Introduction

A couple is said to be infertile if pregnancy does not result after 1 year of normal sexual activity without contraceptives. About 25% of couples experience infertility at some point in their reproductive lives; the incidence of infertility increases with age. The male partner contributes to about 40% of cases of infertility, and a combination of factors is common.

Diagnostic Survey

During the initial interview, the clinician can present an overview of infertility and discuss a plan of study. Separate private consultations are then conducted, allowing appraisal of psychosexual adjustment without embarrassment or criticism. Pertinent details (eg, sexually transmitted disease or prior pregnancies) must be obtained. The ill effects of cigarettes, alcohol, and other recreational drugs on male fertility should be discussed. Prescription drugs that impair male potency should be discussed as well. The gynecologic history should include queries regarding the menstrual pattern. The present history includes use and types of contraceptives, douches, libido, sex techniques, frequency and success of coitus, and correlation of intercourse with time of ovulation. Family history includes repeated abortions and maternal DES use.

General physical and genital examinations are performed on both partners. Basic laboratory studies include complete blood count, urinalysis, cervical culture for chlamydia, serologic test for syphilis, rubella antibody determination, and thyroid function tests. Tay-Sachs screening should be offered if both parents are Jews and sickle cell screening if both parents are black.

The patient is instructed to chart her basal body temperature orally daily on arising and to record on a graph episodes of coitus and days of menstruation. Self-performed urine tests for the midcycle LH surge enhance temperature observations relating to ovulation. Couples should be advised that coitus resulting in conception occurs during the 6-day period ending with the day of ovulation.

The male partner is instructed to bring a complete ejaculate for analysis. Sexual abstinence for at least 3 days before the semen is obtained is emphasized. A clean, dry, wide-mouthed bottle for collection is preferred. Condoms should not be employed, as the protective powder or lubricant may be spermicidal. Semen should be examined within 1-2 hours after collection. Semen is considered normal with the following minimum values: volume, 1.5-5 mL; concentration, 20 million sperm per milliliter; motility, 60%; and normal forms, 35%. If the sperm count is abnormal, further evaluation includes a search for exposure to environmental and workplace toxins, alcohol or drug abuse, and hypogonadism.

A. First Testing Cycle
While the contribution of cervical factors to infertility is controversial, most gynecologists include a postcoital test in their workup. The test is scheduled for just before ovulation (eg, day 12 or 13 in an expected 28-day cycle). Preovulation timing can be enhanced by serial urinary LH tests. The patient is examined within 6 hours after coitus. The cervical mucus should be clear, elastic, and copious owing to the influence of the preovular estrogen surge. (The mucus is scantier and more viscid before and after ovulation.) A good spinnbarkeit (stretching to a fine thread 4 cm or more in length) is desirable. A small drop of cervical mucus should be obtained from within the cervical os and examined under the microscope. The presence of five or more active sperm per high-power field constitutes a satisfactory postcoital test. If no spermatozoa are found, the test should be repeated (assuming that active spermatozoa were present in the semen analysis). Sperm agglutination and sperm immobilization tests should be considered if the sperm are immotile or show ineffective tail motility.

The presence of more than three white blood cells per high-power field in the postcoital test suggests cervicitis in the woman or prostatitis in the man. When estrogen levels are normal, the cervical mucus dried on the slide will form a fern-like pattern when viewed with a low-power microscope. This type of mucus is necessary for normal sperm transport.

The serum progesterone level should be measured at the midpoint of the secretory phase (21st day); a level of > 3 ng/mL confirms ovulation.

B. Second Testing Cycle
Hysterosalpingography using an oil dye is performed within 3 days following the menstrual period. This x-ray study will demonstrate uterine abnormalities (septa, polyps, submucous myomas) and tubal obstruction. A repeat x-ray film 24 hours later will confirm tubal patency if there is wide pelvic dispersion of the dye. This test has been associated with an increased pregnancy rate by some observers. If the woman has had prior pelvic inflammation, one should give doxycycline, 100 mg twice daily, beginning immediately before and for 7 days after the x-ray study.

C. Further Testing
1. Gross deficiencies of sperm (number, motility, or appearance) require repeat analysis. Zona-free hamster egg penetration tests are available to evaluate the ability of human sperm to fertilize an egg.

2. Obvious obstruction of the uterine tubes requires assessment for microsurgery or in vitro fertilization.

3. Absent or infrequent ovulation requires additional laboratory evaluation. Elevated FSH and LH levels indicate ovarian failure causing premature menopause. Elevated LH levels in the presence of normal FSH levels confirm the presence of polycystic ovaries. Elevation of blood prolactin (PRL) levels suggests pituitary microadenoma.

4. Ultrasound monitoring of folliculogenesis may reveal the occurrence of unruptured luteinized follicles.

5. Endometrial biopsy in the luteal phase associated with simultaneous serum progesterone levels will rule out luteal phase deficiency.

D. Laparoscopy
Approximately 25% of women whose basic evaluation is normal will have findings on laparoscopy explaining their infertility (eg, peritubal adhesions, endometriotic implants).

Treatment

A. Medical Measures
Fertility may be restored by appropriate treatment in many patients with endocrine imbalance, particularly those with hypo- or hyperthyroidism. Antibiotic treatment of cervicitis is of value. In women with abnormal postcoital tests and demonstrated antisperm antibodies causing sperm agglutination or immobilization, condom use for up to 6 months may result in lower antibody levels and improved pregnancy rates.

Women who engage in vigorous athletic training often have low sex hormone levels; fertility improves with reduced exercise and some weight gain.

B. Surgical Measures
Excision of ovarian tumors or ovarian foci of endometriosis can improve fertility. Microsurgical relief of tubal obstruction due to salpingitis or tubal ligation will reestablish fertility in a significant number of cases. In special instances of cornual or fimbrial block, the prognosis with newer surgical techniques has become much better. Peritubal adhesions or endometriotic implants often can be treated via laparoscopy or via laparotomy immediately following laparoscopic examination if prior consent has been obtained.

With varicocele in the male, sperm characteristics are often improved following surgical treatment.

C. Induction of Ovulation
1. Clomiphene citrate

Clomiphene citrate stimulates gonadotropin release, especially LH. Consequently, plasma estrone (E1) and estradiol (E2) also rise, reflecting ovarian follicle maturation. If E2 rises sufficiently, an LH surge occurs to trigger ovulation.

After a normal menstrual period or induction of withdrawal bleeding with progestin, one should give 50 mg of clomiphene orally daily for 5 days. If ovulation does not occur, the dosage is increased to 100 mg orally daily for 5 days. If ovulation still does not occur, the course is repeated with 150 mg daily and then 200 mg daily for 5 days, with the addition of chorionic gonadotropin, 10,000 units intramuscularly, 7 days after clomiphene.

The rate of ovulation following this treatment is 90% in the absence of other infertility factors. The pregnancy rate is high. Twinning occurs in 5% of these patients, and three or more fetuses are found in rare instances (< 0.5% of cases). An increased incidence of congenital anomalies has not been reported. Painful ovarian cyst formation occurs in 8% of patients and may warrant discontinuation of therapy. Several studies have suggested a two- to threefold increased risk of ovarian cancer with the use of clomiphene for more than 1 year.

In the presence of increased androgen production (DHEA-S > 200 ug/dL), the addition of dexamethasone, 0.5 mg, or prednisone, 5 mg, at bedtime, improves the response to clomiphene. Dexamethasone should be discontinued after pregnancy is confirmed.

2. Bromocriptine
Bromocriptine is used only if PRL levels are elevated and there is no withdrawal bleeding following progesterone administration (otherwise, clomiphene is used). To minimize side effects (nausea, diarrhea, dizziness, headache, fatigue), bromocriptine should be taken with meals. The initial dosage is 2.5 mg once daily, increased to two or three times daily in increments of 1.25 mg. The drug is discontinued once pregnancy has occurred.

3. Human menopausal gonadotropins (hMG)
hMG or recombinant FSH is indicated in cases of hypogonadotropism and most other types of anovulation (exclusive of ovarian failure). Because of the complexities, laboratory tests, and expense associated with this treatment, these patients should be referred to a specialist.

4. Gonadotropin-releasing hormone (GnRH)
Hypothalamic amenorrhea unresponsive to clomiphene will be reliably and successfully treated with subcutaneous pulsatile gonadotropin-releasing hormone (GnRH). Use of this substance will avoid the dangerous ovarian complications and the 25% incidence of multiple pregnancy associated with hMG, though the overall rate of ovulation and pregnancy is lower than when hMG is used.

D. Treatment of Endometriosis
See above.

E. Treatment of Inadequate Transport of Sperm
Intrauterine insemination of concentrated washed sperm has been used to bypass a poor cervical environment associated with scant or hostile cervical mucus. The sperm must be handled by sterile methods, washed in sterile saline or tissue culture solutions, and centrifuged. A small amount of fluid (0.5 mL) containing the sperm is then instilled into the uterus.

F. Artificial Insemination in Azoospermia
If azoospermia is present, artificial insemination by a donor usually results in pregnancy, assuming female function is normal. The use of frozen sperm is currently preferable to fresh sperm because the frozen specimen can be held pending cultures and blood test results for sexually transmitted diseases, including HIV infection.

G. Assisted Reproductive Technologies
Couples who have not responded to traditional infertility treatments, including those with tubal disease, severe endometriosis, oligospermia, and immunologic or unexplained infertility, may benefit from in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT). These techniques are complex and require a highly organized team of specialists. All of the procedures involve ovarian stimulation to produce multiple oocytes, oocyte retrieval by TVS-guided needle aspiration, and handling of the oocytes outside the body. With IVF, the eggs are fertilized in vitro and the embryos transferred to the uterine fundus. GIFT involves the placement of sperm and eggs in the uterine tube by laparoscopy or minilaparotomy. With ZIFT, fertilization occurs in vitro, and the early development of the embryo occurs in the uterine tube after transfer by laparoscopy or minilaparotomy. The later two procedures are used infrequently, and the rate of live births per retrieval for 383 programs in the United States in 2000 was 31%. Age is an important determinant of success - for couples under the age of 35, the average rate of live birth was 38% per retrieval, while the rate for women over 42 was 6%. In 2000, 53% of pregnancies were multiple.

A recent development is intracytoplasmic sperm injection (ICSI), which allows fertilization with a single sperm. It was originally intended for couples with male factor infertility, but it was used in approximately half of the IVF procedures in 2000.

Prognosis

The prognosis for conception and normal pregnancy is good if minor (even multiple) disorders can be identified and treated; it is poor if the causes of infertility are severe, untreatable, or of prolonged duration (over 3 years).

It is important to remember that in the absence of identifiable causes of infertility, 60% of couples will achieve a pregnancy within 3 years. Couples with unexplained infertility who do not achieve pregnancy within 3 years should be offered ovulation induction or assisted reproductive technology. Also, offering appropriately timed information about adoption is considered part of a complete infertility regimen.

Preferences:
Rosene-Montella K et al: Evaluation and management of infertility in women: the internist’s role. Ann Intern Med 2000; 132:973.

Wright VC et al: Assisted reproductive technology surveillance - United States, 2000. MMWR Surveill Summ 2003;52:1.