INTRODUCTION

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Infertility is a very common condition affecting approximately 13-14% of couples in the reproductive age group (1). Although this prevalence has remained stable over the last few years, the demand for infertility services has increased substantially. This increase is due primarily to the Baby Boom generation entering into the reproductive age group at a time of highly publicized technological advances. Therefore, although infertility represents a small place in the broad intellectual scope of reproductive endocrinology, patients who are infertile represent the mainstay of a clinical reproductive endocrinologist’s practice.

Infertility is defined classically as the inability to conceive after 1 year of unprotected intercourse. This definition is based on the cumulative probability of pregnancy.

Table 1. Cumulative Probability of Pregnancy in Normally Fertile Couples

Assuming a monthly probability of conceiving (fecundability) of 20%, which remains stable from month to month, the cumulative pregnancy rate after 12 months is 93%. Interestingly, after 3 months, approximately 50% of couples should be pregnant; however, from 4-6 months, only another 25% will conceive. This cumulative probability is a key concept to explain to patients. Explaining to the patients that most fertility therapy (other than in vitro fertilization [IVF]) is designed to improve their fecundability to as close to 20% as possible also is important. If the patient responds well to therapy, then continue the therapy until the cumulative pregnancy rate is at least 50%. Finally, these numbers are based on all reproductive-aged women.

PREVALENCE

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The prevalence of infertility is approximately 13-14%. This number is based on data from the National Survey of Family Growth, conducted by the National Center for Health Statistics of the US Department of Health and Human Services in 1976, 1982, and 1988. These surveys were based on face-to-face interviews of a representative cohort of approximately 8000 women. During the 3 years prior to the interview, infertility was designated if the subjects had engaged in regular unprotected intercourse for at least a 12-month period without establishing a pregnancy. When controlled for those patients that were sterilized, the prevalence of infertility remained stable at 13.3% in 1964 and 13.7% in 1988 (1).

Aging and fertility

An inverse relationship exists between female age and fertility. For example, in a select Mormon population that did not practice family control, there was little change in female fertility between adolescence and the mid 30s. During the late 30s, fertility declined to 70% of baseline, and, in patients aged 40-44 years, fertility declined to 62% of baseline. In patients older than 44 years, the baseline fertility rate was 14% of baseline.

Another study in England consisted of 4100 women recruited at family planning clinics. Relative fertility rates were calculated as the pregnancy rate per month for individuals relative to the baseline (25-27 y) age group. The results (see Table 2) show a steady decline with advancing age.

The classic study is that of the Hutterites, a communal sect that condemns contraception. The infertility rate was only 2.4%, and the average age of the last pregnancy was 40.9 years. After age 34 years, 11% of the population bore no children, 33% had children after age 40 years, and 87% were infertile after age 45 years (2). Realizing that all of these studies did not adjust for the natural decline in coital frequency with age and duration of marriage is important.

Table 2. Relative Fertility Rates by Age

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At least one third of women who defer pregnancy until their mid 30s will have problems conceiving; up to 50% of women older than 40 years who defer pregnancy also will have problems with conception. For men, a decrease in testosterone levels and an increase in gonadotropin levels occur and lead to an eventual decrease in sperm counts. The sperm quality also may decrease since a paternal age older than 40 years is associated with a greater than 20% chance of birth defects in the offspring.

DIAGNOSTIC TESTS

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Perform those diagnostic studies that are clearly beneficial and could alter the treatment plan. Multiple causes of infertility exist, as depicted in the following table:

Table 3. Causes of Infertility

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As with any medical issue, a thorough history is critical. Sending a detailed questionnaire to the couple usually is recommended. This allows the opportunity to focus on those issues that are pertinent during the actual clinic visit. The scope of the questions encompass such issues as the following:

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• Coital frequency

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• Prior pelvic infections

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• Duration of infertility

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• Prior pregnancies from either partner

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• Use of contraception

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• Tobacco and alcohol history

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• Employment

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• Family history of miscarriages

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• Birth defects or inheritable disorders

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• Current medical/surgical problems

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• Updated medicine list (including any over-the-counter medicine or herbs)

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• Thorough gynecologic history, including pelvic pain, discomfort with intercourse, menstrual cramps, douching, cycle length, and duration of flow

Ensure that the male partner is present during the initial interview. First, his presence allows the physician to reinforce that this is a couple’s issue. Second, it acquaints the male to the physician’s management style and provides an opportunity for clarification of any tests that may be ordered. Third, it allows the physician to observe the interaction between the couple to see if any potential conflicts or stresses exist that need to be addressed.

Based on the history and physical examination, the initial tests can be selected. If the history is unclear, then tests should be ordered that assess the above-mentioned major categories of infertility.

Testing for ovulatory function

Basal body temperature (BBT) monitoring is an antiquated method for determining when to have coitus. A significant rise in temperature is not noted until 2 days after the luteinizing hormone (LH) peak, which occurs after the day of ovulation. Recent studies show that the best day to introduce sperm into the female reproductive tract is either the day of ovulation or the day before; therefore, BBT monitoring is more retrospective than prospective. Urine LH kits are extremely useful and, at least, predict the day of ovulation. An endometrial biopsy can be obtained to document luteinization of the endometrium due to progesterone from a postovulatory corpus luteum. A lag of 2 days histologically from the patient’s actual menstrual cycle day also indicates a luteal phase defect. Finally, a serum progesterone of greater than 4 ng/mL indicates ovulation.

Another test is the clomiphene citrate challenge test (CCCT). Some physicians prefer this test because it is a provocative test rather than a passive test (5). Clomiphene citrate (100 mg bid) is administered on days 5-10. FSH and estradiol levels are drawn on days 3 and 10. If the day 3 or 10 FSH level is greater than 15 mIU/mL or the day 3 estradiol level is more than 75 pg/mL, the test is considered abnormal. The rationale is that if the patient has an elevated day 10 estradiol level due to the clomiphene, yet her FSH level is not suppressed (estrogen suppresses FSH by a negative feedback mechanism), she has significant decreased ovarian reserve.

Conduct these tests in women older than 30 years, in women with irregular menstrual cycles, or in women with unexplained infertility, including a screening test for ovarian reserve. An abnormal test indicates that the patient has a 1-3% chance of taking home a healthy baby. Traditionally, FSH and estradiol levels were obtained on days 2-4. Each lab has its own cut-off time. Typically, if the FSH level is greater than 15 mIU/mL and/or the estradiol level is greater than 75 pg/mL, the prognosis is poor. In these patients, a low inhibin B (<35) helps to support the diagnosis (4).

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Testing for male factor

Typically, abstinence is required at least 3-5 days prior to semen collection for best results. If the man cannot collect a specimen, special condoms are available for collection during intercourse. The World Health Organization (WHO) recommends the following for normal values:

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• Volume - 2 mL or greater

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• Sperm concentration - 20 million/mL

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• Motility - 50% or more with forward progression

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• Morphology - 30% or more normal forms (14% strict Kruger criteria)

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• White blood cells - Fewer than 1 million/mL

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• Round cells - Fewer than 5 million/mL

Many centers use a second phase to the semen analysis to determine the strength of the sperm. After 60 minutes, the semen is analyzed again with the expectation that, at least, 25% of the sperm will remain motile with forward progression. Also, the semen is placed through a swim-up technique that separates the motile sperm from the nonmotile sperm. At least 1 million total motile sperm is considered adequate.

Testing for tubal disease

A history of pelvic inflammatory disease, septic abortion, ruptured appendix, tubal surgery, or ectopic pregnancy should alert the physician to the possibility of tubal damage. In these patients or in patients with significant pelvic pain on physical examination, proceeding to a diagnostic laparoscopy rather than a hysterosalpingogram is more prudent because the chance of finding significant pathology is very high (6). Even if a hysterosalpingogram reveals patent fallopian tubes in these patients, the likelihood that pelvic adhesions or endometriosis are affecting the mobility of the tubes warrants a diagnostic laparoscopy.

In patients with a noncontributory history or examination, a hysterosalpingogram performed 2-5 days after cessation of menstrual flow is the procedure of choice (7). The overall risk of infection is 1%; therefore, most patients do not require antibiotic prophylaxis. Pretreatment with a nonsteroidal anti-inflammatory drug (NSAID) is recommended, with the rare patient requiring a mild sedative. The procedure takes approximately 10 minutes to complete, and results are conveyed immediately to the patient. This procedure is not only diagnostic but also appears to be therapeutic, primarily when using an oil-based dye. This effect lasts for approximately 6 months (8). If the patient has still failed to conceive, then a diagnostic laparoscopy usually is indicated. In these patients, approximately 50% have some type of pelvic pathology, usually adhesions or endometriosis.

Testing for cervical disease

Women who have had cervical cone biopsies or trauma to the cervix are at risk for cervical abnormalities. Since no good test exists to screen for these abnormalities, relying on the patient’s history is best. The most logical approach is to recommend bypassing the cervix with intrauterine inseminations, especially if the rest of the evaluation is normal. In this situation, use of an intrauterine insemination (IUI) catheter raises the fecundability of the couple to 20%.

In those patients who choose to continue with timed coitus, a postcoital test may be useful. Testing should be periovulatory and based on a urine LH predictor kit. The couple should have intercourse in the morning, and the woman should have her test performed by the late morning or early afternoon. At least 2 hours and no more than 24 hours should elapse between coitus and the postcoital test. If the patient is undergoing a treatment protocol that involves clomiphene citrate, performing the postcoital test after the first coitus is best because of the medicine’s possible negative effect on the cervical mucus. If the test is abnormal, perform an IUI. The following areas are evaluated with the postcoital test along with their reference range values:

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• Mucus stretchability (spinnbarkeit) 8-10 cm

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• Clarity clear

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• Semen pH greater than 7

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• Sperm greater than 1 forward moving per high-power field (HPF)

Since the inception of the postcoital test in 1888, numerous studies have appeared regarding its lack of use in modern fertility therapy. No consensus exists regarding how many sperm should be considered within the reference range. Indeed, in a study of postcoital tests in fertile women, 20% had less than 1 sperm/HPF (11). However, limited usefulness exists for the test. Greater than 20 motile sperm/HPF almost always is associated with a sperm concentration within the reference range on a semen analysis. Quivering sperm that lack forward progression may suggest an antisperm antibody issue. No sperm may indicate an issue with coital practice, such as premature ejaculation. Opaque or yellow mucus may represent a cervical infection, and cultures and/or a wet smear should be obtained to evaluate for bacteria or white blood cells.

Testing for uterine disease

As for tubal disease, obtaining a history from the patient is the most important diagnostic tool. A history of repetitive elective abortions, uterine surgery, postpartum uterine infections, retained products of conception, or postpartum curettage should alert the clinician to a possible uterine factor. Also, a history of abnormal bleeding, such as mid-cycle spotting, may represent an intrauterine polyp or fibroid. Repetitive breech deliveries often suggest a uterine anomaly, such as a septum or bicornuate uterus. Finally, a couple with repetitive miscarriages, especially second trimester, may suggest a uterine cause. A screening transvaginal ultrasound performed after the woman’s menstrual flow has stopped may suggest a uterine leiomyoma (fibroid), adenomyosis, or even an endometrial polyp. Usually, a hysterosalpingogram is performed next to evaluate the fallopian tubes and the uterine cavity. If a uterine cavity defect exists, performing a hysteroscopy further delineates and possibly treats the problem.

If the patient has known blocked tubes and is scheduled for IVF, a sonohysterogram is more appropriate and less uncomfortable for the patient. A small catheter is placed in the uterine cavity, and, under ultrasound guidance, sterile water is instilled to separate the endometrial walls. Then, any defects can be seen clearly. In fact, for fibroids and polyps, this procedure is more sensitive than a hysterosalpingogram. Some physicians prefer to use a smaller, office-based hysteroscope. This procedure is purely diagnostic, except for the possible removal of small polyps or filmy adhesions, yet is attractive because it requires little or no sedation.

Diagnosis of endocrine abnormalities

Any evidence of the following should warrant selective hormonal studies:

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• Hirsutism

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• Abnormal weight gain

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• Oily skin or acne

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• Purple striae on the abdomen

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• Polyuria/polydipsia

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• Irregular menses

If hirsutism exists with or without menstrual irregularity, then androgen studies (eg, dehydroepiandrosterone sulfate [DHEAS], total testosterone, 17-hydroxyprogesterone) should be performed. If unusual weight gain or fatigue develops, a thyroid-stimulating hormone (TSH) test is needed. If galactorrhea or irregular menses occurs, a prolactin level should be considered. Acanthosis nigricans suggests hyperinsulinemia and requires a fasting insulin and glucose level to confirm.

Obtaining panels of tests is inappropriate. An inadequate luteal phase (luteal phase defect) has been reported in the literature as a cause of both infertility and recurrent miscarriages (in approximately 5% of these couples); however, the true clinical value of this test is of concern. Isolated luteal phase defects are observed in 30% of healthy fertile couples (12); therefore, this defect must be a repetitive event to be a true cause of infertility or miscarriage. Traditionally, diagnosis has been determined histologically (a lag of >2 d histologically compared to the day of the cycle, based on the actual day of ovulation). Some physicians prefer to use low luteal phase progesterone (<10 ng/mL) 6 days after ovulation as their method of diagnosis, with good correlation to histology if repeated in 3 separate menstrual cycles. Most studies show that the addition of exogenous progesterone is of little benefit, suggesting an endometrial defect in progesterone use.

Unexplained infertility

TREATMENT

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Treatment of ovulatory dysfunction

If the patient has a normal ovarian reserve, determining the potential cause of the ovulatory defect is prudent. If the patient is obese, polycystic ovarian (PCO) syndrome or Cushing disease may be evident. If the patient is hirsute, she may have elevated androgen levels or hyperinsulinemia, requiring further testing. If the patient's history and physical examination is negative, then considering treatment to help the patient ovulate is appropriate. The following treatment regimens often are used for patients with idiopathic ovulatory dysfunction or PCO:

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• Clomiphene citrate (50 mg days 5-9)

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

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• Clomiphene citrate plus human chorionic gonadotropin (HCG) for ovulation

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• Elevated androgens - Dexamethasone (0.25 mg/d) plus clomiphene citrate

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• Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate

The goal of therapy is to obtain 3 ovulatory cycles, because at least 40-50% of women should be pregnant in this timeframe, barring any other abnormalities. If the patient has not conceived, then investigate other causes of infertility. No more than 6 consecutive cycles are recommended because of the theoretical risk of borderline ovarian tumors and the extremely low success rates after this timeframe.

There is evidence to suggest that starting clomiphene citrate earlier (day 2 or 3)is more beneficial. First, it allows for a more normal cycle length for the patient, typically 28 days.

Second, it promotes ovulation around days 12-16, which is more physiologic. There is evidence suggesting that delayed ovulation creates an "over-mature" oocyte. Evidence from the 1970's on women with documented delayed ovulation (after cycle day 16) revealed a higher miscarriage rate. This was felt to be secondary to meiotic dysfunction within the oocyte the longer it took for the follicle to ovulate. There is also some recent evidence from IVF cycles to support this theory.

Third, it is easier for patients to use ovulation (LH) predictor kits when clomiphene citrate is started earlier. LH is normally elevated after taking clomiphene citrate and the half-life of the medication is five days. Thus, in a cycle day 5-9 regimen, it is easy to see how a patient may get a false-positive reading if she follows the directions on the kit and starts monitoring on cycle days 12-13.

Fourth, a recent study has demonstrated that an earlierstart time allows the endometrium to thicken to a more normal range. Endometrial thinning is a well known adverse effect of clomiphene citrate. A thin endometrium less than 7-8 mm has been associated with a lower pregnancy rate, at least in IVF cycles.

Treatment of male factor

Confirm any abnormal study with a repeat semen analysis. If still 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, intrauterine insemination 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 media (eg, Earl), and centrifuge it for 60 seconds. Resuspend the pellet in another 15-20 mL of media and centrifuge again. The supernatant is removed, and 0.5 mL of the media 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

In the patient with significant tubal disease, IVF offers the best chance for conception. 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 to normalize tubal function, with an emphasis on prevention of adhesion recurrence, offer the patient at least a window of opportunity to conceive either naturally or with minimal types of therapy. Usually, only proximal tubal occlusion occurs. Like an angioplastic procedure in cardiology, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance.

Table 4 Treatment of Tubal Pathology (9,10)

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Treatment of cervical factor

In most patients, IUIs offer the most reasonable option. However, 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 0.625 mg or Estrace 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, 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

Usually, an operative hysteroscopy is required to lyse adhesions or remove endometrial polyps or submucosal fibroids. Intramural fibroids often need to be removed by laparotomy and myomectomy, paying close attention to microsurgical technique and adhesion prevention. Sometimes, subserosal fibroids that may be impinging on a fallopian tube can be removed laparoscopically. 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. Many women with luteal phase defects also have ovulatory dysfunction. Clomiphene citrate, as mentioned above, and luteal phase progesterone supplementation are 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 central nervous adverse effects (eg, depression).

Treatment of unexplained infertility

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

Table 5. Unexplained infertility and pregnancy rates per cycle according to treatment (14) are as follows:

Table 5. Unexplained infertility and pregnancy rates per cycle according to treatment
(14) are as follows:


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In vitro fertilization

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 also has occurred. Thanks to such organizations as RESOLVE, 13 states have the opportunity to provide coverage for these services. Currently, 2 states (ie, Massachusetts, Rhode Island) offer full coverage. Other states exempt health maintenance organization programs (HMOs), 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 that much. A recent study in Massachusetts, which does approximately 5000 IVF cycles per year, figured that the increase is only $25 per year.

THE ROLE OF THE PHYSICIAN

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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. As mentioned above, the routine ordering of tests not indicated by clinical judgment 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 get a second opinion if all treatments have failed, especially before considering donor sperm, donor oocytes, gestational carrier, or adoption. Finally, the physician must help to dispel many myths that patients and other doctors have regarding fertility, which are as follows:

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

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• A dilatation and curettage (D&C) does not make a patient more fertile.

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

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• An office hysteroscopy requires little or no sedation; an operative hysteroscopy requires intravenous-conscious sedation or general anesthesia and should be performed only if a high suspicion for an abnormality exists.

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• A retroverted uterus is not a cause of infertility.

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• Stress, unless associated with ovulatory dysfunction or decreased coital frequency, is not a cause of infertility according to the most recent literature.

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• No significant evidence implicates antiphospholipid antibodies to infertility.