Clomiphene citrate is taken by mouth usually for 5 days soon after
the onset of the menstrual flow (I typically recommend cycle days
5-9). The lowest effective dosage of clomiphene citrate to accomplish
ovulation is best. The pills are marketed in only the 50 milligram
dosage. Common dosages are from 50 mg (1 pill) to 150 mg (3 pills)
per day.
Clomiphene citrate was synthesized in 1956. It was introduced
into clinical trials in 1960 and FDA approval for clinical use
came in 1967. The FDA approval was for a maximum total consumed
dose per cycle of 750 mg (a limit that is frequently surpassed).
Clomiphene citrate is composed of a mixture of two compounds that
share the same chemical composition but have a subtle difference
in shape (stereoisomers), referred to as zuclomiphene and enclomiphene.
Each of these stereoisomers of clomiphene has a different half
life in the circulation. The more bioactive isomer more rapidly
excreted so it will not accumulate from cycle to cycle. The less
active isomer is excreted slowly so it will potentially accumulate
over time if clomiphene is given month after month. The biological
effect of this accumulated clomiphene is not known.
The action of clomiphene citrate depends upon its ability to bind
the cell's nuclear receptors for estrogen for prolonged periods
of time. Clomiphene may bind estrogen receptors for weeks while
natural estrogens bind the nuclear receptors for only hours. This
difference results in a rapid depletion of cellular estrogen receptors,
and the body's cells are no longer able to detect circulating
estrogen accurately. This "perceived" decrease in circulating
estrogen results in an increase in hypothalamic GnRH and pituitary
FSH and LH. Increased FSH results in enhanced egg and follicle
maturation. Therefore, clomiphene citrate acts indirectly to "trick"
the brain into believing there is a lack of estrogen.
The primary site of action of clomiphene citrate in the brain
is the hypothalamus. If clomiphene is given to normally ovulating
women, there is an increase in the frequency of the FSH and LH
pulses but there is no increase in the pulse amplitude. This suggests
that clomiphene enhances hypothalamic GnRH pulse frequency. When
clomiphene is given to anovulatory women, it results in an increase
in the amplitude of the FSH and LH pulses without an increase
in frequency. This suggests that the frequency of the pulsatility
is maximal in the anovulatory women and the primary mechanism
of action of the clomiphene is therefore in terms of increased
amplitude of secretion.
In women with low estrogen concentrations clomiphene theoretically
is not effective, since its mechanism of action is to "trick"
the brain into believing that there is a low circulating estrogen.
When there already is a low circulating estrogen, the FSH and
LH should be near maximal without medication. However, it has
been found clinically that an occasional woman with hypogonadism
(especially if the FSH is also low) will ovulate with clomiphene
and so it can reasonably be tried.
The optimal duration of treatment for clomiphene has not been
clearly established. The literature is conflicting. One classic
study used life table analysis (a sophisticated statistical technique
that calculates rates per month [or other convenient unit of time]
and removes subjects that drop out of the study after a period
of time) to follow the results of clomiphene treatment in about
160 women with ovulatory dysfunction and found that the most important
factor contributing to reduced pregnancy rates was patient discontinuation
of medication. This study suggests that clomiphene treated cycles
have high fecundity rates until at least 10 to 12 months. Other
studies have suggested that 75% of pregnancies to occur on clomiphene
occur within 3 months and that pregnancies are uncommon after
6 months of therapy. To date, there is no really solid information
that can resolve these conflicts. I have used between 3 and 12
months of treatment.
It is not clear if human malformations increase when clomiphene
is taken in early pregnancy, but it is certainly advisable to
carefully avoid its use if there is a chance of pregnancy. In
rats and rabbits, clomiphene taken during pregnancy at the time
of fetal organ development resulted in a dose dependent increase
in malformations. A woman taking clomiphene should always confirm
that she is not pregnant prior to taking the medication. There
is no increase in miscarriages for pregnancies resulting from
clomiphene induced or enhanced ovulation.
The main side effects of clomiphene include (but are not limited
to)
- * hot flashes (up to 10%)
- * abdominal distention and discomfort, breast tenderness,
and headaches,
- * mood swings (which can reportedly be dramatic), and
- * visual alterations (1-2%).
These side effects generally occur when taking the drug. Relatively
long lasting side effects do not usually last for more than a
few days after discontinuing the medication.
Complications of clomiphene may include
- * multiple pregnancies (twinning rate of about 8-10%,
triplets are rare),
- * ovarian cyst development or ovarian hyperstimulation
syndrome (with abdominal bloating, possibly serious dehydration,
and tender sore ovaries) and
- * counterproductive alterations in the cervical mucus
around ovulation (in about 15% of women on clomiphene the peri
ovulatory mucus is less receptive to sperm and may pose a barrier
to fertilization).
Ovarian cyst development is rare but should not go unnoticed.
This is the basis for a clomiphene-check office visit during the
first few days of the menstrual flow that follows the first successful
(ovulatory) cycle on this medication. Additionally, the basal
body temperatures can be reviewed and treated accordingly. Cervical
mucus should be checked for hostility to sperm during a cycle
on clomiphene once the woman is successfully ovulating, via a
postcoital test.
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