Jana Liebenthron

Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women

Fertility-preservation techniques for medical reasons are increasingly offered in national networks. Knowledge of the characteristics of counselled patients and techniques used are essential. The FertiPROTEKT network registry was analysed between 2007 and 2013, and included up to 85 university and non-university centres in Germany, Austria and Switzerland; 5159 women were counselled and 4060 women underwent fertility preservation. In 2013, fertility-preservation counselling for medical reasons increased significantly among nullipara and women aged between 21 and 35 years (n = 1043; P < 0.001). Frequency of GnRH applications slowly decreased, whereas tissue, oocytes and zygote cryopreservation increased. In 2013, women with breast cancer mainly opted for tissue freezing, whereas women with lymphoma opted for GnRH agonist. Women younger than 20 years predominantly opted for GnRH agonists and ovarian tissue cryopreservation; women aged between 20 and 40 years underwent a variety of techniques; and women over 40 years opted for GnRH agonists. The average number of aspirated oocytes per stimulation cycle decreased as age increased (< 30 years: 12.9; 31-35 years: 12.3; 36-46: 9.0; > 41 years: 5.7). For ovarian tissue cryopreservation, removal and cryopreservation of fewer than one ovary was preferred and carried out in 97% of cases in 2013.

The impact of culture conditions on early follicle recruitment and growth from human ovarian cortex biopsies in vitro

OBJECTIVE To investigate the effects of a dynamic fluidic culture system on early in vitro folliculogenesis in standardized ovarian cortex biopsies. DESIGN Cortical small strips were cultured for 6 days in a conventional static or in a dynamic fluidic culture system. SETTING University-affiliated laboratory with an associated cryobank facility. PATIENT(S) Ovarian cortex from postpuberal female cancer patients (26.1 ± 1.3 y) who opted for cryopreservation of their tissue for fertility protection before gonadotoxic cancer therapy. With informed consent of the Institutional Ethics Committee, part of the tissue was available for patient-related research studies. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The viability and proliferative capacity of the cortex biopsies were evaluated by chemiluminescent microparticle immunoassay for detection of in vitro produced E2 and P in the supernate, by viable follicle counting via calcein staining, by histologic analyses, and by total RNA preparation and reverse transcription for real-time polymerase chain reaction of selected early folliculogenesis genes. RESULT(S) The data support the notion that early follicle development can be better achieved in vitro in a dynamic fluidic culture system. The findings are based on the presence of more viable follicles, higher expression levels of early folliculogenesis genes KIT-L, INHB, and GDF9, and the absence of premature luteinization of follicles. CONCLUSION(S) This study provides evidence that dynamic fluidic culture is a promising approach for investigating early follicular recruitment and growth in cortical biopsies. It may serve as a first step in a multistep culture system to design a complex in vitro system for complete folliculogenesis.

Fertility protection: complications of surgery and results of removal and transplantation of ovarian tissue

Fertility-preserving measures are becoming important for patients receiving oncological treatment. One method involves cryopreservation of ovarian tissue and transplanting it when treatment is completed. We report complications resulting from surgical and fertility medicine, and the results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. A survey using a structured questionnaire was conducted among the FertiProtekt network centres between November 2015 and June 2016. The analysis included surgical techniques used to remove and transplant ovarian tissue, surgical complications and results. Laparoscopic removal and transplantation of ovarian tissue have a low risk of complications. Surgical complications occurred in three of the networks 1373 ovarian tissue removals (n = 1302) and transplantations (n = 71); two complications (0.2%) occurred during removal and one during transplantation. Menstruation resumed in 47 out of 58 women (81%) who underwent ovarian tissue transplantation. Hormonal activity occurred in 63.2% of transplantations with a follow-up of 6 months or over. Sixteen pregnancies occurred in 14 patients, with nine births. The risks and complications of removal and transplantation of ovarian tissue are similar to those of standard laparoscopy. These procedures are becoming standard for fertility protection in cancer patients.

Fertilitätserhalt bei präpubertären und pubertären Kindern und Jugendlichen

BACKGROUND Due to rising survival rates in cancer and autoimmune diseases fertility preservation before gonadotoxic therapies has become increasingly important. Although fertility can be significantly affected by gonadotoxic therapies, the possibility of fertility preservation during childhood has not been sufficiently considered so far. METHODS Selective literature research with presentation of fertility preservation methods, their indications, implementations, risks and efficacy. RESULTS Measures are indicated in all girls and boys at high risk of gonadal damage. The complexity of the techniques requires special expertise in the counseling and implementation, which is offered to girls in counselling Germany especially in the centers of FertiPROTEKT (www.fertiprotekt.com). In girls, mainly cryopreservation of ovary tissue is considered. In postpubertal girls cryopreservation of oocytes is also possible. In postpubertal boys sperm can be preserved. Freezing of testicular tissue is still experimental in prepubertal boys. Success rates are still difficult to quantify; birth rates of about 50% are discussed. All procedures are not covered by health insurance. CONCLUSION In children and adolescents, measures of fertility preservation should be considered in cases of highly gonadotoxic therapies, and appropriate advice should be given by specialists.

Chapter 15 Development of a Nationwide Network for Ovarian Tissue Cryopreservation

Ovarian tissue cryopreservation is gaining much interest since the publication of the first live birth after retransplantation of frozen-thawed tissue in 2004 (Donnez et al., Lancet 364:1405-1410, 2004). In contrast to cryopreservation of gametes and embryos, ovarian tissue freezing is a complex requiring a proper approach in order to make this a viable option for fertility preservation of cancer patients. Due to the need in terms of laboratory space, equipment, personnel, and adequate logistics, an ovarian tissue cryobank is most economic if managed as a centralized service unit that interacts with numerous clinics covering the surgical part. Transportation of ovarian tissue under appropriate conditions from the surgical unit to the cryobank for subsequent preparation and freezing has been shown to have no impact on cryo-survival (Schmidt et al., Hum Reprod 18:2654-2659, 2003; Isachenko et al., Fertil Steril 91:1556-1559, 2009). Several children have been born after retransplantation of such tissue that was derived from the cryobank in Bonn, Germany (Homepage FertiPROTEKT. http://www.fertiprotekt.de ). This cryobank is one of the largest in the world with more than 1300 tissue samples that were frozen from 2003 until today. It is integrated in the network FertiPROTEKT (Homepage FertiPROTEKT. http://www.fertiprotekt.de ) and is served by 108 surgical centers that are located all over Germany. The concept of this cryobank is a blueprint for success and has recently been used for another regionally centralized cryobank in Beijing, China. In this chapter the most important topics that need to be considered while creating a centralized cryobank within a national or regional network are highlighted.

Is Ovarian Tissue Cryopreservation and Transplantation Still Experimental? It Is a Matter of Female Age and Type of Cancer

TO THE EDITOR: We read with great interest the update of the American Society of Clinical Oncology (ASCO) guideline on fertility preservation in patients with cancer. The authors spent much effort evaluating the current evidence on gonadotropinreleasing hormone agonists, because new evidence has accumulated since the first update of the ASCO guideline published in 2013. However, cryopreservation and transplantation of ovarian tissue were mentioned only briefly, even though this technique has also evolved considerably. The authors provided a general statement that this technique is still experimental; however, current evidence indicates that an overall classification of this technique should be replaced by a more sophisticated classification, which takes into consideration female age and type of cancer. For this reason, we would like to deepen the discussion regarding this point; in our opinion, it should be discussed much more intensively. Defining a technique as experimental or established is indeed difficult, because clear criteria are required. Provoost et al, representing the Special Interest Group Ethics in Law and the Special Interest Group Safety and Quality, both part of the European Society of Human Reproduction and Embryology, proposed a framework that distinguishes between experimental, innovative, and established therapies. They suggested applying the criteria of efficacy, safety, procedure, and effectiveness to assess new technologies and treatments. If all these criteria are fulfilled, a technique can be classified as established. These criteria can also be applied to classify ovarian tissue cryopreservation and transplantation in children, adults with malignant disease with a high risk of malignant cells in the ovaries (eg, those with leukemia), and adults with malignant disease with a low risk of malignant cells in the ovaries (eg, those with Hodgkin lymphoma or breast cancer). Proof of principle (efficacy) is still lacking in children, because a live birth has only been achieved in one woman who had ovarian tissue frozen in the peripubertal stage, but not in the prepubertal stage. Accordingly, the effectiveness (effectiveness) is also still unknown. Data on safety (safety) and technical performance (procedure) in children are also poor. Therefore, cryopreservation of ovarian tissue and transplantation must still be classified as experimental in children. This is in line with the recommendations of the expert meeting of the European Society for Blood Marrow Transplantation, which also classified this technique as experimental. In diseases such as leukemia, proof of principle (efficacy) has been demonstrated, because one child was born after transplantation of tissue frozen from a woman with leukemia. In this case, the tissue transplantation was performed after small samples were grafted into immunodeficient mice without developing signs of leukemia. However, safety data (safety) are still poor. The technique of cryopreservation is comparable between laboratories, but the technique of evaluating tissue before transplantation is not (procedure). Accordingly, data on the overall effectiveness (effectiveness) are also still poor, and therefore, cryopreservation and transplantation of ovarian tissue in adults with malignant disease and with a high risk of malignant cells in the ovaries, such as in leukemia, must still be classified as experimental. This is in line with Dolmans et al, who described the risk of ovarian metastasis as high in leukemia, neuroblastoma, and Burkitt’s lymphoma. In diseases with a low risk of ovarian metastasis, proof of principle (efficacy) has been demonstrated. Midterm safety data have been provided, qualifying this technique as comparatively safe (safety). The procedure of cryopreservation by slow freezing, and evaluation of small tissue samples to exclude metastasis by histology is comparable between laboratories (procedure). The effectiveness has been proven, with a cumulative live birth and ongoing pregnancy rate of 37.7% (effectiveness). In the largest case series published so far, 16 deliveries were reported, six from women with previous Hodgkin lymphoma and six from women with previous breast cancer. In conclusion, we agree with the authors that this technique is still experimental in children and in adults with malignant disease with a high risk of malignant cells in the ovaries, such as in leukemia. However, in those with a low risk of ovarian metastasis, using the criteria of efficacy, safety, procedure, and effectiveness, as introduced by Provoost et al, this technique should be classified as established and no longer experimental. This is also in line with the German, Austrian, and Swiss guidelines on fertility preservation. We therefore strongly recommend categorizing this technique according to female age and previous malignant disease, because an inaccurate classification has not only clinical implications regarding counseling but also political implications regarding reimbursement.

S2k-Leitlinie: Fertilitätserhaltende Maßnahmen bei onkologischen Erkrankungen

ZusammenfassungOnkologische und nichtonkologische Erkrankungen können die gegenwärtige oder zukünftige Fertilität beeinträchtigen, entweder durch die Krankheit selbst oder durch notwendig chirurgische Eingriffe, hormonelle und/oder gonadotoxische Behandlungen. Sie erfordern damit einen adäquaten fertilitätsprotektiven Ansatz – sprich eine unbedingte Beratung und, wenn die Voraussetzungen gegeben sind, auch eine entsprechende fertilitätsprotektive Therapie. Die Kryokonservierung von Oozyten stellt zumeist die Methode der ersten Wahl bei postpubertären Frauen dar. Metaphase-II-Oozyten-Kryokonservierung mittels Vitrifikation ist dabei die bevorzugte und empfohlene Option. Aber auch der kumulative Nachweis der Wiederherstellung der endokrinen Ovarialfunktion und der daraus resultierenden spontanen bzw. nach orthotoper Transplantation von kryokonserviertem Ovarialgewebe und Einsatz unterstützender assistierter reproduktionsmedizinischer Techniken resultierenden Schwangerschaften und Geburten spricht für diese Methode als offene klinische Anwendung – insbesondere bei präpubertären Mädchen, die nicht minder von keimzellschädigenden Behandlungen betroffen sind als adoleszente oder adulte Patientinnen im fertilen Alter und bei denen keine andere nachweislich wirksame Option zum Fertilitätserhalt derzeit verfügbar ist.AbstractOncological and nononcological diseases can affect current or future fertility, either through the disease itself or through necessary surgery, hormonal and/or gonadotoxic treatments. They therefore require an adequate fertility-protective approach—i. e. counselling is essential and, if the prerequisites are met, an appropriate fertility-protective therapy. Cryopreservation of oocytes is usually the first-choice method for postpubertal women. Metaphase II oocyte cryopreservation by vitrification is the preferred and recommended option. However, cumulative evidence of restoration of ovarian endocrine function and resulting spontaneous pregnancies and births, or after the use of assisted reproductive techniques, after orthotopic transplantation of cryopreserved ovarian tissue also advocates this method as an open clinical application, especially in prepubertal girls who are no less affected by germ cell-damaging treatments than adolescent or adult patients of reproductive age and for whom no other possible option for fertility preservation is currently available.

Concept Paper on the Technique of Cryopreservation, Removal and Transplantation of Ovarian Tissue for Fertility Preservation

The cryopreservation of ovarian tissue with subsequent transplantation of the tissue represents an established method of fertility protection for female patients who have to undergo gonadotoxic therapy. The procedure can be performed at any point in the cycle and thus generally does not lead to any delay in oncological therapy. With the aid of this procedure, more than 130 births to date worldwide have been able to be recorded. The birth rate is currently approximately 30% and it can be assumed that this will increase through the further optimisation of the cryopreservation and surgical technique. The concept paper presented here is intended to provide guidance for managing cryopreservation and transplantation of ovarian tissue to German-speaking reproductive medicine centres.

Fertility Preservation for Patients with Malignant Disease. Guideline of the DGGG, DGU and DGRM (S2k-Level, AWMF Registry No. 015/082, November 2017) – Recommendations and Statements for Girls and Women

Aim The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline. Methods This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40). Recommendations The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patientʼs personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities.

10 Jahre FertiPROTEKT@@@10 years FertiPROTEKT: Bericht vom 12. Arbeitstreffen des Netzwerks für Fertilitätsprotektion in Heidelberg@@@Report of the 12th workshop of the Network for Fertility Protection in Heidelberg

GynäkologischeEndokrinologie 2017 · 15:85–86 DOI 10.1007/s10304-016-0100-4 Online publiziert: 25. Oktober 2016