Infertility, Female

Essentials of Diagnosis

• Pregnancy does not result after 12 months of normal sexual activity without contraceptives

General Considerations

• About 20% of couples experience infertility at some point

• The incidence increases with age, with a decline in fertility beginning in the early 30s and accelerating in the late 30s

• The male partner contributes to about 40% of cases of infertility, and a combination of male and female factors is common

Symptoms and Signs

• Obtain history of sexually transmitted disease or prior pregnancies

• Discuss ill effects of cigarettes, alcohol, and other recreational or prescription drugs on male fertility

• Discuss factors that may lead to scrotal hyperthermia, such as tight underwear or frequent use of saunas or hot tubs

• The gynecologic history should include

  • The menstrual pattern

  • Use and types of contraceptives

  • Libido

  • Sexual practices

  • Frequency and success of coitus

  • Correlation of intercourse with time of ovulation

• Family history should inquire about family members with repeated abortions

• General physical and genital examinations for both partners

Differential Diagnosis

• Male factor infertility (hypogonadism, varicocele, alcohol or drug use, immotile cilia syndrome)

• Polycystic ovary syndrome

• Premature ovarian failure

• Hyperprolactinemia

• Hypothyroidism

• Inadequate luteal progesterone or short luteal phase

• Endometriosis

• Uterine leiomyomas (fibroids) or polyps

• Prior pelvic inflammatory disease

• Pelvic adhesions, eg, pelvic surgery, therapeutic abortion, ectopic pregnancy, septic abortion, intrauterine device use

Diagnostic Procedures

INITIAL TESTING

• Complete blood count, urinalysis, cervical culture for Chlamydia, rubella antibody determination, and thyroid function tests

• A luteal phase serum progesterone above 3 ng/mL establishes ovulation

• Ovulation predictor kits have largely replaced basal body temperatures for predicting ovulation

• While basal body temperature charting is a natural and inexpensive way to identify most fertile days, it cannot predict ovulation but rather only retrospectively confirm that ovulation occurred

• Coitus resulting in conception occurs during the 6-day period ending with the day of ovulation

• Before additional testing, an ejaculate from the male partner for semen analysis is obtained after sexual abstinence for at least 3 days

• Semen should be examined within 1–2 h after collection

  • Normal semen: volume, 2 mL; concentration, 20 million sperm per milliliter; motility, > 50% forward progression, > 25% rapid progression; and 30% normal forms

  • If the sperm count is abnormal, search for exposure to environmental and workplace toxins, alcohol or drug abuse, and hypogonadism

FURTHER TESTING

• Gross deficiencies of sperm (number, motility, or appearance) require a repeat semen analysis

• A screening pelvic ultrasound and hysterosalpingography to identify uterine cavity or tubal anomalies should be performed

• Obstruction of the uterine tubes requires either microsurgery or in vitro fertilization

• Absent or infrequent ovulation requires additional laboratory evaluation

  • Elevated follicle-stimulating hormone (FSH) and LH levels indicate ovarian insufficiency

  • Elevated LH levels in the presence of normal FSH levels may indicate the presence of polycystic ovaries

  • Elevation of blood prolactin (PRL) levels suggests pituitary microadenoma

  • A markedly elevated FSH (> 15–20 international units/L) on day 3 of the menstrual cycle suggests inadequate ovarian reserve

  • Measurement of FSH on day 10 after administration of clomiphene from day 5–9, should be completed to determine if diminished ovarian reserve indicates need for donor eggs

• Hysterosalpingography

  • Can demonstrates uterine abnormalities (septa, polyps, submucous myomas) and tubal obstruction

  • A repeat radiograph 24 hours later can confirm tubal patency if there is wide pelvic dispersion of the dye

  • Evidence suggests that an oil-based rather than water-soluble contrast medium may improve pregnancy rates; however, reports of complications associated with oil-based media resulted in its decreased usage

Medications

INDUCTION OF OVULATION

• Clomiphene citrate

  • After a normal menstrual period or induction of withdrawal bleeding with progestin, give clomiphene 50 mg once daily orally for 5 days, typically on days 3–7 of the cycle

  • If ovulation does not occur, increase dosage to 100 mg once daily for 5 days

  • If ovulation still does not occur, the course is repeated with 150 mg once daily for 5 days, and then 200 mg once daily for 5 days

  • Ovulation and appropriate timing of intercourse can be facilitated with the addition of chorionic gonadotropin, 10,000 units intramuscularly

  • Monitoring of the follicles by transvaginal ultrasound usually is necessary to appropriately time the human chorionic gonadotropin injection

• Letrozole

  • Dose is 5–7.5 mg daily, starting on day 3 of the menstrual cycle

  • Appears to be at least as effective as clomiphene for ovulation induction in women with polycystic ovary syndrome

  • Advantages include a reduced risk of multiple pregnancy, a lack of antiestrogenic effects, and a reduced need for ultrasound monitoring

  • Preferred in women who have a history of estrogen-dependent tumors (such as breast cancer) because estrogen levels with this drug are much lower

• Bromocriptine or cabergoline

  • Used only if PRL levels are elevated and there is no withdrawal bleeding following progesterone administration (otherwise, clomiphene is used)

  • Initial cabergoline dosage is 2.5 mg once daily orally, increased to 2.5 mg two or three times daily in increments of 1.25 mg

  • Discontinue once pregnancy has occurred

  • Cabergoline is often used in patients who do not respond to bromocriptine or who cannot tolerate its adverse effects

  • While cabergoline causes fewer adverse effects than bromocriptine, it is much more expensive

• Human menopausal gonadotropins (hMG) or recombinant FSH is indicated in cases of hypogonadotropism and most other types of anovulation resistant to clomiphene (or letrozole) treatment

• See Endometriosis for its treatment

Surgery

• Fertility can be improved with excision of ovarian tumors or ovarian foci of endometriosis, and microsurgical relief of tubal obstruction due to salpingitis

• Some cornual or fimbrial block can be relieved. Peritubal adhesions or endometriotic implants often can be treated via laparoscopy

• Sperm characteristics are often improved following surgical treatment of varicocele in the male partner

Therapeutic Procedures

• Treat hypothyroidism or hyperthyroidism

• Give antibiotics for cervicitis if present

• 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

• In cases of male partner azoospermia, artificial insemination by a donor usually results in pregnancy if female evaluation is normal

Prognosis

• The prognosis for normal pregnancy is good if minor disorders can be treated

• However, the prognosis for normal pregnancy is poor if the causes of infertility are severe, untreatable, or of prolonged duration (> 3 years)

• 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, assisted reproductive technology (ART), or information about adoption

• Women over the age of 35 should be offered a more aggressive approach, with consideration of ART within 3 to 6 months if pregnancy is not achieved with more conservative approaches

When to Refer

• Refer to reproductive endocrinologist for ART or surgery