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Meanwhile, improving data and optimization of the available techniques have allowed a realistic portrayal of the efficacy and risks of the most commonly used methods, as well as recommendations for the use of the techniques, alone or in combination.
Several guidelines and recommendations have been published in Europe [ 1 ], the United States [ 2 ], and elsewhere. These guidelines mainly focus on scientific evidence, but are less practically orientated. We have, therefore, prepared an update of practical recommendations published in by the Ferti PROTEKT network, a network and society of physicians and biologists specializing in fertility preservation in Germany, Austria, and parts of Switzerland [ 3 ].
As the topic has become too broad for one single paper, we have prepared two articles. Part I focuses on the diseases and provides information essential in decision making for or against fertility preservation, such as prognosis of the disease and disease-specific therapy and risks for loss of fertility.
In this second article, Part II, we provide recommendations specifically on the fertility preservation techniques. The decisive factor in ovarian stimulation is maximization of the oocyte yield and minimization of the complication rate, so that oncological treatment can be started immediately after follicular aspiration. It should be noted that fertilized oocytes can only be transferred to the woman after the consent of both partners, which is why preserving some oocytes in an unfertilized state should be considered, even in the case of a stable partnership.
Ovarian stimulation can now be initiated at any time during the menstrual cycle [ 4 — 7 ]. In addition, double stimulation [ 8 ] and stimulation directly after ovarian tissue removal are also possible [ 9 ]. The number of oocytes collected depends on the age of the patient and the underlying ovarian reserve, which varies individually. First case series confirm these calculated success rates.
In 90 women who had cryopreserved oocytes, embryo transfers were performed, which led to the birth of 35 children birth rate Since the number of frozen oocytes is decisive for the later chances of conception, double stimulation could increase the number of cells. Estimated live birth rate after ovarian stimulation, based on the number of retrieved oocytes and registry data. Cryopreservation of oocytes is now usually performed by vitrification.
Pregnancy rates were not significantly different. These data were confirmed in a later meta-analysis [ 14 ]. The effectiveness of oocyte vitrification has also been confirmed in cancer patients [ 15 ]. In 11 women whose oocytes were removed before gonadotoxic therapy at an average age of Ovarian stimulation can lead to side effects caused by the medication, as well as complications during the puncture.
However, clinically relevant bleeding during follicular aspiration or inflammation is rare. The standard protocol for stimulation is the antagonist protocol with ovulation induction using GnRH agonists triptorelin 0.
According to a study by Kuang et al. Depending on the cycle phase, stimulation can be carried out as follows Fig. In double stimulation [ 8 ], stimulation with a classical antagonist protocol as well as ovulation induction with a GnRH-agonist is initially performed.
It can be assumed that the first stimulation can also be started in any cycle phase random start stimulation. Small follicles are not aspirated. The time required for double stimulation is ca. To reduce the increasing estrogen concentrations during ovarian stimulation, the addition of aromatase inhibitors, e. The number of mature oocytes obtained and their fertilization capacity is not reduced by the addition of letrozole [ 5 ]. The previous studies have not shown increased malformation rates in children after low dose stimulation with letrozole [ 20 ].
Ovarian stimulation can be combined with cryopreservation of ovarian tissue to increase the success rate after highly gonadotoxic treatment Fig. According to the studies carried out so far, there is no increased complication risk and the number of oocytes obtained is not significantly reduced after removal of ovarian tissue. The time required for the combination of both treatments is about 2.
Combination of the three main techniques to preserve fertility before gonadotoxic therapy. If there is a sufficiently high ovarian reserve, part of the ovarian tissue can be cryopreserved for later transplantation. Since the cryopreserved tissue volume is not very large and some of the follicles degenerate during cryopreservation and transplantation, the transplants are only active for a few years. Therefore, the transplant does not serve to restore long-term ovarian function, which would replace hormone replacement therapy, but only to achieve a pregnancy.
Transplantation for the induction of puberty [ 22 , 23 ] as well as postponement of the menopause [ 24 ] have been reported; however, since transplantations for these indications are of limited use endocrinologically [ 25 ], the cryopreservation of ovarian tissue should only be performed to establish a fertility reserve.
In principle, the higher the ovarian reserve i. The data for assessing effectiveness are still limited. However, since data from previously published case series show similar success rates, the probability of birth per transplant can already be roughly estimated. In a case series from Denmark with 41 women, 53 transplantations were performed [ 26 ]. A total of 42 transplants were performed in 32 women because of a wish to conceive. A sub-analysis of the 40 women who received their first transplant for POI included 11 pregnancies and 9 births.
According to data from Denmark, some pregnancies are generated after repeated transplantations; therefore, a higher success rate per woman is expected in the future. Since transplantation techniques are being further optimized, a similar success rate to ovarian stimulation and cryopreservation of oocytes could possibly achieved. This case report shows that transplantation can lead to pregnancies even after prepubertal cryopreservation of ovarian tissue.
This is supported by two case reports, which have shown an induction of puberty by the transplantation of prepubertal cryopreserved ovarian tissue [ 22 , 23 ]. The removal and transplantation of ovarian tissue requires a laparoscopy, the transplant another laparoscopy, possibly a laparotomy. When removing ovarian tissue, there is an increased risk of infection and bleeding depending on the oncological disease e. According to the Ferti PROTEKT register, one complication per laparoscopies which necessitates surgical revision is expected for the removal of ovarian tissue [ 29 ].
The surgical risks for the transplantation of ovarian tissue are not higher than for any other laparoscopy. In high-risk cases, cryopreservation of ovarian tissue should be considered as experimental and the patient should be informed that the tissue might not be used or can only be used after further establishment of the techniques mentioned below.
Before the removal of ovarian tissue, the ovarian reserve should be determined to avoid cryopreservation in women with a low ovarian reserve. Ovarian tissue should not be taken from the side of the corpus luteum, as the quality of the ovarian tissue may be restricted. The removal of an entire ovary is only recommended for prepubertal girls due to the small size of the ovaries. The wound surface is rinsed to identify the small, mostly subcortical sources of bleeding and to selectively coagulate them.
A closure of the wound surface is not necessary. A small sample from the removed ovarian tissue is placed in formalin and handed to the pathologist to exclude metastases. The removed ovarian tissue should be transferred immediately after removal into a sterile transport medium e.
A clean room laboratory with a contamination-free environment and a sterile class II lamina air flow should be available for preparation, where sterile and cooled dissection can be performed.
The ovarian medulla should be carefully dissected from the ovarian cortex using a precision scalpel and anatomical forceps and a thin residual stroma should be left, so that an optimal starting point for the neovascularization of the transplants is available later. Depending on the size and quality, rectangular pieces of cortex, ca. In a computer-controlled slow-freezing process, the samples are cooled according to a modified program by Gosden et al.
The number of tissue fragments to be transplanted is determined using the ovarian reserve, and if possible the follicular density after histological determination, and the age of the patient at the time of removal of the tissue.
The ovarian tissue is mainly transplanted orthotopically, i. Which localization leads to the highest chances of pregnancy is still unclear. How much ovarian tissue should be transplanted is also still open to discussion. During the transplantation, the patency of the tubes should be checked and, if necessary, a hysteroscopy should also be considered.
Transplantation of ovarian tissue I: A subperitoneal pocket is bluntly dissected and the pieces of tissue are placed, so that the cortex surfaces face the pelvis Fig. The pieces of tissue should lie side by side. Peritoneal closure is usually performed with single interrupted sutures for example, with PDS Fig. The tissue is usually placed into the larger ovary and thus usually into the organ from which the ovarian tissue did not originate before gonadotoxic therapy.
The ovary is incised Fig. The tissue pieces are transplanted into the pocket, so that the cortex surfaces face the ovarian surface if possible. The closure of the ovary is usually performed with sutures Fig. A transplant onto the ovary surface requires the tissue pieces to be of a sufficient size, so that they can be fixed. The ovary is, for example, incised on the surface using scissors, which opens a wound gap that is bluntly dilated.
The tissue pieces can be fixed onto this with single interrupted sutures e. If the tubes are open and no other relevant sterility factor is present, a spontaneous pregnancy may be attempted.
Cycle monitoring is often performed, ovulation is induced with hCG, and the timing of sexual intercourse is optimized. The many spontaneous pregnancies [ 27 ] confirm that spontaneous conception can initially be attempted.
If a pregnancy does not occur or a different relevant sterility factor is present, then IVF, possibly combined with ICSI, can be carried out. Gonadotropin stimulation for the generation of several follicles can be attempted, but this often does not lead to a multifollicular reaction due to the low ovarian reserve and is also associated with higher costs. Since it is currently unclear which transplant location is ideal and how much tissue should be transplanted, the transplantation of ovarian tissue should only be carried out within the scope of clinical trials if possible.
However, activation of the primordial to secondary follicles is gonadotropin-independent, so a protective influence cannot be plausibly explained this way [ 35 ].
Thus, the mode of action of GnRHa is currently unclear. Most meta-analyses since showed a significantly lower rate of POI occurrence after chemotherapy-accompanying GnRHa administration. The risk can be reduced by about half, admittedly in a heterogeneous data situation [ 35 — 39 ]. A significant influence on the likelihood of a later pregnancy has not been proven so far. There is currently still a need for clarification and the need for complementary prospective randomized studies on the use of GnRHa for this indication.
In principle, GnRHa can lead to climacteric symptoms such as hot flushes, etc. However, during chemotherapy, the ovarian function is suppressed anyway, and such symptoms are possible a few days earlier at the most because of the previously administered GnRHa. Regardless of this, it should be noted that GnRHa may theoretically affect the efficacy of chemotherapy on estrogen-sensitive tumours. This negative effect on chemotherapy has not been confirmed, however, but was rather disproved.
After the initial GnRHa application, a gonadotropin flare up is noted. However, whether this flare up is relevant is currently unclear, as the primordial follicles are not gonadotropin sensitive. The aims of ovarian transposition are the preservation of hormonal ovarian function and the possibility of pregnancy, even after oncological treatment. The effects of radiotherapy on ovarian function are considerable. Ovarian transposition should be considered when targeted radiotherapy is performed in the pelvic area.
In addition to the benefits and risks, alternatives such as cryopreservation should be discussed. A combination of different fertility preservation techniques is also possible.
Ovarian transposition is not appropriate in patients who undergo total body irradiation. The question of whether ovarian transposition should be performed prior to radiotherapy can only be decided individually. In addition to the expected gonadal toxicity, the possible wish for a unilateral transposition plays a role to allow spontaneous conception via the remaining ovary. The results of ovarian transposition before radiotherapy depend on various factors and are, therefore, difficult to quantify.
In a meta-analysis of 32 publications with a total of patients, the success rate in the sense of preserved ovarian function is stated as Publication bias is to be assumed, since many cases or studies with a poor success rate may not be published [ 44 ].
Furthermore, the success rate of ovarian transposition is also determined by the surgical technique. Different techniques such as cranial, lateral, medial, and anterior transposition have been described [ 45 ]. Due to the inhomogeneity of the cases and the absence of prospective randomized studies, it is not possible to make a reliable statement on the comparison of the different techniques, whereby cranial transposition is the safest technique for reducing the dose of radiation.
However, the importance of the new position of the ovaries has been proven. In this respect, close collaboration between the surgeon and radiologist is necessary before the planned transposition. The positioning height of the ovary is also a relevant prognostic factor. In a multivariate analysis, the positioning height with an odds ratio of Overall, ovarian transposition is assumed to be highly effective in the sense of preserving ovarian function. However, pregnancies are rare [ 50 ].
On one hand, patients may no longer wish to have children after completing oncological treatment [ 51 ]. On the other hand, radiotherapy to the uterus significantly reduces pregnancy chances.
The radiation-induced alteration of the endometrium also influences the success rate of cryopreservation of the ovaries before radiotherapy. The surgical risks of ovarian transposition are low. In most cases, the procedure is possible via laparoscopy. If laparotomy is performed because of another indication, ovarian transposition can be carried out simultaneously without a substantial increase in the complication rate.
Ovarian tissue can also be removed during this procedure for cryopreservation. Ovarian cysts sometimes develop postoperatively which are a sign of disturbed ovarian function [ 43 ].
In most cases, however, these cysts do not require treatment. The infundibulum is prepared cranially until tension-free fixation of the ovary in the desired position is possible. Blood flow can be well controlled by inspection of the tube, whereas this is not possible with the ovary.
The ovary is placed in the desired position, e. To avoid intestinal obstruction, the vascular pedicle should also be fixed to the abdominal wall. There are numerous other techniques in addition to those mentioned. Only in vitro maturation IVM is also used in humans.
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See properties located closest to the centre first with confirmed availability for your dates from our partners. Schiller's Hotel und Bistro. Hotel offers wifi and have their own excellent restaurant with bar. In particular, the hotel staff was very welcoming and our room was Hotel garni Zur Friedenseiche. With its dated furniture and decoration the Hotel radiates a charming seventies atmosphere.
I was pleased with the personal service upon arrival and throughout my stay. The room was very comfortable and well equipped. The WiFi was excellent thought my stay Hotel Mitte "Alte Susswarenfabrik".
I prefer it here over the large hotels and will use this lovely place in the future Arrived early evening in the dark so wanted an easy to find place. The website is basic but the premises looked tidy and adequate for our needs. The website is however misleading. The reason being that our friends wanted to return to the area to retrace the
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