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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5809_Библиотеки_им_академика_М_И_Перельмана.pdf
Ultrasound inFollicle Monitoring
forOvulation Induction/IUI
JosefBlankstein, PeterAziz, ShumalMalepati,
andJawariaAmir
15
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 [1–3].
Recent advances in reproductive endocrinology have led to greater understanding of the basic
regulatory mechanisms governing the reproductive process. It is tting to introduce our topic by
outlining the major morphological changes of the
menstrual cycle that can be visualized by
ultrasound.
J. Blankstein (*)
Rosalind Franklin University of Medicine
and Science, Chicago, IL, USA
Mount Sinai Hospital, Department of Obstetrics
and Gynecology, Chicago, IL, USA
e-mail: josef.blankstein@sinai.org
P. Aziz
Mount Sinai Hospital, Department of Obstetrics
and Gynecology, Chicago, IL, USA
S. Malepati
Trios Medical Group– Obstetrics & Gynecology,
Kennewick, WA, USA
J. Amir
Rosalind Franklin University of Medicine
and Science, The Chicago Medical School,
Chicago, IL, USA
Follicular Selection: Morphological
andUltrasound Observations
In the beginning of each ovarian or menstrual
cycle, many follicles may start developing;
however only one is selected to continue 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
phenomenon.
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 toward maturation. Studies supporting
the “dominant follicle theory” support that new
follicular growth is arrested in the presence of a
single dominant follicle. The provision of more
gonadotropins in stimulated or induced cycles by
clomiphene citrate or human menopausal gonadotropins or both will violate the normal monovular quota. Moreover, the responsiveness of other
follicles to human menopausal gonadotropins
(hMG) therapy was found to be suppressed in the
© Springer Nature Switzerland AG 2019
L. A. Stadtmauer, I. Tur-Kaspa (eds.), Ultrasound Imaging in Reproductive Medicine,
https://doi.org/10.1007/978-3-030-16699-1_15
249
250
Fig. 15.1 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.
(Reprinted from Hodgen
[53]. With permission from
Springer)
Menses
Recruitment Selection
J. Blankstein et al.
Ovulation
Dominance
DF
Estrogen
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.15.1).
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 programed cell death within the
oocyte (apoptosis).
Ovarian secretion of estradiol (E
) and estrone,
2
from the granulosa cells, promotes follicular maturation by increasing follicular sensitivity to
gonadotropins stimulation. This is accepted to be
a gonadotropin receptor-mediated process.
The temporal relationship between hormonal
prole and follicular development with respect to
ovulation is summarized in Fig.15.2.
The dominant follicle is selected due to its
responsiveness to elevated circulatory FSH levels. It is not uncommon to observe two, or more,
Cohort of
Growing
follicles
DF
N
1 – 35 – 79 – 11 13 – 15
N-1
Days of the menstrual cycle
Maturation
Atresia
DF
N-1
N-1
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
36hours of its “surge.”
Small follicles can be visualized easily as
echo-free, smooth-walled structures and usually
lie toward the periphery of the more echogenic
ovarian tissue. As the follicle matures, more
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 one mm, is
surrounded by a cluster of granulosa cells. This
complex surrounding the oocyte is termed the
cumulus oophorus. It measures approximately
1mm 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 oats
freely within the follicle’s center. Today, even
with the enhanced resolution afforded by TVS,
the attached or oating cumulus is only rarely
seen. However new technological develop-
mm
12
66
Ovulation
Ultrasound biomicroscopy Histology
15 Ultrasound inFollicle Monitoring forOvulation Induction/IUI
251
Hours before ovulation
FSH
LH
Estrogens
Progesterone
Follicular diameter (Mm)
20
10
0
12
10 108
82
4422
Days before Days after
32
Fig. 15.2 Temporal relationships between hormonal pro-
le and follicular development with respect to ovulation.
Signicant hormone levels and their preovulatory peaks
17
15
21
24
8
0
hCG
8
are given in hours prior to ovulation (circled numbers).
(From Blankstein etal. [54])
Fig. 15.3 Antrum,
granulosa (GC), and the
theca cells (TC) in a
preovulatory follicle.
(Reprinted from Palleres
etal. [55]. With
permission from
Elsevier. https://www.
fertstert.org/article/
S00150282(08)01146-1/
fulltext)
ments, mainly high-resolution probes (40MHz),
have enabled clinical researchers to clearly
visualize the antrum, granulosa (GC), and the
theca cells (TC) in a preovulatory follicle
(Fig.15.3).
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
TC
GC
1 mm
together with a measurement of endometrial
thickness. The mean follicular growth rate is
1.4mm/day in spontaneous menstrual cycle and
1.7mm during ovarian stimulation cycles [4].
Mature follicles, those containing a mature
oocyte, typically measure from 17 to 25mm in
average inner dimension. The optimal follicular
size before triggering ovulation in intrauterine
insemination cycles with clomiphene citrate or
252
J. Blankstein et al.
letrozole was found to be in the 23–28 mm
range. The optimal size of the leading follicle
was not statistically signicantly 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 “deated.” The fresh corpus
luteum usually appears as a hypoechoic structure with an irregular internal wall and may contain some internal free-oating or xed echoes
that correspond to hemorrhage. As the corpus
luteum develops 4–8 days after ovulation, it
appears as an echogenic structure of approximately 15mm in size. Its wall is thickened due
to the process of luteinization. TVS shows the
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 uid. It is normal to have approximately 1–3 mL of intraperitoneal uid in the
cul-de-sac throughout the cycle. When ovulation occurs, there typically is between 4 and
5mL of uid within the cul-de-sac. The intraperitoneal 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.15.4).
The Role ofDoppler
inReproduction
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 the development
of the follicular microvasculature.
A study done by Shrestha etal. [6] to deter-
mine whether ovarian perifollicular blood ow
(PFBF) in the early follicular phase (EFP) is
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. Furthermore, a study done by
Vural etal. [39] concluded that well-vascularized
follicles are associated with good-quality oocytes
ab
Fig. 15.4 Corpus luteum ultrasound study. (a) Note the irregular cystic mass with crenulated borders and low-level
echoes. (b) Doppler ndings of a hypervascular corpus luteum with low resistance index
15 Ultrasound inFollicle Monitoring forOvulation Induction/IUI
253
and embryos, a well-vascularized endometrium,
and increased pregnancy rates. However, a systematic review by Huyghe etal. [40] indicates
that while PFBF could be a good prognostic
marker for pregnancy rate after IVF/ICSI, this
was not observed in studies utilizing only IUI.
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≥10cm/s
in at least one follicle on the day of hCG administration more often became pregnant than those
with PSV <10cm/s (P=0.05). Nargund etal. [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 <10cm/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 etal. [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 identication of these
cycles would be valuable in terms of counseling
with regard to the potential outcome in that
cycle. Ideally, the identication 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 nancially
and emotionally. However, further longitudinal
data would be needed before this form of pro-
spective 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 high- grade 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 prospective study by Ivanovsky etal. [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 ow. Obviously more
studies are needed to conrm their results.
The relationship between endometrial and
subendometrial blood ow and pregnancy after
intrauterine insemination was examined in a prospective study. The main outcomes measured
were vascularization index (VI), ow index (FI),
and vascularization ow index (VFI) of the endometrium as well as those of subendometrial
region. These measurements were analyzed in
relation to IUI outcome in pregnant vs. 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.15.5).
Ovulation Induction
andIntrauterine 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
254
J. Blankstein et al.
a
Fig. 15.5 Three-dimensional power Doppler images
generated using VOCAL software. (a) Endometrial. (b)
Subendometrial blood ow parameters on the day of IUI.
b
(Reprinted from Kim et al. [12]. With permission from
Elsevier. https://www.fertstert.org/article/S0015-
0282(09)00754-7/fulltext)
15 Ultrasound inFollicle Monitoring forOvulation Induction/IUI
255
bypassed; therefore, more sperm reaches the egg,
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 (uLH)
testing 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 in
diameter, 10,000 IU hCG was given to trigger
ovulation, and IUI is timed 36+ or −2hours 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. [23] 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.
Manzi et al. [13] 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 antagonists have been proposed to prevent premature LH surge [14]. These drugs do
not produce are-up effect. 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. It has been
shown that a minimal dose of leuprolide depot is
sufcient to prevent premature LH surge in the
in vitro fertilization (IVF) programs [41].
However, Wadhwa et al. [42] showed that the
delayed administration of GnRH antagonists in
mild ovarian hyperstimulation (MOH) with IUI
cycles when follicle size is ≥16mm is benecial
in terms of preventing the occurrence of premature LH surge but with no improvement in pregnancy rates.
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 Table15.3).
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 of
Reproductive Medicine). In the USA such regulations remain voluntary, while in many other
countries, such guidelines are legislated and
strictly enforced.
Low-dose stimulation, 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 etal. [15]
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 etal. [16] concluded that aspiration of
excess oocytes in stimulated IUI cycles reduced
cancellation rates and further reduced multiple
256
J. Blankstein et al.
pregnancy rates. Additional studies are needed to
better dene the criteria and methods for oocyte
aspiration of preovulatory follicles prior to hCG
administration.
Polycystic Ovarian Syndrome (PCOS)
A signicant 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
the PCOS, we cannot escape the suspicion that
we are facing a whole series of interrelated disorders leading to manifestations often classied
under this single title (Fig.15.6).
The Classical Picture ofPCOS
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-gray color,
and small, embedded, bluish cysts (2–6mm in
diameter). Microscopically, the ovarian capsule
is thick (approximately 144–595 u wide as
opposed to 100 u in normal ovaries) and 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 lutei have
been reported. The walls of the atretic follicles
often display hyperplasia of the theca interna
cells.
Fig. 15.6 PCOS ultrasound study (note the peripheral
small cysts, “string of pearls”)
Ultrasound Diagnosis [17]
The criteria for ultrasound diagnosis of PCO
have recently been revised in the light of
improved ultrasound technology and better
understanding of the condition [17]. Polycystic
ovarian morphology is dened as at least one
ovary with an ovarian volume of greater than
10 cm3 (or 10 mL) or an increased number of
antral follicles (i.e., those that can be visualized
as cysts in the ovarian cortex measuring 2–9mm
in diameter). The exact number of antral follicles, that is, the antral follicle count, to establish
15 Ultrasound inFollicle Monitoring forOvulation Induction/IUI
257
the diagnosis of polycystic ovarian morphology
using modern high- frequency transvaginal ultrasonography probes is now at least 12 if not
higher [48].
If a large follicle is present (over 10mm), then
the volume should be calculated on a repeat scan
when the ovary is quiescent to prevent overestimation of ovarian volume. Ovarian morphology
is a more reliable diagnostic tool than ovarian
volume for diagnosing PCOS.
Remember that imaging 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 rm diagnosis is
made.
Induction ofOvulation
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 of pregnancy. Commonly used ovulation induction medications include clomiphene
citrate, human menopausal gonadotropin, puried FSH, and recombinant gonadotropins.
Although all of these medications result in the
development of multiple follicles, they act via
different mechanisms.
Transvaginal sonography has a vital role in
monitoring the follicular growth rate in women
receiving ovulation induction medications.
In an elegant prospective study, Baerwold [4]
compared the growth rate of ovarian follicles during natural cycle and ovarian stimulation cycles
using standardized techniques.
While the growth rate in natural cycles was
1.42 mm per day, the growth in stimulated
cycles was signicantly greater, i.e., 1.7 mm
per day. Continued research on the effect of
greater follicular growth rates and shorter intervals to ovulation are being conducted
(Fig.15.7).
The baseline scan of the pelvis is mandatory
to rule out ovarian or uterine pathology and
assess the ovarian reserve; moreover, one needs
to rule out the presence of ovarian cysts [3].
The objectives of a baseline scan are as
follows:
1. To rule out ovarian or uterine pathology
requiring attention prior to beginning infertil-
ity treatment (Table15.1)
A common adnexal nding, endometriosis
[19], can be seen in over 30% of women with
clinically dened infertility. Endometriosis is
dened as the extrauterine presence of endometrial tissue and is likely due to retrograde menstruation and/or immunologic variations or
deciencies within the peritoneal cavity.
In mild cases small lesions are often located
on the ovarian and peritubular surfaces. Cases of
minimal endometriosis are not amenable to ultrasonographic diagnosis. However in more moderate cases, one can visualize an endometrioma,
i.e., a cystic structure which is lined with endometrial epithelium which can involve one or both
ovaries, uterosacral ligaments, etc.
Endometrioma may appear as an ovarian cyst
with an echo-dense appearance of blood within a
cyst; the appearance may range from anechoic to
solid, depending on the amount and organization
of the blood within the cystic structure; commonly one can visualize low-level echoes evenly
distributed throughout the cyst (Fig.15.8).
It is important for the physicians to familiarize
him with the ultrasonographic picture of endometrioma in order to avoid aspirating the cyst
because of an increased risk of infection, compared with aspiration of a simple cyst.
Since ovarian teratomas are the most common ovarian neoplasm especially in reproductive-age women [20], one may encounter them
during a baseline scan; the ultrasonographic
ndings will depend on which elements are present: ectoderm, mesoderm, etc. Very often one
can appreciate an echogenic mass with acoustic
shadowing. The presence of ectodermal elements gives irregular and variable internal echogenicity (Fig.15.9).
258
ab
cd
ef
J. Blankstein et al.
Fig. 15.7 Serial transvaginal ultrasonographic images of
the right ovary of a research participant on days 1 (a), 4
(b), 7 (c), 11 (d), 16 (e), and 17 (f) of a spontaneous menstrual cycle. The same ovarian follicle is identied
throughout the growth phase in (a)–€. The corresponding
2. To check ovarian reserve, which will help
identify the ideal treatment protocol
corpus luteum on the day of ovulation is shown in (e).
(Reprinted from Baerwald et al. [4]. With permission
from Elsevier. https://www.fertstert.org/article/S0015-
0282(07)04116-7/fulltext)
and hence may predict stages of reproductive
aging including the menopause transition.
Assessment of ovarian reserve includes measure-
Markers of ovarian reserve are associated with
ovarian aging as they decline with chronologic age
ment of serum follicle-stimulating hormone
(FSH), anti-Müllerian hormone (AMH), and