Infertility Update 2002
Presented at Ob/Gyn Grand Rounds
The Christ Hospital
December 2002
Sherif G. Awadalla, M.D.

During the past two decades dramatic changes have occurred in the field of reproductive endocrinology. Revolutionary changes in therapy were heralded by the birth of the world’s first test-tube baby in 1978. As we reflect back on two decades of change in the field, we also look forward to the new millennium, and utilizing a variety of techniques to improve the outcome of patients in the field of reproductive medicine. The purpose of this talk will be to outline changes in the way the diagnostic workup is now completed. We will also discuss techniques that are gaining prominence in the treatment of the infertile patient.

DIAGNOSIS OF INFERTILITY

The infertility workup traditionally has included a semen analysis, hystersalpingogram, mid-luteal progesterone, as well as possibly a post-coital test. Although the semen analysis traditional parameters are still important, new techniques of analysis have come in the forefront. The critical elements of the semen analysis have always been the sperm count, the motility, as well as the grade. Recent efforts have been focused on categorizing morphology more accurately. The old system, which was developed by the world health organization, did not provide us with sufficient detail regarding sperm morphology. Today, a much more useful parameter is critical morphology.

Critical morphology is a very specific technique of identifying the number of completely normal sperm, including analysis of the dimensions of the head, mid piece and tail of the sperm. The sperm are then graded into normal, slightly abnormal and severely abnormal forms. In addition to this, in our lab we categorize the number of abnormal sperm with normal acrosomes. We find that these are also functionally, nearly normal. Critical morphology analysis has caused a great deal of confusion because it is not uncommon to have a normal count and normal motility, but to have a critical morphology that is in the low single digits, such as 2-3%. Critical morphology was designed to aid the clinician in determining whether the sperm would naturally fertilize the oocyte in vitro or whether ICSI would have to be utilized. In additional to this, critical morphology has to be viewed in the totality of the semen parameters. Suffice it to say that a sperm density of greater than 20 million/ml, a sperm motility of greater than 45%, and a grade of greater than, or equal to 2, combined with a critical morphology of 4% normal forms, would probably be considered normal. Additionally if the morphology index, which is the number of normal and slightly abnormal sperm, is greater than or equal about 20%, sperm will generally fertilize the egg without doing ICSI. If the count motility and grade are normal, and the critical morphology, for example, is only 2%, we then have to look at the number of slightly abnormal forms. If the number of slightly abnormal forms is zero, then sperm potential is diminished. If the number of slightly abnormal forms is 10-20%, then the potential would be considered reasonable.

If, for example, we had a count of 110 million with 65% motility and a grade of two, we would look next at the critical morphology, and if that were 0% normal and 3% slightly abnormal, that would lead us to consider a brief trial of insemination and then proceed to in vitro fertilization, probably with ICSI. Conversely, if the sperm count is 16 million with 45% motility and a grade to two, we would look to the critical morphology to see if insemination would be a reasonable thing to do. If in that same context the critical morphology is 10% normal, we would consider doing insemination perhaps a little bit longer prior to turning to in vitro fertilization. Another example would be a sperm count of 16 million/ml with 10% motility with a grade of 0-1. If the critical morphology in this case were 2% normal, we would be probably thinking about in vitro fertilization with ICSI sooner because the total reproductive potential from this type of analysis is limited. As with any new system of analysis, it takes some time to become acclimated to the numbers. Our major goal of analysis is to determine whether insemination can reasonably be successful or whether we have to turn to in vitro fertilization earlier. If you need any assistance analyzing the data, please feel free to contact us, or Dr. Behnke’s lab, who will be happy to aid you.

The hystersalpingogram (HSG) has remained a valuable part of the infertility workup without much change in the last two decades. There is a new technique called "utero sonography". This technique involves putting some saline in the uterus and doing vaginal sonography to image details of the endometrium. While the technique shows polyps and other abnormalities easily, it is really not effective for documenting tubal anatomy or tubal patency. Because of this, the HSG has maintained its dominance. Uterosonography may be valuable in the setting of the post menopausal patient with bleeding. It can be valuable in identifying any anatomic lesions.

The mid-luteal progesterone remains a valuable part of the workup for evaluating ovulatory quality. While basal body temperature graphing is still widely utilized, it is notoriously inaccurate. There are many examples of patients with normal BBT’s that have very low progesterone levels. I would accept a progesterone level of greater than 7 ng/ml as normal. Values of less than 2 suggests an anovulatory state. Values between 3 and 7 suggest luteal phase dysfunction. I generally will obtain a mid-luteal progesterone between days 20 and 22 of the cycle. If the patient has not manifested an adequate production of progesterone at that point, she probably, at least, has luteal phase dysfunction. The post-coital test still remains at the center of controversy. It has not been proven to be valuable based on randomized prospective studies. However, I feel that it can be of value in many clinical situations. In the course of ovulation induction, I like to conduct a post-coital test. If this shows diminished mucous or sperm numbers, then I generally recommend insemination earlier than I would otherwise. Also, in some cases, the male partner is reluctant to obtain a semen analysis, and in that case, a post-coital test can be helpful to get an idea of sperm entry in the reproductive tract. Post-coital tests are always difficult to time. In most patients, it can be ideally timed on days 12-14 of the cycle. The patient should be seen approximately 2-12 hours following intercourse for an examination of the mucous. Probably 1-2 motile sperm in a high power field can be considered normal.

ENDOSCOPY

Endoscopic examination, in the form of hysteroscopy or laparoscopy, remains the gold standard for judging pelvic anatomy. While the HSG is a valuable screening test, it is not uncommon to have a patient with a normal HSG that has significant endometriosis or pelvic adhesions. Hysteroscopic procedures can be quite valuable in terms of excision of a uterine septum or removal of polyps or fibroids. Additionally, as experience with hysteroscopy has increased, we are now noticing that the appearance of the tubal ostium is also important. I know of several cases where the HSG appeared normal, examination of the tubal ostium revealed partial occlusion by either adhesions or internal mucous plugging. In those cases we have been able to catheterize the fallopian tubes and improve outcome. In patients with proximal occlusion at the time of hysteroscopy the patient can also be catheterized, either by hysteroscopic or fluoroscopic technique. Catheterization is generally successful in greater than 50% of cases. Also, conception rates are approximately 50% within six months of fallopian tube catheterization. This is a simple, noninvasive, technique that can be done easily in conjunction with hysteroscopy. Because of this it is routine to perform the HSG prior to laparoscopy in order to get some initial idea of tubal anatomy in case catheterization is required.

The laparoscopic examination remains a valuable procedure in cases that are otherwise unexplained, or in cases where the patient has been refractory to therapy. Also, patients who are older with longer duration infertility probably should undergo endoscopic examination sooner. Laparoscopy is valuable in terms of defining the pelvic anatomy, evaluation for endometriosis or pelvic adhesions. Also, the fimbrial anatomy should be carefully examined. In some cases, there exists some fimbrial agglutination that can be endoscopically treated. At the time of laparoscopy, I always perform chromotubation even if the patient has had a prior hystersalpingogram. There may be some benefit to chromotubation in terms of improving the functional status of the fallopian tubes. In patients with endometriosis, there is now a documented benefit in lasering the implants. It appears that the monthly conception rate will increase following this form of therapy. This has been now validated by a prospective study. Surgical therapy for endometriosis is in contradistinction to medical therapy for mild endometriosis. There is no clear data that medical therapy is effective in improving the fertility rates. Medical therapy is highly effective in terms of treatment of pain. Patients with a history of mild endometriosis, which has previously been treated endoscopically, we now manage with superovulation and intrauterine insemination. This can be done with clomiphene or, if ineffective, with more potent drugs, such as the gonadotropins.

Although the hydrosalpinx has been identified as a cause of infertility for many years, its specific treatment has always been difficult. Conception rates with salpingostomy for hydrosalpinx are, at best, 20%. Generally, this is reserved for the patient with a hydrosalpinx without marked dilatation of the fallopian tube. Also, it is preferable that the patient not have massive adhesions surrounding the hydro. Also patients with surgical repair following hydrosalpinx have higher ectopic pregnancy rates. Conception time, with hydrosalpinx, can be as great as one year to 18 months. In the past, for patients with hydrosalpinx, if surgical therapy were not successful, we would proceed to IVF. Also, in some cases, we just left the hydrosalpinx intact, and proceeded to IVF immediately. Within the past five years, articles have been appearing suggesting that the presence of a hydrosalpinx diminishes pregnancy rates with IVF. Some studies have shown pregnancy rates as low as 15-20% with hydrosalpinx in situ. Similar studies, without hydrosalpinx, show conception rates in the range of 30-45%. New data shows that once the hydrosalpinx has been excised, pregnancy rates return to 30-45%. Because of this, if a patient presents with hydrosalpinx, then some form of management has to be instituted prior to IVF. Generally, we will attempt to repair the favorable hydrosalpinx and excise the large hydrosalpinx with significant adhesions.

EFFECT OF AGE

A new area of interest has been evaluation of ovarian reserve. It has become increasingly clear that ovarian reserve decreases significantly beyond the age of 32 on a year-by-year basis. It has now become routine in our practice to screen any patient who is 35 years of age or older with a day 3 FSH level. In discussing this with the patients, it is important to emphasize that day 1 is the first day of obvious menstrual flow. Also, if your office is not open 7 days a week, the patient should be given a laboratory slip requesting the FSH value and instructed to go to the hospital lab if day 3 falls on a week-end. Day 3 FSH values of less than 10 mIU/ml are considered normal. In our lab, ideal values are between 5 and 8. Values in excess of 12-15 are considered abnormal, and are consistent with a poor prognosis. There is clear data from in vitro fertilization to indicate that conception rates plummet when the FSH values are greater than 12-15. The data is also accumulating with conventional therapy that the prognosis is uniformly poor with high FSH levels. If the FSH levels are questionable, or more data is necessary, then we can perform a clomiphene challenge test. We obtain a day 3 FSH level, and then give clomiphene 100 mg on days 5-9. A day 10 FSH value if then obtained. Both values should remain below 10-12. Also, it is preferable if the second value shows a slight decrease. The theory behind clomiphene challenge testing is as clomiphene is administered, the follicles develop and inhibin is produced. Inhibin is a product of the healthy follicle which diminishes FSH production. Therefore, if the patient has good ovarian reserve when the medication is administered, inhibin should be produced by the active follicles and the FSH level should decrease. Clomiphene challenge testing is now routinely done in many IVF programs to exclude patients with a poor prognosis.

GENETICS

Genetic screening has been receiving an increased amount of attention. In the routine history taking portion of the patient interview, it is recommended that we ask both husband and wife for a history of cystic fibrosis, hemophilia, muscular dystrophy, and mental retardation. These represent states for which we can do preconceptual diagnosis. In addition, African Americans should be offered hemoglobin electrophoresis to determine if they are carriers of the sickle cell trait. Patients from a Mediterranean ancestry should be offered a CBC to evaluate them for thalassemias. Individuals from an Eastern European Jewish ancestry should be offered screening for Tay-Sachs disease. Also, in the near future, ACOG will recommend that cystic fibrosis screening be offered to all couples who are interested in conceiving. Genetic screening is expected to gain more attention in the future.

POLYCYSTIC OVARIAN DISEASE

Turning our attention to therapeutic treatment regimens, I would like to discuss changes in the management of polycystic ovarian disease (PCOD). PCOD was first adequately described by Drs. Stein and Leventhal in 1935. The prevalence of PCOD is estimated to between 5 and 10%. PCOD is one of the more common clinical causes of oligoovulation that we see in practice. Some new attention has been given to its associated risks including coronary vascular disease, diabetes, and endometrial carcinoma. Clinical features of PCOD include oligoovulation, polycystic ovaries by ultrasound, hirsutism, android obesity, acne, and occasionally, androgenic alopecia. Endocrinological features of this disease include slight elevations in serum testosterone associated with elevations of free testosterone due to a decrease in SHBG. Also, the LH to FSH ratio is frequently greater than 2. Many patients have slight elevations in DHEAS.

Patients with PCOD have been known to be insulin resistant. A number of studies in the 1980s clarified this issue. Insulin resistance can be documented in 20-40% of patients with PCOD. There is a correlation between increased body weight and insulin resistance. The insulin resistance is thought to be secondary to a post-receptor signaling mechanism. Hyperinsulinemia is thought to increase ovarian androgen production by stimulating theca cells. Also, hyperinsulinemia may stimulate the basal cells of the skin which causes acanthosis nigricans. This can be seen as a velvety hyperpigmentation in the neck or in the inner aspect of the thigh. It is also suspected that hyperinsulinemia may affect the vascular endothelium in an adverse fashion which would generate hypertension and coronary vascular disease. Traditional workup for PCOD includes the history and physical exam. Endocrine testing includes TSH and prolactin levels. Also, if there is evidence of hyperandrogenism, then generally the testosterone and DHEAS are obtained to rule out the possibility of tumor.

If the patient with PCOD does not wish to conceive, then, in may cases, management with oral contraceptives is effective in terms of obtaining cycle regularity and in decreasing hyperandrogenic manifestations. The estrogen component of the OCP will increase sex hormone binding globulin and will decrease the amount of free androgens. Also, OCPs will shut down gonadotropin production to a great extent and decrease the secretion of androgens by the ovary. GnRH agonist have also been used effectively. However, the hypoestrogenic state associated with them generally does not allow for long-term therapy.

The newest agents available for treatment of PCOD include the new insulin sensitizers, such as metformin (Glucophage) and troglitazone (Rezulin). Glucophage is a relatively benign agent that can be easily administered. Rezulin is more complex to administer and can be associated with hepatotoxicity. There have been several deaths associated with Rezulin use. Because Glucophage has fewer complications, we will focus our discussion on its use in the primary care setting. Because there is a correlation between insulin sensitivity and obesity, generally it is the patient with increased body weight that will benefit from this therapy rather than the PCOD patient with normal body weight.

Glucophage is usually given at a dosage of 500 mg. po t.i.d. It is helpful to begin dosage once a day and then increase gradually to three times daily because of side effects. Side effects are primarily nausea and diarrhea. In early experience with Glucophage, it appears to induce ovulation in 34% of cases versus 4% for a placebo. Glucophage, in combination with 50 mg. of clomiphene, was also shown in a population with increased body weight to produce an ovulation rate of 90%, compared to clomiphene 50 mg. alone, which produced an ovulation rate of 8%. Pregnancy rates can be expected to be in the range of 20-25%. While this may not appear very impressive, remember that many of these cases are very heavy individuals that generally would do poorly with clomiphene alone as a single agent. In clinical practice, for the patient with increased body weight, we may attempt Glucophage for 3-6 months. If she does not spontaneously conceive, then clomiphene or gonadotropins can be added. In normal weight patients with PCOD, generally, I would initiate therapy with ovulation inducing agents first. If response is poor, then we can attempt use of an insulin sensitizer, or we may consider obtaining a fasting insulin level to see if this therapy would be beneficial.

I V F

In vitro fertilization has improved dramatically in the last two decades. There have been a number of new additions that make it particularly valuable. Intracytoplasmic sperm injection (ICSI) has allowed us now to treat male factor cases where we would have been completely unsuccessful previously.

We now routinely are able to treat cases where the sperm count is zero. Sperm is aspirated from the testes. We generally can identify just a few functional sperm. The sperm are then individually identified and injected within the egg under a phase contrast microscope which is equipped with micromanipulators. We are able to generate high-quality embryos and establish pregnancies in such cases. A great deal of interest is also focused on reduction of multiples. We are now transferring most of our embryos 3-6 days following oocyte retrieval. At three days, we expect to have a 6-8 cell embryos.

If the patient is under 30 years of age, we would select two high-quality embryos for transfer. In the early 30’s, we would consider the transfer of three embryos. Patients greater than the age of 35 have a less favorable prognosis, and in those cases, four embryos can be transferred. There is also a lot of interest in the culturing embryos further to the final stage (blastocyst stage).

At this stage we would generally transfer two embryos in most cases. While blastocysts transfer is appealing, it is important to recognize that we lose a great deal of embryos while waiting for them to go to blastocyst. It is, therefore, a technique that is ideal for younger women with a large cohort of embryos from which one can be selective.

For patients greater than the age of 40, oocyte donation offers the best opportunity. With oocyte donation, pregnancy rates of approximately 50% can be obtained readily. This is due to the fact that the donors are young and have normal ovarian function. A typical donor is less than the age of 32, has normal body weight and is a non-smoker. Our current waiting list for oocyte donors is approximately one year. If you have any patients that you think would consider the procedure, we would greatly appreciate your having them contact us. We will provide them with written information, and then we will meet with them and carefully discuss oocyte donation. In an attempt to be prudent with the procedure, we limit oocyte donation to two attempts in women who have not finished childbearing. In women who are finished with childbearing, we allow donation for 3-4 cycles. Oocyte donation generally involves superovulation of the ovaries by injectable agents, followed by transvaginal oocyte retrieval, which is done under ultrasound direction and with heavy sedation. Most donors are very pleased to have had an opportunity to participate in the program. Embryo donation is also available. This is on a limited basis for patients who have extra embryos and have successfully conceived from IVF. Embryo cryopreservation is an effective adjunct to in vitro fertilization. It allows us an ethical option for patients who have extra embryos that cannot be immediately transferred. Conception rates for frozen embryo transfers are in the range of 20-30% per cycle, depending on the age of the individual. The tables below give general pregnancy statistics for 1999 at The Christ Hospital program.

1999 Data through 10/20/99 (Only clinical pregnancies are reported)

FRESH EMBRYO TRANSFERS

AGE	% Pregnant/retrieval	% Ongoing/retrieval
<30	50.0%	47.9%
30-34	46.4%	43.8%
35-39	35.7%	31.5%
40+	28.2%	28.2%

FROZEN EMBRYO TRANSFERS

AGE	% Pregnant/transfer	% Ongoing/transfer
<30	36.4%	36.4%
30-34	23.6%	18.2%
35-39	14.6%	14.6%
40+	10.0%	10.0%

***A comparison of clinic success rates may not be meaningful because patient medical characteristics and treatment approaches may vary from clinic to clinic.

Looking to the future, there is a great deal of interest in preimplantation genetic diagnosis. This could, for example, be offered to carriers for cystic fibrosis. We would be able to biopsy the embryos and transfer embryos that would not have the disease state. Also, there is a great deal of interest in oocyte cryopreservation. Unfortunately, there is not currently an effective protocol for freezing eggs. We anticipate that this will occur in the next 2-5 years. If you are interested in a more detailed analysis of IVF related innovations, please go to the full text IVF article section in this web site.

MALE FACTOR

Therapy for male factor has remained somewhat controversial. For example, an individual with compromised semen parameters may have a varicocele. While varicocelectomy may improve the semen parameters, there are many cases where it does not. It is clear that patients with extreme oligoasthenospermia will not benefit from varicocele repair. Although there is no consensus at present, it is our recommendation that patients with large varicoceles undergo repair. Also, if the patient displays a stress pattern on semen analysis, there may be a benefit from repair. Empiric therapy with clomiphene is not highly effective. However, some patients will respond to clomiphene 25 mg. for the first 25 days of every month. Generally, this therapy should be reserved for patients with low FSH levels. There is a new citrus drink called Proxeed. This can be used on a b.i.d. basis. There appears to be in some cases improvement in the semen parameters. This is a non-pharmacologic simple therapy. If interested, please go to http://www.proxeed.com for details.

Intrauterine insemination remains a commonly used therapy for oligoasthenospermia. Generally, this is effective if we do not have severe abnormalities. For example, if the sperm count is in the range of 18 million/ml with a normal motility and normal grade, insemination may be successful. If the sperm count is in the range of 1-2 million with low or normal motility, it is unlikely that we would be successful. Testicular sperm aspiration has emerged as a valuable technology for patients with azoospermia with normal FSH levels. Some patients have congenital absence of the vas, which is associated with the carrier state for cystic fibrosis. In some cases, we have other anatomical obstructions. Testicular sperm aspiration can also be used for the individual who has undergone a vasectomy but is a poor candidate for reversal. ICSI is probably the most important new treatment modality for male factor cases. ICSI has allowed us to generate births in cases of extreme oligospermia. It is also a valuable tool in cases of mild oligospermia where other therapy is not successful. Therapeutic donor insemination still remains a low-cost option for some couples. The advent of ICSI, however, has decreased the utilization of TDI.

Use of ovulation inducing agents has been increasingly valuable in the care of the infertile patient. This can be done either in conjunction with intrauterine insemination for cases of unexplained infertility, male factor infertility, or endometriosis associated infertility. Also, ovulation inducing agents can be used as primary agents without insemination for patients with ovulatory dysfunction. Experience with clomiphene citrate is extensive. Ovulation rates in the range of 90% can be achieved. However, conception rates are typically 35-40%. The discrepancy is accounted for by the fact that clomiphene use results in decreased mucous production and thinning of the lining of the uterus, decreasing the implantation rate. If patients do not conceive with clomiphene, with or without insemination, they next become candidates for gonadotropins. The older gonadotropin preparations were urinary extracts. These include Pergonal, Humegon, Repronex, Metrodin, Fertinex. The new preparations are recombinant agents. These are agents that are produce in the laboratory using recombinant DNA technology. These agents include Gonal-F and Follistim. For ovulation induction, these agents offer the advantage of subcutaneous use, which is more convenient for the patient. For IVF, they may offer slightly conception rates. These agents contain only FSH. The older urinary products contain preparation of FSH and LH.

In recent years, the number of articles in the lay media have questioned the use of ovulation inducing agents. In particular, there were concerns about increasing the risk of ovarian cancer. As we all know, infertility is a risk factor for ovarian cancer. The original scientific article which raised this issue was published by Whittmore et al, in 1992 in the American Journal of Epidemiology. Since then, eight major publications have refuted this finding. As expected, they have received little attention in the lay media. The most recent publication is in Lancet, November 1999 issue. Venn et al studied nearly 30 thousand women referred for IVF in Australia. They found that the incidence of breast and ovarian cancer was not increased over that expected. They found no association between the number of IVF cycles and any increase in the incidence of uterine or ovarian cancer. They did find that unexplained infertility was a risk factor for ovarian cancer, irrespective of drug use. This data serves to confirm that infertility itself is a risk factor for ovarian cancer and not drug therapy.

One final topic that is worthy of increased attention is the issue of high-order multiples. High-order multiples are pregnancies with more than twin gestations. The most common variety of this is the triplet gestation. Fortunately, quadruplets and higher-order pregnancies are extremely rare. However, triplets do pose a major risk factor for diminished pregnancy outcome. In general, although twins are associated with a higher incidence of perinatal morbidity and mortality, the prognosis is excellent. At the present time, our major focus is on reduction of triplets. Triplet gestations generally are either from in vitro fertilization or from use of gonadotropins. With advancing technology with IVF, it will soon be possible to transfer two embryos in most cases. We, therefore, anticipate that control of multiples from IVF will come sooner than ovulation inducting agents. The difficulty with ovulation inducing agents is that there is mounting data that ultrasound evaluation of mature follicles is not sufficient to control multiples. Retrospective studies have shown that patients who have singleton pregnancies have preovulatory ultrasounds that are remarkably similar to those who have multiples. However, it is clear that younger patients have higher risks for high-order multiple pregnancies. It is our general protocol to use minimal drug dosages in patients in their 20’s, which is contradistinction to patients in their late 30’s and early 40’s. It is anticipated, through a variety of approaches, that control of multiples will be superior in the future. This will greatly improve perinatal outcome for patients who conceive from infertility therapy.

In conclusion, a variety of techniques are now able to enhance the care of the infertile patient. As we look to the future, we expect that with in vitro fertilization our pregnancies rates will continue to improve, and because of this, the technology will become even more dominant. Additionally, a variety of other non-invasive techniques, such as tubal catheterization, will become more effective. One challenge which we, as a specialty, must accept is to disseminate more information about the effect of age on reproductive function. As women become more entrenched in the workforce, they tend to defer reproduction to later and later, at such a point ovarian function is frequently compromised. We should encourage patients, if possible, to attempt conception prior to the age of 32. This allows us some time to work with them with normal ovarian function if they should have difficulty. Also, patients 35 years and older, who have attempted conception unsuccessfully, should probably be evaluated after 6 months rather than the traditional one year interval.