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Infertility and Assisted Reproductive Technologies
Clinical Keys for This Chapter
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Eighty to eighty-five percent of fertile couples will conceive after 1 year of frequent attempts. Infertility is defined as an undesired absence of fertility for 1 year despite frequent intercourse. About 10-15% of couples in the United States are infertile. Most infertility is subfertility, and relatively few couples are sterile.
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A steady decrease in fertility begins at about age 24 years (female partner), when the fecundity (live-birth) rate is about 22% per monthly cycle, and declines to about 5% per cycle by 40 years of age. Evaluation for infertility should begin before 1 year when the female partner's age reaches 35 years or there is an obvious problem such as oligomenorrhea (fewer than nine menstrual cycles per year).
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The known causes of infertility include male coital problems, anatomic problems involving the uterus and/or the fallopian tubes, peritoneal problems such as endometriosis and/or pelvic adhesions, and problems with the quantity or quality of cervical mucus. About 10-15% of couples are found to have unexplained infertility. Evaluation of infertility in women younger than 35 years of age should begin at 1 year.
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Evaluation of sperm quantity and quality, ovulatory function, normal reproductive anatomy, and cervical mucus should occur after history-taking and physical examination are completed. Because about 40% of infertile couples have more than one factor present, the evaluation should be complete so that a second or third factor is not overlooked and thus left untreated. Conventional treatment includes ovarian stimulation with or without intrauterine insemination, destruction of endometriosis when found, and possible surgical intervention for uterine or tubal disease. About 50-60% of couples will conceive with adequate conventional treatments.
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Assisted reproductive technologies include in vitro fertilization, intracytoplasmic sperm injection, embryo transfer without or with embryo freezing, and oocyte donation for women with abnormal or absent ovarian function. Up to 85% of couples will conceive with the addition of adequate advanced treatment.
About 10-15% of couples in the United States are involuntarily infertile. Couples are considered infertile after unsuccessfully attempting to achieve pregnancy for 1 year. Most of these couples are more accurately described as have varying degrees of subfertility, with some of them conceiving spontaneously during and after episodes of fertility treatment. New assisted reproductive technologies (ARTs), such as controlled ovarian stimulation with or without intrauterine insemination (IUI), in vitro fertilization (IVF) and embryo transfer, and intracytoplasmic sperm injection (ICSI), are increasing the success of treatment for infertility and subfertility.
Infertility and the Physiology of Conception
Infertility is termed primary when it occurs without any prior pregnancy and secondary when it follows a previous conception. Some conditions, such as azoospermia (absence of sperm), endometriosis, and tubal occlusion are more common in couples with primary infertility, but virtually all conditions occur in both primary and secondary infertility.
For successful conception to occur, the male and female gametes must join at the optimal stage of maturation, followed by transportation of the newly fertilized conceptus to the uterine cavity at a time when the endometrium is supportive of its continued development and implantation ( Figure 34-1 ; see also Chapter 4 ). For these events to occur, the male and female reproductive systems must both be anatomically and physiologically intact, and coitus must occur with sufficient frequency for the semen to be deposited in close temporal relationship to the release of the oocyte from the follicle. Even when fertilization occurs, it is estimated that more than 70% of resulting embryos are abnormal and fail to develop or become nonviable shortly after implantation. According to the American Society for Reproductive Medicine (ASRM), early documented pregnancy loss (miscarriage) is considered a form of infertility when it is recurrent.
Considering the complexity of the reproductive process, it is remarkable that about 80-85% of couples achieve conception within 1 year. More precisely, 25% conceive within the first month, 60% within 6 months, 75% by 9 months, and 90% by 18 months. The steadily decreasing rate of monthly conception demonstrated by these figures most likely reflects a spectrum of fertility extending from highly fertile couples to those with relative infertility (subfertility). After 18 months of unprotected sexual intercourse, the remaining couples have a low monthly conception rate without treatment, and many may have absolute defects that are preventing fertility (sterility). Table 34-1 lists the known causes of infertility as well as treatments for it, and Box 34-1 lists some important terms and definitions.
TABLE 34-1
Etiologic Factors, Diagnostic Tests, and Treatment Options for Infertility
| Known Causes of Infertility | Diagnostic Tests and Procedures | Treatment Options | Comments |
|---|---|---|---|
| Male Factors (20-40%) | Semen analysis; testing for antisperm antibodies when suspected | IUI with washed sperm; IVF-ET with ICSI; donor insemination | Frequency of coitus without the use of toxic lubricants should be determined; paternal age could be a factor in miscarriage |
| Female Factors (50-65%) * | |||
| Ovulation problems | Mid-luteal serum progesterone; LH predictor kits; serial ultrasounds | Clomiphene citrate or letrozole with or without hCG trigger for ovulation; lower-dose gonadotropins; IVF-ET; donor egg IVF-ET | Tests for ovulation are indirect and may be falsely positive; the only absolute proof of ovulation is pregnancy |
| Anatomic (uterine-tubal) problems | Hysterosalpingogram; saline infusion sonography; hysteroscopy; laparoscopy with chromotubation † | Tubal anastomosis to reverse sterilization procedures; tuboplasty for tubal damage; IVF-ET | When laparoscopy is performed, the tubes should be tested for patency; recent higher IVF-ET success rates make IVF-ET preferable to tubal surgery |
| Peritoneal problems (pelvic adhesions and endometriosis) | Laparoscopy with chromotubation † as part of infertility workup | Ablative procedures (electrocautery, laser) for endometriosis and lysis of adhesions; medical treatment for endometriosis (see Chapter 25 ); IVF-ET | Surgical removal of endometriomas may compromise ovarian reserve |
| Cervical mucus problems | Spinnbarkeit; postcoital test (Sims-Huhner); cultures for suspected infections | IUI with washed sperm; treatment for any detected infection | Postcoital test not performed by many practitioners, because of low predictive value |
| Unexplained Infertility (10-15%) | Laparoscopy to confirm diagnosis with negative findings | Ovarian stimulation; IVF-ET; donor insemination; donor IVF-ET; adoption | |
hCG, Human chorionic gonadotropin; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF-ET, in vitro fertilization and embryo transfer; LH, luteinizing hormone.
* Prevalence can vary in some populations due to differences in causes (e.g., infection or endometriosis).
† The use of a colored fluid such as indigo carmine to test for tubal patency.
Box 34-1
Important Terms and Definitions
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Infertility: Lack of fertility after 1 year of frequent attempts
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Subfertility: A decrease, but not an absence, of fertility potential
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Sterility: Complete inability to achieve fertility
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Fecundity: Probability of achieving a live birth in one menstrual cycle
Evaluation of the Infertile Couple
Conception requires adequate function of multiple physiologic systems in both partners. Infertility may result from either one major deficiency (e.g., tubal occlusion) or multiple minor deficiencies. Failure to realize this important dictum may lead the inexperienced practitioner to overlook additional factors that might be more amenable to treatment than the one that has been identified. Infertility in about 40% of infertile couples has multiple causes. Therefore, for treatment to be most effective, a complete infertility evaluation should be performed for each couple. The psychological stress that is known to occur when conception is desired and is not occurring should not be overlooked or minimized. Participation in support groups such as RESOLVE ( www.resolve.org ) may help couples to cope with this stress and adjust to their situation. Couples should also be offered preconception counseling (see Chapter 7 ) and genetic screening for carrier status as part of their infertility care.
Age substantially decreases the rate of conception because of reduced embryo quality and likely reduced coital frequency. On the basis of a large study of donor insemination (ensuring proper timing of exposure), the strictly age-related reduction appears to be about one-third for women ages 35 to 45 years. It is reasonable to begin the basic evaluation at 6 months in older patients and to consider starting treatment for unexplained infertility earlier in women older than 35 years of age.
Evaluation and therapy may be started earlier (<1 year) when obvious defects are identified, or they may be delayed (e.g., when a correctable factor such as infrequent intercourse is identified).
In general, the first 6 to 8 months of evaluation involve relatively simple and noninvasive tests as well as the performance of a radiologic evaluation of tubal patency (hysterosalpingography [HSG]), which can sometimes have a therapeutic effect. In some studies, use of an oil-based dye approximately doubled the success rate following HSG. Operative evaluation by laparoscopy is reserved for the small proportion of couples who have not conceived after 18 to 24 months or who have specific abnormalities or indications of a probable pelvic factor.
To keep the status of the evaluation in mind, it is helpful to arrange the workup under a series of five categories that can be mentally reviewed at each visit. Table 34-1 shows the approximate incidence and the tests involved in the evaluation of each factor. In 10-15% of couples, no explanation can be found; their infertility is classified as unexplained.
Etiologic Factors
Male Coital Factors
History
The evaluation of the male occurs early so that questions about coital frequency can be addressed and azoospermia or severe oligospermia or asthenospermia (low motility) can be identified. The history-taking from the male partner should cover any pregnancies previously sired; any history of genital tract infections, such as prostatitis or mumps orchitis; surgery or trauma to the male genitalia or inguinal region (e.g., hernia repair); and any exposure to lead, cadmium, radiation, or chemotherapeutic agents. Excessive consumption of alcohol or cigarettes or unusual exposure to environmental heat should be elicited. Some medications, such as furantoins and calcium channel blockers, reduce sperm quality and/or function.
Physical Examination
A physical examination is done upon referral to a urologist when semen analysis is abnormal. The normal location of the urethral meatus should be noted. An abnormal anatomic location could result in the deposition of semen in a less favorable location during intercourse. Testicular size should be estimated by comparison with a set of standard ovoids. The presence of a varicocele should be elicited by asking the patient to perform a Valsalva maneuver in the standing position.
Investigations
A semen analysis should be performed following a 2- to 4-day period of abstinence. The entire ejaculate should be collected in a clean, nontoxic container. Until relatively recently, the full range of normal variation was not appreciated. The characteristics of a normal semen analysis by percentile are shown in Table 34-2 .
TABLE 34-2
World Health Organization Reference Values for Semen Characteristics
| Characteristics | Percentiles | ||||
|---|---|---|---|---|---|
| 5th * | 25th | 50th | 75th | 95th | |
| Semen volume (mL) | 1.5 | 2.7 | 3.7 | 4.8 | 6.8 |
| Sperm concentration (million/mL) | 15 | 41 | 73 | 116 | 213 |
| Total sperm (million/mL) | 39 | 142 | 255 | 422 | 802 |
| Total motility (%) † | 40 | 53 | 61 | 69 | 78 |
| Normal forms (%) | 4 | 9 | 15 | 24.5 | 44 |
Data were generated from semen parameters of fertile men whose partners achieved a pregnancy within 12 months.
An excessive number of leukocytes (>10 per high-power field) may indicate infection, but special stains are required to differentiate polymorphonuclear leukocytes from immature germ cells. Semen quality varies greatly with repeated samples. An accurate appraisal of abnormal semen requires at least three analyses. Periodic reassessment is necessary.
Endocrinologic evaluation of the male with subnormal semen quality may uncover a specific cause. Hypothyroidism can cause infertility, but there is no place for the empirical use of thyroxine. Low levels of gonadotropins and testosterone may indicate hypothalamic-pituitary failure. An elevated prolactin concentration may indicate the presence of a prolactin-producing pituitary tumor. An elevated level of follicle-stimulating hormone (FSH) generally indicates substantial parenchymal damage to the testes, as inhibin, produced by the Sertoli cells of the seminiferous tubules, provides the principal feedback control of FSH secretion. A response to any treatment is unlikely in the presence of an elevated level of FSH. However, the level of FSH is not helpful in predicting whether sperm will be recovered with testicular sperm extraction.
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