Reproductive and Endocrine Outcomes in a Cohort of Danish Women following Auto-Transplantation of Frozen/Thawed Ovarian Tissue from a Single Center.

Ovarian tissue cryopreservation (OTC) is a method of fertility preservation in girls and young women prior to gonadotoxic treatment. It is a safe and promising method to restore fertility. The initial recovery of endocrine function is high, but the longevity of the grafted tissue varies. In this single-center, combined retro- and prospective cohort study, we report the reproductive outcome and hormonal recovery following ovarian tissue transplantation (OTT) and evaluate possible predictors of the chance of pregnancy. The study includes 40 women from eastern Denmark undergoing 53 OTTs between 2003 and 2021. Permission to obtain retrospective data was given by the Danish Patient Safety Authorities and prospective data-collection by informed consent. Initial recovery of endocrine function was seen in 18/19 women with POI, and ongoing function of the grafted tissue in 7/14 two years from OTT. Live birth rate (LBR) was 41%, with 20 children to 39 women trying to conceive. Women who conceived had higher AFC at the time of OTC than women who did not (p ± 0.04). Repeated transplantations were not successful in terms of delivery. Half of all pregnancies were achieved by ART, but PRs were lower after ART than by spontaneous conception. LBRs after OTT are encouraging. Chance of pregnancy after OTT is correlated to ovarian reserve at OTC. Repeated transplantations were not successful in terms of unfulfilled pregnancy wish.

How Do Young Women with Cancer Experience Oncofertility Counselling during Cancer Treatment? A Qualitative, Single Centre Study at a Danish Tertiary Hospital.

BACKGROUND: Adolescents and young adults (AYAs) with cancer are at risk of therapy-induced infertility. The importance of initial and specialized fertility counselling to this patient group is undisputed. Despite international guidelines, oncofertility counselling is still inadequate. The purpose of this study was to examine how female AYA cancer patients and survivors experienced initial and specialized oncofertility counselling, and to present their specific suggestions on how to improve the oncofertility counselling. METHODS: Twelve individual semi-structured interviews were performed with AYAs aged 20-35 with cancer or who were survivors. Participants were recruited via a youth support centre and social organization for AYAs with cancer. Data was analysed using thematic analysis. RESULTS: Three main themes were found: Support is needed for navigating the fertility information jungle; The doctor's approach determines the content of the patient consultation; Inadequate and worrying information causes mistrust and frustration. CONCLUSION: Results indicate a continuing problem regarding insufficient oncofertility counselling to AYAs with cancer. To ensure adequate and uniform information, especially in the initial oncofertility counselling, national guidelines for oncology specialists are suggested including multidisciplinary effort and collaboration between oncology and fertility specialists in mind. In addition, participants suggest focus on communication skills.

Surgery versus conservative management of endometriomas in subfertile women. A systematic review.

INTRODUCTION: Endometriomas are present in up to 44% of all women with endometriosis and have a detrimental effect on fertility. However, it is controversial whether endometriomas should be surgically removed before assisted reproduction technology. Our purpose was to evaluate whether surgical stripping of endometriomas in subfertile women improves the chance of a live birth. Secondary outcomes were impact on ovarian reserve and pain. MATERIAL AND METHODS: We conducted a systematic review and meta-analysis with results reported in accordance to the PRISMA guidelines. A summary of findings table was developed using GRADE. We searched Medline and Embase. Two reviewers performed the screening. RESULTS: Of 686 manuscripts, we included one randomized controlled trial and nine retrospective cohort studies, mostly of low quality. The odds ratio for live birth after surgery [compared with conservative management before in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)] was 0.87 (95% CI 0.64-1.18, six studies, I2  = 3%; ⨁◯◯◯, VERY LOW quality). The mean difference of antral follicle count was -2.09 (95% CI -4.84 to 0.67, four studies). No difference was observed regarding antral follicle count between the two groups (MD -2.09, 95% CI -4.84 to 0.67, four studies, ⨁◯◯◯, VERY LOW quality). Pain outcome was not reported in the included studies. CONCLUSION: The very low quality evidence suggests no difference in odds ratio of live birth between women who underwent surgery for endometriomas before IVF/ICSI compared with conservative management. Further high quality studies are needed, but due to a lack of convincing evidence favoring surgery, we recommend considering conservative treatment if the only indication is subfertility.

Comparative pharmacology of a new recombinant FSH expressed by a human cell line.

Recombinant FSH proteins are important therapeutic agents for the treatment of infertility, including follitropin alfa expressed in Chinese Hamster Ovary (CHO) cells and, more recently, follitropin delta expressed in the human cell line PER.C6. These recombinant FSH proteins have distinct glycosylation, and have distinct pharmacokinetic and pharmacodynamic profiles in women. Comparative experiments demonstrated that follitropin delta and follitropin alfa displayed the same in vitro potency at the human FSH receptor, but varied in their pharmacokinetics in mouse and rat. While follitropin delta clearance from serum depended in part on the hepatic asialoglycoprotein receptor (ASGPR), follitropin alfa clearance was unaffected by ASGPR inhibition in rat or genetic ablation in mice. The distinct properties of follitropin delta and follitropin alfa are likely to contribute to the differing pharmacokinetic and pharmacodynamic profiles observed in women and to influence their efficacy in therapeutic protocols for the treatment of infertility.

Hallmarks of Human Small Antral Follicle Development: Implications for Regulation of Ovarian Steroidogenesis and Selection of the Dominant Follicle.

Regulation of human ovarian steroidogenesis differs from other species and precise knowledge on how human small antral follicles (hSAF) develop and acquire competence for continued growth and steroid output is still incomplete. The present study has characterized almost 1,000 normal hSAF collected in connection with cryopreservation of ovarian tissue for fertility preservation. The antral follicles (ranging from 3 to 13 mm) were generally aspirated from one ovary surgically removed during the natural cycle, and the follicular fluid (FF) and the granulosa cells (GC) were isolated and snap-frozen. In FF, the following hormones were measured: inhibin-B, inhibin-A, AMH, follistatin, PAPP-A, estradiol, progesterone, testosterone, and androstenedione. In GC, mRNA gene expressions using q-PCR were measured for the following genes: FSHR, AMH, CYP19, and AR. All samples in which one of the abovementioned parameters was measured were included, but typically multiple parameters were measured. Highly significant differences in concentration and follicular content in relation to follicular diameter were found for all measured hormones despite massive variability in-between follicles for any given diameter. The results demonstrate that profound changes take place in the hormonal microenvironment around follicular diameters of 8-11 mm corresponding to when follicular selection occurs. At this point, inhibin-B and inhibin-A showed distinct peaks concomitant with a significant reduction in both AMH protein and mRNA expression. Concentrations of inhibins, androgens, FSHR, and AR were intimately associated, and it is suggested that inhibin-B in combination with PAPP-A and thereby IGF2 activity exerts important paracrine signaling at follicular selection. At the same time upregulation of estradiol synthesis and CYP19 mRNA expression increased steroid output profoundly. Furthermore, the highly significant association between FSHR and AR mRNA gene expression enforces important functions of androgens in follicular development. Collectively, these data reintroduce the understanding of the follicular phase as two parted in which regulation of steroidogenesis differs. The profound changes taking place around follicular selection highlight important paracrine actions of TGF-ß family members and IGFs for securing dominance of the selected follicle.

The Fertility Assessment and Counseling Clinic - does the concept work? A prospective 2-year follow-up study of 519 women.

INTRODUCTION: The Fertility Assessment and Counseling (FAC) Clinic was initiated to provide women with information about their current fertility status to prevent infertility and smaller families than desired. The aim was to study the predictive value of a risk assessment score based on known fertility risk factors in terms of time to pregnancy. MATERIAL AND METHODS: Prospective cohort study of the first 570 women attending the FAC Clinic from 2011 to 2013 at Rigshospitalet, Denmark. A consultation included: risk assessment score sheet with items on infertility risk factors, anti-Müllerian hormone and ultrasound. The risk score was categorized as low, medium or high. After 2 years an email-based questionnaire was distributed regarding subsequent pregnancies. RESULTS: The follow-up questionnaire was answered by 519 women (91.1%). The mean age was 35 years and 38% were single at inclusion. The majority (67.8%, 352/519) tried to conceive within 2 years after attending the FAC Clinic. At follow up, 73.6% (259/352) had achieved a pregnancy, 21% (74/352) were still trying and 5.4% (19/352) had given up. Two-thirds (65%) with only low risk scores conceived spontaneously within 12 months, although this figure was only 32% for women with at least one high risk score (n = 82). Accordingly, presence of at least one high risk score reduced the odds of achieving a pregnancy within 12 months by 75% (OR 0.25, 95% CI 0.12-0.52). CONCLUSION: The new FAC Clinic concept seems usable and offers a tool for fertility experts to guide women on how to fulfill their reproductive life-plan.

Young female cancer patients' experiences with fertility counselling and fertility preservation-a qualitative small-scale study within the Danish health care setting.

INTRODUCTION: Fertility counselling for young women newly diagnosed with cancer is an important field of preconceptional counselling. This qualitative, small-scale study explored how young women newly diagnosed with cancer experienced specialized fertility preservation counselling and treatment in the public Danish health care system. METHODS: Semi-structured, in-depth interviews were conducted with five women below 40 years recently diagnosed with cancer. All women received fertility counselling by a fertility specialist at the Fertility Clinic, University Hospital of Copenhagen, Denmark before initiation of cancer treatment. Participants were interviewed at a place chosen by them, and interviews were recorded and transcribed verbatim. Data were analysed using systematic text condensation developed by Malterud and inspired by Giorgi's phenomenological analysis. RESULTS: None of the participants were aware that chemotherapy could destroy their eggs. The participants described how specialized fertility counselling and fertility preservation contributed to a belief in life after cancer, which gave them hope that they would survive their cancer disease. Further, the women described how the possibility of fertility preservation removed a huge concern and enabled them to concentrate on their cancer treatment and on getting better. CONCLUSION: Overall, the specialized fertility counselling and treatment to preserve fertility was highly valued. The women felt it gave them a choice about their future fertility. The fertility expert presented the various fertility-preserving scenarios, and the women were content that they had an actual choice.

Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience.

INTRODUCTION: The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. MATERIAL AND METHODS: A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. RESULTS: Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1:3). CONCLUSIONS: Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.

Treatment history and outcome of 24 deliveries worldwide after autotransplantation of cryopreserved ovarian tissue, including two new Danish deliveries years after autotransplantation.

PURPOSE: To report another two successful pregnancies and deliveries resulting from autotransplanted cryopreserved ovarian tissue several years after the autotransplantation procedure took place. Further, to review the literature on the treatment history, number of live births and their outcome so far reported worldwide. METHODS: Two women underwent fertility preservation with cryopreservation of their ovarian tissue prior to a potentially sterilizing treatment with bone marrow transplantation. One woman suffered from paroxystic nocturnal hemoglobinuria and one woman from relapse of Hodgkin's lymphoma. Both suffered from premature ovarian insufficiency after treatment. Because of a pregnancy wish they later had pieces of thawed cortical tissue transplanted to the remaining ovary and the anterior abdominal wall. PubMed was searched for reports of deliveries resulting from cryopreserved ovarian tissue in peer-reviewed papers. RESULTS: Five years after the autotransplantation the first patient became spontaneously pregnant and delivered a healthy baby boy at term. The second patient became pregnant after undergoing one cycle of in vitro fertilisation five years after the autotransplantation. She delivered a healthy baby boy at gestational week 36. Twenty healthy singletons and two sets of twins have been born according to peer-reviewed publications. CONCLUSION: Contrary to most of the published deliveries our latest two cases occurred several years after the autotransplantation procedure took place. This proves that ovarian grafts are capable of functioning for several years after the autotransplantation has occurred. Today, a total of 26 healthy children have been born as a result of cryopreservation of ovarian tissue.