JBUON 2017; 22(4): 844-852

ISSN: 1107-0625, online ISSN: 2241-6293 • www.jbuon.com

E-mail: [email protected]

REVIEW ARTICLE

Current strategies and future perspectives in fertility pres-

ervation for cancer patients
Romeo Micu1*, Bogdan Petrut2,5*, Cristina Zlatescu-Marton1, Alexandra Traila3,4, Radu Harsa1,
Patriciu Achimas-Cadariu3,4
1
University of Medicine and Pharmacy “Iuliu Haţieganu”, Department of Human Assisted Reproduction of 1st Gynecology
Clinic, Cluj-Napoca; 2University of Medicine and Pharmacy “Iuliu Haţieganu” Department of Urology, Cluj-Napoca; 3University
of Medicine and Pharmacy “Iuliu Haţieganu”, Department of Oncology, Cluj-Napoca; 4“Ion Chiricuta” Institute of Oncology,
Department of Surgical and Gynecologic Oncology, Cluj-Napoca; 5“Ion Chiricuta” Institute of Oncology, Department of Urol-
ogy, Cluj-Napoca, Romania

*These authors contributed equally to this study

Summary
Nowadays, cancer is being detected at younger ages. Health register the current state of fertility preservation procedures
care providers should consider cancer patients’ desire to- available for male and female cancer patients.
wards fertility preservation before the initiation of possibly
sterilizing treatments. The aim of the current review was to Key words: cancer patients, fertility preservation

Introduction
There is an ongoing trend to detect cancer cy rates than the general population. The impact
at earlier stages and in younger patients. There- on fertility depends on many factors, with survi-
fore, lately, preservation of fertility in this popu- vors of leukemia showing lowest rates for preg-
lation has become a matter of great interest. nancy, and testicular cancer and Hodgkin lym-
Furthermore, we are witnessing an increased phoma showing increased rates over time [4].
pressure on health care providers to offer fertil- The aim of the current review was to es-
ity preservation to cancer survivors which are at tablish the current state of fertility preserva-
reproductive age [1,2]. tion procedures. A review of the literature was
Almost half of cancer patients are able to completed using advanced search on PubMed
bear children or want to do so at the time of with the following terms “ovarian tissue cryop-
diagnosis [3]. Additionally, health care providers reservation”, “embryo cryopreservation“, “oocyte
should not presume that older men may not be cryopreservation“, “ovarian transposition“, “live
as interested in fathering children, as some may birth”, “pregnancy”, “male infertility”, and “can-
desire children later in life or with a different cer”. We included all relevant articles from
spouse. However, survivors have lower pregnan- 2004-2016.

Correspondence to: Christina Zlatescu-Marion, MD, PhD student. University of Medicine and Pharmacy “Iuliu Haţieganu”, De-
partment of Human Assisted Reproduction of the 1st Gynecology Clinic, Clinicilor 3-5, Cluj-Napoca, Romania.
Tel: +40 264 431 864, E-mail: [email protected]
Received: 22/11/2016; Accepted: 15/12/2016
 Fertility preservation in cancer patients 845

Fertility preservation in female patients used the Letrozole and FSH protocol in patients
with estrogen sensitive breast cancer reported no
Chemotherapeutic agents affect severely the significant increase risk in short-term recurrence
reproductive and endocrine function of the ova- and number of embryos obtained comparable with
ries, and most women developing amenorrhea other ovarian stimulation protocols. [15-17].
and never regaining menstrual cycles [5]. Stud- Embryos and oocytes can be cryopreserved us-
ies show that premature ovarian failure increases ing: slow freezing and vitrification. Until recently,
with age and varies with regimen, duration and efforts to freeze oocytes with the slow freezing pro-
total cumulative dose of chemotherapy [6]. It has tocol remained one of the biggest weaknesses of
been estimated that 60-80% of women who are assisted reproduction, as survival rates were much
treated with cyclophosphamide, methotrexate lower than those of cryopreserved-thawed embry-
and 5-fluorouracil will develop premature ovarian os. Nowadays, the vitrification technique has revo-
failure (POF) [7,8]. Several studies have observed lutionized cryopreservation techniques and has
that a significant number of younger patients who now become the standard procedure for embryo
did regain ovarian function after chemotherapy and oocyte conservation with high survival and
were at risk of undergoing premature menopause pregnancy rates. A study published by Levi-Setti
a number of years after treatment. The beneficial et al., conducted over a period of 5 years showed
effects of adjuvant chemotherapy for breast can- that cryopreservation of oocyte by vitrification had
cer may result, in part, from suppression of the a higher survival rate than cryopreservation of
ovarian function [9,10]. oocytes by slow freezing. Pregnancy chances were
Radiation therapy also has severe adverse significantly higher when using fresh or cryopre-
impact on endocrine and reproductive function served embryos compared to using embryos ob-
depending on patient age, administered dose and tained from cryopreserved oocytes [18].
the irradiation field [11]. POF can be induced di- In case of patients for whom delaying treat-
rectly or by affecting the hypothalamic-pituitary ment is not an option or for whom ovarian stim-
axis [12,13]. ulation is not indicated by health care provid-
The choice of fertility preservation method ers, immature oocyte retrieval followed by in
in a practical manner depends on patient age, vitro maturation could be considered. Immature
possibility to delay chemotherapy or radiation, oocytes are extracted from the antral follicles and
presence of male partner or willingness to use matured in vitro, in order to produce embryos that
a sperm donor and whether patient malignancy increase the likelihood of conceiving for these pa-
permits ovarian stimulation. According to Chian tients. In vitro maturation (IVM) can be performed
et al. strategy, we present an update of the cur- regardless of the patients’ menstrual cycle phase,
rent fertility preservation methods in female pa- without affecting oocyte quality. Maturation and
tients [14]. fertilization rates are comparable after luteal
phase and follicular phase retrieval [19].
Embryo and oocyte cryopreservation
In 2014 Prasath et al. reported the first case
For reproductive age women with available of live birth after IVM in a patient with bilateral
male partner (or a willing to use a sperm donor), borderline serous carcinoma of the ovary [20].
and for whom health care providers (oncologist, There is an ongoing concern about the tim-
fertility specialist) decide that treatment can be de- ing of cryopreservation of the immature oocytes,
layed to perform ovarian stimulation; embryo cryo- since performing it at the germinal vesicle stage
preservation is the current option. Oocyte conser- may cause certain damage in its quality [21].
vation is suitable for women without a partner, or IVM can be combined with ovarian tissue
for those who do not accept embryo freezing [14]. cryopreservation (OTC). According to a study
Both options require ovarian stimulation, published by Hourvitz et al. in which 255 can-
transvaginal oocyte retrieval, thus making both cer patients were included in fertility conserva-
techniques available only for post pubescent girls tion programs, employing a combination of OTC,
who have sufficient time to undergo ovarian stim- oocyte aspiration and in vitro maturation (AIVM),
ulation, before starting oncological treatment. and with oocyte retrieval from ovarian tissue
The conventional ovarian stimulation pro- (OTIVM) resulted in more oocytes (p<0.001), more
tocols can increase estrogen levels up to twenty metaphase II oocytes (p<0.001), better matura-
times, raising concerns about the estrogen sensi- tion rate (p<0.01) and more cryopreserved oocytes
tive tumors growth. To avoid the undesirable ef- (p<0.05) than by employing just OTIVM or OTC.
fects of estrogen, new protocols that use Letrozole Also, the same study found that compared to us-
and FSH have been developed. Some authors who ing just ovarian tissue oocyte cryopreservation,

JBUON 2017; 22(4): 845

846 Fertility preservation in cancer patients

more oocytes with better maturation rate are ob- plantation). Orthotopic transplantation is the
tained if oocyte aspiration is performed right be- most used method of transplantation and with
fore ovarian tissue cryopreservation [22]. Ovarian this technique several pregnancies were obtained;
tissue cryopreservation meanwhile, heterotopic transplantation offers a
Ovarian cortex biobanking, as a method of series of advantages regarding its monitoring, but
preserving fertility, is considered as an option for there have been no pregnancies reported yet using
women, in whom need of chemotherapy is imme- this method [29].
diate or for pre pubertal girls for whom ovarian The endocrine function duration after trans-
stimulation and in vitro fertilization (IVF) can’t be plantation varies between 9 months and 3 years.
applied [23]. An important amount of follicles are lost right af-
The main advantage of this method applied ter transplantation due to local ischemia leading
for ovarian tissue resides in the fact that the ovar- to repeated grafting procedures [30,31].
ian cortex is the source of primordial and primary OTC is an invasive procedure and still consid-
follicles [24], assuring a high amount of female ered experimental for young patients, although in
gametes. Also, retrieval can be performed with- some countries, such as Israel, efforts were made
out delay in a minimally invasive manner. While to reconsider this [32]. The American Society for
the structure of the tissue can remain unaltered, Reproduction Medicine guidelines classifies OTC
its function can be destroyed irreversibly [25]. The as experimental and recommends applying it on
method needs the use of cryoprotective agents carefully selected patients [33]. The American
because of the risk of ice crystal formation. Tox- Society of Clinical Oncology Practice Update also
icity of these agents is another problem limiting labels OTC as experimental and recommends this
the technique’s success [26] and it depends on the procedure only in experienced centers [34]. Both
chemical properties of each agent, duration of ex- publications raise the theoretical problem concern-
posure, and temperature [27]. Several studies sug- ing transplantation of cancer cells with the graft.
gest that primordial follicles are more resistant In 2004 Donnez et al. reported the first live-
to cryoinjury and to cryoprotectants due to their birth after cryopreservation and orthotopic trans-
dormant metabolic state [28]. plantation of ovarian tissue in a woman with stage
The strategy underlying this procedure is to IV Hodgkin lymphoma. Five months after trans-
harvest and store the ovarian tissue fragments un- plantation, hormone levels and ultrasound findings
til the patient is ready for transplantation, aiming were consistent with ovulatory cycles and after 11
at the restoration of endocrine and reproductive months pregnancy was confirmed by ultrasound.
functions, otherwise destroyed by chemotherapy. The patient delivered at term. Concerning the
The ovarian tissue grafts can be transplanted to theoretical aspect, regarding the transplantation
the pelvis, near the original ovary sites blood sup- of malignant cells, histological assessment was
ply (orthotopic transplantation) or to other sites completed showing no such findings [35]. Several
such as abdomen or forearm (heterotopic trans- pregnancies followed this success (Table 1).

Table 1. Ovarian tissue cryopreservation outcomes (2004-2016)

Orthotopic / heterotopic Endocrine function
Year of publication/ authors [Ref] Pregnancy / live birth
transplantation restoration (months)
2004, Donez et al [35] +/- 5 1/1
2005, Meirow et al [36] + 8 1/1
2007, Demeestere et al [37] +/+ 5 1/0
2010, Demestere et al [38] +/+ 33 1/1
2008, Andersen et al [39] +/- 4 2/2
2010, Ernst et al [40] +/- 4 1/2
2011, Donez et al [41] +/- 2-5-6 13/13
2010, Roux et al [42] +/- 4 1/1
2010, Sanchez-Serrano et al [43] +/- 2 1/2
2012, Muller et al [44] +/- 3 1/1
2014, Macklon et al [45] +/- 1 1!
2015, Tanbo et al [46] +/- ? 2/2
2016, Dunlop et al [47] +/- 3,5 1
2016, Meirow et al [32] +/- 1-6 16/10

JBUON 2017; 22(4): 846

 Fertility preservation in cancer patients 847

In 2006 a cooperation network to aid fer- from the irradiation field. Ovaries can be moved
tility preservation for oncologic patients (both to the parabolic gutters, above the pelvic brim,
women and men) was founded in Germany. Since in line with the iliac crests or anterior the psoas
then, it has extended to more than 100 institu- muscle, depending on the radiation field, by open
tions across the country and in Switzerland and surgery, laparoscopy or robotic surgery. Metal
Austria. In 2016, the largest case series published clips are placed in order to identify and confirm
by Fertiprotekt network reports 21 pregnancies that the ovary is out of the irradiation field. The
and 17 live-births after orthotopic ovarian cortex procedure should be done as close as possible to
transplantation [35]. For the purpose of improv- the beginning of radiotherapy, and remains the
ing some aspects of the procedure Oktay et al. standard of care for patients treated with pelvic
performed ovarian tissue transplantation using a radiation. It may be combined with oocyte, em-
human extracellular tissue matrix scaffold in two bryo or ovarian tissue cryopreservation. Some-
patients diagnosed 12 and 7 years respectively times, to achieve pregnancy, re-transposition is
before, with hemophagocytic lymphohistiocytosis necessary. A recent approach is to transpose one
and non-Hodgkin lymphoma. The transplantation ovary and remove the other one for cryopreserva-
performed was minimally invasive. One pregnan- tion [37,41,44].
cy was ongoing at the time of publishing and one Complications regarding this procedure are
patient delivered a healthy baby [36]. Even though relatively rare, but sometimes chronic pelvic pain,
official peers consider OTC as an experimental adhesions, fallopian tube infarction, ovarian mi-
method of preserving fertility, efforts should be gration and metastasis to the transposed ovaries
made to offer this for whom other options are not can occur. The hormonal function is preserved in
available. 70-93% with ovarian transposition before radio-
therapy in patients < 40 years. Thibaud et al. re-
Ovarian transposition ported the first results of 18 children born after
Ovarian transposition is a surgical procedure ovarian transposition – 2 of them became amenor-
that should be considered in order to preserve reheic, 16 had menstruated and 2 pregnancies oc-
fertility in female patients with genital (cervical curred on a follow-up of 8.6 years [45].
cancer, vaginal cancer), urinary (rhabdomyosar- Terenziani et al. reported a number of 14
coma of the bladder) and hematologic (Hodgkin’s pregnancies – 12 live births (1 twin) and 3 miscar-
disease) malignancies as well as sarcomas of the riages after ovarian transposition in 11 patients
pelvic region (Ewing’s sarcoma), anorectal cancer with Hodgkin’s lymphoma, after a follow-up of
or neurologic malignancies that are treated with 14 years. None of these patients needed artificial
pelvic radiation. Oophoropexy reduces ovarian insemination or ovarian de-transposition [46].
exposure to only 5-10% [37-40]. Ovarian transposition in pediatric patients
Pelvic radiotherapy may cause ovarian and is still inadequately studied, but the success rate
uterine damage. Radiation tolerance of the uter- seems to be 60-83%. In adults’ long-term outcome
us and the ovaries depends on the total radiation studies, only a few pregnancies have been report-
dose, the fractionation schedule, the volume of ed – 5 pregnancies in 10 patients with Hodgkin’s
the tissue which is irradiated and the patient’s lymphoma [47] – 3 pregnancies in 107 cervical
age. The more younger the patient, the higher the cancer patients [48] and 3 pregnancies in 12 pa-
chance she has to preserve residual ovarian func- tients (9 Hodgkin’s lymphoma, 3 rectal cancer)
tion. The dose of irradiation at which ovarian fail- [49], but the ovarian hormonal function was well
ure occurs in 97.5% (ESD – the effective steriliz- preserved [38].
ing dose) of patients after treatment is 20.3Gy at A surrogate pregnancy may be a valid op-
birth, 18.4Gy at 10 years, 16.5Gy at 20 years and tion for women with cervical cancer treated with
14.3Gy at 30 years. Fractionated doses of radia- radical hysterectomy, lymphadenectomy and
tion are less toxic than a single dose [41,42]. oophoropexy, followed by ovarian stimulation,
Radiation damages the DNA of the ovarian oocyte retrieval from the genetic mother, IVF
follicle which might lead to decreased follicular and embryo transfer to the surrogate mother.
reserve. Mature follicles are more radiosensitive Legislation in many countries forbids this ap-
than primordial follicles. To destroy half of the proach [50].
follicular reserve, less than 2Gy is needed. Ovar- Köhler et al. described in a study published
ian failure is produced by a dose of irradiation of in 2016 a successful delivery after ovarian trans-
24Gy, if it is applied conventionally [40,43]. Ovar- position and uterus fixation in a patient with anal
ian transposition, also known as oophoropexy is a cancer followed by chemo-radiation and recto-
procedure in which one or both ovaries are moved anal resection [51].

JBUON 2017; 22(4): 847

848 Fertility preservation in cancer patients

Fertility preservation in male patients faster recovery of spermatogenesis, nor do gona-

dotropin releasing hormone antagonists prevent
Cancer, treatment and fertility long term infertility when high doses of chemo-
Cancer itself may influence spermatogenesis, therapy are used [59].
though the mechanisms are not well understood. Combination chemotherapies have been de-
Preexisting poor quality of germ cells, systemic veloped to reduce the negative effects and po-
effects of cancer, endocrinological or immunologi- tentiate the efficacy of the agents used, and have
cal effects probably exert some effect [52,53]. All become the golden standard in the treatment of
cancer therapies - radiotherapy, chemotherapy, several cancers. Although this synergy is desir-
stem cell transplantation, surgery - can impact able against cancer cells, it also has a detrimental
fertility, either directly affecting spermatogenesis impact on fertility, with the possibility of incur-
or hormone production. It is important to explain ring permanent azoospermia. For instance MOPP
their different risks and benefits, as these may in- (mechlorethamine, oncovin, procarbazine and
fluence patients’ treatment decision [54]. prednisone) used for Hodgkin’s lymphoma can
Unfortunately, there are no available options cause azoospermia in 90% of men for up to 4 years
for the protection of the gonadal epithelium. Pre- after treatment. The combination of bleomycin,
pubertal age is not a protective factor from gona- etoposide and cisplatin used in some testicular
dotoxic injury, as the cytotoxic treatment directly cancers has been associated with increased sperm
affects the early germ cells that undergo sponta- DNA abnormalities [60]. A recent animal study
neous degeneration before the haploid stage [55]. has described a protective effect of the humanin
analogue against spermatotoxic effects during
Radiotherapy chemotherapy, but no human studies are avail-
able [61].
Radiotherapy has been utilized in the treat-
ment of prostate, bladder, penile, testicular and Surgery
rectal cancer. The initial modalities for radiation
delivery have evolved from conventional external Surgery may also affect fertility, either direct-
beam radiotherapy to fractionated intensity mod- ly by affecting the integrity of the genitourinary
ulated radiotherapy. However, it may still have tract (for instance in bladder or prostate surgery)
irreversible detrimental effects on fertility and or its function (for instance, causing retrograde or
spermatogenesis. The gonadal epithelium is very anejaculation by affecting the lumbar sympathetic
sensitive to radiation because of its rapid division plexus or hypogastric plexus during retroperi-
rate. While Leydig cells can resist to doses up to toneal lymphadenectomy for testicular cancer).
20Gy in prepubescent males (and 30Gy in adult Many pelvic operations may also affect the erec-
males), immature spermatogonia are more sensi- tile function. As such, even though sperm quality
tive, with doses of 0.1Gy able to influence their may not be changed, there is a possible permanent
shape and number. Radiation doses under 0.8Gy loss of fertility, which the patient should be aware
lead to oligozoospermia, while doses up to 2Gy of. Currently, there is an effort to develop and de-
can lead to temporary azoospermia. Higher doses ploy nerve sparing techniques whenever possible
can lead to permanent sterility [56]. to maintain erectile and ejaculatory function, with
The radiation to the testis may result either good results.
from direct exposure or scattered radiation, with
some authors mentioning that 18.7% of radiation Surgical approaches to fertility preservation
administered in pelvic cancers is received by the Several surgical methods for preserving fer-
testis [57]. It may take 10 to 24 months for the tility have been described - testis sparing surgery,
sperm to return to pretreatment levels. The im- testis transposition, sperm retrieval, testicular
pact of radiation therapy on sperm DNA integrity stem cell transplantation.
is not yet known [58]. Although rare, synchronous and metachro-
nous bilateral germ cell tumors occur in 2-5% of
Chemotherapy
the patients, and bilateral orchiectomy will lead
Similarly to radiotherapy, chemotherapy may to permanent infertility as well as cardiovascu-
alter the function of Leydig cells and cause hypog- lar, metabolic and psychological problems. Thus,
onadism. The amount of damage is also dependent in extremely selected cases, there is an option for
on the type of regimen, the age of the patient and organ sparing surgery, provided the tumor is lim-
the total dose administered. However, it has been ited to the testis and of small size (less than 2 cm)
proved that hormonal therapies do not lead to [62]. Because of an increased risk of local recur-

JBUON 2017; 22(4): 848

 Fertility preservation in cancer patients 849

rence or adjacent testicular intraepithelial neo- sperm, or sperm with suboptimal motility or
plasia, close follow-up is required in all patients morphology.
undergoing enucleation. Ideally, semen collection
is performed prior to surgery, or at least before de- Fertilization methods
finitive radiotherapy. Organ sparing surgery may After treatment, many men may need artifi-
also be an option in the rare cases of Leydig cell cial reproductive techniques to procreate as IVF/
tumors, which account for 0.8-3% of all testicular ICSI. Of these, 15% will require the use of cryo-
tumors [63]. preserved semen due to persistent azoospermia.
Testicular transposition is a rarely used tech- No studies have so far proven any increase in the
nique, that may allow for fertility preservation in rate of malignancy or congenital abnormalities
patients requiring radiotherapy in the pelvic re- in children born fathered by cancer survivors, but
gion (for instance, for rhabdomyosarcoma of the close follow up is recommended. In a large cohort
bladder, prostate, or paratesticular tumors). The study published by Boice et al. the incidence of
testicle to be preserved is transposed to the thigh anomalies in children of cancer survivors was
or anterior abdominal wall, and later replaced in the same as in the general population. This held
the scrotum following completion of local irradia- true for patients who fathered children after un-
tion [64,65]. Due to the rarity of the procedure, its dergoing radiation therapy or alkylating agent
role in normal practice has yet to be defined. therapy [71]. A recent Swedish and Danish study
has shown a modest but statistically significant
Sperm extraction and preservation
increase in the risk of congenital abnormalities
In a study on adolescent patients, Bahadur et in children of males who had undergone cancer
al. reported that adequate semen samples were treatment, irrespective of means of conception
obtainable in the majority of patients regardless (natural or ART). The study involved the analysis
of cancer type (86.1%) [66]. If there is no ejacu- of a cohort of 8670 children with paternal history
lation or the patient has a history of retrograde of cancer treatment. Of these, 508 children were
ejaculation, a urine analysis following masturba- conceived using ARTs. The children of male can-
tion should be performed to assess the presence of cer survivors were more likely to have major con-
sperm in urine. If positive, alpha agonists may be genital defects than the control group, (RR = 1.17,
tried to direct the flow of sperm forward. Failing 95% CI=1.05-1.31, p=0.0043, 3.7 vs 3.2%). Interest-
that, a trial of urine alkalization, collection post ingly, the data available allowed the comparison
ejaculation and isolation of viable sperm may be of incidence of congenital abnormalities in chil-
performed. If no ejaculation can be achieved, vi- dren born from semen preserved pre-treatment
brostimulation or electroejaculation can be per- versus post-treatment, and proved to be equal in
formed, usually under general anesthesia [67]. In both groups (4.4%), indicating that factors other
azoospermic men surgical means of sperm ex- than anticancer therapies may be causing this
traction may be required, such as microsurgical trend [58].
sperm extraction (microTESE), testicular sperm ART in cancer survivors seems to be as ef-
extraction or microsurgical epididymal sperm as- fective as in the general population. Garcia et al.
piration (MESA). In men with azoospermia prior reported that the use of cryopreserved semen is
to chemotherapy due to their cancer pathophysi- about 10% and the success rate for live births is
ology, oncological testicular sperm extraction comparable to that of non-cancer patients [72].
may be performed, as described by Schrader et al.,
which uses microsurgical dissection and extrac-
tion of seminiferous tubules during the initial go-
Conclusions
nadal surgery [68].
Embryo and sperm cryopreservation are es-
For prepubertal males there are limited op-
tablished methods of fertility preservation. Other
tions for fertility preservation, focusing on in
options, such as ovarian or immature testicular
vitro generation of sperm from harvested sperma-
tissue cryopreservation are still in their infancy,
togonial stem cells or preservation of immature
but regarded with high hope. More research and
testicular tissue [69]. Once collected, cryopreser-
funding are needed to embrace the need of rein-
vation allows the sperm to remain in a suspended
stating and maintaining cancer patients’ fertility.
animation state and able to be stored for up to
15 years [70]. Current assisted reproduction tech-
niques - ARTs (in vitro fertilization - IVF - and Conflict of interests
intracytoplasmic sperm injection - ICSI) allows
for conception using testicular and epididymal The authors declare no confict of interests.

JBUON 2017; 22(4): 849

850 Fertility preservation in cancer patients

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