It goes without saying that normal ovarian function is essential for a woman to become pregnant. Making the diagnosis of abnormal ovarian function is easy when a woman has significant irregular menstrual cycles, when she has stopped menstruating completely or when she shows evidence of some other obvious hormone problem.
The dilemma arises in those women in whom it is suspected but not proven that their ovaries may not be functioning normally. Until recently, we did not have good techniques for evaluating this — now we do.
The transition from normal ovarian function to menopause as a woman ages is not an abrupt change but a gradual one. At menopause, it is not like suddenly turning off the light switch — it is if a dimmer were used to reduce the intensity step by step.
If a woman is trying to become pregnant, particularly if she is over the age of 35, or if she has already undergone unsuccessful infertility treatment, it is critically important to determine how her ovaries are functioning. Newer data clearly shows that if the ovaries are not producing their eggs and hormones the way they ought to, the chances of a successful pregnancy are very poor — regardless of what technique is used to try to achieve that pregnancy.
The term now used for this is “Ovarian Reserve.” There are several ways to assess ovarian reserve. To understand these tests, it is important to understand how the body normally controls ovarian function.
As I have mentioned in other pamphlets, a woman is born with all the eggs she will ever have — about 1 million at birth, 400,000 at puberty and essentially “0” at menopause. Although it cannot be definitively proven, it is generally believed that a woman ovulates her best eggs at a younger age. As she gets older, the eggs that remain in her ovaries are not the best of her eggs. These eggs don’t function properly and the body has to work harder to get these eggs to ovulate.
The following explanation obviously oversimplifies what is a very complex process. However, I believe it will provide the necessary insights for you to understand exactly what is going on.
The pituitary gland produces two principal hormones that control the ovary — FSH or Follicle Stimulating Hormone, and LH or Luteinizing Hormone. FSH can be thought of as the hormone that controls egg development and LH controls hormone production.
Your endocrine system controls itself in a manner very similar to the way your thermostat at home controls the temperature of your house. This is called “negative feedback”. When you are at home, and if you are cold, you go to the thermostat and raise the temperature setting. The thermostat then sends a signal to the furnace. The furnace produces heat which raises the temperature of the house to your desired level. The thermostat senses this and turns off the furnace. Later, should the temperature of the house fall on its own, the thermostat will sense this automatically and turn the furnace on once again.
Think of your ovaries as the furnace and think of your pituitary gland as the thermostat. Just as the signal from the furnace to the thermostat is the temperature of the house, the signal from your ovary to the pituitary gland is estrogen.
As a woman ages and ovarian function declines, ovarian estrogen production will begin to fall. The pituitary gland senses this and tries to generate more estrogen. The signal it sends to the ovary is FSH. The increased production of FSH by the pituitary gland is an attempt to increase estrogen production by the ovary. Adequate estrogen production can be equated to normal egg development.
If your furnace were not functioning properly, your thermostat would have to send a stronger and stronger signal to the furnace to try to get the temperature of the house higher. So too, the pituitary gland, as the ovary fails, sends a stronger and stronger signal to the ovary.
If women are monitored very carefully as they age, the earliest sign that the ovaries are functioning abnormally and are beginning that long transition into menopause is a rising level of FSH. We take advantage of this to assess ovarian function in determining a woman’s chances of subsequently conceiving.
The first test that came along that showed real value is called “Cycle Day 3 FSH”. This test was almost discovered by accident. It turns out that for most IVF programs, hormone stimulation begins on cycle day 3 and many facilities routinely drew blood on their patients prior to the initiation of a cycle. This blood was then stored and analyzed at a future date.
As studies were done that correlated the cycle day 3 FSH level with the subsequent success of the IVF cycle, it quickly became apparent that those women with higher FSH levels were less likely to conceive. As more and more data became available, it became possible to segregate women into three categories — those with a good chance of success with IVF, those with almost no chance of success and those who fell somewhere in between.
An ideal day 3 FSH is less than 10. Values between 10 and 15 fall into a gray zone. A day 3 FSH is over 15 is a poor prognostic sign.
As more and more data began to accumulate, other studies looked at different hormone levels and it quickly became apparent that the serum estradiol on day 3 is also a predictor of ovarian reserve. If a woman has a high serum estradiol level on cycle day 3 (over 75), this is also an indicator of an ovary that is not functioning properly and is also a poor prognostic sign.
In endocrinology, dynamic testing often gives better results than simply drawing a single blood test. With this idea in mind, the GnRH stimulation test and the “Clomiphene Citrate Challenge Test” have been devised. The “Clomiphene Citrate Challenge Test” was invented many years ago, whereas the GnRH test is new and probably better.
Newer studies have come up with what is probably an even better way of assessing ovarian reserve - the GnRH stimulation test. This test begins on cycle day 2 at which time an Estradiol, Progesterone, FSH, and LH levels are obtained.
The woman then begins GnRH - either Synarel or daily Lupron.
Repeat blood tests are then obtained on cycle days 3,4, and 5. (Some studies have indicated that repeat tests on only days 3 and 4 are necessary). However, eliminating the cycle day 5 hormone levels may draw erroneous conclusions from the tests.
Four different patterns of Estradiol response to the GnRH have been demonstrated.
In the most optimum response, the Estradiol level from day 2 to day 3 will increase by at least 100% or even more. Therefore, it will double. It then slowly declines over the next two days.
The second response shows no change between day 2 and day 3 but the Estradiol level then increases between day 3 and day 4 or increases between day 4 and day 5.
The third response is a slow steady increase of the Estradiol level over all 4 days.
The fourth response is a virtual flat line over all five days.
The first and second responses are what is hoped for. Published success rates with in vitro fertilization show pregnancy rates of 46% with the first response pattern and 38% with the second response pattern.
Pregnancy rates of only 16% are seen with the third response pattern and if the woman’s Estradiol level shows virtually no increase over the four days of the tests (the fourth response pattern) the pregnancy rates were only 6%.
Because of the nature of this test and because it is often impossible to obtain laboratory studies on Sunday (and often on Saturday), this type of testing can only be carried out when your menstrual cycle begins either on Sunday, Monday, or Tuesday. (It may be sometimes possible to also perform the testing if your period begins on Wednesday but not if it begins on a Thursday, Friday, or Saturday).
The “Clomiphene Citrate Challenge Test” relies on the fact that Clomiphene is an anti-estrogen. Therefore, if there is any significant compromise of ovarian function and the pituitary gland is already beginning to work harder to produce more FSH, anything that tips it a little bit over will actually produce an exaggerated rise in FSH.
The Clomiphene Citrate Challenge Test (CCCT) is very easy to carry out. Baseline blood is drawn on cycle day 3.
The woman takes 100 mg. (2 tablets) of Clomiphene beginning on cycle day 5 for 5 days. Recent data suggests that brand name Clomid or Serophene should be used to make sure that the test is performed with as little room for error as possible and to insure consistent results from one physician to another. Blood is then drawn on cycle day 10. An FSH level is over 15 indicates an ovary that is failing. If the FSH is over 25, the likelihood of a pregnancy is very poor.
Because of advances in our knowledge and technology, there are several other newer studies that can also help assess ovarian reserve. The first is measuring the hormone “Inhibin”. Inhibin is a hormone produced by the early developing follicles in the ovary and one of its functions is to inhibit the production of FSH by the pituitary gland. Therefore, a reduced number of healthy follicles results in a lower level of Inhibin and this is no doubt one of the factors contributing to the increase in FSH that serves as a marker for diminished ovarian reserve.
It is now possible to measure Inhibin directly and, again, a low level of Inhibin early in the cycle indicates diminished ovarian reserve.
As has been discussed elsewhere, women are born with all the eggs they are ever going to have. As the pool of eggs is used up, logic would tell you that the size of the ovary will decrease. In fact, this is the case, and another way to assess ovarian reserve is to actually measure ovarian volume. Newer ultrasound machines, such as the one we have in our office, can calculate ovarian volumes. If the volume of an ovary is less than 3 cc’s, that ovary most likely has an insufficient egg pool.
Another study looked at the FSH to LH ratio on cycle day 3. The authors of this study found that if that ratio is more than 3.6 then, again, there is diminished ovarian reserve.
One of the issues currently being debated revolves around which tests should be used, is there any one definitive test, and how significant are these tests. It may be several more years before we have a definitive answer. Most of the studies suggest that the cycle day 3 FSH, the cycle day 3 Estradiol, and the cycle day 10 FSH following a Clomiphene Citrate Challenge Test are the three most important tests. However, additional studies are needed.
These tests have little “positive” predictive value. In other words, they will not tell you who will become pregnant.
However, they do have very high “negative” predictive value. If the tests results show poor ovarian reserve, that woman needs donor eggs - a poor test indicates a very low chance of conception, regardless of what infertility therapy is used.
All women over 35 and any woman under age 35 who has gone through unsuccessful infertility therapy in the past should undergo Ovarian Reserve testing.
There are several issues that must be kept in mind when discussing ovarian reserve and its impact on infertility. First, decreasing ovarian reserve is a normal part of the aging process. Although some studies have suggested that diminished ovarian reserve, as measured by the cycle day 3 FSH, is a better predictor of infertility therapy success, most Reproductive Endocrinologists would agree that age is still the number one factor that compromises a woman’s ability to become pregnant. Age and diminished ovarian reserve are usually synonomous, but not always.
In looking at the success of standard infertility therapy, all other things being equal, the older the woman, the less likely she is to become pregnant. One study looked at a large number of women with unexplained infertility who were going through super ovulation using Clomid combined with IUI. This study showed that regardless of the age of the woman, 85% of the pregnancies that were achieved occurred in the first four treatment cycles. However, the actual numbers from this study showed that for women under 30, 50% were pregnant after four treatment cycles; if the woman was between 31 and 35, 40% conceived; for women between 36 and 40, 26% conceived and for women 41 and older, 24% conceived. Again, these numbers show once again that the woman’s age is perhaps the most important factor, all else being equal.
It is also important to understand that these tests of ovarian reserve are not absolute. Unless the tests indicate that you are actually quite close to menopause, there will always be an occasional patient who becomes pregnant, even when the numbers say that it shouldn’t happen.
As an example, a large study looking at IVF cycle cancellation rates yielded the following results. If the cycle day 3 FSH was less than 15, only 5% of the cycles had to be canceled.
If the FSH was less than 20 - 10% were canceled; less than 25 - 20% cancellation rate; and if the FSH was over 30, 40% of the cycles had to be canceled.
This particular study did not mention pregnancy rates even in those cycles with elevated FSH levels that were not canceled. However, other studies have definitely shown that the higher the FSH, the lower the pregnancy rate.
These studies also point out one other trap for the unwary - namely, that most of them deal with IVF. There are not that many studies looking at pregnancy rates in women going through standard infertility treatments such as Clomiphene/IUI or Gonadotropin/IUI. Nonetheless, what few studies are available, combined with common sense, suggests that the higher the FSH, the less likely the woman is to become pregnant.
Nonetheless, since there will be women who do conceive even when the numbers say they shouldn’t, we would never arbitrarily deny therapy unless the numbers clearly indicated menopause. However, women with diminished ovarian reserve must understand that their chances of becoming pregnant are certainly less than those of women whose ovaries appear to be functioning normally.