Infertility, the inability to conceive after a year of trying, has resulted in an increasing number of physician visits over the last 2 decades.

The Centers for Disease Control and Prevention reported that in 1995, 15% of women (over 9 million) between the ages of 15 and 44 received an infertility service.¹ This has increased by 3% over the decade prior to the report. Two thirds of these patients consulted for advice or investigation. Only one third of the patients consulted a physician for infertility treatment such as ovulation induction, surgery or assisted reproductive technology (ART). Therefore, the primary care physician has a significant role to play in providing infertility services to women. Furthermore, many causes of infertility are associated with significant medical problems that a primary care physician should manage.

Higher prevalence of infertility and greater availability of successful treatment account for the increase in infertility services. The trend of delayed marriage and childbirth is the main social cause of infertility. Twenty percent of women have their first child after the age of 35.

The most common causes of infertility are listed in Table 1.

Tubal Disease
Tubal disease is still the most common cause of infertility in U.S. The most common cause of tubal disease is previous pelvic inflammatory (PID). Most cases of PID in the U.S. are caused by sexually transmitted disease. Westrom demonstrated 20 years ago that subsequent tubal infertility developed in 12% of women after one episode of PID, in 23% of women after 2 episodes of PID, and in 54% of women after 3 episodes of PID. Mild cases of tubal disease can be treated with laparoscopic surgery. In moderate and severe cases of tubal disease, in vitro fertilization (IVF) is associated with better pregnancy rates with a smaller incidence of ectopic pregnancy.

Endometriosis
Endometriosis is another common cause of pelvic disease that is associated with significant pelvic pain and infertility. It is characterized by the presence of endometrial glands and stroma outside of the uterus. The disease process is associated with reflux of menstrual debris into the peritoneal cavity. However, since this occurs in the majority of women, there must be an associated immunologic or genetic abnormality that allows the development of the disease. A variety of cellular and humoral abnormalities have been reported in these patients. The peritoneal cavity has an increased number of activated macrophages. These macrophages secrete a variety of cytokines that might be associated with the observed peritoneal inflammatory reaction. The peritoneal cavity might have a wide spectrum of lesions ranging from a few peritoneal implants to severe adhesive disease that involves all pelvic organs.

Male Factor Infertility
A significant part of infertility is due to the male factor. Environmental toxins, drugs such as cimetidine, heavy cigarette, marijuana and alcohol use can be associated with decreased sperm parameters and reduced fertility. Chemotherapy and radiotherapy for the treatment of malignancies are associated with severely depressed sperm counts that are sometimes irreversible. Counseling of these patients to cryopreserve sperm before initiating treatment is important. Excellent success rates have been reported with the use of this sperm.⁶ Increased scrotal temperature as a result of a febrile illness can cause a temporary alteration of semen parameters that is only identified 2 to 3 months after the episode. This is the time required for a germ cell to develop into a mature spermatozoon. Radiant heat, such as experienced by welders or foundry workers, may also affect semen quality. However, conditions that result in a minor increase in scrotal temperature only, such as tight underwear, have not been shown to alter sperm function.⁷

Several genetic abnormalities are associated with male factor infertility. Congenital bilateral absence of the vas deferentia (CBAVD) is associated with mutations of the cystic fibrosis transmembrane regulator gene. Chromosomal abnormalities have been detected in about 10% to 15 % of azoospermic males and about 5% of oligospermic males. Sex chromosome aneuploidies such as Klinefelter's syndrome are the most commonly reported. Microdeletions of the long arm of the Y chromosome are also associated with severe oligospermia or azoospermia.

Anovulation
The most common cause of anovulation in North America is polycystic ovarian syndrome (PCOS). PCOS is a metabolic disorder with a primary reproductive manifestation. The term PCOS is a misnomer in that there are no "cysts" in the classical gynecologic sense. Many subcapsular follicles of less than 10 mm with increased thecal and stromal tissue characterize the morphology of the PCOS ovary. Most women with PCOS have insulin resistance that is independent of weight.⁸ Fasting and postprandial hyperglycemia are uncommon at this stage of the disease process when patients present with infertility. However, these patients are at greater risk to develop noninsulin-dependent diabetes at a younger age than the general population.⁹ There usually is a strong family history of diabetes or abnormal glucose tolerance. PCOS patients that achieve pregnancy often have gestational diabetes. Obesity is an independent disorder with associated endocrine changes that influence the phenotypic expression of PCOS patients.

It appears that there is a genetic predisposition to insulin resistance. Insulin resistance is most likely due to a post-receptor abnormality such as with a glucose transporter rather than a receptor defect. Insulin can directly influence enzymes that are involved in androgen steroidogenesis as well as decreasing sex hormone binding globulin.

Other causes of anovulation are listed in Table 2.

Deep dyspareunia and dysmenorrhea are the most common symptoms reported in patients with endometriosis. Pelvic examination is best carried out during a menstrual period. During this time specific areas of tenderness and modularity can be more easily identified.

PCOS should be suspected if there is a history of a menstrual disorder such as amenorrhea or oligomenorrhea associated with androgen excess. PCOS usually starts at puberty and is associated with irregular periods and some manifestation of hyperandrogenism. The androgen excess could be a clinical manifestation such as acne or hirsutism, or a laboratory finding of an elevated androgen (Table 3). Increasing weight will influence the expression of the disease. A variety of medical problems are associated with PCOS (Table 4).

Many reproductive endocrinologists feel that an assessment of ovarian reserve should be performed in all infertile patients above the age of 34. Younger patients should be assessed if there is a history of ovarian surgery, a poor response to previous infertility treatment or a family history of early menopause. Patients who have received gonadotoxic drugs should also be assessed. Patients with no detectable cause of infertility (idiopathic infertility) should also have this assessment. All patients should be screened before beginning intensive infertility treatment such as in vitro fertilization (IVF).

Two commonly used tests measure ovarian reserve. Both measure serum follicle stimulating hormone (FSH) levels. If the levels are increased above a specified level, the probability of achieving pregnancy is reduced. Many laboratories report a level above 10 mIU/mL in the early follicular phase as abnormal. The prognostic significance of this test depends on the assay used by the laboratory. Therefore, it is important to validate that the laboratory meets published criteria. Increased FSH levels appear to be related to decreasing production of inhibin by the granulosa cells.

A serum FSH and estradiol is obtained on the third day of the menstrual cycle. In practice, the test is equally valid when performed on days 2, 3, or 4 of the cycle. Numerous studies have shown that an abnormal test result, an elevated level of FSH, is associated with 95% to 100% failure to conceive with IVF.¹⁰ Upper limits used range from 11-14 IU/L. The test has been validated in patients who will be undergoing superovulation for IVF or insemination and not in a general infertile population. An abnormal test result is associated with a poor pregnancy rate irrespective of age. An elevated day 3 estradiol (greater than 80 pg/mL) is also associated with a poor response to medical treatment of infertility. It is important to remember that a normal test result does not mean that a patient will achieve pregnancy with IVF. A more sensitive test for ovarian reserve is the clomiphene challenge test (CCT). Twice as many patients were identified as poor responders with the CCT than with a day 3 FSH level alone^.11,12 Clomiphene citrate 100 mg daily is prescribed from days 5 to 9 of the cycle and a day 3 and a day 10 FSH is drawn. If any level is more than 10-12 mIU/mL, it is considered an abnormal test.^11,12 Alternatively, the day 3 and day 10 serum FSH levels can be added. In a series by Loumaye et al,¹³ a summed FSH level of more than 26 was associated with a zero pregnancy rate. The test was validated in a general infertility population¹¹ as well as patients undergoing ovarian stimulation with gonadotropins^.12,13 The incidence of abnormal tests increases with age (Table 5). Although the CCT has a predictive value of 95% to 100% for not achieving a pregnancy, it still has a poor sensitivity for identifying patients who will not succeed with infertility treatment.

Serum inhibin is a peptide heterodimer secreted by granulosa cells. The abnormally high serum levels in FSH seen with these tests have been attributed to a decreased production of inhibin. Although serum inhibin may prove to be a better assessment of ovarian reserve, the assay is not available in many centers.

National practice guidelines can be found at the official web site for the American Association of Reproductive Medicine. Essentially all the recommendations have been covered in this chapter. A detailed history will usually give a general idea of the possible causes of infertility. Table 6 outlines the key questions on the history that might point to a particular etiology. A discussion with the patient should include environmental factors that might affect fertility. Smoking and heavy use of marijuana will decrease fertility in men and women. The effect is clear and reproducible in women, whereas it is equivocal in men. Smoking also has a detrimental effect on infertility treatment such as in vitro fertilization (IVF). Alcohol in high quantities will decrease fecundity in women. It is also associated with a large number of pregnancy-related problems such as pre-term deliveries. It is not clear if a low weekly alcohol intake in women (less than 5 drinks per week) is associated with decreased fertility. It is generally accepted to encourage women who are trying to conceive to avoid or limit alcohol intake. Although heavy alcohol intake is associated with reproductive abnormalities in men (such as testicular atrophy), minimal and moderate alcohol intake does not seem to have an effect. Table 7 shows a partial list of other potential toxins associated with decreased fertility. Some studies have linked high caffeine intake with delayed conception.¹⁴ Most lubricants sold in pharmacies and saliva are spermicidal.

A semen analysis, a hysterosalpingogram (HSG) and assessment of ovulation should be included in the initial investigation of all infertile couples (Table 8).

The initial screening evaluation for the male is a detailed history and 2 semen analyses taken at least one month apart. However if the abnormal result is due to an acute insult such as a viral infection, it will take 2-3 months before sperm parameters will change. Therefore, the test should be repeated after an appropriate period of time. A history of testicular injury, viral infection or surgery in a male with an abnormal semen analysis requires a urologic evaluation. The World Health Organization recommended normal values are given in Table 9. If any of the results are out of the normal range, the test is considered abnormal. Most semen parameters reported on a routine semen analysis have a large coefficient of variation (CV). For example, a recent proficiency testing report by the American Association of Bioanalysts (Brownsville, Texas) reported a CV of 20% for sperm count and 39% for morphology. Kruger Strict Criteria rather than the WHO standard are sometimes used to evaluate the morphology of the sperm. Normal is considered to be any result greater than 14%. If the semen analysis is abnormal, the male should be referred for evaluation to a specialist in male reproduction. Endocrine evaluation is indicated for patients with low sperm counts or a history of sexual dysfunction. The initial screening tests are a serum FSH and testosterone. Antisperm antibody testing is considered by some infertility specialists to be part of the standard semen analysis. Others will assess the presence of these antibodies only if the semen analysis results demonstrate an isolated decrease in motility or increased agglutination. A history of testicular trauma, surgery of the testes or vas deferens (such as a vasectomy reversal) or infection requires assessment of these antibodies. Antisperm antibodies that are clinically significant are those that occur on the surface of the sperm. Cystic fibrosis genetic screening, karyotyping and microdeletion analysis of the Y chromosome should be offered in appropriate cases of male factor infertility.

A hysterosalpingogram (HSG) will assess tubal morphology and patency. It is usually performed in the follicular phase after the end of the menses. If a history suggests pelvic inflammatory disease, a sedimentation rate should be obtained and the test postponed if elevated. If it is normal, give doxycycline 100 mg twice a day for 5 days starting 2 days before the procedure. Patients with dilated tubes on HSG are at significant risk of developing an acute pelvic inflammatory disease after the procedure.¹⁵ If dilated tubes are found on HSG, doxycycline 100 mg twice a day for 5 days should be given. Evidence of tubal disease requires referral for laparoscopy. Patients with a documented history of PID should be referred for laparoscopy.

There are several methods to evaluate ovulation. Women with regular monthly periods are unlikely to be anovulatory. Basal body temperature charts are inexpensive and sometimes useful. However they are cumbersome and time-consuming. They should not be over-interpreted. If there is a biphasic pattern, the patient is most likely ovulating. We prefer to measure a single serum progesterone level in the luteal phase. This could be timed on the basis of a home urinary LH test kit. The onset of the LH surge occurs 34-36 hours before ovulation. Most LH kits will detect this surge. Urine is collected between 10 AM and 8 PM. It should not be the first urine after waking. In an ideal 28-day cycle, testing is started on the 10^th day of the cycle. A serum progesterone level is drawn approximately 5 to 7 days later. Levels above 3 ng/mL are indicative of the luteal phase. A serum level above 10 ng/mL is usually associated with an ovulatory cycle with a normal luteal phase. Anovulation or a history of irregular menstrual periods should be investigated with serum thyroid stimulating hormone (TSH), FSH and prolactin levels. If the patient presents with amenorrhea, serum estradiol levels should also be assessed.

If the signs and symptoms suggest PCOS, then serum levels of androgens and 17-hydroxy progesterone should be obtained as well as (Table 3). The serum androgens are usually in the upper range of normal or higher. Serum levels for TSH, prolactin, FSH and luteinizing hormone (LH) should also be obtained. Evaluation of a patient with PCOS should include a simple measure of insulin resistance. We recommend measuring a fasting level of serum glucose and insulin. A ratio of glucose to insulin of less than 4.5 is consistent with insulin resistance^.16 Long-term monitoring for abnormal glucose levels is necessary.

Other disorders that may cause a similar phenotype are 21-hydroxylase deficiency, Cushing syndrome and an androgen secreting adrenal or ovarian tumor.

Ultrasonography and endometrial biopsy are not considered part of the basic infertility investigation. No blood tests or imaging studies can correctly diagnose endometriosis. Although ultrasound might identify an ovarian cyst that includes an endometrioma in the differential diagnosis, it is not conclusive. All serum markers are non-specific. Laparoscopy is still required to make a definitive diagnosis.

Although traditionally evaluation of sperm mucous interaction has been performed with a postcoital test, it is no longer considered a part of routine testing. In this test, cervical mucous is obtained from the cervix within a few hours after sexual intercourse and examined for the presence of motile sperm. Lack of standardization of the test with high intra- and inter-observer variation has limited its usefulness. Furthermore, intrauterine inseminations are used so frequently with many infertility treatments that we are treating any subtle cervical abnormality.

Standard textbooks of reproductive medicine define infertility as the inability to conceive after one year of unprotected intercourse. This does not mean that we would not treat a patient with an obvious problem of anovulation or obstructed fallopian tubes if they have not attempted to achieve pregnancy for one year.

Treatment of endometriosis can be surgical or medical. Hormonal treatments with drugs that suppress the menstrual cycle, such as gonadotropin-releasing hormone (GnRH) agonists, danazol, or progestins, have clearly been shown not to improve fertility.¹⁷ Although there is some controversy as to the success of surgical treatment of early disease, there is clear data to show that surgery is quite effective in treating advanced endometriosis.¹⁷ Surgical treatment of endometriosis can usually be accomplished by laparoscopy, especially with early stages of the disease. Advanced endometriosis with severe adhesive disease can also be managed laparoscopically but many gynecologists prefer to approach the disease by laparotomy.¹⁸ These cases often have rectal involvement and require extensive pelvic dissection. Pregnancy rates are similar with either approach. None of the different energy forms such as lasers have been shown to be associated with a higher pregnancy rate than conventional laparoscopic techniques. If surgery fails or is not an option then assisted reproductive technology (ART) provides an excellent outcome.¹⁹

Once the diagnosis of PCOS is made treatment should focus on modifying insulin resistance. Decreasing insulin levels with metformin or troglitazone will decrease androgen levels and result in ovulatory cycles. Diet and exercise will have the same effect.²⁰ The primary approach is diet, weight loss and exercise. In one study 60 of 67 anovulatory patients with a body mass index (BMI) of 30 kg/m² or more resumed spontaneous ovulation after losing 10 kg.²¹ Of these patients, 77% achieved pregnancy spontaneously (35%) or with the help of medication. The miscarriage rate was significantly reduced. If diet and exercise are not successful, clomiphene citrate, an anti-estrogen drug, can be given to induce ovulation. This drug is started at 50 mg per day from cycle days 5 through 9. If ovulation is not detected, the dose is increased in increments of 50 mg to a maximum dose of 200 mg. If maximal doses of clomiphene do not induce ovulation, additional medication can be given. Metformin 500 mg 3 times per day has been shown to reduce androgen levels and induce ovulation. Low-dose corticosteroids with clomiphene may help if the adrenal androgens are elevated. If ovulation is still not induced, the patient should be referred for ovulation induction with gonadotropins. These patients have a high rate of ovarian hyperstimulation syndrome.

The most recent data for IVF success rates (1997) is available through the CDC. The live birth rates per 100 cycles initiated are 31% for women under 35 years of age, 26% for women between 35 and 37 years of age, 17% for women between 38 to 40 years of age and 8% for women over 40 years of age.

The most dramatic change in treatment of the infertile couple in the last decade is the availability of effective treatment for severe sperm abnormalities. Intracytoplasmic sperm injection (ICSI) is the direct injection of a single spermatozoon or spermatid into the oocyte. This treatment was introduced in the last 7 to 8 years. Success rates have been equivalent to those of IVF cycles with normal sperm. In our experience, the pregnancy rate per embryo transfer is 41%, a rate similar to patients with normal sperm.²² There does not appear to be any developmental problems with the offspring. There may be a slight increase in sex chromosome abnormalities.

Infertility is a medical problem of the couple. There is natural decrease in fertility with age and therefore investigation and management is initiated earlier in some couples. There are many environmental and medical problems that might cause infertility in either partner. Most patients consult physicians for advice and investigation. Therefore, the primary care physician should be aware of the most common causes of infertility. A few basic investigations can be performed before referral to an infertility specialist. Some disorders that cause infertility have a long-term impact on the patient's health.

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