INFERTILITY - Suggestive of probable ovulation
Definition: inability to conceive after 1 year of unprotected
intercourse of reasonable frequency
Primary infertility: no prior pregnancies
Secondary infertility: infertility following at least one prior
conception
Fecundability: probability of achieving pregnancy in ome
menstrual cycle (normal value in young couples: 20%)
1 month: 20-25% 6 months: 75%
3 months: 75% 1 year: >85%
Fecundity: probability of achieving a live birth in one
menstrual cycle
Hypofertile: those with low fecundability who are eventually
able to conceive without treatment
Sterile: those who never conceive without therapy
Semen analysis: most important step in evaluation of male
infertility
Klinefelter Syndrome (47 XXY): most common chromosomal
disorder associated with testicular dysfunction and male
infertility
Abnormalities in menstrual function: most common cause of
female infertility
EVALUATION FOR SPECIFIC CAUSES OF
INFERTILITY
Categorized into:
A. Ovulation
B. Normal female reproductive tract anatomy
C. Normal semen characteristics
Etiology of Infertility in the Female
A. Ovulatory Dysfunction
- due to abnormalities within the hypothalamus
anterior pituitary, or ovaries
- Hypothalamic disorders
o acquired - due to lifestyle e.g excessive
exercise, eating disorders,or stress
o inherited - dysfunction or improper
migration of the hypothalamic GnRH
neurons e.g idiopathic hypothalamic
hypogonadism (IHH) or in Kallmann
syndrome
- Thyroid disease and hyperprolactinemia: contribute
to menstrual disturbances
*Menstrual Pattern
- Menstrual history: excellent predictor of regular
ovulation
o Mittelschmerz: midcycle pelvic pain
associated with ovulation
o Moliminal symptoms: breast tenderness,
acne, food cravings, and mood changes
- Dysmenorrhea: associated with ovulatory cycles
*severe dysmenorrhea, may suggest endometriosis
*Basal Body Temperature
- requires that a woman’s morning oral temperature be
graphically charted
- biphasic temperature pattern: strongly predictive of
ovulation
o Follicular phase: oral temp usually 97.0° to
98.0°F
o Postovulatory rise in progesterone levels
increases BBT by ~ 0.4° to 0.8°F
- Advantage: inexpensive, useful for a couple first
attempting to conceive
- Disadvantage: insensitive in many women, not
favorable as an infertility diagnostic tool
*Ovulation Predictor Kits
- measures the concentration of urinary LH by
colorimetric assay
- woman should begin testing 2 to 3 days prior to the
predicted LH surge (no clear consensus on optimal
time of testing) and should be performed daily since
LH surge spans only 48 to 50 hours
- ovulation mostly occur the day following the urinary
LH peak (If equivocal results are obtained, the test
can be repeated in 12 hrs)
- Advantage: easy to use and provide clear instructions
regarding interpretation; according to study - 100%
sensitivity, 96% accuracy
*Serum Progesterone
- Ovulation can also be tested by measuring
midluteal phase serum progesterone levels. In a classic 28-
day cycle, serum is obtained on cycle day number 21
following the fi rst day of menstrual bleeding, or 7 days
following
ovulation. Levels during the follicular phase are generally _2
ng/mL. Values above 4 to 6 ng/mL are highly correlated with
ovulation and progesterone production by the corpus luteum
(Guermandi, 2001). Progesterone is secreted as pulses, and
therefore
a single measurement is not indicative of overall production
during the luteal phase. As a result, an absolute threshold for
acceptable progesterone levels has not been clearly established
Nevertheless, Hull and colleagues (1982) have reported that a
midluteal progesterone concentration of greater than 9.4
ng/mL
is predictive of higher pregnancy rates than those observed in
patients with progesterone levels less than 10 ng/mL.
Many clinicians choose to empirically treat any patient with
a progesterone level below this value with natural
progesterone.
Although this approach is unlikely to be harmful, the utility
of this management is unproven. Accordingly, the midluteal
progesterone level is best regarded as an excellent measure for
the occurrence of ovulation, but not an absolute indicator of
adequate luteal function.
*Endometrial Biopsy
Adequate progesterone levels are
required for endometrial preparation prior to implantation.
Luteal phase defect (LPD) occurs when suboptimal
progesterone
production results in inadequate endometrial development.
Th us, it was proposed that an endometrial biopsy would
refl ect both corpus luteum function and endometrial response,
and thereby provide more clinically relevant information than
a serum progesterone level alone. Noyes and associates (1975)
described a sequence of histologic events in the endometrium
in the periovulatory, luteal, and early menstrual stages. Th ese
investigators defi ned LPD as a lag in the histologic
appearance
of the endometrium of greater than 2 days relative to the actual
day of the cycle determined retrospectively. Th is discrepancy
in dating is termed an out-of-phase biopsy. Classically, an
endometrial
biopsy is obtained as close to the impending menstrual
cycle as possible based on previous cycle length and more
recently, on the timing of the LH surge.
Unfortunately, the utility of this test is severely hampered
by high intraobserver and interobserver variability (Balasch,
1992; Scott, 1993). Th e estimated frequency of LPD in the
infertile population has ranged widely, but is generally agreed
to be between 5 and 10 percent. Nevertheless, a fi nding of an
out-of-phase biopsy occurs nearly as frequently in fertile as in
infertile women, with a large overlap in incidence between the
two groups (Aksel, 1980; Balasch, 1992; Davis, 1989; Scott,
1993). Th is observation has led many experts to conclude that
LPD may not exist as a clinical entity. Certainly in its current
form, the endometrial biopsy has little predictive value. For all
of these reasons, this test is no longer considered a routine part
of the infertility evaluation.
It is interesting to note that impressive advances are being
made in our understanding of the timing of protein expression
in the endometrial glands and stroma. Potential markers
for uterine receptivity include osteopontin, cytokines
(leukemia
inhibitory factor, colony-stimulating factor-1, and interleukin-
1), cell adhesion molecules (the integrins), and the
L-selectin ligand, which has been proposed to mediate embryo
attachment (Carson, 2002; Kao, 2003; Lessey, 1998). In the
future, endometrial biopsies may again become part of the
diagnostic evaluation if expression patterns of these proteins
prove to be predictive of endometrial receptivity.
*Sonography
- demonstrate the development of a mature antral
follicle and its subsequent collapse during ovulation
- Advantage: excellent approach for supporting the
diagnosis of PCOS
- Disadvantage: time consuming and ovulation can be
missed
B. Female Aging and Ovulatory Dysfunction
- inverse relationship between female age and fertility
- Age-related infertility is most closely linked to the
loss of viable oocytes
o midgestation: ~ 7 million oocytes
o birth:1-2 million
o puberty: ~ 300,000 follicles due to atresia
o onset of menopause: 1000 follicles
-
As a woman ages, risks of genetic abnormalities and
mitochondrial deletions in the remaining oocytes are
substantially increased
These factors result in decreased pregnancy rates and
increased miscarriage rates in both spontaneous and stimulated
cycles.
The overall miscarriage risk in women older than 40 years has
been estimated to be 50 to 75 percent (Maroulis, 1991). For
these reasons, starting at age 35, fertility testing should be
strongly considered after failure to conceive for 1 year, or
perhaps even after six months, in all patients desiring
conception.
Importantly, ovarian reserve can be lost for many reasons
other than chronologic age. As a result, testing should also be
seriously considered in any woman with an unexplained
change
in menstrual cyclicity or a family history of early menopause.
Furthermore, evaluation should be considered in heavy
smokers
or in women with a history of ovarian surgery, chemotherapy,
or pelvic irradiation.
An array of serum and sonographic tests has been developed
to evaluate a patient’s likelihood of conception, and a number
of these are described subsequently. Th e optimal combination
of tests is under ongoing revision. Currently, measurement of
early follicular follicle-stimulating hormone (FSH) and
estradiol
levels is probably the most cost-eff ective approach for the
general practitioner. In general, testing for thyroid disease and
hyperprolactinemia also seems prudent as these disorders may
be associated with ovulatory defects that may be mild and diffi
cult to ascertain by history.
*Follicle-Stimulating Hormone
- simple and sensitive predictor of ovarian reserve w/c
measures FSH levels in early follicular phase
- performed on “cycle day 3” following the onset of
menses (reasonable to test between days 2 and 4)
- ↓ ovarian function  granulosa cells and luteal cells
secrete less inhibin (w/c inhibits FSH)  ↓inhibin 
↑FSH levels in early follicular phase
 Value of 10 mIU/mL: indicates significant loss
of ovarian reserve and should prompt a more
rapid evaluation and more intensive treatment
*Estradiol
- may decrease the incidence of false (-) results of FSH
values alone
- ↑ FSH levels  ↑ stimualtion of ovarian
steroidogenesis  ↑ estrogen levels in older women
early in the cycle
- cycle-day-3 estradiol level of 80 pg/mL is
considered abnormal
! reference levels for estradiol and FSH can vary
between laboratories
*Inhibin B
- additional predictor of ovarian reserve
- measured early in the follicular phase d/t large
fluctuations in serum levels across the cycle
- have not been shown to add substantially to the
information gained from FSH testing, and therefore
this test is falling out of favor
*Antimüllerian Hormone
- most recent to be analyzed as predictor of ovarian
reserve
- AMH is expressed by:
o fetal testes (during male differentiation) -
prevent development of the müllerian
system (f. tube, uterus, and upper vagina)
o granulosa cells of small preantral follicles w/
limited expression in larger follicles
- AMH levels
o may drop prior to observable changes in
FSH or estradiol levels, providing an earlier
marker of waning ovarian function
o may correlate with ovarian primordial
follicle number more strongly than FSH or
inhibin levels
o increased 2-3x in women with PCOS
compared with normally cycling women
* Clomiphene Citrate Challenge Test
- more sensitive indicator of diminished ovarian
reserve than measurement of “unstimulated”
hormone levels
*Clomiphene citrate (Clomid)
o nonsteroidal estrogen-receptor modulator
o exact mechanism is unknown
o believed to block the negative-feedback
inhibition of endogenous estrogens on FSH
secretion
- With the test, a woman takes 100 mg of clomiphene
citrate daily orally on cycle day numbers 5 through 9.
Estradiol and FSH levels are measured on day 3, and
an FSH level is measured on day 10.
o FSH elevations at either time point are
indicative of diminished ovarian reserve.
*Antral Follicle Count
- commonly used in infertility practice as a reliable
predictor for subsequent response to ovulation
induction
- number of small antral follicles reflects the size of the
resting follicular pool (antral follicles bet. 2 - 10 mm
are counted in both ovaries)
o total AFC is usually between 10 and 20 in a
reproductive-aged woman
o <10 predicts poor response to gonadotropin
stimulation
!!Testing Interpretation!!
Abnormal test results from any of the preceding methods
correlate with a poorer prognosis for achieving pregnancy
whatever the woman’s age. Referral to an infertility specialist
is advisable in these patients. Conversely, a normal test does
not negate the impact of a woman’s age on her fertility status.
Th is information may be useful in counseling a couple
regarding prognosis. Poor results in an older woman can
supply an impetus either to attempt donor oocyte IVF or to
pursue alternatives such as adoption. Borderline results in a
younger woman may suggest a need for more intensive
treatment.
c. Tubal and Pelvic Factors
Symptoms such as chronic pelvic pain or dysmenorrhea
may suggest tubal obstruction or pelvic adhesions or both.
Adhesions can prevent normal tubal movement, ovum pickup,
and transport of the fertilized egg into the uterus. A wide
variety of etiologies may contribute to tubal disease, including
pelvic infection, endometriosis, and prior pelvic surgery.
A history of PID is highly suspicious for pelvic adhesions or
damage to the fallopian tubes. Tubal infertility has been
estimated
to follow in 12 percent, 23 percent, and 54 percent of
women following one, two, or three cases of PID, respectively
(Lalos, 1988). Nevertheless, an absent PID history is not
overly
reassuring, as nearly one half of patients who are found to
have
tubal damage have no clinical history of antecedent disease
(Rosenfeld, 1983).
Approximately one third to one fourth of all infertile
women in developed countries are diagnosed with tubal
disease
(Serafi ni, 1989; World Health Organization, 2007). In the
United States, the most common causes of tubal disease are
infection with C trachomatis or N gonorrhoeae (Chap. 3, p.
93).
In contrast, in developing countries, genital tuberculosis may
account for 3 to 5 percent of infertility cases (Aliyu, 2004;
Nezar, 2009). As a result, this diagnosis should be considered
in
immigrant populations from countries with endemic infection.
In these cases, tubal damage and endometrial adhesions are
underlying causes. Genital tuberculosis typically follows
hematogenous
seeding of the reproductive tract from an extragenital
primary infection. Th e likelihood of a return to fertility after
antitubercular treatment is low, and IVF with embryo transfer
remains the most reliable approach (Aliyu, 2004).
Within implants of endometriosis, infl ammation and
chronic bleeding can also lead to fallopian tube obstruction or
development of severe pelvic adhesions. In addition, a history
of ectopic pregnancy, even if treated medically with
methotrexate,
implies the likelihood of signifi cant tubal damage. Residual
adhesions are common after even the most meticulous pelvic
surgery. Th is is particularly true in cases with pelvic infl
ammation
due to blood, infection, or irritation caused by mature
cystic teratoma (dermoid) contents.
Salpingitis isthmica nodosa is an infl ammatory condition of
the fallopian tube, characterized by nodular thickening of its
isthmic portion. Histologically, smooth muscle proliferation
and diverticula of tubal epithelium contribute to this
thickening.
Th is uncommon condition is typically bilateral and
progressive
and leads ultimately to tubal occlusion and infertility
(Saracoglu, 1992). Fertility options include those for proximal
tubal occlusion as discussed in Chapter 20 (p. 540). In
addition,
the risk of ectopic pregnancy is increased with salpingitis
isthmica nodosa.
Testing for tubal patency can be performed by
hysterosalpingography
(HSG) or by chromotubation during laparoscopy.
Chapter 2 (p. 50) contains an additional discussion of
HSG performance. Regarding treatment, fi mbrioplasty may
be considered in cases of distal tubal obstruction without
signifi
cant hydrosalpinx. Attempts may also be made to correct
proximal obstruction with balloon tuboplasty via
hysteroscopy.
However, with the advent of successful pregnancy rates using
IVF, tubal surgery rates are decreasing. All of these options
are
described fully in Chapter 20.
d. Uterine Abnormalities
Congenital Anomalies. Uterine anomalies can be either
inherited or acquired. Common inherited anomalies include
uterine septum, bicornuate uterus, unicornuate uterus, and
uterine didelphys. With the possible exception of a large
uterine
septum, the impact of these anomalies on conception has
been diffi cult to verify, although a subset are clearly
associated
with pregnancy complications. A uterine septum can now
be removed relatively simply and safely with hysteroscopy as
described in Section 42-19 (p. 1174). Most infertility
specialists
will proceed with surgery if this anomaly is identifi ed.
Diethylstilbestrol. In utero exposure to this synthetic estrogen
has been linked to malformations of uterine development in
addition to an increased risk for vaginal adenosis. More
information
on this topic can be found in Chapter 18 (p. 502). Th e classic
uterine appearance is a small, T-shaped uterus. Fortunately,
this problem is seen progressively less frequently in infertility
clinics as this drug is no longer used and most aff ected
women
are leaving reproductive age (Goldberg, 1999).
Acquired Abnormalities. Acquired anomalies include
intrauterine
polyps, leiomyomas, and Asherman syndrome.
Endometrial Polyps. Th ese soft fl eshy growths are
estimated
to be present in 3 to 5 percent of infertile women (Farhi, 1995;
Soares, 2000). Th e prevalence is higher in women with
symptoms,
such as intermenstrual or postcoital bleeding (Chap. 8,
p. 230). Although these complaints typically prompt
hysteroscopic
removal, most data have not clearly demonstrated an
indication for removing polyps in otherwise asymptomatic
women (Ben-Arie, 2004; DeWaay, 2002). Of note, however,
one study has suggested that removal of even small polyps
(under 1 cm) may improve pregnancy rates following
intrauterine
insemination (Perez-Medina, 2005).
Leiomyomas. Th ese benign smooth muscle tumors may also
prevent normal implantation, depending on their size and
location
(Pritts, 2001). Certainly, it is reasonable to assume that
leiomyomas
that obstruct a fallopian tube, distort the uterine cavity,
or fi ll the uterine cavity would be detrimental to implantation.
Th e endometrium overlying these tumors is less vascular and
the
surrounding myometrium exhibits dysfunctional contractility,
both of which may contribute to decreased rates of successful
pregnancy. It seems equally reasonable to postulate that a
subserosal
leiomyoma would not adversely aff ect pregnancy.
Farhi and colleagues (1995) studied the eff ects of uterine
leiomyomas on IVF success rates. In 28 women with a normal
uterine cavity, the pregnancy rate was 30 percent per embryo
transfer. In 18 women with an abnormal cavity, the pregnancy
rate was only 9 percent per transfer. Although this suggests
that
removal of submucous leiomyomas should improve
fecundability,
there are no randomized, prospective trials to confi rm this
conclusion.
Appropriate intervention is even more ambiguous in the
patient with intramural leiomyomas that do not abut the
endometrium
(Stovall, 1998). Th us far, it has not been possible to
develop an algorithm based on number, volume, or location of
these tumors that accurately predicts the need to remove them,
either to improve implantation rates or to decrease pregnancy
complications such as miscarriage, placental abruption, or
preterm
labor. Nevertheless, many experts will consider surgical
removal of a leiomyoma greater than 5 cm or multiple smaller
tumors in this size range. Importantly, surgical benefi ts
should
be weighed against postoperative complications that lower
subsequent
fertility. Th ese include creation of Asherman syndrome
following the removal of large submucosal leiomyomas,
formation
of pelvic adhesions, or the need for cesarean delivery if the
full myometrial thickness is transected.
Asherman Syndrome. Th e presence of intrauterine
adhesions,
also called synechiae, is termed Asherman syndrome. Th is
diagnosis is discussed in detail in Chapter 16 (p. 444).
Asherman
syndrome occurs most frequently in women with a history of
uterine dilation and curettage, particularly in the context of
infection and pregnancy (Schenker, 1996). Th e clinical
history
will often include an acute postsurgical decrease in menstrual
bleeding or even amenorrhea. A woman with an intrauterine
device (IUD) complicated by infection or a woman with
genital tuberculosis is also at high risk for intrauterine
adhesions.
Treatment of Asherman syndrome involves hysteroscopic
lysis of the adhesions as described in Section 42-21 (p. 1178).
Although dilation and curettage has been used, hysteroscopy
provides more precise control with less secondary scarring.
Electrosurgical coagulation is rarely required, as the bands in
most cases are composed of connective tissue with poor blood
supply.
Radiologic and Surgical Approaches for
Evaluation of Pelvic Structures
Th ere are several approaches for evaluating pelvic anatomy:
(1) hysterosalpingography, (2) transvaginal sonography with
or without saline instillation, (3) 3-D transvaginal sonography,
(4) hysteroscopy, (5) laparoscopy, and (6) pelvic imaging by
magnetic resonance (MR) imaging. As shown in Table 19-6,
each has its own advantages and disadvantages.
Hysterosalpingography. Th is radiographic tool can be useful
for evaluating the shape and size of the uterine cavity, in
addition to defi ning tubal status. Hysterosalpingography is
generally performed on cycle day numbers 5 through 10. At
this time, there should be minimal intrauterine clotting that
could block tubal outfl ow or give the false impression of an
intrauterine abnormality. Furthermore, a woman should not
have ovulated and possibly conceived. For this test, iodinated
contrast medium is infused through a catheter placed into the
uterus. Under fl uoroscopy, dye is followed as it fi lls the
uterine
cavity, then the tubal lumen, and fi nally spills out of the tubal
fi mbria into the pelvic cavity (Fig. 19-6).
Tubal Disease. In a large metaanalysis, HSG was
demonstrated
to have 65-percent sensitivity and 83-percent specifi city for
tubal obstruction (Swart, 1995). Tubal contractions,
particularly
cornual spasm, can give the incorrect impression of
proximal fallopian tube obstruction (a false-positive result).
Much less commonly reported is a scenario in which a
falsenegative
result is obtained when the fallopian tube is seen as
patent by HSG, although subsequently it is determined to be
blocked. Many causes of tubal disease aff ect both tubes, and
therefore, unilateral disease is unusual. Unilateral obstruction
with a normal contralateral tube is most likely due to the dye
following the path of least resistance during the HSG
procedure.
However, laparoscopy with chromotubation should be
considered prior to treatment to confi rm a fi nal diagnosis.
Hysterosalpingography is not reliable in detecting peritubal
or pelvic adhesions, although loculations of dye around the
tubes may be suggestive. Th us, HSG is an excellent predictor
of tubal patency, but is less eff ective at predicting normal
tubal
function or the presence of pelvic adhesions. Pregnancy rates
have been reported to be increased following HSG and have
been suggested to result from fl ushing of intratubal debris.
However, these reports followed evaluation with oil-based
dyes
rather than water-based dyes, which are currently preferred.
Uterine Pathology. Hysterosalpingography also provides
analysis of the contour of the intrauterine cavity. A polyp,
leiomyoma,
or adhesion within the cavity will block dye diff usion,
resulting in an intrauterine “defect” in dye opacity on the
radiograph
(Fig. 19-7). Although false positives may be obtained due
to blood clots, mucus plugs, or shearing of the endometrium
during placement of the intrauterine catheter, HSG has been
shown to accurately identify intrauterine pathology. In one
study of more than 300 women in which hysteroscopy was
used
as the gold standard, HSG was determined to be 98-percent
sensitive and 35-percent specifi c, with a positive predictive
value
of 70 percent and a negative predictive value of 8 percent.
Most
misdiagnoses were due to an inability to distinguish polyps
from
submucous leiomyomas. Th is is a minimal problem, as these
patients will undergo further evaluation and treatment in either
case (Preutthipan, 2003; Randolph, 1986). Although other
studies have not provided such impressive results, it is clear
that
HSG is a powerful tool for evaluation of the uterine cavity.
Hysterosalpingography can also defi ne developmental uterine
anomalies (Fig. 19-8). A Y-shaped uterus identifi ed during
HSG may represent either a uterine septum or a bicornuate
uterus. In these cases, the external contour of the uterine
fundus must be evaluated using MR imaging, high-resolution
sonography, 3-dimensional (3-D) sonography, or laparoscopy.
A smooth fundal contour is consistent with a diagnosis of
uterine
septum. Th is is an important distinction, as a septum is
often resected, but a bicornuate uterus is generally not treated.
In general, uterine anomalies do not cause infertility, but may
be associated with miscarriage or later fetal loss, creating a
management dilemma. Accordingly, it may be reasonable to
surgically treat some uterine anomalies in an eff ort to
improve
pregnancy outcome. However, a couple must be carefully
counseled that conception itself is unlikely to be aff ected. A
further discussion of the fertility eff ects of congenital
anomalies
is found in Chapter 18.
Sonography. Transvaginal pelvic sonography may be helpful
in determining uterine anatomy, particularly during the luteal
phase, when the thickened endometrium acts as contrast to the
myometrium. Although 3-D sonography machines are not yet
widely available, their development is advancing the
discriminatory
abilities of sonography (Fig. 19-9).
Th e infusion of saline into the endometrial cavity during
sonography performed in the follicular phase provides another
approach for achieving contrast between the cavity and uterine
walls. Th is procedure has many names including
hysterosonography,
sonohysterography, or saline infusion sonography (SIS).
Details of this procedure are described in Chapter 2 (p. 35).
Saline infusion sonography has been reported to have a
sensitivity
of 75 percent and specifi city of more than 90 percent for
detecting endometrial defects. It has an acceptable positive
predictive
value of 50 percent and an excellent negative predictive
value of 95 percent, which greatly exceeds the negative
predictive
value of HSG (Soares, 2000). Moreover, SIS may be more
sensitive than HSG in determining whether a cavitary defect
is a pedunculated leiomyoma or a polyp (Figs. 8-9 and 8-10,
p. 229). Perhaps more importantly, SIS can help determine
what portion of a submucous leiomyoma is within the cavity,
as only those with less than a 50-percent intramural
component
are approached for hysteroscopic resection.
Th e primary limitation of SIS is that it does not provide
information regarding the fallopian tubes, although rapid loss
of saline into the pelvis is certainly consistent with at least
unilateral patency. Saline infusion sonography is generally
less
painful than HSG and does not require radiation exposure.
Th erefore, it is the preferred method if information about
tubal
patency is not required, such as in patients who are known to
require IVF.
Laparoscopy. Direct inspection provides the most accurate
assessment of pelvic pathology, and laparoscopy is the gold
standard
approach. Chromotubation may be performed, in which
a dilute dye is injected through an acorn cannula placed
against
the cervix or through a balloon catheter positioned within the
uterine cavity (Figs. 42-1.7 and 42-1.8, p. 1102). Tubal spill is
evaluated through the laparoscope (Fig. 19-10). Indigo
carmine
dye is preferable to methylene blue, as the methylene blue
rarely
may induce acute methemoglobinemia, particularly in patients
with glucose-6-phosphate dehydrogenase defi ciency. One 5-
mL
vial of indigo carmine is mixed with 50 to 100 mL of sterile
saline
for injection through the cervical cannula. Laparoscopy allows
both diagnosis and immediate surgical treatment of
abnormalities
such as endometriosis or pelvic adhesions. Laparoscopic
ablation of endometriotic lesions or adhesions may increase
subsequent pregnancy rates (Chap. 10, p. 287).
As laparoscopy is an invasive procedure, it is not advocated
in place of HSG as part of the initial infertility evaluation.
Exceptions include women with a history or symptoms
suggestive
of endometriosis or prior pelvic infl ammation. However,
even in these women, a preliminary HSG may be informative
(De Hondt, 2005).
If laparoscopy is clearly indicated, then hysteroscopy can also
be performed to evaluate the uterine cavity while the patient is
under anesthesia. Moreover, in operative hysteroscopic cases,
laparoscopy can help direct surgery and avoid perforation, for
example, during septal incision.
Laparoscopy also may be considered in patients who fail to
conceive with clomiphene citrate or gonadotropin ovulation
induction. If pelvic disease is found and treated, progression to
IVF may be avoided. With improvements in IVF success rates,
this latter argument is becoming less justifi able, as the cost of
surgery well exceeds the cost of an IVF cycle.
Hysteroscopy. Endoscopic evaluation of the intrauterine
cavity
is the primary method for defi ning intrauterine abnormali ties.
Hysteroscopy can be performed in an offi ce or operating
room. With improved instrumentation, the ability to
concurrently
diagnose and treat abnormalities in the offi ce is increasing.
However, substantially more extensive hysteroscopic surgery
is
possible in the operating room. A fuller discussion of
hysteroscopy
and its indications is found in Section 42-13 (p. 1157).
Cervical Factors
Th e cervical glands secrete mucus that is normally thick and
impervious to sperm and ascending infections. High estrogen
levels at midcycle change the characteristics of this mucus,
and
it becomes thin and stretchy. Estrogen-primed cervical mucus
fi lters out nonsperm components of semen and forms
channels
that help direct sperm into the uterus (Fig. 19-11). Midcycle
mucus also creates a reservoir for sperm. Th is allows ongoing
release during the next 24 to 72 hours and extends the
potential
time for fertilization (Katz, 1997).
Abnormalities in mucus production are most frequently
observed in women who have undergone cryosurgery, cervical
conization, or a loop electrosurgical excision procedure
(LEEP)
for treatment of an abnormal Pap smear. Cervical infection
may
also negatively impact mucus quality, although the data in this
area have been controversial. Implicated agents include C
trachomatis,
N gonorrhoeae, Ureaplasma urealyticum, and Mycoplasma
hominis (Cimino, 1993). Although there may be no advantage
in terms of mucus quality, obtaining cultures for C
trachomatis
and N gonorrhoeae seems prudent to avoid causing ascending
infection during HSG or intrauterine inseminations.
Postcoital Test. Also known as the Sims-Huhner test, this test
can be performed to evaluate cervical mucus (Oei, 1995a,b). A
couple is requested to have intercourse on the day of
ovulation.
Th e woman is seen in the offi ce within a few hours, and a
sample
of the cervical mucus is obtained from the cervical os with
forceps or by aspiration. In the presence of high estrogen
levels,
the mucus should be copious and relatively clear. Mucus
should
be able to be stretched to _5 cm after being placed between
two glass slides. Th ese qualities are summarized by the term
spinnbarkeit. At least fi ve motile sperm per high-power fi eld
should be visible under the microscope, although some
authorities
feel that a single, forward-moving sperm is adequate. Th ere
should be a minimal number of other cell types, such as infl
ammatory
cells. When dried, the mucus should form a ferning
pattern. Th is is crystallization of an increased salt
concentration
in the mucus, which is prompted by increased preovulatory
estrogen levels (see Fig. 19-11A).
Th e most common reason for an abnormal test is improper
timing. If mucus is scanty and thick, often termed hostile,
then sperm motility evaluation is futile, and the test should be
repeated.
Despite the preceding discussion, the utility of the postcoital
test is probably negligible in most circumstances. Th ere is
limited
consensus on the defi nition of a normal test, and the
predictive
value for conception is poor (Oei, 1995b). Moreover,
various approaches to improve an abnormal postcoital test
have
not convincingly increased pregnancy rates. In a prospective,
randomized controlled trial, a normal postcoital test did not
predict increased cumulative pregnancy rates (Oei, 1998
Many infertility specialists recommend literally bypassing
the cervix with intrauterine insemination (IUI) in any woman
with a history of cervical surgery, especially if she has noted a
decrease in midcycle mucus production. Th e remaining utility
of the postcoital test is for couples who will not consider
intrauterine insemination or do not have intrauterine
insemination
readily available. It may also be useful in regions of the
world in which more specifi c testing cannot be obtained, as a
postcoital test will provide basic information regarding mucus
production, appropriate intercourse practices, and presence of
motile sperm.

Sources:
William’s Gynecology 2nd edition
Comprehensive Gynecology 6th edition (Bain, Burton,
McGCavigan)
Harrison’s Internal Medicine 19th edition
Etiology of Infertility in the Male
A. Abnormalities of sperm production
B. Abnormalities of sperm function
C. Obstruction of the ductal outflow tract
Normal Spermatogenesis
Dependent on:
1. High local levels of testosterone
o LH: stimulates production of testosterone
o FSH: increase LH receptors, increases
production of androgen binding protein
2. Testicular volume
o normal: between 15 and 25 mL
o decreased testicular volume is a strong
indicator of abnormal spermatogenesis
3. Genes on the Y chromosome
o genetic abnormalities affects
spermatogenesis
Semen Analysis: core test in evaluation of male fertility status
- assesses the number, morphology and motility of
spermatozoa and also indicate pH and presence or
absence of fructose.
o semen Volume (~80% from seminal
vesicles)
o seminal fluid is ALKALINE (protect sperm
from acidity of prostatic secretions and
vagina) and also provides FRUCTOSE as an
energy source for sperm.
!!! acidic pH or lack of fructose suggests a seminal
vesicle or ejaculatory duct problem
Procedure:
1. Patient is asked to provide a sample (usually by
masturbation), which should be analysed within 2
hours of production.
2. The sample should be kept warm (15–38 _C) during
the interval from production to analysis.
3. Abstinence from sexual activity for a period of 2–3
days is required before submitting a sample for
analysis; otherwise an abnormally low count may be
recorded.
4. The patient should also be advised to keep the sample
away from spermicidal agents, such as those in
condoms.
1. Patient is asked to refrain from ejaculation for 2 to 3
days (abstinence from sexual activity
2. Specimen is collected by masturbation into a sterile
cup. (If masturbation is not an option, use silastic
condoms without lubricants)
3. Sample should arrive in the laboratory within an hour
of ejaculation to allow for optimal analysis.
4. Sample undergoes liquefaction (thinning of seminal
fluid) for 5-20 minutes and allows more accurate
evaluation of the sperm
5. Ideally, two semen samples separated by at least a
month should be analyzed. In practice, frequently
only a single sample is analyzed if parameters are
normal.
a. semen characteristics will vary across time in a single
individual
b. semen analysis results such as morphologic
interpretation, will differ between laboratories.
Disadvantage: does not provide information regarding sperm
function which is the ultimate ability to fertilize an oocyte
Semen Volume
* Low semen volume may due to incomplete specimen
collection or short abstinence interval
- may indicate partial obstruction of the vas deferens (ductus
deferens) or retrograde ejaculation. Partial or complete vas
deferens obstruction may be caused by infection, tumor, prior
testicular or inguinal surgery, or trauma.
Retrograde ejaculation follows failed closure of the bladder
neck during ejaculation and allows seminal fl uid to fl ow
backward into the bladder.
Retrograde ejaculation should be suspected in men with
diabetes
mellitus, spinal cord damage, or a history of prostate or other
retroperitoneal surgery that may have damaged nerves
(Hershlag,
1991). Medications, particularly β-blockers, may contribute to
this problem. A postejaculatory urinalysis can detect sperm in
the bladder and confi rm the diagnosis. If urine is properly
alkalinized,
these sperm are viable and can be retrieved to achieve
pregnancy.
Sperm Count. A male partner may have normal sperm
counts, oligospermia (low counts), or azoospermia (no
sperm).
Oligospermia is defi ned as a concentration of fewer than
20 million sperm per milliliter, and counts less than 5 million
per milliliter are considered severe.
Th e prevalence of azoospermia is approximately 1 percent of
all men. Azoospermia may be due to obstruction in the outfl
ow
tract, termed obstructive azoospermia, such as that which
occurs
with congenital absence of the vas deferens, severe infection,
or
vasectomy. Azoospermia may also follow testicular failure
(nonobstructive
azoospermia). In the latter case, careful centrifugation
and analysis may identify a small number of motile sperm
adequate for IVF use. Alternatively, this latter group may have
viable sperm obtainable through either epididymal aspiration
or
testicular biopsy. Endocrine and genetic evaluation is
indicated
for men with abnormal sperm counts, as will be described
later.
Sperm Motility. Decreased sperm motility is termed
asthenospermia.
Some laboratories will distinguish between rapid
(grade 3 to 4), slow (grade 2), and nonprogressive (grade 0
to 1) movement. Total progressive motility is the percentage
of sperm exhibiting forward movement (grades 2 to 4).
Asthenospermia has been attributed to prolonged abstinence,
antisperm antibodies, genital tract infections, or varicocele.
Th e hypoosmotic swelling test can help to diff erentiate
between dead and nonmotile sperm. Unlike dead sperm, living
sperm can maintain an osmotic gradient. Th us, when mixed
with a hypoosmotic solution, living nonmotile sperm with
normal
membrane function will swell and coil as fl uid is absorbed
(Casper, 1996). Once identifi ed, these viable sperm may be
used for intracytoplasmic sperm injection.
Sperm Morphology. Abnormal sperm morphology is termed
teratospermia. Many laboratories use the original classifi
cation,
in which normal morphology is characterized by more than
50 percent of sperm exhibiting normal shape. More recently,
Kruger and colleagues (1988) have developed strict criteria for
defi ning normal morphology. Th eir studies defi ned a more
detailed characterization of normal sperm morphology, which
showed improved correlation with fertilization rates during
IVF cycles. Th eir criteria require careful analysis of the shape
and size of the sperm head, the relative size of the acrosome in
proportion to the head, and characteristics of the tail, including
length, coiling, or the presence of two tails (Fig. 19-12).
Fertilization rates are highest with normal morphology
percentages
greater than 14 percent. Signifi cantly decreased fertilization
rates are seen when normal morphology percentages falls
below 4 percent.
Round cells in a sperm sample may represent either leukocytes
or immature sperm. White blood cells (WBCs) can be
distinguished from immature sperm using a variety of
techniques,
including a myeloperoxidase stain for WBCs (Wolff ,
1995). True leukocytospermia is defi ned as greater than 1
million
WBCs per milliliter and may indicate chronic epididymitis
or prostatitis. In this scenario, many andrologists consider
empiric antibiotic treatment prior to obtaining a repeat semen
analysis. A common protocol would include doxycycline at a
dosage of 100 mg orally twice daily for 2 weeks. Alternative
approaches include culture of any expressible discharge or of
the semen sample.
Unless a general obstetrician-gynecologist has developed
a particular interest and expertise in the area of infertility,
repeated abnormal semen analyses are an indication for
referral
to an infertility specialist. Although the partner may be
referred
directly to a urologist, it may be more reasonable to refer the
couple to a reproductive endocrinologist, as the female will
also
require evaluation. Treatment is likely to be more complex in
these couples and will typically be directed to both partners.
Th e reproductive specialist can determine the need for further
referral of the male partner to a urologist for investigation of
genetic, anatomic, hormonal, or infectious abnormalities.
Antisperm Antibodies
Although these antibodies may be detected in as many as
10 percent of men, controversy exists regarding the negative
fertility eff ects of antisperm antibodies found in semen. Th
ese
antibodies may be particularly prevalent following vasectomy,
testicular torsion, testicular biopsy, or other clinical situations
in which the blood-testis barrier is breached (Turek,
1994). It is currently felt that only IgG or IgA, bound to the
sperm head or midpiece, are critical for decreasing fertilization
capacity.
Th e most commonly employed assay contains immunobeads,
which are mixed with the sperm preparation. Th ese beads will
bind to antibodies present in a sperm sample. Th is
mixture can be visualized under a standard microscope. With
aff ected individuals, beads bind to antibodies that have bound
to sperm (Fig. 19-13). Treatment historically included
corticosteroids,
but it is unclear that this approach improves fertility.
Moreover, signifi cant side eff ects, including aseptic necrosis
of
the hip, have been reported in treated patients.
Current data suggest that antisperm antibodies do not need
to be tested routinely as part of an infertility evaluation unless
the male partner has a clear risk factor for these antibodies. An
exception would be those patients who will undergo IVF. In
an aff ected antibody-positive population, fertilization rates
are
improved using intracytoplasmic sperm injection.
DNA Fragmentation
During the past 10 years, interest has increased regarding
elevated sperm DNA fragmentation as a cause of male factor
infertility (Sakkas, 2010; Zini, 2009). Although some degree
of
DNA damage is likely repaired during embryogenesis, the
location
and extent of damage may negatively aff ect fertilization
rates and increase miscarriage rates. Increased levels of DNA
damage are associated with advanced paternal age and
external
factors such as cigarette smoking, chemotherapy, radiation,
environmental toxins, varicocele, and genital tract infections.
Studies have observed increased levels of reactive oxygen
species
in sperm samples with abnormal DNA fragmentation rates. In
response to this observation, it has been proposed that dietary
supplementation with the antioxidants vitamin C and vitamin
E may be benefi cial. However, data are currently lacking
regarding the effi cacy of this approach.
A wide array of assays is currently available to analyze for
DNA integrity and include the Sperm Chromatin Structure
Assay (SCSA) and the terminal deoxynucleotidyl
transferasemediated
dUTP nick-end labeling (TUNEL) assay. Th e SCSA
is based on the increased susceptibility of DNA with
singlestrand
or double-strand breaks to denature in weak acid. Th e
TUNEL assay exploits the ability of labeled nucleotides to
inter calate into DNA breaks for subsequent measurement. Th
ese
tests are currently hampered by a lack of consensus regarding
appropriate threshold values and by confl icting data regarding
their ability to predict successful pregnancy. As a result, this
testing is likely beyond the scope of the generalist at this
point.
Nevertheless, the concept that sperm DNA integrity can be
adversely aff ected through multiple mechanisms provides
useful
insight into a previously underappreciated cause of male
infertility.
Assays of Sperm Function
A wide variety of assays to test sperm function have been
developed
during the past few decades. Th e predictive signifi cance
of these assays is questionable, as they are based on highly
nonphysiologic
conditions, and results vary widely from infertility
center to infertility center. Most are no longer used or are
used only intermittently by infertility specialists. Th ese tests
are
briefl y described to provide more complete information to the
general practitioner. However, they should not be considered
part of a basic infertility evaluation.
Mannose Fluorescence Assay. Th e sperm’s ability to
recognize
the zona pellucida of an oocyte is dependent on a number
of proteins and sugars on the zona surface, including the sugar
mannose. Acrosomal mannose-ligand receptor activity has
been
shown to correlate with IVF pregnancy rates (Benoff , 1993).
For this receptor assay, mannose residues in bovine serum
albumin are modifi ed so that they release fl uorescence. A
capacitated
sperm sample from a patient is mixed with this fl uorescent
preparation. In a parallel experiment, sperm from a known
fertile donor is mixed with the same fl uorescent preparation
in
a separate dish. Th e patient’s binding pattern is compared
with
the pattern obtained with the fertile male sample.
Hemizona Assay. Th e hemizona assay is a technique for
analyzing
the sperm’s ability to bind to the zona pellucida. Human
oocytes are bisected (to prevent fertilization) and are mixed
either with the partner’s sperm or with fertile donor sperm.
Th e hemizona index is calculated by dividing the number of
patient sperm bound by the number of control sperm bound
and multiplying by 100 (Burkman, 1988).
Sperm Penetration Assay. Th e sperm penetration assay
is performed by mixing capacitated human sperm with
hamster
oocytes. Th e zona pellucida typically prevents cross-species
sperm binding and must fi rst be removed from these test
oocytes. Th e number of oocytes that are penetrated by sperm
is
calculated. Th e presumption is that more oocytes will be
penetrated
by sperm from fertile men than by sperm from infertile
men (Smith, 1987b).
Acrosomal Reaction. Penetration of an oocyte requires that
sperm undergo an acrosomal reaction, during which the
enzymatic
contents of the acrosome are released on interaction with
the oocyte membrane. Various methods can be used to induce
the acrosomal reaction in a patient’s sperm sample. Th e
percentage
of sperm that undergoes the reaction is compared with
that of a fertile male’s control sample (Sigman, 1997).
Hormonal Evaluation of the Male
Hormonal testing in the male is analogous to endocrine testing
in an anovulatory female. Essentially, abnormalities may
be due to central defects in hypothalamic-pituitary function
or to defects within the testes. Most urologists will defer
testing
unless a sperm concentration is less than 10 million/mL.
Testing will include measurements of serum FSH and
testosterone
levels.
Low FSH and low testosterone levels are consistent with
hypothalamic dysfunction, such as idiopathic
hypogonadotropic
hypogonadism or Kallmann syndrome (Chap. 16, p. 447). In
these patients, sperm production may be achieved with
gonadotropin
treatment. Although frequently successful, at least 6
months may be required for detection of sperm production.
Elevated FSH and low testosterone levels provide evidence
of testicular failure, and most men with oligospermia fall into
this category. In this patient group, it is important to
determine,
based on testosterone levels, whether testosterone replacement
is indicated. Normal spermatogenesis requires high levels of
intratesticular testosterone, which cannot be achieved with
exogenous testosterone. Furthermore, many of these men will
lack spermatogonial stem cells. Th erefore, testosterone
replacement
will not rescue sperm production. In fact, replacement
will decrease gonadotropin stimulation of remaining testicular
function through negative feedback at the hypothalamus
and pituitary. Unless the couple has chosen to use donor
sperm, testosterone replacement should be deferred during
fertility treatment. However, replacement will provide other
benefi ts, such as improved libido and sexual function,
maintenance
of muscle mass and bone density, and a general sense of
well-being.
Additional hormonal testing may be included as part of an
evaluation of the infertile male. Elevated serum prolactin
levels
and thyroid dysfunction impact spermatogenesis and are the
most likely endocrinopathies to be detected (Sharlip, 2002;
Sigman, 1997).
Genetic Testing of the Male
Genetic abnormalities are a relatively common cause of
abnormal
semen characteristics. Approximately 15 percent of
azoospermic
men and 5 percent of severely oligospermic men will
have an abnormal karyotype. Although genetic abnormalities
cannot be corrected, they may have implications for the health
of the patient or his off spring. Th erefore, karyotyping should
be pursued when indicated by poor semen analysis results.
Th e lower limit in sperm concentration for such testing varies
between practitioners but lies between 3 and 10 million sperm
per milliliter.
Klinefelter syndrome (47,XXY) will be a frequent fi nding.
Klinefelter syndrome is observed in approximately 1 in
500 men in the general population and accounts for 1 to 2
percent of male infertility. Classically, these men are tall, are
undervirilized, and have gynecomastia and small, fi rm testes
(De Braekeleer, 1991). As the phenotype varies widely, lack
of
these characteristics should not preclude chromosomal
evaluation.
Conversely, a clinician should strongly consider obtaining
karyotype testing in any male with these characteristics.
Autosomal abnormalities will also be found in a subset of men
with severe oligospermia.
A patient with severely decreased sperm counts and a normal
karyotype should be off ered testing for microdeletion of
the Y chromosome. Up to 15 percent of men with severe
oligospermia
or azoospermia will have small deletions in the region
of the Y chromosome, termed the azoospermia factor (AZF)
region. If the deletion is within the AZFa or AZFb subregions,
then it is unlikely that viable sperm can be recovered for use in
IVF. Most men with an AZFc deletion will have viable sperm
at biopsy. However, these deletions should be presumed to be
inherited by their off spring. Th e clinical signifi cance of
microdeletions
in the recently identifi ed AZFd region is unknown, as
these patients have apparently normal spermatogenesis
(Hopps,
2003; Kent-First, 1999; Pryor, 1997).
Patients may decline testing for microdeletion of the Y
chromosome for various reasons. Beyond infertility, no known
health risks are associated with these deletions. Many couples
with azoospermia will chose to use donor sperm, and thus
identifi
cation of this mutation may not be pertinent. Other couples
reason that if the husband is able to have a child despite this
deletion, there is no signifi cant disadvantage if the
abnormality
is transmitted to any off spring.
Obstructive azoospermia may be due to congenital bilateral
absence of the vas deferens (CBAVD). Approximately 70 to
85 percent of men with CBAVD will be found to have
mutations
in the cystic fi brosis transmembrane conductance regulator
gene (CFTR gene), although not all will have clinical cystic
fi brosis (Oates, 1994; Ratbi, 2007). Conversely, essentially all
men with clinical cystic fi brosis will have CBAVD.
Fortunately,
testicular function in these men is usually normal, and
adequate
sperm may be obtained by epididymal aspiration to achieve
pregnancy
through IVF. Careful genetic counseling and testing of
the female partner for carrier status is critical in these
situations.
Testicular Biopsy
Evaluation of a severely oligospermic or azoospermic male
may include either open or percutaneous testicular biopsy to
determine whether viable sperm are present in the
seminiferous
tubules (Sharlip, 2002). For example, even men with testicular
failure diagnosed by elevated serum FSH levels may have
adequate sperm on biopsy for use in intracytoplasmic sperm
injection. Th e biopsy specimen can be cryopreserved for
future
extraction of sperm during an IVF cycle. However, freshly
biopsied specimens are generally felt to provide higher
success
rates. Th us, the biopsy may have diagnostic, prognostic, and
therapeutic value.