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What
is the purpose of Lupron in IVF?
The
first fertility drug that most women use in an IVF cycle
is Lupron. Lupron causes the pituitary gland to release
high amounts of FSH and LH (luteinizing hormone) for
several days until its stores are depleted. Since continued
use of Lupron prevents the pituitary gland from producing
new supplies of FSH and LH, the amount of these hormones
being released per day becomes very low after 7 to 10
days. The goal that we achieve with Lupron is to ensure
that blood levels of LH are low during the last few
days of follicle growth, since we know that high levels
of LH can lead to poor egg quality and stimulate progesterone
production by the ovaries. A premature rise in progesterone
may cause inappropriate maturation of the uterine lining
and lead to a lesser chance of embryo implantation.
Some
women will be placed on a Lupron "flare" medication
schedule. This involves starting Lupron early in the
menstrual cycle after suppressing pituitary and ovarian
function for up to one month of birth control pills.
The Lupron causes a sudden flare in FSH and LH release
by the pituitary gland and initiates follicular growth.
On the third day after the Lupron starts, the woman
begins shots of FSH or FSH+LH (brand names include Repronex,
Bravelle, Follistim, and Gonal-F). This stimulates the
continued growth of the follicles as the pituitary's
release of FSH begins to decline. Women over age 39
and those with high day 3 FSH blood levels as determined
prior to enrollment are typically treated with a Lupron
"flare" schedule in order to maximally stimulate
the ovaries. Repronex, Bravelle, Follistim, and Gonal-F
are administered as subcutaneous injections (small needle
placed just underneath the skin).
Younger
women or those with polycystic ovaries are usually treated
with Lupron for approximately 10 days prior to beginning
the shots of FSH. With this "long Lupron"
schedule, the pituitary is no longer releasing large
amounts of LH and FSH when Repronex, Bravelle, Follistim,
or Gonal-F is started. Hence, the best treatment schedule
is determined by the unique circumstances of the individual
patient. The average number of follicles that develop
is from 8 to 25, although some women will have more
than 30 and others will develop less than 5.
A
new class of drugs called GnRH antagonists (i.e. Antagon)
may be used in some patients over a shorten time course
to prevent a spontaneous LH surge without overly suppressing
ovarian function. The ideal candidates for the approach
are being determined by research protocols.
With
either the "Lupron flare" or "long Lupron"
schedule, the Repronex, Bravelle, Follistim, or Gonal-F
shots are taken twice daily for 8 to 11 days, depending
on how quickly the follicles mature. We can assess the
ovarian response to these fertility drugs by measuring
the follicle sizes with vaginal ultrasound and by following
the increase in production of estradiol (estrogen) and
progesterone by the cells inside the follicles. When
the largest follicles reach approximately 18 mm in diameter,
the woman takes a shot of hCG (human chorionic gonadotropin
- brand name Profasi, Pregnyl, or Ovidrel). This hormone
stimulates the final steps of maturation of the eggs.
The egg collection occurs 35 hours after the hCG injection.
What
are the side effects of Lupron?
Other
than side effects due to the actual injection (i.e.,
infection, bleeding, bruising, etc.), most of the side
effects of Lupron are due to the menopausal-like state
that the drug induces. Some patients will complain of
hot flashes, vaginal dryness, etc.; however, these often
go away after stimulation begins since estrogen levels
start going up with gonadotropin treatment.
Why
do I need a sonogram prior to the start of each new
IVF, Clomid, or gonadotropin cycle?
The
presence of cysts and elevated estrogen levels early
in the menstrual cycle can inhibit appropriate growth
of new eggs. Clinicians often check for the presence
of cysts before starting follicular stimulation.
How
much bed rest is needed after embryo transfer, and does
it vary whether day 3 or 5 transfer?
During
natural conception, the egg is fertilized in the tube
where it then floats down over 5 - 7 days until it reaches
the uterine cavity where it implants in the endometrium.
When embryos are transferred on day 3 or 5, they still
need to go through those same developmental milestones
for implantation to be accomplished.
There
is much controversy on how much bed rest is necessary
after embryo transfer. During my career, I have seen
recommendations change completely. During my residency
at Hopkins, we used to admit patients to the hospital
and have them stay absolutely still for at least 4 hours;
they would then go home and stay at bed rest for one
week. During my fellowship, we modified that recommendation
and would have them stay down for an hour after embryo
transfer then go home and rest for a few days.
During
my time when I worked in the Air Force's IVF program
at Wilford Hall Medical Center, patients would come
from all over the country for treatment. By necessity,
many of them would have to be on a military transport
airplane back to their home base right after embryo
transfer, and we still had some of the highest IVF success
rates in the state of Texas.
Now,
I follow our Colorado Center's protocol. We transfer
either on day 3 or day 5 and have the patient rest at
our center for one hour. They then go home and stay
at bedrest for the day of the transfer and the following
day. What I am trying to convey with this chronology
of my experience is that there is very little science
to the recommendations we make about bed rest after
embryo transfer. My best advice is to talk to your doctor
about his or her experience and results and then do
what seems to make sense.
What
is a 'good' initial quantitative beta-hCG after transfer
or IUI?
The
hormone, human chorionic gonadotropin (hCG), is secreted
from the cells that form the placenta. The number one
gets from a quantitative pregnancy test reflects how
much placental tissue is releasing this hormone. In
many normal early first trimester pregnancies, the number
goes up quickly (up 100% every 48 hours). Therefore,
initial values markedly vary depending on when one draws
the first pregnancy level.
Since
many IUI or IVF cycles are triggered with an hCG shot,
it is important to wait at least 10 days before checking
a pregnancy level. If it is checked too soon, it is
likely that the test will be a false positive (show
positive when actually due to the shot instead of the
actual pregnancy). For this reason at Houston IVF, we
wait a minimum of 16 days after the hCG trigger shot.
On our hormone analyzer, a level of beta-hCG of 100
mIU/ml is a "good" number; however, we have
had pregnancies as low as 10 mIU/ml make it to term
and deliver.
When
does implantation occur after IUI, day 3 transfer or
day 5 transfer?
For
implantation to occur, embryos must go through a growth
cycle which ends with the embryo at the blastocyst stage
and hatching out of the zona pellucida. Therefore, one
would expect implantation to occur about 5-6 days after
an IUI, about 2-3 days after a day 3 embryo transfer,
and the day of or the day after a day 5 embryo transfer.
How
many follicles is a 'good' number before getting hCG?
In
my practice, the maximum number of mature follicles
I want a patient to have during an IUI cycle is 3 to
4. This decreases the chance of developing a high-order
multiple pregnancy. During an IVF cycle, the minimum
number of mature follicles I want a patient to have
is 3 to 4. Since I can control the number of embryos
that I place in the uterus, I want as many as I can
safely retrieve hereby giving the patient more embryos
to choose from to give her the best chance for pregnancy.
How
do you determine when to give hCG in respect to follicle
size?
In
a natural (unstimulated cycle) or Clomiphene Citrate
cycle, mature follicle size is between 18 - 30 mm. If
triggered, these cycles are typically triggered when
follicle size is between 17-26mm (dependent of the practice
and IVF lab).
In
a gonadotropin cycle, mature follicle size is between
16 - 20 mm. These cycles are typically triggered when
follicle size is between 16 - 20 mm.
Can
you have an ectopic pregnancy with no tubes?
An
ectopic pregnancy is a pregnancy which implants outside
of the uterine cavity. Over 95% of ectopic pregnancies
implant in the tubes. There are rare ectopic pregnancies
where the pregnancy implants in the ovary, abdomen,
or elsewhere.
What
are polyps and fibroids, and causes them to grow in
the uterus?
A
polyp is a general term that describes any mass of tissue
which bulges or projects outward or upward from the
normal surface level. A uterine polyp is an outgrowth
of the uterine lining. They may appear after prolonged
exposure to unopposed estrogen or if the uterine tissue
is not completely sloughed off each month.
Fibroids
are benign smooth-muscle growths that arise from the
uterine muscle. Fibroids, also known as leiomyomas,
are found inside the uterine cavity (submucous), within
the uterine muscle (intramural), and on the outer surface
of the uterus (subserosal). Fibroids grow in response
to estrogen. Up to one third of all reproductive-aged
women will have at least one fibroid in their uteruses.
What
are follicles?
A
woman's eggs develop inside fluid-filled cysts (sacs)
inside the ovaries, called follicles. During a natural
menstrual cycle in which no fertility drugs are taken,
several follicles begin to enlarge around the time when
the woman is having her period.
However,
over the course of the next few weeks, only one of these
follicles develops to maturity, ruptures, and releases
its egg during the process of ovulation. The other follicles
that had begun to develop stop growing and degenerate
(dissolve), therefore, only a small percentage of eggs
present in the ovaries are ever ovulated during the
woman's reproductive life span. We can "rescue"
follicles and eggs that would otherwise degenerate by
giving shots of fertility drugs which contain FSH (follicle
stimulating hormone). This is the same hormone that
the pituitary gland produces to cause one egg to develop.
By increasing the woman's blood level of FSH, several
follicles may grow at approximately the same rate allowing
us to collect more than one mature egg.
How
fast do follicles grow?
Follicles
typically grow 1-3 mm per day in natural and stimulated
cycles.
Can
you see eggs on an ultrasound?
Eggs
are microscopic and cannot be seen on ultrasound. A
clinician can estimate the maturity of the egg based
on the size of the follicle which contains it. There
should be one egg per follicle.
Why
do a vaginal sonogram and not abdominal?
The
closer the ultrasound probe tip is from the object being
viewed, the clearer the sonographic picture. The vaginal
approach allows the probe tip to get much closer to
the ovary than the abdominal approach; therefore, the
sonographic clarity of the ovary is much better using
the vaginal approach.
How can you grow the uterine lining if it is not
thick enough?
The
uterine lining (endometrium) grows in response to estrogen.
Estrogen can be given to patients by oral pills, skin
patches, vaginal pills, or intramuscular injections.
My
uterine lining has been 'homogenous' in preparation
for my donor egg cycle, what can be done to make it
'trilaminar'?
The endometrial cells in the uterine cavity respond
to estrogen and progesterone. Higher levels of estrogen
tend to produce a "trilaminar" or triple pattern.
The presence of progesterone can make the lining appear
homogenous. Some clinics will place patients on Lupron
to try to prevent any endogenous production of progesterone.
How
thick must the uterine lining be for transfer?
Most
of the literature suggests that an optimal uterine lining
should be somewhere between 7 - 12 mm in thickness on
the day of hCG trigger. These values are not absolute.
Our clinic has had implantation with a lining as thin
as 3.5 mm.
What
should you see on sonogram in a pregnancy at 4, 5, 6,
7, 8, and 9 weeks?
At
4 weeks of gestational age (2 weeks post conception),
your doctor should only be able to see a thickened uterine
stripe.
At
5 weeks of gestational age (3 weeks post conception),
the presence of a gestational sac and possibly a yolk
sac are seen.
At
6 weeks of gestational age (4 weeks post conception),
your doctor should be able to see a gestational sac
and a yolk sac. Fifty percent of the time, a fetal pole
will be seen with cardiac activity.
At
7 weeks of gestational age (5 weeks post conception),
ninety percent of the time, a fetal pole will be seen
with cardiac activity.
At
8 weeks of gestational age (6 weeks post conception),
your doctor should see all of the previously mentioned
structures, including a fetal pole with cardiac activity.
The fetal pole should be measuring appropriately for
the gestational age and show appropriate interval growth
between sonograms.
At
9 weeks of gestational age (7 weeks post conception),
your doctor should see all of the previously mentioned
structures, along with increased detail in the fetal
pole. There should now be evidence of a head, trunk,
and extremities.
What
is wrong with fluid being in the uterus prior to embryo
transfer?
The
presence of fluid in the uterus prior to embryo transfer
has been shown to be a negative predictor of pregnancy.
What
is a Hydrosalpinx?
A
hydrosalpinx is a blocked, dilated, fluid-filled fallopian
tube usually caused by a previous tubal infection. The
pelvic infections that lead to hydrosalpinx formation
are usually caused by sexually transmitted diseases.
Diagnosis of hydrosalpinx is usually made by a hysterosalpingogram
(HSG), an x-ray procedure in which a special liquid
is
injected through the cervix into the uterine cavity
to illustrate the inner shape of the uterus and degree
of openness of the fallopian tubes. If the tubes are
open, the liquid will spill out the ends of the tubes.
If the tubes are blocked, the liquid is trapped. Hydrosalpinx
may also be diagnosed by laparoscopy, which is the insertion
of a thin, telescope-like instrument called a laparoscope
into the abdomen through an incision to visually inspect
the tubes. They may also be visualized by ultrasound.
Does
a Hydrosalpinx Cause Symptoms?
Many
patients with a hydrosalpinx suffer from chronic or
recurrent pelvic pain, while others have no symptoms.
Patients with a hydrosalpinx are more susceptible to
repeated acute tubal infections, which cause fever and
pain.
What
Effect Does a Hydrosalpinx Have on Fertility?
If
the fallopian tubes are completely blocked, conception
will not occur without medical intervention. In milder
cases, fertility may be restored by opening the tubes
surgically. However, if the lining of the tubes is badly
damaged, in vitro fertilization (IVF), which bypasses
the tubes, is the treatment of choice. IVF is a method
of assisted reproduction that involves combining an
egg with sperm in a laboratory dish. If the egg fertilizes
and begins cell division, the resulting embryo is transferred
into the woman's uterus where it can implant in the
uterine lining and further develop.
Although
IVF is considered to be the best fertility treatment
for hydrosalpinx, the presence of a hydrosalpinx appears
to reduce the success rates of IVF. Fluid within the
hydrosalpinx seems to reduce the embryo implantation
rates and increase the risk of miscarriage. For these
reasons, some physicians may advise removing the tube
or separating it from the uterus prior to undergoing
IVF.
Are
all fibroids bad for fertility?
Fibroids
are benign smooth-muscle growths that arise form the
uterine muscle. Fibroids, also known as leiomyomas,
are found inside the uterine cavity (submucous), within
the uterine muscle (intramural), and on the outer surface
of the uterus (subserosal). Fibroids grow in response
to estrogen. Up to one third of all reproductive-aged
women will have at least one fibroid in their uteruses.
Fibroids
which distort the normal contour of the uterine cavity
may be detrimental to implantation. Submucous fibroids
clearly can interfere with implantation. It is controversial
whether or not intramural fibroids interfere with implantation,
and subserosal fibroids most likely have no effect on
implantation.
How
high is the hCG before you can see it on sonogram?
Beta-hCG
levels typically need to be above 1500 mIU/ml before
a gestational sac can be seen on transvaginal sonogram.
Is
egg retrieval painful?
Egg
retrieval is usually accomplished by transvaginal ultrasound
aspiration, a
minor surgical procedure that can be performed in the
physician's office or outpatient center. Some form of
anesthesia is generally administered. An ultrasound
probe is inserted into the vagina to identify the mature
follicles, and a needle is guided through the vagina
and into the follicles aspirated (removed) from the
follicles through the needle connected to a suction
device. The egg retrieval is usually completed within
30 minutes.
Some
women experience cramping on the day of the retrieval,
but this sensation usually subsides by the next day.
Feelings of fullness and/or pressure may last for several
weeks following the procedure because the ovaries remain
enlarged.
What
is estradiol?
Estradiol
is the most potent female sex hormone (estrogen) produced
by the ovaries which are responsible for the development
of female sex characteristics. Estrogens are largely
responsible for stimulating the uterine lining to thicken
during the first half of the menstrual cycle in preparation
for ovulation and possible pregnancy. They are also
important for healthy bones and overall health. A small
amount of these hormones is also produced in the male
when testosterone is converted to estrogen.
What
are the usually success rates for clomid for unexplained
infertility?
In
couples whose infertility remains unexplained after
careful and thorough evaluation, empiric treatment with
Clomiphene Citrate (CC) may be justified, particularly
in young couples with a short duration of infertility
and in those unwilling or unable to pursue more aggressive
therapies involving greater costs, risks, and logistical
demands.
The
efficacy of empiric CC treatment may be attributed to
correction of subtle and unrecognized ovulatory dysfunction
and/or "superovulation" of more than a single
ovum. CC treatment is most effective when it is combined
with properly timed intrauterine insemination (IUI),
all in an effort to bring together more than the usual
numbers of ova and sperm at the optimal time.
A
"Special Contribution" published in the American
Society for Reproductive Medicine's journal Fertility
& Sterility in 1998 reviewed the efficacy of infertility
treatments for unexplained infertility and concluded
the following:
Combined
pregnancy rates per initiated cycle, adjusted for study
quality:
No treatment 1.3% - 4.1%
IUI 3.8%
Clomiphene Citrate/timed intercourse 5.6%
Clomiphene Citrate/IUI 8.3%
Gonadotropin/timed intercourse 7.7%
Gonadotropin /IUI 17.1%
IVF 20.7%
GIFT 27.0%
Since
the time of publication, IVF rates have markedly improved,
and the GIFT procedure has almost completely been abandoned.
Are
success rates for unexplained infertility the same regardless
of 2 years versus 7 years of infertility?
Generally
speaking, the longer the duration of unexplained infertility,
the lower the success rates.
What
are the chances of pregnancy after age 40?
Population
studies suggest that nearly 70% of women who start to
try to conceive at age 40 will never have children without
assistance. Assisted reproductive technologies can improve
chances.
What
are the signs of OHSS and who is at risk to develop
it?
Ovarian
Hyperstimulation Syndrome (OHSS) can either be mild
or severe. The mild form occurs in 10% to 20% of cycles
and results in some discomfort but almost always resolves
without complications. The severe form occurs approximately
1% of the time. The chance of OHSS is increased in women
with polycystic ovarian syndrome and in conception cycles.
When severe, it can result in blood clots, kidney damage,
ovarian twisting (torsion), and chest and abdominal
fluid collections. In severe cases, hospitalization
is required for monitoring but the condition is transient,
usually lasting only a week or two. Occasionally, drawing
fluid out of the chest or abdominal cavity decreases
symptoms. The best prevention is to withhold hCG administration
and prevent ovulation when ultrasound or hormone testing
indicates a high risk for severe OHSS. The use of ultrasounds
and/or serum estradiol levels will enable your physician
to predict your risk.
Additional
Frequent Questions Page 2
Contributed
By:
Timothy
N. Hickman, M.D. Medical Director, Houston IVF Memorial
Hermann Memorial City Hospital 920 Frostwood, Suite
680 Houston, Texas 77024 Office (713) 465-1211 FAX (713)
550-1475
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