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17 Ultrasound in Male Infertility
227
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in healthy men. Scand J Urol Nephrol. 2000;34:175.
138. Hernandez AD, Urry RL, Smith Jr JA. Ultrasonographic characteristics of the seminal vesicles after
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139. Tanahashi Y, Watanabe H, Igari D, et al. Volume
estimation of the seminal vesicles by means of transrectal ultrasonotomography: a preliminary report.
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140. Manno M, Marchesan E, Tomei F, et al. Polycystic
kidney disease and infertility: case report and literature review. Arch Ital Urol Androl. 2005;77:25.
141. Pace G, Galatioto GP, Guala L, et al. Ejaculatory duct
obstruction caused by a right giant seminal vesicle
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Ultrasound characterization of the seminal vesicles
in infertile patients with type 2 diabetes mellitus. Eur
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143. Andrade-Rocha FT. Unusual presentation of seminal
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Part III
Ultrasound in Infertility Treatment
Ultrasound in Follicle Monitoring for Ovulation Induction/IUI
Josef Blankstein , Shumal Malepati , and Joel Brasch
1 8
Abbreviations
AFC Antral follicle count
AIUM American Institute of Ultrasound in
Medicine
AMH Anti-Mullerian hormone
AVC Automatic volume calculation
CC Clomiphene citrate
COS Controlled ovarian stimulation
EFG Early follicular stage
EFP Early follicular phase
FI Flow index
FSH Serum follicle-stimulating hormone
GC Granulosa
hCG Human chorionic gonadotropin
HPO Hypothalamic-pituitary-ovarian
IUI Intrauterine insemination
IVF In vitro fertilization
J. Blankstein , MD, ARDMS (*)
Department of Obstetrics and Gynecology,
Rosalind Franklin University of Medicine and Science,
Mount Sinai Hospital, 15th St at California Ave,
Chicago, IL 60608, USA
e-mail: josef.blankstein@sinai.org
S. Malepati , MD
Department of Obstetrics and Gynecology,
Mount Sinai Hospital, Chicago, IL, USA
e-mail: shumal_malepati@yahoo.co.in
J. Brasch , MD
Department of Obstetrics and Gynecology,
Rosalind Franklin University of Medicine and Science,
The Chicago Medical School, Chicago, IL, USA
e-mail: joel.brasch@chicago-ivf.com
IVF-ET Ovulation induction in in vitro
fertilization programs
LH Luteinizing hormone
OHSS Ovarian hyperstimulation syndrome
PCOS Polycystic ovary syndrome
PFBF Perifollicular blood fl ow
TC Theca cells
uLH Urinary LH testing
VFI Vascularization fl ow index
VI Vascularization index
Ovulation induction refers to the treatment in
which ovulation is achieved by medication such
as Clomid and gonadotropins to enhance fertility.
Transvaginal ultrasonography has become the
norm in infertility centers to provide noninvasive
access to the dynamic processes such as ovarian
follicular development, ovulation, and endometrial response to hormonal stimulation [
Recent advances in reproductive endocrinology
have led to greater understanding of the basic regulatory mechanisms governing the reproductive process. It is fi tting to introduce our topic by outlining
the major morphological changes of the menstrual
cycle that can be visualized by ultrasound.
1 – 3 ].
Follicular Selection: Morphological and Ultrasound Observations
In the beginning of each ovarian or menstrual cycle, many follicles may start developing; however, only one is selected to continue
L.A. Stadtmauer, I. Tur-Kaspa (eds.), Ultrasound Imaging in Reproductive Medicine,
DOI 10.1007/978-1-4614-9182-8_18, © Springer Science+Business Media New York 2014
231
232
J. Blankstein et al.
development while the remainders undergo
atresia. While oocyte recruitment and development is predominately dependent upon genetic
endowment, follicular growth, in contrast, is a
gonadotropin and sex steroid regulated phenomena, likely a postreceptor- modulated increase in
hormone sensitivity.
The early follicular phase of the ovarian cycle
is characterized by relatively elevated levels of
FSH and low levels of LH, estrogens, and progesterone. During this early cycle phase, the growth
of a number of follicles, referred to as a cohort of
follicles, is initiated. It has been demonstrated
that this oocyte selection process involves two
main processes. First, a number of follicles are
recruited, and second, a number of growing follicles are selected out of the recruited group to
continue towards maturation. Studies supporting
the “dominant follicle theory” support that new
follicular growth is arrested in the presence of a
single dominant follicle. Provision of more
gonadotropins in stimulated or induced cycles by
clomiphene citrate or human menopausal gonadotropins or both will violate the normal monoovular quota. Moreover, the responsiveness of
other follicles to human menopausal gonadotropin ( hMG) therapy was found to be suppressed in
the presence of the overt dominant follicle, while
the same dose of hMG early in the follicular
cycle increased the number of follicles recruited
and/or selected for maturation (Fig. 18.1 ).
In the normal ovulatory cycle, the dominant
follicle steadily increases in size, while the accompanying smaller follicles are not observed to show
a similar increase. Thus, while one or more follicles will grow to full maturity and ovulate, others
are destined to atresia and degeneration. This follicular atresia appears to involve genetically programmed cell death within the oocyte – a nuclear
cell death referred to as apoptosis.
Ovarian secretion of estradiol (E 2 ) and estrone,
from the granulosa cells, promotes follicular maturation by increasing follicular sensitivity to
gonadotropin stimulation. This is accepted to be
a gonadotropin receptor-mediated process.
The temporal relationship between hormonal
profi le and follicular development with respect to
ovulation is summarized in Fig. 18.2 .
Ovulation
Menses
Recruitment Selection Dominance
DF
DF
N-1
Maturation
DF
N-1
Atresia
9513 7 13
40 ] )
N-1
15 – – – –11
Cohort of
growing
Estrogen
follicles
N
Days of the menstrual cycle
Fig. 18.1 Cyclic ovarian changes: time course for
recruitment, selection, and ovulation of the dominant
ovarian follicle, with onset at atresia among other follicles
of the cohort (Adapted from Hodgen [
The dominant follicle is selected due to its
responsiveness to elevated circulatory FSH levels. It is not uncommon to observe two, or more,
follicles developing to approximately 10 mm,
with one achieving dominance and growing,
while the others regress. LH reinitiates meiosis of
the oocyte, and typically, ovulation occurs within
36 h of its “surge.”
Small follicles can be visualized easily as
echo-free, smooth-walled, structures and usually
lie towards the periphery of the more echogenic
ovarian tissue. As the follicle matures, more fl uid
is released and accumulates into its center. The
granulosa cell mass, lining the inner of the follicle, increases. Microscopically the oocyte itself,
which is less than one-tenth of 1 mm, is surrounded by a cluster of granulosa cells. This
complex surrounding the oocyte is termed the
cumulus oophorus. It measures approximately
1 mm and can occasionally be depicted by transvaginal scan (TVS) adjacent to the wall of a
mature follicle. Immediately prior to ovulation
the cumulus separates from the wall and fl oats
freely within the follicle’s center. Today, even
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI
Hours before ovulation
17
15
FSH
32
21
LH
24
233
hCG
Estrogens
Progesterone
Follicular diameter (mm)
20
10
mm
0
12 1210 10886644202
Days before Days after
Fig. 18.2 Temporal relationships between hormonal
profi le and follicular development with respect to ovulation. Signifi cant hormone levels and their preovulatory
with the enhanced resolution afforded by TVS,
the attached or fl oating cumulus is only rarely
seen. However, new technological developments,
mainly high-resolution probes (40 MHz), have
enabled clinical researchers to clearly visualize
the antrum, the granulosa (GC), and the theca
cells (TC) in a preovulatory follicle (Fig. 18.3 ).
Monitoring ovarian response to ovulation
induction can be achieved by ultrasonography
alone. The dimensions of the growing follicles
are plotted from around day 8 of stimulation
together with a measurement of endometrial
thickness. The mean follicular growth rate is
1.4 mm/day in spontaneous menstrual cycle and
1.7 mm during ovarian stimulation cycles [ 4 ].
Mature follicles, those containing a mature
oocyte, typically measure from 17 to 25 mm in
average inner dimension. The optimal follicular
size before triggering ovulation in intrauterine
82
8
Ovulation
peaks are given in hours prior to ovulation ( circled numbers ) (Courtesy of Dr. Josef Blankstein)
insemination cycles with clomiphene citrate or
letrozole was found to be in the 23–28 mm
range. The optimal size of the leading follicle
was not statistically signifi cantly different
between cycles using letrozole or clomiphene
citrate and was closely related to the endometrial
thickness [ 5 ]. Intrafollicular echoes may be
observed with mature follicles, probably arising
from clusters of granulosa cells that shear off the
wall near the time of ovulation. After ovulation,
the follicular wall becomes irregular as the follicle becomes “defl ated.” The fresh corpus
luteum usually appears as a hypoechoic structure with an irregular internal wall and may contain some internal free-fl oating or fi xed echoes
that correspond to hemorrhage. As the corpus
luteum develops 4–8 days after ovulation, it
appears as an echogenic structure of approximately 15 mm in size. Its wall is thickened due
234
J. Blankstein et al.
Fig. 18.3 Antrum, granulosa ( GC ), and the theca cells ( TC ) in a preovulatory follicle (Reprinted from Palleres et al.
41 ]. With permission from Elsevier)
[
to the process of luteinization. TVS shows the
Ultrasound biomicroscopy Histology
neovascularity within the wall that is associated
with formation of the corpus luteum. In addition
to delineation of changes in follicle size and
structure, TVS can depict the presence of intraperitoneal fl uid. It is normal to have approximately 1–3 mL of intraperitoneal fl uid in the
cul-de-sac throughout the cycle. When ovulation
occurs, there typically is between 4 and 5 mL
within the cul-de-sac. The intraperitoneal fl uid
resulting from ovulation may be located outside
of the posterior cul-de-sac, surrounding bowel
loops in the lower abdomen, and upper pelvis or
in the anterior cul-de-sac superior to the uterine
fundus (Fig. 18.4 ).
The Role of Doppler in Reproduction
Fig. 18.4 Corpus luteum ultrasound study. (1) Note the
irregular cystic mass with crenulated borders and lowlevel echoes. (2) Doppler fi ndings of a hypervascular corpus luteum with low resistance index
The formation of new blood vessels is taking
place in the ovary during folliculogenesis and
corpus luteum formation, as well in the endometrium mainly during the follicular phase. It was
already recognized as early as in 1926 that neovascularization may be of prime importance in
the growth and selection of ovulatory follicles, in
addition to the subsequent development and
function of the corpus luteum. Studies of ovarian
vascular morphology showed that the capillary
network of preovulatory follicles was more
extensive than that of other follicles, consequently proposing that initiation and maintenance
of follicular growth depends on development of
the follicular microvasculature.
A study done by Shrestha et al. [ 6 ] to deter-
mine whether ovarian perifollicular blood fl ow
(PFBF) in the early follicular phase (EFP) is
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI
235
associated with treatment outcome of IVF
showed high-grade ovarian PFBF in the EFP
during IVF to be associated with a higher clinical
pregnancy rate. Coulam et al. [ 7 ] correlated peak
systolic velocity (PSV) of individual follicles
with oocyte recovery, fertilization rate, and
embryo quality in women undergoing in vitro
fertilization (IVF) and embryo transfer. They
assessed the role of quantitative and qualitative
indices of follicular vascularity in predicting
pregnancy after IVF and embryo transfer. Women
who had PSV ≥10 cm/s in at least one follicle on
the day of hCG administration more often
became pregnant than those with PSV <10 cm/s
( P = 0.05). Nargund et al. [ 8 ] demonstrated that
there was a 70 % chance of producing a grade I
or II embryo if the follicular blood velocity was
>10 cm/s, compared with 14 % if the PSV was
<10 cm/s. This study concluded that there is a
physiological relationship between follicular
blood velocity, oocyte recovery, and the production of a high- grade preimplantation embryo,
which may form the basis of a useful clinical
test. Jayaprakasan et al. [ 9 ] on the other hand
concluded that ovarian vascularity as measured
by 3D ultrasound is not decreased in women who
demonstrate poor ovarian response to controlled
ovarian stimulation as part of assisted reproduction treatment.
Perifollicular vascular perfusion appears to be
an important factor in determining the outcome
of stimulated cycles, and may have clinical implications in assisted reproduction therapy. As there
were low pregnancy rates and oocyte retrieval in
the group of women with uniformly low-grade
vascularity, the identifi cation of these cycles
would be valuable in terms of counseling with
regard to the potential outcome in that cycle.
Ideally, the identifi cation of these women (who
may also be “low recruiters”) earlier in the cycle
would be helpful. This could allow the cancellation of treatment after careful counseling, on the
basis of perifollicular vascular perfusion, and
could be cost-effective, both fi nancially and emotionally. However, further longitudinal data
would be needed before this form of prospective
management of treatment cycles could be applied
clinically. The risk of multiple pregnancies and
their implications on the health service is also
well recognized. Since there were higher multiple pregnancy rates in stimulated intrauterine
insemination (IUI) cycles with uniformly highgrade follicular vascularity, perhaps these cycles
in particular should be considered for follicle
reduction or even cancellation. This may potentially reduce the number of developmentally
competent oocytes that have a higher capability
of producing more viable embryos for implantation [ 10 ].
In a recent prospective study by Ivanovsky
et al. [ 11 ], vascular impedance was calculated
using the uterine artery and arcuate artery pulsatility resistance and velocity on the day of hCG
administration. It was found that optimal uterine
receptivity can be accomplished by reduced vascular resistance and increased blood fl ow.
Obviously more studies are needed to confi rm
their results.
The relationship between endometrial and
subendometrial blood fl ow and pregnancy after
intrauterine insemination was examined in a prospective study. The main outcome measured were
vascularization index (VI), fl ow index (FI), and
vascularization fl ow index (VFI) of the endometrium as well as those of the subendometrial
region. These measurements were analyzed in
relation to IUI outcome, pregnant versus nonpregnant. It was found that the pregnant group
had higher endometrium VI, FI, and VFI scores
than the nonpregnant group. The subendometrial
region VI, FI, and VFI scores did not differ
between the groups [ 12 ] (Fig. 18.5 ).
Ovulation Induction and Intrauterine Insemination (IUI)
In conjunction with ovulation induction, IUI is a
way to potentially overcome various fertility
problems such as oligospermia, i.e., low sperm
count, low sperm motility, cervical factor infertility (cervical mucus inactivates sperm motility),
sexual dysfunction, and unexplained infertility.
By placing sperm directly into the uterine cavity, the greatest barrier, the mucus in the cervix, is
bypassed; therefore, more sperm reaches the egg,
236
Fig. 18.5 Three -dimensional
power Doppler images
generated using VOCAL
software. ( a ) Endometrial. ( b )
Subendometrial blood fl ow
parameters on the day of IUI
(see text) (Reprinted from
Kim et al. [
permission from Elsevier)
12 ]. With
J. Blankstein et al.
a
b
creating a better chance of fertilization for the
egg. IUI is usually combined with ovulation
induction. Optimal timing of insemination is
achieved either by the detection of a luteinizing
hormone (LH) surge through urinary LH testing
(uLH) or by ultrasound monitoring of follicular
growth followed by the administration of human
chorionic gonadotropin (hCG). In most centers,
when the leading follicle reached >18 mm
diameter, 10,000 IU hCG was given to trigger
ovulation and IUI is timed 36 + or – 2 h later.
While IUI is a natural starting point for many
treatment schemes, unfortunately this therapy
may be complicated by premature luteinization
and hyperstimulation.
Premature Luteinization: Premature LH surge
will luteinize the follicle which is too small and
not ready to ovulate. Cantineau et al. [ 13 ] studied
the prevalence of premature LH surges in an IUI
program. It has been concluded that 24 % of IUI
cycles suffer from premature LH surge and this
can result in IUI procedure cancellation.
Obviously, this represents economic and psychological stress for the patients.
18 Ultrasound in Follicle Monitoring for Ovulation Induction/IUI
237
Manzi et al. [ 14 ] showed that patients who
underwent controlled ovarian stimulation (COS)/
IUI treatment and had premature LH surge demonstrated much better pregnancy rates in the subsequent cycle when a GnRH analogue was added,
thus avoiding premature LH surge.
GnRH agonist has been, in the past, the standard of care in reducing the incidence of premature LH surge by reversibly blocking pituitary
gonadotropin secretion in IUI-stimulated cycles
[ 15 ]. These drugs are nowadays completely
abandoned in IUI cycles because of their stimulatory effect, with consequent higher incidence of
multiple pregnancy and OHSS and the long pretreatment period required.
An alternative to GnRH agonists, GnRH
antagonists have been proposed to prevent premature LH surge [ 16 ]. These drugs do not pro-
duce fl are-up effect, reducing synchronous
follicular pool recruitment. Moreover, the potential advantage of a GnRH antagonist is that pituitary gonadotropin secretion is suppressed
immediately after the start of the therapy.
Therefore, co-treatment with GnRH antagonists
can be restricted to the time in the cycle where
there is a risk of premature LH rise.
Assisted Reproductive Technologies). In the
USA such regulations remain voluntary, while in
many other countries, such guidelines are legislated and strictly enforced.
Low-dose stimulation and careful follicular
monitoring may help to reduce the risk of multiple pregnancies. The risk of multiple pregnancies
after IUI is dependent on the type of stimulation
(clomiphene citrate vs. gonadotropins) and on the
size and number of follicles. Dickey et al. [ 17 ]
reported a positive correlation of multiple pregnancies with the number of follicles 12 and
15 mm or larger. Offering oocyte aspiration of
excess follicles in an effort to reduce multiple
gestations has been proposed by many researchers, and this method has shown to reduce the risk
of multiple pregnancies.
Stoop et al. [ 18 ] concluded that aspiration of
excess oocytes in stimulated IUI cycles reduced
cancellation rates and further reduced multiple
pregnancy rates. Additional studies are needed to
better defi ne the criteria and methods for oocyte
aspiration of preovulatory follicles prior to hCG
administration.
Polycystic Ovarian Syndrome (PCOS)
Multiple Pregnancies
Another concern with controlled ovarian stimulation COS/IUI cycles is the risk of multiple pregnancies. The problem with multiple gestations is
that they are associated with major maternal and
fetal risks (see Table 18.3 ).
This past decade has shown increasing medical, societal, and regulatory attention to controlling multiple gestations in all areas of assisted
reproduction. Improved outcome-based medical
procedures, such as lower gonadotropin dosages, single embryo IVF transfer, and increased
utilization of cryopreservation of embryos, have
all contributed to the reduction in multiple gestations from ART procedures. Regulatory pressure
to lower multiple gestations has come in the
form of multiple agencies publishing embryo
transfer number guidelines and a national ART
tracking database through SART (Society for
A signifi cant disorder of concern to the reproductive endocrinologist is the polycystic ovary syndrome (PCOS). This is a common cause of
anovulation with multiple etiologies. This disorder affects 5–10 % of women. PCOS patients
respond well to ovulation induction (see below);
however, one has to remember that those patients
are prone to develop hyperstimulation and multiple gestations.
For years, PCOS has been one of the most
controversial entities in gynecologic endocrinology. Despite a vast amount of clinical and laboratory data that have been accumulated since the
initial report of Stein and Leventhal in 1935, our
knowledge of the endocrine metabolism underlying the disease is still fragmentary. The PCOS is
a disorder of multiple etiologies involving a selfperpetuating imbalance between various interdependent endocrine and peripheral structures. In
dealing with patients who exhibit symptoms of
238
J. Blankstein et al.
Fig. 18.6 PCOS ultrasound study (note the peripheral
small cysts “string of pearls”)
the PCOS, we cannot escape the suspicion that
we are facing a whole series of interrelated disorders leading to manifestations often classifi ed
under this single title (Fig. 18.6 ).
The Classical Picture of PCOS
The PCO syndrome is characterized by a variety
of symptoms, all of which are not necessarily
present in every patient. These include (1) a broad
spectrum of menstrual abnormalities, (2) signs
of hyperandrogenism, (3) infertility, and (4)
bilateral polycystic ovaries. Menstrual disorders observed include secondary amenorrhea
(rarely primary amenorrhea may occur) and
oligomenorrhea.
Grossly, the polycystic ovary appears enlarged,
sometimes twice the normal size, and is characterized by a shiny, oyster-grey color and small,
embedded, bluish cysts (2–6 mm in diameter).
Microscopically, the ovarian capsule is thick
(approximately 144–595 u wide as opposed to
100 u in normal ovaries) and fi brous and contains
numerous primordial follicles. In the substance
of the ovary, there are follicles in all stages of
development and atresia, and multiple cystic
follicles are lined with one to three layers of
granulosa cells. Luteinized follicles are present
and occasionally corpora lutea have been
reported. The walls of the atretic follicles often
display hyperplasia of the theca interna cells.
Ultrasound Diagnosis
The criteria for ultrasound diagnosis of PCO
have recently been revised in the light of
improved ultrasound technology and better
understanding of the condition [ 19 ]. The diagno-
sis can be supported when one or more of the following features are demonstrated:
• 12 or more follicles (2–9 mm diameter) are
present in an ovary (either peripheral or diffusely arranged).
• Ovarian volume is over 10 cm 3 (when no follicles measuring over 10 mm in diameter).
Only a single ovary need be affected to make
a diagnosis. If a large follicle is present (over
10 mm), then the volume should be calculated on
a repeat scan when the ovary is quiescent to prevent overestimation of ovarian volume.
Remember that imaging fi ndings alone should
not diagnose PCOS in an asymptomatic patient.
In this situation further supporting evidence in
terms of clinical examination and blood tests
should be obtained before a fi rm diagnosis is
made. Oftentimes, without clear ultrasonographic
or endocrine fi nding consistent with PCO, the
practitioner can still diagnose “suspect PCO”
based upon the ovarian response pattern to exogenous gonadotropins, i.e., greater than expected
estradiol response and fewer than expected
mature follicles – oftentimes, scores of small
(less than 10 mm) immature follicles.
Induction of Ovulation
In patients whose infertility can be attributed to
an ovulation abnormality, ovulation induction is
indicated. Ovulation induction is also used in in
vitro fertilization programs (IVF-ET) to increase
the number of oocytes aspirated, which in turn
increases the number of fertilized conceptus that
may be transferred, thereby increasing the chance