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Chapter 11: Ultrasonography of uterine fibroids
enlarge d, they can also cause co mpressi on of adjacen t pelvi c
structur es. This “mass e ff ect ” may result in bladd er or rectal
frequen cy and occasi onally hydronep hrosis . It should be not ed,
howev er, that fibroids are usually as ymptoma tic, and can often
be an incide ntal findin g on an ultraso und scan.
In pregnan cy, pain is the most co mmon compl ication
caused by fi broids, and can be sever e enoug h to req uire hosp italizat ion. Fibroi d pain is prob lematic as it can precip itate pre term deliver y, which has been reporte d as the most freq uent
cause of neonat al morb idity. The exact mechan ism that cause s
such acute pain is unknown , but it is often accompani ed
by the ultrasonic fi nding of a central anec hoic lesi on w ithin
the fibroi d, w hich sug gests acute degene ration known as “ red
degene ration. ” However, this fi nding is not conclu sive as thes e
appear ances can also be present in asymptoma tic fibroi ds
[ 9,10 ]. Pedu nculated fibroi ds are at in creased risk of torsion
during pregnancy due to the incr easing uterine siz e.
Cesarean rates have been shown to be higher when fibroids
are present, and this is generally due to malpresentation [11 ,12 ].
There is als o a higher incidenc e of postp artum hemo rrhage
and this is most likely due to an as sociated decrea se in ute rine
contra ctility when fi broids are present [9 ,12 ]. Placental abru ption is a much less co mmon complic ation, but has been mildly
associated with fibroids, particularly when submucosal or retroplacental in position [9 ]. Pre viously there has been some
concern that fibroi ds are assoc iated with small -for-dat es babies,
prematu re rupture of membra nes, and retai ned plac enta.
However, a numb er of studies have shown that there is no
signi fi cant link betw een fibroids and any of these obste tric
compl ications [ 9,12 ].
Fertility
The rela tionship of fibroi ds to fertility is of great interest to
those w orking in reprod uctive medi cine, but there are still
many uncert ainties about their true impact. It is helpful to
firs t look generally at how they mig ht a ff ect ferti lity, a nd then
speci fi cally at the impact of fi broids on IVF outcom e.
Implantation
Many studies hav e set out to show the extent of the imp act of
fibroi ds on implant ation. The prec ise e ff ect and me chanism s
have yet to be proven by random ized co ntrolled tr ials (RCT) .
The mechanism s that have been postu lated to a ff ect implantation in clude mechanic al disturban ce (as in the case of a submuco sal fibroi d); reduce d uterin e contra ctility; altered uterine/
endome trial perf usion; abnorm al endocrine patterns ; and
chroni c end ometria l in flamma tion [13 ].
An int ramural fi broid that is sit uated near the cornua may
poten tially cause a physical obstru ction of the ostia, thus a ff ecting spe rm a nd gam ete transfer [13 ].
Implantation and cavity-distorting fi broids
Fibroi ds that signi ficantly disto rt the cavity, as in the case of a
submucosa l (type 0), or an intramura l fibroi d with extensi on
into the cav ity (type s I and II), can cause a signi fi cant adverse
eff ect on implant ation [14 ]. A syste matic review has shown that
submucosa l fibroi ds may de crease the implan tation rates from
11.5% to 3% [ 15]. Studi es of women who have undergone
hystero scopic resect ion of submucosa l fi broids have shown a
signi fi cant improv ement in pregnancy rates, which were co mparab le to ra tes within the contro l gro ups [16 , 17]. The strengt h
of evidence showin g an adverse imp act of subm ucosal fi broids
on fertility, means that their removal has beco me both an
accepted and a recommen ded practice to improve the chances
of pregnanc y [ 15 ,16 ].
Intramural fi broids and implantation
The precise eff ects of intramural fibroi ds on implan tation are
much less certai n, and RC Ts are require d to understand their
true impac t on fertility. Studie s to date hav e given con flicting
results , with some studie s showing an adverse impac t of fi broids
on imp lantation and pregnan cy rates (particu larly w ith larger
fibroi ds) [ 18, 19 ,20 ,21 ], while other studi es show no impac t
[ 22, 23]. Some studie s hav e looked at ferti lity rates followi ng
myome ctomy and hav e shown an encou raging increase in
implan tation rat es [ 24 ,25 ]. The dispa rity of these finding s
makes it difficult no t only to understand the imp act of intramural fi broids but als o to estab lish the best tr eatment options ,
parti cularly for infer tile women .
Studie s indi cate that subserosa l and pedun culated fi broids
have no adverse impac t on implant ation rates [ 21 ].
Miscarriage
Most stud ies that h ave examined the relationship between fibroids
and miscarriage rates have looked predominantly at i ntramural
fibroids, with few data available o n i mpact of submucosal fibroids
[15]. Review of several studies shows a n inc rease i n the miscarriage
rate from 8% to 15% when intramural fibroi ds are present [ 15].
The presence o f m ulti ple fibroi ds has also been shown to be a
significant predictor of spontaneous loss [11]. An adverse impact
of fibroids on pregnancy loss is supported by a review of reports
on miscarriage rates following myomectomy for symptomatic
fibroids, which identified a decrease from 41% to 19% [26].
IVF outcome
The literature suggests that the percentage of women whose
infertilityiscausedsolelybyfibroids is very low (1–2.4%) [27].
One study indicated that fertility is decreased by fibroids and
identified that 43% of women with fibroids, presenting in labor,
had at least a two-year history of infertility [28]. Recent prospective studies looking at how fibroids affect IVF patients have also
shown that IVF outcome is reduced in the fibroid group [19,20].
As mentioned previously, the removal of submucosal fibroids is a generally recognized practice for improving fertility.
However, the value of removing intramural fibroids, particularly when there is no deformation of the cavity, is more
uncertain. Furthermore, there is conflicting evidence on the
impac t of fibroid size, numb er, and exte nt of sympt oms [14 ].
93
Section 2: Ultrasonography in infertility
Studies so far have shown that spontaneous conception
following myomectomy increases significantly (50–60%) [28],
and that the rates of first- and second-trimester miscarriage are
reduced [25,26].
There is general consensus in the literature that fibroids affect
fertility, but what remainstobe establishedis whetherthe surgical
removal of fibroids prior to IVF will significantly improve the
outcome and at the same time outweigh the risks of surgery.
Unfortunately, as yet, no RCTs have been conducted to test
the value of performing a myomectomy, and the methodological limitations of existing studies make it difficult to draw clear
guidelines for the management of fibroids in the IVF patient.
With no conclusive evidence, a case for surgical treatment
prior to IVF could be considered on an individual basis, taking
into account the presence of fibroid symptoms and reproductive history, including any previous failed IVF attempts.
Treatment
Medical treatment
Gonadotropin-releasing hormone analogue therapy
Gonadotropin-releasing hormone analogues (Gn-RHa) are used
as a short-term therapy for women with symptomatic fibroids.
However, as a hormone therapy that alters estrogen and progesterone production, it is not compatible with reproduction and
therefore has no useful therapeutic effect for the subfertile woman.
These analogues can, however, be used in this group of women as
a pre-operative treatment prior to a myomectomy to help shrink
fibroids, restore hemoglobin levels, and possibly reduce operative
blood loss. Ultrasound has been shown to be useful as a predictor
and gauge of response for Gn-RH therapy [29].
Surgical treatment
Hysteroscopic myomectomy
Hysteroscopic myomectomy is the treatment of choice for the
removal of submucosal fibroids. This method often requires a
repeat procedure, and risks include intrauterine adhesions and
uterine perforation.
Laparoscopic myomectomy
The laparoscopic myomectomy procedure is less invasive than
abdominal myomectomy, with a reduced risk of pelvic adhesions. The procedure is restricted to fibroids of a certain size.
Risks include a higher incidence of fibroid recurrence and of
uterine rupture in a subsequent pregnancy.
Abdominal myomectomy
Abdominal myomectomy is required when there are large or
multiple fibroids and when entry into the cavity is expected.
There is a greater risk of bleeding and adhesion formation than
with previous methods. There is also increased risk of hysterectomy, particularly in cases of recurrence.
Radiologic treatment
Uterine artery embolization
Uterine artery embolization is performed under radiologic
control and involves advancing a catheter into the uterine artery
via the femoral artery. Once it is in the uterine artery,
the arterial branches supplying the fibroid are identified,
and injected with an embolic agent (small synthetic particles).
Fibroid shrinkage occurs within 2–3 months and heavy bleeding is usually decreased in the cycle following treatment.
Some studies have indicated an improvement in fertilityrates
post treatment, with one study showing that all types of fibroid
treated have the potential to improve future fertility [30]. Despite
these initial findings, this treatment option is not currently rec-
ommended for women wishing to preserve fertility until there is
more evidence on its impact on fertility [31]. Ultrasound has a
role in pre- and post-treatment assessment for this treatment,
and can identify treatment complications with accuracy [32].
Myolysis
Myolysis is ablation of a fibroid mass by use of radiofrequency
(RF) electricity, cryoprobes or focused ultrasound. The most
recent treatment involves the use of focused ultrasound under
the guidance of MRI – or magnetic resonance imaging-guided
focused ultrasound (MRIgFUS). It has been shown to be a safe
and effective treatment for non-obese patients with symptomatic fibroids [33]. There is, however, a risk of uterine rupture
in a subsequent pregnancy and it is therefore not currently
recommended for the woman wishing to preserve her fertility.
Key points in clinical practice
*
Fibroids occur in 20–40% of women, with a higher
incidence in women of African descent.
*
2D ultrasound provides a low-cost, effective assessment of
fibroids.
*
Fibroids may be located within the uterine cavity, in the
myometrium, or under the serosal layer or may pedunculate
into the pelvic cavity.
*
Fibroids are clearly visualized on ultrasound, appearing
round in shape and heterogeneous in reflectivity. They may
undergo cystic, fibrotic, and calcified changes, all of which
are readily identified on 2D ultrasound.
*
Differential diagnoses for fibroids include adenomyosis,
ovarian masses, leiomyosarcoma, endometrial polyps, some
pelvic masses such as pelvic kidney, lymph nodes, and bowel
lesions.
*
Other ultrasound techniques such as SIS, color Doppler,
HyCoSy, and 3D scanning can offer valuable additional
information
*
Fibroids are generally asymptomatic. If symptoms are
present they include menorrhagia, dysmenorrhea, and a
bulk effect.
94
Chapter 11: Ultrasonography of uterine fibroids
*
Obstetric complications for fibroids include pain, pre-term
delivery, postpartum hemorrhage, and higher cesarean rates.
*
Submucosal fibroids have a significant impact on
implantation and their removal can improve fertility.
*
The impact of intramural fibroids on implantation is less
certain and surgical removal should be considered on an
individual basis.
*
The chance of early miscarriage is increased when fibroids
are submucosal in origin and to a lesser extent when they are
intramural.
*
Medical therapy in subfertile women is restricted to preoperative treatment. Radiologic treatments are not
currently recommended. Therefore surgical removal is the
main treatment for fibroids.
References
1. Practice Committee of the
ASRM. Myomas and
reproductive function. Fertil
Steril 2004; 82: S111–16.
2. Marshall LM, Spiegelman D,
Barbieri RL, et al. Variation in
the incidence of uterine
leiomyoma among
premenopausal women by age
and race. Obstet Gynecol 1997;
90: 967–73.
3. Wamsteker K, de Blok S.
Resection of intrauterine
fibroids In: Lewis BV, Magos
AL, eds. Endometrial
Ablation. Edinburgh, UK:
Churchill Livingstone, 1993.
4. Cohen L, Valle R. Role of
vaginal sonography and
hysterosonography in the
endoscopic treatment of
uterine myomas. Fertil Steril
2000; 73: 197–204.
5. Reddy N, Jain KA, Gerscovich
EO. A degenerating cystic
uterine fibroid mimicking an
endometrioma on
sonography. J Ultrasound Med
2003; 22(9), 973–6.
6. Ferenczy A. Pathophysiology
of adenomyosis. Hum
Reprod Update 1998: 4(4):
312–22.
7. SylvestreC,ChildTJ,Tulandi
T, Tan SL. A prospective
study to evaluate the efficacy of
two- and three-dimensional
sonohysterography in women
with intrauterine lesions.
Fertil Steril 2003; 79(5): 1222–5.
8. Bhatt S. Dopplerimaging of the
uterus and adnexae. Ultrasound
Clin 2006; 1(1): 201–21.
9. Exacoustos C, Rosati P.
Ultrasound diagnosis of
uterine myomas and
complications in pregnancy.
Obstet Gynecol 1993;
82:97–101
10. Katz VL, Dotters DJ,
Droegemueller W.
Complications of uterine
leiomyomas in pregnancy.
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593–
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Benson CB,
Chang-Lee W, Hill JA,
Doubilet PM. Outcome of
pregnancies in women with
uterine leiomyomas
identified by sonography
in the first trimester. J
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12. Qidwai IG, Caughey AB,
Jacoby AF. Obstetric
outcomes in women with
sonographically identified
uterine leiomyomata.
Obstet Gynecol 2006; 107:
376–82.
13. Farhi J, Ashkenazi J,
Feldberg D, Dicker D,
Orvieto R, Ben Rafael Z. The
effects of uterine
leiomyomata on in-vitro
fertilization treatment. Hum
Reprod 1995; 10: 2576–8.
14. Pritts EA. Fibroids and
infertility: a systematic
review. Obstet Gynecol Surv
2001; 56: 483–91.
Chow JS,
15. Klatsky P, Tran D, Caughey
A, Fujimoto V. Fibroids and
reproductive outcomes: a
systematic literature review
from conception to delivery.
Am J Obstet Gynecol 2008:
198(4): 357–66.
16. Shokeir TA. Hysteroscopic
management in submucous
fibroids to improve fertility.
Arch Gynecol Obstet 2005;
273(1) 50–4.
17. Narayan R, Rajat,
Goswamy K. Treatment of
submucous fibroids, and
outcome of assisted
conception. J Am Assoc
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18. Stovall DW, Parrish SB, Van
Voorhis BJ, Hahn SJ, Sparks
AET, Syrop CH. Uterine
leiomyomas reduce the
efficacy of reproduction
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19. Hart R, Khalaf Y, Yeong CT,
Seed
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fibroids on the outcome
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2411–17.
20. Check JH, Choe JK, Lee G,
Dietterich C. The effect on
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compressing the uterine
cavity as determined by a
prospective matched control
study. Hum Reprod 2002;
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21. Elde r-Geva T, Meagher S,
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BrehenyS,WoodC.Effect
of intramural, subserosal,
and submucosal uterine
fibroids on the outcome
of assisted reproductive
technology treatment
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22. Rinehart J. Myomas and
infertility: small intramural
myomas do not reduce
pregnancy rate in vitro
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23. Yarali H, Bukulmez O. The
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24. Surrey ES, Lietz AK,
Schoolcraft WB. Impact of
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patients with a normal
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Steril 2001; 75: 405–10.
25. Bulletti C, De Zeigler D,
Setti P, Cicinelli E, Polli V,
Stefanetti M. Myomas,
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in vitro fertilization. Ann
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26. Buttram VCJr, Reiter RC.
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27. Donnez J, Jadoul P. What
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Hum Reprod 2002; 17(6):
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28. Hasan F, Arumugam K,
Sivanesaratnam V. Uterine
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29. Kanelopoulos N, Dendrinos
S, Oikonomou A,
Panagopoulos P, Markussis
V. Doppler-ultrasound as a
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response to GnRH therapy.
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30. Walker WJ, Bratby MJ
Magnetic resonance imaging
(MRI) analysis of fibroid
location in women achieving
95
Section 2: Ultrasonography in infertility
pregnancy after uterine
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Cardiovasc Intervent
Radiol 2007; 30(5):
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31. ACOG Committee Opinion.
Uterine artery embolization.
Obstet Gynecol 2004; 103(2):
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32. Ghai S, Rajan DK, Benjamin
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33. Mikami K, Murakami T,
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96
Chapter
Ultrasonography of the endometrium
12
Richard Palmer Dickey
Introduction
Recognition of a relationship between endometrial characteristics visualized by ultrasound (US) and ability to become
pregnant in assisted reproductive technology (ART), ovulation
induction, and even spontaneous cycles is one of the important
advances in infertility treatment during the last 20 years.
Ultrasound measurement of the endometrium is now an indispensable part of ovulation induction monitoring and assisted
reproductive technologies. It also has a role in evaluation of
unexplained infertility. Before ultrasound, the condition of the
endometrium could be evaluated only by progesterone challenge to induce withdrawal bleeding or by invasive procedures,
biopsy, curettage, and hysteroscopy. This chapter will describe
the use of ultrasound in the evaluation of infertility and monitoring of ovulation induction for timed intercourse or artificial
insemination, as well as for ART.
Endometrial evaluation
Endometrial pattern
Evaluation of the endometrium in infertility was initially
focused on its app earance or pattern and only later was the
importance of endometrial thickness fully appreciated. Smith
et al. are credited with being the first to use the appearance and
thickness of the endometrium to decide when to administer
human chorionic gonadotropin (hCG) to initiate ovulation [1].
They classified endometrial patterns as: (1) type A, a multilayered “triple-line” endometrium consisting of a prominent
outer and central hyperechogenic line and inner hypoechogenic
or black regions (Figure 12.1); (2) type B, an intermediate
isoechogenic pattern, with the same reflectivity as the surrounding myometrium and a nonprominent or absent central
echogenic line (Figure 12.2); and (3) type C, an entirely homogeneous endometrium without a central echogenic line
(Figure 12.3). Subsequently, Gonen et al., in a report that was
widely cited, reversed the ABC order [2]. The ABC classification is infrequently used in current literature. When endometrial pattern is reported, it is usually described as “triple-line” or
“homogeneous,” the two most common endometrial patterns.
A third term, “post ovulation”, may be used to describe the
bright hyperechogenic pattern seen normally in the mid luteal
phase (Figure 12.4).
Endometrial thickness
Endometrial thickness is customarily measured from outside to
outside in an anterior–posterior view at the widest point; if
measured inside to outside, the difference can be as much as
2mm (Figure 12.5). The difference in how thickness is meas-
ured can explain some of the difference in values critical for
successful implantation reported in the literature. Endometrial
thickness measured by transvaginal US correlates well with
histological endometrial maturation according to Hofmann
et al. [3]. However, others found no relationship between endometrial thickness and histological dating of endometrial tissue
obtained by biopsy[4,5].
Endometrial waves
Endometrial wavelike activity is often seen on ultrasound
throughout spontaneous cycles and during ovulation induction
with human menopausal gonadotropin (hMG) or folliclestimulating hormone (FSH) [6]. The highest rate of activity is
seen during the periovulatory period when opposing waves
from the fundus to the cervix and from the cervix to the fundus
occur in 30–40% of spontaneous cycles at a rate of 3–4 waves
per minute [6]. Endometrial wavelike activity was found in
100% of hMG cycles at the time of ovulation. No waves from
the fundus to the cervix occurred during the mid-luteal phase of
hMG cycles. The clinical importance of endometrial waves is
undetermined. No relationship between the presence or
absence of endometria l waves and the outcome of ovulation
induction (OI) or in-vitro fertilization (IVF) has been reported.
Endometrial changes during spontaneous cycles
In spontaneous cycles, endometrial thickness increases from a
mean of 4.6 mm during menstruation, 9–13 days before the
luteinizing hormone (LH) surge, to 12.4 mm on the day of
the LH surge [7]. Although the increase in thickness is generally
constant, averag ing less than 1 mm per day, thickness may
Ultrasonography in Reproductive Medicine and Infertility, ed. Botros R. M. B. Rizk. Published by Cambridge University Press. © Cambridge
University Press 2010.
Section 2: Ultrasonography in infertility
Figure 12.1. Triple-line pattern (Smith et al. [1] type A; Gonan et al. [2] type C);
follicular phase day 12. The endometrial pattern is multilayered triple-line with a
clearly demarked center line and with the echogenicity of the outer lines less
than half that of the myometrium. The triple-line pattern may be found from
approximately day 6 before the LH surge until 2–5 days after the LH surge, when
the triple-line pattern becomes obscured by the increasingly hyperechogenic
pattern of the postovulation luteal phase endometrium. Implantation does not
occur, or is reduced, if the endometrium lacks a triple-line pattern on the day of
hCG administration in ovulation induction cycles for IVF. With permission from
reference [26].
Figure 12.2. Intermediate pattern (type B, Smith et al. [1], Gonan et al. [2];
follicular phase days 6–8. The endometrial pattern is at an intermediate stage
with a thin central line and echogenicity similar to that of the myometrium. With
permission from reference [26].
Figure 12.3. Homogeneous pattern (Smith et al. [1] type C; Gonan et al. [2] type
A); follicular phase day 3. The endometrial pattern is entirely homogeneous and
hyperechogenic without a central echogenic line; the endometrial thickness is
typically less than 6 mm. With permission from reference [26].
Figure 12.4. Postovulation pattern; follicular phase days 18–24. The normal
endometrial pattern at this time is homogeneous and hypoechogenic;
endometrial thickness is typically 9 mm or greater. With permission from
reference [26].
adenomyosis) in 93.8% of patients with homogeneous endometrial patterns, compared with 30% of patients with triple-line
pattern and endometrial thickness <9mm and 5.8% of patients
with triple-line pattern and thickness >9 mm [10].
98
increase by as much as 2 mm a day in the late proliferative
phase. Endometrial thickness normally decreases by 0.5 mm on
the day of LH surge, before beginning to increase again by an
additional 2 mm during the luteal phase [8]. The endometrial
pattern develops a triple-line appearance from day 6 before the
LH surge until 7 days after the LH surge, when the triple-line
pattern becomes obscured by the increasingly hyperechogenic
pattern of the endometrium [9].
Uterine pathology may affect results of endometrial ultrasound scans. Sher et al. discovered uterine pathology (leiomyomas, severe uterine synechiae, diethyl stilbestrol DES anomalies,
Endometrial changes during ovulation induction
When clomiphene citrate (CC) is used for ovulation induction,
endometrial thickness is often decreased compared with spontaneous cycles during and immediately following the days CC is
taken, because of its antiestrogen effect [7](Figure 12.6). During
the late proliferative phase, endometrial thickness increases at a
faster rate in CC cycles than in spontaneous cycles as it escapes
from the antiestrogen, and the effect of increased estrogen due to
multiple follicle growth becomes manifest. During ovulation
14
12
Chapter 12: Ultrasonography of the endometrium
Figure 12.5. Endometrial measurement. Thickness measured in an anterior–
posterior view at the widest point from outside to outside in an anterior-posterior
view at the widest point (O–O). The pattern is triple-line. With permission from
reference [26].
n
= 14
10
*
8
6
4
2
Double endometrial thickness (mm)
0
Figure 12.6. Double endometrial thickness (mm) in spontaneous (○) and
clomiphene citrate (
hormone surge. *P < 0.05. From Randall and Templeton (1991) [7]. Reproduced
with permission of the authors and the publisher, the American Society for
Reproductive Medicine (The American Fertility Society).
n = 16 n = 18 n = 17 n = 17 n = 17
*
LH – 2LH – 1
Day of cycle
●) cycles (mean + SEM). LH 0 = day of onset of luteinizing
LH 0LH + 1LH – 3LH – 4
induction with hMG and FSH, without CC, endometrial thickness is greater than in spontaneous cycles (Figure 12.7)[11].
During stimulation cycles for IVF, an average increase inlength
of the endometrial cavity by 3.8 mm and length of the cervical canal
by 1.9 mm correlated with increase in endometrial thickness [12].
Critical ultrasound values for ovulation induction
Endometrial pattern
A triple-line pattern on the day of hCG administration has been
reported by some authors to be necessary for implantation in
10
*
8
Endometrial thickness (mm)
6
4
Figure 12.7. Distribution of mean (± SEM) of endometrial thickness at four
points in the cycle.
clomiphene; ▲, clomiphene + ethinyl estradiol. *P < 0.01 compared with the
control cycle result at the same phase of the cycle. From Yagel et al. (1992) [11].
Reproduced with permission of the authors and the publisher, the American
Society for Reproductive Medicine (The American Fertility Society).
–7
○, Controls; ●, human menopausal gonadotropin (hMG); Δ,
–5
Day of cycle
–3 –1
*
controlled ovarian hyperstimulation (COH) cycles, where hMG
or FSH is administered,. However, Dickey et al. found no
difference in initial pregnancy rate between a triple-line pattern
(10.9%) and intermediate pattern (10.2%) in CC and COH
cycles for ovulation induction before intrauterine insemination, but noted a difference in continuing pregnancy rates of
9.4% for the triple-line pattern and 7.3% for the intermediate
pattern [13].
Endometrial thickness
Decreased endometrial thickness is linked to failure to conceive
and biochemical pregnancy in CC, hMG, and spontaneous
cycles[13,14,15]. In a study of endometrial thickness on the
day of hCG administration for timed intrauterine insemination
(IUI), optimal pregnancy and birth (continuing pregnancy)
rates occurred only when endometrial thickness was 9 mm
or greater on the day of hCG administration (Table 12.1).
More imp ortantly, no pregnancies occurred when endometrial
thickness was less than 6 mm in spontaneous, CC, or hMG IUI
cycles [13,14].
The type of drug used for ovulation induction was significantly related to endometrial thickness on the day of hCG
administration [13](Table 12.2) Endometrial thickness was
>9 mm in 59.2% of HMG cycles, compared with 47.2%
of clomiphene cycles and 34.8% of spontaneous cycles.
Endometrial thickness was <6 mm in 9.1% of CC cycles, but
was also <6 mm in 8.7% of spontaneous cycles for donor
insemination. By contrast, endometrial thickness on the day
of hCG was less than 6 mm in only 2.0% of hMG cycles. The
antiendometrial effect of CC was clearly apparent when CC and
hMG (hMG+CC) were used in the same cycle.
99
Section 2: Ultrasonography in infertility
Table 12.1. Endometrial thickness vs. outcome in ovulation induction
intrauterine insemination cycles
Pregnancy/outcome
Biological
Thickness
(mm)
<6 9.1 0 0 0% 0
6–8 43.6 8.1 21.9 15.6 62.5
≥9 47.2 14.0 0 12.2 87.8
Adapted from Dickey et al. [13]. Reproduced with permission of the publisher.
Table 12.2. Endometrial thickness according to ovulation regimen:
percent cycles; figures in parentheses are number of cycles
Regimen No. cycles <6mm 6–8mm >9mm
None 23 8.7% (2) 56.5% (12) 34.8% (8)
CC 197 9.1% (18) 43.6% (86) 47.2% (93)
hMG 49 2.0% (1) 38.8% (19) 59.2% (29)
hMG+CC 205 11.2% (23) 55.6% (114) 33.2% (68)
CC, clomiphene; hMG human menopausal gonadotropin.
Adapted from Dickey et al. [13]. Reproduced with permission of the publisher.
% of total
cycles
Pregnancy
rate (%)
pregnancy
(%)
Clinical
abortion
(%)
Term
(%)
Critical ultrasound values for IVF cycles
Endometrial pattern
The importance of endometrial pattern and thickness to successful outcome in IVF and gamete intrafallopian transfer (GIFT)
was first described by Smith et al. [1]. They fo un d t ha t i mpl ant ation did not occur, or occurred less often, if the endometrium
lacked a triple-line pattern on the day of, or one day before, ovum
retrieval in IVF cycles. This finding was latter confirmed by others
[2,15]. A triple-line endometrial pattern on the day of hCG
administration in IVF cycles is related to serum estradiol level,
the number of mature oocytes, and the number of top-quality
embryos and is unrelated to serum progesterone levels [15 ].
Figure 12.8. Fluid within the endometrial cavity. Gonadotropin cycle.
Endometrial cavity with 3 mm of fluid. Fluid in the endometrial cavity on the day
of embryo transfer in IVF or 6 days after ovulation is incompatible with
implantation. With permission from reference [26].
oocyte donation , end ometria l thickne ss on the day of em bryo
transfer has been found to be crit ical fo r imp lantation.
As is true for OI and IUI, optimal ART pregnancy and birth
rates occur when endometrial thickness on the day of hCG
administration is equal to or greater than 9 mm [10,15]or
10 mm [18 ,19 ]. Endometrium that is too thick, 14 mm or greater
on the day of hCG administration, may reduce the chance of a
clinical pregnancy [15,20]. Increased susceptibility to injury at
the time of embryo transfer has been proposed as the reason for
decreased clinical pregnancies by Dickey et al., who found that
biochemical pregnancies were more frequent in IVF cycles when
endometrial thickness was less than 9 mm or greater than 13 mm
[15 ]. No relationship between endometrial thickness on the day
of hCG and biochemical pregnancy was observed in IVF cycles in
another study [21 ]. An excessively thick endometrium may have
its origins in the previous cycle.It is common practice not to start
ovulation induction in ART and IUI cycles following menstruation when endometrial thickness is greater than 6mm.
100
Endometrial thickness
Pregnan cy does not occur in IVF cyc les, presum ably because of
failure of embryos to implan t, if the end ometrium is too thin on
the day of hCG administrat ion accor ding to the majo rity of
studie s. However, other studi es have reporte d no rela tionsh ip
betw een thickn ess and pregnanc y in IVF cy cles. Man y of the
studie s that faile d to find a relationsh ip between thickness and
outcom e compa red mea n thickne ss in co nception and nonconcepti on cyc les, while most studie s that found a rela tionsh ip
reporte d critical or “ cut-o ff ” values below whi ch no pregnanc ies
occurre d. In most studi es, the crit ical thickness valu e is
reporte d as 6 mm, but the ran ge is from 4 mm [ 16 ]to7mm
[ 17]. On e reaso n for these diff erenc es is that endomet rial thickness can chan ge, either increasin g or decreasin g, be tween the
day hCG is admi nistered and the day implant ation is pres umed
to occur, a di ff erence of 8– 9 day s. Importa ntly, in all studie s of
Other ultrasound findings
Implantation rarely occurs when endometrial fluid is present
on ultrasound on the day of embryo transfer, even when the
fluid is aspirated (Figure 12.8)[22]. Endometrial polyps less
than 2 cm do not decrease pregnancy rates, but there is a trend
toward increased pregnanc y loss ( Figure s 12.9 , 12.1 0) [ 23 ].
Preclinical miscarriage (biochemical pregnancy)
Preclinical miscarriage, also referred to as biochemical pregnancy, in which quantitative hCG levels initially indicate
pregnancy but decrease before a gestational sac can be seen on
ultrasound, and clinical miscarriage of embryos with karyotype
may be the result of inadequate endometrial development.
Because there are no products of conception (POC) for chromosome analysis in biochemical pregnancy, the reason for failure
Chapter 12: Ultrasonography of the endometrium
Figure 12.9. Endometrial irregularity, which could be either an endometrial
polyp or submucosal fibroid. From reference [26].
cannot be determined. However, because the karyotype of the
POC is normal in 52% of spontaneous miscarriages it is sensible
to hypothesize that inadequate endometrial development is
responsible for a proportion of early pregnancy loss [24]. In a
study of the relationship of endometrial thickness and pattern to
pregnancy outcomefollowing ovulationinduction cycles for IUI,
21.9% of pregnancies were biochemical pregnancies if endometrial thickness was 6–8 mm at the time of hCG administration,
compared with none when the thickness was 9 mm or greater
[14](Table 12.1). The incidence of clinical abortion after a gesta-
tional sac had been seen on ultrasound was 15.6% when endometrial thickness was 6–8mm, compared with 12.2% when the
thickness was 9mm or greater. In the same study, biochemical
pregnancies were significantly related to endometrial thickness
and pattern, and were unrelated to maternal age or number of
previous spontaneous abortions. By contrast, clinical abortions
were significantly related to maternal age and previous abortion,
and were unrelated to endometrial thickness or pattern.
Clinical management
For optimal pregnancy and birth results, endometrial thickness
should be 9 mm or greater at the time of spontaneous LH surge
or when hCG is administered in OI cycles for timed intercourse
or IUI and when hCG is administered in IVF cycles. When
endometrial thickness is less than 9 mm but 6 mm or greater, or
there is fluid in the endometrial cavity, three treatment options
are available.
Administration of hCG can be delayed to allow thickness to
increase and fluid to disappear. Delay in administering hCG is
particularly useful in CC cycles, because during the late proliferative phase endometrial thickness increases at a faster rate as it
escapes from the antiestrogen effect of clomiphene than in spontaneous cycles [7](Figure 12.6). If delay is not possible because a
spontaneous LH surge is starting or because estrogen levels are
rising too rapidly, there are still two treatment options.
The OI or IVF cycle can be allowed to proceed and estrogen
can be given in the expectation that endometrial thickness
Figure 12.10. The same patient as in Figure 12.9 scanned using
sonohysterography. The endometrial polyp is sharply outlined on the
sonohysterography scan and clearly distinguished from a submucosal fibroid.
From reference [26].
will increase by the time implantation occurs or embryos are
transferred.
The OI or IVF cycle can be cancelled and a different regimen
of follicle recruitment can be used in a later cycle; or in the case
of IVF, hCG can still be administered and all embryos cryopreserved for transfer at a later time . When the endometrium is too
thin in a CC cycle, endometrial thickness may be improved
in subsequent cycles by starting CC earlier, on menstrual day 3
instead of 5 [13], because the antiestrogen effect of CC lasts no
more than 3–4 days after the last dose: (1) by giving a lower dose
of CC; (2) by giving estrogen along with CC [11](Figure 12.7);
or (3) by switching to tamoxifen, an antiestrogenic structurally
similar to CC that has less antiestrogen effect on the endometrium and cervical mucus. When tamoxifen is used in place of
CC, a dose of 20–25 mg is approximately as effective as 50 mg of
CC in ovulation induction. When the endometrium is too thin
in an hMG or FSH cycle, the dose of gonadotropin can be
increased in a subsequent cycle in the expectation, not always
realized, that estrogen levels will be higher and result in a better
endometrial pattern and thickness.
A potential disadvantage of estrogen administration in nongonadotropin cycles is that high doses may suppress natural FSH
secretion or block a spontaneous LH surge. Therefore, estrogen
should not be started until after hCG is given or an LH surge has
occurred. When oral estrogen is given before an LH surge or
hCG, low doses should be taken 2–4 times daily, instead of a
single large dose once a day, to minimize serum levels. An
alternative method of administrating estrogen in clomiphene
cycles is to start with four times a day and step down one tablet
a day. The rationale for this approach is that it takes approximately 3 days to induce endometrial changes in response to
estrogen. An alternative to oral estrogen is administration by
injection, skin patches, or vaginally; the type of estrogen is not
important. In the author’s clinic a 2 mg micronized estradiol oral
tablet ordinarily prescribed for hormonal replacement in menopause symptoms is self-administered vaginally twice daily. There
101
Section 2: Ultrasonography in infertility
have been several reports of successful use of drugs other than
estrogen to correct a thin endometrium or adverse pattern, but
with the exceptionof low-dose aspirin none has been verified in a
prospective randomized study. Low-dose aspirin (81 mg daily)
increased the incidence of triple-line pattern and pregnancyrates
without significantly increasing endometrial thickness [25].
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