Planning an Effective Infertility Treatment Strategy

referred to Michael Kettel, M.D. and William Hummel, M.D
from San Diego Fertility Center

ESTABLISH A DIAGNOSIS

The normal menstrual cycle is a repetitive process which might be viewed as “reproductive failure.” As the normal physiologic intention of the menstrual cycle is to result in a pregnancy each and every time it occurs, menstrual bleeding might be viewed as failure of this process to occur. The hallmarks of the menstrual cycle include a dynamic coordination of the hypothalamic- pituitary-ovarian-endometrial axis to culminate in the release of a mature oocyte.

This mature oocyte must be successfully retrieved by the fimbriated end of the fallopian tube and made available for fertilization. In an independent process, sperm placed in the vagina at the time of intercourse must successfully survive the hostile environment of the vagina, enter the favourable confines of the cervical mucus and ultimately work themselves into the upper genital tract. The head of each sperm contains specific binding sites for the outer layer of the egg (zona pellucida). Once the sperm has bound to the zona pellucida then the fertilization process can occur. After ovulation, the egg lives for approximately 72 hours. Therefore, intercourse every other day around the mid cycle should successfully result in a condition in which fertilization can be maximized. Realizing the intricacies of this system, the normal fertility curve can be appreciated.

Cycle fecundity is a term used to describe the likelihood of a pregnancy occurring with each individual menstrual cycle. The human is a relatively inefficient reproducer and, in fact, the cycle fecundity is approximately 22%. If one views this fertility curve over time, successful reproduction is a result of repetitive attempts at this intricate fertilization process. Realizing, and keeping in perspective the normal fecundity curve can allow patients and physicians to embark in fertility treatments with realistic expectations.

INFERTILITY EVALUATION

The infertility evaluation consists of a variety of tests to document normal sperm, normal ovulation, fallopian tubal patency, normal endometrial environment, and a normal pelvis. There are multiple, controversial tests that have been proposed to evaluate the reproductive condition and identify particular pathologic disorders. Tests that fall into this controversial category including the following: post coital test, late luteal phase endometrial biopsy, antisperm antibody determinations, penetration tests, and serial ultrasounds to determine the luteinized-unruptured-follicle syndrome. All of these controversial tests have relatively poor sensitivity and specificity and, as a result, are fraught with false negatives and false positives. Using these tests, therefore, should be approached with caution. Certainly many pregnancies have resulted in couples whom antisperm antibodies have been identified…

The diagnosis of “unexplained infertility” then becomes a diagnosis of exclusion. It reflects our lack of understanding of the reproductive process and includes couples that are normal as well as couples who may have subtle defects in the reproductive process. The treatments for unexplained infertility places a couple in a relatively favourable prognostic category. When viewed with other common causes of infertility, unexplained infertility often results in both treatment dependent and treatment independent success.

AGE AND THE REPRODUCTIVE PROCESS

Most people are aware that increasing maternal age leads to a decline in fertility. In fact, this decline occurs fairly acutely after the age of 37 and continues to decline up through the menopause. In almost any arena in which age is evaluated, advancing age leads to a decline in either treatment success or ultimate pregnancy outcome. With advancing maternal age increases also miscarriage rate  and increase chromosomal abnormalities . Once a pregnancy has successfully entered the second trimester, it does not appear that other pregnancy risks are increased. One test which can offer some insight into this aging process is the “day 3” FSH. FSH is the pituitary hormone which is primarily responsible for folliculogenesis. As such, an increasing day 3 FSH reflects ovarian resistance to ovulation. In some studies the day 3 FSH has been shown to be a better predictor of pregnancy success than chronologic age. A day 3 FSH of greater than 25 mIU/mL places the woman in a relatively poor prognostic category whereas a day 3 FSH of less than 15 mIU/ml places the woman in a good prognostic category.  It must be emphasized that the day 3 FSH value varies from cycle to cycle and that a singled isolated, elevated day 3 FSH is not the final bad signal for a woman considering pregnancy.

FORMULATING A GAME PLAN

The treatment of many causes of infertility revolves around a concept to increase cycle fecundity. Cycle fecundity is the likelihood of a pregnancy resulting in any given menstrual cycle. Treatments that increase cycle fecundity can be applied to a multitude of pathologic conditions. These treatments accelerate the “fertility curve” and may improve the otherwise protracted curve of patients with unexplained infertility. There are three basic techniques to increase cycle fecundity:

  1. The first technique is intrauterine insemination(IUI). Intrauterine insemination involves a process that improves the timing of insemination to ovulation, increase the number of motile sperm that reach the fallopian tubes and may increase the number of capacitated sperm that reach the upper genital tract.
  2. The second technique to increase cycle fecundity is superovulation. Superovulation requires the use of fertility drugs. Clomiphene citrate, human menopausal gonadotropins (Pergonal, Humegon, hMG) or rec(recombinant)FSH (Gonal-F, Puregon) have been used to induce a condition of superovulation. When these drugs are prescribed, the expected result is an increase in the number of ovulated eggs per cycle to result in an increase in the likelihood of fertilization occurring. Fertility drugs may also increase the efficiency of folliculogenesis and may improve subtle luteal phase insufficiencies.There is now a body of literature which hasexamined each of these techniques in unexplained infertility. It appears that intrauterine insemination and clomiphene citrate do a relatively poor job of increasing cycle fecundity when used alone. It is the combination of clomiphene citrate plus intrauterine insemination which results in an increase in cycle fecundity. The use of hMG or recFSH either alone or in combination with intrauterine insemination has been shown to increase cycle fecundity. Overall, the best results are seen when these drugs are used together with IUI.
  3. The third technique that results in an increase in cycle fecundity are assisted reproductive technologies, which include a variety of procedures including IVF-ET, ICSI-ET.

 

WHEN TO CHANGE TREATMENT SCHEME

Each treatment cycle should be viewed as an independent event. This means that if the first cycle fails, the next cycle has an equal chance of working! this cycle independence holds true for each type of treatment for three cycles of treatment. If you examine the clinical efficacy of a given treatment protocol, the cumulative pregnancy should be viewed as the likelihood of conception within a reasonable time frame, approximately 3-4 cycles, and NOT after only one attempt.

When deciding when to move from one treatment protocol to another, it is important to review what has been learned from the preceding treatments. Did the ovaries respond appropriately?  Did the endometrium reach a target thickness? Did the follicles release the eggs? Were the hormone levels correct? By examining the response to treatment the patient and physician can decide when it is appropriate to move from one treatment protocol to another.

By and large, if a treatment is going to work, it will be effective within three cycles. The majority of success occur during the first three attempts and this presents a reasonable interval in which to schedule a re-evaluation consultation with your physician. Before this visit, the patient must re-evaluate their feelings and comfort zone about treatments. It is interesting to observe the changes in a couple’s comfort zone as they experience successes and failures with differing treatments. A couple who first thought they would not possibly consider artificial insemination may seriously look at IVF after a few cycles of hMG injections!

WHEN TO STOP TRYING…

The decision to stop treating is probably one of the most difficult decisions faced by any couple who struggles with infertility. A sense of when to stop and when to continue can be reached if a couple has a firm grasp on their objectives. For instance, one couple may have as their goal to have a baby in their home and are willing to consider adoption or egg donation as a route to achieve this goal, whereas another couple is not at all interested in this approach and have decided that if they cannot conceive using their own egg/sperm they would not have children. Very personal choices that differ from couple to couple.

Unfortunately, your doctor may not help much with this decision. Remember…it is the doctor’s job to think of alternatives and choices for you to consider. It is your job to decide which choice is best for you. One couple may enthusiastically proceed with egg donation IVF whereas another stops short of laparoscopy to correct endometriosis.

CONCLUSION

  • Establish a diagnosis
  • Begin treatment at an appropriate level
  • Evaluate a treatment plan at three cycle intervals
  • Keep an open mind and long-term goals in perspective

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