Ovarian stimulation in cancer patients

Hakan Cakmak, M.D. and Mitchell P. Rosen, M.D.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility,
University of California, San Francisco, California

The patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients
treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo
cryopreservation requires an individualized assessment. This review highlights the new
protocols that are emerging to reduce time constraints and emphasizes management
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Key Words: Cancer, fertility preservation, ovarian stimulation, random start
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ancer is not uncommon and

no longer considered to be an
incurable
disease
among
reproductive-age women. More than
790,000 new female cancer cases were
estimated to be diagnosed in 2012 in
the United States (1). Approximately
10% of female cancer cases occur under
the age of 45 years (2). Over the
past three decades, there has been
a remarkable improvement in the
survival rates owing to progress in
diagnosing certain cancers at an earlier
stage and improvements in treatment
(2). From 2002 to 2012, 83% of women
younger than 45 years diagnosed with
cancer survived (2). As a consequence
of the increase in the number of
patients surviving cancer, greater
attention has been focused on the
delayed effects of cancer treatments
on the quality of future life of the
survivor (3, 4).
The treatment for most of the
cancer types in reproductive-age
women involves either removal of the
reproductive organs or cytotoxic

treatment (chemotherapy and/or radiotherapy) that may partially or denitively affect reproductive function (5).
The ovary is particularly sensitive to
the adverse effects of cancer treatments
because of the set number of follicles
present in the postnatal ovary (5).
Reproductive lifespan is determined by
the follicle pool, and therefore, cancer
treatments that cause follicular
depletion accelerate the onset of
menopause (6). The irreversible gonadotoxic effects of some of the
chemotherapeutic agents are well documented, particularly for alkylating
agents (e.g., cyclophosphamide, busulfan, and ifosfamide), which are common components of chemotherapy for
breast cancer, lymphomas, leukemia,
and sarcomas (7, 8). Pelvic radiation
therapy is also known to cause
follicular destruction, and exposure to
510 Gy pelvic radiation appears to be
toxic to oocytes, resulting in
premature ovarian insufciency in
many women (5). The risk of ovarian
failure following cancer therapy

Received January 29, 2013; revised March 16, 2013; accepted March 18, 2013.
H.C. has nothing to disclose. M.P.R. has nothing to disclose.
Reprint requests: Mitchell P. Rosen, M.D., Department of Obstetrics, Gynecology, and Reproductive
Sciences, 2356 Sutter St., 7th Floor, San Francisco, California 94115 (E-mail: rosenm@obgyn.
ucsf.edu).
Fertility and Sterility Vol. 99, No. 6, May 2013 0015-0282/$36.00
Copyright 2013 American Society for Reproductive Medicine, Published by Elsevier Inc.
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appears to be dose related, and the

effect depends on age and ovarian
reserve at the time of treatment (9).
Early loss of ovarian function not
only puts the patients at risk for
menopause-related complications at
a very young age, but is also associated
with loss of fertility (8). In addition,
women in the United States have been
delaying initiation of childbearing to
later in life for social and nancial
reasons. The birth rate for women
aged 3034 years increased from
80.8 births per 1,000 women in 1990
to 96.5 births per 1,000 women in
2011 (10). Similarly, the rate for women
aged 3544 years rose 54% from 1990
to 2011, increasing from 37.2 to
57.5 births per 1,000 women (10). In
other words, more women in their
30s to early 40s are attempting to get
pregnant for the rst time than ever
before. Because the incidence of most
cancers increases with age and many
women wish to conceive using their
own oocytes, delayed childbearing
results in more female cancer survivors
interested in fertility preservation.
Multiple strategies have emerged
aiming to preserve fertility in women
with different types of malignancies.
These include embryo and oocyte cryopreservation, cortical and whole ovary
cryopreservation, ovarian transplantation, ovarian transposition, and GnRH
VOL. 99 NO. 6 / MAY 2013

Fertility and Sterility

agonist protection (11). Currently, embryo and mature oocyte
cryopreservation following in vitro fertilization (IVF) are the
only techniques endorsed by the American Society of Reproductive Medicine, and the other methods are still considered
to be investigational (12, 13).
Controlled ovarian stimulation (COS) for embryo or mature
oocyte cryopreservation is the most preferred method for fertility
preservation in cancer patients, owing to its higher success rates
compared with other, more experimental, technologies (12, 13).
Therefore, it should be recommended as long as the patient's
medical condition does not preclude safely performing COS or
oocyte retrieval and the patient has adequate time to undergo
COS and oocyte retrieval (12, 13). To facilitate initiation of
ovarian stimulation and avoid unnecessary delay, prompt
consultation with a reproductive endocrinologist and
coordination of care are necessary after the cancer diagnosis (14).
The number of oocytes retrieved and their quality are
imperative factors predicting the potential efcacy of the
fertility preservation procedure. Consequently, information
regarding the expected ovarian performance after COS is
crucial when consulting with the patient. Therefore, the
assessment of ovarian reserve with the use of antral follicle
count (AFC) and/or antim
ullerian hormone (AMH) before
ovarian stimulation is necessary to provide more accurate
prediction of ovarian response to COS and to determine the
COS protocol and starting gonadotropin dose (15).

RESPONSE TO OVARIAN STIMULATION IN

CANCER PATIENTS
In cancer patients, both the specic malignancy and the
patient's multisystemic condition may have an impact on
the response to ovarian stimulation (16). The increased
catabolic state, malnutrition, and increased stress hormone
levels associated with the malignancy may affect the
hypothalamic-gonadal axis and decrease fertility (17).
Possible adverse association between the presence of
a neoplastic process and ovarian reserve or oocyte quality is
also suggested (1719). There are mixed reports about how
cancer patients respond to the IVF stimulation protocols:
some reporting no signicant change (2022) and others
demonstrating worse ovarian response in cancer patients
compared with age-matched healthy women (19, 23). In
a recent meta-analysis conducted on seven retrospective
studies, women with malignancies had lower numbers of total
oocytes (11.7
7.5 vs. 13.5
8.4) and mature oocytes
retrieved (9.0
6.5 vs. 10.8
6.8) after COS for fertility preservation compared with healthy age-matched patients (16).
Moreover, the relative risk of poor response leading to cycle
cancellation was higher in cancer patients than in the control
group (risk ratio 1.32, 95% condence interval 0.782.17)
although the observed difference did not reach statistical
signicance, possibly due to the small size of the groups (16).
BRCA genes play an essential role in double-strand DNA
break repair, and their mutations are associated with an
increased risk of breast and ovarian cancers (24). In patients
with BRCA mutations, oocytes may be more prone to DNA
damage, clinically manifesting as diminished ovarian reserve
or earlier menopause (25). In BRCA mutationpositive breast
VOL. 99 NO. 6 / MAY 2013

cancer patients, a low response to ovarian stimulation

occurred more frequently than in patients without BRCA
mutations (33.3% vs. 3.3%) or in breast cancer patients not
tested for their BRCA status (2.9%) (18). Interestingly, all
BRCA mutationpositive patients with a low response to
ovarian stimulation and requiring higher doses of gonadotropins for their stimulation had BRCA-1 mutations, and a low
response was not encountered in women who were positive
for only a BRCA-2 mutation (18).
None of the studies mentioned above compared the ovarian reserve of cancer patients with healthy age-matched
women. In a recent study, ovarian reserve assessed with
AMH was found to be signicantly lower in patients with
lymphoma before chemotherapy compared with healthy
control subjects (26). Moreover, we previously demonstrated
that women with cancer before gonadotoxic therapy may
have signicantly lower AFC compared with healthy women
aged 2540 years (Table 1) (27). This lower AFC in cancer
patients may be explained by either accelerated follicle loss
or a defect in recruitment of antral follicles owing to disease
state. It is well established that AFC correlates directly with
number of follicles, number of mature oocytes retrieved,
and number of embryos obtained during an IVF cycle (28).
In our clinical experience, although the number of mature
oocytes retrieved and embryos obtained may be lower in
cancer patients compared with healthy individuals, they are
appropriate for their given AFC. Moreover, their response to
the gonadotropins and mature oocyte yield (i.e., number of
metaphase II [MII] oocytes/AFC) are similar to those of the
healthy women. Therefore, if lower oocyte and embryo
numbers in patients with malignancy during an IVF cycle
are true, this is not due to poor response to ovarian stimulation, but likely the result of decreased number of available
antral follicles to be stimulated.
In conclusion, candidates for fertility preservation
because of malignancy, especially BRCA-1 mutation carriers,
should be informed that the expected number of oocytes
retrieved after COS may be lower compared with healthy
patients of similar age. However, more studies are needed to
conrm these ndings.

GONADOTROPIN DOSE DURING OVARIAN

STIMULATION
Maximizing the number of embryos and oocytes cryopreserved during a fertility preservation cycle is extremely
important, not only because the patient usually has a single

TABLE 1
Comparison of antral follicle count (AFC) between cancer patients
and healthy women in different age groups (26).
Cancer patients

Healthy women

Age (y)

Median

Range

Median

Range

P value

2530
3135
3640
4145

33
47
49
20

14
11
7
7

158
054
040
120

205
216
227
161

20
15
12
6

458
548
052
122

< .001
.004
< .001
.789

Cakmak. Ovarian stimulation in cancer patients. Fertil Steril 2013.

1477

VIEWS AND REVIEWS

cycle opportunity owing to time constraints, but also to
increase the chance of future pregnancies. Using higher doses
of gonadotropins can be one of the strategies to increase the
embryo and oocyte yield per cycle. In a study comparing
a low-dose antagonist IVF protocol (150 IU FSH) and
a higher-dose antagonist IVF protocol (>150 UI) in cancer
patients, although the number of follicles >17 mm was greater
in the higher-dose group, there was no difference in numbers
of oocytes (13.3
8.7 vs. 12.3
8.0) or embryos (6.3
4.7 vs.
5.4
3.8) generated between the two groups (29). That study
suggests that the use of higher doses of gonadotropins may
not necessarily result in higher oocyte/embryo yield consistent with the theory that higher doses of gonadotropins may
stimulate the recruitment of chromosomally abnormal or incompetent oocytes (30). However, in patients with decreased
ovarian reserve as assessed with the use of AFC and/or
AMH, higher doses of gonadotropins may be required.

FIGURE 1

OVARIAN STIMULATION PROTOCOLS

Conventional Controlled Ovarian Stimulation
The choice of the specic COS protocol is generally
determined based on the policy of preferences in each IVF
center and inuenced by the time available until the initiation
of radio/chemotherapy. Although multiple different COS
protocols are used, the majority of patients are treated with
a GnRH antagonistbased protocol, which likely allows the
shortest deferral of the initiation of radio/chemotherapy. To
date, there are no studies comparing agonist and antagonist
protocols in women with cancer.
Traditional ovarian preparation for IVF requires 914
days of ovarian stimulation with exogenous gonadotropins,
preceded by ovarian suppression with GnRH agonists for
2 weeks to prevent premature ovulation. Because GnRH
agonist is initiated in the luteal phase of the cycle, this may
add up to 3 additional weeks to the process, depending on
when the patient presents for treatment.
The development of GnRH antagonists has signicantly
decreased the interval from patient presentation to
embryo/oocyte cryopreservation (31). In contrast to GnRH
agonists, GnRH antagonists immediately suppress pituitary
release of FSH and LH and do not require the 1014 days
of administration before gonadotropin initiation. GnRH
antagonists are initiated to prevent premature LH surge
when the size of the lead follicle reaches 1214 mm at
approximately day 6 of gonadotropin stimulation which
begins on day 23 of a menstrual cycle (Fig. 1A). This
approach still requires awaiting menses before initiating
gonadotropins, but it decreases the interval to oocyte retrieval
compared to traditional IVF stimulation protocols.
The use of GnRH antagonists during the preceding luteal
phase was explored originally for cancer patients and then for
poor IVF responders as a method to improve ovarian
stimulation by inducing corpus luteum breakdown and
synchronizing the development of the next wave of follicles
(32, 33). For cancer patients, the idea of administering GnRH
antagonists in the luteal phase was driven more by minimizing
potential delays for cancer treatment (32). If a GnRH

1478

Conventional and random-start antagonist IVF protocols for cancer

patients undergoing fertility preservation. COS can be started with
spontaneous menses (A) or with menses following luteolysis
induced by GnRH antagonist (B). COS can also be initiated in the
late follicular (C) or luteal phase following spontaneous LH surge
(D) or after ovulation induction with hCG or GnRH agonist (E).
Cakmak. Ovarian stimulation in cancer patients. Fertil Steril 2013.

VOL. 99 NO. 6 / MAY 2013

Fertility and Sterility

antagonist (e.g., single dose of 3 mg cetrorelix subcutaneously) is
given during the midluteal phase, menses ensues a few days later
(32, 33) (Fig. 1B). As a result, ovarian stimulation would be
initiated more quickly and a GnRH antagonist would be
restarted in a standard fashion, when the lead follicle is at 12
14 mm to prevent premature LH surge (33).

Random-Start Controlled Ovarian

Hyperstimulation
Conventionally, ovarian stimulation for oocyte/embryo
cryopreservation is initiated at the beginning of the follicular
phase with the idea that this optimizes clinical outcomes; it
may require 26 weeks depending on the woman's menstrual
cycle phase at the time of planning the treatment. Adhering to
this convention may result in either signicant delay of
cancer treatments or forgoing of fertility preservation owing
to time constraints. For cases not desirable to wait for the next
menstrual period to start a stimulation protocol owing to the
urgency of the cancer treatment, random-start stimulation
protocols have been proposed (3436).
In a small prospective multicenter study (n 40), a novel
protocol for cancer patients that initiated ovarian stimulation
during the luteal phase of the menstrual cycle was described
(36). Cancer patients in the luteal phase were started on GnRH
antagonists to down-regulate LH and initiate luteolysis. Simultaneously, follicular stimulation was initiated with recombinant
FSH only, thus avoiding exogenous LH activity which might prevent luteolysis. Compared with cancer patients stimulated during
the follicular phase (n 28) with either a short are-up protocol or an antagonist protocol, the luteal-phase group (n 12) had
similar number of aspirated oocytes, number of MII oocytes, and
fertilization rate (36).
A report of three breast cancer patients evaluated the
effectiveness of initiating ovarian stimulation at the time of
patient presentation (menstrual cycle days 11, 14, and 17)
rather than waiting for spontaneous menses (35). GnRH
antagonist was started to prevent premature LH surge when
the lead follicle measured >13 mm. The random-start ovarian
stimulation resulted in a reasonable ovarian response, with
710 embryos cryopreserved per patient (35).

The recent report presenting our clinical experience with

random-start ovarian stimulation demonstrated that late
follicular or luteal phasestart antagonist IVF cycles were
as effective as conventional (i.e., early follicular)start
antagonist IVF cycles in cancer patients (34). The late
follicular phase was dened as after menstrual cycle day 7
with emergence of a dominant follicle (>13 mm) and/or
progesterone level <2 ng/mL. If the cancer patient presented
in the late follicular phase, we proceeded with one of the
following treatment plans. 1) Ovarian stimulation was started
without GnRH antagonist if the follicle cohort following the
lead follicle was <12 mm and continued to be <12 mm before
spontaneous LH surge (Fig. 1C). After the LH surge, GnRH
antagonist was started later in the cycle when the secondary
follicle cohort reached 12 mm to prevent premature secondary
LH surge. Or 2) ovulation was induced with hCG or GnRH
agonist and ovarian stimulation was started in 23 days in
the luteal phase (Fig. 1E) (34). If the cancer patient presented
in the luteal phase or the ovulation was induced, GnRH
antagonist administration was initiated similarly to
conventional ovarian stimulation later in the cycle when the
secondary follicle cohort reached 12 mm to prevent
premature secondary LH surge (Fig. 1D and E) (34). The
numbers of total and mature oocytes retrieved, oocyte yield
(i.e., number of MII oocytes/AFC), and fertilization rates were
similar between groups (34) (Table 2). However, the length of
ovarian stimulation was 2 days longer, and therefore, the
total dose of gonadotropin used was signicantly higher in
late follicular and luteal phasestart groups compared with
the conventional-start group (34) (Table 2). In contrast to earlier belief, the presence of corpus luteum or luteal-phase progesterone levels did not adversely affect the follicular
development, oocyte yield, or possibility of having secondary
spontaneous LH surge in random-start patients (34).
Overall, this approach provides a signicant advantage
by decreasing total time for the IVF cycle, and in urgent settings, ovarian stimulation can be started at a random cycle
date for the purpose of fertility preservation without
compromising oocyte yield and maturity. This is consistent
with a newer concept of ovarian physiology, which indicates
that there are multiple waves of follicle recruitment during

TABLE 2
Comparison of characteristics and outcomes of conventional and random start antagonist IVF cycles in cancer patients.

Age (y)
AFC
Days of ovarian stimulation
Total dose of gonadotropins (IU)
Follicles R13 mm
Oocytes retrieved
Mature oocytes (MII) retrieved
Oocyte/AFC ratio
Mature oocyte/AFC ratio
Fertilization rate after ICSI (2PN/MII)

Conventional start
(n [ 87; 101 cycles)

Random start
(n [ 24; 24 cycles)

P value

33.9
5.2
13 (919)
9 (810)
3,386
1,085
12 (617)
15 (923)
11 (616)
1.1 (0.81.7)
0.8 (0.51.1)
0.77
0.22

34.6
5.0
11.5 (616)
11 (1012)
4,201
1,147
10 (815.5)
12.5 (920.5)
9 (514.5)
1.2 (0.91.7)
0.8 (0.61.2)
0.87
0.15

NS
NS
< .001
.001
NS
NS
NS
NS
NS
NS

Note: Data are presented as mean
SD or median (interquartile range) (32). 2PN two pronuclei; AFC antral follicle count; ICSI intracytoplasmic sperm injection; MII metaphase II; NS not
signicant.
Cakmak. Ovarian stimulation in cancer patients. Fertil Steril 2013.

VOL. 99 NO. 6 / MAY 2013

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VIEWS AND REVIEWS

each menstrual cycle (37). Additional clinical studies are
needed to assess the efcacy of this strategy, especially
regarding the rates of clinical pregnancy and of live-born
infants originating from the use of cryopreserved embryos
and of oocytes obtained by random start ovarian stimulation.

Controlled Ovarian Stimulation in Patients with

Estrogen-Sensitive Cancers
During COS, there is a potential risk that the supraphysiologic
E2 levels resulting from ovarian stimulation with gonadotropins may promote the growth of estrogen-sensitive tumors,
such as endometrial and estrogen receptorpositive breast
cancers (15). The rise in E2 is directly proportional to the
number of follicles recruited to grow; therefore, alternative
and potentially safer protocols have been introduced for
fertility preservation for estrogen-sensitive cancer patients,
including natural-cycle IVF (without ovarian stimulation),
stimulation protocols with tamoxifen alone or combined
with gonadotropins, and stimulation protocols with
aromatase inhibitors to reduce the estrogen production (38).
Natural-cycle IVF gives only one or two oocytes or
embryos per cycle and has a high rate of cycle cancellation.
Therefore, this technique would likely be ineffective and
is not recommended, especially when a chemotherapy
treatment is imminent and the patient does not have a chance
for a second cycle of IVF treatment.
Tamoxifen, a nonsteroidal triphenylethylene compound
related to clomiphene, has a well known antiestrogenic action
on breast tissue with the inhibition of growth of breast tumors
by competitive antagonism of estrogen at its receptor site, and it
is accepted as the rst-line drug in hormonal prevention and
treatment of estrogen receptorpositive breast cancer (39). Tamoxifen, besides its effect in the breast, also has an antagonist
action in the estrogen receptors in the central nervous system
similar to that of clomiphene. The selective antagonist action
of tamoxifen interferes with the negative feedback of the estrogen on the hypothalamic-pituitary axis, leading to an increase
in GnRH secretion from the hypothalamus and a subsequent release of FSH from the pituitary-stimulating follicular development. Tamoxifen can be used for COS alone starting on day 25
of the menstrual cycle in doses of 2060 mg/d, or in combination with gonadotropins, similarly to the use of clomiphene
(38). Even though peak E2 levels in ovarian stimulation with
tamoxifen are not altered, owing to its antiestrogenic effect
on breast tissue, it is desirable to be used in estrogen receptorpositive breast cancer patients. Ovarian stimulation with
the use of tamoxifen for fertility preservation in cancer patients
was shown to increase the mature oocyte and embryo yield
compared with natural-cycle IVF (1.6 vs. 0.7 and 1.6 vs. 0.6,
respectively) and reduce cycle cancellations (40). As expected,
combined protocol with tamoxifen and gonadotropins further
increased the number of cryopreserved oocytes and embryos
(5.1 vs. 1.5 and 3.8 vs. 1.3, respectively) (41).
Aromatase is a cytochrome P450 enzyme complex that
catalyzes the conversion of androstenedione and testosterone
to their respective estrogenic products estrone and E2 (42).
Aromatase inhibitors, such as letrozole, markedly suppress
plasma estrogen levels by competitively inhibiting the
1480

activity of the aromatase enzyme (43). Aromatase inhibitors

signicantly reduce the risk of recurrence in postmenopausal
women with hormone receptorpositive breast cancer owing
to profound estrogen deprivation, especially with thirdgeneration inhibitors (i.e., anastrozole and letrozole) (44).
Centrally, aromatase inhibitors release the hypothalamicpituitary axis from estrogenic negative feedback, increase
the secretion of FSH by the pituitary gland, stimulate follicle
growth, and, thereby, can be used for ovulation induction
(45). In patients with estrogen-sensitive cancers, the main
advantage of adding daily letrozole to gonadotropins in ovarian stimulation protocols is to decrease serum E2 levels to be
closer to that observed in natural cycles (i.e., E2 <500 pg/mL)
without affecting oocyte or embryo yield (46, 47). Stimulation
protocols using letrozole alongside with gonadotropins are
currently preferred over tamoxifen protocols as treatment
with letrozole results in a higher number of oocytes
obtained and fertilized when compared to tamoxifen
protocols (41). In a study comparing the efcacy of the
letrozole plus gonadotropin protocol in breast cancer
patients and the standard IVF protocol in age-matched
noncancer patients with tubal-factor infertility, the breast
cancer patients started to receive letrozole (5 mg/d) on
menstrual cycle day 2 or 3, FSH (150300 IU/d) was added
2 days later, all medications were discontinued on the day
of hCG trigger, and letrozole was reinitiated after oocyte
retrieval and continued until E2 levels fell to <50 pg/mL
(47). This letrozole plus gonadotropin protocol resulted in
similar number of total oocytes retrieved and length of
ovarian stimulation compared with standard IVF protocol
(47). As expected, peak E2 levels were signicantly lower
in the breast cancer patients receiving letrozole plus
gonadotropin compared with the standard IVF group
(483
278.9 pg/mL vs. 1,464.6
644.9 pg/mL) (47). The
studies assessing the effect of letrozole on oocyte maturity
and competence demonstrated that the addition of letrozole
did not change numbers of mature oocytes retrieved and
fertilization rates (47, 48). Similarly, in our practice we
observed similar oocyte maturity (MII oocytes/total oocytes
retrieved; 0.68
0.19 vs. 0.71
0.23) and fertilization rate
(0.77
0.22 vs. 0.78
0.24) in intracytoplasmic sperm
injection cycles with and without letrozole (unpublished
data). The short-term follow-up of breast cancer patients,
who had undergone ovarian stimulation with letrozole plus
gonadotropins for fertility preservation has not been shown
to raise the risk of breast cancer recurrence (49). In addition,
COS with aromatase inhibitors in combination with gonadotropins has been safely used for embryo cryopreservation in
endometrial cancer patients (50).
Letrozole suppresses plasma E2 levels signicantly at
doses of 0.110 mg/d (51). In our clinic, we start letrozole at
2.55 mg/d, depending on the ovarian reserve of the patient,
with the ovarian stimulation (Fig. 1). Given the importance of
keeping E2 levels close to that observed in natural cycles in
patients with estrogen-sensitive cancers, we check E2 levels
in every clinic visit and titrate letrozole dose up to 10 mg/d
to keep E2 levels <500 pg/mL (46). These letrozole doses
are well tolerated by the patients during ovarian
stimulation without any side effects. In addition, the mature
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Fertility and Sterility

oocyte/embryo yield after COS is not affected by letrozole at
any dose used in our clinical practice. We also consider continuing letrozole after the oocyte retrieval if serum E2 levels
are still elevated (i.e., E2 >500 pg/mL). In our experience,
even if E2 levels are >500 pg/mL before retrieval, only a minority of patients requires letrazole after retrieval. Discontinuation of letrazole can either be at menses or with initiation of
chemotherapy. In contrast, anastrozoleanother thirdgeneration aromatase inhibitorfailed to adequately suppress
E2 levels during COS, despite gradually increasing the dose of
anastrozole to a maximum of 10 mg/d, and therefore we do
not recommend its use in fertility preservation cycles (52).
In summary, COS with letrozole plus gonadotropins in
patients with estrogen-sensitive cancers undergoing fertility
preservation is safe, well-tolerated, and yields similar
number of oocytes and embryos compared with standard
protocols while minimizing the risk of high estrogen exposure
and not increasing the recurrence of cancer in the short term.
Therefore, we highly recommend the routine use of letrozole
during COS for fertility preservation in patients with
estrogen-sensitive cancers.

Prevention of Ovarian Hyperstimulation

Syndrome in Cancer Patients
Ovarian hyperstimulation syndrome (OHSS) is the most
serious complication of ovarian stimulation and can be
associated with intravascular depletion, ascites, liver
dysfunction, pulmonary edema, electrolyte imbalance, and
thromboembolic events. Although OHSS is often selflimited with spontaneous resolution within a few days, severe
disease may require hospitalization and intensive care.
Selecting the appropriate ovarian stimulation regimen can
be challenging in embryo/oocyte cryopreservation because
it is important to balance the risk of OHSS and obtaining
sufcient number of oocytes or embryos to maximize the
chance of a successful pregnancy in the future. The impact
of OHSS can be profound in cancer patients because it may
result in delaying or complicating planned life-saving cancer
therapy (53).
Triggering the nal oocyte maturation with hCG carries
the well known risk of inducing OHSS (54). GnRH agonist
also induces this nal oocyte maturation by promoting the
release of endogenous gonadotropin stores from the hypophysis as long as the pituitary gonadotropin receptors are not
down-regulated and can be used as an alternative to hCG
(54). GnRH agonist trigger in GnRH antagonistbased
protocols dramatically reduces the risk of OHSS, owing to
the short half-life of GnRH agonistinduced endogenous
LH surge (55). Moreover, there was a signicantly lower
rate of moderate/severe OHSS in the GnRH agonist
group compared with the patients receiving hCG trigger
(3.7% vs. 21.3%) (56). GnRH agonist trigger is particularly
convenient in cancer patients pursuing oocyte or embryo
banking, because luteal support is not needed to sustain
a pregnancy. In a study comparing GnRH agonist and hCG
as the trigger for oocyte maturation in fertility preservation
cycles, GnRH agonist trigger resulted in at least similar
numbers of mature oocytes and cryopreserved embryos
VOL. 99 NO. 6 / MAY 2013

compared with hCG (56). In addition, although hCG potentiates the endogenous production of estrogen during the luteal
phase owing to its longer half-life, GnRH agonistinduced
endogenous LH may result in lower estrogen production,
which may be an advantage for patients with estrogensensitive cancers (54).
However, in our experience we have observed trigger
failures with GnRH agonist trigger at both 1 mg and 4 mg
dosing. The likely reason is that GnRH agonist is able to
bind to only a portion of the receptors owing to competition
with GnRH antagonist, yielding a limited LH surge (57). It is
possible that with the increase in dose of GnRH agonist or
with hCG supplementation (%1,500 IU) at the time of trigger,
there will be fewer failures. Because of the possibility of
failure, we do not routinely recommend GnRH agonist trigger
for all patients. In our current practice, 4 mg leuprolide
acetate is being used only in patients with high risk of OHSS.
The number of follicles, more specically the follicular
pattern, in combination with serum E2 levels predicts OHSS
with high sensitivity and specicity (58, 59). However, one
caveat is that cotreatment with aromatase inhibitors limits
the use of E2 level to help predict OHSS. In this scenario, it
is important to rely on the follicular pattern and the rate of
E2 rise rather than the absolute of serum E2 levels. If the
E2 levels are rising rapidly while administering letrozole,
especially in the presence of a high number of small
follicles, the patient should be considered to be be at risk for
OHSS and GnRH agonist trigger should be used to lower
that risk.
In conclusion, we recommend GnRH agonist trigger in
GnRH antagonistbased fertility preservation cycles only
for women who are at risk for OHSS. The trigger must be
conrmed the next morning by measuring serum LH level.
In the case of a GnRH agonist trigger failure determined by
low post-trigger LH (in our clinic, we use a cutoff LH level
of <12 mIU/mL), hCG (2,5005,000 IU) trigger can be given
on the same day (60). If the patient has relatively low
post-trigger LH level, but >12 mIU/mL, closer attention
should be given to the oocyte yield during oocyte retrieval.
If no or an inappropriately low number of oocytes are retrieved after aspirating a couple of mature-size follicles, the
oocyte retrieval should be stopped, oocyte maturation should
be triggered again by administering hCG (2,5005,000 IU)
owing to the possibility of failing to trigger oocyte maturation
with GnRH agonist, and then oocyte retrieval should be
attempted again after 3436 hours (60).

Medical Considerations in Cancer Patients

Undergoing COS
The patients referred for fertility preservation owing to
a malignant disease do not represent the typical population
of subfertile patients treated in IVF units. Cancer may affect
multiple tissues throughout the body and can result in variety
of complications during COS. Therefore, the goals during COS
in cancer patients are to prevent these serious life-threatening
complications with prophylaxis, and to recognize and
manage them effectively when they occur.
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Cancer patients undergoing COS are at increased risk of
thromboembolic events because of a hypercoagulable state
induced by their malignancy and supraphysiologic serum
E2 levels (61). Therefore, these patients may require anticoagulation around the time of COS. Currently, there are no
guidelines for anticoagulation during COS. However, the
safety and efcacy of anticoagulation during COS and after
oocyte retrieval have been reported (62). In our practice, we
start prophylactic low-molecular-weight heparin with
ovarian stimulation in high-risk patients and instruct the
patient to take their last dose of medication 24 hours before
the oocyte retrieval. Low-molecular-weight heparin is
reinitiated 12 hours after the retrieval and can be continued
until E2 returns to its baseline level. The other strategy of
preventing thromboembolic events is to use letrozole during
COS to keep E2 levels close to those observed in natural cycles.
Letrozole at 2.5 or 5 mg/d can be started with ovarian
stimulation, as in patients with estrogen-sensitive malignancies, and can be titrated up to 10 mg/d to keep E2 levels
<500 pg/mL. Letrozole can also be continued after oocyte
retrieval for up to a week depending on the E2 level at the
time of ovulation induction.
Malignancies with bone marrow inltration or liver
involvement may create a tendency toward bleeding during
oocyte retrieval owing to thrombocytopenia, platelet
dysfunction, or defective coagulation factor synthesis.
Therefore, platelet count and coagulation panel should be
tested before COS in patients with hematologic malignancies
or with malignancies involving the liver. Platelet or fresh
frozen plasma transfusion should be performed before oocyte
retrieval to prevent excessive bleeding in these patients as
needed.
Higher risk of pelvic infection after oocyte retrieval can
be a problem especially in cancer patients with neutropenia.
Therefore, absolute neutrophil count should be evaluated
before COS in cancer patients with possible bone marrow
inltration. In the case of neutropenia, consultation from
the patient's oncologist for the use of granulocyte colonystimulating factor to increase the neutrophil count should
be obtained, and prophylactic antibiotics should be given
before oocyte retrieval to decrease the risk of infection.
Some of the cancer-related medical conditions, including
respiratory dysfunctions due to tracheal compression,
mediastinal mass, or large pleural effusion, and vascular
disturbances, as in superior vena cava syndrome, may
preclude safe administration of conscious sedation during
oocyte retrieval. Anesthesia consultation should be obtained
in advance for the patients with these conditions. If safety
and difcult intubation in an emergency situation are
concerns, the oocyte retrieval should be performed either
under general anesthesia with endotracheal intubation or
only with local anesthesia.
The patients with recent mastectomies for breast cancer
may have special needs during COS. Owing to decreased
mobility, they may need more assistance during ofce visits.
Intravenous line placements to the upper extremity on the
same side of the axillary node dissection should be avoided,
owing to concerns of lymphatic system damage and
inadequate lymphatic ow. In patients who have had
1482

transverse rectus abdominis myocutaneous ap for breast

reconstruction after mastectomy, abdominal distention, and
therefore OHSS, should be avoided to prevent wound
dehiscence.
The medication list for all cancer patients should be
reviewed before COS. Antiepileptic medications should
denitely be continued during COS in patients with brain
tumor owing to increased risk of seizures. The use of Imatinib
(Gleevec), a specic inhibitor of constitutively activated
Bcr-Abl tyrosine kinase used in chronic myelogenous
leukemia, should be temporarily stopped during COS owing
to its adverse effect on ovarian hormone production and
oocyte recovery (63).

CONCLUSIONS
Given the importance of reproduction for many young
patients faced with cancer, counseling regarding fertility
preservation is an essential part of comprehensive cancer
care. Embryo cryopreservation is the most established method
for fertility preservation, and oocyte cryopreservation has
gained efcacy and is now offered at many centers.
Determination of the COS protocol and gonadotropin dose
for oocyte/embryo cryopreservation requires an individualized assessment. Maximizing the number of embryos and
oocytes cryopreserved during a fertility preservation cycle
without causing OHSS is extremely important, because
most patients have only a single cycle opportunity owing to
time constraints before starting their oncologic treatment.
In urgent settings, random-start ovarian stimulation is
emerging as a new technique for the purpose of fertility
preservation without compromising oocyte yield and
maturity. Letrozole plus gonadotropin protocol is an effective
method for safely inducing COS in patients with estrogensensitive cancers undergoing fertility preservation. Although
newly developed protocols are efcient in inducing COS and
obtaining appropriate number of oocytes/embryos, only
a minority of the patients have undergone thawing and
embryo transfer, so there are not enough consistent data
reported to evaluate the implantation and pregnancy rates
of these new protocols. This issue should be appropriately
addressed in the future to enable prediction of the number
of oocytes/embryos needed to be preserved to offer a realistic
chance for later reproduction in these patients.

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