INVITED REVIEW ARTICLE

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The significance of monitoring

folliculogenesis
Quick Response Code

I. Lebbi, R. Ben Temime1

Department of Assisted Reproduction, Institute of Medicine and Reproductive Biology, Alyssa Polyclinics, 1Department of
Obstetrics and Gynecology A, Charles Nicolle University Hospital, Tunis, Tunisia
Address for Correspondence: Prof. I. Lebbi, Ob-Gyn and Fertility Private Clinic, Dream Center, 1002, Montplaisir;
Tunis, Tunisia. Email:issam.lebbi@planet.tn

About the Author

Professor Issam Lebbi has been the past Head of the Dept of Ob-Gyn (Midwifes School) & Operating Theatre Nurses
at the Superior School of Health of Tunis (1998-2002). He was the Past-President of STGO (Tunisian Society of
Gyn-Obs) and Founder & Past-Executive secretary of STCL (Tunisian Society of Laparoscopic Surgery). He was also
the Past-President & Executive Secretary of SGOM (Mediterranean Society of the Gynaecologists and Obstetricians of
the Mediterranean). He is a Member of the Board of ISIVF since 2009 (International Society of In Vitro Fertilization)
and Honorary Member of the CNOGF since 2010 (French College of Gyn-Obs) . He is the Associate Editor of Frontiers in Surgery &
Ob-Gyn since 2013. He is also a Member of the International Advisory Board of the JJournal of Obstetrics & Gynaecology of India,
IVF lite Journal and Turkish Journal of Gyn-Obs. He has delivered over 200 lectures at several International academic events (Tunisia,
North Africa, Mediterranean and International) focused especially on Endometriosis and Reproductive and Pelvic Surgery.
A B STR A C T
This manuscript describes various uses of ultrasound imaging in assisted reproductive technologies as the principal noninvasive
technique for evaluation of ovarian function and the process of follicular growth. Serial realtime pelvic ultrasonography has been
described as a rapid, reliable method for monitoring follicular growth, rupture, and regression. The evaluation of preovulatory follicles
by ultrasounds relies mainly on the study of the follicle diameter, but also on the follicle growth pattern, the follicular wall thickness,
the perifollicular vascularity and the perifollicular blood flow. Predicting fertility potential has become important as women seek to
use costly assisted reproductive technologies. The term ovarian reserve has been used to describe the capacity of ovaries to
respond to stimulation with gonadotropins and therefore predict fertility potential. Ultrasounds can evaluate the ovarian reserve by
the study of the antral follicle count and the study of the ovarian volume. Ultrasounds monitoring is important in assisted reproductive
techniques. During controlled ovarian stimulation(COS), ultrasonographic evaluation of follicle growth and number will influence
gonadotropin dose in the next days or the cancellation of the cycle if no response is documented. Monitoring of follicle growth
and its vascularization at the end of COS could certainly increase the quality of the retrieved oocytes considerably. Moreover, the
better monitoring of controlled ovarian stimulation invitro fertilizationintracytoplasmic sperm injection permits a final good outcome.
Key Words: Controlled ovarian hyperstimulation, follicle growth, ovarian monitoring, perifollicular vascularization monitoring,
ultrasound

INTRODUCTION
Our perceptions of human follicle growth and ovulation
have changed since highresolution ultrasonography has
been available. The sonographic visualization of ovarian
follicles was first performed by Kratoscwil in 1972. Since
that time, many advances have been reached, including the
sonagraphic monitoring of follicle growth by Hackeloer

in 1977, the transabdominal follicle puncture by Leitz in

1981, the ultrasonographically guided puncture with vaginal
probe by Dellenbach in 1984 and finally, the transvaginal
puncture using vaginal probe by Wikland in 1985.
During the past 50years, it has been accepted that
folliculogenesis begins with recruitment of a group or
cohort of follicles in the late luteal phase of the preceding

IVF Lite Foundation Published by Medknow. All rights reserved.

Please cite this article as: Lebbi I, Temime RB. The significance of monitoring folliculogenesis. IVF Lite 2015;2:6-13.
DOI: 10.4103/2348-2907.151971

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Lebbi and Temime: Monitoring folliculogenesis

menstrual cycle followed by visible follicle growth in the

next follicular phase.[1,2] The group or cohort of follicles
begins growth and by the midfollicular phase, around day
7, a single dominant follicle appears to be selected from
the group for accelerated growth. The dominant follicle
continues to grow at a rate of about 2mm/day.[3] In women,
a preovulatory follicle typically measures 18-20mm
when a surge of luteinizing hormone(LH) is released
from the pituitary to trigger ovulation. Ovulation occurs
approximately 36h after LH release.[4,5] However, this
model failed to explain why or how women had variable
menstrual cycle lengths or anovulatory follicles. In 2003,
the old model of the menstrual cycle was superseded when
follicle growth was shown to occur in waves.[6,7]
This manuscript describes various uses of ultrasound
imaging in assisted reproductive technologies as the
principal noninvasive technique for evaluation of ovarian
function and the process of follicular growth.
EVALUATION OF PREOVULATORY FOLLICLES
BY ULTRASOUNDS
Serial realtime pelvic ultrasonography has been described
as a rapid, reliable method for monitoring follicular growth,
rupture, and regression. This approach provides good
presumptive, but not definitive evidence of ovulation. The
evaluation of preovulatory follicles by ultrasounds relies
mainly on the study of the follicle diameter but also on
the follicle growth pattern, the follicular wall thickness, the
perifollicular vascularity and the perifollicular blood flow.
Follicle diameter
Transverse and longitudinal scans are performed on both
ovaries, and the mean diameter of each follicle is calculated.
Secondary antral follicles, approximately 2mm in diameter,
are the first follicular structures that may be visualized and
investigated reliably by the common ultrasound device.
Ovulation is deemed to have occurred if the follicle
reached a mean diameter of 18-25mm and subsequently
changed in size, shape, or sonographic density. Gore etal.
developed the method to identify, map, characterize and
monitor growth, movement, positioning and interaction
of individual follicles noninvasively using twodimensional
ultrasound imaging along with computer modeling, which
enabled threedimensional modeling of the ovary. They
also introduced a set of visual criteria for the prediction
of the follicle status and cycle outcome(ovulatory vs.
non ovulatory) by investigating growth dynamics of the
entire visible antral follicle population during natural,
spontaneous cycles. [8] An important finding was the
drastic reduction of the antral follicle population at the
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end of the luteal phase, followed by a rapid increase in

the population(new antral follicle growth). Vlaisavljevic
studied the relationship between follicle diameter and the
time remaining to ovulation. The diameter of the dominant
follicle at time of LH surge ranged from 18.1mm to
22.6mm. Alinear growth rate was found before LH surge
ranging from 1.4mm/day to 2.2mm/day. The follicular
growth increased very quickly after the LH peak. The
mean time remaining to ovulation was 2days and 18h
for a follicle diameter of 14mm, 1day and 18h for a
follicle diameter of 20mm and 1day and 6h for a follicle
diameter of 24mm.[9] In a study reported by Kerin, the
diameter of the dominant follicle increased from 12mm
to 23mm over the 5days preceding ovulation, and the
range of diameter of follicles at ovulation was 18-29mm.[10]
This relatively large range makes it difficult to predict the
day of ovulation prospectively. Asimilar linear relation
between follicle diameter and plasma E2 levels was reported
by Bryce and al., but the variation within and between
the two parameters was too large to predict ovulation to
within<1.41.2days.[11]
Follicular vascular flow
The vascular network surrounding the dominant follicle
can be appreciated easily with highresolution color flow
Doppler imaging. The capillary structure of preovulatory
follicles is physiologically different from subordinate follicles
in that it is more extensive, and vessels are permeable for
nutrient/hormone exchange.[12] Angiographic studies of
preovulatory follicles using 2D color Doppler ultrasound
device show that the perifollicular blood flow velocities
gradually increase in the periovulatory period. This increase
starts approximately 29h before ovulation and continues
for at least 72h later, and that may be the consequence
of the penetration of blood vessels into the granulosa
cell layer. In the same period, the pulsatility index remains
relatively constant, and the vascular resistance index in
perifollicular vessels shows low to moderate values. These
findings suggest a marked increase in blood flow at the
periovulatory period.[13] Furthermore, a marked increase
in blood flow at the base and a decrease in blood flow at
the apex of the follicle is noted during follicle growth. This
feature of perifollicular circulation may be of essential
importance for the later release of a mature oocyte.
Perifollicular vascularity has also been assessed in some
human clinical ART programs.[1418] Clinical pregnancy
rates were higher when oocytes were retrieved from
follicles with higher levels of vascular flow prior to
oocyte retrieval compared to low levels of follicle vascular
flow. [1417,19] However, no differences were observed
in the perifollicular vascularity and ovarian vascularity
7

Lebbi and Temime: Monitoring folliculogenesis

responses to ovarian stimulation between normal and

poor responders in a clinical in vitro fertilization(IVF)
study. Although the relationship between perifollicular
vascularity and pregnancy rates has been demonstrated
in some laboratories, not all investigators regard vascular
measurement to be a useful predictor. Further assessments
of individual follicles and the probability of the fertilization
of their oocytes are required before this modality can be
included as a part of routine clinical care.[20,21]
SONOGRAPHIC INDICES OF OVULATION
The changes in the ultrasound image of the follicle that
rupture are:(a) disappearance or sudden decrease in
size,(b) increased echogenicity,(c) irregularity of the
follicular wall, and(d) appearance of free fluid in the cul
de sac of Douglas. Disappearance or sudden decrease in
follicle size has been found to be the most frequent sign of
ovulation.[19] Sensitivity and specificity of ultrasonography
to document ovulation is 84% and 89%, respectively, and
accuracy is about 85%.
In order to assess whether a follicle is destined to
ovulate, color flow Doppler interrogation can be used to
differentiate the contrast between the increased vascularity
of a healthy preovulatory follicle wall and the thin bright
hyperechoic avascular wall of a follicle destined for atresia.
Follicles destined to ovulate tend to have vascular walls,
clear antral fluid, produce an exponentially increasing
amount of estradiol and grow at a rate typical of other
menstrual cycles for a given individual.[2023]
Ovulation could be identified with transabdominal
ultrasonography in 50-80% of natural menstrual cycles
on day 14 of the standard menstrual cycle. [24,25]
Highresolution transvaginal ultrasonography has made
it possible to visualize, in realtime, the process of follicle
rupture and the evacuation of follicular fluid and the
cumulusoocyte complex.[5]

of this highly metabolic tissue. Both color flow Doppler

and gray scale imaging are useful for the identification
of the corpus luteum. Degradation of vascular flow
accompanies luteolysis, the regression of the corpus
luteum in the late luteal phase of each menstrual cycle, in
the absence of conception.
ASSESSMENT OF OVARIAN RESERVE
Predicting fertility potential has become important as women
seek to use costly assisted reproductive technologies. This
has become more critical as women attempt to conceive
when they are older and less fertile.[2630] The term ovarian
reserve has been used to describe the capacity of ovaries
to respond to stimulation with gonadotropins and therefore
predict fertility potential.[31] Ultrasonography, endocrine
tests, clomiphene citrate challenge tests, and GnRH
agonist stimulation tests all have been used to predict the
ovarian reserve. Each of these methods attempts to
determine whether the capacity to conceive present from
the perspective of ovarian function to predict the response
to fertility therapy and plan the most efficacious and safe
therapy. Ultrasounds can evaluate the ovarian reserve by
the study of the antral follicle count and the study of the
ovarian volume.
The antral follicle count
Ultrasonography is routinely used to evaluate ovarian
follicle number as a means to estimate ovarian reserve
in women. Amarked reduction in the number of antral
follicles and the change of ovarian volume resulting from
a decline in follicles may raise the suspicion for or confirm
early ovarian failure.[3235] The decreased ovarian reserve,
reflected by low antral follicle counts has then been used to
predict a poor response to ovarian stimulation.[3540] Counts
done between day 3 and day 7 of the menstrual cycle have
been used to predict how many follicles will develop with
ovarian stimulation.[35,37,4042]

The time required for ovulation from the initial fluid

leakage to the complete apposition of the follicle walls
varied from<1min to>20min. Evacuation of follicular
fluid during ovulation averaged approximately 10 min.
The new site of ovulation could be identified as soon as
ovulation occurred by examining the external surface of
the ovary for the point of rupture.

A higher probability of poor ovarian stimulation occurred

when women had fewer than five follicles under 10mm in
diameter prior to the onset of therapy.[42] As women age,
there is a gradual decline in the number of ovarian follicles
and responsiveness to gonadotropin stimulation. Awide
individual variation in ovarian response to exogenous
gonadotropin stimulation occurs in women of advanced
reproductive age.[31,33,38,43]

The corpus luteum can be recognized when the former

follicle walls meet after follicle fluid is released and
appear as two thickened slightly hypoechoic parallel tissue
interfaces. The corpus luteum becomes increasingly
hypoechoic and thicker, reflecting the increasing vascularity

Deb compared twodimensional ultrasound imaging with

automated threedimensional ultrasound imaging for
the measurement of antral follicle number and size.[44]
Twentyfour subjects aged<40years underwent transvaginal
ultrasound examination in the early follicular phase of the

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Lebbi and Temime: Monitoring folliculogenesis

menstrual cycle. Threedimensional US of both ovaries

and analyzed using sonographybased automated volume
count(SonoAVC). Five predefined size categories of antral
follicle count(AFC): 2.0-5.0mm, 2.0-6.0mm, 2.0-8.0mm,
2.0-9.0mm and 2.0-10.0mm. The antral follicle count in
each of the five predefined size categories was significantly
lower with SonoAVC than with twodimensional ultrasound
imaging(P<0.05). However, SonoAVC took significantly
less time to measure the size and record the number
of antral follicles than did twodimensional ultrasound
imaging(meanstandard deviation, 132.0556.23 s vs.
324.47162.22 s; P<0.001).
Antral follicles count as a predictor of invitro
fertilization outcome
Antral follicle counts may be estimated at specific times
of the menstrual cycle and correlated to gonadotropin
therapy responsiveness, either alone or combined with
IVF therapy.[3639] The first report on the usefulness of the
number of antral follicles in predicting ovarian response
was performed by Ng etal. and showed that the number
of antral follicles presents before stimulation was a better
predictor than ovarian volume or age alone.[45] In this study,
the number of antral follicles correlated with the number
of retrieved oocytes, and ovarian volume correlated with
the number of antral follicles, but not with the number of
retrieved oocytes.
The results of Chang etal. confirmed those of Ng and
found that in the cycles with less than three antral follicles
before stimulation, there was a higher chance of cycle
cancellation, the lower E2 levels and a need for higher doses
of gonadotropins were reported.[46]
Jayaprakasan K concluded that AFC is a better
twodimensional or threedimensional imaging predictor
of ovarian response and IVF outcome than the ovarian
volume and the ovarian blood flow.[47] Hendriks investigated
by a metaanalysis the predictive capacity of ovarian
volume as an ovarian reserve test(ORT) in comparison
to the antral follicle count.[48] This metaanalysis included
a total of 10 studies reporting on ovarian volume and 17
studies on AFC a tool for the prediction of IVF outcome.
The AFC performed statistically significantly better than
ovarian volume in the prediction of poor response. The
overall accuracy for predicting nonpregnancy was poor for
both tests. The clinical value in poor response prediction
was only evident for the AFC as a considerable number
of cases can be identified who will have a high chance of
producing a poor response to stimulation. The clinical
value for nonpregnancy was virtually absent for both tests.
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In conclusion, The predictive performance of ovarian

volume toward poor response was clearly inferior compared
with that of AFC. Therefore, Hendriks concluded that
the AFC may be considered a test of first choice when
estimating quantitative ovarian reserve before IVF. For the
prediction of cases with a very low chance for pregnancy,
ovarian reserve testing with the use of ultrasound appears
inadequate.
Broer conducted a systematic review and metaanalysis
of the existing literature for the outcome of excessive
response in IVF patients in relation to antiMllerian
hormone(AMH)/AFC.[49] Nine studies reporting on
AMH and five on AFC could be detected. Summary
estimates of sensitivity and specificity for AMH were
82% and 76%, respectively and 82% and 80%, respectively
for AFC. Comparison of the summary estimates and
ROC curves for AMH and AFC showed no statistical
difference. This review was recently reupdated in order
to evaluate whether ORTs add prognostic value to patient
characteristics, such as female age, in the prediction of
excessive response to ovarian hyperstimulation in patients
undergoing IVF, and whether their performance differs
across clinical subgroups.[50] A total of 4,786 women for
the main analysis, with a subgroup of 1,023 women with
information on all three ORTs. Fiftyseven studies were
included reporting on 32 databases. Female age had an
area under the receiver operating characteristic curve of
0.61 for excessive response prediction. AFC and AMH
significantly added prognostic value to this. Amodel with
female age, AFC, and AMH had an area under the receiver
operating characteristic curve of 0.85. The combination of
AMH and AFC, without age, had similar accuracy. Broer
concluded that AFC and AMH add value to female age
in the prediction of excessive response and that, for AFC
and FSH, the discriminatory performance is affected by
female age.
However, it remains unclear whether the probability of
oocyte fertilization and pregnancy can be estimated by
assessing the ovarian reserve with antral follicle counts. The
capacity of an oocyte to be fertilized in older women has
not been predicted solely by the agerelated decline in antral
follicle number.[27,31,43] Some young women with low antral
follicle counts and poor responsiveness to stimulation have
a higher IVF conception rate than the rate of conception
seen in older poor responders. Alower agerelated risk for
aneuploidy may contribute to the higher IVF conception
rate observed in younger poor responders.[27] While low
antral follicle counts signal a poorer response to ovarian
stimulation, additional predictors of ovarian reserve are
needed to identify which oocyte has the capacity to be
9

Lebbi and Temime: Monitoring folliculogenesis

fertilized and progress to clinical pregnancy following

ART.[31]
Vlaisavljevic studied the live birth rate per cycle compared
to the AFC. The rate was 33.3% for an AFC between 4
and 7 and increased to 68.1% for an AFC between 15 and
26.[9] Majunder K investigated whether AMH is better than
AFC in predicting oocyte yield and embryo quality after
controlled ovarian stimulation(COS) for IVF.[51] The author
conducted a prospective observational study involving 162
women (<40yearold) undergoing their first IVF cycle.
AMH and AFC measurements were made on day 3 of the
cycle within 3months of starting ovarian stimulation. Of
the 137 women who had fresh embryo transfer, 52 became
pregnant(32.1% pregnancy rate per cycle started) and 38
had a live birth(23.5% live birth rate per cycle started).
Both AMH and AFC had highly significant correlations
with the number of oocytes retrieved, and the number
of oocytes fertilized(P<0.001). The two markers were
also significantly associated with a number of top quality
embryos available for transfer and the number of embryos
frozen(P<0.01). About live birth, AMH performed better
than AFC(P<0.01 and P<0.05, respectively), but both
markers were more valuable in predicting the absence rather
than the occurrence of live birth(negative predictive value
84%). Therefore, about live birth, AMH performed better
than AFC.
The ovarian volume
Ovarian volume has been explored with twodimensional
and threedimensional ultrasonography to quantitate
ovarian reserve. The idea was that volume was believed to
be dependent upon follicle number.[3638,45] Ovarian volume
can be used as an estimate of ovarian reserve and to predict
ovarian responsiveness to stimulation and conception after
hypothalamic suppression has been excluded.[27,38,48,52,53]
Syrop etal. showed that ovarian volume has predictive
importance for ovarian response to ovulation induction.[36]
Later, Lass etal. indicated a strong association between
ovarian volume and ovarian reserve, and they recommended
that this parameter should be measured in all patients prior
to IVF.[40] Their results showed that small ovaries were
associated with poor response to human menopausal
gonadotropin and with a high cancellation rate during IVF.
Kuspesic etal. showed the number of retrieved oocytes
and the conception rate to be higher in patients with a
greater ovarian volume and a greater ovarian vascularity,
but these parameters were not independent of the total
antral follicle number.[54] Despite its promising predictive
importance in the beginning, it is nowadays accepted that
10

ovarian volume has a limited predictive value because it

is not an independent factor in the prediction of cycle
outcome. Sharara observed that in a group of IVF women
with small ovarian volumes(<3 cm3) the implantation and
pregnancy rates could be comparable to those with larger
ovarian volumes if they were treated with higher doses of
gonadotropins.[55]
ULTRASOUNDS AND ASSISTED
REPRODUCTIVE TECHNIQUES
The aim of COS using Gonadotrophins is to obtain
a multiple leading or dominant follicles containing a
mature oocyte. Before ultrasonography became a routine
method for monitoring of follicle development, this role
was attributed to serum estradiol(E2). After it had been
demonstrated that a direct correlation exists between
follicular growth and E2 level, ultrasound was introduced
for follicular growth, which previously had been so
indirectly evident. Ultrasound correlated precisely with E2
assays and the number of mature follicles. In the middle
of the follicular phase during COS, ultrasonographic
evaluation of follicle growth and number will influence
gonadotropin dose in the next days or the cancellation of
the cycle if no response is documented.[2] Monitoring of
follicle growth and its vascularization at the end of COS
could certainly increase the quality of the retrieved oocytes
considerably. Moreover, ultrasound is a useful tool to
measure the endometrial thickness during COS and thus
to evaluate the endometrial receptivity.
Kwan reported a metaanalysis about monitoring of
stimulated cycles in assisted reproduction(IVF and
intracytoplasmic sperm injection[ICSI]).[56] The author
concluded that there is no evidence from randomised trials
to support cycle monitoring by ultrasound plus serum
estradiol as more efficacious than cycle monitoring by
ultrasound only on outcomes of live birth and pregnancy
rates. Collectively, the studies reported in this metaanalysis
indicated that ultrasound recording of follicular size was
a useful adjunct or reference method for the timing of
ovulation. Serial ultrasound determination was expensive.
Current practice is to use other methods of ovulation timing
and to perform two or three ultrasonic measurements of
follicular size close to the time of ovulation to confirm
follicular maturation or collapse.
As mentioned previously, there is no doubt, that antral
follicle counts and their relative diameters are important
predictors of ovarian reserve, and they may be measured
with an acceptably high level of agreement both between
and within observers. Threedimensional ultrasound,
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Lebbi and Temime: Monitoring folliculogenesis

however, has not been shown to offer any significant

advantage over twodimensional imaging in determining
the number of antral follicles even at higher counts when
interobserver reliability is reduced. If we accept that the
threedimensional assessment of ovarian volume and
antral follicle count offers no significant advantage over
conventional assessment, then the only other parameter
to support a role for threedimensional ultrasound is the
assessment of vascularity through the quantification of the
power Doppler signal.[57]
Whilst the value of threedimensional ultrasound in
predicting suboptimal ovarian response is limited,
it may have a role in identifying those women who
are prone to an exaggerated response. Pan etal. used
threedimensional ultrasound on the day of human
chorionic gonadotropin(hCG) administration to study
patients demonstrating an exaggerated response to COS,
as defined by an estradiol level above 3000pg/mL on the
day of hCG administration or the retrieval of 15 oocytes
or more.[58] Ovarian volume and vascularity were found to
be significantly higher in 23 so called hyperresponders
compared with 35 normally responsive controls. The author
added that further work is warranted but probably using
a more generally agreed definition of hyperstimulation
in a larger patient population as the prevalence of
overstimulation will be less.
Today the better monitoring of COS in IVFICSI permits
a final good outcome and the prevention of multiple
pregnancies.
Finally, Embryo transfer with ultrasound guidance has
been shown to significantly increase the chance of embryo
implantation, but there is no standard evidence based
protocol.[59]
CONCLUSION
This manuscript is a review of the literature about
the various uses of ultrasound imaging in monitoring
folliculogenesis in natural cycles as well as in assisted
reproductive technologies, as the principal noninvasive
technique for evaluation of ovarian function and the
process of follicular growth. Serial realtime pelvic
ultrasonography is a rapid, reliable method for monitoring
follicular growth, rupture, and regression.
The evaluation of preovulatory follicles by ultrasounds
relies mainly on the study of the follicle diameter but also
on the follicle growth pattern, the follicular wall thickness,
the perifollicular vascularity and the perifollicular blood
flow.
IVF Lite | January-April 2015 | Vol 2 | Issue 1

Ultrasounds can also evaluate the ovarian reserve by the

study of the antral follicle count and the study of the
ovarian volume.
Finally, ultrasounds monitoring is important in assisted
reproductive techniques. During COS, ultrasonographic
evaluation of follicle growth and number will influence
gonadotropin dose in the next days or the cancellation of
the cycle if no response is documented. Monitoring of
follicle growth and its vascularization at the end of COS
could certainly increase the quality of the retrieved oocytes
considerably. Moreover, the better monitoring of COS in
IVFICSI permits a final good outcome.
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Source of Support: Nil, Conflict of Interest: None declared.

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