Complications of these medications (menotropins) might include
multiple pregnancies, ovarian hyperstimulation syndrome, premature
LH surge, irregular follicular development, and ovarian torsion.
Theoretically, there is a potential association with ovarian cancer.
(1) multiple pregnancy
* Multiple pregnancies associated with menotropins are
more common and of higher order than those associated with clomiphene
citrate. In natural cycles, the twinning rate (in the USA) is
about 1 in 90 and the triplet rate about 1 in 8000. In clomiphene
cycles, the twinning rate is about 1 in 12 and the triplet rate
is about 1 in 150. In menotropin cycles, the twinning rate is
about 1 in 4, the triplet rate about 1 in 20 and quadruplets or
quintuplets are uncommon.
* At the point of triplets or more, the combined risks
of morbidity or mortality to the pregnant woman and fetuses are
greater than that of the selective reduction procedure (at a center
with significant experience in performing this procedure). Selective
reduction is a procedure that is done to reduce the number of
pregnancies, typically down to two. It does involve terminating
one or more growing pregnancies and therefore should be discussed
carefully by the couple. A decision on selective reduction may
involve moral, ethical, religious, medical, personal and emotional
factors. The decision ideally should be made prior to the initiation
of a cycle, while the couple is able to consider the variables
without time limitations or the stress of knowing that there is
a triplet or greater order multiple pregnancy growing.
(2) ovarian hyperstimulation syndrome (OHSS)
* OHSS is a potentially serious and often uncomfortable
complication of menotropin therapy. The syndrome may occur days
to a few weeks following ovulation (the Profasi shot) when more
than one follicle has developed. OHSS is caused by an unknown
process that occurs within the ovaries, producing a substance
(not yet identified) that allows the water from within the body's
blood to leak out of the blood vessels into the pelvis and abdomen
(resulting in abdominal distention, bloating and dehydration).
The ovaries become very fragile (easily traumatized) so that any
sudden motion or even relatively mild flexion (bending) at the
hip (such as typing at a desk) can cause pelvic pain. The patient
must drink large amounts (1-2 liters) of a balanced electrolyte
solution (Gatorade or Pedialyte are good) to replace the water
that is collected in the pelvis (rehydration). She also must try
to limit her activities to avoid ovarian trauma and pain.
* In severe cases of OHSS, hospitalization with an intravenous
catheter (for fluid replacement) may be required. Rarely, fluid
can also collect around the lungs to limit breathing (resulting
in shortness of breath), or the dehydration can be so severe that
the patient is at risk for renal (kidney) failure (shutdown),
abnormal blood clotting and/or pulmonary emboli. The treatment
of OHSS is fluid replacement, limited activity (possibly bedrest)
and supportive care. Medications to assist in kidney function
(such as IV dopamine) and/or mechanical removal of some of the
abdominal fluid that has collected (with a needle ideally under
ultrasound guidance) can be quite helpful.
* As a rule, OHSS will not occur if the hCG (Profasi) injection
is withheld. This results in the slow removal of the follicles
that have developed and also prevents (in all but rare cases)
ovulation. The risk for severe OHSS is correlated (roughly) to
the number and size of the ovarian follicles (on ultrasound) and
the serum estradiol concentrations (in the monitored bloodwork).
Therefore, cycle monitoring is absolutely essential during controlled
ovarian hyperstimulation with menotropins.
(3) premature LH surge
* A premature LH surge (trigger to ovulate) may occur during
menotropin therapy. There is apparently a substance (not yet identified)
that inhibits ovulation during the maturation of eggs using menotropins.
In a natural cycle, the signal from the brain to the ovary to
trigger ovulation (the LH surge) appears to occur once the serum
estradiol level reaches a certain concentration (about 250 pg/ml)
for a certain length of time (about 2 days). In a cycle using
menotropins, the serum estradiol level may be greater than 250
pg/ml for much longer than a week without triggering ovulation.
Therefore, the existence of a natural "ovulation inhibitor"
has been postulated. In possibly 5-20% (1 in 20 to 1 in 5) of
women undergoing menotropin therapy there may be a premature LH
surge. If this occurs, the use of a GnRH agonist such as Lupron
or Synarel may prevent ovulation in future cycles. These medications
suppress the ovaries so that higher dosages of menotropins are
usually required to accomplish multiple follicular development.
(4) suboptimal development of mature eggs
* Irregular or limited development of follicles can occur
on menotropins. At the onset of a menstrual flow follicles prepared
for the cycle have begun to develop (FSH normally rises a few
days prior to the onset of menstrual flow). In some cycles of
COH only 1 or 2 eggs mature. In these cycles, the FSH is apparently
taken up by one or two follicles that have developed enough FSH
receptors and blood supply to "outcompete" the other
follicles for FSH. This is an expensive and disappointing way
of developing 1 mature egg since most women using the medication
mature one egg per cycle on their own. GnRH agonists (such as
Lupron and Synarel) suppress ovarian follicular development so
that when started about 1 week prior to the expected menstrual
flow they "even out" follicle development at the onset
of the upcoming cycle. This improves the chance for multiple egg
maturation if the patient has a history of irregular egg development
on menotropins.
(5) ovarian torsion
* ovarian torsion is the twisting of an ovary on its ligamentous
supports. The ovary is essentially tethered between the uterus
and the pelvic sidewall by the uteroovarian ligament (between
the uterus and ovary) and the infundibulopelvic ligament (between
the ovary and the pelvic sidewall). If the ovary becomes very
large and irregular, there is an increased chance that the ovary
will twist on these supporting structures. These ligaments that
hold the ovary in place also contain the blood supply to the ovary,
so if they twist there can be both a great deal of discomfort
as well as an interruption in the ovarian blood supply. The torsed
ovary can become necrotic ("dead") in which case it
will usually need to be removed. Fortunately, ovarian torsion
with COH is uncommon.
(6) ovarian cancer
* a serious potential complication of these ovulation promoting
medications is ovarian cancer. Overall, about 1 in 70 women in
the USA develop ovarian cancer in their lifetime, with widely
recognized risk factors for ovarian cancer including low parity,
decreased fertility and delayed childbearing. It is also known
that oral contraceptive pills decrease the incidence of epithelial
types of ovarian cancers, presumably as a result of inhibition
of ovulation. This epidemiological information has led to the
theory that "the more a woman ovulates the greater her chance
for developing ovarian cancer." Unfortunately, there is almost
no appropriate information available to either support or reject
this theory. The follow up theory as it relates to fertility medications
is that "fertility medication that causes the maturation
and release of more than one egg in a month may enhance the chances
of developing ovarian cancer." Again, no adequate information
is available to either accept or reject this theory.
* Concern with an association between ovulation and ovarian
cancer is not new.
* As early as 1971 it was proposed that each ovulation
results in a small area of trauma at the ovulation site that is
then repaired. A disruption in the repair process may somehow
result in an abnormal and uncontrolled growth of this tissue (cancer).
* In 1978, it was noted that the inclusion cysts that are
occasionally found in epithelial ovarian cancers resemble the
inclusion cysts that result from some ovulation and repair cycles,
and the theory was proposed that the inclusion cysts in some way
cause epithelial ovarian cancers. Since the 1970s, the thought
has persisted that fertility drugs enhancing the number of ovulations
(albeit generally a small increase in comparison to the total
number of ovulations in a typical reproductive lifespan) may also
increase the chance for an accident in the repair process that
results in ovarian cancer.
* Articles published on these concerns have been widely
publicized by the mass media. Unfortunately, the information collected
in the published reports does not allow a firm position on the
issue of a relationship between fertility drugs and ovarian cancer.
* One widely publicized article from 1992 (A.S. Whittemore
and colleagues) reviewed the data from 12 case control studies
and suggested that the risk of developing ovarian cancer is increased
in women who have used "fertility drugs." The risk was
greatest in women who had never been pregnant. On critical review
of this study, it is seen that detailed information on fertility
drugs was only available in 3 of the 12 studies (leaving a total
number of 96 infertile women with cancer compared to a control
group of only 135 infertile women) and the particular fertility
drugs used by these women was not identified. Perhaps the most
important criticism of this study regards the ages of the cancer
patients in comparison to the dates that the cancers were diagnosed.
The average age at diagnosis was 53 and the time of diagnosis
was 1977-1981, meaning that if it is assumed that the women were
30-40 at the time of fertility medication treatment then the actual
years of treatment were between 1954 and 1967. Clomiphene citrate
was not FDA approved until 1967, menotropins until 1969 and bromocriptine
until 1978, so that it appears impossible that these were the
drugs referred to in the reviewed articles.
* The National Cancer Institute of the The National Institutes of
Health issued a call for abstracts ("RFP NCI-CP-40513-21" 1993)
to study the association between ovarian cancers and "fertility evaluation
and treatment" soon after this publication, and suggested that given the
relative rarity of the disease (1 in 70 in the USA) a reasonable
study of relative risk would need to include 10,000 women.
This is a far greater number of subjects and total amount of exposure than is
contained in any study to date.
* A second widely publicized article from 1994 (M.A. Rossing
and colleagues) compared a cohort of 3800 plus women evaluated
for infertility between 1974 and 1985 in Seattle and found that
there were 11 ovarian cancers among these women as compared to
an expected number of 4.4. The 11 cancers consisted of 5 borderline
tumors, 4 invasive epithelial cancers, and 2 granulosa cell tumors.
Of the 11 women developing cancer, 9 had used clomiphene citrate.
Comparisons of cancer developing in infertile clomiphene users
to infertile women who had not used clomiphene demonstrated no
significant difference in the clomiphene group. However, when
infertile women who used clomiphene for 12 or more months was
compared to the control group, an increased risk was identified.
Oddly, the risk for clomiphene users if 12 or more cycles was
greater in gravid women than in nulligravid women, since gravity
is known to be protective. Also, most cause and effect relationships
have a dose dependent increase in outcome, such that the risk
of cancer should be directly proportional to the amount of clomiphene
used. In this study, there was a mild protective effect if up
to 11 cycles of clomiphene was used and then suddenly there was
an increase in the risk when 12 cycles were used. The number of
cases in this study is also quite small, with only 5 cases of
cancer being considered when looking at infertile women with 12
or more cycles of clomiphene use.
* In 1995 an Australian group followed 10,000 plus IVF
patients, about 5,000 of whom used ovulation enhancing medications
and about 5,000 of whom underwent natural cycle IVF (without menotropins)
or did not receive treatment. This group found that the age standardized
incidence ratios for ovarian cancer was not statistically different
between those who used fertility medication and those who did
not. This group did identify a significant increase in risk for
ovarian cancers in couples with "unexplained infertility"
as compared to the infertile controls. Unfortunately, the follow-up
period for this important study was only 5-10 years.
The potential association between fertility drug use and ovarian
cancer is quite important. Hopefully, there will continue to be
interest in this field over the next several years. Unfortunately,
there is not enough information at this time to firmly express
an opinion based on fact. One interesting observation of my own
is that at national meetings this subject is occasionally approached
by very conservative and elderly infertility specialists who all
seemingly recount that their own extensive experience with fertility
drugs does not suggest an association with ovarian cancers.
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