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Options for Fertility Preservation in Cancer Patients

Introduction

Increasing survival rates for cancers patients and an increasing awareness of the quality of life

after chemo-/radiotherapy have focused attention on the preservation of fertility after cancer 

treatmend. Due to great progress in reproductive medicine, measures that make it possible for 

affected women to have children after recovering from the disease can now be offered.

The effects of malignant disease on gonadal function are caused in most cases indirectly by the

influence of cytotoic theraphy. !hemotherapy and/or radiotherapy very often lead to partial or 

complete impairment of the ovaries and spermato"oa, severly reducing or eliminating fertility.The gonadotoic effects are strongly dependent on the patient#s age $older age correlating to

higher risk%, the type, dose and duration of chemotherapy and radiation therapy. $Table &, '%.

The aim of the present article is to provide basic information on fertility-preserving measures and

to enhance awareness among medical staff treating affected patients that such measures are

available. (ur main focus is on fertility preservation for women, but options for are also

mentioned.

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Options for

Fertility Preservation in Women

In general, disesase that require treatment that is gonadotoic represent as indication for 

measures to protect the ovary. )ertility-preserving measures have to be costumi"ed to match the

 patient#s individual clinical situation. *spects to be taken into account include the time available

 before the start of oncological therapy, patient#s age, relationship status, potential ovarian

involvement in the cancer, and gonadotoic measures that are to be used $)ig.&%. If possible, it

should be ensred that operations are carried out as fertility-conserving surgeries. In terms of 

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radiotherapy, attention must be paid to sufficient gonad protection by the choice of treatment

fields and lead aprons.

Transposition of the Ovaries (Ovariopexy)

In patients with +odgkin or non-+odgkin lymphomas, cervical carcinoma, colorectal carcinoma,

or other solid malignancies which require radiotherapy t the pelvis, the ovaries can be surgically

repositioned away from the radiotherapy field before starting treatment. The ovaries are

laparoscopically mobili"ed after transection of the ovarian ligaments or by opening the

retroperitoneum via bilateral fivision of the peritoneum along the infundibulo-pelvic ligament, so

that a transection of the fallopian tube is not necessary in most cases. ubsequently, the

mobili"ed ovary is fied cranio-laterally to the peritoneum of each paracolic gutter. (varies can

 be marked with radiopaque metal clips, so their location can be checked during treatment. The proportion of patients years of age who recover regular ovulatory cycles after radiotherapy

with this technique is up to 01 2. ' The success rate with this method depends on applied

radiation dosage and scattered radiation. 3are complications include pain during ovulation, cyst

formation, thrombosis, and ischemia 4.

GnR !nalo"ues

5onadotropin-releasing hormone $5n3+% agonists may be utili"ed to inhibit the re- lease of 

follicle-stimulating hormone in postpubertal women, inducing transient hypogonadotropic

hypogonadism and placing the ovaries in a 6resting7 state. +ereby, it is anticipated that follicles

can be protected and fertility be preserved. The latest meta-analysis including only randomi"ed

controlled studies $n 8 9% re- ported a reduced rate of premature ovarian failure with 5n3+

agonist administration, with an odds ratio of 4.1 :;.

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istered at least & week before starting chemotherapy due to the initial increase in the release of 

gonadotropins $known as the 6flare-up7 effect%, and administra- tion should continue for at least

&' weeks after the last chemotherapy cycle. If the time window before the start of chemotherapy

is less than a week, it is possible to combine 5n3+ agonists with 5n3+ antagonists in order to

reduce flare-up :0;. ide effects of 5n3+ ana- logues can include menopausal symp- toms

$although this is also possible with chemotherapy alone% and a reduction in bone mass if the drug

eposure is longer than 9 months. It should also be noted that possible negative effects of 5n3+

analogues on the prognosis for patients with estrogen receptor-positive diseases $e.g., breast

carcinoma% have not yet been clarified. This method is currently regarded as safe, noninvasive,

and easy to administer :B; and may be considered on an individual basis in combination with

other fertility-protecting measures if possible. tatements regarding the chance of pregnancy

cannot be made at the present time and must be discussed in detail during the information talk 

with the patient. )urther randomi"ed prospec- tive studies are lacking.

Cryopreservation of #nfertili$ed and Fertili$ed Oocytes

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*nother *3T is the cryopreservation of unfertili"ed oocytes. Despite publication of the first birth

after cryopreservation of unfertilised oocytes with a slow free"ing protocol in humans &B09 :&;,

this tech- nique was considered controversial due to the low survival rates of the cells. ased on

improved survival rates due to slight modifications of slow free"ing and vitrification protocols,

the cryopreserva- tion of unfertili"ed oocytes now repre- sents an effective *3T.

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of the stimulation procedure, which already needs at least & days, is at the beginning of the

follicular phase. @hen the patient is in the luteal phase, it is necessary to wait until bleeding oc-

curs. *n alternative is already to initiate the ovarian stimulation in the luteal phase together 

with the administration of 5onadotropin-3eleasing +ormone an- tagonist $5n3+-antagonist%,

which is administered to induce immediate luteo- lysis. The success of this application was

already shown by von @olff et al in 'B :'; and recently at the ?eeting of the >uropean

ociety of +uman 3eproduc- tion and >mbryology in '&, where the results of 9E cases of 

luteal phase stim- ulation were presented :'&;.

In%vitro maturation

In-vitro maturation $IJ?% involves ob- taining immature oocytes, maturing them, and then

fertili"ing them. Imma- ture oocytes from small antral follicles are obtained by transvaginalaspiration after short stimulation with follicle-stim- ulating hormone $)+% and/or human

chorionic gonadotropin $+!5%, if neces- sary. +arvested oocytes are matured in- vitro into

fertili"able metaphase II oo- cytes and can then be cryopreserved. It is unnecessary to epose

 patients to high- dose gonadotropin therapy with this method, and the time required before fol-

licular puncture is shorter than with con- ventional stimulation, making it easier to avoid a delay

in the start of chemothera- py. Immature oocytes can also be ob- tained during processing of 

 biopsied ovarian tissue. IJ? of oocytes during cryopreservation of ovarian tissue offers an

additional option of fertility preserva- tion without additional risk and epense for the patient

:'';. +owever, with the eception of results from a few research groups, data on pregnancy

rates with this procedure are still very limited and the reported rates are lower than those with

conventional in-vitro fertili"ation $IJ)% :'4, ';.

Cryopreservation of Ovarian Tissue

!ryopreservation of ovarian tissue has been investigated as a method of fertility preservation for 

more than a decade and has recently achieved considerable suc- cess. (ver '1 live births have been reported following transplantation of cryo- preserved ovarian tissue $:'1; and per- sonal

communication%. Technically, ova- rian etraction is a simple procedure. (varian tissue can be

obtained using minimally invasive techniques during laparoscopy, with unilateral ovariectomy or 

 partial ovariectomy. !ryopreservation of ovarian tissue can be carried out inde- pendent of 

menstrual phase and, there- fore, does not lead to any delay in onco- logical therapy $Table 4%. In

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centers that offer cryopreservation of ovarian tissue the procedure can be performed & day af- ter 

the patient#s first visit. *fter the tissue has been removed, it can be processed immediately or 

transferred in specific transportation containers to a center that is speciali"ed in the

cryopreservation of ovarian tissue with an associated cryobank.

* transport duration of 1 hours before cryopreservation is possible without any problems :'9;.

In addition, the viability of the tissue appears also to be preserved for longer periods of time

$overnight transport%, as the first live birth in 5er- many after re-transplantation of cryopre-

served ovarian tissue has demonstrated :'E;.

In general, cryopreservation of ovarian tissue involves similar cryogenic process- es as those

utili"ed for cryopreservation of oocytes or embryos. 6low free"ing7 is currently recommended

for free"ing ovarian tissue due to current higher effi- ciency with this method. In all previously published births following retransplanta- tion of cryopreserved ovarian tissue, the tissue

underwent slow free"ing :'';. (f note, however, eperimental tests demon- strate increasingly

 better results for vitri- fication :'0;.The main purpose of cryo- preservation of ovarian tissue is to

 pre- serve viable ovarian tissue for potential reimplantation if ovarian function fails following

cancer treatment. (varian tissue is usually reimplanted at the natural site $orthotopically%, in a

 peritoneal pock- et, or in the residual ovarian bed, in order to allow spontaneous conception. The

first reimplantation of ovarian tissue in 5ermany was performed in 'E at the Department of 

5ynecology at >rlangen Gniversity +ospital :'B;. 3esumption of hormonal function in

reimplanted tissue has now been documented on many occa- sions, and there have been over '1

recent- ly reported births following orthotopic reimplantation of cryoconserved ovarian tissue.

The first birth after reimplantation of cryoconserved ovarian tissue in 5er- many occurred on

(ctober &, '&& :4;. The first international surveys of birth rate per ovarian tissue

transplantation re- port a success rate of approimately &12, which is likely to increase in the

future..

The possibility that tumor cells may be concurrently reimplanted is a problem that must be

discussed with the patient. To date, there have been no cases in which this has been confirmed,

although considerable caution is advised regard- ing cryopreserved tissue from patients with

leukemia, borderline ovarian tumor, or with a high risk of ovarian metastases $e.g., in

adenocarcinoma of the cervi or stage IIIIJ breast cancer% :4&, 4';. *n option for these patients

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could be the maturation of follicles in vitro without transplantation. The ability of primordial

follicles of ovarian tissue to fully mature in vitro and produce fertili"able, viable ova has only

 been demonstrated in a few animal model reports. Total in-vitro maturation of human oocytes

from cryo- preserved ovarian tissue is not yet possi- ble :44;. +owever, it is quite conceivable

that in the net few years this technique will be successful in humans :4;.

*nother option is ovarian tissue eno- transplantation. (varian tissue is trans- planted into a

surrogate host, such as im- munodeficient mice $e.g., !ID mice%, which do not have reFection

reactions against foreign tissue. )ollicles that ma- ture can be punctured to obtain oocytes.

This method has been used eperimen- tally to test the vitality of fro"en ovarian tissue and to

assess any malignant con- tamination :4'; $Table %.

Com&ination of 'ifferent Techniues

To increase the effectiveness of individu- al measures, a combination of the de- scribed fertility

 preservation strategies could be considered. )or eample, when ' weeks are left before starting

chemo- therapy, ovarian stimulation could be performed and on the day of oocyte re- trieval,

ovarian tissue could also be har- vested for cryopreservation at the same time :41;. 3emoving

ovarian tissue first and starting ovarian stimulation approi- mately &' days later is an

alternative approach. The partial removal of ovarian tissue does not substantially affect the

average number or quality of oocytes re- trieved after ovarian stimulation :49;. ?oreover,

5n3+ analogues could also be administered simultaneously with the induction of ovulation in

these patients, thereby protecting remaining follicles.

Options for Fertility Preservation in en

In men, cryopreservation of eFaculate or testicular tissue are established means of creating a

fertility reserve. * therapeutically effective method that protects testicular function from

gonadotoic effects of chemotherapy or radiotherapy has to be developed :4E;. +ormonal

suppression of spermatogenesis in cytostatic chemotherapy $e.g. using 5n3+ analogues% has

 been attempted, but does not provide sufficient gonadal protection :40;. In radiotherapy,

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shielding of the testes from radiation or removal from the radiation field offers an effective

measure to prevent unwanted damage and is widely practiced.

Cryopreservation of *perm

!ryopreservation of an eFaculate is the established method of choice. ?ultiple sperm

donations can be provided and a fro"en depot created and maintained in reproductive medical

centers, prior to the start of gonadotoic treatment. This reserve could be used for *3T-

measures at a later date. permato"oa are relatively cryoresistant and post-thaw survival rate is

high. ?any pregnancies have been achieved using this method :4B;.

)or prepubertal boys, cryopreservation of sperm is inappropriate because provision of an

eFaculate is not yet possible. )or adolescent boys undergoing puberty, germ cells can be obtained

for cryo- preservation through etraction from testicular biopsies or by electroeFaculation.

+owever, both methods are invasive procedures :;.

Cryopreservation of *perm from Testicular Tissue (T+*+)

* testicular biopsy could be performed to isolate spermato"oa from testicular tissue when no

spermato"oa are found in the eFaculate. @ith this method, sperm cells are present in up to E12 of 

cases. T>> is an established process and is combined with intracytoplasmic sperm inFection

$I!I% for later fertility. +owever, the success rate depends on the amount of viable spermato"oa

 present in testicular tissue at the time of cryopreservation :&;.

The socalled (nco-T>> is particularly useful in patients with unilateral or bilateral testicular 

tumors, as well as patients with a"oospermia before or after gonadotoic therapy. >ven for long-

term survivors of oncological diseases with a"oospermia, (nco-T>> can be offered as an

opportunity for future fatherhood :';.

+xperimental !pproaches

3ecovery of testicular tissue via biopsy provides a method for recovery of germ line stem cells

 before the start of treatment which can be maintained through cryopreservation. This is

currently the only conceivable method to preserve fertility for prepubertal boys and, therefore,

the cryopreservation of immature testicular tissue should be considered for these patients. *fter a

successful treatment, the tissue or the germ line stem cells contained therein could be used for 

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 process es which initiate the differentiation of germ cells. The intact tissue could be transplanted

ectopically or orthotopically $autografts or ectopic enografting%. )uture studies should elucidate

the most appropriate method for clinical applica- tion :41;.

Conclusion

In view of the good treatment options recently available for oncological diseas- es, it is now

virtually essential to provide patients of reproductive age with coun- selling regarding fertility

 preservation. )ertility preservation is of great impor- tance to many young women and men

diagnosed with cancer, and in general the quality of counselling performance re- garding fertility

 preservation is highly valued by patients :4;. Today, there is a large range of potential fertility

 preserva- tion techniques available. )or men, sperm cryopreservation remains the gold

standardA by combination of cryopreser- vation with T>>/?>* or T>>/I!I there is a good

chance to reali"e a desire to have children. In women, transposi- tion of the gonads before

radiotherapy, the use of 5n3+ analogues, and cryo- preservation of embryos, oocytes and

ovarian tissue are available. The decision as to which treatment is most suitable in the patient#s

individual situation has to be made during a personal discussion with her and requires intensive

interdis- ciplinary communication, among oncol- ogists, radiotherapists, and reproductive

medicine specialists. The individual ap- proach is determined above all by the pa- tient#s age, thenature of the tumor entity, the remaining time before oncological treatment, the planned

treatment mea- sures, and the urgency of the patient#s wish to have children. upport and ad- vice

are available in 5erman-speaking countries from centers affiliated with the )ertiKT

network, as well as from the present authors.

Conflict of Interest

The authors certify that there is no con- flict of interest with any financial organi"ation regarding

the material discussed in the manuscript.