Evaluation and Treatment of the Infertile Couple





You and your partner should be interviewed during first visit. The doctor should ask you about you and your partner's age, duration of infertility, previous pregnancies and surgeries, coital frequency, pain during intercourse, erection failure, e.g., dyspareunia, impotence, lack of orgasm or lack of libido and problems encountered during intercourse.

Problems are assessed and treated.

Obese women are at higher risk for infertility as they are less likely to ovulate i.e. Release an egg.

Smoking⁸ and long-term use of nonsteroidal anti-inflammatory drugs can lead to infertility.

Age

Women fertility and pregnancy rates decreases after reaching 30 years of age. By the age of 40, a woman's monthly fecundity is less than 5%.¹¹ Poor oocyte (egg) quality is the predominant factor responsible for this decline in pregnancy rate.

Male fertility also diminishes with age. Sperm quality declines, and the frequency of ejaculation decreases as men grow older. Nearly 50% of the infertility experienced by couples older than 40 years is caused by problems associated with advancing age.¹² Therefore, age is an independent risk factor that is instrumental in determining a couple's chance of achieving a successful pregnancy.

The duration of infertility

Is an important independent risk factor as the age of the couple. The longer the duration of infertility, the lower is the probability of achieving a successful pregnancy.

Male Infertility

Is the primary cause of infertility in approximately 33% of couples who seek help.¹⁰

Causes:

Testicular injury
Infection
Surgery
Radiation
Chemotherapy

Hypospadius urethral opening on the lower surface of the penis
Cryptorchidism (un-descended testis)
Varicoceles.

If any of the above 3 anomaly is present  the patient should see urologist for evaluation and treatment.

After the initial physical examination, a semen analysis should be performed.

The specimen is collected after 48 hours of abstinence from coital activity and evaluated no more than 1 hour after collection.¹³ If any parameters are abnormal [see Table 2 -- omitted], two additional semen analyses should be performed 2 weeks apart. Persistent abnormalities may warrant urologic evaluation and workup for diabetes mellitus, prolactin elevation, and chromosomal abnormalities. Other tests that can be performed are the sperm penetration assay and the immunobead-binding assay. These tests can detect abnormalities in sperm penetration and motility, respectively, but may not indicate the true nature of a patient's problem. If the results of the semen tests are normal and the female partner's evaluation appears normal, a diagnosis of unexplained infertility is appropriate [seeUnexplained Infertility -- omitted, below]. Idiopathic oligospermia is the most common cause of infertility in men. Although there is no cure for this problem, treatment may include in vitro fertilization (IVF) with microinjection of sperm into egg (intracytoplasmic sperm injection [ICSI]) [see Table 3 -- omitted]. In severe cases of infertility, this technique can achieve fertilization rates as high as 65%.¹⁴

Female Infertility

Tubal and Pelvic Factors

Nearly 35% of the infertility experienced by couples and 40% of the infertility in women is of pelvic origin. Uterine, tubal, and other pelvic abnormalities are responsible for this type of infertility. The practitioner should elicit information regarding any history of sexually transmitted diseases, pelvic inflammatory disease, appendicitis with rupture, pelvic tuberculosis, or adnexal surgery. Many patients with tubal or pelvic damage have a history that includes a previous diagnosis of endometriosis, ectopic pregnancy, or submucous myomas. Although uterine myomas seldom cause infertility, they may cause recurrent early pregnancy loss and preterm labor. Hysterosalpingography (HSG) is one of the initial diagnostic tests used to evaluate uterine, tubal, and pelvic abnormalities. This test is performed during the early proliferative phase, after the cessation of menstrual flow (cycle day 5 to 10). HSG can help identify abnormalities of uterine filling caused by submucous myomas, polyps, uterine synechiae (adhesions), and congenital malformations. Tubal patency should be evaluated at the time of HSG. A delayed set of radiographs can detect pelvic adhesions and other pelvic abnormalities that prevent the release of contrast material into the pelvis. Once the site of blockage (which may be proximal or distal) has been identified, it can be dealt with accordingly.¹⁵ Patients who are known to be anovulatory may forgo an initial HSG. If ovulation induction is successfully attempted for at least four consecutive cycles and conception does not occur, however, HSG should be performed. HSG should never be performed on a woman with acute salpingitis, a tender pelvic mass, or allergy to iodine. Women with a known contraindication are better evaluated directly by laparoscopy. Patients who undergo HSG should receive prophylactic treatment for chlamydial infection; oral doxycycline, 100 mg twice daily for 7 days, is effective. Laparoscopy with chromotubation (intrauterine injection of colored liquid [indigo carmine] to confirm tubal patency) is indicated for patients with abnormal findings on HSG and for patients with unexplained infertility. This procedure may be omitted from the diagnostic workup if IVF is the main focus of treatment. However, surgical resection of the diseased tube should be considered for patients who are diagnosed with a hydrosalpinx on the basis of HSG or laparoscopy. Studies indicate that the mere presence of a hydrosalpinx can adversely affect embryo implantation and the success of IVF.¹⁶ If the laparoscopy and chromotubation reveal tubal occlusion, surgery may be indicated. Isolated proximal or distal tubal occlusions may be treated by various surgical techniques. However, combined proximal and distal occlusions are not well corrected with surgery, and IVF should be recommended as the treatment of choice to achieve pregnancy in these patients. Age is also important when deciding between tubal surgery and IVF. Older couples should be encouraged to have IVF rather than tubal surgery because the probability of their achieving a pregnancy is higher with IVF.

Cervical Factors

Abnormal cervical mucus is the recognized cause of infertility in 5% to 10% of couples trying to conceive. The postcoital test provides information regarding both the quality of the cervical mucus and its interaction with sperm. This test is performed on cycle day 11 to 13 (24 to 48 hours before ovulation); the male partner must abstain from ejaculation for 48 hours before testing. The cervical mucus is examined 2 to 8 hours after intercourse. The consistency of the cervical mucus is examined and the number of motile sperm per high-power field (hpf) is determined. Normal mucus is acellular, clear, thin, and elastic; the mucus should stretch approximately 8 to 10 cm when placed on a glass slide and pulled. This elasticity of the cervical mucus is known as spinnbarkeit. The mucus should also contain at least 5 to 10 progressively motile sperm/hpf. Cervical mucus that is of poor quality (i.e., thick and nonelastic) will demonstrate a globular rather than a fernlike pattern after drying on a microscope slide. Absent or poor-quality cervical mucus may reflect either inaccurate timing of the test or an abnormality in mucus production. Cervical trauma and infection have been implicated as antecedents to abnormal mucus production. Sperm that are both shaky and immotile on microscopic inspection are found in the cervical mucus of women who produce antisperm antibodies. When all the sperm from a postcoital test are found to be immotile, the patient should be asked whether lubricants or spermicides were used during coitus. Intrauterine insemination (IUI) is the treatment of choice for those patients with cervical factor infertility.¹⁷ This procedure bypasses the cervix and allows the physician to place washed sperm directly into the endometrial cavity.¹⁸

Ovulatory Factors

Ovulatory dysfunction is the cause of 15% of the infertility detected in couples and 40% of the infertility found in women. Anovulation and oligo-ovulation account for most menstrual abnormalities. Shortened menstrual cycles and luteal phase defects are less common causes of ovulatory dysfunction. A patient's ovulatory status can be determined by several techniques. The cheapest and least invasive technique is to have the patient chart her basal body temperature (BBT). When done correctly, charting can aid the clinician by providing indirect evidence of ovulation. A biphasic temperature curve (i.e., an elevated temperature for at least 11 to 16 days) is an indication that ovulation probably occurred. The patient's own assessment of premenstrual molimina further strengthens the indirect evidence of ovulation. Measurement of the progesterone level on day 21 of the menstrual cycle also provides an indirect assessment of ovulatory status. This method is less time-consuming than BBT charting. Progesterone values of more than 15 ng/ml are consistent with ovulation. A value of less than 5 ng/ml may indicate that ovulation has not occurred. Because progesterone is secreted in a pulsatile manner, only elevated values of progesterone are diagnostically useful. Levels between 5 and 15 ng/ml probably indicate ovulation but give insufficient information regarding the adequacy of the luteal phase. Of all menstrual cycles in normally menstruating women, 5% to 30% involve a luteinized unruptured follicle. Although ovulatory symptoms and elevated progesterone levels occur during these cycles, an oocyte is not released and fertilization is impossible. Thus, the predictive value of indirect measures of ovulatory status is limited. An endometrial biopsy can be performed on cycle days 23 to 26. This test can assess both the ovulatory status of the patient and the adequacy of the luteal phase. A luteal phase defect is defined as a lag in the histologic development of the endometrium by 2 or more days when compared with the cycle day of sampling. This defect in the luteal phase is presumably caused by inadequate progesterone secretion from the corpus luteum. Treatment has entailed prolonging the luteal phase by administering progesterone either intramuscularly or intravaginally. The benefit of this approach, however, has not been substantiated.

Anovulation

Measurement of the prolactin level should be done during the initial evaluation of patients who are believed to be anovulatory [see Figure 2 -- omitted].¹⁹ Elevated prolactin levels have a negative feedback effect on the hypothalamus, preventing the pulsatile release of gonadotropin-releasing hormone (GnRH). This, in turn, prevents secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Consequently, follicular development and ovulation do not occur. Hyperprolactinemia is responsible for 15% of all ovulatory disturbances.²⁰ If the patient has an elevated prolactin level, with or without galactorrhea, the thyroid-stimulating hormone (TSH) level should be measured to rule out primary or secondary hypothyroidism. If the TSH level is normal, a computed tomography scan or magnetic resonance image of the head should be obtained to determine whether the patient has a prolactinoma. Of import is that prolactin levels may also be elevated as a result of the use of specific medications. Pharmacologic agents that deplete dopamine reserves (i.e., antidepressants, antipsychotics, and other psychotropic agents) may also result in hyperprolactinemia and anovulation. If the CT or MRI findings are abnormal or reveal a pituitary adenoma, the patient should be treated with oral bromocriptine, starting at a dosage of 2.5 to 5 mg daily, or oral cabergoline, 0.25 mg twice weekly [see 16:I Amenorrhea -- omitted]. These medications should be titrated until prolactin levels return to normal. When prolactin levels are normalized, restoration of ovulatory function should occur.²¹ Patients with symptomatic macroadenomas may require ablative therapy with either surgery or radiation if medical therapy does not reduce the size of the tumor or if symptoms associated with the tumor persist or worsen. Patients with hyperprolactinemia and oligomenorrhea (except those with primary and secondary hypothyroidism, who require thyroid hormone replacement) should be treated with bromocriptine only if they are bothered by symptoms (i.e., galactorrhea) or desire fertility. If a patient remains anovulatory despite treatment with bromocriptine, oral clomiphene citrate, starting at a dosage of 50 mg daily for 5 days, can be added as an adjunctive therapy to stimulate ovulation. If, at the time of initial examination, the patient is determined to be hypoestrogenic (i.e., she has an atrophic vagina and perineum and reports hot flashes and lack of lubrication during coital activity), the clinician should obtain serum levels of FSH, LH, and estradiol (E₂). These values will identify patients with hypogonadotropic hypogonadism and those with ovarian failure. Patients with hypogonadotropic hypogonadism should be evaluated with a GnRH-stimulation test to determine whether the problem is reversible. Special attention should be given to anovulatory women who have normal levels of estrogen and prolactin and who have signs of hyperandrogenism and virilization. In these patients, measurements should be made of dehydroepiandrosterone sulfate (DHEAS), total testosterone, 17-hydroxyprogesterone, and 8 A.M. free urine cortisol levels. These tests will help to identify patients with polycystic ovary syndrome (PCOS), ovarian and adrenal neoplasms, congenital adrenal hyperplasia, or Cushing syndrome [see 16:V Polycystic Ovary Syndrome -- omitted]. Patients with PCOS that is associated with elevated insulin or glucose levels who wish to conceive may benefit from a combined regimen of oral metformin, 850 mg twice daily, and clomiphene citrate. Studies have shown that women treated with this combination have a higher rate of ovulation than those treated with clomiphene citrate alone.²² Hirsutism and acne should not be treated medically during ovulatory induction cycles. Elevated levels of both FSH and E₂ on cycle day 3 signify a decrease in ovarian reserve (i.e., a decrease in the total number of follicles present for maturation and ovulation). The diagnosis of premature ovarian failure is reserved for women who are younger than 40 years and have gonadotropin (FSH and LH) levels in the menopausal range. Depending on the incipient age of ovarian failure, a complete autoimmune profile and possibly a genetic karyotype should be considered to establish a diagnosis.²³ Women with an autoimmune disorder are at increased risk for developing multiple organ failure and should be screened annually. These women should be counseled to consider IVF with donor eggs or adoption.

Unexplained Infertility

The incidence of unexplained infertility is estimated to be between 15% and 20%. Couples who do not receive treatment have a monthly fecundity of 3% and a cumulative 3-year pregnancy rate of 60%. However, when a couple has experienced long-standing infertility (> 3 years) and the female partner is older than 35 years, the probability of achieving a pregnancy is markedly reduced.²⁴ The treatment for couples with unexplained infertility includes inducement of superovulation with either clomiphene citrate or gonadotropins^25,26 and IUI or one of the assisted reproductive technologies (e.g., IVF, gamete intrafallopian transfer, and zygote intrafallopian transfer).²⁷ IUI with ovulation induction using gonadotropins produces higher pregnancy rates for couples with male-factor or unexplained infertility than does either procedure performed alone.¹⁷     

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