lower in women with a poor response and an abnormal CCC test than in those with a normal test. The sensitivity, specificity, and positive and negative predictive values of the CCC test for cycle cancelation were found to be 43 %, 76 %, 37 %, and 80 %, respectively, while those for non-conception were 93 %, 31 %, 84 %, and 15.6 %, respectively. In patients with an elevated day 10 or 11 FSH level, which could not be detected using only basal FSH screening (43.8 %), the cancelation rate (48 vs. 19.8 %, P < 0.01), the rate of transfer cycles (48 % vs. 72.3 %, P < 0.05), and the mean number of retrieved oocytes (4.9 ± 2.5 vs. 6.4 ± 3.1, P < 0.01) were all significantly different from the normal test group [16]. The results of Yong et al. [16] were in sharp contrast to a previous study [30] comparing basal FSH and the full CCCT demonstrating that the CCCT showed a poor specificity in predicting poor response and nonpregnancy and has hardly any additional value [30].
24.2.5 Ultrasound Indices of Ovarian Reserve
Transvaginal ultrasonography is an easy-to-perform and noninvasive method that provides essential predictive information on ovarian responsiveness [19]. Ultrasound measurements of ovarian volume, baseline AFC, and Doppler measurements of ovarian stromal blood flow now make it possible to predict low response to IVF therapy. Low response can be expected if the ovary has a volume <3 cm3, the mean ovarian diameter in the two longest planes is <20 mm, or with AFC ≤3 in each ovary [5]. Significantly lower ultrasound indices of ovarian reserve, such as mean ovarian volume (MOV) and mean follicle count (MFC) (p < 0.001) have been demonstrated in women with diminished ovarian reserve. The lower MOV and MFC values correlated with significantly higher basal FSH (p < 0.05) and lower basal and induced inhibin B levels (p < 0.05) in poor responders undergoing IVF/ICSI compared to normal responders. Ovarian volume alone was reported to be better than age and basal hormones in predicting poor ovarian response [18] Data on ovarian stromal blood flow are still unclear, but an ovarian peak systolic velocity of <10 cm/s is associated with low response. If low response is anticipated based on baseline ultrasound scan, effective stimulation protocols that can reduce cancelation rates and improve pregnancy rates should be used for IVF [5].
24.2.5.1 Antral Follicle Counts (AFCs)
Estimation of the antral follicle numbers with a diameter of 2–5 mm by transvaginal ultrasonography on the first or second day of menstruation, or just before the administration of exogenous gonadotropins, enables the prediction of the ovarian response and pregnancy results of patients undergoing ARTs. Antral follicle counts have been significantly correlated with patient age, day 3 serum FSH level, use of gonadotropins, serum estradiol concentration, number of oocytes retrieved, and, later, number of oocytes or embryos transferred. Significantly higher cycle cancelation rates (68.8 % vs. 5.3 % and 0, respectively) and no pregnancies (0, 23.7 %, and 36.8 %, respectively) have been reported in patients with a low AFC (≤3) compared with patients with AFCs = 4–10 or ≥11 [31]. AFC evaluation has been considered as a first choice test in the assessment of ovarian reserve prior to IVF, more accurate than basal FSH [32].
A comparative study between the three-dimensional ultrasound parameters (AFC, ovarian volume, and ovarian vascularity indices) with AMH and other conventional endocrine markers for the prediction of poor response following controlled ovarian hyperstimulation (COH) during assisted reproduction demonstrated that AFC and AMH were the most significant predictors of poor response to ovarian stimulation. The sensitivity and specificity for prediction of poor ovarian response were 93 % and 88 % for AFC and 100 % and 73 % for AMH (at optimum cutoff values of ≤10 and ≤0.99 ng/mL, respectively). While AMH and AFC had a similar predictive accuracy either alone or in combination, they were not shown to be predictive of non-conception, which is dependent on the woman’s age [19].
24.2.6 Combined Predictors
A newly devised ovarian response prediction index (ORPI) [ORPI = AMH (ng/ml) × AFC (2–9 mm)/patient age] exhibited an excellent ability to predict a low ovarian response and a good ability to predict the retrieval of greater than or equal to 4 MII oocytes, an excessive ovarian response, and the occurrence of pregnancy in infertile women. The ORPI might be used to improve the cost-benefit ratio of ovarian stimulation regimens by guiding the selection of medications and by modulating the doses and regimens according to the actual needs of the patients [33]. Predictors of ovarian reserve, such as the woman’s age, AMH, and FSH, also serve to predict the FSH dosage nomogram for ovarian stimulation, which clinicians could apply during their daily clinical practice. They could predict a starting FSH dose <225 IU in 55.1 and 25.9 % of women younger and older than 35 years, respectively [34].
24.3 Limitations of Ovarian Reserve Markers
However, certain drawbacks of the use of ovarian reserve markers to predict ovarian response to stimulation are as follows: (i) they seem to be affected by common ovarian toxicants, such as smoking, which advance the age at menopause; (ii) the clinical use of these markers is limited by the variety of assays, lack of definitive thresholds, and their intercycle variability in older women [14]; (iii) they do not necessarily reflect the extent and quality of the primordial follicle pool or accurately predict ovarian response to hormonal stimulation [1]; and (iv) most ORTs evaluated have only modest-to-poor predictive properties for the occurrence of poor ovarian response owing to a modest test accuracy and a poor pregnancy prediction accuracy and are, therefore, far from suitable for relevant clinical use [9]. Whether the a priori identification of actual poor responders in the first IVF cycle has any prognostic value for their chances of conception in the course of a series of IVF cycles remains to be established. High thresholds used to prevent couples from wrongly being refused IVF result in a very small minority of IVF-indicated cases (approximately 3 %), identified as having unfavorable prospects in an IVF treatment cycle [9]. Hence, results should be conveyed with caution when highly discrepant with age, in the obese, and in women with irregular menstrual cycles. Further research is needed to assess their predictive value for determining fertility in the general population [14].
24.4 Management of Poor Responders
The management of poor ovarian response remains one of the most significant challenges posed to clinicians practicing assisted conception [5, 8], the most important problems in evaluating the available evidence being the lack of a sufficiently homogenous population despite attempts at a consensus on the definition of a poor responder and a poorly understood etiology [35, 36]. As a result, much controversy exists on how to manage a poor responder in assisted conception and every new suggestion has proved contentious [36]. Very few large prospective randomized trials have compared different protocols [6].
Ovarian stimulation is a significant step in the management of poor responders. Numerous interventions, including high doses of gonadotropins, recombinant FSH, flare-up GnRH agonist protocols, luteal initiation GnRH agonist “stop” protocols, GnRH antagonist protocols, adjuvant therapy with growth hormone (GH) or GH-releasing factors, use of corticosteroids, and pretreatment with combined oral contraceptives and natural cycle IVF, have been proposed to improve the ovarian response to stimulation in poor responders. However, few have been shown to be beneficial for all such patients [35]. Controversies exist regarding the selection of gonadotropin preparation, choice of adjuvant therapy with GnRH analogs, and use of oral contraceptive pills, and results in low responders have remained suboptimal both in terms of ovarian response and oocyte/embryo quality in spite of a variety of stimulation regimens used [5].
The evidence regarding the clinical efficacy of these protocols in improving the ovarian response in poor responders is detailed below.
24.4.1 Types of Gonadotropins
The few available relevant studies do not indicate that recombinant FSH (rFSH) improves the outcome of ovarian stimulation in poor responders [8]. Recombinant FSH has no advantage over urinary human menopausal gonadotropin (hMG) on ovarian performance or the outcome of IVF-ET in poor responders’ IVF cycles [37]. Comparable results have been observed in poor responders (>37 years) when rFSH was used alone or in combination with hMG, except for the quality and the number of embryos transferred, which were better in the rFSH + hMG group [38].
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