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Clomiphene Citrate
Clomiphene citrate (Clomid, Serophene) is the most commonly used medication for women with impaired fertility. Clomiphene is relatively inexpensive and is taken orally. Clomiphene fools the pituitary into thinking that the ovaries are not producing any estradiol by blocking the effect of estradiol on the pituitary. In other words, although there may still be plenty of estradiol around, the pituitary does not think so because it can't see it. The pituitary responds to this apparently low estradiol level by increasing the production of FSH, which in turn increases the stimulation to the ovary. In response to higher levels of FSH, the ovary becomes more likely to produce a mature egg.
Clomiphene is most useful in women with irregular, or even absent, ovulation. Clomiphene is typically given for five days beginning on either day four or day five of the cycle. The lowest dose of clomiphene is fifty milligrams, or one tablet. This should almost always be the starting dose. The response to clomiphene can be monitored with any combination of the tests mentioned above, including temperature charts, ultrasounds and progesterone levels. At the lower doses (fifty or 100 milligrams per day), simple recording of a BBT and a progesterone level in the mid-luteal phase are probably adequate. At higher doses (some physicians will use doses up to 250 milligrams), ultrasounds should be performed and hCG (see below) given if the follicle(s) has reached mature size. hCG functions as a signal to the follicle, just as LH does, that it is time to release the egg, or ovulate.

Side Effects of Clomiphene
Clomiphene is associated with a fair number of side effects. A small percentage of women will experience mild headaches, bloating, hot flashes or visual symptoms (you should notify your physician if you experience visual effects). A rather large percentage of couples report that the use of
clomiphene results in some emotional instability. If you are taking clomi-
phene and find that your emotions are a little hard to control, especially in the second half of the cycle, blame it on the clomiphene.

There are no known risks to the fetus or adverse effects on the infant should conception occur. Ovarian cysts may occur in some individuals on clomiphene, but if no additional clomiphene is given, the cysts will almost always resolve on their own. For this reason a pelvic exam or an ultrasound should be performed between cycles of clomiphene to be sure the ovaries have returned to normal before more clomiphene is taken. There is some increase in the risk of multiple pregnancies with clomiphene. Women who conceive have about a seven percent chance of twins. The risk of triplets, quadruplets, etc. is not really increased.

Other Considerations Concerning Clomiphene
Either a dose works, or it doesn't. If taking fifty milligrams a day does not result in normalization of ovulation (and therefore your cycle) one month, there is no point in trying that dose again. The dose needs to be increased the next month. More is worse, not better. Once the dose that normalizes the cycle and results in good ovulation and progesterone production is determined, there is no point in increasing the dose further. In fact, increasing the dose further may actually make it harder or even impossible to get pregnant. Remember: Clomiphene functions by preventing the pituitary from seeing the estradiol that is present. It does the same thing to the cells that produce the cervical mucus and to the cells that line the uterus if they don't see the estradiol, the cells of the cervix won't produce the mucus, or the cells lining the uterus won't develop to an extent adequate to allow implantation. Everyone has a threshold dose of clomiphene (the dose that normalizes ovulation). Going beyond that dose does more harm than good.

Clomiphene is an antiestrogen. This means that it does indeed prevent some cells from seeing the estradiol and because of this blocks the action of estradiol on those cells. The possibility of this type of effect needs to be checked once the threshold dose is achieved. This should include a post-coital test to be sure that there is adequate cervical mucus production, and a measurement of the thickness of the endometrium by ultrasound to be sure that it is developing to an adequate thickness. Normal endometrium develops to about ten millimeters in thickness; an endometrial thickness of seven millimeters or less is associated with very poor pregnancy rates. This is often a problem at some of the higher doses of clomiphene although it results in ovulation, there is enough of an antiestrogen effect on the cervical mucus or endometrium to prevent pregnancy from occurring even though ovulation is normalized.

The vast majority of the pregnancies that occur as the result of the use of clomiphene occur within the first four ovulatory cycles. Once the threshold dose is achieved, there is really little point in pursuing the use of clomiphene beyond four, or certainly six, cycles at most. (The chances of conceiving in a cycle of clomiphene beyond the fourth may be as low as three to four percent, and decrease even further soon thereafter.) There is another reason for limiting the number of cycles of clomiphene. There is at least one study suggesting that the use of clomiphene for more than a year is associated with an increase in the risk of ovarian cancer.

Finally, and perhaps most importantly, there is no role for clomiphene in a woman with regular ovulatory cycles. There is absolutely no good evidence that clomiphene improves pregnancy rates in women with normal cycles. It is not a fertility enhancer and, in fact, because of its anti-estrogen properties, it can actually make it harder to get pregnant rather than easier.