Infertility Evaluation: A Critical First Step

In cases of infertility, where because of the woman's age (>39 years) or diminished ovarian reserve her biological clock is running out of time, the imperative often exists to move directly to IVF. However, since the majority of infertility (of male and/or female origin) occurs in situations where the woman is younger and has adequate ovarian reserve, there is usually ample opportunity to first consider other less invasive, less expensive and insurance-covered, non IVF options. In such cases, nothing is more fundamental to optimal management than is the initial performance of a detailed and comprehensive basic infertility work-up.

Preparatory Tests

1. On the third day of a spontaneous or progesterone withdrawal menstruation, blood is drawn for the measurement of estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH) and selectively, for Inhibin-B.


2. Blood should also be drawn (any time) for the measurement of Prolactin, TSH and antisperm antibodies (ASA).


3. Commencing on the second day (2nd) of the menstrual cycle, a basal body temperature chart should be initiated. A thermometer is placed in the mouth for a period of two (2) minutes upon awakening (prior to the ingestion of food/liquid and brushing of your teeth). The temperature should be documented graphically on the basal body temperature chart provided.


4. For women under 35 yrs of age without evidence or symptoms suggesting underlying organic pelvic disease (eg; endometriosis, chronic inflammation, pelvic adhesions, fibroids etc):
   A hysterosalpingogram (HSG) should be performed within a week of the cessation of menstruation. This outpatient procedure involves injection of a radio-opaque dye which outlines the Fallopian tubes allowing the diagnosis of tubal blockage . To a lesser degree, it permits the detection of surface lesions inside the uterine cavity.
   OR
   For all women over 35 yrs of age and for younger women who have evidence or symptoms pointing to underlying organic pelvic disease (e.g., endometriosis, chronic inflammation, pelvic adhesions, fibroids etc): A laparoscopy/hysteroscopy should be performed within a week of the cessation of menstruation. Laparoscopy is a procedure where a telescope-like instrument is introduced through the belly button into the abdominal/pelvic cavity allowing diagnosis and treatment of ovarian cysts/endometriomas/benign tumors, uterine fibroids , tubal blockage, ectopic pregnancy, appendicitis, pelvic adhesions etc. Laparoscopy is usually performed as an out-patient procedure with the patient under general anesthesia. It is one of the only ways to diagnose early pelvic endometriosis accurately. Hysteroscopy is a procedure where a telescope-like instrument is inserted, via the vagina through the cervical canal into the uterine cavity, for the evaluation of the interior of the uterus. It is an important procedure because it allows for diagnosis and treatment of small surface lesions inside the uterine cavity (e.g. polyps, scarring or adhesions) that adversely affect the ability of an embryo to attach to the uterine lining. Such lesions are often missed through the performance of an HSG.


5. Commencing at least 17 days before the expected next menstrual period( ie; usually about 10 days following the initiation of menstruation), urine should be collected twice daily and tested for the onset of the spontaneous LH surge. The initiation of the LH surge usually precedes ovulation by 8 to 36 hours. In order to detect the onset of the LH surge as early as possible, it is important that urine be tested at least twice daily. This is done as follows:
   

A. The bladder is emptied first thing in the morning, upon awakening. One half-hour later urine is collected (only a very small amount is required) and tested using an over-the-counter LH kit (obtainable at a drug store). The earliest sign of any color change should be documented. It need not be a pronounced color change as suggested by the insert in the kit. Any alteration in coloration is significant.

B. The same process of testing is then repeated at night before retiring.

C. At the earliest sign of a color change the couple should:
· Have intercourse, then arrange to have the first in-office physician’s assessment within 6-18 hours following intercourse.
· The woman should RUSH IN to the physician’s office ASAP to have her blood drawn for the measurement of estradiol (E2) l level. Timing is critical, because within approximately 6 hours of detecting LH in the urine, (which roughly coincides with 12 hours after the actual onset of the LH surge), blood estradiol levels start to fall precipitously. If blood is drawn too late, the measurement of estradiol will be of little value.

Note: If the color change is observed in the early morning, the woman should schedule the “first in-office assessment” at the doctor’s office for the afternoon of the same day. If it occurs at night, the doctor’s office should be contacted first thing the next morning and the “first office assessment” should take place within hours.

The First In-Office Assessment

1. A Post-Coital Test (PCT) or Huhner test is performed on the cervical mucus. The purpose of the PCT is to assess sperm survival within the mucus. Since sperm can only survive for six hours in the vagina, a positive PCT is indicative of:
   
   A. Good quality sperm.
   B. Good sperm/cervical mucus interaction, suggesting that there will be safe passage of sperm to the uterine cavity.
   C. Absence of anti-sperm antibodies (ASA) in the sperm or mucus.
   D. That the production of estrogen is adequate.
   E. That the endometrial lining is well primed by estrogen, which is essential for adequate preparation of the uterine lining for implantation.


2. Cervical mucus is cultured for:
   A. Ureaplasma Urealyticum (this requires a specialized medium to transport the specimen to the laboratory).
   B. Chlamydia and Gonococcus (these also require a specialized transport medium).
   C. Aerobic and anaerobic pathogens.


3. A sample of the cervical mucus is allowed to dry on a glass slide and is examined under the microscope for specific features such as “ferning”, which is indicative of an adequate estrogen effect.


4. A vaginal ultrasound examination is performed to detect the presence of at least one dominant follicle that measures 18mm in mean diameter, thus helping confirm that ovulation is imminent. It also allows for the assessment of the thickness and appearance of the endometrial lining. A normal endometrium should measure at least 9 millimeters in sagital diameter at this time.

The Second In-Office Assessment

This visit is scheduled three (3) days after the first office assessment. At this visit, a vaginal ultrasound exam is performed to check whether ovulation has occurred (i.e. whether the egg has been released). The presence of small amount of fluid collecting in the lowermost region of the pelvis or a change in the shape of the follicle is suggestive of ovulation.

The Third In-Office Assessment

The third visit takes place five (5) days after the 2nd visit. At this visit, blood is drawn for the measurement of progesterone (P4) and Estradiol (E2)

The Fourth In-Office Assessment

The fourth and final visit is scheduled for five (5) days after the office assessment. At this visit, an endometrial biopsy is performed. This is a simple in-office procedure, whereby a sliver of uterine lining (endometrium) is removed and sent to the laboratory to evaluate histologic changes in the endometrium.

INTERCURRENT TESTING (i.e. any time in the cycle):

Tests On The Female Partner

1. An immunologic work-up may be required in certain cases of female infertility or where there is a past history of recurrent pregnancy loss. This workup includes measurement of: 1) antiphospholipid antibodies (APA), 2) antithyroid antibodies (ATA) 3) a Natural Killer Cell activity (NKa) test, a.k.a. K-562 Target Cell Test. In select cases, both partners should be tested for alloimmune similarities (DQa and HLA). The blood should be sent to a specialized Reproductive Immunology Reference laboratory, as such tests cannot usually be performed in regular Laboratories because the methods they employ are neither sensitive nor specific enough to be of value in cases of reproductive failure.


2. For patients who anticipate going into an In Vitro Fertilization cycle sometime in the near future, blood should be drawn for the measurement of HIV, Hepatitis B surface antigen, Hepatitis C antibody and RPR (a Syphilis test), blood grouping, RH testing as well as a Rubella antibody test . Such tests will usually not be required in the course of a routine basic infertility work-up. Their performance should be confined to cases where it is anticipated that Assisted Reproductive Technology (ART) procedures such as In Vitro Fertilization or GIFT, will be the primary approach.


3. In select cases, a diagnostic laparoscopy and concomitant hysteroscopy should be performed. The former is the only reliable way to evaluate for endometriosis and to assess tubal patency. A hysteroscopy permits examination of the uterine cavity for surface lesions (polyps, scar tissue, fibroids) and developmental abnormalities (e.g. a uterine septum) all of which can affect reproductive performance.

Tests On The Male Partner

1. A semen analysis is required for accurate measurement of sperm motility and count. Sperm morphology is assessed employing “strict Kruger criteria.” Semen should also be cultured for Ureaplasma Urealyticum, Chlamydia, Gonococcus and for aerobic/anaerobic pathogenic organisms.


2. In addition, the man’s blood should be tested for anti-sperm antibodies (ASA).


3. If In Vitro Fertilization is being considered, the man should also undergo blood testing for Hepatitis B surface antigen, Hepatitis C antibodies, RPR (Syphilis) and HIV.


4. Ideally, the semen should also be sent for a Sperm Chromatin Structure Assay (SCSA) to assess the DNA Fragmentation Index (DFI) which ideally should be <30%.