Infertility

Diagnostic Algorithm

  Secondary Amenorrhea Testing Algorithm

Clinical Background

Infertility is a common problem in the U.S., affecting millions of couples and creating significant cost for fertility treatments.

Epidemiology

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

Etiology

• Female factors – account for about 50% of the cases
  • Ovarian dysfunction
    • Aging
    • Endocrine disorders
    • Polycystic ovarian syndrome (PCOS)
    • Premature ovarian failure
  • Tubal factors
    • Obstruction – history of pelvic inflammatory disease (PID), tubal pregnancy, tubal or pelvic surgery
    • Endometriosis
  • Uterine/cervical factors (uncommon etiologies)
    • Congenital anomaly
    • Fibroids
    • Polyps
    • Poor cervical mucous quality
  • Lifestyle
    • Tobacco
    • Alcohol
    • Caffeine
    • Body mass
  • Endocrine/metabolic disorders
    • Congenital adrenal hyperplasia (CAH)
    • Virilizing tumors
    • Adrenal failure
    • Cushing syndrome
    • Hypo/hyperthyroidism
    • X chromosome abnormalities
• Male factors – account for about 25% of the cases
  • Primary/secondary hypogonadism
  • Orchitis
  • Altered sperm
  • Y chromosome abnormalities/microdeletions
  • Trauma-related
  • Exposure to toxic agents (chemotherapy, radiation)
  • Testicular tumor
  • Unknown
• Unexplained – account for about 25% of the cases

Clinical Presentation

• Female
  • Irregular menses
  • Galactorrhea
  • Signs of hyperandrogenism (eg, hirsutism)
• Male
  • Varicocele or hydrocele
  • Signs of androgen deficiency (eg, small testes)
  • Signs of infection (eg, epididymitis)
  • Obstruction/absence of the ejaculatory ducts
  • Testicular tumor

Treatment

• Ovulation induction
• Intrauterine insemination
• In vitro fertilization (IVF)
  • Ovarian stimulation followed by egg retrieval
  • Egg fertilization, embryo culture
  • Embryo transfer to uterus
• Intracytoplasmic sperm injection (ICSI)
• Egg donation/ donor insemination

Diagnosis

• Indications for testing – inability to achieve pregnancy within 12 months
• 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
    • Determine etiology if ovulatory dysfunction is suspected – follicle stimulating hormone (FSH), prolactin, thyroid stimulating hormone (TSH), 17-hydroxyprogesterone, testosterone
    • 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 
    • Assess anatomic dysfunction – transvaginal ultrasound, hysterosalpingography, laparoscopy
  • Male
    • Full physical exam and complete medical history
    • Assess androgen deficiency – LH, FSH, testosterone
    • Assess spermatic function – semen analysis (at least 2 specimens)
      • Normal semen parameters
        • Volume ≥2.0 ml
        • pH 7.2-8.0
        • Sperm concentration ≥20x10⁶/ml
        • Total sperm count ≥40x10⁶/ejaculate
        • Motility (within 60 min. of ejaculation)
          • ≥25% with rapid progression
          • ≥50% with forward progression
        • Vitality
          • ≥75% live
          • ≤25% dead
        • Morphology ≥30% normal forms
        • White blood cells <1x10⁶/ml
        • Immunobead test and mixed antiglobulin reaction for antisperm antibodies <50%
    • Y chromosome studies – Y chromosome microdeletions, chromosome analysis
    • If absence of the vas deferens, CFTR gene analysis to exclude cystic fibrosis (CF)
    • Consider infection evaluation – complete blood count (CBC), gonorrhea and chlamydia cultures, and urinalysis

Pharmacogenetics and Therapeutic Drug Monitoring

Screening

Monitoring

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Testosterone, Females or Children 0081058 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry
Testosterone, Free & Total (Includes Sex Hormone Binding Globulin), Females or Children 0081056 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay The concentration of free testosterone is derived from a mathematical expression based on the constant for the binding of testosterone to sex hormone binding globulin.
Testosterone, Bioavailable & Sex Hormone Binding Globulin (Includes Total Testosterone), Females or Children 0081057 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay The concentrations of free and bioavailable testosterone are derived from mathematical expressions based on constants for the binding of testosterone to albumin and/or sex hormone binding globulin.	Determine etiology of infertility
Inhibin B 0070413 Method: Enzyme-Linked Immunosorbent Assay
Follicle Stimulating Hormone, Serum 0070055 Method: Electrochemiluminescent Immunoassay	Determine etiology of infertility
Progesterone 0070110 Method: Electrochemiluminescent Immunoassay	Determine etiology of infertility
Estriol, Serum 0070051 Method: Chemiluminescent Immunoassay

Guidelines

Cited References

General References

References from the ARUP Institute for Clinical and Experimental Pathology®