Controlled ovarian hyperstimulation (COH) has contributed to the success of assisted reproduction techniques (ART), in vitro fertilization (IVF) and embryo transfer (ET). The efficacy of these techniques seems to depend on a personalized protocol of COH for each patient. The response to ovarian stimulation protocols is not always as expected or the same in many patients.

A poor responder was first described in 1983 as one who, on a standard stimulation regimen (150 IU human menopausal gonadotrophin), had a peak estradiol concentration of <300 pg/mL and who had poor follicle production leading to a smaller number of eggs retrieved and, therefore, a smaller number of embryos transferred.

Recently, the European Society of Human Reproduction and Embryology (ESHRE) working group reported that in order to define a poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for poor ovarian response (POR); (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). 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. By definition, the term POR refers to the ovarian response and, therefore, one stimulated cycle is considered essential for the diagnosis of POR. 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 for ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as an ‘expected poor responder’ (³).

The occurrence of poor response to ovarian stimulation is not infrequent; the prevalence of poor responders varies in the literature between 9 and 24% (²). This range is wide as it depends on the definition of a poor responder that individual IVF centers employ. Data from the ASRM¹/SART² registry showed that 14.1% of initial cycles were cancelled; at least 50% of these were poor responders (⁴).

There is no universal definition for “poor responders”, although numerous criteria have been proposed by researchers to describe this situation (⁵). The number of developed follicles and the number of oocytes retrieved after a standard stimulation protocol are the most important criteria. The proposed quantity varies among authors and ranges from less than three to less than five dominant follicles on the day of hCG administration noted on ultrasound and/or less than three to less than five retrieved oocytes (⁶–¹¹).

Another correlative criterion that has been proposed is the peak E2 level. A peak E2 level of <300 to <500 pg/mL or a level <100 pg/mL has been reported as crucial for defining poor response (⁸, ⁹, ¹²). Others have proposed the total gonadotropin dose used and/or the daily stimulation dose along with the duration of stimulation to be a defining criterion for poor responders. Shaker et al. reported an increased number of hMG or FSH ampoules used (>44), while Toth et al. considered a daily dose >300 IU/day to be the criterion for a poor response to the used gonadotropin (¹³, ¹⁴).

An (day 3) elevated basal serum FSH (≥7 to ≥15 mIU/mL) is an additional criterion (¹⁵–¹⁸). In addition, there are other criteria such as calculation of FSH/LH ratio as proposed by Yang et al. and measurement of basal E2 levels proposed by Manzi et al. and Ibrahim et al. A client's advanced age (≥40 years) is sometimes considered the cause (¹⁹–²²). Some authors use a combination of the aforesaid parameters (¹²). However, a poor ovarian response can be confirmed only after having had a failed standard ovarian stimulation, and at least one cancelled IVF cycle (²³).

Loutradis et al. considered a poor responder as a patient who fulfilled the following criteria: three or fewer recruited follicles or collected oocytes and a serum estradiol concentration lower than 300 pg/mL (if one follicle) or 500 pg/mL (if 2 or 3 follicles) at the time of hCG administration (⁹). Sallam et al. defined poor responders as patients undergoing treatment with ICSI, IVF, or TESE/ ICSI from whom fewer than 5, 6, or 8 oocytes are retrieved, respectively (²⁴). Kailasam et al. considered poor responders to be those patients who fail to develop more than three preovulatory follicles after using more than 300 IU of daily FSH or when it requires more than 3000 IU FSH to recruit less than four follicles (²⁵). Yarali et al. considered poor responders as those patients who have a day 3 FSH >10 mIU/mL, day 3 E >60 pg/mL, or bilateral antral follicle count <6 or a history of poor ovarian response defined as cycle cancellation, peak E ≤500 pg/mL, or retrieval of less than four oocytes upon using the luteal long GnRH-a protocol (²⁶).

The different definitions proposed for poor ovarian response can be roughly categorized into two subgroups; those in whom poor ovarian response has been observed in previous stimulated cycles (retro-spective definition), and those in whom poor ovarian response is expected based on ovarian reserve tests or other factors such as age, ovarian surgery, etc (prospective definition) (²).

Some researchers classify poor responders into two subgroups; the first, includes young (age ≤37 years) and slim-bodied (weight ≤70 kg) patients who develop less than five follicles following 9 days of ovarian stimulation with 225 IU/day and do not reach oocyte retrieval, or those who require >600 IU of gonadotropin per retrieved oocyte if they reach that stage. The second, includes patients who are >37 years old and weight >70 kg and their cycles have been cancelled due to the production of less than five follicles following 9 days of ovarian stimulation with 300 IU/day of gonadotropins (²⁷).

Another classification categorizes patients into the ones with a low response to previous IVF in the presence of normal basal FSH levels, young patients with non-fluctuating high FSH levels and older patients with an abnormal endocrinological profile. However, none of these classifications has any clinical significance, because no significant differences in ovarian response have been observed among different groups (²⁸).

The etiology of poor response to ovarian stimulation is unknown. Despite being highly correlated with maternal age, the condition is also common in younger women in whom low ovarian reserve represents the most frequent etiological factor (²⁹–³¹). In addition, low ovarian reserve may be associated with advanced endometriosis, prior ovarian surgery, pelvic adhesions, increased body mass index, or smoking (³²–³⁷). However, this condition might also occur, unexpectedly, in young women who are non-smoker and have apparently normal ovarian reserves (³⁸).

Studies have shown that poor ovarian response is the first sign of ovarian aging (early ovarian failure or early menopause) (³⁸–⁴⁰). This is clinically displayed by a shortened follicular phase which limits the time available to recruit an adequate number of follicles. Suggested mechanisms for poor ovarian response include: decreased number of FSH receptors in granulosa cells, defective signal transduction after FSH receptor binding, an inappropriate local vascular network for the distribution of gonadotropins, the presence of autoantibodies against granulosa cells, an excess of vascular growth factor receptor (VEGFR-1), abnormality in IGF-I and IGF-II levels, and diminished circulating gonadotropin surge-attenuating factor (GnSAF) bioactivity (⁴¹–⁴⁷).

Ovarian response to follicle-stimulating hormone (FSH) action differs considerably among women. Recently, new insights have been gained in the investigation of variability in the gene that encodes FSH receptor (FSHR) gene or genes of the estrogen pathway. Several polymorphisms of the FSHR gene have been discovered, but Ser680Asn and Thr307Ala are the two most studied. The Ser680Asn polymorphism of the FSHR gene has been found to influence the ovarian response to FSH stimulation in women undergoing in vitro fertilization (IVF), and in women with the genotype Ser/Ser, in whom the FSHR appears to be more resistant to FSH action. The clinical implications of this finding are highly important; the ultimate goal is to apply genetic markers as routine diagnostic tests before ovarian stimulation to predict ovarian response, determine the required FSH dose, and avoid the possible complications related to FSH stimulation (⁴⁸).

Despite being difficult, it is of extreme importance to predict who will be a poor responder, because stimulation protocols should be individualized according to the conditions of each case. However, several tests have been proposed to predict ovarian reserve, which can give an idea about the ovarian response. These include static and dynamic tests:

Different sonographic tests have also been proposed as predictors of ovarian response. These include:

1. Decreased ovarian volume (OVVOL): It is hardly suitable as a routine test for ovarian reserve assessment (⁵²–⁷¹). A meta-analysis showed that ovarian volume measurement with a cut-off value of 3 cm³, had the specificity for the prediction of cycle cancellation and non-pregnancy of 92% and 93%, respectively (⁷²).
2. Decreased antral follicle count (AFC): The accuracy of the AFC for predicting poor response in regularly cycling women is adequate at low threshold levels (⁷³, ⁷⁴). It will not be suitable as a diagnostic test, but it may be used as a screening one directing further diagnostic steps in the first IVF attempt (⁵², ⁷⁵). Another meta-analysis showed that women having AFCs less than four were more likely to have cancelled cycles and less likely to get pregnant than women having AFCs of four or more (⁷²).
3. Decreased ovarian stromal blood flow: The clinical value of doppler studies for ovarian stromal blood flow has been unclear (⁷², ⁷⁶).