Achieving a Successful Outcome
Through Intrauterine Insemination and
Ovulation Induction
by Scott M. Slayden,MD
Joe B. Massey, MD



Drs. Slayden and Massey are physicians
Reproductive Biology Associates
Atlanta, Georgia

June 9, 2005 - The United States Census Bureau has released our country's latest census results indicating a total U.S. population of nearly 300 million. This statistic suggests that exceptional fertility is an inherent trait of the human species - this is far from the truth. With peak normal pregnancy rates of only 15 - 25% per month between the ages of 18 -35, it is no wonder that, as a species, we are particularly devastated by conditions leading to subfertility. In fact, it is not at all unusual for an otherwise healthy but subfertile couple to experience a pregnancy rate less than 5% per month. Oftentimes, we are left with unanswered questions and frustration when an infertility investigation in such couples uncovers no particular abnormality - ie: open tubes (normal HSG), normal natural ovulation each month, and a normal semen analysis. Although a subsequent laparoscopy may uncover stage I-II endometriosis or a repeat semen analysis may reveal mild abnormalities, it still seems that patients experiencing such subtle problems are the ones who "should have been pregnant".  If this situation sounds familiar, please read further to understand how the use of intrauterine insemination (IUI) and ancillary technologies such as ovulation induction (OI), PAF sperm treatment and more can raise pregnancy rates back to baseline levels and beyond.

NATURAL EVENTS

Natural conception results when adequate numbers of normal motile sperm are deposited in the vagina and become activated (capacitated) while traversing through normal cervical mucus. Of the 100 - 200 million sperm found in a typical ejaculate, 50% are motile and only 0.1% ever reach the end of the tubes where fertilization of a single egg occurs. When these and other hurdles are taken into consideration (sperm count, cervical mucus interactions, sperm attrition, and timing) it is no small miracle that successful union of sperm and egg occurs at all.

 IUI is a technique that addresses the inefficiency associated with many of these natural hurdles by increasing the probability that appropriate numbers of sperm will be present around an egg (or eggs) at the appropriate time. Ovulation induction (OI) involves the use of fertility drugs to increase the number of eggs to serve as targets for sperm during an IUI procedure. Generally speaking, OI techniques can increase monthly egg production and correct undiagnosed ovulation defects but may not correct poor egg quality. Nonetheless, success or failure of OI often relies on the random chance that some of the additional eggs produced per cycle are of better quality than the single egg generated in a natural cycle. The following sections will review the three basic situations where OI- IUI may provide benefits to infertility patients:

I.  Male factor infertility
II. Unexplained infertility
III. Endometriosis.

I.      Male Factor Infertility - it takes more than one 

Within each sperm head, a small enzyme filled area called the acrosome awaits the call to action. The acrosome is filled with enzymes that degrade the cells (cumulus) and membrane (zona pellucida) around an egg so that fertilization can occur. A single sperm provides a negligible amount of enzymatic activity to have any impact on the fertilization process. In actuality, it takes many thousands to millions of activated healthy sperm to "dissolve" a pathway to the inner egg membrane so that a single sperm can penetrate and fertilize the egg. So, an important concept to understand relates to the total number of motile sperm (TMI) available to interact with the egg. This number is a product of the semen volume (mL), sperm count per mL, and the percent of sperm moving (motility). Normal sperm shapes (morphology) are also very important although they are not part of the calculated final TMI. Abnormalities of any one of these parameters may or may not drop the total number of available sperm below a threshold level where conception rates will suffer. A second important concept to be aware of relates to sperm function - or lack thereof. As will be discussed below, diminished sperm function may be partly to blame for the low pregnancy rates seen in male factor couples despite seeing enhanced numbers of motile sperm through IUI techniques.

Preparation of semen for IUI will enrich the final sample with the most motile sperm. Thus, the endpoint of an IUI prepared semen sample is the total motile inseminating count (TMI). For male factor infertility patients undergoing IUI, a TMI   2-5 million is preferred. Unfortunately, a maximum pregnancy rate of only 10% per attempt (cycle) is seen even if a good TMI is generated. Thus, couples experiencing male factor infertility need to be prepared to undergo 3-4 IUI cycles before and consider moving on to IVF if they desire a better pregnancy rate. Alternatively, immediate progression to IVF (without preceding IUI) should be considered when a very low TMI is encountered (< 1 million/ml) or significant male factor infertility coexists with either female age >35 year range or female pelvic pathology such as endometriosis. (1)

Considering the disappointment and cost associated with multiple unsuccessful IUI cycles, we are constantly searching for new ways to predict which male factor infertility patients will conceive with IUI versus IVF. Evaluation of sperm function is one method of evaluation. Traditionally, sperm function tests have served this purpose, with the hamster egg sperm penetration analysis (SPA) being the most popular. However, the SPA is expensive and may fail to predict outcome. Thus, we are currently evaluating the hyaluron binding assay (HBA) - a new, less expensive sperm function test. (2) We are hopeful that the HBA may predict outcomes more effectively than the SPA and subsequently allow us to better individualize therapy. However, it remains to be seen whether patients with abnormal HBA results should seriously consider pursuing IVF with ICSI instead of spending their resources on 3-4 months of IUI therapy.  

IUI PROTOCOLS & TECHNIQUES ENHANCE OUTCOME

Timing of IUI in relationship to ovulation appears to be critical - conception will not occur if exposure to sperm occurs >24 hours after ovulation. (3) However, there is controversy regarding the need for absolutely precise IUI timing as long as the procedure is performed within this time constraint. Nonetheless, many clinics utilize ultrasound follicular monitoring combined with urinary LH surge testing to predict the appropriate timing of the IUI procedure. Detection of a natural LH surge should be noted when follicles have reached their maximal diameter of 18-24 mm. Sometimes, a natural LH surge fails to occur, particularly when gonadotropin (FSH) injections are given to stimulate ovulation. In these cases, a single hCG injection is given as a substitute for the natural LH surge when follicles have reached a mature size. Otherwise, ovulation will usually occur 12-24 hours after a natural LH surge is detected in urine or 38-44 hours after a single hCG injection. Thus, an IUI is usually scheduled the morning after an LH surge or approximately 36 hours after a patient self-administered evening hCG injection.

Preparation of a semen sample with Platelet Activating Factor (PAF) for IUI takes approximately 2 hours. Our standard technique washes sperm from seminal fluid using several centrifugation steps. The washed sperm are then incubated with platelet activating factor (PAF) for 15 minutes to enhance motility. In our non-male factor patient population, we demonstrated that PAF incubation increased pregnancy rates to 30% per cycle versus 18% per cycle in non-PAF treated samples. (4)  Our continued observations of a subgroup of IUI patients receiving follitropin-beta OI (FSH injections administered by a pen device) has demonstrated a surprisingly high pregnancy rates of 48% per cycle. (5) This data is particularly exciting when it is compared to and found to exceed the national IVF pregnancy rate of 42.5% noted by the CDC in 2002. (6) Unfortunately, IUI pregnancy rates for male-factor patients were not improved with the PAF wash, with pregnancy rates hovering around 10% per cycle. Nonetheless, we are hopeful that our continued research on PAF treatment will demonstrate benefits for male factor patients too.

Dual IUI's - Traditionally, patients undergo a single IUI per cycle. However, some studies have shown improved pregnancy rates when dual IUI's are used. (7,8,9) Thus, for the past several years, we have encouraged this technique for patients with normal semen parameters (non-male factor patients). In this technique, ovulation is triggered with a nighttime hCG shot and the first IUI is performed the next day and the second, more important IUI is performed the following day approximately 36 hours after hCG administration. Some patients will choose to undergo a single IUI per cycle as a cost savings measure. In these cases, a single IUI is performed approximately 36 hours after a nighttime hCG shot or 12-24 hours after a positive urinary LH surge is detected.
 
Ovulation Induction - Based on the majority of available medical evidence, we strongly encourage treating the wife with fertility drugs (ovulation induction) so that more eggs are available during the IUI process. Pregnancy rates are clearly enhanced by this combination when compared to IUI in natural (unstimulated) cycles. (10) For some patient categories, use of FSH injections (gonadotropins) will result in higher pregnancy rates than use of clomid. Again, ultrasound monitoring should be used to determine that an appropriate number of mature follicles are produced (2-4 generally) and to enhance timing of the IUI procedure - usually with an hCG injection. It is a basic premise of OI-IUI cycles that some risk of multiple pregnancy must be taken in order to achieve a reasonable per cycle pregnancy rate. This risk is a direct result of the extra eggs produced - the more produced, the greater the pregnancy rate and the greater the risk of triplets and above. Ultrasound monitoring further allows us to counsel our patients about their multiple pregnancy risks based on the number of follicles counted. However, all methods of predicting multiple pregnancy are inherently imprecise. Patients need to maintain awareness of this situation and realize that IVF with controlled limited embryo transfer continues to be the most effective method of generating high pregnancy rates while greatly minimizing the risk of triplets or more. 

 

II. UNEXPLAINED INFERTILITY:
Using OI-IUI to Enhance Pregnancy Rates in Ovulatory Women with Open Tubes

Unexplained infertility is a relatively common diagnosis that occurs when the basic infertility investigation fails to uncover any problems. This situation is found primarily among infertile women with regular, ovulatory menstrual cycles. By definition, the semen analysis and HSG are normal, there is no known cervical factor, and normal findings at laparoscopy have been noted. In actuality, there may be clinically subtle but functionally major defects in sperm function, cervical hostility, tubal dysfunction, abnormal sperm-egg interaction, poor egg quality, genetic, environmental and implantation defects. The watchword here is "functionality" which is inherently difficult to test in a meaningful, accurate fashion. Without treatment, pregnancy rates are usually less than 10% per cycle. Following, IUI with OI will be discussed as a proven method of enhancing pregnancy rates in patients with unexplained infertility.

 

1.  Using IUI to compensate for Possible Undiagnosed Sperm Function Defects

It may be recalled that in normal cases, interaction of the sperm with cervical mucus results in sperm capacitation. Without capacitation, the sperm cannot attain maximal motility and cannot undergo the release of their acrosomal enzymes near the egg (acrosome reaction). Because it is not practical to test for capacitation, many fertility specialists rely on the ability of IUI preparation techniques to induce capacitation.  It is this effect, combined with the increased numbers of sperm introduced into the uterine cavity, that may explain some of the benefit of performing IUI in unexplained infertility patients.


2.   Using IUI to Bypass Hostile Cervical Mucus
 
Patients with unexplained infertility may have "hostile" cervical mucus that can be easily bypassed by IUI. In the past, a postcoital test (PCT) was performed to diagnose this condition. However, more recently, the PCT has fallen into general disfavor due to its inherent inaccuracies and patient inconvenience. In fact, IUI has become so effective for unexplained infertility that evaluation for abnormal "hostile" cervical mucus is now usually bypassed in favor of moving directly to IUI.


3. Utilizing OI-IUI to Compensate for Possible Poor Egg Quality

Ovulation induction with a goal of producing multiple eggs per month can be helpful for patients with unexplained infertility. Treatment with this goal in mind can compress several months of "natural" fertility into one month, thereby enhancing pregnancy rates. It is theorized that compressing all of this reproductive capacity into one month somehow compensates for an undiagnosed egg quality issue. Many patients wonder if they have poor quality eggs and are aware that the "Day 3 FSH Level" and the" Clomiphene Citrate Challenge Test - CCCT" are tests for inherent ovarian reserve problems or poor egg quality. (11) Day 3 Estradiol levels, inhibin levels, ovarian volume measurements and basal antral follicle counts (BAF) may also provide similar information. If any one of these tests is abnormal in a patient >35 years old, an egg problem probably exists and the infertility case is no longer "unexplained". However, these tests have limitations. For example, an abnormal single test in a woman <35 years old may have less clinical significance than expected whereas a normal test in women at any age doesn't always confirm normal egg quality. Alternatively, poor egg quality is usually suggested by the presence of multiple abnormal tests.

Again, stimulation of multiple eggs may produce a higher pregnancy rate in these patients and IUI clearly adds to the success rate. (10) Thus, for many patients with unexplained infertility we advise pursuing 2-3 cycles of OI-IUI prior to undergoing IVF, especially if they are less than 35 years old. Generally speaking, FSH shots (gonadotropins)/IUI generate higher pregnancy rates than clomid/IUI. A relatively new treatment protocol utilizing the aromatase inhibitor letrozole (Femara) is being investigated as a non-FDA approved OI regimen. When combined with gonadotropin injections and IUI, Letrozole is emerging as another powerful choice in our armamentarium. (12,13) Ultimately, the increasing number of regimens available will allow us to tailor therapy to a patient's individual needs with respect to her economic situation and willingness to risk multiple pregnancy. Although a generalization, the following table provides some information regarding our clinical experience with some of these ovulation induction regimens:

Table 1.  PROTOCOLS FOR OI-IUI CYCLES

Protocol

Pregnancy

Rate

Cost

Multiple PPr   Preg Rate

Clomid/IUI

Good

Low

Low
to mod

FSH/IUI

Highest

Highest

Highest

Femara + FSH/IUI

High

Mod

Highest

Femara/IUI

Good to Moderate

Low

Lowest


4.  Utilizing OI-IUI to Compensate for Possible Abnormal Ovulation and Luteal phase Defects

Unexplained infertility patients may experience subtle ovulation deficiencies that include the lack of an appropriate LH surge or a luteal phase defect (LPD). These abnormalities can be very difficult to diagnose and may therefore fall into the category of unexplained infertility. Fortunately, the use of ovulation induction (OI) with hCG ovulation triggering (artificial LH surge injection) can treat the majority of these problems resulting in increased pregnancy rates. Additionally, some clinicians use progesterone to supplement a possibly deficient luteal phase while others rely on the enhanced natural progesterone production resulting from the use of OI medications to produce similar results.
 
III.     ENDOMETRIOSIS: Improving Pregnancy Rates with OI-IUI
 
Endometriosis is diagnosed when endometrial implants are visualized within the pelvis during laparoscopic evaluation. The abnormal growth of endometrial tissue in the pelvis causes an inflammatory condition that may be toxic to sperm, eggs, and embryos. Infertility results when inflammation either produces severe scarring (Stage III-IV Endo) or leaves the pelvis undamaged but nonetheless inhospitable to conception (Stage I-II Endo). Sperm survivability within the female reproductive tract may be greatly diminished.

It takes a surprisingly small amount of endometriosis to significantly impair pregnancy rates. (14) Ovulatory patients with a normal basic infertility investigation are often found to harbor endometriosis at high frequencies. In other words, we suspect endometriosis in the patient who "should be pregnant". Although useful in predicting a successful diagnosis, a history of painful menses or painful intercourse need not be present. A family association is frequently absent in confirmed cases.

For many patients, particularly ones in their early 30's and beyond, laparoscopic evaluation without actual surgical treatment of disease (laser vaporization, excision, or cautery) followed by observation simply isn't effective therapy. Pregnancy rates as low as 2.5% per month have been reported when using this ultra-conservative approach. Moreover, pregnancy rates of only 5% per month may be seen if the disease is actually vaporized at the time of laparoscopic diagnosis and not followed by OI-IUI therapy. (14) Thus, once endometriosis is suspected, we generally advise laparoscopic diagnosis with simultaneous vaporization of the disease implants immediately followed by OI-IUI for several cycles in patients with lower stage disease. Pregnancy rates over 17% per month may be attained with this management strategy, particularly with Stage I- II disease. (15) IVF is recommended if pregnancy doesn't result after 2-4 appropriately responsive OI/IUI cycles in the post-operative interval. Generally speaking, more surgery or use of depot-Lupron do not enhance pregnancy rates in this situation. Patients with Stage III-IV disease are treated surgically but will usually require IVF instead of OI-IUI to achieve reasonable pregnancy rates.

SUMMARY

Our practice has achieved remarkable success with our IUI program by adopting a detailed and fairly aggressive management approach with these cycles. We advise ovarian stimulation in conjunction with IUI for the majority of our patients. Using dual IUI's and PAF sperm treatment has increased pregnancy rates in our patient population. Patients with suspected endometriosis may have higher pregnancy rates when the disorder is diagnosed and treated with laparoscopic surgery early in the course of therapy. We also direct some patients rapidly towards IVF if their prognosis with IUI appears to be poor. Other patients may choose IVF instead of IUI if they desire the highest pregnancy rate possible.  In other words, IUI can be very successful if used in the correct patient population and much less rewarding if used in an inappropriate patient population. We are hopeful that continued research will enable more patients to achieve conception through use of enhanced IUI techniques.


REFERENCES

1. Dickey et al. Fertil Steril 71(4):684-9, 1999.
2. Roudebush et al. New England Fertility Society Annual Meeting 2004.
3. Wilcox et al. New England Jour Med 333(23):1517-21. 1995.
4. Roudebush et al. Fertil Steril 82(1) 2004.
5. Roudebush et al. in print; Abstract of annual ASRM meeting, 2005.
6. www.cdc.gov/reproductivehealth/ART02/
7. Ragni et al. Fertil Steril 72(4):619, 1999.
8. Silverberg et al. Fertil Steril 57(2):357, 1992.
9. Matilsky et al. Journal Andrology 19(5):603, 1998.
10. Guzick et al. NEJM 340(3):177, 1999.
11. Scott et al. Fertil Steril 63:1, 1995.
12. Mitwally et al. Hum Repro 18(8):1588-97, 2003.
13. De Ziegler. Hum Repro 18(8):1598-1602, 2003.
14. Marcoux et al, NEJM 337(4):217, 1997.
15. Guzick et al. Fertil Steril 70(2):207, 1998.


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