Ovulation and Fertility

Abnormalities of Ovulation

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 available were the Basal Body Temperature Chart (BBT), 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. By current standards, these procedures and tests belong in the history books but not in clinical practice.

BBT charts will tell you if a woman ovulated but cannot tell you if "normal" ovulation occurred. Furthermore, many women may ovulate normally with a very bizarre looking BBT chart.

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

Changes in the cervical mucus or changes in the vaginal smear may also tell you if ovulation occurred but that is about all and even then, they are very inaccurate.

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 permitted us to determine, with a high degree of accuracy, exactly what a normal menstrual cycle ought to look like. We know what the hormone levels ought to be. We know how large the follicles should get when looked at by ultrasound and by evaluating all of these factors, we can now assess the normalcy of ovulation .

As a result of this, we have been able to learn that there are many women who do not ovulate normally and, for these women, this has been of great benefit in helping them achieve a pregnancy.

It is also becoming apparent that many women with other obvious problems, such as tubal disease, male factor infertility or endometriosis may have an abnormality of ovulation. These are very often the couples who end up seeking infertility care.

I am convinced that couples with only a single problem (unless that problem is severe) will often achieve a pregnancy spontaneously. It is when a couple has multiple problems, none of which may be all that bad, that an infertility problem results. This is particularly true in those situations where the woman has endometriosis ( even the mildest cases ) and her partner is sub-fertile.

The modern assessment of ovulation abnormalities is now common place. Assessing ovulation requires seeing the women 5 or 6 times during her menstrual cycle. The initial visit occurs very early in the cycle (sometime between the 3rd and 5th day). 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.

The next important time to evaluate the menstrual cycle is at the time of ovulation. Several visits are usually required, often on a daily basis. Blood tests determine that the amount of estrogen produced is normal. This indicates that the follicle is healthy. Ultrasound is used to correlate the size of the follicle with the estrogen level to make sure that the follicle has achieved full mature development.

At this time, the cervical mucus is also checked and a post coital test is done.

The women 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.

The traditional way that progesterone production is assessed is to perform an endometrial biopsy, a procedure in which a small piece of the endometrium (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 uncomfortable, even if techniques are employed to reduce the pain.

I do perform endometrial biopsies but not for the reasons that most are done. The reason for this is simple - there is no evidence that it means anything or makes any difference in the overall treatment of an infertile couple.

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, many physicians give their patients progesterone following ovulation.

As much as common sense says this should work, all the research that had been done clearly shows that it doesn't. There is no evidence that giving women progesterone increases their chances of becoming pregnant. There is also no evidence that giving women progesterone after they have conceived helps them "hold" the pregnancy, even though many physicians give progesterone to their patients for that purpose. This is true even in women with biopsy-proven abnormalities.

There is now some evidence that endometrial biopsies to determine whether normal ovulation is taking place may have been done at the wrong time of the cycle. Some 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 preliminary information. Until the argument is settled, the preceding paragraphs still hold.

There are 2 principal reasons why endometrial biopsies (as they are usually performed) have no place in modern infertility. First, the way they are done by general OB/GYN's is such that they are meaningless. This is not the fault of the OB/GYN, it is the fault of the system - especially managed care. It would take about an hour to explain why this is true.

Second, the term "luteal phase defect" is supposed to mean that the woman is producing insufficient amounts of progesterone during the luteal phase of the cycle. There is an underlying assumption that an abnormal biopsy is synonomous with diminished progesterone production. Unfortunately, this is not true. 50% of women with abnormal biopsies are producing normal amounts of progesterone. The defect is in the endometrium, not the amount of progesterone. Given this fact, you can appreciate that giving progesterone is useless - the endometrium is incapable of responding. Again, we can explain this more in detail if you are interested.

Keep in mind that European Reproductive Endocrinologists do not do biopsies. There is no reason to do them on this side of the pond either.

There is evidence that progesterone supplementation is important in stimulated cycles - i.e., those cycles in which the woman is receiving Clomiphene or injectable Gonadotropins. This is necessary because it has been known for sometime that in such artificial cycles, the luteal phase may not be normal. This is the result of inadequate progesterone production, not an endometrial receptor defect. Furthermore, the woman may show a problem in some cycles but not in others. It is easier and simpler to treat women with progesterone supplementation rather than test each woman to see whether she needs it or not.

Endometrial biopsies do have a role in infertility to detect endometritis (not endometriosis), a chronic inflammation of the endometrium. If present, it will keep a woman from conceiving. It needs to be diagnosed and the endometrial biopsy is the only way. It is doing endometrial biopsies for hormonal evaluation that I feel is unnecessary.

At each visit, the endometrium (lining of the uterus) is also evaluated by ultrasound. The endometrium also goes through a series of changes during the menstrual cycle. 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. Such women will 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 detect this, and, if present, requires that the woman be switched to Pergonal.

There is one important thing to keep in mind, namely that 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. 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 problem will show that problem most 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 situation.

When searched for appropriately and carefully documented, we now recognize that abnormalities of ovulation are a significant factor in 25 to 30% of all infertile couples.

In order to understand how ovulation is assessed, it is necessary to understand what happens during a normal menstrual cycle. In a normally ovulating woman, each month an egg begins to grow and develop within a structure called the follicle. The follicle is comprised of the egg and the surrounding ovarian cells that are necessary for the growth and development of the egg. The cells of the follicle wall also serve as the source of estrogen which is produced during the menstrual cycle.

The brain controls the menstrual cycle as it controls every bodily function. The hypothalamus is the part of the brain that controls the endocrine system. The hypothalamus produces a hormone, Gonadotropin Releasing Hormone (GnRH) , which makes the pituitary gland produce, store, and eventually release FSH and LH, the two hormones which control the ovary. The ovary (and the testicle) are the gonads; hence, FSH and LH are called Gonadotropins.

As the follicle develops, fluid begins to collect inside it and at the time of ovulation when the follicle is fully developed, the follicle is approximately 1 inch (25 millimeters) in diameter and contains about 1/2 teaspoon of fluid. The follicle is, by strict definition, a small cyst. Because of the fluid which the follicle contains, it is easy to visualize it on ultrasound and this, of course, is very important in tracking an infertile woman during her menstrual cycle.

Once the follicle has reached full maturity, the follicle wall ruptures and the egg is expelled. This is the process of ovulation.

As the follicle matures, estrogen is produced in increasing amounts. The estrogen level peaks and then falls. Approximately 12-16 hours after the estrogen level peaks, the pituitary gland releases a very large amount of LH - an event called the LH SURGE. It is this release of large amounts of LH that can be detected in the urine by the home ovulation kits sold in drugstores. The LH surge triggers ovulation. Ovulation occurs 12-16 hours after the LH surge. The LH surge also serves to initiate the transformation of the follicle into the corpus luteum.

After the egg is released from the follicle, it is picked up by the fallopian tube. Fluid accumulates in the deep pelvis behind the uterus where it can be seen on ultrasound. This is one of the indicators that ovulation has occurred.

After ovulation takes place, the follicular cells undergo a transformation and the structure that was once the follicle now becomes the corpus luteum. Prior to ovulation, the follicle produces estrogen; after ovulation, the corpus luteum produces estrogen and progesterone.

If it is determined that a woman is not ovulating normally, drugs are used to try to stimulate normal ovulation. The hormones that control ovulation (GnRH, FSH & LH) are used to enhance and/or modify the ovulatory process. These drugs may be used by themselves, in combination with other drugs, or drugs may be used to stimulate the increased production of the body's own hormones.

GnRH may be given to stimulate normal ovulation. Under normal circumstances, GnRH is produced by the hypothalamus in "pulses" every 90 minutes. To mimic normal ovulation, GnRH must therefore be given every 90 minutes. Since GnRH is a protein, it cannot be taken by mouth. The method of administration is to use an insulin pump strapped to the woman's waist. The drug is administered by placing a small catheter under the skin. Since it takes 2 weeks to develop a mature egg under normal conditions, it takes 2 weeks of GnRH to achieve the same results. The main drawback to the use of natural GnRH is the inconvenience of having to wear the pump continuously for 2 weeks. Nonetheless, it is an effective method of inducing ovulation.