Superovulation for Treatment of Infertile Patients
I. Normal Pregnancy Rates
The chance of conception in any given month among fertile couples attempting to conceive is approximately 20%. Clinical studies of couples having unexplained infertility of mild endometriosis, however, have indicated that the chance of achieving a pregnancy in any given month (referred to as "fecundity") is severely reduced compared to normal couples. Only 2-5% of these couples conceive each month. The appropriateness of any therapy for these patients must be decided only after that therapy has been shown to increase the monthly fecundity rate beyond the 2-5% noted in couples receiving no therapy.
II. Early Developments and History
In Vitro Fertilization (IVF) was originally devised as an alternative treatment for women with irreparable or absent fallopian tubes. Its success, however, has lead to the application of In Vitro Fertilization (IVF) to treat fertility problems other than tubal abnormalities, (endometriosis, unexplained infertility, cervical factors and even male infertility). Further studies indicated that IVF is generally as effective for treatment of these "non-tubal" problems as it is for tubal disorders. The notable exception was male infertility.
The rational for IVF in women with blocked fallopian tubes is easy to understand. Fertilization outside the body and placement of early pre-embryos directly into the uterus bypasses the blocked fallopian tube. The application of IVF in patients with disorders other than tubal problems is not as easily understood.
Physicians began to notice pregnancies in patients who had received Pergonal, but for various reasons did not complete their IVF cycle. This lead investigators to suspect that many IVF successes in patients with normal fallopian tubes might be due to factors other than fertilization outside the body. Perhaps these pregnancies were due to other aspects of the IVF treatment protocol, such as the release of more eggs as a result of Pergonal stimulation.
Since the initial publications in 1985 there have been a number of clinical studies that have confirmed a significantly improved pregnancy rate with Pergonal stimulated superovulation. This improvement in fecundity (monthly pregnancy rate) was noted in couples having: cervical factors, luteal phase defects, mild endometriosis or infertility of unknown etiology and who have failed the usual therapeutic approaches.
III. Explanation of Procedure
"Fertility drugs" usually Serophene (clomiphene), Gonal-F, Follistim, Repronex, Pergonal, or Humegon or (potent and widely used drugs to induce ovulation called gonadotropins) are administered beginning on the second or third cycle day and given for six to nine consecutive days. While Serophene is taken orally, the others are administered by subcutaneous injection in the abdomen or thigh or intramuscular injection in the buttocks. Response to these drugs is monitored by frequent vaginal ultrasounds and blood estrogen determinations. At a time in the cycle when the ovarian follicles reach a designated size, and estrogen levels are appropriate, an injection of the hormone hCG is given to trigger ovulation. Ovulation usually occurs 36-48 hours after the hCG injection. Thus, intercourse or insemination should be timed accordingly.
For some patients, a combination or Serophene and gonadotropins provides an easier, less costly alternative. Serophene is administered as one or two tablets orally for five days from the third through the seventh day. An injectable gonadotropin is then prescribed either on a daily basis or as a single injection one to two days after the last clomiphene tablet. . A follow-up ultrasound on or about the tenth to twelfth cycle day helps evaluate your response and will determine whether an hCG injection will be required. Urinary LH monitoring will insure that you don't ovulate too early. This protocol minimizes drug dosages, ultrasound examinations and blood tests. It may cost half as much as a regular daily injections of gonadotropins and insemination cycle. Not all women have a satisfactory response from the ovary. In that event, future cycles will use only injectable medications.
Performing intrauterine insemination may result in an increase in the number of sperm at the site of fertilization in the fallopian tube. Generally only 1 of 2000 sperm ejaculated into the vagina make can later be found in the fallopian tube. Therefore, adding insemination to gonadotropin-stimulated cycles may further improve the pregnancy rate. Although there is no "proof" that adding intrauterine insemination to gonadotropin induced superovulation definitely improves the chance of pregnancy, most scientific reports suggest an increased pregnancy. One of these reports demonstrated a 26% pregnancy rate per cycle with intrauterine insemination and superovulation versus 6% with superovulation alone. Other studies address the issue of whether to perform one or two inseminations each cycle. Conflicting results are seen. While some studies show benefit with insemination performed 18 and again at 42 hours after hCG injection, others show no improvement in pregnancy rates when compared to a single insemination performed at approximately 36 hours after the injection. At this point, we recommend adding intrauterine insemination to superovulation, based on the results of these studies. The decision to perform a single or multiple inseminations each cycle is individualized after discussion with the physician.
The additional cost and risk of insemination are minor. In order to perform the intrauterine insemination (I.U.I) the man produces the sperm specimen by masturbation. The sperm are concentrated and "washed" by a centrifugation technique. The specially prepared and concentrated sperm are then placed directly into the uterus through the cervix with a small plastic tube. The specimen can be obtained at home using a special condom and sperm nutrient media. Care must be taken to insure that the specimen does not get chilled or overheat prior to processing. If the specimen is obtained in the office, about 45 minutes to one hour will be required for processing. The insemination procedure is usually no more painful than a pap smear. After this minor office procedure the patient remains lying flat for ten minutes and then can resume all normal activities. Some patients bring candles and music to make the occasion special!
Several reports in the fertility literature discuss the results of superovulation and intrauterine insemination. For couples with normal fallopian tubes and sperm, the chance of becoming pregnant in a treatment cycle was consistently between 10-20%. If the same couple was treated for three or four cycles, they had a cumulative pregnancy rate of between 30% and 50%. These results were also noted in the recent evaluation at the University of Minnesota. Figure 1. The diamond line represents the 5% fecundity expected in couples receiving no therapy at all. The boxed line represent the fecundity expected in normally fertile couples. The triangle line demonstrates the pregnancy rate found in patients treated with superovulation and I.U.I.
Another key issue is that the monthly cycle fecundity is the same for the first four to six treatment cycles. Thus the chance of conceiving during any of the first four cycles is identical and a couple should not become discouraged if they do not become pregnant in the first few treatment cycles. Unfortunately, it also appears that after approximately four to six cycles of treatment, the chance of obtaining a pregnancy with further superovulation treatment falls off dramatically. This has lead most infertility clinics to recommend no more than a four-cycle trial of this therapy.
V. Potential Risks
The major risk of superovulation is directly related to the use of these potent ovulation-inducing drugs. Gonadotropin induced superovulation has been shown to have an increased multiple pregnancy rate. Approximately 20% have twins, 2-3% are triplets and 1% or less have 4 or more. Gonadotropin stimulated cycles may have a slightly higher than normal incidence of miscarriage. The incidence of premature delivery will also be higher if a multiple pregnancy in conceived.
Some studies have indicated an increased frequency of tubal pregnancies in patients undergoing superovulation with gonadotropins. This is probably the result of the multiple eggs ovulated during a treatment cycle. Early pregnancy monitoring is suggested to determine the number of pregnancies conceived as well as ruling out a tubal pregnancy. A tubal pregnancy usually requires surgery for its removal.
Another possible side effect of gonadotropin administration is ovarian hyperstimulation. This condition results from enlarged tender ovaries often beginning approximately one week after ovulation. Mild ovarian hyperstimulation is common, rarely causes difficulty, and is self-limited. In severe ovarian hyperstimulation the ovaries become very large and painful. The woman may have swelling from retaining excessive amounts of body fluid in the tissues. Fluid may leak from the vessels into the abdomen and chest resulting in serious fluid and electrolyte imbalance and potentially significant complications. Fortunately, severe hyperstimulation is rare, occurring in only about one percent of treatment cycles. If pregnancy and ovarian rupture do not occur, the syndrome resolves in approximately one week. Should the patient become pregnant, the syndrome may last for several weeks.
This problem rarely occurs if the ovulatory dose of hCG is withheld. The major reason for the lower incidence of severe hyperstimulation is the close monitoring with frequent blood estrogen determinations and ultrasounds during the critical part of the treatment. If a patient is judged to be at high risk for hyperstimulation, the gonadotropin injections are stopped and the hCG injection is withheld. Unfortunately, however, even close monitoring cannot completely eliminate the risk of hyperstimulation.
Recent studies have suggested that patients having taken clomiphene for 12 cycles or more may be at greater risk for developing ovarian cancer. If intrauterine insemination is used as part of the treatment protocol, it has its own risks different from those of gonadotropins. Two potential risks of intrauterine insemination have been identified. The cervix and its mucus are a natural barrier to infection. In the process of intrauterine insemination, this natural barrier is bypassed by placing the sperm into the uterine cavity. If the sperm or the cervical mucus is infected with bacteria, an infection could be introduced into the uterus and, subsequently, the fallopian tubes. An infection in the uterus or fallopian tubes is potentially serious and could result in irreparable tubal blockage and subsequent sterility. A recent study in California of approximately 100 patients undergoing intrauterine insemination found a 5% risk of pelvic infection following intrauterine insemination. Our own experience has indicated an even smaller risk than 5%. Even though the chance of a damaging infection is small, its potential consequences may be serious.
A rare, but potentially severe side effect of intrauterine insemination is a sudden allergic reaction to the sperm similar to the dramatic allergic reaction that some people experience to bee stings, certain foods, or medications. This type of allergic reaction can be severe and even result in death. Fortunately, this potential severe reaction is extremely rare.
Uterine cramping, both during or following insemination, is common and does not denote either an allergic reaction or an infection. The development of fever, pelvic tenderness, or abdominal pain within the first week following an intrauterine insemination may be the signs of an early infection and should be reported immediately.
VI. Cost Benefit Analysis
As with any medical treatment, attention needs to be paid to the relative costs and benefits of treatment. The expected benefit of superovulation and I.U.I. is a normal pregnancy. Each couple can only determine the value of a biological pregnancy. The cost can be broken down into four categories:
Financial cost. A combined Serophene/gonadotropin/IUI cycle will cost approximately $1,500. A single cycle of Gonadotropin-induced superovulation combined with intrauterine insemination usually costs between $2,000 and $3,000. Your health insurance may cover all, part, or none of the expense.
Time cost. While Serophene/gonadotropin/IUI usually involves only three or four office visits, gonadotropin superovulation is more involved and may take up to ten office visits to complete a cycle. Because of the specialized ultrasound monitoring and need for frequent blood estrogen determinations, these appointments must grouped between 7:30 a.m. and 9:00 a.m. each morning. Once a treatment cycle has begun, daily drug administration and monitoring are necessary until ovulation occurs. Every attempt will be made to expedite your appointment and minimize the amount of time spent in the office.
Physical Health Risk. As previously discussed, there are risks of ovarian hyperstimulation syndrome, multiple births and their potential complications, risks associated with insemination and potential increased risk of ovarian cancer.
Emotional Cost. There is often a significant amount of stress associated with the prolonged treatment with injectable gonadotropin ovulation induction. Even couples who have noted only minimal stress associated with their infertility treatment often note a significant decline in their coping skills when undergoing this type of therapy.
Unfortunately, a number of couples have infertility of unknown etiology, or have failed to conceive following the standard therapies for endometriosis, cervical factor, and ovulatory dysfunction. Superovulation with or without insemination offers a pregnancy rate approximately equal to one third to one half that of in vitro fertilization if the semen analysis is normal and there are no tubal factors. Because this alternative is less expensive and less stressful, it may be reasonable to consider superovulation and intrauterine insemination before attempting in vitro fertilization.
This information is not intended as a substitute for medical advice of physicians. The reader should regularly consult a physician in matters relating to his or her health and particularly with respect to any symptoms that may require diagnosis or medical attention.