What is diminished ovarian reserve?

Females are born with their lifetime supply of oocytes (eggs) and cannot create new ones. The number of oocytes that a female possesses is commonly referred to as her “ovarian reserve,” and the reserve (number of remaining eggs) declines as ovarian aging occurs.^i,ii Diminished ovarian reserve (DOR) is a term used for females with low ovarian reserve, which is most often due to advanced age.ⁱⁱⁱ

Sometimes, diminished ovarian reserve (DOR) is confused with poor ovarian response (POR) or primary ovarian insufficiency (POI). This confusion makes it harder for females diagnosed with any of these conditions to learn more about their diagnosis.

Diminished ovarian reserve (DOR) vs. poor ovarian response (POR)

Females with DOR are also commonly characterized as having a poor ovarian response (POR). POR means that they have a lower-than-expected response to the hormonal treatment given to stimulate the ovaries to grow multiple follicles as part of in vitro fertilization (IVF).^iv (This medication is often called ovarian stimulation medication or “stims.”) A 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.^v Patients without DOR can be poor responders as well, meaning there are other reasons for POR besides DOR.^vi,vii

Diminished ovarian reserve (DOR) vs. primary ovarian insufficiency (POI)

DOR is also sometimes 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 follicle-stimulating hormone (FSH) level for females younger than 40 who have not had menses (a menstrual period) for at least three consecutive months.^viii,ix

Essentially, the female’s ovaries are depleted, and menses 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 due to infectious, genetic, autoimmune, gonadotoxic, or idiopathic causes.^x,xi

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.^xii,xiii

How is diminished ovarian reserve diagnosed?

Although there is no test that can determine the exact number of oocytes that remain in the ovaries, testing 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 ovarian reserve tests are often referred to as “markers of ovarian reserve” and can be used to diagnose DOR.

The most used tests are for follicle-stimulating hormone (FSH) levels, anti-Müllerian hormone (AMH) levels, and antral follicle count (AFC). The first two are determined by bloodwork, while the third one requires ultrasound screening.

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; moreover, they are reliable predictors of response to ovarian stimulation during in vitro fertilization.

Follicle-stimulating hormone (FSH) blood test

During the menstrual cycle, follicle-stimulating hormone (FSH) is released from the pituitary gland (at the base of the brain) to promote the growth and maturation of ovarian follicles. These growing follicles produce estrogen and inhibin, which then send a message to the brain (called negative feedback) that the follicles have reached sufficient size. When the message is received, the pituitary gland lowers production of FSH (see Figure 1).

Females with DOR have a lower number of follicles developing and estrogen and inhibin levels do not rise as high as they should. Therefore, the negative feedback does not work effectively; the 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 issue is why FSH levels become elevated as females age and/or have diminishing ovarian reserve. For regularly menstruating individuals, this test is most accurate when done on day 2 or 3 of their menstrual cycle. An FSH level higher than 10I U/mL is often associated with DOR as well as poor response during an IVF cycle.^xiv,xv

Anti-Müllerian hormone (AMH) blood test

Anti-Müllerian 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.^xvi 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 females taking hormonal treatments can have artificially lower AMH levels, which should be considered when timing the AMH bloodwork.^xvii

Antral follicle count (AFC) ultrasound

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 (see Figure 1). Unlike FSH and AMH, AFC is determined by ultrasound, where the healthcare provider will count the number of small antral follicles, typically on day 2 or 3 of the menstrual cycle. AFC is typically reduced in females with DOR.^xviii,xix

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 females with DOR, there are fewer growing follicles, so there is less suppression of FSH levels, resulting in elevated FSH levels.

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 (DOR) and/or primary ovarian insufficiency (POI). There is no single cause for DOR, and many factors can influence a DOR diagnosis.

Age is the most important contributor to the loss of ovarian reserve.^xx Other risk factors that have been associated with a reduced oocyte pool are listed below. Having one of these factors does not necessarily mean that a female will have DOR or POI, but rather that these factors have been shown to influence ovarian reserve.

Although there is no known way to prevent diminished ovarian reserve, 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 to suggest that other lifestyle changes that could reduce the incidence of DOR. For females with a known risk of developing reduced ovarian reserve, and who want to get pregnant in the future, it may be worthwhile to consider fertility preservation in the form of cryopreservation (egg freezing).^xxvii

What are the symptoms of diminished ovarian reserve?

There are no overt symptoms for most patients with DOR, and they only reach a diagnosis when they experience difficulties trying to conceive.^xxviii Instead, indicators such as low AMH, low AFC, and high FSH (all discussed above) are used to determine a DOR diagnosis.

In contrast, POI can cause symptoms that are similar to menopause, such as irregular cycles, cessation of menstruation, and hot flashes, among others.^xxix,xxx

Getting pregnant with diminished ovarian reserve

Currently there are no available evidence-based medical treatments for patients with diminished ovarian reserve (DOR), and this condition cannot be reversed. However, assisted reproductive technology (ART) interventions such as in vitro fertilization may be used for females 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 females of similar ages.^xxxi 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 females with DOR that can conceive naturally. However, studies have shown that females 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.^xxxii,xxxiii

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 (POR, meaning the follicles/eggs do not respond well to the follicle stimulating hormone (FSH) and luteinizing hormone (LH) medication). It is important to note, however, that not all patients with poor ovarian response have DOR. ^xxxiv,xxxv Similarly not all patients with DOR will have a poor ovarian response.^xxxvi,xxxvii

In a 2015 analysis of patients undergoing fertility treatment in the U.S., it has been shown that although the percentage of patients diagnosed with DOR increased from 19 to 24 percent from 2004 to 2011, the incidence of poor response (defined as cycle cancelled or fewer than four retrieved eggs) decreased from 32 to 30 percent.^xxxviii

Furthermore, in the same analysis, the live birth rate for those with DOR increased from 15 to 17 percent.^xxxix 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, but classified poor response as a cancelled cycle or fewer than four eggs retrieved.^xl

IVF modifications for poor ovarian response

For patients with poor ovarian response (POR) 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 POR are included below. The outcomes below may be applicable to those with diminished ovarian response (DOR), but it is important to remember that not all POR is due to DOR.

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.^xli A recent randomized controlled trial divided 63 poor respondent patients into three arms: long testosterone (treatment with 12.5 mg/day testosterone gel for 56 days before stimulation), short testosterone (same dosage, but for 10 days before stimulation), and a control group.^xlii 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.^{xliii,xliv,xlv} Definitive conclusions on the clinical use of DHEA for fertility patients with POR/DOR require 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, which then increases synchronization of oocyte size and 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.^xlvi For example, in a prospective randomized controlled trial of 323 poor respondent patients, 163 patients received pretreatment with estradiol (4 to 6 mg orally) and showed no statistically significant difference in number of retrieved oocytes or clinical pregnancy rates compared to the control group.^xlvii

Another retrospective study comparing pretreatment with GnRH antagonist (45 cycles) to no pretreatment (76 cycles) showed an increase in number of oocytes retrieved (average 3.0 +/- 2.0 GnRH group vs 2.1 +/- 2.0 control group) but clinical pregnancy rates were not significantly different among both groups.^xlviii

In addition, a meta-analysis comparing 15 studies evaluating the effectiveness of oral contraceptive (birth control pills) pretreatment found no significant difference in clinical pregnancy rate between those taking oral contraceptives versus the control group.^xlix

Pretreatment with coenzyme Q10 (CoQ10)

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.^l However, this increase did not result in any changes to clinical pregnancy or live birth rates in the treatment versus control groups.^li

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.^lii Given the lack of high-quality evidence, intra-ovarian PRP is considered experimental and not routinely recommended.^liii

Growth hormone (GH)

Co-treatment and/or pretreatment with GH has an uncertain effect on outcomes for individuals with a history of poor ovarian response.^liv,lv,lvi In the largest and most recent meta-analysis, there was a 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.^lvii

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.^lviii,lix One randomized controlled study that enrolled 114 poor ovarian response patients tested the addition of CC on day 3 to 7 or placebo on patients starting stimulation on two different gonadotropin doses.^lx They found no difference in the number of retrieved oocytes between the CC and control groups.^lxi

Letrozole (LZ) co-treatment

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.^{lxii,lxiii,lxiv,lxv} 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 in vitro fertilization.^lxvi

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.^lxvii 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.^lxviii

High gonadotropin doses

Administering high dosages of gonadotropins during controlled ovarian stimulation does not appear to be beneficial in improving outcomes for people with poor ovarian response, according to a 2018 meta-analysis.^lxix It is also worth noting that statistical significance in a study does not always translate into clinical significance. This truth 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 diminished ovarian reserve (DOR). However, 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 for pregnancy are available?

Individuals with DOR have various fertility options, including intrauterine insemination (IUI) and in vitro fertilization (IVF), as well as the option for use of donor eggs or embryos in certain cases.

Intrauterine insemination (IUI)

Some patients with DOR may consider IUI. The success rate of IUI has been shown to be similar in patients with normal and diminished ovarian reserve of comparable age.^lxx,lxxi Therefore, those with DOR should work with their provider to decide if IUI may be a potential option.

Donor eggs or embryos

For some patients with DOR, a physician might recommend the use of donor eggs or embryos as a last resort after considering factors such as age, ovarian reserve, and previous fertility outcomes. There are no clear guidelines on when patients with poor prognoses should be recommended to use donor oocytes or embryos. The process might be considered if the patient is of advanced maternal age or if there have been multiple failed IVF cycles.^lxxii

Diminished ovarian reserve does not affect a female’s ability to carry a pregnancy. Therefore, the chances of having a live birth using oocyte or embryo donation are similar to other females of comparable age,^lxxiii unless there is an additional cause of infertility or contraindications to carrying a pregnancy for patients with DOR.

Conclusion

Diminished ovarian reserve (DOR) refers to a decline in reproductive potential due to the declining number of oocytes in the ovaries (known as the ovarian reserve). Patients using in vitro fertilization (IVF) for infertility due to DOR may experience a poor ovarian response (POR) to the IVF stimulation medication, which generally produces a lower oocyte yield and decreased success rates. There are various treatments or protocol modifications that have been proposed for improving in vitro fertilization outcomes in females 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.