Infertility

Infertility is a common problem in the U.S., affecting millions of couples who incur significant expense for fertility treatments. An integrated analysis of both partners including medical history, laboratory testing, imaging, and procedures to evaluate the genitourinary system is conducted to identify the cause of infertility.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

Indications for Testing

  • Inability to achieve pregnancy
    • Within 12 months with regular, unprotected intercourse
    • Within 6 months with regular, unprotected intercourse
      • If ≥35 years or
      • With additional risk factors for infertility
  • Known infertility

Laboratory Testing and Clinical Assessment

  • Female
    • Ovulation testing
      • Serum progesterone
        • Documents ovulation
        • Collect approximately 1 week before start of menses (eg, day 21 of a 28-day cycle)
        • Progesterone ≥3 ng/mL implies ovulation
    • Ovarian reserve testing (American Society for Reproductive Medicine (ASRM, 2015)
      • Determine number and quality of eggs remaining in ovaries to be released and fertilized
      • Adds more prognostic information; should not be sole criteria to determine treatments – limited predictive ability
      • Available testing
        • Anti-Mullerian hormone (AMH)
          • Assess decreased ovarian reserve
          • Relatively consistent throughout menstrual cycle – can be collected on any day
          • High levels associated with polycystic ovarian syndrome (PCOS); low levels associated with poor reserve and poor response to ovarian stimulation
        • Follicle stimulating hormone (FSH) and estradiol
          • Measure on day 2-4 of menstrual cycle
          • High FSH associated with difficulty conceiving and poor ovarian stimulation (required for in vitro fertilization [IVF] treatment)
          • Estradiol alone not a recommended test – only assists with interpretation of FSH
        • Clomiphene citrate challenge
          • Administer clomiphene citrate 100mg daily
          • Measure FSH day 3 and day 10 of cycle
    • Further testing for etiology of anovulatory cycles
      • Serum prolactin
        • Evaluate in women with irregular menses, galactorrhea, or other signs or hyperprolactinemia
        • If prolactin is elevated and computed tomography (CT)/magnetic resonance imaging (MRI) of sella is negative, consider macroprolactin testing
        • Do not perform prolactin testing as part of routine infertility evaluation in women with regular menses (Choosing Wisely, ASRM, 2015)
      • Thyroid stimulating hormone (TSH)
        • Evaluate for hypothyroidism
        • Correction can restore regular cycles
      • Hyperandrogenism/PCOS
        • Testosterone
          • Use test for children and females (done by mass spectrometry or liquid chromatography tandem mass spectrometry [LC-MS/MS]) – able to detect low levels of testosterone
        • Use for evaluation of suspected PCOS
          • Signs and symptoms – acne, hirsutism, irregular periods, male pattern baldness
          • Patient will have anovulatory cycles
  • Male
    • Sperm analysis
      • Assess spermatic function
      • Semen analysis of at least 2 specimens (after 2-3 days of abstinence)
      • If repeat analysis required, repeat after 3 months due to 2 month sperm regeneration time
      • Up to 40% of subfertile men have normal sperm analysis
      • Normal semen parameters – 5th percentiles (95% confidence intervals in parentheses) (Cooper, WHO, 2010)
        • Volume – ≥1.5 mL (1.4-1.7)
        • pH – ≥7.2
        • Sperm concentration – ≥15x106 spermatozoa/mL (12-16)
        • Total sperm count – ≥39x106/ejaculate (33-46)
        • Motility – within 60 minutes of ejaculation
          • Total motility – ≥40% (38-42)
          • Progressive motility – ≥32% (31-34)
          • High viability with a low motility suggestive of structural defects (eg, primary ciliary dyskinesia)
        • Vitality – ≥58% live (55-63)
        • Morphology – ≥4% normal forms (3-4)
    • Testosterone (see Hypogonadism topic)
      • Assess androgen status using testosterone
        • Morning total testosterone is appropriate initial test
      • Most useful if oligospermia or azoospermia noted on semen analysis
    • FSH and luteinizing hormone (LH)
      • In combination with testosterone levels, assists with determination of primary or secondary hypogonadism
    • Additional analysis – consider if initial screen is negative and other signs and symptoms indicate reasons for testing
      • Ferritin – elevated iron levels may indicate hereditary hemochromatosis
      • TSH – hypothyroidism
      • CBC, sexually transmitted infections (STI) testing – evaluate for infectious disease
      • Testing for pituitary tumor
    • Genetic testing
      • Warranted when sperm density <5x106/mL or when nonobstructive azoospermia or clinical suspicion present
      • Karyotyping
        • Klinefelter syndrome (XXY) is most common abnormality (see HypogonadismBackground)
          • Associated with normal semen volume but low sperm
          • Typically low testosterone with elevated FSH
      • Y chromosome microdeletion
        • Typically normal semen volume, low sperm count, normal or elevated FSH
        • Not detected with standard karyotyping
        • Deletion is in azoospermia factor (AZF) regions
        • Associated with successful assisted reproductive technology
      • CFTR gene analysis to exclude cystic fibrosis
        • When vas deferens absent
        • Typically low semen volume

Differential Diagnosis

See Etiology in Background.

Background

Epidemiology

  • Prevalence – 10-15% of couples in U.S. (~2 million couples)
  • Definition – inability to conceive after 12 months of regular, unprotected intercourse

Etiology

Clinical Presentation

ARUP Lab Tests

Aid in the workup of suspected infertility, detection of ovulation, and assessment of the luteal phase

Assist in determining etiology of infertility

Estimate ovarian reserve

Aid in determining etiology of ovulatory or androgen dysfunction

Suitable for measurement of estradiol in adult premenopausal women

In all other groups, the preferred test is estrogens, fractionated by tandem mass spectrometry

Screen for anterior pituitary tumor

Determine if elevated prolactin is cause of infertility

Exclude prolactinoma

Use to assess thyroid function

Reflex pattern: if the thyroid stimulating hormone is outside the reference interval, then free thyroxine (T4) testing will be added

Most sensitive test for detection of hyperandrogenemia in women and children

Acceptable test for androgen deficiency in men

Suggested for women and children due to an improved sensitivity of testosterone by LC-MS/MS

Method

Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
Total Testosterone and SHBG are measured and free testosterone is estimated from these measurements.

Determine if etiology of infertility is male related

Cornerstone evaluation of male infertility

Limitations 

Time-sensitive test

2 semen samples should be evaluated (collected 7 days apart; 3 months after any febrile illness)

Samples are collected after a period of abstinence of >48 hours, but <7 days

Specimens should be analyzed within 1 hour of collection

Semen Analysis % Abnormal

Aid in the evaluation of suspected hypogonadism in men

Monitor testosterone replacement therapy

Not recommended for use in women and children

Aid in determining etiology of ovulatory or androgen dysfunction

Aid in determining cause of azoospermia or oligospermia

Predict effectiveness of assisted reproductive technologies in men with Y chromosome microdeletions

Clinical sensitivity: ~5-10% for men with nonobstructive azoospermia or severe oligospermia

Breakpoints of identified microdeletions will not be determined

Variants within individual genes included in the azoospermia factor (AZF) regions will not be detected

Male infertility due to causes other than the common Y chromosome microdeletions tested will not be detected

Confirm diagnosis of a known aneuploid syndrome or detect a chromosome translocation

This test is intended for constitutional studies; refer to cytogenomic SNP microarray for the PREFERRED FIRST-TIER test for intellectual disability, multiple anomalies, and autism-spectrum disorders

For chromosome analysis to evaluate for an oncology finding, order chromosome analysis, leukemic blood

For individuals with suspected cystic fibrosis (CF) but without 2 pathogenic variants detected by the CF 165 pathogenic variants test

Clinical sensitivity: 97%

Diagnostic errors can occur due to rare sequence variation

Breakpoints of large gene deletions/duplications and regulatory region and deep intronic variants will not be detected

Rule out infection

Order for organisms for which no stand-alone cultures are available

Use for uncommon organisms such as Streptobacillus moniliformis, Haemophilus ducreyi, and others; Neisseria gonorrhoeae specimens not approved for nucleic acid amplification testing (NAAT)

Not recommended for routine detection of Chlamydia trachomatis

Use to detect C. trachomatis in medicolegal settings and to assess suspected treatment failure

May be considered for anatomic locations for which amplified testing has not been validated

NAAT is recommended for detection of C. trachomatis from endocervical or urethral specimens; refer to C. trachomatis by transcription-mediated amplification (TMA)

Screen for various metabolic and kidney disorders

Related Tests

Preferred test for screening and monitoring of thyroid function

Use in conjunction with free testosterone in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

Aid in the evaluation of suspected hypogonadism in men with a total testosterone level at the lower limit of the normal range

Not recommended for females or children

Acceptable test for the evaluation of suspected hypogonadism in men

Not recommended for females or children

Aid in the evaluation of suspected hypogonadism in men with a total testosterone level at the lower limit of the normal range

Not recommended for females or children

May be used for infertility evaluation

Use to differentiate ovarian tumor with normal CA 125 as stromal or mucinous epithelial tumor

May be used for monitoring recurrence of stromal ovarian tumors

Indicator of fetal well-being and placental function

Direct measure of free estradiol in serum

Most accurate measure of bioactive estradiol

Useful to ensure the highest chance of obtaining meaningful results from fetal specimens

When tissue culture is unsuccessful or if the results of the chromosome analysis are normal, then testing reflexes to genomic microarray

Use for intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired, pregnancy loss or termination in the presence of fetal anomalies, further characterization of fetal chromosomal abnormalities seen by conventional cytogenetic methods, multiple fetal losses of unknown etiology, or POC samples that fail to grow in culture

Medical Experts

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References

Additional Resources
  • 28228319

    Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Reproductive Endocrinology and Infertility. Electronic address: ASRM@asrm.org

    Fertil Steril

    2017
    107
    1
    52-58
    PubMed
  • Resources from the ARUP Institute for Clinical and Experimental Pathology®