Clomiphene citrate and femara are fertility drugs taken orally for the purpose of inducing ovulation (the release of one or more eggs). It is often a first line of treatment in young women (less than 40 years of age) who fail to ovulate (anovulatory), ovulate irregularly (oligo-ovulatory), and women who ovulate abnormally with associated hormone imbalance (dysovulatory). These medications have never been associated with the development of birth defects in humans.
Clomiphene and femara are administered for five days during the early menstrual cycle. Some clinicians prescribe the drug from the 5th through the 9th day of the cycle. However, we prefer that the drugs be taken from cycle day 1 through 5 because there is some evidence that the earlier the drug is administered, the more likely it is to promote the development of the optimal number of follicles (fluid-filled spaces in the ovaries that contain the maturing eggs and produce the hormone estrogen) without affecting the lining of the uterus.
Clomiphene citrate is rarely associated with life-endangering complications. Some women experience hot flashes, minor visual disturbances, flatulence, and a reduction of menstrual flow after prolonged clomiphene use. However, these symptoms are all reversible upon discontinuing clomiphene therapy. In some cases, cysts will develop and remain for 4-6 weeks following discontinuation of Clomiphene therapy. These cysts are harmless. Very rarely, a large number of cysts will develop in association with very high levels of estrogen, resulting in accumulation of free fluid in the abdominal cavity and symptoms such as vomiting, diarrhea, and abdominal distention. This is referred to as hyperstimulation syndrome and is very rare in association with clomiphene citrate. It occurs more commonly (although still fortunately unusually) in association with hMG/FSH therapy. The reported pregnancy rate following the appropriate use of clomiphene is between 15% and 20% per ovulatory cycle of treatment, provided that there is no associated pelvic disease, that the husband is fertile, and that the primary problem relates to irregular or abnormal ovulation. However, this rate is much less for women who are ovulatory without the medication.
Clomiphene acts by blocking the ability of cells in the hypothalamus (a specialized area of the brain which orchestrates the body’s hormonal changes), to detect the amount of estrogen (a hormone produced by the ovarian follicles) in the blood. When the hypothalamus senses a deficiency of estrogen, it responds by releasing messages to the pituitary gland (a small structure suspended by a stalk from the base of the brain, located above the roof of the mouth). The pituitary gland in turn releases superphysiological amounts of FSH. FSH initiates the growth of ovarian follicles.. Estrogen prepares the uterine lining to receive the embryo(s) about six days after ovulation. As soon as estrogen levels rise sufficiently, either in response to clomiphene or in natural cycles, it will initiate a sudden release of luteinizing hormone (LH – also produced by the pituitary gland). LH triggers the ovulation process while at the same time causing maturation of the eggs to be released. When clomiphene is administered, a spontaneous LH surge will usually take place. However, in order to ensure that ovulation actually occurs, we sometimes recommend the administration of human Chorionic Gonadotropin (hCG, a hormone produced during pregnancy which is similar to LH in structure and effect), at the time the follicle(s) have attained optimal growth as indicated by ultrasound examination. Patients who receive clomiphene from cycle day 2 through 6 can expect the peak response around cycle day 12 of treatment. Therefore ultrasound examinations are performed at about this time and the follicles are expected to be 20 to 24 mm. In mean diameter. HCG has an action similar to that of LH. Accordingly its administration on the 12th day of the stimulated clomiphene cycle is an effort to assure that ovulation occurs even if the pituitary gland does not initiate its own LH surge.
Although clomiphene is only administered for five days, its effect is maximal in the period following discontinuation of its administration. At the time of ovulation, blood levels of clomiphene are very low. Because clomiphene alters the ability of cells to respond to estrogen, it is necessary for the ovaries to produce increased amounts of estrogen to promote the development of an endometrial lining (endometrium) which is thick enough to allow proper implantation to occur. In natural cycles, 150-200pg/ml of estrogen will produce a good lining. Because of the anti-estrogenic effect of clomiphene, it is necessary for the ovaries to produce two or three time this amount (a plasma estradiol concentration of 400-600 pg/ml) in clomiphene cycles. This requires the development of three or more follicles. Older women (more than 40 years of age), often do not have the capability of producing that many follicles and accordingly are poor responders to clomiphene. Indeed, some women, especially women with polycystic ovary syndrome, have no response to clomiphene, and it is necessary to proceed to injectable drugs.
There is a higher multiple pregnancy rate in women who conceive following clomiphene citrate therapy (5%-10%). The incidence is far less than that which has been reported in association with hMG and/or FSH therapy (25%-30%). In most cases, the multiple pregnancies will be twin gestations
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