Ovulation -- Normal and Abnormal

Normal ovulation

Normally, one of the ovaries releases a single mature egg every month, and this is called ovulation. Women may notice pain or abdominal discomfort at the time of ovulation and occasionally have some slight vaginal bleeding. The presence of regular periods, premenstrual tension and dysmenorrhoea (period pains) usually indicate that the menstrual cycles are ovulatory.

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Eggs are stored in the ovaries in follicles. Follicles exist in two major categories - growing and non-growing (primordial). Eggs in the primordial follicle are in a very immature form. In this state they are not capable of being fertilized by a sperm until they undergo a maturing process that culminates in their release from the ovary at the time of ovulation. Egg maturation and ovulation is stimulated by two hormones secreted by the pituitary - follicle stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones must be produced in appropriate amounts throughout the monthly cycle for normal ovulation to occur. Every month, at the start of the menstrual cycle, in response to the FSH produced by the pituitary gland, about 30-40 primordial follicles start to grow. Of these, only one matures to form a large fluid-filled structure, called a Graafian follicle that contains a mature egg, while the others die (a process called atresia). The mature egg is released from the follicle when the follicle ruptures in response to a surge of LH produced by the pituitary.

After ovulation has occurred, the follicle from which the egg has been released forms a cystic structure called the corpus luteum. This is responsible for progesterone production in the second half of the cycle.

Most women who have regular periods have ovulatory cycles. Women who fail to ovulate or who have abnormal ovulation usually have a disturbance of their menstrual pattern. This may take the form of complete lack of periods (amenorrhoea), irregular or delayed periods (oligomenorrhoea) or occasionally a shortened cycle due to a defect in the second part (luteal phase) of the cycle.

Detecting ovulation - do you ovulate?

Menstrual period timing (Calendar method)

To determine the length of the menstrual cycle, one only needs to note the date of the beginning of the menstrual period (first day of flow) for two consecutive periods, and then count the day from one date to the next. Keeping track of the length of menstrual cycles will help determine the approximate time of ovulation, because the next period begins approximately two weeks from the date of ovulation.

The rough rule to calculate the approximate date of ovulation is: NMP minus 14 days, where NMP is the (expected) date of the next menstrual period. This is because the luteal phase for most women is 14 days long.

Keeping track of the menstrual cycle by charting it can indicate other ovulatory disturbances. For example, if a menstrual cycle that is normally 28 days starts to occur every 35 or 40 days, this may mean that ovulation is disturbed, and an evaluation is needed.

Basal Body Temperature (BBT) chart

During the luteal phase of the cycle, the corpus luteum produces the hormone progesterone, which elevates the basal body temperature. When the basal body temperature has gone up for several days, one can assume that ovulation has occurred. However, it is important to remember that the BBT chart cannot predict ovulation it cannot tell you when it is going to occur!

The basal temperature chart can be a useful tool. It allows the patient to determine for herself if she is ovulating as well as the approximate date of ovulation - but only in retrospect. Basal body temperature charts are easy to obtain and the only equipment required is a special BBT thermometer.

General instructions for keeping a basal body temperature chart include the following:

1. The chart starts on the first day of menstrual flow. Enter the date here.

2. Each morning immediately after awakening, and before getting out of bed or doing anything else, the thermometer is placed under the tongue for at least two minutes. This must be done every morning, except during the period.

3. Accurately record the temperature reading on the graph by placing a dot in the proper location. Indicate days of intercourse with a cross.

4. Note any obvious reason for temperature variation such as colds, or fever on the graph above the reading for that day.

The major limitation of the BBT is that it does not tell you in advance when you are going to ovulate - therefore its utility in timing sex during the fertile period is small. Interpreting the BBT chart can be tricky for many patients rarely do the charts look like those you see in textbooks! Also, keeping a BBT chart can be very stressful - taking your temperature as the first thing you do when you get up in the morning is not much fun. What is worse is that you start to let the BBT chart dictate your sex life. This is why though the BBT chart used to be a useful method in the past, it's utility is limited today - and newer methods are available which are more accurate. Manufacturers have now incorporated a microprocessor along with the digital thermometer to create an electronic fertility management device, called the Bioself Fertility Indicator. This makes calculation of the "fertile days" much easier, because it combines and optimizes both the basal body temperature and calendar method of ovulation prediction.

Fertility Software Programs

Newer software programs (easily available on the internet), such as CycleWatch (at http://www.cyclewatch.com), help you learn about your body's fertility signs by giving you the tools to document and analyze your observations. For women who are comfortable with computers, this is a useful tool to organize your cycle data and analyze your cycles to determine fertile times. You can also create and print out a personalized ovulation calendar that highlights your "fertile" days at http://www.stadtlander.com/fertility/calendar.cgi.

Endometrial biopsy

After ovulation, the endometrium is prepared for implantation of the fertilized egg by the progesterone secreted by the corpus luteum. In order to determine if ovulation is occurring normally, an endometrial biopsy may be done. During this procedure, a small amount of endometrium from inside the uterine cavity is extracted and sent for pathologic examination under a microscope. This is a standard procedure usually done just before the period begins. It can be done in the doctor's clinic or in an operating theatre. No anesthesia or hospitalization is needed. However, it does cause discomfort during the procedure (about as much as a severe menstrual cramp) and an analgesic can be taken a half-hour prior to the procedure to decrease this discomfort.

When examining the endometrial biopsy, the pathologist looks for the influence of the estrogen and progesterone hormones on the endometrial glands. If progesterone has been produced in that cycle, the endometrial glands show secretory changes. In fact, the effect of progesterone on the endometrium is so predictable that the biopsy can be "dated" - that is, the pathologist can predict on which day the next period will start! If there is a "lag" between the predicted day and the actual day, then this suggests a luteal phase defect, which means that the production of progesterone is deficient. If no progesterone at all has been produced, then the endometrium will be reported as being proliferative (under the influence of only estrogen) - which suggests that the cycles are anovulatory (i.e., ovulation did not occur in that cycle).

Curettage

A curetting used to be the commonest procedure done for infertile patients. In fact, a number of infertile patients will request that a curetting be done for them, since they feel that the curetting will "clean out" the dirt they have in their uterus and allow them to conceive. This is an old wives' tale and is based on: "I know someone who got a baby after a curetting". The correct technical term for curetting is D & C dilatation and curettage which means the cervix is stretched (dilated) and the uterine cavity scraped (curetted) to collect the endometrium). This is an obsolete procedure for an infertile woman, and can actually be harmful. The only use of a D&C is to provide endometrial tissue which can be examined under the microscope to see if the woman is ovulating or not. It has absolutely no fertility-enhancing role whatsoever. Since this endometrium can be obtained much more easily, safely and cheaply with an endometrial biopsy (in which only a strip of endometrium is removed) there should rarely be any need to do a D&C for an infertile woman. Patients have often had repeated D&Cs - and these can actually damage the cervix and even block the tubes, if infection occurs after surgery. The only possible role for a D&C today is when tuberculosis of the uterus is suspected.

Blood test for progesterone

The progesterone level in the blood may be measured to confirm that ovulation has taken place. This test is done one week before the date of the next expected menstrual period. A high level indicates that the corpus luteum is producing enough progesterone, and is good retrospective evidence that ovulation occurred. A very low level means that the cycle was most probably anovulatory. An intermediate level may suggest a luteal phase defect (in which the corpus luteum does not secrete enough progesterone).

While the above tests will tell a woman whether or not she ovulates, the following symptoms and tests which can be used in order to determine when you ovulate are of greater importance, since they provide information which can be used to identify the "fertile period" prospectively.

Cervical mucus (Billing's method)

By checking your cervical mucus daily, as described in the chapter on the cervical factor, you can determine when you ovulate. Just before ovulation, your cervical mucus is thin, profuse, clear and stretchy, like raw egg whites. After ovulation, the mucus becomes thick, tacky, scanty and sticky. You can learn to appreciate this change in your mucus (by seeing and feeling it) and this allows you to predict when ovulation occurs quite accurately.

Abdominal pain

Approximately 25 per cent of women may experience a pain on one side of the abdomen that is associated with ovulation. This is called mittelschmerz (a German word, which means midcycle pain) and is usually related to the release of an egg from the rupturing follicle. It is a good idea to mark the date when it occurs since this information is helpful in determining when ovulation occurs.

The Role of ultrasound

The egg develops within a follicle in the ovary. This follicle is a thin-walled structure containing fluid with the egg attached to the wall. Usually, only one follicle develops per month. This follicular growth can be measured by vaginal sonography, with a painless procedure called ultrasound, usually done with a vaginal probe, which projects an image of the ovary onto a screen. The follicle appears as a circular fluid-filled bubble on the screen, and can be seen when it is about 7 to 8 mm in size. It grows at about 1 to 2 mm per day, and is ready for ovulation when it measures 18 to 25 millimeters in diameter. Following ovulation, the follicle usually disappears from the scan picture completely and this is the best evidence of ovulation. Often, at the same time, fluid can also be detected in the abdomen behind the uterus this is the follicular fluid that is released when the follicle ruptures. Defects detectable by ultrasound are follicles that do not grow at all, or do not grow to a big enough size, or occasionally follicles that do not rupture at the appropriate time (luteinised unruptured follicle). Since ultrasound allows assessment of follicular development, it is especially useful for patients having timed intercourse or having ovulation regulated with fertility drugs. It is usually done on a daily basis, from about the 11th day of the cycle.

Follicle tracking on ultrasound usually takes about 5 minutes to perform. No preparation is needed except that the bladder must be emptied before the scan. Ask to see the picture of the follicle on the monitor - and you should be able to see the growth of the follicle and its rupture for yourself on the screen.

Older ultrasound machines used abdominal probes. These require that the patient has a full bladder, so that the sound waves can reach the ovary. Not only are they much more uncomfortable for the patient (who has to sit waiting till the bladder is almost bursting) but the quality of the pictures is also much poorer as compared to the vaginal scan.

Commercially available ovulation prediction kits (OPK)

Ovulation prediction test kits (OPK) are available at leading over the counter. These kits detect LH, which is produced in large quantities shortly before ovulation and can be found in the urine. Once the LH surge has occurred, ovulation usually takes place within 12 to 44 hours. Urine testing is started about two days prior to the expected day of ovulation and continues until the test becomes positive. The urine should be collected at the same time every day - and testing the first morning urine sample is a good idea.

If your menstrual cycles are irregular, testing should be timed according to the earliest and latest possible dates of ovulation. For example, if your cycle ranges between 27 and 34 days, you could possibly ovulate between days 13 and 20. Therefore, testing should begin on day 11 and continue until ovulation is indicated or through day 20. There is an 80 percent chance of detecting ovulation with five days of testing and a 95% chance with ten days of testing. Occasionally, ovulation may not occur in a particular cycle. If the ovulation prediction test has been timed and performed accurately and has not turned positive, you should discontinue testing and begin again with your next menstrual cycle. Persistent failure of the test to turn positive may indicate a problem with regard to ovulation.

Once a test has registered positive, indicating that ovulation is about to take place, it is no longer necessary to continue testing. Remaining tests in a kit may be saved and used in the following menstrual cycle if pregnancy does not occur.

Ovulation prediction kits offer the advantage that they allow you to predict when ovulation will occur - thus maximizing the chances that intercourse will be timed at your most fertile period. They can also be done in the privacy of your own home. However, they are expensive; and some of the kits have very tedious and involved testing procedures, so that errors are not uncommon.

A newer device, The ClearPlan EasyTM Fertility Monitor is a palm-sized, electronic system, that provides information about fertility status by interpreting the levels of two hormones, estrogen and luteinizing hormone, in the urine. You need to test your urine for the presence of these, using dipsticks, and the information is then input into the system, which uses it to calculate your fertile days.

Salivary ferning

Another way of monitoring ovulation is by using a pocket microscope to check for the phenomenon of "saliva ferning." You need to let your salivary dry on a glass slide, and then examine it under the device, to check for ferning. Prior to ovulation, the saliva shows the presence of crystallization or ferning when it dries, and this suggests that ovulation will occur soon. Though these devices are now commercially available, their reliability is still unclear.

Blood tests

The maturing follicle secretes the hormone estradiol in increasing amounts and its blood level rises rapidly several days prior to ovulation. If ovulation is being induced through fertility drugs, estradiol blood tests may be done on a daily basis in order to determine if the developing follicles are growing properly. Normally, the estradiol blood levels should increase rapidly (as a rule of thumb, they double every 24 hours). Each mature follicle produces about 200-300 pglml of estradiol.

Since the luteinizing hormone (LH) blood level rises rapidly just before ovulation (this is called the LH surge), frequent blood samples for measuring the LH level can also be taken a few days prior to the anticipated time of ovulation in an attempt to predict when the follicle is mature and ready for ovulation.
Abnormal ovulation

Abnormalities of ovulation may appear in several ways. Menstrual cycles shorter than 21 days or longer than 35 days are often associated with anovulation. In addition, patients may skip menstrual periods for time intervals of three months or more and this is called oligomenorrhea (infrequent periods). If the periods stop entirely, this is called amenorrhea.

Many hormonal systems work together to produce regular menstrual periods, and the blood levels of the hormones that make up these systems need to be tested in order to determine the reason for the ovulatory disorders.

The hormone blood tests, which are usually done on the third day of your cycle, include:

The FSH level: The FSH level gives a good idea of the ovarian reserve a index of the number of eggs remaining in the ovaries. A high FSH level suggests that the ovary has either failed or has started to fail. If the FSH level is very high (in the menopausal range) then the diagnosis is ovarian failure. If the level is elevated then some doctors will do a clomiphene stimulated FSH level which allows for an earlier diagnosis of failing ovaries. On the other hand, a low FSH level suggests hypogonadotropic hypogonadism. This seemingly verbose term simply means that the ovary in these patients is not working properly because of inadequate production of FSH by the pituitary gland. However, in most anovulatory patients, the FSH level will be in the normal range, and this can be reassuring.

The LH level: This is the other gonadotropin hormone produced by the pituitary; and provides much the same information the FSH level does. Another useful test is the LH:FSH ratio, which is normally 1:1.

If, however, the LH level is much higher than the FSH level, this suggests a diagnosis of polycystic ovarian disease.

Thyroxine and TSH: These tests for thyroid function. The thyroxine level is high in patients with overactive thyroid glands (hyperthyroidism). In patients with decreased thyroid function (hypothyroidism), the TSH level is increased.

Prolactin: Prolactin is a hormone produced by the pituitary gland that induces lactation or milk formation. High prolactin levels (hyperprolactinemia) can interfere with ovulation. A milky discharge from the breast nipple, not related to pregnancy or nursing, is called galactorrhea, and this is a telltale symptom of high prolactin levels and needs to be investigated. If the prolactin level is elevated, the doctor will need to recheck it to confirm it is persistently high. There are many reasons for an elevated prolactin level, including certain drugs as well as stress. In some women, the reason for a high prolactin level can be a small tumor in the pituitary gland. This is called a prolactinoma or microadenoma, and the doctor may advise you to have an X-ray of the skull (or even a CT scan or MRI scan) to rule out this possibility. However, most infertile women with hyperprolactinemia can be easily treated with a medicine called bromocryptine, which is a dopamine agonist medication. Another medication which can be used to treat hyperprolactinemia is oral cabergoline, which is usually taken twice a week. Only if the pituitary tumor is very large (macroadenoma) is surgical removal needed, and this is very uncommon.

Ovarian failure

Ovarian failure is a condition in which the ovaries fail to produce eggs. This is uncommon, occurring in only about 10% of women whose periods do not occur at all, a condition called amenorrhea (absence of periods). Ovarian failure may be genetic (for example, in girls with Turner's syndrome, a chromosomal disorder) or may be acquired (for example, following radiation or chemotherapy for cancer; surgery to remove the ovaries for treating ovarian cancer or severe endometriosis; autoimmune ovarian failure; or for unexplained reasons.) Ovarian failure is diagnosed by finding a high FSH level. In such patients it is usually not possible to stimulate ovulation, because they do not have any eggs, and they suffer a premature menopause. The only effective medical treatment for these patients is the use of egg donation for IVF or GIFT. However, in a very small proportion of these patients, ovulation can resume spontaneously.

Induction of ovulation

What forms of treatments are available for inducing ovulation?

The most commonly prescribed medicines for induction of ovulation include the following: clomiphene citrate, human menopausal gonadotrophin (HMG) and follicle stimulating hormone (FSH), HCG (human chorionic gonadotropin), bromocriptine, GnRH (gonadotropin releasing hormone) and GnRH analogue.

For women with hypogonadotropic hypogonadism (low FSH and LH levels), the treatment of first choice is HMG. This is effective replacement therapy; and excellent pregnancy rates can be achieved in these women.

For women affected by hyperprolactinemia, the drug of first choice is bromocriptine.

For most other women, the drug of first choice is clomiphene - the "workhorse" of ovulation induction. If this does not work, then HMG is resorted to.

Poor responders to HMG can be treated with GnRH analogues in conjunction with the HMG; or by adding a hormone called the human growth hormone (HGH).

HCG (human chorionic gonadotropin) is given to trigger off the release of the egg.

In patients with high androgen levels (high blood levels of male hormones), dexamethasone can be used as an adjunct, since this suppresses androgen production.

Often ovulation induction requires an investment of considerable time, money, energy and emotion before a satisfactory response is achieved. After all, every woman is different and there can be no standard "formulae". Careful monitoring of the response to ovulation induction is the key to therapy - and this usually involves daily ultrasound scans and/or blood tests. It is often a tedious process - which may involve "trial and error" to tailor the therapy to the individual patient's ovulatory response. With the treatments available today, however, correcting ovulatory dysfunction is one of the most rewarding and successful of infertility treatments.

Credits: Dr. Aniruddha Malpani, MD and DR. Anjali Malpani,