1 Evaluation of the Female for Infertility Bryan D. Cowan Evaluation of women with infenility is an increas. ingly important part of the primary care practi tioner’s role, Reproductive dysfunction affects more than 2 million married couples during their reproductive lives, and approximately 10-15% of women between the ages of 25 and 45 scck office ‘consultation coaceming reproductive dysfunction As a perspective, the ferlity rate in the United States has remained nearly constant for more than ‘a docade at 2.1 live births per reproductive-age female, This is coincident with the ideal fect rate that maintains a population profile consistent ‘with “zero population growth” Because our soci- ‘ety has this population growth philosophy, there is sreat pressure on couples to have their families at fa time that is convenient for them personally and professionally. Thus many couples seek fertility services 10 Overcome acquired diseases, enhance natural decreasing fertility associated with age, and accommodate life style agendas. Confirmation of Infertility Infertility is established when 2 couple attempts 2 [pregnancy for 12 months or longer and conception fils. It is important to remermber that tbe natural fertility rate is expressed in two ways. The overall cumulative pregnancy rate is the expected proba bility of conception within a population when all the pregnancies have occurred. The second impor- tant factor to consider is the oseurtence of preg nancy with each opportunity (ovulation) for con- ception. In young. unencumbered couples. this fecundity rate is approximately 20% per month. “Three important factors sre associated with infer: tility. They are represented by major disturbances in male gamete production, female gamete pro- duction, and female tuboperitoneal diseases. Although the distribution of these defects varies with infertility populations, it is convenient to con- sider that about 40% of couples have male factor dysfunction, ovulatory dysfunction occurs in 205, and anatomic abnormalities are present in 30% (Table 1~1). Ten percent of couples have no iden tiable cause oftheir reproductive dysfunction after 1 thorough infertility evaluation, Strategy for Infertility Testing Once the diagnosis of infertility is confirmed, thorough cvaluation correctly classifies the cause of infertility in 85-90% of patients. Most of the evaluation is conducted in an office eavironment fand usually requires no more than 60-90 days to complete. The timing of the tests is generally coor- inated with the female ovarian menstrual cycle. Figure [-1 illustrates the hormone levels during the ‘menstrual cycle, It is usually convenient to sched- tle tests throughout the course of two cycles to avoid disruption ofthe ovarian menstrual cycle and poxential errors in interpretation if tests conflict Male Factor Evaluation ‘The history from the male partner should include ‘important information concerning a history of pre- viously fathered pregnancies, testicular feuma oF infection, cavironmental exposure to toxins or beat, and coital and sexual performance. If a physical ‘examination can be performed, the genitalia are inspected and the developmental stage classified. ‘The scrotum is evaluated for masses, varicocele, of inguinal herniaTanti 1-1. Cavses of Infenility Semen Analysis Peeameters Came = ate eer 0 Ovulation defect, 20 Pelvic ducases 30 Unexplained 0 many parameters can be measured, the volume, total number of ejaculated sperm, percent motility of the sperm, and percent normal forms (Table 1-2) represent the major and most important parameters. I is important to remember that the time required ‘0 complete a eycle of sperm production is 70-80 days. Thus if antecedent illness, stress, o injury bas occurred, it is advisable to repeat the semen analysis after an appropriate interval of time has lapsed that would ensure measurement of an unaf: fected sperm cycle, ‘Adjuncts to the traditional semen analysis have been sought to assess the fertilizing capability of the semen or the fertility of the man. These adjuncts include a postcoital test, zona-free hamster pene- 24 6 € 10 12 18 16 16 20 22 24 26 28 Tou: 1-1, Hormone levels during the menstrual cycle During the proliferative phase (days I~14) estiogen v= ek progressively rise. Ovulation (day 14) is preveded by an increase in the gonadotropins and is signaled by a ‘harp rise in loeinizing hormone (LH). During the secre- tory phase (days 15-28) the corpus luteum produces increasing levels of progesterone. In the absence of fer- tization, menstruation (days 1-8) occurs as the endo- smetrium is shed, Saal 7280 0X 10° spermatneaa/mnt 240 X 10° spermatozod/ejaculate 250% forward progresion or 1=25% rapa progression 2305; neal foro 215 live Source: WHO, 192. tration, zona binding assays, cervical mucus pene tration assays, and seminal antibody detection. Detecting antibody on sperm has been associated with the prediction of infertility, particularly if the antibody is recognized to be a head-to-head agglu- Uipating antibody of the immunoglobulin G class. Unfortunately, except for antibody testing, other adjunctive tests are less helpful, difficult to per- form, and expensive. In particular, most authorities recommend that routine use of the postecital test be abandoned. This testis difficult to interpret and dependent on female cervical mucus production during the ovarizn menstrual cycle; moreover, u form norms have not been established. Addition- ally, critical evaluation of reported case series reveal an inability of the test to predict fer Thas we believe that semen analysis represents the single and most important test for evaluating the man. When necessary, this test should be repeated at 2- to 3-week intervals to encompass a complete 70-1 80-day sperm cycle. Other than seminal anti- sperm antibodies, other routine adjunctive tests of sperm function are not justifiable and shouldbe used only for special indications. Assessment of Ovulation ‘The history of the female partner should include the time of menarche, the interval between men- stnial cycles, the presence or absence of molimina, the duration of menstrual flow, and the presence ot absence of dysmenorthea. Women with regular, predictable cycles (26-34 days) can be predicted 10 be ovulatory with a high degree of certainty (99.8%). In perspective, only two to three of every 1000 women who offer a history of regular, pre- ictable cycles are discovered to be anovulatory. It is important to remember that the menstrual history reflects subjective information, and confir- mation of ovulatory status should be’ determined bby appropriate laboratory tests. Three office-based procedures are used to Confirm that ovulation has1. Evaluation of the Female for Infertility 3 ‘TaMLe 1-3. Assessment of Ovulatory Status Ta Timing Bar ‘Complete ele Serum progesterone Mictuteal Endoroctal opey Late teal Sonography [ate folicuise LH testing Late folicuae [BBT, basal body temperate: LH, tenting hormone. occurred, and two additional office-based proce- dures are used to determine that ovulation will occur in the immediate future. To determine that ovulation has occurred, most clinicians use basal body temperature (BBT) chart ‘monitoring, luteal phase serum progesterone meas- ‘urements, or secretory phase endometrial biopsy. BBT chart monitoring typically reveals a tempera- ture below 98°F during the follicular phase (Table 1-3). Afer ovulation the temperature rises 0. 6° and is sustained for 9-13 days during the luteal phase. Immediately before or coincident with the onset of menses, the temperature falls below 98°F. This typical “biphasic” profile is demon- sirated repeatedly in ovulatory women, Use of BBT chart monitoring to determine dys. functional ovulation (in contrast to the absence of ‘ovulation) is generally not helpful. Unfortunately, parameters such as the number of temperature-le- vated days and the magnitude of the temperature rise have correlated with other measures of luteal function (progesterone, endometrial biopsy) and have not been used reliably to initiate therapy. Thus BBT chart monitoring can establish ovulation but is unable to determine the presence or absence of ovulatory disturbances. ‘Serum progesterone concentrations are higher than 5 ng/ml during the luteal phase. Most clini- cians use the luteal phase progesterone level to establish both ovulation and the quality of ovula- tion. If the serum progesterone is higher than 5 ‘ng/ml, ovulation is confirmed. This measurement ‘can apply to any day of the luteal phase. When more rigorous criteria are set for the time of progesier- ‘one measurement (6-8 days prior to the onset of menses—typically day 20-22 of the eycle), several investigators have reported that the “quality” of ‘ovulation can be determined. The precise threshold value of progesterone is controversial, but most agree that a mid-luteal progesterone level of less than 10 ng/ml is consistent with luteal dysfunction, Additionally, most authors agree that a serum pro- ‘gesterone level higher than 20 ng/ml is consistent ‘with adequate luteal function. There is no consen- sus on what a serum progesterone level of 10-20 ng/ml indicates about luteal function, but it clearly ‘means that ovulation has occurred. Endometrial biopsy is typically performed during the lete luteal phase to classify the morphologic transformation of the secretory endometrium. The “luteal phase defect” has been defined as endo- ‘metrium that is more than 48 hours “out of phase” with the cycle. The proper interpretation of this test requires three pieces of information: (1) the date the test was performed; (2) the date natural menstrua- tion occurred; and (3) the morphologic dating of the endometrial specimen. For example, a specimen obiained on day 26 of a 28-day cycle that was inter- ‘preted as consistent with day 23 endometrium would ‘be considered out of phase, but a specimen obtained 6 days before the onset of menstruation consistent with day 23 secretory endometrium would be con- sidered in phase. Finally, interest has emerged con- ‘ceming adjunctive measurement of endometrial pep- tides. In particular, some integrins are known 10 be ‘expressed at unique times during the secretory phase. Measurement of these factors may increase the accu- racy of properly classifying endometrial specimens. Endometrial biopsy is inconvenient to the pa- tient, is associated with mild discomfort, and is approximately four to six times more expensive than serum progesterone measurements. Unfortu- nately, there isa mixed degree of agreement regan ing serum progesterone measurements and endo- metrial maturity. Hence these two tests currently stand at the “discretion of the practitioner” as inde- pendent but not correlated tests. Follicular measurements (sonography) have been used to predict ovulation. In general, a natu- rally growing follicle expands at approximately 2-3 ‘mm per day and ruptures after the follicular diam eter approaches 20-22 mm. In contrast, a clomi- phene citrate-stimulated follicle ruptures when the iameter approaches 24-26 mm. After rupture the follicle generally collapses, and fluid collects in the cul-de-sac, Commonly, a luteal structure can be observed in the ovary. Finally, urinary measure- ments of mid-cycle luteinizing hormone (LH) can detect the preovulatory LH surge. Because urinary LH measurements are done infrequently (usually ‘once or twice dil), itis reasonable 19 estimate that ovulation will occur 24-36 hours after detes- tion of the surge. Anatomic Defects Figure 1-2 reviews the anatomy of the female pelvic organs. Two principal anatomic defects deserve evaluation for couples with infertility. Uter-