Category Archives: Ovarian Reserve

Ovarian Reserve

Anti-Mullerian Hormone: The Blood-Based Biological Clock?


Many women choose to delay starting a family for various reasons, but how long is too long to wait? Is there some way to determine the time remaining on a woman’s “biological clock” to help guide family planning? A new biomarker measured in blood, anti-Müllerian hormone (AMH), has been proposed to do exactly that but there are some important limitations that must be considered before rushing out to the closest doctor’s office to request an AMH measurement.

First, some background. Women are born with approximately one million primordial ovarian follicles and only about one thousand of these remain when a woman reaches menopause. Over the course of a woman’s reproductive years, these primordial follicles come out of hibernation and develop into immature follicles by accumulating theca cells that produce testosterone and granulosa cells that convert testosterone to estradiol. Each cycle, in response to follicle-stimulating hormone (FSH), one of these immature follicles becomes the dominant, mature follicle that ultimately releases an egg through the process of ovulation. Some immature follicles exit the development pathway and become nonviable while others continue to develop for possible selection as the dominant follicle in a subsequent cycle. The key point is that the granulosa cells of these immature follicles produce AMH, which can be measured in serum or plasma as a direct reflection of the number of immature follicles. If more immature follicles are present, the serum/plasma AMH concentration will be higher. If fewer immature follicles are present, the AMH concentration will be lower. At first glance, measuring AMH would seem to be the ideal way to determine a woman’s reproductive lifespan – if AMH is high, many immature follicles remain and menopause is years away.

Unfortunately, it’s not quite that simple. While elevated AMH concentrations do reflect a large number of immature follicles, this doesn’t necessarily guarantee fertility. Polycystic ovary syndrome (PCOS) is a condition marked by the presence of many immature AMH-secreting follicles and women with PCOS typically have elevated serum/plasma AMH concentrations. AMH has been shown to inhibit the effects of FSH and AMH excess prevents immature follicles from reaching the final stages of development, resulting in impaired fertility for many women with PCOS. While an AMH concentration within the age-appropriate reference interval is a favorable indicator of fertility, higher is not necessarily better as very high AMH concentrations may indicate an underlying anovulatory condition.

At the other extreme, low age-specific serum/plasma AMH concentrations have been associated with impaired fertility in women in their 30s and may predict earlier menopause but low AMH concentrations are substantially harder to interpret in girls and younger women – precisely the population for whom an early estimate of reproductive lifespan would be most valuable. Low AMH concentrations in healthy women in their teens and 20s have not been associated with impaired fertility and survivors of childhood cancers with low AMH concentrations have achieved pregnancy. Furthermore, circulating AMH concentrations are reduced by lifestyle factors like oral contraceptive use and smoking, complicating the connection between AMH concentration and reproductive lifespan.

While studies of large numbers of women show that a low age-specific AMH concentration is associated with earlier menopause, it’s difficult to predict the age at menopause for an individual woman using a serum/plasma AMH concentration. The rate of decline in serum/plasma AMH concentrations varies from woman to woman, meaning that two women with identical AMH concentrations one year may have very different AMH concentrations the following year. Furthermore, the onset of menopause is a complex trait determined by genetic factors, environmental exposures and other influences like smoking, alcohol consumption and previous pregnancies. Ultimately, while AMH does reflect the number of immature follicles, its ability to predict onset of menopause and guide family planning decisions is questionable at the present time.

Currently, the most appropriate clinical use of AMH measurement is to predict response to ovarian stimulation in women undergoing in vitro fertilization (IVF). Women with a high AMH concentration (and a large number of immature follicles) who undergo IVF are at increased risk of ovarian hyperstimulation syndrome (OHSS), a potentially fatal condition marked by abdominal fluid retention, blood clots, altered electrolyte concentrations and kidney failure. Using a moderate ovarian stimulation protocol in women with a high AMH concentration has been shown to reduce the risk of OHSS while increasing the number of pregnancies and live births per IVF cycle started. At the other end of the spectrum, women with a low AMH concentration are enrolled in a more intensive stimulation protocol to maximize egg retrieval while those with undetectable AMH are offered alternate treatment options as the chance of IVF success is low.

It’s possible that one day AMH may be routinely measured to predict the onset of menopause but for now, its most promising uses are limited to PCOS diagnosis (still some kinks to be worked out there too) and customization of ovarian stimulation protocols to improve IVF outcomes while minimizing the occurrence of OHSS.

“Should I freeze my eggs?”


Ovary with eggs"A question some women face: when to freeze their eggs." This was the start of a news piece I heard on NPR as I drove to work this morning. It caught my attention and I realized we haven't spent much time on this blog exploring the tests used to help achieve pregnancy.

The premise of "ovarian reserve" testing is rather straightforward: they are supposed to help a woman concerned about fertility decide whether she should freeze her eggs for future use or if she can wait to conceive because time is still on her side.

Unlike sperm, which are produced continually over a man's reproductive lifetime, the number of eggs in the female ovaries peaks during fetal development, declines over time, and do not regenerate. Thus, female fertility declines with each year of life. Tests of ovarian reserve are supposed to reflect the number and quality of remaining eggs, a key element in reproductive potential. Ovarian reserve tests include both blood tests and ultrasound tests. This post will focus on the blood tests.

FSH

With normal ovarian function, the developing eggs in the ovary secrete hormones which keep the concentration of follicle-stimulating hormone (FSH) in its normal range during the first few days of the menstrual cycle. When the number of developing eggs is decreased, the concentration of FSH is increased. Thus, measuring FSH on day 3 of the menstrual cycle is a test of ovarian reserve and higher values are associated with lower fertility.

Estradiol

Estradiol is released from developing eggs during the first few days of the menstrual cycle. Estradiol concentrations are usually low during days 2-4 but increase thereafter. A high value at this time suggests poor ovarian reserve.

AMH

Anti-Müllerian hormone (AMH) is produced by the granulosa cells of eggs and so its concentration reflects the size of the ovarian pool of eggs. As the number of eggs declines, so too does AMH. But while the concentration of AMH predicts the quantity of eggs, it does not predict their quality.

Inhibin B

Inhibin B is another hormone released by eggs and so it is similar to AMH in evaluating the number of eggs in the ovary. Because inhibin B helps to regulate FSH concentrations, a low inhibin B is associated with a high FSH. Unlike AMH, inhibin B shows a lot of variation across menstrual cycles so it's not a recommended test of ovarian reserve.

Clomiphene Citrate Challenge Test

Clomiphene is a selective estrogen receptor modulator that causes the pituitary gland to release the hormones needed to stimulate ovulation. This test is performed by measuring FSH on cycle day 3 (before giving Clomiphene) and again on day 10 (after giving Clomiphene, daily, on days 5-9). In women with normal ovarian reserve, the rising inhibin B and estradiol concentrations produced from the developing eggs would suppress FSH. However, in women with decreased ovarian reserve, FSH is elevated on day 10 due to the lower concentrations of inhibin B and estradiol.

Not surprisingly, no single test is adequate to evaluate a woman's ovarian reserve. To address that, it is not unusual for doctors to perform several of these tests in an effort to provide a more definitive answer. Unfortunately, there is still no universally agreed upon definition of "decreased ovarian reserve" and evidence of decreased reserve (biochemical or otherwise) does not correlate very well with the inability to conceive.

So while there is a very strong desire to have definitive tests to predict a woman's fertility potential in an effort to help her decide if she can wait to conceive or take action such as harvesting and freezing eggs for future use, such answers are not yet available from lab tests alone.