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Caitlin Dunne, MD, FRCSC

Infertility: Testing and diagnosis


for the community physician
The workup for couples who fail to conceive should include
confirmation that ovulation is occurring, measurement of hormone
levels, hysterosalpingography, and semen analysis.

I
ABSTRACT: Infertility is a condition levels on day 3 of the menstrual cy- nfertility is defined as the failure
commonly encountered by family cle. Additional ovarian reserve tests to achieve a pregnancy after 12
physicians in the community. Timely such as anti-Müllerian hormone as- months of unprotected intercourse.
diagnosis and treatment of infertility say and/or antral follicle count (done It is a prevalent condition that affects
can help to mitigate the clinical and by ultrasound in a fertility clinic) can about 15% of couples1 and is com-
emotional consequences for the pa- improve sensitivity, specificity, and monly encountered by family physi-
tient and her partner. Investigations convenience. Uterine-tubal evalua- cians in the community. The majority
for infertility should be initiated af- tion may be undertaken with hystero- of couples conceive within the first
ter a year of trying without pregnan- salpingography while hysteroscopy 3 months of trying, after which time
cy, although a community physician or sonohysterography can be used to the chances of pregnancy decline sub-
would be advised to order testing further investigate the endometrial stantially.1 After 1 year, 85% of cou-
before a year of trying in four com- cavity as needed. Semen analysis ples will have achieved a pregnancy,
mon clinical situations: female age is a fundamental part of the workup while after another year only an ad-
over 35 years, presence of oligomen- because the male factor accounts ditional 5% to 8% of couples will be-
orrhea, presence of risk factors for for approximately 35% of infertility. come pregnant.2
tubal disease, and suspicion of male Infertility investigations should start Peak fecundability occurs during
factor infertility. Standard investiga- after 6 months of trying for women the fertile window, which encom-
tions include ovulation testing such over 35 years, and for women over passes the 6 days up to and including
as cycle tracking, use of ovulation 40 years investigations should be the day of ovulation.1 In a study of
predictor kits, basal body tempera- initiated immediately. Consultation 221 couples, similar pregnancy rates
ture charting, and serum progester- with a gynecologist or fertility spe- were achieved with daily intercourse
one measurement. Ovarian reserve cialist is covered by provincial health (37%) and intercourse every other day
testing should be undertaken to insurance and should be considered (33%).1 When frequency of sexual
assess the monthly cohort of hor- for couples with abnormal test re-
mone-responsive (pre-antral and sults and for couples who fail to con- Dr Dunne is a co-director at the Pacific Cen-
antral) follicles. The most common ceive despite normal test results. tre for Reproductive Medicine and a clini-
endocrine ovarian test involves mea- cal associate professor at the University
suring follicle-stimulating hormone of British Columbia. She is certified by the
Royal College of Physicians and Surgeons
in both obstetrics and gynecology and in
This article has been peer reviewed. reproductive endocrinology and infertility.

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Infertility: Testing and diagnosis for the community physician

intercourse was reduced to weekly, Detecting ovulation steroid of the corpus luteum: proges-
the pregnancy rate fell to 15%.3 Preg- The surest sign of ovulation is a regu- terone.6 Peak production of progester-
nancies were recorded with sperm as lar menstrual cycle of 21 to 35 days. one is achieved approximately 8 days
old as 3 days, although the highest However, many women choose ad- after ovulation; at this moment the CL
chances of conception were seen with junctive methods to help them detect is one of the most vascular areas of the
intercourse 2 days before ovulation ovulation in order to better predict body.6 The luteal phase usually lasts
and on the day of ovulation itself.1,3 the most fertile time of each month. 14 days from the time of the LH surge.
Sperm has been found to survive for Numerous devices and products are Therefore, unless the CL receives on-
up to 7 days in the cervical mucus and available for detecting ovulation. going stimulation in the form of beta-
to retain the ability to fertilize a human However, if a patient finds the process human chorionic gonadotropin from
egg in vitro after 5 days.4,5 Following stressful she should be reassured that a pregnancy, progesterone production
ceases and menses ensues. The calen-
dar method assumes that if you count
backwards 14 days from the first day
of menses you can estimate the date
of ovulation in retrospect and use this
The surest sign of ovulation is a regular information to predict future cycles.
Some smart phone apps allow a wom-
menstrual cycle of 21 to 35 days. an to record her menses and then use
this information to predict her fertile
window using a personalized monthly
average cycle length.

Use of ovulation predictor kits


ovulation, an egg may be ready for ovulation tracking is not a require- Ovulation predictor kits (OPKs)
fertilization within 20 minutes and re- ment for conceiving and be directed available from pharmacies and online
mains usable for 12 to 24 hours.6 In the to simply have regular intercourse can be used to detect a high amount of
fertility clinic, we often tell patients around mid-cycle. luteinizing hormone in a urine sam-
that “The sperm should be waiting for ple. Follicle rupture occurs 34 to 36
the egg.” A period of abstinence lon- Cycle tracking hours after the onset of the LH surge
ger than 5 to 10 days can have detri- Cycle tracking, otherwise known as at mid-cycle and LH is generally de-
mental effects on sperm motility and the calendar method, is one of the old- tectable in the urine for most of this
concentration.7 Conversely, normal est ways to determine when ovulation time.9 Patients are advised to test mor-
sperm counts can be maintained even is likely to occur. A review of the nor- ning urine, which is the most concen-
with daily ejaculation.7 Patients can mal physiology of the corpus luteum trated. The LH surge is responsible
therefore be advised that intercourse (CL) permits a better understanding for maturation of the oocyte through
every day or every other day during of this method. resumption of meiosis (from prophase
the late follicular phase will optimize The granulosa cells of a dominant I to metaphase II) and for release of
their chances of conceiving. Coital follicle—the cells responsible for the oocyte from the dominant fol-
position does not affect the chances making estradiol in response to fol- licle.6 Digital ovulation kits purport
of conceiving and women can be safe- licle-stimulating hormone (FSH) in to have increased accuracy by adding
ly reassured that they do not need to the follicular phase—undergo several daily detection of a urinary metabol-
remain supine for any length of time important changes around the time of ite of estrogen, estrone-3-glucuronide
after intercourse.8 Sperm have been ovulation. First, they acquire luteiniz- (E3G). Some brands use a smiley face
found within the cervical canal within ing hormone (LH) receptors in the late to indicate when E3G levels are high
seconds and in the fallopian tube with- follicular phase to enable them to re- (correlating with a growing dominant
in minutes of ejaculation.8 Thereafter, spond to the mid-cycle LH surge and follicle) to identify the fertile win-
the cervix may serve as a reservoir for ovulate. Second, they become vascu- dow leading up to the LH surge and
sperm and fertilization will remain larized and therefore capable of trans- ovulation.
possible in the following days. forming cholesterol into the principal

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Infertility: Testing and diagnosis for the community physician

Basal body temperature charting hysterosalpingography, and semen Box. Workup for infertility
Basal body temperature (BBT) chart- analysis ( Box ).
ing requires that a woman measure It is generally recommended that When to investigate by female age:
her temperature orally each morning investigations for infertility be initi- • After 1 year for patients < 35 years.
before rising and before eating or ated after a year of trying without a • After 6 months for patients 35–40 years.
exercising. The thermometer should pregnancy. There are, however, four • Immediately for patients > 40 years.
be capable of detecting 0.1 °C in- common clinical situations where a
Clinical factors warranting earlier
crements. Daily temperature can be community physician would be ad- investigation:
charted on a preprinted graph (many vised to order testing before a year • Female age > 35 years.
are available online) or using a smart of trying: female age over 35 years, • Oligomenorrhea.
phone app. A biphasic monthly tem- presence of oligomenorrhea, presence • Tubal risk factors.
perature pattern indicates ovulation. of risk factors for tubal disease, and • Male infertility risk factors.
Typically, a rise in body temperature suspicion of male factor infertility.
Most common causes of infertility:
of 0.5 °C can be seen after ovula- Advancing female age is becom-
• Male factor.
tion owing to the production of pro- ing an increasingly prevalent cause of
• Ovulatory dysfunction.
gesterone. Although this rise in BBT infertility. British Columbia has the
• Tubal/pelvic disease.
means a woman’s most fertile days highest age of first birth in Canada at
• Advanced female age.
have passed, she can use this infor- 30.5 years versus 30.3 years in On-
mation to predict ovulation in future tario.11 Over the past 3 decades the in- Standard investigations:
cycles. Around the time of ovula- dustrialized world has seen a dramatic • Ovulation confirmation (serum
progesterone > 10 nmol/L).
tion a woman may also observe egg increase in the age of first birth.12,13
• Cycle day 3 follicle-stimulating hormone
white cervical mucus that thickens According to Statistics Canada, 2010 (< 7–10 IU/L) + estradiol (< 200 pmol/L).
and turns yellow after progesterone marked the first time in our history • Hysterosalpingography.
is produced. In mid-cycle some wo­ that more women in their 30s were • Semen analysis.
men experience mittelschmerz, one- having children than women in their
sided lower abdominal pain associ- 20s.14 In 2011, there were 52.3 babies Additional ovarian reserve testing with
anti-Müllerian hormone (AMH) assay:
ated with ovulation. born per 1000 women age 35 to 39, • AMH reported in pmol/L in Canada and
compared to 45.7 per 1000 women ng/mL in the US.
Serum progesterone age 20 to 24.15 In BC, the percentage • Testing can be done on any day of the
measurement of live births to women age 35 years cycle.
In the mid-luteal phase (day 21 to 23 and older rose from 11% in 1990 to • Patients must pay privately ($70).
of a typical cycle) a serum progester- 23% in 2011, while the percentage
one level greater than 10 nmol/L is of live births to women age 20 to 34
evidence of ovulation. Because pro- fell from 83% to 74% over the same
gesterone is released in response to period.16 By far the most common marginally higher for women age 30
pulsatile stimulation by LH, which reason women reported for not pursu- to 34 at 8% to 21%. By age 35 to 39
in turn is influenced by progesterone ing childbearing earlier was lack of a the rate is 17% to 28%, and over age
exposure at the level of the hypothal- partner.13 40 the rate is 34% to 52%.6 According
amus, values can fluctuate throughout The consequences of delaying to a computer simulation model, 32 is
the luteal phase.6,10 Patients are thus childbearing are increasing rates of the maximum age at which couples
encouraged not to dwell on the abso- infertility, embryo aneuploidy, and should start trying to conceive in or-
lute value of a progesterone measure- miscarriage. These are largely at- der to have a 90% chance of having a
ment as long as it is above 10 nmol/L. tributed to aging oocytes with failing one-child family; for a two-child fam-
meiotic spindles and other ooplasm ily the maximum age is 27; and for a
Investigations for infertility deficiencies such as mitochondrial three-child family the maximum age
In addition to confirming ovula- dysfunction. Oocyte aging and the re- is 23.17 For women age 35 to 40, fer-
tion, the basic workup for infertil- sulting chromosomal errors explains tility investigations are indicated af-
ity includes ovarian reserve testing why miscarriage rates in natural preg- ter 6 months of trying and for women
with a follicle-stimulating hormone nancies for women younger than age over 40 years they should be initiated
test, uterine-tubal evaluation with 30 are only 7% to 15% and become immediately.1

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Infertility: Testing and diagnosis for the community physician

Oligomenorrhea warrants early ovarian aging over 40 years ago.21 As was initially described in the 1940s
investigation for infertility because it follicular growth progresses in the regarding its role in sexual differen-
is almost always the result of anovu- early menstrual cycle, production of tiation of the male embryo.25 Spe-
lation. If a woman’s intermenstrual estradiol and inhibin B results in a cifically, AMH production by testis
interval is greater than 35 to 40 days, negative feedback loop with the pitu- Sertoli cells in the late first trimester
she may be ovulating infrequently, itary, and FSH secretion declines.6 For was shown to result in regression of
unpredictably, or not at all. The most this reason, it is customary to avoid the Müllerian ducts, while persistence
common causes of oligomenorrhea falsely reassuring results when mea- of the Wolffian ducts was shown to re-
are polycystic ovary syndrome, peri- suring day 3 FSH by checking that sult in formation of the internal male
menopause, endocrine disturbances the estradiol level is low (less than structures (epididymis, seminal ves-
such as thyroid disease, and endo- 200 pmol/L, approximately) and FSH icles, and vas deferens).6 In 2002 it
metrial pathology such as polyps, fi- is not being suppressed. At meno- was discovered that AMH is closely
broids, or hyperplasia. pause, when the follicular pool is de- correlated with the number of oocytes
pleted, FSH is no longer suppressed retrieved during an IVF cycle.26 This
Ovarian reserve testing by estradiol and inhibin B and there- led to a huge resurgence of interest in
Ovarian reserve testing aims to esti- fore remains indefinitely elevated. the hormone for assessing women’s
mate the number of oocytes a woman When FSH is high (above 20 IU/L) reproductive physiology. Although
has remaining. It is more accurately it is a reliable indicator of severely AMH is a functional ovarian reserve
termed functional ovarian reserve diminished ovarian reserve or peri- test, it represents a very accurate as-
testing because we cannot actually menopause. A day 3 FSH level in the sessment of a woman’s remaining egg
count the number of nongrowing normal range (less than 10 to 15 IU/L) number.20
primordial follicles in vivo.18 There- is not specific. While some research- A blood sample is required for an
fore, contemporary ovarian reserve ers have reported on FSH thresholds, AMH assay, and in BC this test is not
tests assess the monthly cohort of there is no level of FSH that can be covered by provincial health insur-
hormone-responsive (pre-antral and considered definitively reassuring ance. The cost per assay is typically
antral) follicles to obtain a more ac- for confirming fertility potential. In $70, which is paid to the collecting
curate reflection of the true ovarian a study of 3519 subfertile women, outpatient laboratory. AMH can be
reserve.19,20 FSH levels above 8 IU/L were asso- measured on any day of the menstrual
Female age is still one of the ciated with a reduced probability of cycle because it is only produced by
best predictors of oocyte quality and spontaneous pregnancy in the next 12 the pre-antral and antral follicles, not
quantity. A female attains her life- months (HR 0.93 per IU/L).22 In cy- the dominant follicle.27 Some cycle-
time maximum of oocytes (6 to 7 mil- cles of in vitro fertilization (IVF), the to-cycle variability of AMH does oc-
lion) at around 20 weeks gestational live birth rate was maximal when the cur, but it is not significant enough to
age in utero.6 By the time she is born FSH level was less than 7 IU/L at all warrant repeated measurement.28 One
that number has already dropped to 1 ages, and the live birth rate was below study found that AMH was 19% low-
million and by the time she reaches 2% when the FSH level was above 18 er in users of the oral contraceptive
puberty it is less than half that.18 Oo- IU/L.23 Measuring FSH can be incon- pill compared with nonusers.29 Other
cyte number declines throughout life, venient for patients since levels must patient characteristics and lifestyle
dropping more rapidly after age 35 be obtained on cycle days 2 to 4 and factors associated with lower AMH
until the menopause threshold, when are prone to intercycle fluctuations. levels include pregnancy, African-
approximately 1000 oocytes remain.18 For this reason, offering additional American and Hispanic ethnicity, and
Follicle-stimulating hormone ovarian reserve tests such as anti- obesity.30-32 Interestingly, smoking
measured on day 3 of the menstrual Müllerian hormone (AMH) assay has been consistently associated with
cycle is the most common endocrine or antral follicle count (done by ul- earlier menopause but not with low-
ovarian test. FSH is a gonadotropin trasound in a fertility clinic) can im- er AMH values.33,34 Research studies
produced by the anterior pituitary and prove sensitivity, specificity, and have incorporated AMH to improve
it acts on granulosa cells in women to convenience. menopause forecasting but the wide
stimulate folliculogenesis and estro- Anti-Müllerian hormone has confidence intervals and marked vari-
gen production.6 Elevations in FSH been called the “holy grail” of ovar- ation between women make it diffi-
were first described as a marker of ian reserve testing.24 The hormone cult to use clinically.35 The principal

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Infertility: Testing and diagnosis for the community physician

utility of AMH is in assessing ovar- 10 days). If the patient has risk fac- times, however, it is not commonly
ian reserve and predicting a woman’s tors for postprocedure infection such performed for tubal assessment with-
response to controlled ovarian stimu- as hydrosalpinx or previous pelvic out other indications for surgery.
lation for an IVF cycle. AMH mea- inflammatory disease, then antibiotic
surement has also been used to record prophylaxis is recommended (e.g., Semen analysis
ovarian reserve before and after treat- 100 mg doxycycline PO, twice daily Semen analysis is a fundamental part
ments known to damage the ovary, for 3 to 5 days, beginning the day be- of the workup because the male factor
such as chemotherapy, radiation, and fore the procedure ).37 HSG is a good accounts for at least 35% of infertil-
ovarian surgery. test for ruling out tubal pathology ity.6 The process of spermatogenesis
The normal values of AMH are such as obstruction or hydosalpinx. takes approximately 70 days and con-
highly age-specific and require care- One meta-analysis reported 65% tinues throughout a man’s lifetime, al-
ful interpretation. It is also impor- sensitivity and 83% specificity for lowing many men to maintain fertility
tant to note that Canadian labs report tubal obstruction. 38 HSG is less in perpetuity.6 Once a spermatozoon
AMH in pmol/L, which can be mul- specific for endometrial pathology is deposited in the vagina, it must sep-
tiplied by 0.14 for conversion to the such as polyps, submucous fibroids, arate itself from the seminal fluid (a
American units of ng/mL. Although and adhesions. Diagnostic tests in product of the seminal vesicles and
there is no universal definition of high the form of hysteroscopy or sono- prostate gland) and swim through the
AMH, a level above 21.0 pmol/L (3.0 hysterography can be done to further cervical mucus and endometrial cav-
ng/mL) is considered by many as a investigate the endometrial cavity ity to wait for the oocyte in the fallop-
risk factor for hyper-response to IVF as needed. When a hysterosalpin- ian tube. A complex set of activities
stimulation.36 There is no upper level gogram suggests bicornuate uterine in the sperm is required for successful
of AMH that is diagnostic of poly- configuration, imaging of the uterine fertilization, including capacitation
cystic ovary syndrome. AMH levels corpus must be done to differentiate and the acrosome reaction, which al-
below 8.0 pmol/L (0.7 to 1.1 ng/mL) between septate and bicornuate Mül- low for penetration of the cumulus
are considered low and can be a mark- lerian anomalies. This can be done oophorus and zona pellucida (egg
er for poor egg yield during the IVF with 3D ultrasound, magnetic reson- shell).6 Once the sperm head fuses
process.36 ance imaging, or concurrent hystero­ with the oolemma it will undergo
scopy with laparoscopy. Some studies nuclear decondensation to form the
Uterine-tubal evaluation have reported an increase in spontan- male pronucleus and eventually fuse
Estimates suggest that tubal and pel- eous pregnancy rates following HSG with the female pronucleus to create
vic disease cause 35% of infertility.6 with water-based contrast medium,39 an embryo.6
In BC the most readily available test although historically this benefit has An optimal sample for semen
for tubal patency is hysterosalpingog- been attributed to oil-based contrast analysis is obtained after 2 to 5
raphy (HSG), which involves trans­ HSG.40 A recent study followed over days of abstinence and processed
cervical instillation of radiopaque 1000 infertile women randomly as- for analysis after 15 to 30 minutes
fluid and use of fluoroscopy to visual- signed to undergo HSG with water- of observed liquefaction. The nor-
ize the internal contour of the uterus based or oil-based contrast.41 There mal values for semen parameters in
and the spill of fluid through the fal- were significantly more live births the current World Health Organiza-
lopian tubes into the pelvis. HSG is in the oil-based group (39% versus tion (WHO) laboratory manual (5th
generally scheduled in the follicu- 28%, OR 1.38, 95% CI 1.17–1.64). edition) were obtained from a retro-
lar phase to avoid interfering with a The underlying mechanism for this spective examination of fertile men
pregnancy. Many facilities require the possible benefit may involve dislodg- whose partners conceived within 12
patient to phone for an appointment ing of mucus plugs and endometrial months.42 The lowest fifth percentile
when a menstrual period begins and or immunomodulatory effects.41 In was used as a cutoff. A semen analysis
to perform a pregnancy test the day BC hysterosalpingography is usually uses one-sided lower limits for refer-
before HSG. For women who do not performed with water-based contrast. ence: volume (1.5 mL), concentration
have a regular menstrual cycle, ex- The gold standard for tubal and pel- (15 M/mL), total sperm count (39 M),
ogenous progestin can be used to in- vic evaluation is laparoscopy with total motility (40%), progressive mo-
duce a withdrawal bleed (e.g., 10 mg chromopertubation. Because of the tility (32%), vitality (58%), and mor-
medroxyprogesterone acetate PO for inherent risks of surgery and long wait phology (4%).43 For fertility, the chief

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Infertility: Testing and diagnosis for the community physician

prognostic parameters are sperm con- hysterosalpingography, and semen longed storage of human spermatozoa at
centration and motility, with mor- analysis. Measurement of day 3 FSH room temperature or in a refrigerator. Fer-
phology being of lesser importance. should be ordered in conjunction with til Steril 1985;44:254-262.
Sperm concentration can vary sub- measurement of estradiol to confirm 6. Fritz MA, Speroff L. Clinical gynecologic
stantially from sample to sample in appropriate timing. Physicians should endocrinology and infertility. 8th ed. Phile-
both fertile and infertile men.42 When be aware that because FSH is a late delphia: Lippincott Williams & Wilkins;
the concentration is lower than 15 M/ marker of diminished ovarian reserve, 2011.
mL fertility is reduced, while increas- there is no level of FSH considered 7. Levitas E, Lunenfeld E, Weiss N, et al. Re-
es above this level are not consistent- reassuring. AMH is an accurate and lationship between the duration of sexual
ly associated with better pregnancy convenient test, but interpretation is abstinence and semen quality: Analysis of
rates.42 Sperm motility can be affect- highly age-specific. HSG is a useful 9,489 semen samples. Fertil Steril 2005;
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length of time to processing, and ex- be investigated further with hyst- namics of rapid sperm transport through
posure to heat or toxins.42 An abnor- eroscopy with laparoscopy or sono- the female genital tract: Evidence from
mal test result warrants repeat testing, hysterography. Semen analysis is a vaginal sonography of uterine peristalsis
allowing a break of at least 2 to 3 key component of the basic infertil- and hysterosalpingoscintigraphy. Hum
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1000x magnification to consider the by provincial health insurance and levels to ovulation in women and infrahu-
head, mid-piece, and tail according to should be considered for couples with man primates. Am J Obstet Gynecol
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