Infertility

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 (STIs)
- Document ovulation – midluteal progesterone level, urinary luteinizing hormone (LH)
- Determine etiology if ovulatory dysfunction is suspected – follicle stimulating hormone (FSH), prolactin, thyroid stimulating hormone, 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; anti-Müllerian hormone; inhibin B
- 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 of at least 2 specimens (cornerstone test for male infertility)
  - Up to 40% of subfertile men have normal sperm analysis
  - Normal semen parameters
    - Volume ≥1.2 mL
    - pH 7.2-8.0
    - Sperm concentration ≥15x10⁶ spermatozoa/mL
    - Total sperm count ≥39x10⁶/ejaculate
    - Motility (within 60 min. of ejaculation)
      - ≥25% with rapid progression
      - ≥50% with forward progression
      - High viability with a low motility is suggestive of structural defects (such as primary ciliary dyskinesia)
    - Vitality
      - ≥75% live
      - ≤25% dead
    - Morphology ≥40% normal forms
    - White blood cells <1x10⁶/ml
    - Immunobead test and mixed antiglobulin reaction for antisperm antibodies (present in 4-8% of infertile men) only considered clinically significant if >50% of spermatozoa are coated
- Y chromosome studies – Y chromosome microdeletion, chromosome analysis
- If absence of the vas deferens, CFTR gene analysis to exclude cystic fibrosis
- Consider infectious evaluation – CBC, gonorrhea and chlamydia cultures, and urinalysis
- Inhibin B – differentiate cryptorchidism from anorchia

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 frequent, unprotected intercourse

Etiology

Female factors (~50% of cases)
- Ovarian dysfunction
  - Aging
  - Endocrine disorders
  - Polycystic ovarian syndrome (PCOS)
  - Premature ovarian failure
- 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
- 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 (~50% of cases)
- Primary/secondary hypogonadism
- Orchitis (usually infectious, eg, mumps)
- Altered sperm (eg, cystic fibrosis)
- Y chromosome abnormalities/microdeletions
- Trauma
- Exposure to toxic agents (chemotherapy, radiation)
- Testicular tumor
- Unknown

Clinical Presentation

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

Treatment

Ovulation induction
Intrauterine insemination
In vitro fertilization
- Ovarian stimulation followed by egg retrieval
- Egg fertilization, embryo culture
- Embryo transfer to uterus
Intracytoplasmic sperm injection
Egg donation/ donor insemination
Gonadotropin treatment for men with gonadotropin deficiency

Tests generally appear in the order most useful for common clinical situations

Test name: Luteinizing Hormone and Follicle Stimulating Hormone

ARUP #: 0070193

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Determine etiology if ovulatory or androgen dysfunction suspected

Test name: Progesterone

ARUP #: 0070110

Methodology: Chemiluminescent Immunoassay

Use:

Determine if progesterone associated with ovulatory dysfunction

Test name: Prolactin

ARUP #: 0070115

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Determine if elevated prolactin is cause of infertility

Test name: Macroprolactin

ARUP #: 0020765

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Exclude prolactinoma

Test name: 17-Hydroxyprogesterone

ARUP #: 0070005

Methodology: Quantitative Radioimmunoassay

Use:

Assist in determining etiology of infertility

Test name: Thyroid Stimulating Hormone

ARUP #: 0070145

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use:

Determine thyroid function

Test name: Testosterone Free, Females or Children

ARUP #: 0081059

Methodology: Quantitative 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.

Use:

Assess for hyperandrogenism or PCOS

Limitations:

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

Test name: Anti-Mullerian Hormone

ARUP #: 2002656

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Estimate ovarian reserve

Diagnose PCOS

Test name: Estradiol, Adult Premenopausal Female, Serum or Plasma

ARUP #: 0070045

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Estimate ovarian reserve

Test name: Semen Analysis % Abnormal

ARUP #:

Methodology:

Use:

Determine if etiology of infertility is male related

Cornerstone evaluation of male infertility

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

Test name: Y Chromosome Microdeletion

ARUP #: 2001778

Methodology: Polymerase Chain Reaction/Electrophoresis

Use:

Determine etiology of azoospermia or severe oligospermia

Test name: Chromosome Analysis, Peripheral Blood

ARUP #: 2002289

Methodology: Giemsa-Band Analysis

Use:

Diagnose Klinefelter syndrome

Detect structural abnormalities of the Y chromosome associated with male infertility

Test name: Cystic Fibrosis (CFTR) Sequencing

ARUP #: 0051110

Methodology: Polymerase Chain Reaction/Scanning/Sequencing

Use:

Screen for cystic fibrosis mutations in males with congenital bilateral absence of the vas deferens

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Rule out infection

Test name: Gonorrhea Culture

ARUP #: 0060110

Methodology: Standard reference procedures for N. gonorrhoeae culture and identification

Use:

Rule out STI

Test name: Chlamydia trachomatis Culture

ARUP #: 0060850

Methodology: Cell Culture/Immunofluorescence

Use:

Rule out STI

Test name: Urinalysis, Complete

ARUP #: 0020350

Methodology: Reflective Photometry/Microscopic by Yellow IRIS

Use:

Rule out infection

Additional Tests Available

Test name: Testosterone, Females or Children

ARUP #: 0081058

Methodology: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments:

Test name: Testosterone, Free & Total (Includes Sex Hormone Binding Globulin), Females or Children

ARUP #: 0081056

Methodology: Quantitative 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.

Comments:

Test name: Testosterone, Bioavailable & Sex Hormone Binding Globulin (Includes Total Testosterone), Females or Children

ARUP #: 0081057

Methodology: Quantitative 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.

Comments:

Test name: Inhibin B

ARUP #: 0070413

Methodology: Quantitative Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Follicle Stimulating Hormone, Serum

ARUP #: 0070055

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

Test name: Estriol, Serum

ARUP #: 0070051

Methodology: Quantitative Chemiluminescent Immunoassay