Abnormalities of Ovulation

30 – 40% of all Infertility

At one time, about the only thing you could tell by testing was whether a woman ovulated or did not ovulate. Even then, you couldn’t always be sure. The techniques that were available were the Basal Body Temperature (BBT) Chart, careful evaluation of changes in the cervical mucus, changes in the appearance of the cells of the vagina when appropriate smears were made, and the measurement of a metabolite of progesterone in the urine called Pregnanediol.

BBT charts will tell you if a woman ovulated but cannot tell you if “normal” ovulation has occurred. Many women ovulate quite normally with very bizarre looking BBT charts.

The measurement of the urinary pregnanediol could tell you if ovulation occurred. However, it is not a valid test to determine whether normal ovulation is occurring.

Changes in the cervical mucus or changes in the vaginal smear again may tell you if ovulation occurred but that is about all and they are very inaccurate and subject to numerous influences.

The ability to measure the concentration of hormones in the blood using highly accurate techniques combined with the development of ultrasound – first abdominal and now vaginal – has permitted us to study the normal menstrual cycle literally day by day. This has allowed us to determine, with a fairly high degree of accuracy, exactly what a normal menstrual cycle ought to look like. I know what the hormone levels ought to be. I know what the lining of the uterus ought to look like both before and after ovulation. I know how large the follicles should get when looked at by ultrasound and by evaluating all of these factors, I can now assess the normalcy of ovulation with a high degree of accuracy.

As a result of this, I have been able to learn that many women who ovulate do not do so normally. For many women, making this determination has been of great benefit in helping them achieve a pregnancy.

It is also true that many women with other obvious problems, such as tubal disease, male factor infertility or endometriosis may also have an abnormality of ovulation. There is evidence that a previous pelvic infection may affect future ovarian function. It has been known for many years that women with Endometriosis frequently do not ovulate normally. These are very often couples who end up seeking infertility care.

I am convinced that couples with only a single problem (unless that problem is very severe) will often achieve a pregnancy on their own. It is when a couple has multiple problems, none of which may be all that bad, that infertility results. Studies have shown that if infertile couples are followed for 5 years without therapy, approximately 50% will achieve a pregnancy. Often, treatment of the infertile couple does not achieve higher pregnancy rates, it only helps the couple achieve a pregnancy sooner.

The modern assessment of ovulatory abnormalities is now common and requires seeing the women 5 or 6 times during her menstrual cycle. The initial visit occurs early in the cycle, ideally on Day 3 (day 2, 3, or 4 is acceptable). Blood tests obtained at that time are very valuable in predicting the success of future therapies. An ultrasound obtained at that time is used to evaluate the ovaries at the time in the menstrual cycle when they are at their least active state.

Depending on the age of the woman, her history, and what other therapies she has undergone, a Clomiphene Citrate Challenge Test (CCCT) or a GnRH stimulation test may be performed. These are tests to assess “Ovarian Reserve” – a measure of the functional reserve capacity of the ovaries to produce normal eggs. (See section below)

The next important time to evaluate the menstrual cycle is at the time of ovulation. Several visits are required, often on a daily basis. Blood tests make sure that the amount of estrogen and other hormones produced are normal. This indicates that the follicle is healthy. Ultrasound is correlated with the estrogen level to make sure that the follicle has achieved full mature development and that the lining of the uterus has also developed properly. Failure to develop a normal uterine lining is a much more common cause of infertility than was formerly believed.

At this time, the cervical mucus is also checked and a post coital test is done. This is often as good a test of male fertility as the traditional semen analysis. Some studies have shown that the post-coital test is actually better than a semen analysis, at least in terms of predicting future pregnancies.

The woman is next seen shortly after ovulation to make sure that the follicle has ruptured and that the egg has actually been expelled from the ovary. Failure to observe that ovulation has actually occurred is a strong clue that the woman has endometriosis.

The last visit is later in the cycle about 1 week after ovulation. Again, hormone levels and an ultrasound are performed to evaluate the endometrium (the lining of the uterus).

The traditional way that progesterone production is assessed is to perform an endometrial biopsy, a procedure in which a small piece of the endometrium (the lining of the uterus) is removed and sent to a pathologist for evaluation. This is usually done just prior to the onset of the menstrual period. Endometrial biopsies are done in the office and can be painful, even if techniques are employed to reduce the pain.

I rarely perform endometrial biopsies in infertile women. The reason for this is simple – there is no evidence that (for the reasons a biopsy is usually done), it means anything or makes any difference in the treatment of an infertile woman. European Reproductive Endocrinologists do not do endometrial biopsies for this very reason.

If a woman produces too little progesterone during the second half of the menstrual cycle after ovulation has occurred (the luteal phase), then that woman is said to have a “luteal phase defect”. Common sense says that a woman with a luteal phase defect should have trouble conceiving and for this reason, some physicians give their patients progesterone (often in the form of vaginal suppositories or cream) following ovulation.

As much as common sense says this should work, all the research that has been done clearly shows that it doesn’t. There is no evidence that giving progesterone to an infertile woman increases her chances of becoming pregnant. There is also no evidence that giving women progesterone after they have conceived helps them “hold” the pregnancy. IVF is an exception to this – progesterone supplementation is mandatory.

There is evidence that endometrial biopsies to determine whether normal ovulation is taking place may have been done at the wrong time of the cycle. Some researchers now feel that if a biopsy is going to be done, it should be at the time of implantation (7-8 days after ovulation). This is still an unresolved issue. Until the argument is settled, the preceding paragraphs still hold.

Newer information indicates why progesterone therapy is ineffective. A luteal phase defect, by definition, means that the woman is producing less progesterone during the luteal phase of her cycle than normal. Studies have shown that at least 50% of women with a “luteal phase defect” as diagnosed by endometrial biopsy have normal progesterone production during the luteal phase of the cycle. The evidence indicates that the real problem is not inadequate progesterone production but an abnormal response of the endometrium to progesterone. These women have an endometrial progesterone receptor defect. The first studies showing this were published many years ago. Giving extra progesterone will not overcome this inherent abnormality in the endometrium.

Endometrial biopsies do have a role in infertility to detect endometritis (not endometriosis), a chronic inflammation of the endometrium. Endometrial biopsies are also necessary to measure endometrial integrins – a newly discovered group of molecules that make cells “sticky”. This may be of value in women with unexplained infertility but the test is not covered by most insurances and is expensive.

Endometritis, if present, it will keep a woman from conceiving. It needs to be diagnosed and the endometrial biopsy is the only way.

The endometrial integrins are molecules that help cells stick to each other. There is evidence that they are necessary for the embryo to attach itself to the endometrium. Women have been identified who are infertile, have no obvious reason for their infertility and who are found to be deficient in endometrial integrins. Newer evidence also indicates that women with early stage endometriosis are also deficient in endometrial integrins. This may explain their infertility or sub-fertility. This is all new information and it will take several more years until it is sorted out. None-the-less, measuring endometrial integrins may be of benefit in women with otherwise unexplained infertility.

At each visit, the endometrium is also evaluated by ultrasound. The endometrium also goes through a series of changes during the menstrual cycle. Recent data has shown something that was suspected for a long time, namely that if the endometrium is not properly developed prior to ovulation, a pregnancy will not occur even if all other factors are normal. Many women with totally normal hormone levels will not have a normal endometrium. This is why giving progesterone does not help. Such women require special therapies to achieve a pregnancy.

This assessment is very important in women taking Clomiphene. It has been known for a long time that Clomiphene will adversely affect the cervical mucus. By the same mechanisms, Clomiphene will also interfere with the normal development of the endometrium. Ultrasound monitoring will often detect this, and, if present, requires that the woman be switched to Pergonal or a similar drug. Taking a baby aspirin every day also helps, in some cases, to overcome the adverse effects of the Clomiphene.

There is one important thing to keep in mind – no woman ovulates normally every cycle. If you were to study 100 women chosen randomly, you would find that 25 to 30% of them would ovulate abnormally in any one given menstrual cycle. The incidence is probably higher in infertile women. Therefore, if a problem with ovulation is detected, it is mandatory that the woman be evaluated in a subsequent menstrual cycle. Only in this way can you be sure that the problem you have detected and may wish to treat truly exists. A woman with a significant problem will show that problem almost everytime she is evaluated. If a woman has a problem in one cycle but is completely normal in the next cycle, then that problem probably either does not exist or is of lesser significance in terms of her overall infertility.

This is another reason why progesterone therapy is ineffective. Studies have clearly shown that women with biopsy proven luteal phase defects do not show that defect in every cycle, when multiple biopsies are done over many cycles. Furthermore, it is rare to have a woman conceive in the cycle a biopsy is done. Therefore, if a woman has a biopsy proven luteal phase defect, I have no way of knowing whether the problem was present in the cycle in which she conceived. It is apparent from all the data currently available that those women who conceived, even with a properly proven luteal phase defect, ovulated normally in the cycle of conception and any progesterone given was coincidental to the pregnancy which would have occurred anyway.

There are a number of other reasons why endometrial biopsies are unreliable (the way they are usually done). The vast majority of women who have been told they lave a luteal phase defect have not had the diagnosis established by valid means. Therefore, those women who were told they had this problem, were treated for it, and then conceived are mistaken in their belief that the therapy had anything to do with the successful pregnancy.

There is another very, very important reason why abnormalities of ovulation should be documented before therapy is begun. It has been a very common practice in infertility to give Clomiphene (Clomid or Serophene) to infertile women, often without a proven need for it. In fact, under the rules established by Aetna-USHealthcare’s infertility program, a woman had to be given 3 cycles of Clomiphene by her general OB/GYN before she could be referred to a Reproductive Endocrinologist.

A recent study proved what had long been suspected and for which a great deal of indirect evidence already exists, namely that giving Clomiphene to a normally ovulating woman may actually decrease her chances of becoming pregnant! More recent data has shown that sophisticated ultrasonic evaluation of follicles generated by Clomiphene are often not normal, further supporting the fact that giving Clomiphene just because the woman is not becoming pregnant may not always be appropriate. Proving whether a woman ovulates normally or not is an essential part of the evaluation process as it will play a major role in determining which therapies are best for that couple.

 

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