TREATMENT	Section 5 of 8
Author Information Introduction Prevalence Diagnostic Tests Treatment The Role Of The Physician Pictures Bibliography

Treatment of ovulatory dysfunction

If a patient has a normal ovarian reserve, determining the potential cause of the ovulatory defect is prudent. The practitioner should consider the following scenarios prior to initiating treatment. In the presence of obesity and chronic anovulation, polycystic ovarian (PCO) syndrome or Cushing disease may be evident and in the case of hirsutism, the patient may have elevated androgen levels or hyperinsulinemia, requiring further testing. If the physical examination findings are unremarkable, ovulation induction is the next treatment approach to consider.

The following clomiphene citrate (CC) treatment regimens are often used for ovulation induction in patients with idiopathic ovulatory dysfunction or PCO syndrome:

• Clomiphene citrate (50 mg on days 5-9)

• Clomiphene citrate (100 mg on days 2-6) plus FSH (1-2 amps starting on day 8)

• Clomiphene citrate plus human chorionic gonadotropin (hCG) for ovulation induction

• Elevated androgen levels – Dexamethasone (0.25 mg/d) plus clomiphene citrate

• Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate (Many women spontaneously ovulate on metformin alone; thus, many clinicians allow a trial of 1-3 mo prior to adding clomiphene citrate.)

• Aromatase inhibitors (Letrozole) (2.5 mg PO on cycle days 3-7) has been shown in early studies to work as well as clomiphene citrate to induce mono-ovulation and to have little or no adverse affect on endometrial thickness.

The goal of therapy is to achieve 3 ovulatory cycles; 40-50% of women should become pregnant in this timeframe in the absence of any other abnormalities. If conception has not occurred after 3 clomiphene citrate cycles, the practitioner should investigate other causes of infertility. No more than 6 consecutive cycles are recommended because of the theoretical risk of borderline ovarian tumors and extremely low pregnancy success rates after this point.

Evidence suggests that starting clomiphene citrate earlier (day 2 or 3) is more beneficial because this conforms to a more typical cycle length of 28 days. Beginning a clomiphene citrate cycle on day 2 or 3 promotes ovulation around days 12-16, which is more physiologic and may avoid delayed ovulation and excessive maturity of the oocyte. Studies from the 1970s in women with documented delayed ovulation (after cycle day 16) revealed a higher relative miscarriage rate. This was believed to be caused by meiotic dysfunction within the oocyte.

Ovulation (LH) predictor kits are much easier for patients to use when clomiphene citrate is started on day 2 or 3. LH levels are normally elevated after the patient takes clomiphene citrate, and the half-life of the medication is 5 days. Thus, in a cycle day 5-9 regimen, a patient may receive a false-positive reading if she follows the directions on the kit and starts monitoring on cycle days 12-13.

Evidence demonstrates that a day 2 or 3 clomiphene citrate start allows the endometrium to thicken to a more normal, physiologic range. Endometrial thinning is a well-known adverse effect of clomiphene citrate. An endometrium that is thinner than 7-8 mm has been associated with a lower pregnancy rate in IVF cycles.

Treatment of male factor

Confirm any abnormal study result with a repeat semen analysis. If the results remain abnormal, refer the patient to a urologist to eliminate any genetic, anatomic, hormonal, or infectious causes. If the volume is less than 1 mL, consider retrograde ejaculation and obtain an analysis of the urine.

If the sperm concentration is less than 20 million/mL, yet the swim-up extraction yields at least 1 million total motile sperm, IUI is the treatment of choice. Simple sperm washing can be performed in the office if a centrifuge is available. Allow the semen to liquify on a warming plate at 37°C; then, suspend the semen in approximately 15-20 mL of washing medium (eg, Earl) and centrifuge it for 60 seconds. Resuspend the pellet in another 15-20 mL of medium and centrifuge again. The supernatant is removed, and 0.5 mL of the medium is used to resuspend the sperm pellet. Using an intrauterine catheter, deposit the sperm into the uterus on the day of ovulation

Treatment of tubal disease

IVF offers the best chance for conception in patients with significant tubal disease. Often, if only 1 tube is affected, ovarian stimulation with gonadotropins produces mature oocytes in the ovary near the patent tube. In patients with minimal or moderate tubal disease, laparoscopic lysis of adhesions and procedures should be performed to normalize tubal function, with an emphasis on prevention of adhesion recurrence. In patients with an irreparable hydrosalpinx, removing the tube or disconnecting it from the uterus may reduce the risk of a tubal pregnancy and enhance embryo implantation if the patient requires IVF.

Pregnancy rate following treatment can be dependent upon location of tubal disease (see Table 4).

Laparoscopic lysis of adhesions offers the patient a window of opportunity to conceive either naturally or with minimal types of therapy. If only proximal tubal occlusion is present, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance similar to the common angioplastic procedure in cardiology.

Table 4. Treatment of Tubal Pathology

Procedure	Pregnancy Rate (3-6 mo)
Lysis of adhesions	50%
Mild distal obstructive disease	80%
Moderate distal obstructive disease	30%
Severe distal obstructive disease	15%
Proximal tubal obstruction:	30%

Treatment of cervical factor

In most patients, IUIs offer the most reasonable option for treatment. Some patients remain adamant that they want to continue with timed coitus despite a cervical issue. In women with thick mucus (poor spinnbarkeit), the addition of conjugated estrogen (Premarin at 0.625 mg or Estrace at 2 mg) 8-9 days prior to ovulation has its supporters but lacks clear clinical value. In some studies, if the pH is less than 7.0, a precoital douche of 1 tablespoon of sodium bicarbonate in 1 quart of water has shown good results. The presence of antisperm antibodies in the female or male warrants IUIs. If the antibodies are on the sperm itself, washing the sperm with a chymotrypsin/galactose preparation may improve sperm motility.

Treatment of uterine factor

An operative hysteroscopy is usually required to lyse adhesions or remove endometrial polyps or submucosal fibroids. Intramural fibroids often must be removed by laparotomy and myomectomy, paying close attention to microsurgical technique and adhesion prevention. Many times, subserosal fibroids may impinge on a fallopian tube. In severe cases of intrauterine adhesions that encompass most of the uterine cavity, the best option for conception may be through the use of a gestational carrier.

Treatment of endocrine abnormalities

Ensure that any endocrine abnormality is normalized prior to attempts at conception. Keep in mind that women with luteal phase defects also have ovulatory dysfunction. Clomiphene citrate, as previously mentioned, and luteal phase progesterone supplementation may be potentially effective treatments. The recommended progesterone is either micronized progesterone in vaginal suppositories (50-100 mg bid) or progesterone vaginal cream (Crinone 8%; 90 mg/d). Oral micronized progesterone may be used but causes significant somnolence and adverse central nervous system effects (eg, depression).

Treatment of unexplained infertility

The choice of treatment protocol depends on how aggressive the couple wants to be with their efforts to conceive. Most physicians start with either clomiphene citrate or gonadotropins in conjunction with IUIs. Involve the couple in the decision-making process, and ensure that they completely understand the success rates (see Table 5) and the risks of multiple pregnancy with each treatment protocol.

Table 5. Unexplained Infertility and Pregnancy Rates per Cycle According to Treatment

Protocol	Pregnancy Rate, %
No treatment	1.3-4.1
IUI alone	3.8
Clomiphene with timed coitus	5.6
Clomiphene with IUI	10
Gonadotropins with timed coitus	7.7
Gonadotropins with IUI	17.1
IVF	35-50

In vitro fertilization (IVF)

The first IVF pregnancy was achieved in 1978. Since then, the number of IVF centers and IVF procedures performed has increased dramatically. An intense effort to obtain insurance coverage for these services has also occurred. With the support of organizations such as RESOLVE (ie, the National Fertility Association), 13 US states have the opportunity to provide coverage for these services. Currently, 2 states (Massachusetts and Rhode Island) offer full coverage. Other states exempt health maintenance organization programs, private insurers, or companies with few employees. Other states offer lifetime limits to their coverage (eg, Ohio, $2000; Arkansas, $15,000). Still other states require insurers to offer coverage but do not require employers to purchase plans that actually provide that coverage. The actual cost per paid subscriber is not substantial. A recent study in Massachusetts, which has approximately 5000 IVF cycles per year, calculated that the increase is only$25 per year per subscriber.

As a result of the Fertility Clinic Success Rate and Certification Act, the US Centers for Disease Control and Prevention (CDC) gathers information from 391 of the 428 fertility clinics throughout the United States. Information from 2002 shows that 115,392 ART cycles were performed. See Image 1 for details on the different types of procedures performed.

Assisted reproductive techniques

Gamete intrafallopian transfer (GIFT) was developed in 1984 for women with unexplained infertility. At that time, GIFT provided much better pregnancy rates, had a much greater degree of naturalness, and was more acceptable in certain religious and ethnic communities (in which fertilization inside the woman's body is the only type allowed). During this procedure, the patient undergoes a controlled ovarian hyperstimulation. The oocytes are retrieved transvaginally under ultrasonographic guidance, and 3-4 oocytes are placed via laparoscopy into one of the fallopian tubes along with sperm.

Zygote intrafallopian transfer (ZIFT) is used for couples with a significant male factor. The oocytes are retrieved similar to GIFT, but they are allowed to fertilize in vitro in the laboratory. At the 2-pronuclear stage (usually 24 h later), 3-4 embryos are transferred via laparoscopy into one of the fallopian tubes. If the embryos are allowed to develop to greater than a 2-cell stage, the procedure is termed tubal embryo transfer (TET). The only benefit to a ZIFT or TET versus the more traditional IVF is for women who are thought to have compromised embryo quality due to embryo in vitro culture. Placing these zygotes or embryos back into their own natural incubators is thought to enhance subsequent development, with improved pregnancy rates.

With the development of enhanced culture media, the success rates for IVF are now comparable, if not better, to those of GIFT and ZIFT.

Interpreting IVF success rates

Comparing one program's success rate to another is difficult because of all the variables involved. For instance, perhaps a program is very selective with its patients, allowing only those with a chance for success based on diagnosis, age, or ovarian reserve. Programs in states that are mandated to cover fertility therapy may be more likely to treat patients with a low chance for success simply because the patient has insurance or, perhaps, because the programs may perform more IVF cycles than programs in states without such a mandate. Some have suggested that programs in mandated states, due to the treatment algorithms enforced by the insurance companies, often have to treat patients without a male or tubal factor for many months with insemination cycles before getting approval for IVF coverage. Thus, these patients may actually be the most difficult patients to treat when they eventually get to IVF.

On the other hand, programs in states without a mandate may be dealing with more difficult patients who have had multiple surgeries and other covered or less costly therapy before ultimately deciding on IVF. However, some argue that many of these programs often take patients directly to IVF, or after a few insemination cycles, and, thus, these patients are more likely to be successful.

In general, like any statistical analysis, the more IVF cycles a program has performed, the more valid the numbers. The cancellation rate is a critical number. If the rate is high, the program is possibly very selective for those patients it allows to proceed to egg retrieval. This type of program would rather cancel the patient's procedure than have a low chance for success that may ultimately hurt its overall success rates. The pregnancy rate per retrieval is higher compared with the pregnancy rate per transfer. If this difference is large, it may reflect the quality of the laboratory. The implantation rate refers to thepregnancy rate divided by the number of embryos transferred. If the implantation rate is low and the pregnancy rate is high, this suggests that the program is transferring a large number of embryos per patient to achieve that success. Chances are good that the program's multiple pregnancy rate is high. Optimally, the better programs have a low cancellation rate and good pregnancy and implantation rates.

The ultimate critical number is the birth rate because this represents the final goal of the patient and the physician. This goal is also less vulnerable to misinterpretation than the pregnancy rate (single positive hCG vs serial increases) or the clinical pregnancy rate (gestational sac vs fetal pole vs fetal pole with heartbeat).

IVF outcomes

In 2002, 115,392 IVF cycles were reported started with a 14.6% cancellation rate, and, 45,751 pregnancies were confirmed delivered. One of every 2.5 IVF cycles started ended in a live birth. See Image 3 for the detailed success rates. When observing cycles that ended in a uterine pregnancy (30.5%), most ended in a singleton birth. The miscarriage rate is no higher than that with a spontaneous pregnancy (ie, 16.1%). These rates are detailed in Image 4.

Guidelines for embryo transfer

In response to the significant numbers of higher order multiple pregnancies generated from ART, the American Society of Reproductive Medicine (ASRM) released guidelines for the number of embryos transferred in 1999. Image 5 shows the risk of having a multiple-fetus pregnancy using fresh, nondonor embryos.

In 2002, the total multiple-fetus pregnancy rate was 36%. A lower number of deliveries of triplets or more compared to pregnancies suggests that these pregnancies were either iatrogenically reduced, spontaneously reduced, or resulted in a miscarriage.

Increasing the number of embryos transferred from 1 to 2 not only increases the chance for a live birth but also increases the likelihood of a multiple-infant pregnancy. However, transferring more than 2 embryos may not increase the overall live birth rate.

Many variables affect the decision of how many embryos to transfer. Factors such as the patient's age, embryo quality, number of prior failed IVF cycles, and use of frozen-thawed embryos are important to consider. New data from Europe suggests that a single embryo transfer in the appropriate patient results in approximately a 35% pregnancy rate with a less than 1% multiple pregnancy rate. These patients typically have embryos that are frozen, ensuring that their cumulative pregnancy rate using either fresh or frozen embryos is similar to transferring 2 or more embryos. Images 6 and 7 show the relationship between the number of embryos transferred and the risk of having a multiple-infant birth in women of all ages and in women younger than 35 years. Single embryo transfer is appropriate in certain situations where the likelihood of a multiple pregnancy is high. This may include women younger than 35 years, women who conceived with first IVF cycle, women with only tubal factorinfertility, women with concerns about multiple gestation, and donor egg recipients.

Factors contributing to IVF success

The most important factor that determines a successful cycle is the female patient's age. As mentioned previously, decreases in fecundity rates are observed beginning as early as age 30 years. The dramatic effect that age has on fecundability is also observed in ART (see Image 7). Most egg donors are aged 20-35 years, allowing for an optimal control group to observe these differences.

Ultimately, the success of ARTs mimics the overall fecundity trend observed in the general fertile population. That is, pregnancy and live birth rates start to decrease beginning around age 30 years and continue to decrease until the chance of having a live birth is so low that the benefit of ARTs must be evaluated. In women older than 40 years, the chance of having a liveborn infant with a chromosomal abnormality also increases. Image 7 shows the live birth rate with ARTs based on the patient's age and whether she uses her own oocytes or donor eggs, which are typically harvested from women aged 20-35 years.

Oocyte retrieval

Oocyte retrieval is performed approximately 36 hours after 10,000 U of hCG is administered to allow for the resumption of meiosis, cytoplasmic maturation, and loosening of the oocytes within the follicle. This allows for a lower optimal vacuum pressure during aspiration and ultimately less oocyte damage.

The 3 basic methods to retrieve oocytes are laparoscopic, transabdominal, or transvaginal. The laparoscopic approach was used frequently in the 1980s, especially when a GIFT procedure was planned. Often, only the follicles that could be seen on the surface of the ovary were removed, and, if the ovary was very mobile, traction was required to support the ovary as the follicles were aspirated. Associated morbidity occurred with the procedure, which included infection and injury to the pelvic organs. General endotracheal anesthesia was usually used, and the patient's recovery often lasted 2-3 days. As the quality of ultrasonographic images and culture media improved, the need for laparoscopy decreased.

In 1981, ultrasonographic-guided aspiration was first described. Initially, the transabdominal approach was used, usually with the aspirating needle going through the bladder, which, when full, provided a window of visualization for the person operating the abdominal ultrasonographic probe.

Although still used for retrieval of oocytes from ovaries that are adhered high up in the pelvis or to the fundus of the uterus, the transabdominal approach was superseded by the transvaginal approach. The first transvaginal retrieval was performed in 1984 and has now become the procedure of choice because of its ease and low morbidity.

Micromanipulation

Intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples in whom the male partner has azoospermia or severe oligospermia. ICSI is also indicated for men with significant antisperm antibodies, low sperm motility, or significantly abnormal sperm morphology (Kruger strict morphology <4%).

ICSI is used when poor fertilization occurs with regular insemination techniques in the laboratory. ICSI may be used when a limited amount of sperm is available, such as in couples where the man has stored sperm prior to chemotherapy. ICSI is indicated in certain preimplantation genetic (PGD) procedures—specifically those cases being evaluated for single-gene recessive disorders. This prevents the potential contamination of the specimen with sperm that may be attached to the egg.

Sperm can be obtained from the ejaculate or directly from the epididymis. Recently, success was obtained with spermatids from testicular biopsies. See Image 8 for success rates with ICSI.

The potential transmission of a genetic abnormality is a possibility when ICSI is performed. The normal barrier for morphologically abnormal sperm that tend to have genetic abnormalities (ie, zonal pellucida) is bypassed with ICSI. Morphologically normal sperm may also have genetic abnormalities. Approximately 10% of sperm from healthy men have chromosomal abnormalities. Men who are infertile have a 5-7% chance of having a chromosomal abnormality. Chromosomal abnormalities include microdeletions of the long arm of the Y chromosome in areas AZFa, AZFb, and AZFc (DAZ or deleted in azoospermia region). These deletions can be passed on to male offspring, with resulting oligospermia.

Some data suggest a 30% increase in birth defects in children conceived with ICSI. Overall, this implies that the risk of having a child with a birth defect from ART with ICSI goes from a normal baseline of 3% to, at most, 4%.

Approximately 1-2% of men with azoospermia have genetic translocation, Klinefelter syndrome (47XXY), or a congenital bilateral absence of the vas deferens, which is associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene or the 5T allele.

In the situation where the male partner has the CFTR mutation, the female partner should also be screened for cystic fibrosis. In any couple undergoing ICSI for male factor infertility, a karyotype and Y-DNA mapping should be considered if the sperm concentration is less than 5 million/mL, and genetic counseling should be offered. Prenatal testing of ICSI pregnancies has revealed an incidence of 0.83% of sex chromosome abnormalities (higher than those reported for spontaneous pregnancies).

	THE ROLE OF THE PHYSICIAN	Section 6 of 8
Author Information Introduction Prevalence Diagnostic Tests Treatment The Role Of The Physician Pictures Bibliography

Most patients with infertility are anxious, knowledgeable, familiar with the Internet, and know other people who went through the fertility process. Therefore, the physician should strive to be calm, informative, a good listener, and willing to allow the patient to be involved. The routine ordering of unindicated tests is not advised. Realizing that a substantial number of pregnancies occur in infertile couples without therapy is important, irrespective of the diagnosis. Many couples move from fertility center to fertility center, and some conceive, despite no changes in therapy. The physician should be willing to seek a second opinion if all treatments have failed, especially before considering donor sperm, donor oocytes, a gestational carrier, or adoption. Finally, the physician must help to dispel many myths that patients and other doctors have regarding fertility. These may include the following:

• A routine low-transverse cesarean delivery is not a frequent cause of intrauterine adhesions.

• A dilatation and curettage does not make a patient more fertile.

• A spontaneous first-trimester miscarriage does not increase the risk of adhesions or inflammation.

• A diagnostic office hysteroscopy requires little or no sedation; an operative hysteroscopy requires intravenous conscious sedation or general anesthesia and should be performed only if an abnormality is strongly suggested.

• A retroverted uterus is not a cause of infertility.

• Stress, unless associated with ovulatory dysfunction or decreased coital frequency, may be a cause of infertility but has not been convincingly supported in the literature.

• No significant evidence implicates antiphospholipid antibodies to infertility.

	PICTURES	Section 7 of 8
Author Information Introduction Prevalence Diagnostic Tests Treatment The Role Of The Physician Pictures Bibliography

Caption: Picture 1. Assisted reproduction technique procedures. Rates from the United States in 2003. Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 2. Live births per retrieval for different types of assisted reproduction technique procedures (2003). Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 3. 2003 success rates for assisted reproduction technique cycles using fresh nondonor eggs. Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 4. Outcomes of pregnancies from assisted reproduction technique cycles using fresh nondonor eggs or embryos (2003). Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 5. 2003 multifetal pregnancy rates from assisted reproduction technique cycles using fresh nondonor oocytes or embryos. Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 6. 2003 live birth and multiple-infant birth rates using fresh nondonor oocytes or embryos by number of embryos transferred. Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 7. Live birth rates per transfer for fresh embryos by age (top image) and from patient or donor eggs (bottom image) (1996, 2002, 2003). Adapted from the Centers for Disease Control and Prevention.
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Caption: Picture 8. 2003 success rates using intracytoplasmic sperm injection in couples with male-factor infertility. Adapted from the Centers for Disease Control and Prevention.
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	BIBLIOGRAPHY	Section 8 of 8
Author Information Introduction Prevalence Diagnostic Tests Treatment The Role Of The Physician Pictures Bibliography

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Assisted Reproduction Technology excerpt