Infertility

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)
          • Fragile X carrier screening is recommended in individuals <40 years of age who receive an elevated FSH result or who have ovarian insufficiency without an apparent cause (American College of Obstetricians and Gynecologists [ACOG], 2019)
        • Estradiol alone not a recommended test – only assists with interpretation of FSH
      • Clomiphene citrate challenge
        • Administer clomiphene citrate 100 mg 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
      • Prolactin
      • Growth hormone – see Growth Hormone Deficiency topic for appropriate stimulation testing
  • 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 Hypogonadism, Background)
        • 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

• Female factors – 30-40% of cases
  • Ovarian dysfunction
    • Aging
    • Endocrine disorders
    • Polycystic ovarian syndrome
    • Premature ovarian failure
    • Single ovary
    • Previous ovarian surgery
    • History of chemotherapy or radiation
  • Tubal factors
    • Obstruction – history of pelvic inflammatory disease, tubal pregnancy, tubal or pelvic surgery
    • Endometriosis
  • Uterine/cervical factors – uncommon etiologies
    • Congenital anomaly
    • Fibroids
    • Polyps
    • Poor cervical mucous quality
  • Lifestyle
    • Tobacco consumption
    • Excess alcohol consumption
    • Elevated or low body mass
    • Excessive exercise
  • Endocrine/metabolic disorders
    • Congenital adrenal hyperplasia
    • Virilizing tumors
    • Adrenal failure
    • Cushing syndrome
    • Hypo/hyperthyroidism
    • Diabetes mellitus
    • X chromosome abnormalities
  • Genetic disease
    • Cystic fibrosis
    • Turner syndrome
• Male factors – 30-40% of cases
  • Primary/secondary hypogonadism
  • Orchitis – usually infectious (eg, mumps)
  • Altered sperm (eg, cystic fibrosis)
  • Y chromosome abnormalities/microdeletions
  • Trauma
  • Exposure to toxic agents (eg, chemotherapy, radiation)
  • Testicular tumor

Clinical Presentation

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