Diagnostic Evaluation of the Infertile Female
Women who are unable to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse require infertility evaluation.
Nearly 85% of couples are expected to achieve pregnancy without medical help within one year. Assessment is indicated for 15% of couples.
Earlier evaluation is warranted after six months if efforts to conceive in women over 35 years are unsuccessful. Earlier tests are also warranted in women missing periods, have uterine or Fallopian tube disease or have adhesions or endometriosis. Male subfertility warrants investigation.
It is best if assessment of the couple is done at the same time.
Methods for the evaluation of the male partner are described in a separate document.
Women who are planning to attempt pregnancy via insemination with sperm from a known or anonymous donor may also merit evaluation before such treatment begins.
At Initial Consultation your fertility specialist would obtain comprehensive history, a thorough physical examination, preconception care counseling and relevant genetic screening.
Questionnaire would include:
How long have you been trying for a baby?, previous evaluation and treatment
Your menstrual cycle details (menarche, cycle characteristics, molimina, and painful periods ‘dysmenorrhea’, severity)
Pregnancy history (number of pregnancy, number of births, pregnancy outcome i.e. miscarriage, ectopic, preterm birth, and complications
Contraception methods used and how long?
Sexual intercourse frequency and dysfunction
Pelvic inflammatory disease or exposure to sexually transmitted infections
Pelvic pain
Abdominal pain
Pain with deep intercourse (deep dyspareunia)
Past surgery or injuries (procedures, indications, outcomes complications) in particular pelvic surgery
Previous illnesses and hospitalizations
Thyroid gland disease
Milk secretion (galactorrhea)
Hirsutism (excess facial and body hair ‘male distribution’),
Previous abnormal pap smears and treatment
Current medications
Allergies
Family history of birth defects / abnormality and mental retardation
Family history of early menopause or reproductive failure or compromise
History of exposure to Chemotherapy and or Radiation.
Occupational exposure to known agents i.e. chemicals
Environmental hazards
Use of tobacco, alcohol
Use of recreational or illicit drugs
Your fertility specialist would examine and document:
Weight, body mass index (BMI)
Blood pressure and pulse
Thyroid enlargement and nodules or tenderness
Breast secretions and their character
Signs of androgen excess, facial or body hair, acne
Vulval, Vaginal or cervical abnormality, secretions, or discharge
Pelvic or abdominal tenderness, organ enlargement, or masses
Uterine size, shape, position, and mobility
Adnexal masses or tenderness
Cul-de-sac (the area between uterus and rectum) masses, tenderness, or nodularity
Diagnostic tests to identify all relevant factors should be
Systematic
Expeditious
Cost-effective
Initially least invasive
Detect the most common causes of infertility.
The pace and extent of evaluation depend on
Couple's preferences
Patient age
Duration of infertility
Couple's medical history and physical examination
Ovulation
Fifteen per cent of all infertile couples show ovulatory dysfunction. Ovulation dysfunction causes 40% of women’s infertility. Ovulatory dysfunction leads to obvious menstrual disturbances such as long cycles or no periods (oligomenorrhea /amenorrhea), but can be more subtle.
The cause should be identified to start the specific treatment. In some conditions ovulation disorder may have other health implications and consequences.
The most common causes of ovulatory dysfunction:
Polycystic ovary syndrome
Obesity
Weight gain
Weight loss
Strenuous exercise
Thyroid problems
Hyperprolactinemia
The specific cause of ovulatory dysfunction may remain unknown.
Ovulatory Function Evaluation:
Menstrual history:
In most ovulatory women, menstrual cycles are regular every 25–35 days with consistent flow characteristics, and consistent pattern of moliminal symptoms. A degree of variation is entirely normal. In infertile women although a history of regular menstruation strongly suggests normal ovulatory function an objective measure is warranted.
Women with abnormal uterine bleeding, oligomenorrhea (infrequent periods), or amenorrhea (no periods) generally do not require specific diagnostic tests to establish a diagnosis of anovulation.
Serial basal body temperature (BBT) measurements:
Is a simple and inexpensive method to track ovulation. Your basal body temperature is your body’s temperature at rest. After ovulation, your basal body temperature will shift up by at least four-tenths of a degree. If your temperature remains elevated for at least three days, you can be pretty sure that ovulation has occurred on the day before the temperature rise. Because the shift in temperature is so small, it’s important to take your temperature at the exact same time every morning, before you get up or move. Before you go to bed at night, place a thermometer within your reach by your bed. It’s very important that you can reach this thermometer without needing to get up or move around when you wake up. Getting out of bed, or even sitting up, will throw off your temperature and skew the results. You should take your temperature at the same time every morning, with no more than a 30 minute difference from morning to morning. When you wake up, reach for your thermometer and take your temperature. Do not get up to go to the bathroom, and don’t get up to turn off your alarm (keep that near-by). You can take your temperature orally or vaginally. Choose one and stick with it day to day. Take your temperature vaginally if you sleep with your mouth open. Follow the directions for your thermometer to get the best reading. If you’re using a mercury thermometer, make sure you leave it in place four or five minutes to get a final reading. (Be sure to shake the mercury thermometer down before you go to bed at night). After you take your temperature, write it down. Some BBT thermometers have a memory function. Keep a pen and paper by your bed so you can jot down your temperature and the time you woke up, until you have time to fill this information into your chart. You need to have slept at least four straight hours for your temperature to be accurate. Basal body temperature charting does not work for everyone.
If you don’t notice a sustained rise in temperature, it doesn’t necessarily mean that you are not ovulating.
While basal body temperature charting can pinpoint when ovulation occurred, it isn’t a good way to predict ovulation. Since you need to have sexual intercourse before ovulation if you want to get pregnant, you should look for other signs of ovulation so you can time sexual intercourse better.
One way to predict ovulation is by tracking your cervical mucus.
In cycles monitored with BBT, the period of highest fertility spans the seven days prior to the mid-cycle rise in BBT.
Ovulatory cycles generally are associated with clearly biphasic BBT recordings. Some ovulatory women cannot document clearly biphasic BBT patterns.
An-ovulatory cycles typically result in monophasic patterns.
Grossly short luteal phases (<10 days of temperature elevation) may identify women with more subtle ovulatory dysfunction.
The test cannot reliably define the time of ovulation and can become tedious.
BBT is no longer considered the best or preferred method for evaluating ovulatory function for most infertile women.
Serum progesterone level:
Obtained at the appropriate time in the cycle provides a reliable and objective measure of ovulatory function. A serum progesterone measurement should be obtained approximately one week before the expected onset of the next menses. A progesterone concentration more than 9.54 nmol/L provides presumptive but reliable evidence of recent ovulation. Higher values have been used commonly as a measure of the quality of luteal function (=31.8 nmol/L). This criterion is not reliable because corpus luteum progesterone secretion is pulsatile and serum concentrations may vary up to 7-fold within an interval of a few hours.
Urinary luteinizing hormone (LH) tests:
Using various over the counter ovulation predictor kits can identify the mid-cycle LH surge that precedes ovulation by one to two days. Urinary LH detection provides indirect evidence of ovulation. It helps to define the interval of greatest fertility i.e. the day of the LH surge and the following two days. Midday or Evening Urinary LH particularly correlates well with the peak in serum LH.
Accuracy, ease of use, and reliability vary among ovulation predictor kits, and testing may yield false positive and false negative results.
Endometrial Biopsy and Histology:
Can demonstrate secretory change in endometrium due to action of progesterone and thus implies ovulation.
Endometrium Dating using histologic criteria was the gold standard for evaluating the quality of luteal function and for diagnosis of luteal phase deficiency (LPD). Now Endometrium Dating is not a valid diagnostic method because it lacks both accuracy and precision and the test cannot distinguish fertile from infertile women. It is no longer recommended for the evaluation of ovulatory or luteal function in infertile women. It is indicated only in women strongly suspected to have specific endometrial pathology e.g., neoplasia or chronic endometritis.
Transvaginal ultrasound:
Determines the size and number of developing follicles
Provides presumptive evidence of ovulation and luteinization by demonstrating progressive follicular growth, sudden collapse of the pre-ovulatory follicle, a loss of clearly defined follicular margins, the appearance of internal echoes, and an increase in cul-de-sac fluid volume.
Because of the associated cost and logistical demands, the method generally should be reserved for women in whom simpler methods fail to provide the necessary information and those receiving ovarian stimulation for purposes of ovulation induction.
Other Evaluations may be Indicated for An-Ovulatory Infertile Women.
Serum thyroid-stimulating hormone (TSH) and prolactin
Tests can identify thyroid disorders and/or hyperprolactinaemia, which may require specific treatment.
In women with amenorrhea, serum follicle-stimulating hormone (FSH) and estradiol measurements can distinguish
Women with ovarian failure (high FSH,low estradiol), who may be candidates for oocyte donation, from
Women with hypothalamic amenorrhea (low or normal FSH, low estradiol), who will require exogenous gonadotropin stimulation for ovulation induction.
In an-ovulatory infertile women, failure to achieve pregnancy after three to six cycles of successful ovulation induction should be viewed as an indication to perform additional diagnostic evaluation or, if evaluation is complete, to consider alternative treatments.
OVARIAN RESERVE
The concept of ovarian reserve views reproductive potential of a woman as a function of the number and quality of her remaining oocytes.
Decreased or diminished ovarian reserve (DOR) describes women of reproductive age having regular menses whose response to ovarian stimulation or fecundity is reduced compared to those women of comparable age.
Ovarian Reserve Assessment Tests
Cycle day 3 FSH and Estradiol measurements
Clomiphene Citrate Challenge Test CCCT
Antral Follicle Count in early follicular phase (transvaginal ultrasound)
Serum Anti-Mullerian Hormone (AMH) level.
These tests may provide prognostic information in women at increased risk of diminished ovarian reserve,
1) Women over age 35 years
2) Women who have a family history of early menopause
3) Women who have a single ovary or history of previous ovarian surgery, chemotherapy, or pelvic radiation therapy
4) Women with unexplained infertility
5) Women who have demonstrated poor response to gonadotropin stimulation
6) Women who are planning treatment with Assisted Reproductive Technology.
Ovarian Reserve Tests
Do not establish a diagnosis of diminished ovarian reserve.
Help to predict response to ovarian stimulation with exogenous gonadotropins.
Help to a, lesser extent, predict the likelihood for achieving a successful pregnancy with ART.
Poor results with any of the tests however, do not necessarily imply inability to conceive.
Cycle Day 2-3 FSH and Estradiol
FSH obtained on cycle day2–5 is commonly used as a measure of ovarian reserve. High values (10–20 IU/L) have been associated with both poor ovarian stimulation (usually defined as < 2–3 follicles or = 4 retrieved oocytes) and the failure to conceive. Basal estradiol has value only as an aid to correct interpretation of a ‘‘normal’’ basal serum FSH value. When the basal FSH concentration is ‘‘normal’’ but the estradiol level is elevated (>220 pmol/L – 294 pmol/L) in the early follicular phase, there is limited evidence for an association with poor response, increased cancellation rates, and lower pregnancy rates.
Clomiphene Citrate Challenge Test (100 mg daily, cycle days 5–9)
Serum FSH is measured before day 3 and after treatment with clomiphene citrate day 10. An elevated FSH concentration after clomiphene stimulation therefore suggests DOR. Cycle day 10 FSH levels have a higher sensitivity but lower specificity compared to cycle day 3 FSH concentrations.
Antral Follicle Count (AFC)
Is the sum of antral follicles in both ovaries, as observed with trans-vaginal ultrasound during the early follicular phase. Antral follicles have been defined as measuring 2–10 mm or 3–8 mm in mean diameter in the greatest 2 dimensional plane. A low AFC (range 3–10 total antral follicles) has been associated with poor response to ovarian stimulation and with the failure to achieve pregnancy.
Serum Antimullerian Hormone (AMH) Level
AMH produced by granulosa cells of early follicles, are Gonadotropin-Independent and therefore remain relatively consistent during menstrual cycles and can be obtained on any day of the menstrual cycle. Overall, lower AMH levels (<1 ng/mL) / (2.5 pmol/L) have been associated with poor responses to ovarian stimulation, poor embryo quality, and poor pregnancy outcomes in IVF.
Cervical Factors
Examination of cervical mucus may reveal gross evidence of chronic cervicitis that warrants treatment.
Abnormalities of cervical mucus production or sperm/mucus interaction rarely are the sole or principal cause of infertility.
The Post-Coital Test (PCT): a specimen of cervical mucus obtained within hours after intercourse and shortly before expected ovulation is examined microscopically for the presence of motile sperm. PCT was the traditional method for diagnosis of cervical factor infertility. PCT is no longer recommended for the evaluation of the infertile female because the test:
Is subjective
Has poor reproducibility
Is inconvenient to the patient
Rarely changes clinical management
Does not predict inability to conceive
UTERINE ABNORMALITIES
Anatomical or functional abnormalities are uncommon causes of infertility but should be excluded. The uterus is evaluated by the following methods:
· Hysterosalpingography (HSG) defines the size and shape of the uterine cavity and can reveal
a) Developmental anomalies
1. Unicornuate
2. Septate
3. Bicornuate
b) Acquired abnormalities
1. Endometrial polyps
2. Submucous myomas
3. Synechiae(Adhesions)
All have potential reproductive consequences. However, HSG has relatively low sensitivity (50%) and positive predictive value (PPV; 30%) for diagnosis of endometrial polyps and submucous myomas in asymptomatic infertile women.
· Ultrasound can diagnose uterine pathology, including myomas / fibroids.
· Sonohysterography: transvaginal ultrasound after introduction of saline into the uterine cavity, better defines the size and shape of the uterine cavity and has high positive predictive value PPV (>90%) and negative predictive value (NPV) for detection of intrauterine pathology e.g.endometrial polyps, submucous myomas, synechiae.
· Hysteroscopy is the definitive method for the diagnosis and treatment of intrauterine pathology. As it is also the most costly and invasive method for evaluating the uterus. Hysteroscopy is generally reserved for further evaluation and treatment of abnormalities defined by less invasive methods such as HSG and sonohysterography as it is costly and invasive.
TUBAL PATENCY
Tubal diseases and obstruction are important cause of infertility and should be diagnosed. The methods to evaluate tubal patency complement each other.
Diagnosis and effective treatment of tubal obstruction often requires more than one technique:
Hysterosalpingography (HSG), using either a water or lipid soluble contrast media and X-Ray, is the traditional and standard method for evaluating tubal patency and may offer some therapeutic benefit. HSG can
Document proximal and distal tubal occlusion
Demonstrate salpingitis isthmica nodosa.
Reveal tubal structure detail of potential prognostic value.
Suggest the presence of fimbrial phimosis (narrowing) when escape of contrast is delayed.
Suggest the presence peritubular adhesions when escape of contrast becomes loculated.
HSG PPV and NPV are 38% and 94%, respectively.
HSG findings of proximal tubal obstruction require further evaluation to exclude false negative result from transient tubal / myometrial contractions or relating to catheter position.
Saline infusion sonography (SIS) determines tubal patency using fluid and ultrasound. Although tubal patency can be observed by the appearance of fluid in the cul de sac with the saline infusion, the test does not differentiate between unilateral or bilateral patency.
Laparoscopy and chromotubation with a dilute solution of methylene blue or indigo carmine (preferred) introduced via the cervix can demonstrate tubal patency or document proximal or distal tubal obstruction. The procedure also can identify and correct tubal factors such as fimbrial phimosis or peritubal adhesions, which may not be identified with less invasive methods such as HSG.
Hysteroscopic / Fluoroscopic selective tubal cannulation can confirm or exclude proximal tubal occlusion suggested by HSG or laparoscopy with chromotubation. Hysteroscopy and specialized catheter can correct obstruction via recanalization.
Chlamydia Antibody Test (CAT)
Chlamydia trachomatis antibodies detection has been associated with tubal pathology; however, this test has limited clinical utility. Compared to laparoscopy, CAT has modest sensitivity (40%–50%) and Positive Predictive Value (60%), but high Negative Predictive Value (80–90%) for detection of distal tubal disease.
PERITONEAL FACTORS
Peritoneal factors such as endometriosis and pelvic or adnexal adhesions can cause or contribute to infertility. History and/or physical examination findings may raise suspicion but rarely are sufficient for diagnosis. Peritoneal factors also should be considered in women with otherwise unexplained infertility.
Transvaginal ultrasonography can reveal unrecognized pelvic pathology that may cause infertility i.e. endometrioma.
Laparoscopy with direct visual examination of the pelvic reproductive organs is the only method available for specific diagnosis of peritoneal factors that may impair fertility.
The impact of minimal endometriosis on fertility is relatively small.
Most women with significant adnexal adhesions have
Historical risk factors (pelvic pain, moderate or severe endometriosis, previous pelvic infection or surgery) or
An abnormal HSG.
Laparoscopy therefore is most clearly indicated for women with symptoms or risk factors or an abnormal HSG or ultrasonography who have no other clear indications for ART (e.g., severe male factor infertility).
Laparoscopy yield in asymptomatic women with normal imaging is low. Given individual circumstances, there may be a place for diagnostic laparoscopy for young women with a long period (> 2-3 years) of infertility but no recognized abnormalities.
SUMMARY
Evaluation of ovulatory function should be an initial diagnostic step in the evaluation of all infertile women. When the menstrual history is grossly abnormal, no additional evaluation is required to establish a diagnosis of anovulation. Otherwise, an objective measure of ovulatory function is warranted. If appropriately timed, a serum progesterone concentration greater than 9.54 nmol/L provides reliable objective evidence for recent ovulation.
In anovulatory infertile women, failure to achieve pregnancy after three to six cycles of successful ovulation induction should be viewed as an indication to perform additional diagnostic evaluation or, if evaluation is complete, to consider alternative treatments.
Ovarian reserve should be assessed in selected women at increased risk of diminished ovarian reserve. Options include cycle day 2-3 FSH and estradiol, clomiphene citrate challenge test, US to assess antral follicle count, or serum AMH.
Histologic endometrial dating is not a valid method for evaluation of luteal function or for diagnosis of luteal phase deficiency.
Endometrial biopsy should be limited to those in whom specific endometrial pathology (e.g., hyperplasia/ neoplasia, chronic endometritis) is strongly suspected.
The Post Coital Test is not a valid method for evaluation of cervical factors and should not be included in the evaluation of the infertile female.
Routine use of PCT and EMB has not been shown to be beneficial and are no longer recommended as part of the standard evaluation of the infertile female.
Examination of the uterine cavity is an important part of the evaluation of infertile women and can be accomplished using hysterosalpingography, sonohysterography, or hysteroscopy.
Evaluation of tubal patency is a key component of the diagnostic evaluation of infertile women. All methods for the evaluation of tubal patency have technical limitations that must be considered when interpreting test results. A second and different test should be considered when the diagnosis remains in doubt.
Laparoscopy may be indicated when there is evidence or strong suspicion of advanced stages of endometriosis, tubal occlusive disease, or significant adnexal adhesions.
CONCLUSIONS
A careful history and physical examination can identify a specific cause of infertility and help to focus the diagnostic evaluation on the most likely cause(s).
