21 July 2016

Testing Your Ovarian Reserve

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As a women ages, her supply of eggs decrease both in quantity and quality and don’t regenerate.
Factors such as genetics, lifestyle, environment, and medical issues, including endometriosis, ovarian surgery, chemotherapy, and radiation, can influence the quantity and quality of a woman’s eggs. Although this reproductive decline occurs with age, there is significant variation in fertility among women of similar age, which  highlights the unpredictability and individuality of the reproductive aging process.

Even before birth, a woman’s eggs begin to diminish in number. During the 20th gestation week, a female embryo contains about seven million eggs. At birth, the number of eggs has already dropped to about 1-2 million at birth and  300,000-500,000 at puberty. The number of eggs continues to decline as the woman ages, until no eggs remain (menopause).
Factors such as genetics, lifestyle, environment, and medical issues, including endometriosis, ovarian surgery, chemotherapy, and radiation, can influence the quantity and quality of a woman’s eggs.
Although this reproductive decline occurs with age, there is significant variation in fertility among women of similar age, which  highlights the unpredictability and individuality of the reproductive aging process.
Fortunately, women are naturally equipped with an ample supply of extra eggs. The number of eggs a woman has at birth far exceeds the average number of menstrual cycles she will have during her lifetime. Therefore, when women undergo fertility treatment to boost egg production, the risk for premature menopause is no different than it would be for other women

Therefore, as a woman ages, her supply of eggs gradually declines over time until the eggs are depleted at menopause. Although we expect the ovary to age in a certain way, there are times when it doesn’t behave as predicted. That’s why screening for ovarian reserve is a fundamental part of the initial evaluation for infertility patients of any age. 

What is Ovarian reserve?

The term “ovarian reserve” refers to a woman’s current supply of eggs, and is closely associated with reproductive potential. In general, the greater the number of remaining eggs

the better the chance for conception. Conversely, low ovarian reserve greatly diminishes a patient’s chances for conception

The main goal of ovarian reserve testing is to identify those individuals who are at risk of decreased or diminished ovarian reserve.

Although ovarian reserve testing cannot predict the end of one’s reproductive years, results outside the range expected for a patient’s age can encourage the individual to pursue more aggressive treatment options to achieve pregnancy.

When test results suggest decreased or diminished ovarian reserve, if appropriate, an infertility evaluation should be initiated. It is reasonable to consider  that the  window of opportunity to conceive may be shorter than anticipated, and attempting to conceive sooner rather than later is encouraged.

Compared with women of similar age, women with diminished ovarian reserve commonly have regular menses but a reduced quantity of ovarian follicles and, thus, may have a limited response to ovarian stimulation with fertility medications and reduced fecundity (probability of achieving a live birth in a single reproductive cycle). At this time, ovarian reserve testing results cannot be extrapolated to predict the likelihood of spontaneous conception.

Methods of Assessing Ovarian Reserve

Since a woman’s chronological age is the single most important factor in predicting a couple’s reproductive potential, age has often guided infertility treatment choices. However, age alone doesn’t tell the whole story. Consequently, researchers have developed more refined methods of predicting a couple’s response to infertility treatment.

Some of the more sophisticated tools for assessing fertility potential include the measurement of FSH, LH, estradiol, and inhibin-B . Additionally, because patients should not be subjected to all tests, decisions regarding which method(s) to use are guided by practitioner experience.

Even though several sophisticated tools exist for measuring ovarian reserve, most fall short of what we consider ideal sensitivity and specificity. Also, how best to interpret ovarian reserve tests is controversial, since clinical experience with these tests is still evolving. Even so, most infertility patients should be periodically evaluated for the possibility of impaired ovarian reserve before pursuing any advanced fertility treatment.

The Effects of Maternal Age on Ovarian Reserve

Menstrual cycles that occur near the end of the ovaries’ lifetime are associated with older eggs of poorer quality [2]. In general, ovarian age parallels chronological age. But since that is not always the case, it is vitally important for clinicians to assess an infertility patient’s ovarian reserve. This is particularly true for women over the age of 35.

Passive Ovarian Reserve Testing:

Measuring FSH

Eearly follicular-phase FSH levels played an important role in pregnancy outcomes.

Day 3 FSH (measured by a blood test) could be very useful in predicting response to ovulation induction and IVF.

As a woman ages, FSH becomes elevated in an attempt to force the aging ovary to respond. However, the exact mechanism responsible for this adaptive response remains unknown. A rise in early follicular-phase FSH is also accompanied by a decline in oocyte quality, and some investigators have linked such FSH elevations to fetal abnormalities . In fact, it has been theorized that subtle but measurable increases in FSH precede menopause by approximately five years in some women .

While FSH values may not change significantly from days 2 through 5 within a given cycle, fluctuations of day 3 FSH from cycle to cycle are more important to detect. When FSH does fluctuate, subsequent menstrual cycles will likely produce oocytes of varying quality. This principle has emerged as a fundamental belief in human reproductive physiology [26]. Patients with low FSH values (suggesting satisfactory ovarian reserve) generally show the least fluctuation, while those with elevated FSH levels have broader ranges. Wide FSH fluctuations from month to month present a difficult “moving target” for laboratory assessment. In such cases, it is difficult to precisely estimate ovarian reserve.

Measuring LH

LH measurement may also have predictive value for ovarian reserve, but FSH is considered a better marker since as menopause approaches, FSH rises sooner and more dramatically than LH [30,31]. There may be a place for combined FSH+LH testing to estimate ovarian reserve, as some investigators have suggested an increased FSH:LH ratio may predict an elevation in FSH alone .

Measuring Estradiol

Low day 3 E2 levels, combined with normal FSH, have been associated with improved stimulation response, higher pregnancy rates , and lower cycle cancellation rates [36]. Interestingly, researchers reported that measurement of E2 one day earlier (on cycle day 2) did not enhance the predictive value of ovarian response..

High levels of E2 early in the menstrual cycle suggest an inappropriately advanced stage of follicular development. This may occur as the ovary ages, or when ovarian follicular cysts remain from a prior menstrual cycle. The follicular cysts can interfere with egg “recruitment” in the treatment cycle, naturally leading lead to a poor response to fertility treatment.

Measuring Progesterone

A decline in ovarian reserve has also been associated with a short follicular phase, early LH surge, and premature elevation of progesterone (P4) .

Initially, it was thought P4 might be a useful tool for ovarian screening. However, daily E2 and P4 testing performed in volunteers with ovulatory cycles revealed no differences in E2 or

P4 as a function of age . Researchers then turned their attention from “static” P4 assessment to the study of P4 patterns in the context of dynamic testing

In that setting, some investigators found high P4 levels  on day 10 of clomiphene citrate challenge tests (CCCT) to be associated with short follicular phases, diminished ovarian reserve, and reduced potential to achieve pregnancy.

 Measuring Inhibin-B

Inhibin-B is an ovarian hormone that inhibits FSH release . Although present in ovulating women, it is not normally found in postmenopausal women.

Although measuring inhibin-B is still considered investigational as a way to screen ovarian reserve, a number of advances have helped make measurement of inhibin-B a clinical reality. Nevertheless, it is critical for clinicians using inhibin-B in ovarian reserve testing to understand exactly which assay is being used, and acknowledge limitations in measurement methods.

Inhibin-B may prove to be a beneficial marker for ovarian reserve assessment because it fluctuates during the menstrual cycle, and is significantly reduced in women over the age of 35.

Although early reports confirm that inhibin-B can enhance current tools that measure ovarian reserve, more data are needed before meaningful normal ranges for inhibin-B can be routinely applied in clinical practice .

Measuring AMH

AMH, or anti-mullein hormone is a substance produced by granulosa cells in ovarian follicles.

It is first made in primary follicles that advance from the primordial follicle stage. At these stages follicles are microscopic and can not be seen by ultrasound.

AMH production is highest in prenatal and small antral stages (less than 4mm diameter) of development.

Production decreases and then stops as follicles grow. There is almost no AMH made in follicles over 8mm.

Therefore, the levels are fairly constant and the AMH test can be done on any day of a woman’s cycle.

Since AMH is produced only in small ovarian follicles, blood levels of this substance have been used to attempt to measure the size of the pool of growing follicles in women.

Research shows that the size of the pool of growing follicles is heavily influenced by the size of the pool of remaining primordial follicles (microscopic follicles in “deep sleep”). Therefore, AMH blood levels are thought to reflect the size of the remaining egg supply - or “ovarian reserve”.

With increasing female age, the size of their pool of remaining microscopic follicles decreases. Likewise, their blood AMH levels and the number of ovarian antral follicles visible on ultrasound also decreases.

Women with many small follicles, such as those with polycystic ovaries have high AMH hormone values and women that have few remaining follicles and those that are close to menopause have low anti-mullerian hormone levels.

Women with higher AMH values will tend to have better response to ovarian stimulation for IVF and have more eggs retrieved. In general, having more eggs with IVF gives a higher success rate.

AMH levels probably do not tell us much about egg quality, but having more eggs at the IVF egg retrieval gives us more to work with - so we are more likely to have at least one high quality embryo available for transfer back to the uterus.

Transvaginal Ultrasound: Antral Follicles count

Antral follicles are small follicles (about 2-9 mm in diameter) that we can see - and measure and count - with ultrasound. Antral follicles are also referred to as resting follicles.

Vaginal ultrasound is the best way to accurately assess and count these small structures.

Antral follicle counts (along with female age) are by far the best tool that we currently have for estimating ovarian reserve, the expected response to ovarian stimulating drugs, and the chance for successful pregnancy with in vitro fertilization.

The number of antral follicles visible on ultrasound is indicative of the number of microscopic (and sound asleep) primordial follicles remaining in the ovary. Each primordial follicle contains an immature egg that can potentially develop and ovulate in the future.

When there are only a few antral follicles visible, there are far fewer eggs remaining as compared to when there are more antral. As women age, they have less eggs (primordial follicles) remaining and they have fewer antral follicles.

Antral follicle counts are a good predictor of the number of mature follicles that we will be able to stimulate in the woman’s ovaries when we give injectable FSH medications that are used for in vitro fertilization.

The number of eggs retrieved correlates with IVF success rates.

  1. When there are an average (or high) number of antral follicles, we tend to get a “good” response with many mature follicles. We tend to get a good number of eggs at retrieval in these cases. Pregnancy rates are higher than average.
  2. When there are few antral follicles, we tend to get a poor response with few mature follicles. Cancellation of an IVF cycle is much more common when there is a low antral count. Pregnancy rates are lower overall in this group. The reduction in success rates is more pronounced in women over 35 years old.
  3. When the number of antral follicles is intermediate, the response  is not as predictable. In most cases the response is intermediate. However, we could also have either a low or a good response when the

Dynamic Ovarian Reserve Testing:

Clomiphene Citrate Challenge Test

In contrast to the static measurements of ovarian reserve mentioned previously, the clomiphene citrate challenge test (CCCT) is a dynamic approach. Its purpose is to stimulate the ovary to initiate egg production in response to a fertility drug called clomiphene (Clomid). In theory, the CCCT was designed to detect low ovarian reserve that would not be discovered by a single FSH and/or E2 measurements.

The CCCT is based on the assumption that adequate ovarian reserve is associated with a healthy group of developing follicles. This healthy group of follicles should be capable of producing enough inhibin and E2 to suppress FSH production and resist the effects of clomiphene.

When undergoing CCCT, the first step is to measure day 3 FSH and E2. Then 100mg of clomiphene is administered on cycle days 5 through 9, and FSH and E2 measurements are repeated on cycle day 10 . In general, a high day 10 FSH suggests poor ovarian reserve.

Gonadotropin-releasing Hormone Agonist Stimulation Test

gonadotropin-releasing hormone agonist (such as Buserline ) initially elevates E2, then profoundly suppresses both FSH and LH [69]. This is sometimes called a “flare-effect”. More than a decade ago, it was theorized that low ovarian reserve might be detected by evaluating differences in LH, FSH, and E2 levels following the administration of GnRH-a during IVF [24]. This approach was later formalized as a diagnostic tool known as the GnRH-a stimulation test, or GAST .

The purpose of GAST is to evaluate changes in E2 on cycle day 2 and 3 following administration of leuprolide acetate (Lupron). Patients with greater elevations of E2 have correspondingly higher pregnancy rates.
GAST has been a better predictor of the functional abilities of the ovary than either FSH or age . Because the GnRH-a is costly and involves an injection and repeated blood tests, the GAST is not widely used in clinical practice.

The Value of Medical Records

Clinicians can often uncover valuable information about possible ovarian reserve from records describing a patient’s response to earlier ovulation induction attempts. Unlike any of the other assessment tools described, knowing how a patient responded previously shows reproductive performance over the broadest possible range. When available, such records represent the ultimate dynamic test of ovarian status.

Obviously, records would not be available for patients who have no prior ovulation induction attempts. However, the availability of old stimulation records does not mean that repeat assessment of ovarian reserve can be left out. Prior stimulation records can guide both the estimation of ovarian reserve and the selection of the appropriate treatment plan in an upcoming cycle

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