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Suheil
J. Muasher, MD, F.A.C.O.G.
Professor of Obstetrics and Gynecology
Medical Director, The Muasher Center
for Fertility and IVF,
Fairfax,VA
CLOMID, (Clomiphene Citrate) is the most used and
abused medication for infertility treatment. It was
introduced to the clinical market in 1967 and almost
immediately replaced the surgical procedure - wedge
resection of the ovaries - for primary treatment of
anovulation in patients with polycystic ovarian disease
(PCOD, Clomid and PCOS).
Clomid is still widely used
by gynecologists for that purpose and others. It is
important to remember that proper use of the
medication
will usually yield gratifying results while expanding
its use to lesser indications may be counterproductive
and often results in unsuccessful outcomes.
Clomid's best
and most common indication is for induction of ovulation
in euestrogenic, normoprolactinemic, and anovulatory
patients. The majority of these patients will have PCOD,
which is a clinical diagnosis of chronic anovulation
with symptoms and signs of Hyperandrogenism.
The definition implies that there is adequate
endogenous estrogen production and that hyperprolactinemia
has been excluded. Patients with hypoestrogenic anovulation
are not good candidates for Clomid as it works as an
antiestrogen at the hypothalamus level.
Examples of patients with hypoestrogenism
are those with premature ovarian failure, exercise-related
amenorrhea, and low body weight with anorexia. Clomid does not work well in patients who are overweight.
The second indication for clomiphene use is for the
purpose of superovulation, in ovulating patients, in
conjunction with assisted reproduction such as intrauterine
insemination (IUI) or in-vitro fertilization (IVF).
Clomid
may also be used to treat patients with luteal phase
defects in conjunction with progesterone supplementation
in the luteal phase. The wide use of Clomid to treat
patients with unexplained infertility can be counterproductive
as Clomid can have adverse effects on the cervical mucus
and on implantation at the endometrial level.
Clomid
can be considered in young patients (< 30 years)
but certainly for no longer than three cycles and with
proper monitoring. (Patients should be on a basal body
temperature chart and a post coital test should be performed.)Clomid
is started at a dose of 50 mg / day for 5 days in anovulatory
patients. It is important to remember that these patients
do not have cycles and the conventional "cycle
day 5 - 9" should not be used. Rather, the first
day of clomiphene use can be conveniently called day
1 of the cycle. Patients should look for ovulation,
wither by a BBT chart or using an ovulation predictor
urinary test, 7 to 10 days after the last clomiphene
pill or on days 12 - 15 of the clomiphene cycle (first
day of Clomid is day 1).
Clomid in some thin patients dosed at 25 mg / day for
five days can be adequate. A post coital test can be
performed in the first cycle of clomiphene use to check
for adequate mucus production. f patients ovulate on
the 50 mg clomiphene dose, they should be kept on it
for 3 - 4 months before re-evaluation. If patients do
not ovulate on the lower dosage,clomiphene should be
increased in increments of 50 mg / day for subsequent
cycles.
It is important to remember that 70 -80% of patients
who will respond to Clomid will ovulate on the 50 -
100 mg dosage and of those who get pregnant 80 - 90%
will do so within 3 - 4 ovulatory cycles.
What to do about Clomiphene failures? When clomiphene
fails, it is extremely important to distinguish between
ovulation and conception failure
.1.Clomid
Ovulation Failure: This is arbitrary defined as
failure to ovulate on doses of 150 mg / day for 5 days
(even though 10 - 20% of patients can ovulate on higher
dosages, it is important to re-evaluate the patient
at this stage. Clomiphene is also approved by the FDA
for a maximum dose of 750 mg / cycle.)
a)Clomid doses can be increased to a maximum of 250
mg / day for five days or consider increasing the duration
(100 mg / day for 8 days).
b) Clomid does not work well in extremely obese patients
(> 200 lbs or BMI > 30).These patients usually
have insulin resistance and those patients should be
highly encouraged to lose weight before induction of
ovulation. Insulin sensitizing agents such as Metformin
(Glucophage) should be the primary treatment. Metformin
can be started at the dose of 500 mg / day for one week,
increased to 500 mg p.o., b.i.d. for the next week,
and maintained at 500 mg p.o. t.i.d. from the third
week onwards.
Patients
should be placed on a BBT chart while on Metformin therapy.
Approximately, 35 % of patients will ovulate on Metformin
and weight loss only within 2 to 3 months of therapy.
For those patients who fail to ovulate on Metformin
alone, Clomid can be added at a dosage of 50 mg
/ day for five days. 80-90% of those patients will ovulate
on Metformin and clomiphene therapy.
c) Low dosage gonadotropin treatment (75 IU / day) can
be used for those patients who fail to ovulate using
the above regimens. It is important not to increase
this dose for at least 12-14 days as the object in these
patients is to make them ovulate and not to super-ovulate
them. This treatment should only be used by a reproductive
endocrinologist with experience in the use of Gonadotropins.
d) Laparoscopy with multiple electrocoagulations of
the follicles (modern day wedge resection or "golfball"
procedure) on the surface of the ovaries can be considered
as a last resort as it is a surgical procedure and ovarian
adhesions can result from it.
e)
IVF can also be considered for these patients who should
be watched for multiple pregnancy and ovarian hyperstimulation
syndrome (OHSS).
2. Clomid Conception Failure: This is defined as
failure to conceive after six documented ovulatory cycles
on clomiphene. These patients become like any other
patients with unexplained infertility and care should
be taken to complete the infertility work-up if it has
not been done yet including a semen analysis, HSG, post
coital test, endometrial biopsy and laparoscopy to check
for pelvic adhesions and or / endometriosis.
What
are our opinions for these patients:
a) Low dose gonadotropin use with IUI can be considered
although these patients are at risk for multiple pregnancy
and OHSS.
b)
IVF should be strongly considered, as this can be a
diagnostic as well as a therapeutic procedure.
Clomid
patients should be properly monitored to maximize the
success and guard against potential side effects, including
adverse affects on the cervical mucus and ovarian cyst
formation. Patients should not be put on Clomid for
more than 3 cycles before re-evaluating the treatment.
Clomid
use for longer than 12 cycles has been associated with
an increase incidence of ovarian cancer; therefore,
the medication should be used judiciously and whenever
the benefits outweigh the risks.
Clomid
is usually successful within 3 to 4 ovulatory cycles.Use
beyond this time frame is generally not recommended.
As such it is extremely important for the gynecologist
to be familiar with the proper indications and the limitations
of this therapy.
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