Women are born with a finite number of eggs (oocytes) that comprise their reproductive potential throughout their lifetime. In other words, they are born with their lifetime supply of oocytes and cannot create new eggs. The number of oocytes that a woman possesses is commonly referred to as the “ovarian reserve,” and the reserve (number of remaining eggs) diminishes as aging occurs.i,ii Diminished Ovarian Reserve (DOR) is a term used for women with low ovarian reserve, which is most often due to their advanced age.iii,iv
Diminished ovarian reserve (DOR) vs Poor Ovarian Response (POR) vs Primary Ovarian Sufficiency (POI): what is the difference?
Women with DOR are commonly characterized as also having a poor ovarian response (POR). POR means that they have a lower-than-expected response to hormonal treatment (often called stimulation medication or “stims”) given to stimulate the ovaries to grow multiple follicles as part of IVF.v This reduced, or poor, response typically results in fewer eggs retrieved during an IVF cycle.
Although DOR and POR are frequently used interchangeably, they are not the same thing. Having a diminished ovarian reserve is only one of multiple criteria used to predict poor ovarian response in a patient.vi Patients without DOR can be poor responders as well, meaning there are other reasons for POR besides DOR.vii, viii
DOR is sometimes also confused with another condition called Primary Ovarian Insufficiency (POI), previously known as Premature Ovarian Failure (POF). POI is caused either by loss of ovarian follicles or by dysfunctional ovarian follicles. This condition is diagnosed with the finding of an elevated FSH level for women younger than 40 who have not had menses for at least 3 consecutive months.ix,x Essentially, the woman’s ovaries are depleted, and menses (periods) stops before the age of 40. While markers of ovarian reserve are usually abnormal in POI, this condition is distinct from DOR because it is not a consequence of normal aging, but is rather caused by infectious, genetic, auto-immune, gonadotoxic, or idiopathic causes.xi, xii, xiii It is important to distinguish between POI and DOR because individuals with POI have medical challenges beyond infertility and may require other types of healthcare interventions accordingly.xiv,xv The terms DOR, POI, and POR are often incorrectly used interchangeably and can be poorly defined. This makes it harder for women diagnosed with any of these conditions to learn more about their diagnosis.
How is DOR diagnosed?
Although there is no test that can determine the exact number of oocytes that remain in the ovary, tests can help estimate ovarian reserve. Ovarian reserve is evaluated at the beginning of the menstrual cycle (typically day 2 or 3 of the cycle) by a combination of blood tests and ultrasounds. Collectively, these tests are often referred to as “markers of ovarian reserve” and can be used to diagnose DOR.
The most utilized tests are follicle-stimulating hormone (FSH) levels, anti-mullerian hormone (AMH) levels, and antral follicle count (AFC). The first two are determined by bloodwork, while the third one requires ultrasound screening.
FSH. During the menstrual cycle, FSH is released from the pituitary gland (brain) to promote the growth and maturation of ovarian follicles. These growing follicles produce estrogen and inhibin which send a message to the brain (negative feedback) that the follicles have reached sufficient size, and this in turn lowers production of FSH (figure 1).
Women with DOR have a lower number of follicles developing and therefore estrogen and inhibin levels do not rise as high as they should. As such, the negative feedback does not work effectively – in other words, estrogen and inhibin do not rise enough to cause the FSH levels to lower. As a result, the pituitary continues to secrete FSH in an attempt to grow more follicles. This is why FSH levels become elevated as women age and/or have diminishing ovarian reserve. For regularly menstruating women, this test is most accurate when done on the 2nd or 3rd day of their menstrual cycle. An FSH level higher than 10IU/mL is often associated with DOR as well as poor response during an IVF cycle.xvi,xvii
AMH. Anti-mullerian hormone (AMH) is produced by small growing follicles and is measured to provide a general indication of the number of those follicles. Higher levels of AMH are associated with better ovarian reserve, whereas lower levels of AMH are usually indicative of a smaller ovarian reserve.xviii AMH levels remain constant throughout the menstrual cycle and can be tested at any point throughout it. It is worth noting that it has been shown that women taking hormonal treatments can have artificially lower AMH levels and this should be considered when timing the AMH bloodwork.xix
AFC. Antral follicle count (AFC) is the sum of the number of late-stage follicles present in both ovaries in the early follicular phase of the menstrual cycle (Figure 1). Unlike FSH and AMH, AFC is determined by ultrasound, where the health care provider will count the number of these small antral follicles, typically on Day 2 or 3 of the menstrual cycle. AFC is typically reduced in women with DOR.xx, xxi
Figure 1. The development of follicles (from small pre-antral follicles to pre-ovulatory follicles) and the related hormones. The oocyte(egg) is inside of the growing follicle. AMH is determined by bloodwork to help estimate the number of small follicles. AFC is counted on ultrasound to detect the number of small antral follicles near the start of the reproductive cycle. FSH causes growth and maturation of follicles and oocytes. Estrogen is released from the developing follicles. FSH levels are normally suppressed via negative feedback (-) by estrogen from growing follicles. However, in women with DOR, there are fewer growing follicles, so there is less suppression of FSH levels, resulting in elevated FSH levels.
Although there is no consensus on the best way to diagnose diminished ovarian reserve, AMH and AFC have been found to be the most useful predictors of ovarian reserve, and moreover reliable predictors of response to ovarian stimulation during IVF.xxii
What causes lowered ovarian reserve, including DOR?
There are various factors that can lower ovarian reserve. These risk factors can be associated with diminished ovarian reserve (DOI) and/or POI (primary ovarian insufficiency). It is important to note that there is no one single cause for DOR, and many factors can influence a DOR diagnosis.
Age is the most important contributor to the loss of ovarian reserve in women.xxiii Other risk factors that have been associated with a reduced oocyte pool are listed below. Having one of these factors does not mean that a woman will necessarily have DOR or POI, but rather that these factors have been shown to Influence ovarian reserve.
Risk factors for lowered ovarian reserve (DOR or POI)xxiv
Genetic conditions, mostly those involving the X chromosome, such as Fragile X and Turner syndrome;xxv
Infections, including HIV, mumps, tuberculosis and cytomegalovirus, though the actual incidence of infertility as a sequela of these diseases remains unknown;xxvi
Autoimmune diseases, in which the body produces antibodies against steroid cells (steroid-cell antibodies, SCA) or various hormonal receptors;xxvii
Exposure to environmental factors, such as cigarette smoke, also associated with earlier menopause in women;xxviii
Injury to the ovary during surgery to the pelvic area, removal of the ovary, as well as surgeries to remove ovarian cysts or ovarian endometriosis, as damage to the ovary can lead to a reduced ovarian reserve;
Cancer treatments such as chemotherapy or radiation, which can reduce the number of remaining eggs in the ovary at varying degrees depending on the type of cancer and treatment regimen.xxix
Although there is no known way to prevent DOR, there may be some beneficial lifestyle modifications that could help reduce the risk of DOR, such as avoiding smoking. However, there is a lack of research suggestive of other lifestyle changes that could reduce the incidence of DOR. For women with a known risk of developing reduced ovarian reserve, and who would want to get pregnant in the future, it may be worthwhile to consider fertility preservation in the form of egg freezing (cryopreservation).xxx
What are the symptoms of DOR?
For most patients with DOR there are no overt symptoms, and they only reach a diagnosis when they experience difficulties trying to conceive.xxxi The symptoms cannot be felt physically, and indicators (discussed above) are instead used to determine a DOR diagnosis. Again, these indicators (i.e., low AMH and low AFC, high FSH) can be detected by bloodwork and ultrasound, but do not cause any overt physical symptoms. This is in contrast to POI, which can cause symptoms similar to menopausal symptoms, such as irregular cycles, cessation of menstruation, and hot flashes, among others.xxxii, xxxiii
Getting pregnant with DOR
Currently there are no available evidence-based treatments for patients with DOR, and this condition cannot be reversed. However, for women presenting with infertility, assisted reproductive technology interventions such as IVF may be used to help them become pregnant if they are having difficulty conceiving naturally. Recent studies have shown that even though the number of eggs is reduced in patients with DOR, their quality is comparable to that of women of similar ages.xxxiv As such, pregnancy either naturally or via ART is possible.
DOR and natural pregnancy
Since DOR is usually diagnosed when patients have difficulty conceiving, it is challenging to know the percentages of women with DOR that can conceive naturally. However, studies have shown that women with DOR are able to conceive naturally, and that fecundity (time to conceive) and incidence of pregnancy loss is comparable to patients with normal ovarian reserve markers.xxxv,xxxvi
DOR, IVF and poor response
The major challenge for patients with DOR undergoing fertility treatment is retrieving enough eggs after stimulation. For this reason, most DOR patients are characterized as having a poor ovarian response (meaning the follicles/eggs do not respond well to the FSH and LH medication, explained above). It is important to note, however, that not all patients with POR have DOR. xxxvii, xxxviii Similarly not all patients with DOR will necessarily have a poor ovarian response.xxxix, xl Conversely, not all patients with POR have DOR.
According to recent analysis of many patients undergoing fertility treatment in the US, it has been shown that although the percentage of patients diagnosed with DOR increased from 19 to 24 percent, the incidence of poor response (defined as cycle cancelled or fewer than four retrieved eggs) decreased from 32 to 30 percent.xli Furthermore, in the same analysis, the live birth rate for those with DOR increased from 15 to 17 percent.xlii It is not clear why these improvements in the DOR population occurred and it may be speculated that it resulted from more personalized treatments, modifications to stimulation protocols, some other reason, and/or purely by chance. It should also be noted that this study did not use the standard definition of POR,xliii but classified poor response as a cancelled cycle or fewer than four eggs retrieved.xliv
For patients with poor ovarian response during IVF, there are various modifications to traditional fertility treatments that have been proposed to potentially improve the number and quality of retrieved eggs. However, the effectiveness is not always clear due to inconsistency in results between studies. Some of the protocol modifications for poor ovarian response are included below. The outcomes below may be applicable to those with DOR, but it is important to be mindful that not all POR is due to DOR.
Protocol modifications:
- Testosterone: Pretreatment with testosterone has been suggested to increase the number of growing follicles. However, recent clinical trials have shown no significant benefit in the number of mature oocytes in patients with POR.xlv A recent randomized controlled trial (study) divided 63 poor respondent patients into three arms: long testosterone (treatment with 12.5mg/day testosterone gel for 56 days before stimulation), short testosterone (same dosage, but for 10 days before stimulation) and a control group.xlvi Although small, this study showed no difference in the number of oocytes retrieved between the three groups.
- Dehydroepiandrosterone(DHEA): DHEA is a hormone necessary for producing androgens and estrogen. Although many individual small studies have shown some benefit to using DHEA, meta-analyses have observed that these results are hard to interpret given the small number of patients, varying dosage and formulations of DHEA, differences in characterization of DOR patients, and the fact that many studies used the same patients as controls.xlvii, xlviii, xlix Definitive conclusions on the clinical use of DHEA for fertility patients with POR/DOR requires future well-designed studies.
- Pituitary suppression: Pretreatment with pituitary suppressors (GnRH agonists, estradiol and oral contraceptive pills) is done toward the end of the cycle directly before IVF stimulation begins. It is hypothesized to suppress follicle growth until stimulation with IVF medications to increase synchronization of oocyte size and thus mature oocyte yield during retrieval. However, some studies have shown moderate to no difference in pregnancy rates for patients with low oocyte numbers using this approach.l For example, in a prospective randomized controlled trial of 323 poor respondent patients, 163 patients received pretreatment with estradiol (4-6mg orally) and showed no statistically significant difference in number of retrieved oocytes or clinical pregnancy rates compared to the control group.li Similarly, a retrospective study comparing pre-treatment with GnRH antagonist (45 cycles) to no pretreatment (76 cycles) showed an increase in number of oocytes retrieved (average 673.0 +-2.0 GnRH group vs 2.1 +-2.0 control group) but clinical pregnancy rates were not significantly different amongst both groups.lii In addition, a meta-analysis comparing 15 studies evaluating the effectiveness of oral contraceptive (birth control pills) pre-treatment found no significant difference in clinical pregnancy rate between those taking oral contraceptives versus the control group.liii
- Pretreatment with Coenzyme Q10: CoQ10 is an antioxidant believed to play a role in oocyte maturation. In one study of 169 patients with poor ovarian response (76 in the treatment group and 93 controls), they found that pre-treatment with CoQ10 for 60 days prior to ovarian stimulation was shown to improve ovarian response, measured by the increased number of retrieved oocytes.liv However, this did not result in any changes to clinical pregnancy or live birth rates in the treatment vs control groups.lv
- Pretreatment with intraovarian Platelet Rich Plasma (PRP): PRP has also been explored for patients with diminished ovarian reserve as an intra-ovarian injection. While no randomized controlled studies exist yet, a systematic review of uncontrolled studies showed that intraovarian PRP infusion increases mature oocyte yield, fertilization rate, and good quality embryo formation rate.lvi Given the lack of high-quality evidence, intra-ovarian PRP is considered experimental and not routinely recommended.lvii
- Growth Hormone (GH): Co-treatment and/or pretreatment with GH has an uncertain effect on outcomes for those with history of POR.lviii,lix,lx cent meta-analysis, there was suggestion of possible improvement in the number of eggs retrieved and the clinical pregnancy rates, but because of inconsistency in study methods, no definitive conclusions could be made.lxi
- Clomiphene Citrate (CC): co-treatment with CC, an estrogen modulator commonly used for ovulation induction, has been suggested to increase follicle recruitment, although no significant clinical benefit has been shown for patients with history of poor ovarian response.lxii,lxiii One randomized controlled study that enrolled 114 poor ovarian response patients tested the addition of CC on Day 3-7 or placebo on patients starting stimulation on two different gonadotropin doses.lxiv They found no difference in the number of retrieved oocytes between the CC and control groups.lxv
- Letrozole co-treatment: Letrozole (LZ) is an inhibitor of estrogen production and is commonly used for ovulation induction. It has been hypothesized to increase follicular response in poor responders and some small studies have shown limited improvements in outcomes with use of LZ.lxvi, lxvii, lxviii, lxix However, a more recent systematic review and meta-analysis found that the use of letrozole did not significantly improve the number of oocytes retrieved compared to those not using letrozole during IVF.lxx
- GnRH agonist vs antagonist cycles: Long agonist protocols, flare regimens, and microdose flare regimens have been compared with antagonist protocols to determine if one option may improve outcomes in patients with poor ovarian response. One meta-analysis including six studies of IVF patients with POR, found that there was no difference in ongoing pregnancy rate between those on the agonist versus antagonist protocol.lxxi The lack of large randomized controlled studies investigating these different treatments in the POR/DOR population has made it difficult to determine if either of these protocols could potentially improve IVF outcomes in this patient population.lxxii
- High Gonadotropin Doses: Administering high dosages of gonadotropins during controlled ovarian stimulation does not appear to be beneficial in improving outcomes for those with poor ovarian response, according to a 2018 meta-analysis.lxxiii It is also worth noting that statistical significance in a study does not always translate into clinical significance. This becomes evident in studies where the number of oocytes retrieved is statistically significant (albeit only marginally), but ultimately does not result in improvements in clinical pregnancy rate or live births. This point is particularly important when studying patients with DOR and/or POR given that the number of oocytes retrieved are generally low, making researching different protocols in this patient population exceptionally challenging.
In summary, various modifications to traditional fertility treatments have been proposed for patients with poor ovarian response (POR) caused by DOR (but recall that not all POR is due to DOR). The effectiveness of many of these interventions is inconclusive due to the low quality of evidence available and the lack of consistency in how patients with DOR and/or POR are represented in research.
What other options are available?
Some patients with DOR may consider intrauterine insemination (IUI). The success rate of IUI has been shown to be similar in patients with normal and diminished ovarian reserve of comparable age,lxxiv,lxxv so those with DOR should work with their provider to decide if IUI may be a potential option.
For some patients with DOR, a physician might recommend use of donor eggs or embryos as a last resort after considering factors such as age, ovarian reserve, and previous fertility outcomes in determining a poor prognosis. There are no clear guidelines on when patients with poor prognoses should be recommended to use donor oocytes or embryos. This might be considered if the patient is of advanced maternal age or if there have been multiple failed IVF rounds.lxxvi
Diminished ovarian reserve does not affect a woman’s ability to carry a pregnancy, and therefore the chances of having a live birth using oocyte or embryo donation are similar to those of woman of comparable age.lxxvii Unless there is an additional cause of infertility or contraindications to carrying a pregnancy for patients with DOR, the use of donor eggs/embryos should provide pregnancy and live birth rates comparable to women of similar age without DOR.
Thus, individuals with Diminished Ovarian Reserve (DOR) have various fertility options, including Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF), and the consideration of donor egg or embryos in certain cases.
Conclusion
Diminished Ovarian Reserve (DOR) refers to a decline in reproductive potential due to the declining number of oocytes in the ovaries (the ovarian reserve). Patients using In Vitro Fertilization (IVF) in the case of infertility due to DOR may experience a poor ovarian response (POR) to the IVF stimulation medication. This generally produces a lower oocyte yield and decreased success rates. There are various treatments or protocol modifications that have been proposed for improving IVF outcomes in those with poor ovarian reserve that may be due to DOR. Additionally, egg or embryo donation is an option in cases of multiple IVF failures and/or advanced maternal age. Despite the complexities surrounding DOR, individuals can navigate their fertility choices with informed decisions.
