Clomiphene
(Clomid or Serophene)
Clomiphene is a drug that is used to either stimulate ovulation in women who do not ovulate at all or, occasionally, it is used to help correct abnormalities of ovulation. It may also be used to help control the day of ovulation in women who must undergo other types of infertility procedures such as donor insemination.
Clomiphene works by blocking the estrogen receptors in the brain. This fools the brain into thinking that the estrogen level in the body is lower than it really is. The brain responds by increasing the hypothalamic production of GnRH and the pituitary production of FSH and LH - the hormones that stimulate ovulation. The increased FSH and LH production then stimulates the ovary to initiate the production of a mature egg.
Imagine what would happen if you wrapped your thermostat at home with an ice-pack. The thermostat would sense that your home is colder than it really is and would respond by turning on the furnace. Clomiphene produces the same effect. The hypothalamus is the thermostat, GnRH is the signal, and the pituitary is the furnace. The increased FSH & LH produced by the furnace would by the heat.
It is critically important to understand that estrogen is the principal stimulatory hormone for the entire female reproductive tract. Clomiphene not only blocks the effect of estrogen in the brain, it blocks the effect of estrogen everywhere in the body.
Clomiphene is an effective drug. If a woman does not ovulate at all, and if she has a menstrual period when given Provera, she is a good candidate for Clomiphene and 90% ovulation rates can be expected. However, only 40% of women who take Clomiphene will conceive.
There are many reasons for this gap between ovulation rates and pregnancy rates and most are probably the result of Clomiphene's ability to block estrogen function everywhere in the body. Clomiphene may, therefore, interfere with cervical mucus production which is necessary for sperm transport. It may interfere with the development of the lining of the uterus. It may interfere with the activity of the fallopian tube which is necessary to transport both the sperm and the egg. As proof of this last fact, it is now well documented that women who conceive while taking Clomiphene have a increased incidence of tubal pregnancies.
Another reason for the discrepancy between ovulation rates and pregnancy rates is the fact that even though Clomiphene may induce ovulation, that ovulation is not always "normal". The hormone production (i.e. progesterone) following ovulation may be below normal. Other hormonal abnormalities are also created that make conception less likely.
Estrogen is also responsible for the development of the endometrium (the tissue that lines the uterus). If endometrial development is poor, the early embryo will not have a proper place to implant and grow. A great deal of attention has recently been paid to the development of the endometrium and we have discovered that a large group of women with otherwise unexplained infertility have significant abnormalities in the development of the endometrium.
Since estrogen stimulates the endometrium and since Clomiphene is an anti-estrogen, it is not surprising that women on Clomiphene will often have poor endometrial development.
Various options have been devised to help correct these problems. The simplest and easiest way to make sure that adequate progesterone is produced after ovulation is to give every woman on Clomiphene a shot of HCG at the time of ovulation. This stimulates the progesterone production following ovulation. Some physicians have advocated the use of progesterone, either orally or as suppositories, but I have found the HCG is easier, though the other therapies are also effective.
The reason for this approach is that it is simple. The ideal way would be to test each woman with an endometrial biopsy or hormone levels to see if she truly has an ovulatory abnormality while taking Clomiphene. If she had a problem, then additional therapies would be given. The woman would, however, have to be retested to make that the problem had been corrected. This would add several extra months to the whole process, it would add extra expense and endometrial biopsies are often painful.
Furthermore, some women would have a problem in one cycle but not in others. Therefore, a shot of HCG at ovulation is simply the easiest and cheapest of making sure that progesterone production following ovulation in the woman taking Clomiphene is adequate.
The problems created by the anti-estrogen effects of the Clomiphene are another matter altogether. It would seem logical to simply give estrogen and indeed, this has been tried. Unfortunately, it does not work. The levels of estrogen necessary to create good mucus or a good endometrial cavity are so high that they block the ovulation-stimulating effect of the Clomiphene. Therefore, the only effective therapy for the woman with poor mucus or a poor endometrial cavity is to switch to Pergonal.
There has been some evidence that aspirin improves the quality of the endometrium even if the thickness does not increase. However, it is preliminary data and my opinion is that Pergonal is the better approach.
Clomiphene is usually a well tolerated drug. There are no serious side effects associated with its use and there are no known risks of the drug itself.
Clomiphene is associated with a slightly increased rate of multiple pregnancies. 3-5% of women who conceive on Clomiphene will have a multiple pregnancy, usually twins or rarely triplets.
Side effects from Clomiphene are also uncommon. Hot flashes may occur. Occasional women will notice some mood changes; visual symptoms may also occur. Some women will notice bright flashing lights and occasionally will notice some blurred vision. These latter symptoms may be somewhat annoying but have never been shown to be dangerous.
Recent studies suggest that Clomiphene should only be given to women with a documented ovulation problem. Many infertile women are given Clomiphene without any reason other than a "try it to see if it works" philosophy. In fact, Aetna-USHealthcare's infertility program (canceled as of April 1,1998) actually required the general OB/GYN to give the woman 3 cycles of Clomiphene before she could be referred to a Reproductive Endocrinologist. If Clomiphene is given to a woman who is ovulating normally, there is some evidence that it may actually lower her chances of becoming pregnant.
Dosage and Monitoring
Clomiphene is a tablet. It is started on the 3rd day of your menstrual cycle. (The first day of your menstrual flow is always counted as "day 1". Count only the first day of the true flow - any premenstrual spotting or staining should not be counted.)
The Clomiphene tablets are usually taken for 5 days. The time of day that the medication is taken is not important. It may be taken with milk or food and it does not interact with any other drugs.
If it is necessary to take higher doses of Clomiphene, I would ask that you split up the dosage. If you are taking two tablets a day, please take one in the morning and one in the evening.
If you are taking 3 tablets a day, a breakfast, dinner and bedtime regimen should be followed.
For those women taking 4 tablets a day, take 2 in the morning and 2 in the evening.
The first cycle that you take the Clomiphene, I will need to see you in the office the day you will begin taking the Clomiphene. Baseline hormone levels and an ultrasound evaluation is obtained. I will then also see you back on the day after the last Clomiphene for another evaluation. In this way, I can determine whether the Clomiphene is working properly, whether your "Ovarian Reserve" is normal, and whether it is an effective drug for you. If it is not, there is no sense prolonging what we now recognize may be a less than effective therapy.
If the days you should be seen falls on a weekend or holiday, I would like to see you the last day I am in the office before the weekend or holiday.
At the time of your office visits, blood tests and ultrasound examinations will be carried out to determine how your ovary has responded to the medication.
I will see you next at the time of your cycle when the egg(s) will be mature and ready to ovulate. I would also ask that you have intercourse prior to this office visit. Ideally, you should have intercourse the morning of your visit. However, some people's schedule are such that this is not practical. In such instances, please have intercourse the night before.
At the time of your visit, I will also check your cervical mucus. Although the effect of Clomiphene on cervical mucus has been exaggerated, it nonetheless can occur. Doing a post coital test is the only way to determine whether your cervical mucus has been affected or not.
Please tell the office staff if you are to have a post-coital test so that it can be done before the ultrasound.
At the time of your visit or at some time thereafter, depending upon the blood tests and ultrasound measurements, the HCG is given to trigger ovulation and to insure proper hormone production following ovulation.
If a woman does not conceive in any one cycle, she can expect her menstrual period 16-18 days following the HCG injection. If more than 18 days elapse, please let us know immediately because it means that you are probably pregnant.
Studies have shown that if Clomiphene is going to be successful, it will work in the first 4 cycles. 90% of the pregnancies that are going to occur on Clomiphene will occur in the first 4 good ovulatory cycles. If 4 cycles have been tried and a pregnancy has not resulted, alternative studies and therapies should be considered.
Risks
Women with liver disease should not use clomiphene citrate. Patients with abnormal or irregular uterine bleeding should be examined for endometrial or cervical abnormalities before treatment. This medicine should not be given to patients with ovarian cysts, since they may grow larger. It should not be taken by a patient who may be pregnant, although there is no proof of fetal damage. If a patient has not had a menstrual period for a significant length of time, there may a benefit from inducing menstruation with progesterone before using clomiphene citrate therapy.
Some patients who use clomiphene citrate get blurred vision or other visual symptoms. In these cases, driving and operating machinery may be dangerous, especially in conditions of variable lighting. If eye symptoms persist, therapy should be stopped, and the patient should have a complete eye examination. Common side effects include ovarian cysts and ovarian enlargement. Some women feel "throbbing" in the ovaries before ovulation, and others report occasional "hot flashes," insomnia, or irritability. About six percent of clomiphene citrate-induced pregnancies are multiple pregnancies, which is more common than for spontaneous ovulation. Most of the multiple pregnancies are twins.
Clomiphene Abuse
Too often, doctors give clomiphene to women with unexplained infertility before the couple has a fertility workup, or even after they have a workup, but there is no evidence of an ovulation disorder. This empiric therapy may create new problems, such as interfering with fertile mucus production, and often delays further evaluation that can lead to a specific diagnosis and proper treatment.
For a woman who has normal, spontaneous ovulation, driving the pituitary harder with clomiphene won't make ovulation any more normal. If a woman has taken clomiphene for several cycles without becoming pregnant, then she and her fertility specialist should investigate other conditions that may be preventing her pregnancy.
After noting a good postcoital test (PCT) during a fertility workup, some doctors fail to repeat the test after placing a woman on clomiphene. A PCT needs to be repeated to check the quality of the woman's cervical mucus while she is on clomiphene, since 25 percent or more of women who take the drug develop cervical mucus problems. It's important for a woman to monitor her cervical mucus production during every cycle while trying to become pregnant, including her cycles while taking clomiphene
