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Chapter 13b
Ovulation -- Normal and Abnormal

from the book How to Have a Baby: Overcoming Infertility
by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.

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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 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 which 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 have 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 abroad (or in India at a few chemists) 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 percent 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 maximising 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 dip sticks, and the information is then input into the system, which uses it to calculate your fertile days.

Salivary ferning

Another way of monitoring ovulation uses a pocket microscope, to check for the phenomenon of "saliva ferning." You need to let your saliva dry on a glass slide, and then examine it under the devise, to check for ferning. Prior to ovulation, the saliva shows the presence of crystallisation 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 growing 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).

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 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 borderline, 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 tumour in the pituitary gland. This is called a prolactinoma or microadenoma, and the doctor may advise you 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 tumour is very large ( microadenoma) is surgical removal needed, and this is very uncommon.

Ovarian failure

Ovarian failure is a disease in which the ovaries fail to produce eggs. This disease 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 cancers; 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 and they 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 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.

by Dr. Aniruddha Malpani, MD and Dr. Anjali Malpani, MD.

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