Infertility

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Inability to achieve pregnancy within 12 months with regular, unprotected intercourse

Laboratory Testing and Clinical Assessment

  • Female
    • Full physical examination and complete medical history
    • Cervical cytology and screening for sexually transmitted infections
    • Document ovulation – midluteal progesterone level, urinary luteinizing hormone (LH)
      • Progesterone ≥5 ng/mL implies ovulation
    • Determine etiology if ovulatory dysfunction is suspected – follicle stimulating hormone (FSH), prolactin, thyroid stimulating hormone, 17-hydroxyprogesterone, testosterone
      • Elevated FSH drawn on day 3 of cycle is associated with infertility
      • If prolactin is elevated and CT/MRI of sella is negative, consider macroprolactin testing
    • Assess ovarian reserve – FSH and estradiol measures on day 3 of menstrual cycle; anti-Müllerian hormone; inhibin B
    • Assess anatomic dysfunction – transvaginal ultrasound, hysterosalpingography, laparoscopy
  • Male
    • Full physical exam and complete medical history
    • Assess spermatic function – semen analysis of at least 2 specimens (after 2-3 days of abstinence)
      • Up to 40% of subfertile men have normal sperm analysis
    • Assess androgen status using LH, FSH, testosterone
      • Most useful if oligospermia or azoospermia noted on semen analysis
    • Consider infectious evaluation – CBC, gonorrhea and chlamydia cultures, and urinalysis
    • Consider systemic disease – usually have low testosterone, FSH
    • Genetic testing
      • Warranted when sperm density <5x106/mL, nonobstructive azoospermia present, or clinical suspicion
      • Karyotyping
        • Klinefelter syndrome (XXY) is most common abnormality (see Hypogonadism, Clinical Background section)
          • 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

  • Refer to etiology in Clinical Background

Infertility is a common problem in the U.S. affecting millions of couples who incur significant expense for fertility treatments.

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

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Luteinizing Hormone and Follicle Stimulating Hormone 0070193
Method: Quantitative Electrochemiluminescent Immunoassay

Progesterone Quantitative by HPLC-MS/MS, Serum or Plasma 2008509
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Macroprolactin 0020765
Method: Quantitative Chemiluminescent Immunoassay

17-Hydroxyprogesterone Quantitative by HPLC-MS/MS, Serum or Plasma 0092332
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Anti-Mullerian Hormone 2002656
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Estradiol, Adult Premenopausal Female, Serum or Plasma 0070045
Method: Quantitative Chemiluminescent Immunoassay

Limitations

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

Semen Analysis % Abnormal

Limitations

Time-sensitive test

Two 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

Testosterone, Adult Male 0070130
Method: Quantitative Electrochemiluminescent Immunoassay

Follow Up

Not recommended for use in women and children

Y Chromosome Microdeletion 2001778
Method: Polymerase Chain Reaction/Electrophoresis

Limitations

Breakpoints of identified microdeletions will not be determined

Mutations within individual genes included in the AZF regions will not be detected

Rare diagnostic errors may occur due to primer-site mutations

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

Chromosome Analysis, Peripheral Blood 2002289
Method: Giemsa Band

Limitations

Breakpoints of identified microdeletions will not be determined

Mutations within individual genes included in the AZF regions will not be detected

Rare diagnostic errors may occur due to primer-site mutations

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

Cystic Fibrosis (CFTR) Sequencing 0051110
Method: Polymerase Chain Reaction/Sequencing

Limitations

Diagnostic errors can occur due to rare sequence variation

Breakpoints of large deletions/duplications and regulatory region and intronic mutations are not detected

CFTR gene sequencing may identify mutations of unknown clinical significance

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Unusual Organism Culture 0060714
Method: Culture

Chlamydia trachomatis Culture 0060850
Method: Cell Culture/Immunofluorescence

Limitations

Nucleic amplification testing is recommended for detection of C. trachomatis from endocervical or urethral specimens; refer to C. trachomatis by Transcription-Mediated Amplification (TMA)

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Related Tests

Guidelines

Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Male Reproduction and Urology. Evaluation of the azoospermic male. Fertil Steril. 2008; 90(5 Suppl): S74-7. PubMed

Practice Committee of American Society for Reproductive Medicine in collaboration with Society for Reproductive Endocrinology and Infertility. Optimizing natural fertility. Fertil Steril. 2008; 90(5 Suppl): S1-6. PubMed

Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2012; 98(2): 302-7. PubMed

Practice Committee of the American Society for Reproductive Medicine. Optimal evaluation of the infertile female. Fertil Steril. 2006; 86(5 Suppl 1): S264-7. PubMed

Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008; 23(3): 462-77. PubMed

General References

Balen AH, Rutherford AJ. Management of infertility. BMJ. 2007; 335(7620): 608-11. PubMed

Brassard M, AinMelk Y, Baillargeon J. Basic infertility including polycystic ovary syndrome. Med Clin North Am. 2008; 92(5): 1163-92, xi. PubMed

Centola GM. Semen assessment. Urol Clin North Am. 2014; 41(1): 163-7. PubMed

Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW Gordon, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010; 16(3): 231-45. PubMed

Fritz MA. The modern infertility evaluation. Clin Obstet Gynecol. 2012; 55(3): 692-705. PubMed

Kamel RM. Management of the infertile couple: an evidence-based protocol. Reprod Biol Endocrinol. 2010; 8: 21. PubMed

La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio C, Stabile G, Volpe A. Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update. 2010; 16(2): 113-30. PubMed

Lewis SE M. Is sperm evaluation useful in predicting human fertility? Reproduction. 2007; 134(1): 31-40. PubMed

Lindsay TJ, Vitrikas KR. Evaluation and treatment of infertility. Am Fam Physician. 2015; 91(5): 308-14. PubMed

Robins JC, Carson SA. Female fertility: what every urologist must understand. Urol Clin North Am. 2008; 35(2): 173-81, vii. PubMed

Schlegel PN. Evaluation of male infertility. Minerva Ginecol. 2009; 61(4): 261-83. PubMed

Smith RP, Coward RM, Lipshultz LI. The office visit. Urol Clin North Am. 2014; 41(1): 19-37. PubMed

Van Voorhis BJ. Ultrasound assessment of the ovary in the infertile woman. Semin Reprod Med. 2008; 26(3): 217-22. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Gronowski AM, Fantz CR, Parvin CA, Sokoll LJ, Wiley CL, Wener MH, Grenache DG. Use of serum FSH to identify perimenopausal women with pituitary hCG. Clin Chem. 2008; 54(4): 652-6. PubMed

Hammoud AO, Carrell DT, Gibson M, Peterson M, Meikle W. Updates on the relation of weight excess and reproductive function in men: sleep apnea as a new area of interest. Asian J Androl. 2012; 14(1): 77-81. PubMed

Hammoud AO, Meikle W, Peterson M, Stanford J, Gibson M, Carrell DT. Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. Asian J Androl. 2012; 14(6): 855-9. PubMed

Hammoud AO, Meikle W, Reis LOliveira, Gibson M, Peterson M, Carrell DT. Obesity and male infertility: a practical approach. Semin Reprod Med. 2012; 30(6): 486-95. PubMed

Hammoud AO, Wilde N, Gibson M, Parks A, Carrell DT, Meikle W. Male obesity and alteration in sperm parameters. Fertil Steril. 2008; 90(6): 2222-5. PubMed

Kushnir MM, Naessén T, Wanggren K, Rockwood AL, Crockett DK, Bergquist J. Protein and steroid profiles in follicular fluid after ovarian hyperstimulation as potential biomarkers of IVF outcome. J Proteome Res. 2012; 11(10): 5090-100. PubMed

Ray JA, Kushnir MM, Bunker A, Rockwood AL, Meikle W. Direct measurement of free estradiol in human serum by equilibrium dialysis-liquid chromatography-tandem mass spectrometry and reference intervals of free estradiol in women. Clin Chim Acta. 2012; 413(11-12): 1008-14. PubMed

Thienpont LM, Van Uytfanghe K, Blincko S, Ramsay CS, Xie H, Doss RC, Keevil BG, Owen LJ, Rockwood AL, Kushnir MM, Chun KY, Chandler DW, Field HP, Sluss PM. State-of-the-art of serum testosterone measurement by isotope dilution-liquid chromatography-tandem mass spectrometry. Clin Chem. 2008; 54(8): 1290-7. PubMed

Medical Reviewers

Last Update: April 2016