Paradigm of Diminished Ovarian Reserve (DOR)
Nowadays, women are postponing their pregnancies due to various reasons. Mostly, the fertility decline is noted in women starting from late 20s to early 30s. This is mostly related to decrease in ovarian reserve. Poor ovarian response criteria have been based on quantity decline, while the age criteria that reflects quality, is included when the female age is ≥40 years.
In general, fertility is defined as the capacity to produce a child. The indicators of monthly fecundability (or the probability of pregnancy per month) are highest during the first 3 months of trying, and about 80% of couples reach pregnancy within the first 6 months after trying. At the same time, infertility is defined as the inability to achieve a successful pregnancy after 12 or more months of regular unprotected intercourse or sperm exposure. Monthly fecundability rates decline by close to 50% between the ages of 35 and 39 years as compared to the same rates noted between the ages of 19 and 26 years.
The natural conception rates decline from early to mid-30s and steeper decline is expected after 40 years of age. Not surprisingly, IVF treatment outcome clearly shows that pregnancy and live birth rates decline with advancing female age. Female age is actually the most important factor determining live birth in IVF treatment. A decrease in the birth rate in IVF treatment begins in the early ’30s. Then this decline becomes more pronounced after the mid-30s. Steeper decline is seen at and after age of 40s.
The fertility trends suggest that the age of first birth in women is increasing around the globe. In Ukraine, while birth rate decline is observed in teenage girls and in women between 20 and 29 and 30–34 years of age, birth rate increase is noted within the age groups of>35–39 years old. Therefore, females are postponing their pregnancies until later years of the reproductive age.
The most important reflection of delayed childbearing in females is fertility decline as expected by advancing age. This decrease in fertility is associated with diminished ovarian reserve and diminished oocyte/embryo quality with aging. Diminished ovarian reserve can also be observed at any age when women suffer from infertility. Although female fertility decreases with aging, the pace of reproductive decline can be different in each woman.
Paradigm of Diminished Ovarian Reserve (DOR)
Diminished ovarian reserve is one of the recent challenges that clinicians and patients alike face in infertility treatment. Since the controlled ovarian stimulations became a norm in assisted reproductive technology (ART) cycles, it has been realized that some women just do not respond well to ovarian stimulation, while others suffer from ovarian hyperstimulation syndrome (OHSS).
Generally, diminished ovarian reserve is defined as “reduced fecundity related to diminish ovarian function; includes high follicle-stimulating hormone (FSH) or high estradiol measured in the early follicular phase or during a clomiphene citrate challenge test; reduced ovarian volume related to congenital, medical, surgical or other causes; or advanced maternal age (>40)”.
In average, diminished ovarian reserve diagnosis is much more frequently made, while the proportion of women at or ≥35 years of age undergoing ART has increased by close to 2%. This discrepancy may be due to the more widespread use of ovarian reserve assessment before ART. In addition, more couples may be visiting fertility centers for infertility associated with diminished ovarian reserve, and diminished ovarian reserve may be becoming a more frequent indication for ART.
Poor Ovarian Response (POR)
The European Society of Human Reproduction and Embryology (ESHRE) came up with a consensus definition for poor ovarian response (POR) for in vitro fertilization (IVF). Many studies on POR used differing criteria and reported variable conclusions whether any particular IVF stimulation protocol results in better IVF outcomes. The rationale was if there is a unified definition for POR, future research could be performed on such patient populations to come up with a unified global IVF treatment protocol for such patients. Shortly after its implementation, the criticisms followed since once again, one unified paradigm did not fit all.
Although the majority of the POR may be due to diminished ovarian reserve, some POR cases just cannot be explained with Bologna criteria. In addition, POR definition heavily relies on conventional IVF stimulation protocols, which mostly focus on retrieving as much oocytes as possible after a treatment cycle, since in such protocols it is believed that the number of oocytes retrieved is the most important treatment outcome parameter to predict clinical pregnancy and live birth. The Bologna criteria actually indirectly supports high-dose IVF stimulation protocols as the legitimate treatment approaches for such patients by mentioning about poorly defined “maximal stimulation.”
Various endocrine and ultrasound markers and even some dynamic tests have been utilized to predict POR. Accordingly, POR has been defined by various criteria until the Bologna criteria for POR was recommended through consensus so that such patients could be defined in a unified manner so that the treatments can also be unified in such patients.
However, recently these criteria have been the focus of criticism since some patients showing poor response simply does not meet the Bologna criteria. This is in spite of the complaints that there was no accepted definition of POR, and therefore it will always be difficult to compare the results in published studies. In addition, POR may be due to systemic inflammatory diseases, nutritional disorders, advanced-stage cancers without presence of the diminished ovarian reserve per the age, anti-Müllerian hormone (AMH), and antral follicle count (AFC) criteria.
Then Bologna consensus may not meet the needs. The criteria used for all such definitions rely on the female age equal or above 40 years, the serum markers like AMH and ultrasound markers like AFC, the number of oocytes collected in prior treatment cycles, highest estradiol levels achieved, and history of gonadotoxic treatments or ovarian surgery. Still the threshold levels for AFC and AMH vary in the latest Bologna criteria, while measurement of these two parameters is open to subjective and methodological biases, respectively.
The AFC assessment of ≥2 mm antral follicles by transvaginal ultrasound as a marker of ovarian aging was first reported in 1996. It was noted that antral follicle counts decreased by aging. This measurement later evaluated to be one of the best predictors of ovarian response. Over the years, there were debates about the upper limit of antral follicle size or diameters measured by ultrasound. Diameters between 2 mm and 10 mm were included in some guidelines like Rotterdam criteria defining polycystic ovary morphology. However, to better assess the controlled ovarian stimulation outcome, different upper thresholds less than 10 mm was proposed. One study reported that the number of antral follicles 2–6 mm decreased by age, but those between 7 mm and 10 mm stayed constant. It was demonstrated that AMH expression is strongly observed in secondary, pre-antral, and small antral follicles up to the diameter of 4–6 mm.
The AMH expression then decreases with further follicle growth and disappears in follicles measuring>8 mm in diameters. As expected, AMH expression is not observed in primordial follicles, and it is only weakly expressed in some primary follicles. It was reported that the antral follicles measuring between 2 mm and 6 mm could be the best predictor for the number of mature oocytes retrieved at oocyte retrieval and was strongly associated with serum AMH levels. Therefore, it is reasonable to focus on antral follicles between 2 mm and 6 mm while performing AFC.
Poor Ovarian Response Criteria per Prognostic Factors
There is another recent classification of patients with expected POR. It was proposed a classification of POR patients into four groups per age. The presentation of unexpected POR, if previously stimulated, predicted poor prognosis, AFC, and AMH levels. The main reason for this new stratification effort for POR was due to the fact that Bologna criteria are disregarding female age effects on pregnancy outcomes regardless of the number of oocytes retrieved. It was intended to change the paradigm from POR to low prognosis concept. Therefore, clinically more relevant criteria were suggested. Two new groups were brought for defining low-prognosis patients according to how they responded to a conventional ovarian stimulation for IVF.
First one is “suboptimal response” defined as the retrieval of four to nine oocytes, which is associated, at any given age, with a significantly lower live birth rate compared with normal responders defined those with 10–15 oocytes, in which authors supported this definition by quoting a retrospective study.
Second one is “hypo-response” for those needing higher dose of gonadotropins and prolonged stimulation to retrieve more than three oocytes which may be due to genetic issues as authors quoted another study to support this definition. Then the age threshold of 35 years in relevance to expected embryo aneuploidy rate, and AMH and AFC, as the ovarian reserve markers are also included to define groups. This is also a more dynamic assessment since it includes before, during, and after stimulation observations.
It was believed that the low prognosis concept will better help to personalize ART treatment protocols. It may also lead to define those patients with genetic polymorphism related to gonadotropins and their receptors.
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