The Road to Successful Ovulation

Diagnosing and Treating Trapped Egg Syndrome
Trapped egg syndrome (luteinized unruptured follicle, LUF) seems to occur more frequently in women taking fertility drugs and in women who have had pelvic inflammatory disease. When this occurs the follicular surface fails to dissolve and release the egg, even though it's stimulated by an LH spike. However, the follicle continues to evolve into the corpus luteum as expected.

LUF is very difficult to detect. All of the routinely performed tests will indicate that you've ovulated. Your BBT will rise, your midluteal phase progesterone will be elevated, and an endometrial biopsy will be normal. So if you do not become pregnant within four or five Serophene induced ovulatory cycles, I may perform an ultrasound scan prior to ovulation and just after your temperature rise. This noninvasive procedure will allow me to see your ovary, the developing follicle, and the formation of the corpus luteum. The signs of ovulation include:

• Complete disappearance of the follicle

   

• Loss of the circular shape of the follicle

   

• Thickening of the follicle wall

   

• Replacement of the clear, lucent follicle by an irregular spongy area (corpus luteum)

   

• Fluid behind the uterus

   

To prevent trapped egg syndrome, some doctors try to further stimulate follicular growth by giving Pergonal/Humegon (LH plus FSH). Some add Parlodel (bromocriptine) during midcycle to ensure that an elevated prolactin level is not interfering with ovulation. Others prescribe a midcycle hCG (LH) injection to stimulate ovulation. Ultrasound examination (or if necessary a laparoscopy) will confirm the effectiveness of these approaches.

Treating Clomiphene Resistance: the Metrodin Short Course
If you are developing follicles with clomiphene but they are not reaching maturity, supplementing your LH and FSH with Metrodin injections may provide the results you want.

With the Metrodin Short Course you usually take clomiphene from cycle day three through cycle day seven. On cycle day eight, I will have you begin Metrodin injections for three days before checking an ultrasound to see if your uterine lining has developed and a follicle is maturing.

The exact procedures used during this treatment must be individualized according to your response to the clomiphene. If, for example, ultrasound indicates that with clomiphene alone you develop several follicles, your doctor will have to add Metrodin very gingerly to avoid stimulating multiple follicles. If you are quite resistant to clomiphene, however, more Metrodin may be required. Some physicians prefer trying the short course because it has fewer side effects and is more convenient than Metrodin or Pergonal treatment alone (see below). Many studies show that as a rule women who fail to respond to clomiphene because of severe polycystic ovaries, may be poor candidates for Pergonal induction therapy.

Clomiphene Side Effects
The most commonly observed side effect of clomiphene (Serophene, Clomid) therapy is poor cervical mucus. The anti-estrogenic effects of the drug can prevent the mucus from thinning out and ferning in up to 50 percent of women. If the postcoital test reveals live motile sperm in the mucus, pregnancy may be possible. However, in these cases I may recommend insemination with the husband's sperm (IUI), since it works very well.

Ovarian cysts and enlargement occur in about 15 percent of women taking clomiphene, but complications from them are rare. Small percentages of women report hot flashes, abdominal bloating, nausea, breast soreness, and visual blurring. In addition, I may hear a few complaints about headaches, weight gain, fatigue, and nervous tension. Sometimes it's difficult to say whether these symptoms are due to the drug itself or to the stress of ovulation induction therapy.

Clomiphene does not increase the odds that you'll have an early pregnancy loss or that your baby will have birth defects. The rates of abortion, multiple pregnancies, and congenital abnormalities are all within normal limits.

Recent studies have suggested that women who have used clomiphene for more than twelve cycles may have a greater risk of developing ovarian cancer. If they conceive, or if they have used oral contraceptives for more than one year the protective benefit reduces the risk to normal.

Success Rates with Clomiphene
Of the women who have a withdrawal bleed following to Provera, 70 to 90 percent will ovulate in response to clomiphene citrate; and 40 to 60 percent will conceive within six to twelve cycles. Taking clomiphene will not make you super-fertile. The conception rate approaches that of normal couples: approximately 20 percent per month for women in their twenties. When clomiphene therapy fails, other fertility factors should be examined more closely.

Normally the hypothalamus secretes GnRH to stimulate LH and FSH production by the pituitary gland. Figure11-1 The gonadotropins (LH and FSH) act on the ovaries to initiate follicular development, estrogen production, and ovulation. Sometimes, however, due to an intrinsic problem with the hypothalamus or pituitary gland, the pituitary cannot produce adequate amounts of these hormones. As a result, the understimulated ovaries fail to produce estrogen and fail to ovulate. Typically these women will not withdraw to progesterone unless an estrogen supplement is used to prime the growth of the uterine lining. If elevated FSH levels indicate ovarian failure, gonadotropin therapy will not be successful.

The Treatment Regimen with Humegon, Pergonal or Metrodin
There are many different ways to use these injectable medications, but a few standards must be strictly followed. Estrogen assays and ultrasound examinations must be performed regularly in order to avoid multiple births and life-threatening complications. If your doctor prescribes any of these medications without taking these precautions, I suggest you consult with a different physician.

Gonadotropin injection treatment can be very demanding and expensive, averaging about $2,000 per treatment cycle. In addition to daily injections, the woman must come to the doctor's office for periodic blood tests, and for ultrasound evaluations. You and your spouse must be prepared for the rigors of this schedule or you won't make it.

I'd like to share with you the experience Tammy and Ken J. had with Pergonal treatments for her problem with polycystic ovarian syndrome (PCOS). They had really been through the wringer. After five disappointing years I was the third doctor they had consulted. Tammy had received Pergonal before, but her doctor had used started with three ampoules of Pergonal each day and each cycle had to be canceled when she developed too many eggs. Since we have learned to begin injections at a very low dose for PCOS women, pregnancy rates have improved markedly. An added benefit of this "slow and steady" approach seems to be a lower risk of multiple births and ovarian hyperstimulation syndrome. So I recommended that they give it another try.

Studies show that for PCOS women, a month or two of pretreatment with birth control pills will lower abnormally elevated levels of LH as well as abnormal production of male hormones by the ovary. A month before starting Pergonal I gave Tammy estrogen one month of birth control pills. Because Tammy's ovaries contained were enlarged with many cysts and her male hormone levels were elevated, I decided to begin treatment with Lupron after two weeks of birth control pills. Lupron is administered with a very tiny needle as a daily injection just under the skin.

After Tammy's period began, I gave her one ampoule of Metrodin (75 units FSH) for seven consecutive days. At that time I performed a vaginal ultrasound and measured her estrogen (estradiol) level. If the medication was adequately stimulating follicular growth, her estradiol should approach 100 pg/ml. Since I saw no significant increase in her estradiol, I increased the dosage by 1/2 ampoule (to 1 1/2 ampoules per day) and repeated the ultrasound after five more days of drug treatment. I would repeat this procedure until she achieved an estrogen response indicative of follicular development. Once Tammy's blood estradiol level reached 100 pg/ml, I knew that she would respond to that dose.

After the twelfth day of treatment, I began more frequent monitoring of follicular growth with an ultrasound examination every two to three days. We all nearly cheered out loud when I found three good-sized follicles. When the dominant follicle reached 12 mm in diameter, I began scanning her daily. At 16 mm I stopped giving her Metrodin and ordered an hCG injection later that evening to stimulate ovulation.

I knew Tammy would ovulate within forty-two to forty-eight hours later, so I advised her to have intercourse that evening and return with her husband the next morning. I performed a postcoital examination to make sure her cervical mucus could support the sperm migration and survival. If I found a problem, I would need to recommend an intrauterine insemination to insure the best possibility of conceiving. But, since gonadotropins usually do not degrade the mucus as clomiphene does, I expected to find all was well-and it was.

About five days after Tammy's hCG injection, I repeated the ultrasound examination and drew a blood sample for progesterone to make sure she'd ovulated and to confirm the formation of the corpus luteum. Her ovaries were not overly enlarged and three corpora lutea were seen, just as we'd hoped.

Because she had received Lupron, additional hormonal support with either additional hCG injections or progesterone vaginal suppositories was needed during the luteal phase (second half) of her cycle. She had previously used progesterone vaginal suppositories after Pergonal therapy and developed a vaginal irritation. So, five days after the first hCG injection, I gave her a second hCG injection to prevent corpus luteum failure (inadequate luteal phase). (The second injection may be given four to eight days after the first.) I cautioned her to monitor her weight each day and call me if it rose more than five pounds. I explained that women with PCOS who receive extra hCG shots may have a greater risk of hyperstimulation (ovarian enlargement). But since her ovaries were not too large, I felt hCG could be safely used instead of suppositories.

Tammy did not conceive in the first cycle' so we tried again when her period started. I began the second round at the same dosage level that produced follicular growth during the first cycle. This cut a week or so off the initial regimen. We all got excited when two follicles reached maturity at the same time. Even though we knew she might have twins (music to her ears), I gave her the hCG injection. Nine months later Tammy and Ken delivered an eight-pound twelve-ounce baby girl.

Side Effects
If estrogen levels become extremely high (usually over 2,000 picograms per milliliter: 2,000 pg/ml) or if ultrasound reveals numerous large follicles, withholding the hCG injection and canceling the treatment cycle will prevent life-threatening complications. But, some couples choose other options. In the first option, about 38 hours after hCG, I give pain medication and a local anesthetic. Using vaginal ultrasound to guide the way, I place a needle through the vagina into each of the ovaries. All but a three or four follicles are drained and the fluid is discarded. An insemination is performed at the same time. Although there are no guarantees, I believe this may lower the risk of ovarian hyperstimulation and multiple births. A second option is to convert the cycle to in vitro fertilization (IVF). As above, the ovarian follicles are drained using ultrasound guidance. But in this scenario, I drain all the follicles. The eggs are identified and mixed with sperm in the laboratory. Two days later, a few of the fertilized pre-embryos are transferred back to the uterus. More about this in Chapter 21. Another precaution I may use in patients with very high estradiol value who do not elect to cancel there treatment is intravenous albumin infusion. This treatment appears to be very effective in preventing ovarian hyperstimulation in IVF patients.

Mild ovarian hyperstimulation, which occurs in 10 to 20 percent of all gonadotropin treatment cycles, may result in a doubling of ovarian size and cause lower abdominal discomfort. After the next menstrual period the swollen ovaries usually return to normal proportions on their own.

Moderate hyperstimulation after an hCG injection occurs in 1 to 6 percent of the treatment cycles. With this more serious form of hyperstimulation, the ovaries become cystic and in this fragile condition may hemorrhage, rupture, or twist to cut off their blood supply (torsion). Bed-rest, and increased fluid intake usually prevent complications. Rarely, the patient is hospitalized to provide pain medication and intravenous fluids.

Moderate hyperstimulation usually resolves in three to ten days, with complete recovery occurring in four weeks. Unless hemorrhage or torsion is highly suspected, surgery should not be attempted. The ovaries are so fragile during this period that pelvic examinations should be avoided and surgical intervention should be avoided as it usually ends with the surgeon having to remove the ovary.

Severe hyperstimulation, a very rare occurrence, causes massive ovarian enlargement, accumulation of fluid in the abdominal cavity which can lead to life-threatening fluid/electrolyte shifts, and vascular collapse. Immediate hospitalization and emergency measures must be taken to prevent death. Intravenous fluids, careful blood chemistry monitoring, as well as drainage of excess abdominal fluid usually result in resolution of this syndrome. An interesting note is that a majority of these patients are subsequently found to be pregnant and luckily, the treatment has no ill effects on the pregnancy. The possibility of severe ovarian hyperstimulation is very real for patients who are not closely monitored during Pergonal, Humegon or Metrodin therapy.

Close monitoring of estrogen levels and regular ultrasound examinations will also help guard against multiple gestations. Each mature follicle contributes 200 to 250 pg/ml of estrogen. During each cycle there may be as many as a dozen follicles growing, with each one contributing some amount to the estrogen pool. Studies show that as long as the total estrogen level is below 2,000 pg/ml the odds of having a "litter" are small. When estrogen rises above 2,000 pg/ml, or multiple follicles are seen on ultrasound, withholding the hCG injection or draining the follicles may prevent multiple births and hyperstimulation.

How Well Do Humegon, Pergonal and Metrodin Work?
Ninety-nine percent of women taking gonadotropins will ovulate and two-thirds will conceive. Since the chances for conceiving during any one treatment cycle are 15-20 percent, most women get pregnant within three treatment cycles. For estrogen-deficient women the pregnancy rate after six cycles approaches 90 percent if there are no other fertility problems. For PCOS women who have failed to ovulate with clomiphene, conception rates are lower, about 50 percent after six courses of therapy.

Frequently, superovulation (Humegon, Metrodin, Pergonal) is combined with intrauterine insemination for male factor infertility or unexplained infertility. Pregnancy rates for these couples depend on a number of factors. Your physician will need to review all fertility factors before attempting to predict the likelihood of success.

Studies show that up to two-thirds of gonadotropin patients will get their miracle baby. As encouraging as these reports are, you must also take into consideration that one-third of the Pergonal-induced pregnancies will terminate spontaneously (compared to a 15 to 25 percent abortion rate for women taking clomiphene and for women in the normal population).

About one-fourth of these conceptions will be multiple births-twins, approximately 2-3% will be triplets and 1 out of 200 pregnancies may result in four or more fetuses.

Multiple gestation can be a devastating problem for couples seeking to start a normal family. Medical bills for triplet pregnancies can be over $100,000. Babies frequently require prolonged hospitalization in a neonatal intensive care unit and may end up with lifelong medical problems. The stress of raising three infants may tax even the strongest marriage. While careful monitoring, canceling stimulation cycles or draining follicles may limit the risk of multiple births, this cannot be guaranteed. I now of one patient with a single follicle on ultrasound with an estradiol of 300 pg/ml who had triplets.

After careful consideration, some couples choose a new procedure called selective reduction. This procedure involves terminating all but two of the pregnancies to limit the health risk to the remaining fetuses and the mother. Obviously, partial pregnancy termination is an emotionally charged issue that many women find ethically unacceptable. It is my hope that as our knowledge improves, fewer couples will be faced with this unpleasant option.

Women have often thought that Humegon, Pergonal or Metrodin therapy is a last resort. Now that superovulation and intrauterine insemination and in vitro fertilization offers additional options, however, gonadotropin therapy is far from being the final opportunity for getting your miracle baby. We'll discuss more about that in a later chapter.

For years Europeans have been using GnRH to stimulate the pituitary to function normally. Research shows that GnRH therapy seems to avoid the risks associated with hyperstimulation and multiple births. GnRH may also eliminate the need for daily injections and monitoring, and ultimately may reduce treatment costs.

Treatment Regimen
GnRH therapy may restore fertility to women who have hypothalamic disorders and an intact pituitary gland. A normal hypothalamus pulses GnRH every ninety minutes to permit pituitary function. So when you supplement GnRH, it must be pulsed in a similar manner. Recently, relatively inexpensive automatic pumps been developed for intravenous injections: for example, Lutrepulse from Ferring Laboratories. These battery-powered devices are so portable that you can carry your mechanical hypothalamus anywhere you go.

Although some women cannot tolerate the semipermanent intravenous delivery system, many appreciate the relative freedom this treatment option promises: no more daily injections and blood tests, no more frequent visits for ultrasound examinations, and no more concern about multiple births and hyperstimulation. After ovulation you discontinue intravenous therapy and receive an hCG injection every three to four days to support the corpus luteum.

Results
Pulsatile intravenous GnRH injection almost always results in ovulation. The pregnancy rate appears to be around 25 to 30 percent per month. It does not appear effective for most women with PCOS. At present the cost for pulsatile GnRH therapy is about half that of Pergonal treatment. With similar results, added convenience, lower cost, and reduced this option may be an attractive option for many women.

A few years ago women with hypothalamic-pituitary insufficiencies had no hope. Now the wonder drugs clomiphene, GnRH, Humegon, Metrodin and Pergonal give thousands of women an opportunity to have their miracle babies.

For more information on your initial visit to your physician read the
INCIID Routine Fertility Workup or IVF.com Homepage.

Miracle Babies and Other Happy Endings
for Couples with Fertility Problems
Copyright © 1986 Mark Perloe M.D., and Linda Gail Christie.