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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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