Women Who Do Not Ovulate Regularly:
Anovulation & Oligoovulation
This information was provided by Richard T. Scott Jr., MD. This
information is provided as an educational service to physicians
and the patients that are treated by Organin Inc.
The failure to have any ovulatory cycles (anovulation) or to have
only very irregular cycles (oligoovulation) are among the most
common causes of infertility. The causes of these types of ovulatory
disorders are quite diverse, and may include problems within the
developing follicles or ovary, or both.
Hypothalamic-Pituitary Problems
Some women fail to ovulate because there is little or no stimulation
coming from their pituitary glands. This can result from a problem
with their hypothalamus (the part of the central nervous system that
communicates with the pituitary gland) and is common in women
who exercise vigorously, are under a lot of stress, or who have
anorexia or related eating disorders. These individuals do not
produce sufficient LH and FSH to stimulate any of the follicles in
the ovaries to maturity. Treatment consists of either stimulation the
pituitary to release LH and FSH (see genre stimulation), or to
simply replace the missing LH and FSH by administering it directly
(see injectable gonadotropins).
Premature Ovarian Failure
Other women fail to ovulate simply because they have very few or
no eggs remaining in their ovaries. When this happens prior to the
age of 40, it is termed “premature ovarian failure” or “premature
menopause." There are a number of reasons why women deplete
their supply of eggs at a very young age, including prior
chemotherapy of radiation therapy while treating a malignancy,
prior removal or the ovaries, and various genetic abnormalities.
However, there is usually no obvious explanation and these women
are believed to have simple exhausted their supply of eggs at a very
young age. These women have no viable eggs remaining and thus
are not candidates foe ovulation induction.
Polycystic Ovarian Disease, Chronic
Anovulation, and Related Syndromes
The vast majority of women who fail to ovulate regularly have a
pituitary gland which is functional and have plenty of egg
containing follicles remaining in their ovaries. The problem appears
to be in the relationship between the stimulatory effects of the LH
and FSH released from the pituitary and the ensuing response of the
follicles. While the specific source of the problem may vary widely
and is not known for most patients, many of these women will have
the clinical signs of polycystic ovarian disease which include
multiple small follicles within the ovary which are visible on the
ultrasound, and abnormal levels of LH and FSH in there blood
stream (Figure 3). Although the cause of the disorder and the
clinical symptoms which the patient have may vary, a common
finding is that these women lack sufficient FSH stimulation to keep
their follicles developing to maturity.
Figure 3 The normal balance of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) secretion from the pituitary
results in the development and release of a single healthy egg each
cycle (A). In women with polycystic ovarian disease, there is a
relative excess of LH and s deficiency of FSH action (b).
Clomiphene citrate results in an increase in FSH levels and may
allow a follicle to complete development and ovulate a healthy egg.
Most of the approaches to treatment focus on raising FSH levels to
the point where follicular growth and development resume,
ultimately in the release of a healthy mature egg (ovulation).
Ovulation Induction in Women with
Anovulation and Oligoovulation
Clomiphene Citrate
Clomiphene citrate is the simplest, and thus the most common,
starting point for treating women with either anovulation or
oligoovulation. The medication is classified as an anti-estrogen,
which means that it blocks the effects of estrogen throughout the
body. This blockage means that the pituitary gland perceives that
only low levels of estrogen are present in the circulation. The
pituitary’s response to low estrogen levels is to secrete more FSH in
an effort to provide more stimulation to the follicles and thus
produce more estrogen (Figure 3). This rise in FSH is very
important since these patients have a relative lack of FSH
stimulation. In most cases the rise in FSH is sufficient to stimulate
the follicles to resume growth, complete maturation,
and eventually ovulate.
The normal starting dose in women who are either anovulatory or
oligoovulatory is one pill (50 mg) per day for 5 days. If ovulation
fails to occur at this level, the dosage may be sequentially increase
by one pill per day until the effective dose is determined.
Occasionally, the dose may need to be increased to as many as five
pills per day. The medications are generally taken on days 5 through
9 of a menstrual cycle but the best timing may vary from patient to
patient. Ovulation occurs in approximately 4 out of 5 women and
generally occurs five to nine days following completion
of the medication.
Once a woman begins clomiphene citrate therapy, it is important to
determine if the treatment has been successful in inducing
ovulation. Monitoring for ovulation can be accomplished in a
number of ways. Basal body temperature charts (BBT’s) which
show an elevation in basal temperature levels of 0.5`F for several
says indicate ovulation has occurred. Infertile couples should keep
in mind that the rise in temperature occurs after ovulation and thus
at times may not be detected until the day after ovulation (i.e. the
temperature rise at the time of ovulation may occur later on the day
of ovulation than the time the basal temperature is taken), and thus
BBT’s are n inefficient way to tome intercourse
for becoming pregnant.
Ovulation predictor kits which detect the midcycle surge of LH also
provide presumptive evidence of ovulation. They have the added
advantage of turning positive prior to the time of ovulation which
allows effective timing of intercourse. Many physicians recommend
that the couples have intercourse the day the predictor kits turns
positive and again the following day. Blood tests are ultrasounds
may also be used to determine the ovulation in more complex cases
where more precise monitoring of the time of ovulation is required.
Finally, a progesterone level checked 5 to 10 days following the
presumed date of ovulation may reaffirm that ovulation took place
and that hormonal support during the second half of the
cycle is adequate.
Unfortunately, not all women who ovulate will become pregnant.
The majority of pregnancies occur in the first three ovulatory
treatment cycles. Very few pregnancies are achieved in patients who
do not conceive in the first six ovulatory cycles. The cumulative
pregnancy rates after several ovulatory cycles on clomiphene citrate
are less than 50% (Figure 4). Significantly, five to ten percent of the
pregnancies will be twins.
Figure 4 Cumulative pregnancy rates attained with multiple cycles
of clomiphene citrate therapy in women who do
not ovulate regularly.
Relatively few effects are generally associated with clomiphene
citrate. An occasional side effect is the blockage of estrogen’s
favorable effect on mucus production by the cervix. In some
patients, cervical mucus may become “hostile” and inhibit the
ability of the sperm to swim from the vagina through the uterus and
into the fallopian tubes where fertilization normally occurs. The
absence of this side effect may be confirmed by a simple post coital
test (an evaluation of the nature of the cervical mucus and the
number and viability of any sperm swimming there) once the
effective dose of clomiphene citrate has been determined. Other
reported side effects include hot flashes, an upset stomach or
bowels, headaches, sensitivity to bright light, visual disturbances,
mood swings, and breast tenderness.
Injectable Gonadotropins (LH and FSH)
Some women will not ovulate following clomid therapy and others
will ovulate but not become pregnant. While there are a number of
possible reasons, in many cases the LH rise which is attainable with
clomid is either to low or does not last long enough to provide
sufficient FSH stimulation to correct the underlying problem. In
many of these cases, the women will respond to better if higher
levels of FSH can be attained over longer periods of time. These
higher levels of FSH are achieved by directly injection FSH in the
form of injectable gonadotropins.
There are two types of injectable gonadotropin preparations
available. Once contains LH and FSH and the other contains
principally FSH with only trace amounts of LH. LH and FSH are
the hormones which the pituitary would normally produce and
release to stimulate the follicles developing within the ovary. The
use of injectable gonadotropins gives the physician control over the
amount and duration of the FSH stimulation being provided to the
developing follicles. Thus, it is possible to attain levels which are
sufficient to stimulate follicular development, oocyte maturation,
and ovulation in vast majority patients.
In patients with anovulation or oligoovulation, the goal is to provide
enough FSH to stimulate the development of a single follicle. To
this end, a number of different stimulation regimens have been
described. Some patients, especially the anovulatory patient with a
very large number of small follicles, may respond best to relatively
low doses of medications given over prolonged periods of time (up
to several weeks). These are the so called “low and slow” protocols
(Figure 5). In contrast, other patients may require higher doses of
injectable gonadotropins to achieve adequate ovarian responsive,
but will typically require the medication for less time (apt. 7 to 12
days). In either case it is not always possible to achieve the goal of
having a single follicle develop and at times these patients may have
several follicles mature and release several eggs. The release of
several eggs leads to the high incidence of multiple pregnancies
encountered in these cycles.
Figure 5 Women with PCOS do not ovulate regularly, but do have
a number of partially matured follicles present at any given time
(A). The administration of relatively small amounts of exogenous
gonadotropins provides additional stimulation and allows a single
follicle to develop to maturity (B). These treatments may be
particularly effective in women who do not have spontaneous
ovulatory cycles and who fail to respond to clomid therapy.
Women who have normal ovulatory cycles and are undergoing
superovulation are also generally stimulated with injectable
gonadotropins. While the medications are the same as those used in
the treatment of anovulatory women, the goals of treatment are
quite different. The goal of superovulation is not to provide a
“normal” ovulatory cycle with the release of a single oocyte but
rather to provide an environment with proportionally elevated FSH
stimulation to result in the release of multiple eggs (Figure 6).
Women undergoing superovulaton typically receive higher doses of
injectable gonadotropins.
The development of multiple follicles may be attained by giving relatively large quantities of gonadotropins and maintaining elevated levels of FSH for a period of several days. This type of ovulation induction cycle is used commonly during insemination cycles and is an important part of many of the assisted reproductive technologies.
Monitoring
Careful monitoring of treatment cycles using injectable
gonadotropins is very important. This is because the normal control
relationships between the follicles developing in the ovary and the
pituitary gland are bypassed when the LH and FSH are given
directly. The goal of monitoring is to make sure that sufficient, but
not excessive, stimulation is being provided to the developing group
of follicles. Most cycles are monitored with a combination of
ultrasounds, to determine the number and size of the developing
follicles, and blood work to measure the estrogen being produced
(Figure 7). The results of the monitoring along with knowledge
about the duration of the stimulation and the woman’s individual
history allow the physician to optimize the dosage of the
medications being administered. It can then be determined when the
follicles are mature and ready to ovulate.
Figure 7 Ovulation induction cycles with injectable gonadotropins
require close monitoring with serial ultrasound examinations of the
developing follicles and measurements of serum estradiol levels.
hCG is administered to induce actual ovulation when the follicles
are judged to be a mature. A pregnancy test may be performed
approximately 2 weeks later to determine if the woman is pregnant.
A mid-cycle LH surge is required to induce the final maturational
changes in the egg, to release the egg from the wall of the follicle, a
and to stimulate the actual release of the egg from the follicle. Most
women will not have a spontaneous LH surge during stimulated
cycles. A "surrogate" LH surge may be provided by the injection of
the hCG, a hormone which is generally produced after a woman
becomes pregnant. It has the same stimulatory effects on the ovary
that LH does, but is less expensive and has a longer duration of
action which makes it more practical and effective.
Success Rates
The vast majority of women stimulated with indictable
gonadotropins will ovulate, but not all will conceive. Most
pregnancies occur in the first three to six treatment cycles. A
number of factors influence pregnancy rates including the age of
the patient, the presence of absence of endometriosis or adhesions in
the woman's pelvis, any problems with the tubal function,
abnormalities of the lining of the uterus where implantation should
occur, and the quality of the partner's sperm. Patients who fail to
become pregnant following ovulation induction with the indictable
gonadotropins may still be excellent candidates and attain
pregnancy rates with some of the assisted
reproductive technologies.
Figure 8 Distribution of singleton and multiple pregnancies in
women undergoing ovulation induction with
injectable gonadotropins.
Multiple Pregnancies
The nature of ovulation induction in women with anovulation or
oligoovulation and superovulation in ovularoty women means that
there may be multiple eggs released in a given cycle. These patients
are then at risk for having multiple pregnancies are twins (Figure 8),
but high multiple pregnancies with three or more
implantation's may occur.
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