Diagnostic Workup for Infertility

1
Diagnostic Workup for Infertility

• Association of Reproductive Health Professionals
• www.arhp.org

2
Learning Objectives

• List the steps for a male infertility workup.
• List the steps for a female infertility workup.
• Determine possible diagnosis based on infertility
  workup results.

3
Basic Services for Infertile Couples
1. Educate on infertility causes and prevention
2. Conduct appropriate diagnostic workup
Stewart GK. 1998
4
Female Factors

• Over age 35
• Irregular menses
• Severe progressive dysmenorrhea or dyspareunia
• Past IUD use
• Past pelvic infection
• Past surgery on an ovary, tube or uterus
• Suspected damage to pelvic organs

Stewart GK. 1998.
5
Female Infertility Diagnostic Categories

• Ovulation disorders
• Uterine disorders
• Tubal disorders
• Peritoneum disorders
• Idiopathic causes

Nelson AL, Marshall JR. 2004.
6
Male Factors

• Chronic medical conditions (neurologic,
  endocrinologic, respiratory, other nongenital)
• Chemotherapeutic drugs
• Surgery
• Infection (UTI, STIs)
• Congenital (undescended testicle)
• Environmental

7
Male Infertility Diagnostic Categories

• Endocrine disorders
• Spermatogenesis abnormalities
• Sperm motility abnormalities
• Sexual dysfunction
• Idiopathic causes

Nelson AL, Marshall JR. 2004.
8
Additional Factors

• Environmental and occupational toxin exposure
• Substance use
• Stress level and psychosocial status

Harkness C. The Infertility Book. 1992.
9
Male Infertility Workup

• Medical history
• Physical exam
• Laboratory evaluation
• Scrotal/rectal ultrasound

Nelson AL, Marshall JR. 2004. Harkness C.
1992. Ho LM, et al. J Androl. 2007. OShea DL, et
al. Fertil Steril. 1993.
10
Male Infertility WorkupMedical History

• Sexually transmitted diseases
• Exposure to toxins
• Substance use (tobacco, alcohol, other drugs)
• Medications
• Surgery
• Radiation
• Physical exertion/heat

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Male Infertility WorkupPhysical Exam

• Examine Penis
• Hypospadias
• Surgical or traumatic scars
• Induration plaques
• Phimosis
• External urethral meatus
• Ulceration or urethral discharge
• Size

more
Rowe PJ, et al. 1993.
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Male Infertility WorkupPhysical Exam (continued)
Examine Testes
Rowe PJ, et al. 1993.
13
Male Fertility AssessmentPhysical Exam

• Examine Epididymis
• Normal epididymis
• Barely palpable
• Regular outline
• Soft consistency

Rowe PJ, et al. 1993.
14
Male Infertility WorkupPhysical Exam

• Examine Epididymis
• Painful nodules
• Epididymitis
• Sperm granulomata
• Caput epididymitis

more
Rowe PJ, et al. 1993.
15
Male Infertility WorkupPhysical Exam (continued)

• Examine Prostate Gland
• Rectal exam
• Identify central groove
• Normal prostate
• Soft
• Regular
• Not painful

more
Rowe PJ, et al. 1993.
16
Male Infertility WorkupPhysical Exam (continued)

• Inguinal Exam
• Inguinal scars
• Presence of pathological enlargement of inguinal
  lymph nodes

Rowe PJ, et al. 1993.
17
Male Infertility Workup Laboratory Evaluation

• Sperm/semen analysis
• Sperm agglutination
• STD screening
• Prostatic fluid expression
• Post-orgasm urine
• Hormone determinations
• Additional tests

more
Rowe PJ, et al. 1993.
18
Male Infertility Workup Laboratory Evaluation
(continued)
Semen Analysis
Harkness C. 1992. Nelson AL, Marshall JR. 2004.
19
Male Fertility AssessmentLaboratory Evaluation
Semen Analysis
Normal volume count lt1520 x 106 mL

• If decreased motility, consider
• Antibody tests, if clumping
• Infection
• Varicocele
• Transrectal sonography
• Referral to andrologist if semen analysis or
  endocrine parameters abnormal

Fourcroy JL. 1996.
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Male Infertility Workup Laboratory Evaluation
Semen Analysis

• Methods
• Done at beginning of workup
• Perform after 23 days of abstinence
• Collect entire ejaculate
• Repeat if results are abnormal

more
Meldrum DR. 1998. Rowe PJ, et al. 1993.
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Male Infertility Workup Laboratory Evaluation
(continued)
Semen Analysis

• WBCs gt1 million leukocytes/mL
• May indicate infection
• 2 samples to determine normal semen
• A few weeks should pass between samples

Meldrum DR. 1998.
22
Sperm/Semen Analysis Results
Rowe PJ, et al. 1993.
23
Male Infertility Workup Laboratory Evaluation

• Sperm Agglutination Assay
• Detects anti-sperm antibodies
• Intrauterine insemination or indirect MAR
• Immunobead most appropriate for screening

Positive if gt10 of motile sperm coated with
antibodies
more
Rowe PJ, et al. 1993.
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Male Infertility Workup Laboratory Evaluation
(continued)

• STI Screening
• Test for past chlamydia infection
• Immunoglobulin G (IgG)/IgM

more
Rowe PJ, et al. 1993.
25
Male Infertility Workup Laboratory Evaluation
(continued)

• Prostatic Fluid Determination
• Obtained during rectal exam
• Examined wet in phase-contrast or clear-field
  illumination
• If not obtained, use first 10 mL of urine

Abnormal gt5 WBCs/HPF
more
Rowe PJ, et al. 1993.
26
Male Infertility Workup Laboratory Evaluation
(continued)

• Post-orgasm Urine
• Determine retrograde ejaculation
• Urine voided after ejaculation

Cloudy appearance of urine strongly supports
diagnosis of retrograde ejaculation
more
Rowe PJ, et al. 1993.
27
Male Infertility Workup Laboratory Evaluation
(continued)
Hormone Determinations
more
Rowe PJ, et al. 1993.
28
Male Infertility Workup Laboratory Evaluation
(continued)

• Hormone Determinations
• Total or free testosterone, FSH
• Cystic fibrosis testing
• If further endocrine evaluation is needed
• LH
• Prolactin
• Estradiol
• Thyroid profile

Fourcroy JL. 1996.
29
Male Fertility Assessment Laboratory Evaluation

• Additional Tests
• Scrotal thermography
• Doppler ultrasonography
• Imaging the hypothalamo-pituitary region
• Testicular biopsy

Rowe PJ, et al. 1993.
30
Male Infertility Workup Laboratory Evaluation

• Additional Tests
• Fructose test
• Vasography
• Testicular biopsy
• Endocrine lab testing
• Hemizona assay

Nelson AL, Marshall JR. 2004. Harkness C.
1992. Ho LM, et al. J Androl. 2007. OShea DL, et
al. Fertil Steril. 1993.
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Duration of Male Infertility
Rowe PJ, et al. 1993.
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Assess Expectations for Male Infertility
Treatment
What treatments were previously recommended?
Were they followed correctly?
What results were obtained?
Rowe PJ, et al. 1993.
33
Female Infertility Workup

• Medical history and physical exam
• Laboratory evaluation, including
• Ovulation/endocrine profile
• Serum progesterone
• TB test
• Hormone levels
• Biopsy and imaging tests

• LH urine
• BBT
• PCT

Nelson AL, Marshall JR. 2004. Harkness C. 1992.
34
Female Infertility WorkupMenstrual History

• Age at menarche
• Menstrual cycle details
• Cycle length, days of menstruation
• Amount of menstrual flow, changes in flow
• Dysmenorrhea
• Moliminal symptoms
• First day of last menstrual period
• Menopausal symptoms

more
Rowe PJ, et al. 1993.
35
Female Infertility WorkupMenstrual History
(continued)
Rowe PJ, et al. 1993.
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Female Infertility Workup Physical Exam

• Body mass index (BMI) kg/m2
• Weight change gt10 within past year
• Blood pressure
• Body shape and stature
• Abdominal scars
• Abnormalities in body systems
• Assessment of hirsutism

more
Rowe PJ, et al. 1993. Franks S. Medicine. 2005.
37
Female Infertility Workup Physical Exam
(continued)

• Assess secondary sex characteristics
• Record Tanner stage for women not mature
• Examine nipple discharge microscopically

Rowe PJ, et al. 1993.
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Female Infertility Workup Pelvic Exam

• External genitalia
• Inflammation
• Clitoral enlargement
• Intact hymen
• Pubic hair distribution

more
Rowe PJ, et al. 1993.
39
Female Infertility Workup Pelvic Exam
(continued)
Rowe PJ, et al. 1993.
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Female Infertility Workup Laboratory Evaluation
more
Rowe PJ, et al. 1993.
41
Female Infertility Workup Laboratory Evaluation
(continued)

• Ovulation and Endocrine Profile
• Prolactin estimation
• Thyroid function tests
• Serum or plasma estrogen estimation
• Plasma FSH
• Progestin withdrawal test

more
Rowe PJ, et al. 1993.
42
Female Infertility Workup Laboratory Evaluation
(continued)

• Serum Progesterone
• Assess whether ovulation is occurring
• Blood test between days 2024 of menstrual cycle
  for 28-day cycle

Mid-luteal progesterone level gt5 ng/mL indicates
ovulatory activity
more
Meldrum DR. 1998.
43
Female Infertility Workup Laboratory Evaluation
(continued)

• Pelvic Tuberculosis
• If suspected, premenstrual endometrial biopsy or
  menstrual fluid must be cultured by guinea pig
  inoculation or microbiological culture

more
Rowe PJ, et al. 1993.
44
Female Infertility Workup Laboratory Evaluation
(continued)

• Hormone Levels
• FSH determined early in menstrual cycle can be
  significant indicator of ovarian age
• Serum FSH
• Serum estradiol

Inhibin b Low day 3 values reflect increased
ovarian aging
more...
Rowe PJ, et al. 1993.
45
Female Infertility Workup Laboratory Evaluation
(continued)

• LH Urine Test
• Predict ovulation by detecting LH levels above a
  certain threshold
• Home test available OTC
• Most test kits can detect urinary LH levels as
  low as 2040 IU/L

more
Levine DL. 2004.
46
Female Infertility Workup Laboratory Evaluation
(continued)

• Basal Body Temperature Charting
• Indirect measure of ovulation based on biphasic
  pattern of progesterone secretion
• Measure of womans temperature upon awakening
  before ANY activity
• BBT charts cannot predict fertile days

Jennings VH, et al. 1998.
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Female Infertility WorkupBasal Body Temperature
Jennings VH, et al. 1998.
48
Female Infertility Workup Laboratory Evaluation

• Postcoital Test
• No longer widely recommended
• Assess number and motility of spermatozoa that
  have entered cervical canal
• Collect endocervical mucus via pelvic exam 212
  hours after intercourse, usually in morning
• Microscopic exam of mucus

Male Infertility Best Practice Policy Committee.
2001. Meldrum DR. 1998. Nelson AL, et al. 2004.
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Female Infertility WorkupPostcoital Test
more
Male Infertility Best Practice Policy Committee.
2001. Meldrum DR. 1998.
50
Female Infertility WorkupPostcoital Test
(continued)

• Spinnbarkeit
• Assess quality of cervical mucus
• Can be used for charting
• Schedule test near expected day of ovulation
• pH paper is put in contact with cervical mucus
  and lifted vertically
• Mucus should thread gt6 cm
• pH should be 6.5

more
Meldrum DR. 1998.
51
Female Infertility WorkupPostcoital Test
(continued)

• Ferning
• Assess when ovulation
• is occurring
• Dried cervical mucus
  examined microscopically
• Pattern resembling fern leaves should be apparent
  near ovulation

Meldrum DR. 1998.
52
Female Infertility Workup Biopsy

• Endometrial Biopsy
• Assess whether uterus can sustain a pregnancy
• Usually performed close to menstruation
• Small plastic catheter inserted through cervical
  canal, piece of endometrial lining removed
• Biopsy should be examined microscopically and
  reveal a postovulatory histologic pattern

Meldrum DR. 1998.
53
Female Infertility WorkupLaparoscopy

• Assess exterior of uterus, tubes and ovaries
• Scope inserted through umbilical incision
• Endometriosis, tubal disease, pelvic adhesions
  may be seen

Harkness C. The Infertility Book. 1992.
54
Female Infertility WorkupImaging Tests

• Sonohysterogram
• Evaluate uterine cavity
• Saline injected through cervix during
  transvaginal ultrasound
• Fibroids, polyps, or adhesions may be seen

more
Harkness C. The Infertility Book. 1992.
55
Female Infertility WorkupImaging Tests
(continued)

• Hysteroscopy
• Evaluate interior surface of uterus
• Scope inserted through cervical os
• Fibroids, adhesions, or polyps may be noted

Harkness C. The Infertility Book. 1992.
56
Assess Female Infertility Treatment History
Expectations

• Obtain records of past infertility treatments, if
  any
• Assess expectations for infertility treatment

Rowe PJ, et al. 1993.
57
Female Diagnoses

• Endometriosis
• Hyperprolactinemia
• Absence of GnRH
• Luteal Phase Defect
• Polycystic Ovarian Disease
• Premature Ovarian Failure
• Post-Pill Amenorrhea

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Endometriosis Definition

• Growth of endometrial cells outside uterus
• Most commonly found
• On ovaries or tubes
• On exterior of uterus
• On bowel
• On bladder
• Within abdominal cavity

Jennings VH, et al. 1998.
59
Endometriosis Prevalence
3040
1525
of all female surgical patients have endometriosis
of women with endometriosis experience fertility
problems
of infertile women are diagnosed with
endometriosis
Jennings VH, et al. 1998.
60
Endometriosis Etiology
Blood and endometrial cells back up through
uterus and tubes and implant or attach to other
sites
Sampson JA. 1927. Jennings VH, et al. 1998.
61
Endometriosis Presentation

• May be asymptomatic
• Endometrial implants respond to hormone level
  fluctuation
• Similar to normal endometrial lining
• May bleed during menstruation
• Endometriomas sometimes form
• Usually reaches maximum severity in 30s40s

more
Jennings VH, et al. 1998.
62
Endometriosis Presentation (continued)

• Pain throughout cycle, with menses or intercourse
• Lower abdominal cramps
• Heavy and/or irregular periods
• Rectal pain with defecation
• Urinary discomfort
• Infertility

more
Jennings VH, et al. 1998.
63
Endometriosis Presentation (continued)

• American Fertility Society Stages

Minimal, mild signs, usually no ovarian or tubal
disease

Moderate disease
Severe implants, cysts, and/or adhesions
Jennings VH, et al. 1998.
64
Hyperprolactinemia
Jennings VH, et al. 1998. Peak MM, et al. Sem
Reprod Med. 2002
65
Hyperprolactinemia Presentation

• Galactorrhea
• Amenorrhea
• Block or impair ovulation
• Luteal phase defect
• Decreased vaginal secretions
• Prolactin above 020 ng/mL

Jennings VH, et al. 1998.
66
Absence of GnRH

• GnRH triggers release of LH and FSH
• Hypothalamus may stop producing GnRH due to
  stress
• Treatment is FSH injections

Jennings VH, et al. 1998.
67
Luteal Phase Defect

• Defect occurs if duration 9 days or inadequate
  progesterone is secreted
• Uterine lining is not able to support
  implantation or gestation of embryo
• Significance is unclear and controversial

Luteal phase Last 1014 days of menstrual cycle
Jennings VH, et al. 1998. Bukulmez O, et al.
Obstet Gynecol Clin N Am. 2004
68
Luteal Phase Defect Diagnosis

• LPD is poorly characterized no definite
  consensus in diagnosis
• Serum progesterone
• Endometrial biopsy

Nelson AL, et al. 2004. Bukulmez O, et al.
Obstet Gynecol Clin N Am. 2004.
69
Polycystic Ovarian Disease

• Prevalence/incidence
• 14 of all women
• 50 of women with secondary amenorrhea
• Etiology
• Genetic defect
• Associated with insulin resistance

Jennings VH, et al. 1998.
70
Polycystic Ovarian Disease Presentation

• History of irregular menstrual cycles
• Hirsutism on the face, breasts, abdomen
• Infertility
• Obesity
• Enlarged or multicystic ovaries
• Elevated androgen levels

Jennings VH, et al. 1998.
71
Premature Ovarian Failure

• Ovaries stop releasing eggs and producing
  hormones before natural menopause
• Occurs in 10 of women with ovulation problems
  associated with infertility
• Irreversible

Jennings VH, et al. 1998.
72
Premature Ovarian Failure Etiology

• Decreased numbers of oocytes
• Destruction of oocytes
• Acceleration of natural disintegration process
• Radiation or chemotherapy
• Autoimmune response
• Some chromosomal abnormalities
• Genetic tendency
• Idiopathic

Jennings VH, et al. 1998.
73
Post-Pill Amenorrhea
Jennings VH, et al. 1998.