VIEWS AND REVIEWS

Ovarian follicular waves during the

menstrual cycle: physiologic insights
into novel approaches for
ovarian stimulation
Angela Baerwald, Ph.D., M.D., C.C.F.P.,a and Roger Pierson, M.S., Ph.D., F.E.A.S., F.C.A.H.S.b
a
Department of Academic Family Medicine and b Department of Obstetrics and Gynecology, College of Medicine,
University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Elucidation of multiple waves of antral ovarian follicular development during the menstrual cycle has challenged traditional concepts
of female reproductive physiology and foundations of assisted reproductive therapies. Approximately two-thirds of women develop two
follicle waves throughout an interovulatory interval and the remainder exhibit three waves of follicle development. Major and minor
waves of follicle development have been observed. Major waves are those in which a dominant follicle develops; dominant follicles
either regress or ovulate. In minor waves, physiologic selection of a dominant follicle is not manifest. Knowledge of waves of antral
follicular development has led to the global adoption of novel ovarian stimulation strategies in which stimulation can be initiated
at various times throughout the cycle. Random-start and luteal-phase ovarian stimulation regimens have had important clinical appli-
cations for women requiring urgent oocyte or embryo cryopreservation for fertility preservation prior to chemotherapy. Ovarian stim-
ulation twice in the same cycle, referred to as double stimulation, may be used to optimize clinical outcomes in women with a poor
ovarian response to stimulation as well as in those requiring fertility preservation before chemotherapy. (Fertil SterilÒ 2020;114:
443–57. Ó2020 by American Society for Reproductive Medicine.)
Key Words: Follicle, follicle waves, luteal-phase stimulation, random start ovarian stimulation, double stimulation
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/30540

within the first 2 weeks of the average

T
he human ovary is a dynamic not allow multiple investigations over
endocrine organ that undergoes 28 day menstrual cycle, termed the time and serial endocrine assays pro-
profound changes in both struc- ‘‘follicular phase,’’ while the corpus vide only indirect measures of ovarian
ture and function throughout the men- luteum grows in the absence of function. The advent of transvaginal
strual cycle. The growth and regression follicles during the last 2 weeks of the ultrasonography in the late 1980s pro-
of follicles and resultant development cycle, the ‘‘luteal phase’’ (16). vided a new tool for evaluating antral
of luteal glands within the ovary are Ovulation of a physiologically selected follicle development in both humans
responsible for cyclic hormonal dominant follicle marked the and animal species (17, 18). A model
changes. Early studies in the 1950s- transition between the follicular and depicting multiple waves of antral
1970s to characterize antral follicular luteal phases. In the absence of follicular development during the hu-
development during the menstrual conception, menses followed the man menstrual cycle has emerged
cycle were based on histologic charac- luteal phase and marked the transition with the use of both ultrasonographic
terizations of ovarian structure (post- to a new follicular phase (16). and endocrinologic methods. Coinci-
mortem or after oophorectomy) or Early histologic and endocrino- dentally, the most recent documenta-
endocrinologic markers of ovarian logic studies characterizing the men- tions of follicular waves in women
function over time (1–15). From those strual cycle have been fundamental (19, 20) supported early histologic
initial studies, it became generally for understanding female reproductive and ultrasonographic studies (4, 5, 18,
accepted that antral follicles grow physiology. However, histology does 21, 22). Collectively, there is now evi-
dence to validate the idea that multiple
Received May 15, 2020; revised and accepted July 7, 2020.
A.B. has nothing to disclose. R.P. has nothing to disclose. waves of antral folliculogenesis occur
Reprint requests: Angela Baerwald, Ph.D., M.D., CCFP, Department of Academic Family Medicine, Col- throughout the human menstrual cycle,
lege of Medicine, University of Saskatchewan 3311 Fairlight Drive, Saskatoon, Saskatchewan SK
S7M 3Y5, Canada (E-mail: [email protected]).
similarly to those previously reported
in several other mammalian species
Fertility and Sterility® Vol. 114, No. 3, September 2020 0015-0282/$36.00 (23, 24). The concept of follicular waves
Copyright ©2020 American Society for Reproductive Medicine, Published by Elsevier Inc.
https://doi.org/10.1016/j.fertnstert.2020.07.008 has challenged traditional models of

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VIEWS AND REVIEWS

ovarian physiology and led to the optimization of ovarian

FIGURE 1
stimulation protocols for women undergoing assisted repro-
duction (25–27).
The objective of the present minireview is to summarize A
the different theories of human antral folliculogenesis, novel
ovarian stimulation approaches that have recently been
developed, clinical applications for these novel protocols, ov ov
and directions for future research.

MATERIALS AND METHODS

A literature search was conducted in the United States Na-
tional Library of Medicine’s PubMed database. The following
search terms were used from article title fields: random start
stimulation, luteal phase stimulation, duostim, double stimu-
lation, luteal, ovarian stimulation, follicle waves, waves,
ovarian, and emergency IVF. Only English-language articles
were chosen for review. Original and review articles were
included. B

THEORIES OF ANTRAL OVARIAN FOLLICULAR

DEVELOPMENT DURING THE MENSTRUAL ov ov
CYCLE
Collectively, studies over the past 70 years have resulted in the
development of three theories of antral follicular development
(Fig. 1).

1) Continuous Recruitment Theory

Research conducted in animals (rats, sheep) and women led
investigators to conclude that antral follicles %4–6 mm in
size were ‘‘recruited’’ for growth continuously throughout
the estrous and menstrual cycle, independently from FSH C
and LH (8, 28–34). From the continuous pool of recruited
antral follicles, a single dominant follicle developed in the
early follicular phase, resulting in ovulation at mid-cycle. ov ov
The dominant follicle was thought to be selected because it
was at an optimal stage of maturity to be able to respond to
rising FSH following luteal regression.

2) Cyclic Recruitment Theory

In contrast to the concept of continuous recruitment of folli-
cles %4–6 mm in size, recruitment has been described as a M
cyclical increase in the number of antral follicles 2–5 mm in
size from a continuous supply of smaller follicles, occurring
once, in the late luteal phase or early follicular phase of the Luteal Follicular
cycle (35–37). Rising FSH, following luteal regression, was Phase Phase
thought to be responsible for the recruitment of a cohort of
follicles 2–5 mm in size that left the resting pool of Three theories of antral follicular development: (A) continuous
recruitment theory; (B) single recruitment episode theory; and (C)
primordial follicles around the same time several months wave theory. M ¼ menses; OV ¼ ovulation. Reproduced with
previously (38). Therefore, antral follicle recruitment was permission from Baerwald et al. (70).
referred to as secondary recruitment, as distinguished from Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.
the primary recruitment of preantral follicles from the
primordial pool (39).
Secondary recruitment of the antral follicular cohort was (CL) were thought to suppress FSH and resultant growth of
thought to result from either stimulation (38, 40) or preven- antral follicles >4 mm in size throughout the luteal phase
tion of atresia (41–46) by FSH. In women and nonhuman (8, 12, 35, 44, 47–57). Follicles detected histologically in the
primates, estradiol and inhibin A from the corpus luteum luteal phase were found to be atretic (44), which was

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interpreted to mean that limited growth of healthy follicles was longer in women with three versus two waves (29 vs.
occurred under the influence of the CL. 27 days) (19).
From the single recruited cohort of follicles 2–5 mm in Major waves were characterized as those in which a
size, a dominant follicle was shown to be selected for prefer- dominant follicle develops (20). Dominant follicles were
ential growth in the early to middle follicular phase, resulting defined as those that developed to R10 mm and whose
in ovulation (4, 35, 42, 45, 46, 58–61). On day 6–9 of the continued growth exceeded the diameter of the next largest
follicular phase, at a mean diameter of 10 mm, the follicle in the wave by R2 mm. In all women, the final ma-
dominant follicle continued to grow while the underlying jor wave of the IOI was ovulatory, whereas preceding major
(i.e., subordinate) follicles regressed (4, 35, 42, 45, 46, 61). waves were anovulatory. Minor waves were defined as
From the FSH threshold/window/gate hypothesis, it was those in which a dominant follicle did not develop; all mi-
proposed that the duration of the rise in FSH above a nor waves were anovulatory (20). The following patterns of
critical level determines the number of dominant follicles major and minor follicular wave dynamics were docu-
selected from the recruited cohort (28, 40, 62, 63). mented: minor major (29/50, 58%), major major (5/50,
Increasing the duration of the rise in FSH above the 10%), minor minor major (10/50, 20%), minor major major
threshold, as seen with exogenous gonadotropin use during (3/50, 6%), and major major major (3/50, 6%). A schematic
ovarian stimulation, thereby allows multiple follicles to be diagram depicting two versus three waves of antral follicle
selected simultaneously (64). development is shown in Figure 2) (70). More recently,
The introduction of transabdominal ultrasonography in ovulation of a luteal-phase dominant follicle during
the late 1970s resulted in the ability to monitor follicle growth menses was reported in a woman during the perimenopause
over time, albeit at suboptimal resolution. No, or nonsignifi- (71). Three ovulations occurred within 45 days. Ovulation
cant, increases in the numbers of antral follicles 2–5 and 2–10 was confirmed on all three occasions by a rise in serum
mm throughout the cycle were initially reported (45, 65). The LH, followed by ultrasonographic detection of a CL in asso-
nonsignificant rises in antral follicle count in the early luteal ciation with a rise in serum P. These study findings pro-
phase were thought to reflect interindividual differences and vided the first documentation of spontaneous ovulation
to be of limited biologic importance (45). of a luteal-phase dominant follicle (71).
The hormonal regulation of antral follicular waves
throughout the menstrual cycle is not fully understood. Pre-
3) Follicular Wave Theory liminary data suggest that the emergence of each follicular
In contrast to notions of continuous recruitment, or a single wave throughout the IOI is preceded by a rise in serum FSH
episode of cyclic recruitment, cohorts of antral follicles, (20), which is consistent with previous reports in domestic
referred to as waves, have been shown to emerge multiple farm animals (72). In women of reproductive or advanced
times during the menstrual cycle. The earliest reports of follic- reproductive age, dominant follicles developing within the
ular waves in women were based on histologic evaluation of luteal phase may, or may not, produce E2 (20, 71). Thus, the
ovaries (4). Subsequent studies used transabdominal (18, 21, potential exists for both luteal and follicular origins of E2 dur-
22) and transvaginal ultrasonography (19, 20) to further sup- ing the luteal phase. The development of luteal-phase domi-
port the notion that multiple waves of antral follicles devel- nant follicles in women of advanced reproductive age has
oped throughout the menstrual cycle in healthy women. been associated with lower P, lower inhibin A, and reduced
A follicular wave is defined as the synchronous growth of luteal growth (71, 73). Continued research is required to
a group of antral follicles 2–5 mm in size that occurs at reg- more fully understand the pituitary and ovarian factors influ-
ular intervals during the menstrual/estrous cycle; follicles in encing the emergence of multiple antral follicle waves and the
each wave are similar, but not identical, in diameter (17, 19, selection of more than one dominant follicle at different times
24, 66). Thus, the term ‘‘wave’’ is synonymous with ‘‘second- during the menstrual cycle.
ary recruitment.’’ Either two or three waves of antral follicle
development have been reported in 100% (50/50) of
reproductive-age women evaluated with the use of transvagi-
nal ultrasonography (19, 20). An interovulatory interval (IOI) CLINICAL APPLICATIONS OF OVARIAN
versus menstrual cycle was used as an ovarian versus uterine FOLLICULAR WAVES
reference point for characterizing ovarian function and to The goal of ovarian stimulation is to induce the growth of
maintain consistency with follicular wave patterns reported multiple dominant follicles before intrauterine insemination
in domestic farm animal species (17, 23, 67–69). An IOI is or in vitro fertilization in patients undergoing assisted repro-
the period of time from one ovulation to the subsequent duction. The collective knowledge of waves of antral follicu-
ovulation, which conceptually represents a menstrual cycle logenesis in women has now been applied to the development
(intermenstrual interval) shifted forward or backwards by of novel strategies for ovarian stimulation. New strategies,
2 weeks. Sixty-eight percent of women (34/50) developed adopted globally, have been of particular clinical relevance
two waves throughout an IOI and 32% developed three waves for women requiring urgent ovarian stimulation and oocyte
(Fig. 2). In women with two follicular waves, waves emerged, or embryo freezing before chemotherapy, as well as for
on average, on days 1 and 14 (day 0 ¼ ovulation no. 1) (19). women with a poor response to conventional ovarian stimu-
In women with three follicular waves, waves emerged, on lation. Examples of conventional versus novel ovarian stim-
average, on days 0, 12, and 18 (19). The length of the IOI ulation strategies are shown in Figure 3.

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FIGURE 2

Schematic of two versus three waves of antral follicular development during one interovulatory interval/menstrual cycle in women. OV ¼ ovulation.
Reproduced with permission from Baerwald et al. (70).
Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.

Conventional Ovarian Stimulation Regimens preceded by hormonal contraception to control the timing
(Early Follicular-Phase Starts) of initiating FSH and synchronize cycles among patients
(80). The withdrawal of hormonal contraception before
Ovarian stimulation protocols have evolved over the past 50 initiation of ovarian stimulation allows the synchronization
years, in which exogenous FSH is initiated in the early follic- of stimulation with the timing of wave emergence (81).
ular phase, typically on day 2 or 3 following menses (74). Day Short or long GnRH agonist (GnRH-a) protocols for
2–3 of the cycle reflects the average timing of secondary ovarian stimulation have been developed to control the
recruitment, more recently referred to as emergence of the timing of stimulation initiation and to prevent a premature
first follicular wave of the menstrual cycle (19, 20). LH surge. In long protocols, GnRH-a is administered for 2
Recombinant, urinary, or highly purified FSH is adminis- weeks, and then hMG or rFSH is initiated (82–85). GnRH-a
tered to induce the growth of multiple follicles (38, 75–78). is continued until timing of trigger before IVF to prevent a
The gonadotropin dose is adjusted throughout stimulation premature LH surge. In short protocols, GnRH-a is typically
based on the number of developing follicles and serum E2 initiated on day 2 of the follicular phase, continuing concom-
concentrations. LH may be added to the stimulation itantly with hMG or rFSH until trigger.
regimen in the mid to late follicular phase (79). Initiation of GnRH antagonists (GnRH-ants) are administered in either
urinary FSH (hMG) or recombinant FSH (rFSH) may be a fixed or a flexible protocol to prevent a premature LH surge

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FIGURE 3

Random-start stimulation: an example of early follicular-phase (conventional) versus late follicular-phase versus luteal-phase ovarian stimulation
protocols. Reproduced with permission from Cakmak et al. (93).
Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.

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before oocyte retrieval for IVF (86, 87). In the fixed protocol, initiation of therapy in the mid to late follicular or luteal
GnRH-ant is administered 6 days after initiating hMG or phase are described below (and summarized in Table 1).
rFSH. In the flexible protocol, GnRH-ant is administered after Mid to Late Follicular-Phase Starts. Initiation of ovarian
initiating hMG or rFSH, when the largest follicle reaches stimulation in the mid to late follicular phase has been defined
12–14 mm. Clomiphene citrate also has been used to prevent as starting therapy >7 days after menses in the presence of a
an endogenous premature LH surge. Clomiphene citrate is dominant follicle >13 mm in size and/or P is <2 ng/mL (93).
typically initiated on day 8 of the cycle, as an adjuvant to go- Both urinary and recombinant FSH formulations have been
nadotropins, and continued daily until trigger (88–90). used, with or without LH (Table 1). Protocols combining exog-
In women undergoing IVF, hCG or GnRH-a is adminis- enous FSH with aromatase inhibitors (tamoxifen, anastrazole,
tered when one or more follicles reach >17–18 mm to induce or letrozole) have been studied (79, 80). Letrozole is the rec-
final oocyte maturation before oocyte retrieval (91). GnRH-as ommended aromatase inhibitor for oncofertility patients
are typically used instead of hCG for oocyte maturation in pa- because it reduces serum E2 concentrations without compro-
tients at risk for ovarian hyperstimulation, owing to the luteo- mising clinical outcomes (98).
lytic effect of GnRH-a (92). GnRH-ant protocols have been used with random-start
stimulation in a variety of different ways. In women undergo-
ing elective oocyte cryopreservation, GnRH-ant fixed proto-
Random-Start Ovarian Stimulation cols have been developed in which the GnRH-ant is started
Documentations of ovarian follicular waves during the men- concomitant to initiating hMG or rFSH and continued until
strual cycle have provided opportunities for initiating ovarian trigger (99). Antagonists have also been administered on
stimulation at multiple times during the menstrual cycle. day 10 and continued until E2 <60 pg/dL (100). Flexible
Theoretically, stimulation at different times of the cycle takes GnRH-ant protocols also have been used, in which a GnRH-
advantage of inducing the growth of follicles from whichever ant is administered only after a dominant follicle R13 mm
wave is present at the time of initiation. From a practical in size is detected (101).
perspective, it is difficult to predict when a wave will emerge In a separate study, if the first subordinate follicle (i.e., the
within a given woman owing to the variability in timing of largest follicle underlying the dominant follicle) at the time of
wave emergence. Therefore, the practice of ‘‘random start starting FSH was <12 mm and remained <12 mm before a
stimulation’’ has arisen, in which ovarian stimulation can spontaneous surge, GnRH-ant was not initiated until after a
be initiated at any time of the cycle (93, 94). spontaneous LH surge and ovulation occurred. A luteal-
Conventional ovarian stimulation protocols require 2 phase follicular wave then emerged and GnRH-ant was initi-
weeks of exogenous gonadotropin administration, sometimes ated to prevent a subsequent endogenous spontaneous LH
preceded by up to 2 weeks of GnRH-a, before oocyte retrieval. surge (93). In comparison, if the first subordinate follicle ex-
Women with cancer may present for therapy at any stage of ceeded 12 mm in the late follicular phase, GnRH-ant was
their menstrual cycle, so the use of protocols that require initi- started before the spontaneous LH surge and continued until
ation of therapy in the early follicular phase are likely to delay trigger. The follicular phase was prolonged because the spon-
cancer treatment. Random-start stimulation regimens have taneous LH surge was suppressed, a follicular wave was
become standard of practice for oncofertility patients (95). induced to grow, and GnRH-a trigger was administered on
The use of aromatase inhibitors as an adjunctive therapy to day 19 (93). From those earlier studies, many clinicians
exogenous FSH has been implemented in these patients to have adopted the practice of starting a GnRH-ant based on
minimize any potential risk of supraphysiologic E2 from stim- the diameter of the largest follicle at the time of the mid to
ulation for promoting the growth of estrogen-sensitive tu- late follicular phase. That is, if a dominant follicle (defined
mors (e.g., endometrial and estrogen receptor–positive as >10 or >14 mm) is not present in the mid to late follicular
breast cancer) (78). phase, rFSH or hMG is initiated and GnRH-ant started at a
Endometrial development is not synchronized with later date in either a fixed or a flexible protocol (94, 102,
ovarian function in random-stimulation starts. Therefore, 103). If a dominant follicle >10 mm in size is present, a
these protocols require oocyte retrieval, oocyte/embryo cryo- GnRH-ant may be started concomitant to rFSH or hMG
preservation, and subsequent thawed embryo transfer. Ad- (102, 104). Alternatively, if a dominant follicle >14 mm in
vancements in oocyte and embryo cryopreservation, size is present at the initial visit in the mid to late follicular
particularly vitrification, have allowed the tailoring of phase, ovulation may be induced and a luteal-phase stimula-
ovarian stimulation protocols in oncofertility patients. Cur- tion (LPS) pursued (105) (described below). When one or more
rent oocyte and embryo vitrification protocols are associated follicles attain a diameter of >17–18 mm, hCG or GnRH-a is
with greater clinical pregnancy and live birth rates than tradi- administered to induce final oocyte maturation. Oocytes are
tional slow freezing (96). Furthermore, ongoing pregnancy retrieved, vitrified, or fertilized for transfer at a later date.
rates in frozen (vitrification) versus fresh cycles have been Clomiphene citrate may be used as an alternative to
shown to be similar: 44% and 42%, respectively (97). Thus, GnRH-a or GnRH-ant for suppressing a premature LH surge
random-start stimulation followed by oocyte or embryo vitri- (88–90). As with conventional stimulation, clomiphene
fication is a novel approach in which ovarian and uterine citrate is initiated on approximately day 8 following FSH
functions are decoupled to provide patient-oriented initiation and continued daily until trigger. In addition,
reproductive medicine. Random-start protocols comparing progestins may be initiated daily from cycle day 2–3,

448 VOL. 114 NO. 3 / SEPTEMBER 2020

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TABLE 1

Comparison of random-start ovarian stimulation protocols.

Day of Total no. of Clinical
stimulation Stimulation Stimulation Trigger oocytes Fertilization pregnancy
Study Design Sample n Age, y start regimen duration, d method retrieved rate rate

von Wolffe Prospective Fertility FPS ¼ 28 27.6  4.9 RS FPS: GnRH-a þ rFSH or hMG 10.6  2.5 hCG 13.1 51.1 –
et al. 2009 preservation LPS ¼ 3 31.2  5.7 LPS: rFSH þ concom. GnRH-ant 11.4  2.6 10.0 60.8
Bedoschi Case report Fertility 2 31 17 GnRH-ant concom. rFSH þ rLH 7 hCG 12 83 –
et al. 2010 preservation 24 22 7 12 –
Sonmezer Case report Fertility 3 29 14 rFSH þ letrozole þ GnRH-ant 9 hCG 9 87.5 –
et al. 2011 preservation 26 11 5 d later 12 17 83.3
26 17 9 16 69.2
Nayak Case report Fertility 4 33 – rFSH þ GnRH-ant (flex) 10 GnRH-a 40 96.7 –
et al. 2011 preservation 30 17 8 24 93.3
31 10 10 18 100
24 10 13 14 100
Cakmak Retrospective Fertility EFPS ¼ 93 33.8  5.3 RS rFSH and/or hMG þ GnRH-ant 9.3 (9.0–9.5) GnRH-a or hCG 14.4 72 –
et al. 2013 preservation LFPS ¼ 13 34.2  4.6 (random start, total) (flex) þ letrozole 10.5 (9.6–11.4)a 13.0 85
LPS ¼ 22 11.2 (10.5–12.0)a 15.5 88
Buendgen Prospective Normal EFPS ¼ 30 31.7  3.6 2–3 EFPS: hMG þ GnRH-ant (fixed) 9.1  1.2a hCG 10.0 27 30
et al. 2013 responders LPS ¼ 10 31.4  2.6 19–21 LPS: hMG þ concom. GnRH-ant 11.7  1.6a 8.8 33 10
Rashidi Case series Fertility FPS ¼ 11 29.1  4.8 RS rFSH þ GnRH-ant (flex) 7.8  1.0 hCG or GnRH-a 7.8 – –
et al. 2014 preservation LPS ¼ 3 28.1  2.5 8.7  2.0
Martinez Pilot study Normal responders, FPS ¼ 9 26.8  3.0 (total) 2 FPS: rFSH þ GnRH-ant (flex) 10.4  1.7 GnRH-a 16.7 73.3 62.5
et al. 2014 (cross-over) oocyte donors LPS ¼ 9 15 LPS: rFSH þ concom. GnRH-ant 9.9  1.3 22.5 76.5 58.3
Wang Retrospective Normal responders FPS ¼ 1,287 30.8  3.0 2–3 FPS (mild): GnRH-a þ CC þ 9.6  2.0 GnRH-a 3.7a – 43.7
et al. 2015 FPS ¼ 745 30.4  3.2 2–3 letrozole þ hMG and/or 8.2  1.7 9.1b 41.9
LPS ¼ 708 30.5  3.0 1–3 after OPU GnRH-ant (flex) 10.4  1.8 10.9a 46.2
FPS (GnRH-a): GnRH-a þ CC þ
letrozole þ hMG and/or
GnRH-ant (flex)
LPS: hMG þ letrozole þ MPA
Kim et al. Retrospective Fertility EFPS ¼ 6 33.5 (24–39) RS rFSH  letrozole þ GnRH-ant 11.8 (10–13) hCG or GnRH-a 11.5 – –
2015 preservation LFPS ¼ 11 29.0 (17–37) (flex) 10.7 (9–14) 18
LPS ¼ 5 30.6 (20–39) 12.3 (11–13) 9
Cai et al. Case report Fertility 1 17 RS rFSH 10 GnRH-a 17 – –
2016 preservation
von Wolffe Retrospective Fertility EFPS ¼ 472 29.3  5.8 1–5 EFPS: rFSH or hMG þ GnRH-ant 10.8  2.4 hCG or GnRH-a 11.6 a
– –
et al. 2016 preservation LFPS ¼ 109 29.6  5.8 6–14 (fixed) 10.6  2.7a 13.9a
LPS ¼ 103 30.4  5.7 R15 LFPS: rFSH or hMG þ GnRH-ant 11.5  2.2a 13.6
(flex)
LPS: rFSH þ concom. GnRH-ant
Li et al. Retrospective POR FPS ¼ 98 39.3  3.5 3 FPS: CC  hMG þ GnRH-ant 7.8  4.2 hCG 2.0a – 17.7
2016 LPS ¼ 33 40.5  4.0 1–2 after OV (flex) 10.3  5.5 2.8a 20.0
LPS: CC þ hMG
Cavagna Prospective Fertility EFPS ¼ 11 30.7  3.5 rFSH or hMGþ letrozole  10.0  1.4 GnRH-a 9.2 – –
et al. 2017 preservation LFPS ¼ 19 31.0  5.3 tamoxifen þ enoxaparin þ 9.7  0.5 10.9

Fertility and Sterility®

LPS ¼ 10 30.0  4.2 GnRH-ant 10.2  1.2 13.7
Pereira Retrospective Elective oocyte CS ¼ 859 36.9  3.7 RS CS: GnRH-a flare or GnRH-ant 9.5 (8–11) hCG and/or GnRH-a 13.1 – –
et al. 2017 cryopreservation EFPS ¼ 342 37.1  3.3 (flex) þ rFSH or hMG 9.5 (8.5–12) 12.7
LFPS ¼ 42 37.1  3.4 EFPS/LFPS/LPS: rFSH þ letrozole 11.5 (7.5–13.5) 13.0
LPS ¼ 59 37.2  3.1 þ GnRH-ant (flex) 11 (8–12) 13.2
Sarais Retrospective Fertility FPS/SA ¼ 40 SA ¼ 30.4  5.4 RS SA: SA rFSH þ letrozole þ GnRH- 10.6a GnRH-a 11.3 – –
et al. 2017 preservation FPS/LA ¼ 40 LA ¼ 31.0  6.2 ant (flex) 11.4a 13.7
LPS/SA ¼ 22 LA: LA rFSH þ letrozole þ GnRH-
LPS/LA ¼ 38 ant (flex)
449

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450

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TABLE 1

Continued.

Day of Total no. of Clinical

stimulation Stimulation Stimulation Trigger oocytes Fertilization pregnancy
Study Design Sample n Age, y start regimen duration, d method retrieved rate rate

Cavagna Prospective Fertility EFPS ¼ 42 31.4  3.5 RS EFPS: hMG þ tamoxifen þ 9.9  1.3 GnRH-a 11.0 – –
et al. 2018 preservation LFPS ¼ 20 29.8  5.4 GnRH-ant (flex) 9.7  1.3 10.4
LPS ¼ 47 31.9  4.4 LFPS: hMG þ tamoxifen þ 10.3  1.5 12.8
concom. GnRH-ant
LPS: rFSH þ tamoxifen þ GnRH-
ant (flex)
(enoxaparin used in all protocols)
Jin et al. Prospective POR FPS ¼ 52 37.6  5.7 3 FPS: CC or letrozole þ hMG þ 8.9  2.4 hCG 2 (range 1–4) 89.3 30.4
2018 LPS ¼ 132 37.0  5.2 1–3 post OV GnRH-ant 11.2  3.0 3 (1–5) 79.4 40.0
LPS: CC þ hMG
Campos Prospective Fertility FPS ¼ 13 32.8  1.4 1–14 rFSH þ GnRH-ant (flex) 10.6  2.1 GnRH-a 20.4 – –
2018 preservation LPS ¼ 13 30.3  2.6 15–28 10.0  0.4 18.5
Muteshi Retrospective Fertility EFPS ¼ 103 32.6 (31–34)* RS RS: GnRH-ant for 3 d þ rFSH þ 11.5 (11.2–12.0)* hCG or hCG 11.9 60.5 –
2018 preservation RS ¼ 24 30.5 (28–33)* GnRH-ant 12.2 (10.7–13.7)* 12.9 45.7
Zhang Retrospective POR FPS ¼ 231 37.4  4.8 3 FPS: CC þ hMG 8.1  2.8 hCG 2.4  1.5 80.0 33.0
2018 LPS ¼ 154 39.1  4.8 2–7 after OV LPS: hMG þ CC þ progestin 11.3  3.6 2.7  2.1 83.9 28.4
Note: Data are presented as mean  standard deviation, unless specified otherwise. *Data are presented as median  IQR or mean (range). CC ¼ clomiphene citrate; concom. ¼ concomitant with; CS ¼ conventional stimulation; EFPS ¼ early follicular-phase stimulation;
fixed ¼ fixed protocol; flex ¼ flexible protocol; FPS ¼ follicular-phase stimulation; GnRH-a ¼ GnRH agonist; GnRH-ant ¼ GnRH antagonist; IQR ¼ interquartile range; LA ¼ long-acting FSH; LFPS ¼ late follicular-phase stimulation; LPS ¼ luteal-phase stimulation; MPA ¼
medroxyprogesterone acetate; OPU ¼ oocyte pick-up; OV ¼ ovulation; POR ¼ poor ovarian responder; rFSH ¼ recombinant FSH; rLH ¼ recombinant LH; RS ¼ random-start stimulation; SA ¼ short-acting FSH.
a
Significant difference between groups (P<.05).
Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.
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 Fertility and Sterility®

concomitant to hMG, and have been shown to effectively Double stimulation, referred to as the DuoStim protocol, has
inhibit a premature LH surge (106–109). specific clinical applications for women with a poor response
Luteal-Phase Starts. Several studies have been published on to conventional stimulation (122). Women can undergo a sec-
the use of ovarian stimulation in the luteal phase, referred to ond stimulation in the luteal phase rather than waiting for a
as luteal-phase-only starts. Luteal-phase starts have been new cycle to reinitiate therapy. DuoStim protocols have also
defined as those initiated at least 14 days after menses, in been used in women before chemotherapy to increase the to-
which P is >3–7 ng/mL and/or a CL is visualized ultrasono- tal number of oocytes available for cryopreservation (123). An
graphically (93, 110–112). Similarly to stimulations example of a DuoStim protocol is shown in Figure 4 (124).
initiated during the follicular phase, both rFSH and hMG The dose and timing of follicular-phase stimulation (FPS)
with or without LH have been used (Table 1). The dose of versus LPS used in DuoStim protocols are consistent with
gonadotropins used is often dependent on AFC at the time those described individually for random-start stimulation
of initiation; the gonadotropin dose is adjusted throughout (as summarized in Table 2). In some reports, withdrawal of
stimulation based on the number of developing follicles and ovarian suppression by oral contraception or E2 is used to
serum E2 concentrations (111). Letrozole and clomiphene synchronize wave emergence and initiation of stimulation
citrate have been used as adjunctive therapies (Table 1). among patients (124–127). FPS is initiated on day 2–3 of
The use and timing of GnRH-ant administration has been the cycle with the use of either recombinant FSH (125),
variable with luteal-phase ovarian stimulation because of a urinary FSH (100, 122, 128), or both recombinant and
lack of understanding about luteal influences on dominant urinary FSH (129); adjunctive therapy with clomiphene
follicle development. In many studies, rFSH and a GnRH- citrate (122, 128), letrozole (122, 123), and/or LH has been
ant have been administered in parallel, beginning at any stage reported. Moderate and minimal stimulation protocols have
of the luteal phase (105, 110, 113, 114). Sonmezer et al. (94) been used (Table 2). Either a fixed or a flexible GnRH-ant pro-
reported starting a GnRH-ant 5 days after initiating ovarian tocol is typically used for FPS.
stimulation in the luteal phase and continuing to trigger. In A GnRH-a or hCG is used to trigger oocyte maturation
comparison, Muteshi et al. (115) reported initiating a GnRH- once at least two follicles reach a diameter R17–18 mm. In
ant for 3 days during the luteal phase followed by FSH on some studies, a GnRH-a is preferred over hCG for the FPS
the 4th day; both medications were continued until the time trigger, in accordance with the hypothesis that the long
of trigger. GnRH-ant flexible protocols, in which GnRH-ant half-life of hCG may have a negative effect on the growth
is initiated once a follicle R12–14 mm in size is detected, of follicles from the subsequent LPS (126). Oocytes are aspi-
also have been reported (93, 99, 101, 104, 111, 116, 117). rated 36 hours after trigger and vitrified or fertilized
Alternatively, the lack of GnRH-ant use during LPS has in vitro for later transfer.
been described (118, 119). It has been proposed that endoge- The transition from FPS to LPS occurs 2–5 days after the
nous P from the CL during the luteal phase suppresses a pre- first oocyte retrieval. Stimulation is reinitiated using the same
mature endogenous LH surge; therefore, exogenous P may protocol as with FPS, regardless of the number of antral fol-
not be required during LPS. Knowledge of endogenous P licles present (118, 124, 125, 127). Fixed and flexible
from the CL suppressing a premature LH surge during LPS GnRH-ant protocols have been used for LPS (100). Alterna-
has resulted in the administration of progestins during tively, no GnRH-ant has been used in LPS (118, 126, 130).
random-start stimulation protocols (see above). In three studies, ibuprofen was administered at the time of
Regardless of the exogenous FSH regimen used, hCG or trigger in place of a GnRH-a or GnRH-ant to inhibit prema-
GnRH-a is used to trigger final oocyte maturation once one ture follicle rupture for both FPS and LPS (122, 128, 130).
or more follicles reach >17–18 mm. Oocytes are aspirated, Progestin supplementation has been proposed for LPS
vitrified or fertilized in vitro, and a thawed embryo transfer within DuoStim protocols. In one study, a progestin was given
cycle planned. from the time of the first oocyte retrieval throughout the dura-
In addition to IVF, luteal-phase ovarian stimulation has tion of LPS. The reasoning was that exogenous P would post-
been used in conjunction with in vitro maturation. Three pone menstruation (131).
cases have been documented in which immature oocytes Generally, a GnRH-a or hCG is used to induce final oocyte
were retrieved on random days of the luteal phase prior to maturation. A second attempt is made for oocytes to be vitri-
chemotherapy; oocytes underwent subsequent successful fied or fertilized in vitro. The resulting embryos are trans-
in vitro maturation and cryopreservation (120). More ferred at a later date, owing to asynchrony between uterine
recently, 17 oocytes were obtained from a 17-year-old and ovarian status. If no oocytes are available following
woman undergoing urgent LPS before a blood stem cell trans- FPS, LPS is initiated on day 18–20 of the cycle and oocyte
plantation; ten mature oocytes were cryopreserved, and the retrieval is followed by oocyte cryopreservation or fertiliza-
remaining seven underwent in vitro maturation and were tion (118, 125).
subsequently frozen (121).
CLINICAL OUTCOMES
Double Ovarian Stimulation Random-Start Stimulation
Double ovarian stimulation protocols have been developed in Various clinical outcomes have been reported from studies
which conventional stimulation in the early follicular phase is comparing random-start versus conventional ovarian stimu-
followed by a second stimulation within the same cycle. lation to date. In a minority of studies, luteal-phase-only

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VIEWS AND REVIEWS

FIGURE 4

An example of a double-stimulation protocol. OPU ¼ oocyte pick-up. Reproduced with permission from Ubaldi et al. (124).
Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.

stimulation was associated with an increased duration of further research to evaluate pregnancy and live birth out-
stimulation (103), increased cumulative FSH dose (93, 110, comes is required.
112, 122), and increased oocyte retrieval rate (103, 119,
132) compared with conventional early FPS. However, in
CONCLUSION
most studies, no differences in outcomes were reported be-
tween random-start versus conventional stimulation Waves of ovarian follicular development have been identified
(Table 1). and characterized in every mammalian species in which serial
Greater oocyte retrieval and fertilization rates have been measurements of follicle development and hormone produc-
reported with letrozole versus tamoxifen (79, 80) as adjunc- tion have been simultaneously obtained (70). It has now been
tive therapy for random-start stimulation in oncofertility pa- 70 years since the original histologic reports (4, 5) and almost
tients. Similar oocyte maturity and fertilization rates have 20 years from the combined ultrasonographic and endocrino-
been reported in IVF and ICSI cycles with versus without le- logic characterizations of follicular waves in women (19, 20).
trozole (81, 82). These results can be interpreted to mean Research conducted to date has led to novel luteal-phase,
that letrozole does not provide a deleterious effect on stimu- random-start, and DuoStim protocols for ovarian stimulation
lation with FSH. that have become standard of care in women requiring oocyte
No differences in fertilization or clinical pregnancy rates cryopreservation before chemotherapy or those with a previ-
have been reported between conventional versus random- ous or anticipated poor response to stimulation.
start stimulation (Table 1). In two studies, no differences in Poor ovarian responders represent 17% of infertile
live birth rates between LPS versus FPS were reported (131, women in Canada (Canadian Assisted Reproductive Technol-
133). In contrast, Wang et al. reported greater live birth rates ogies Register Statistics 2019, Canadian Fertility and Androl-
after LPS compared with conventional FPS, and similar live ogy Society) and 30% of infertile women in the United States
birth rates for LPS versus minimal FPS (132). Further research (136). Various stimulation strategies have been investigated
is needed to evaluate live birth rates with random-start versus in the poor-responder population of women, with limited
conventional ovarian stimulation. Preliminary data to date overall success in increasing the probability of a live birth.
have shown no differences in neonatal outcomes or incidence DuoStim appears to provide a safe and patient-oriented
of congenital malformations between LPS versus conven- means of increasing the number of oocytes obtained without
tional stimulation starts (132, 133); however, data obtained compromising pregnancy outcomes. Continued prospective
to date are limited. randomized trials are required to confirm whether the use of
DuoStim protocols increases the probability of delivering a
healthy baby.
More than 7 million women were diagnosed with some
Double Stimulation form of cancer from 1975 to 2012, i.e., 95,000 women of
Greater cumulative hMG doses (118, 122, 125, 126, 130, 131, ages 20–40 years (75). From 2002 to 2012, 83% of women
134, 135), duration of stimulation (118, 135), and oocyte <45 years of age with cancer survived, owing to diagnostic
retrieval rates (125, 129) have been documented for LPS and therapeutic advancements (75). Therefore, counseling
versus FPS within DuoStim protocols. Cancellation rates are regarding options for future childbearing in young female
reportedly similar between FPS and LPS (122, 125, 134). cancer patients has become common practice. Rapid access
Despite initial controversy, it has been shown that aneuploidy to strategies for preserving fertility is required in this popula-
rates are similar with follicular-phase versus luteal-phase tion, owing to the gonadotoxic nature of chemotherapy (76).
starts in DuoStim protocols (124). A similar incidence of Random-start stimulation has now become standard practice
OHSS (100) has been documented between FPS versus LPS for women requiring fertility preservation before chemo-
with the use of DuoStim. Similarly, no differences have therapy (26). DuoStim has also been shown to increase the to-
been reported in clinical pregnancy rates with the use of Du- tal number of oocytes available for cryopreservation in these
oStim versus conventional stimulation (Table 2); however, women without delaying cancer therapy (123).

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TABLE 2

Comparison of double ovarian stimulation protocols.

Stimulation No. of oocytes Clinical
Day of stimulation duration, d: Cumulative FSH dose (IU): retrieved:a pregnancy
Study Design Sample Age, y n start: FPS, LPS Stimulation regimen: FPS, LPS FPS, LPS FPS, LPS Trigger method FPS, LPS rate: FPS, LPS

Xu et al. 2013 Case report POR 41 1 3 FPS: CC þ hMG 15 – hCG  ibuprofen 0 –

18 LPS: CC þ hMG 5 1
Kuang et al. 2014 Prospective POR 36.4  5.0 38 D3 FPS: CC þ letrozole þ hMG þ ibuprofen 10.2 326.4  248.9 b
GnRH-a 1.7 71
2–4 after OPU 1 LPS: hMG þ letrozole þ MPA 10.8 1,802.5  712.7b 3.5 48
Checa et al. 2015 Prospective Oocyte 25.8  3.7 5 10 FPS: rFSH þ GnRH-ant (fixed) 12.2 1,966.7  559 GnRH-a 17.0 60
donors 20 LPS: GnRH-ant daily until E2 <60 pg/mL, 10.6 1,837.5  580 18.4 40
rFSH þ GnRH-ant fixed)
Ubaldi et al. 2016 Prospective POR 39.2  3.4 42 2 FPS: rFSH þ LH þ GnRH-ant (flex) 9.6 – GnRH-a 5.1 71.4
5 after OPU 1 LPS: rFSH þ LH þ GnRH-ant (flex) 10.3 5.7 62.5
Tampras et al. 2017 Prospective Fertility 31.1 10 RS FPS: hMG þ aromatase inhibitor þ GnRH- 11.6 – hCG 8.1 –
preservation ant (fixed) 11.6 8.2
LPS: hMG þ aromatase inhibitor þ GnRH-
ant (fixed)
Vaiarella et al. 2018 Prospective POR 40.0  3.0 310 2–3 after menses FPS: luteal E2 priming þ rFSH þ rLH þ – – GnRH-a 4.0 (MII) 39.5
5 after OPU 1 GnRH-ant (flex) 4.7 (MII) 49.4
LPS: rFSH þ rLH þ GnRH-ant (flex)
Cardoso et al. 2017 Prospective POR 40.9 13 2 FPS: hMG þ rFSH þ GnRH (flex) – – FPS: hCG 6.7b –
5 after OPU 1 LPS: hMG þ rFSH þ GnRH (flex) LPS: GnRH-a 11.7b
Jin et al. 2018 Prospective POR 36.9  6.2 76 3 FPS: CC or letrozole for 5 d þ hMG þ 7.5 b
22.4 (tubes) GnRH-a or hCG 1b 35
1-3 after OPU 1 or OV GnRH-ant (flex) 8.3b 25.2b (tubes) 2b 37.5
LPS: CC or letrozole for 5 d þ hMG
Nakasuji et al. 2018 Retrospective Fertility – 34 after OPU 1 FPS/LPS: GnRH-a þ hMG or FSH þ letrozole 9.0 1,290.5  586.2b GnRH-a or hCG 8.7 –
preservation or FPS/LPS: hMG or FSH þ letrozole þ 11.3b 1,9571  1,030.2b 10.0
GnRH-ant (flex)
Cimadomo Case-control POR 40.0  2.9 188 2 FPS: rFSH þ rLH þ GnRH-ant (flex) 10.1 3,799.7  698.7 GnRH-a 3.6b (MII) 42.4
et al. 2018 5 after OPU 1 LPS: rFSH þ rLH þ GnRH-ant (flex) 11.0 4,110.2  731.0b 4.3b (MII) 53.8
Zhang et al. 2018 Retrospective POR 39.9  4.7 61 3 FPS: CC þ hMG þ 7.9 1,388.2  731.8 hCG 1.3b 13.8
2–7 after OV or OPU 1 LPS: CC for 5 d þ hMG þ progestin 6.9 2,336.8  848.8b 1.8b 21.4
Rashtian et al. 2018 Prospective POR 42.4  0.5 69 – FPS: CC þ rFSH þ letrozole þ GnRH-ant 8.3 334.7  53.5b GnRH-a 1.6 –
1 after OPU 1 (flex) 7.9 2,336.8  848.8b 1.9
LPS: CC þ rFSH þ letrozole
Madani et al. 2019 Prospective POR 37.5  4.8 104 3 FPS: CC þ hMG þ letrozole 8.0 343.5  196.2 GnRH-a  ibuprofen 1.5 –
When >2 follicles LPS: hMG þ letrozole 7.8 1,726.8  682.3b 1.5
2–8 mm detected
Note: Data presented as mean  standard deviation, unless specified otherwise. CC ¼ clomiphene citrate; fixed ¼ fixed protocol; flex ¼ flexible protocol; FPS ¼ follicular-phase stimulation; GnRH-a ¼ GnRH agonist; GnRH-ant ¼ GnRH antagonist; LPS ¼ luteal-phase
stimulation; MPA ¼ medroxyprogesterone acetate; OPU ¼ oocyte pick-up; OV ¼ ovulation; POR ¼ poor ovarian responder; rFSH ¼ recombinant FSH; rLH ¼ recombinant LH; RS ¼ random-start stimulation.
a
Total number of oocytes retrieved is reported when available; otherwise, number of metaphase II (MII) Oocytes are reported.
b
Significant difference between groups (P<.05).
Baerwald. Ovarian follicular waves: clinical applications. Fertil Steril 2020.

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453
VIEWS AND REVIEWS

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