Franca Agresta

First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy.

Ovarian tissue cryopreservation and transplantation is a form of fertility preservation offered to young women at high risk of losing ovarian function after cancer treatment. While there have been successful births resulting from orthotopic site grafts, we report the first case of an ongoing pregnancy from a heterotopic graft in a patient who had previously undergone bilateral oopherectomy for a granulosa cell tumour. Frozen-thawed ovarian tissue was transplanted to the anterior abdominal wall. Subsequent ovarian stimulation and transabdominal ultrasound-guided oocyte retrieval from the grafts resulted in two oocytes. These were fertilized with ICSI and two embryos were transferred. Serial ultrasounds have confirmed an ongoing 26-week intrauterine twin pregnancy. Thus, this first demonstration of a pregnancy from a heterotopic graft site provides unequivocal evidence that cryopreservation preserves complete follicle development and that normal ovarian function can occur at a non-ovarian site. This provides optimism for further efforts to assist women who have had oophorectomy and pelvic surgery or radiotherapy, without an appropriate orthotopic site for grafting.

Delivery of twins following heterotopic grafting of frozen-thawed ovarian tissue

Sir, We have recently published a case report in your journal (Stern et al., 2013) describing the first reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy. At the time of writing the article the patient had a 26-week intrauterine twin pregnancy and we would like to provide an update on the outcome of this pregnancy. As described, the patient had undergone oophorectomy for a granulosa cell tumour 9 years previously followed by prophylactic removal of the remaining ovary and subsequent ovarian tissue cryopreservation. After repeated assessments revealed no tumour recurrence, and no evidence of tumour in the stored tissue, she had frozen-thawed ovarian tissue grafted to the anterior abdominal wall on two occasions. There was no evidence of tumour seen at either laparoscopy. The patient underwent low-dose stimulation and in vitro fertilization resulting in two embryos which were transferred. Her pregnancy proceeded uneventfully apart from a brief admission at 26 weeks for threatened preterm labour and a shortened cervix, which remained stable. The patient subsequently had an elective lower segment Caesarean section at 37 weeks and delivered two healthy girls weighing 3320 and 3262 g. At operation there was macroscopic evidence of tumour involving the diaphragm and a peritoneal deposit at the left pelvic brim. There was no evidence of tumour in the graft sites. All macroscopic tumour was resected and histology confirmed granulosa cell tumour. Recurrent tumour development could be directly related to grafting of ovarian tissue. It could also be due to a recurrence of peritoneal deposits precipitated by the hormonal environment provided by a pregnancy, in a tumour known to be sensitive to hormonal stimulation. Whilst the absence of tumour extraperitoneally at or near the graft sites might support hormonal reactivation, we cannot exclude the possibility that tumour recurrence resulted from the grafted tissue. The patient will commence hormonal suppression with an aromatase inhibitor once breastfeeding is discontinued and a further laparoscopy is planned. While the prognosis for this patient remains excellent, this unfortunate outcome serves to remind us of the possibility of tumour cell transmission with grafting despite comprehensive prior histological and biochemical assessment.

Creating a Global Community of Practice for Oncofertility

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.

Reproductive concerns of children and adolescents with cancer: challenges and potential solutions

The diagnosis of a potentially life-threatening cancer is one of the most traumatic events that can befall a young person and his or her family. However, fortunately, most young people will survive their cancer and its treatment and go on to lead a long and healthy life, with an appropriate expectation of being able to have their own genetic family. However, cancer treatment, including surgery, chemotherapy, and radiotherapy, can have temporary and permanent effects on fertility, including damage to the uterus and pituitary gland, and reduction, or obliteration, of gonadal function, with consequential loss of oocytes or spermatozoa, which may result in ovarian or testicular failure. As the gamete pool is nonrenewable, permanent gonadal failure precludes subsequent fertility with a patients own genetic material. Awareness and acknowledgement of the likely future fertility implications of cancer treatment is an essential part of any discussion about proposed therapies. Options for girls and young women include freezing mature oocytes and ovarian tissue, as well as attempting to protect the ovaries from the gonadotoxic effects of treatment. Options for boys and young men include semen collection and storage as well as testicular biopsy with freezing of testicular tissue or spermatozoa retrieved from the tissue. Fertility options can now be offered with increasing optimism about success and the provision of a genuine opportunity for having a family. While the initiation of cancer treatment is sometimes truly urgent, the opportunity for a detailed discussion about implications for fertility is of paramount importance for patients and their families and provides both reassurance and optimism about the future.

Success and challenges in fertility preservation after ovarian tissue grafting

We read with great interest the Lancet Series on fertility preservation, particularly Dominic Stoop and colleagues’ paper Fertility preservation for age-related fertility decline (Oct 4, p 1311). The clinical outcomes of cryopreserved ovarian transplantation are reported from centres around the world, with a worldwide livebirth rate quoted as 30% (as of September, 2014). A major limitation of understanding the effi ciency of this technique is the general absence of reporting of the denominator, that is, the total number of times the grafting procedure has been done. The way the data from our centre were presented in Stoop and colleagues report illustrates this point (one transplant, one pregnancy, and two babies). We would like to take this opportunity to clarify the results from our centre. 18 transplantations have been done in 14 patients (as of September, 2014), with two pregnancies (one at 31 weeks’ gestation at present) and two babies (twins) born by use of in-vitro fertilisation. With three fetal heart pregnancies and 21 embryos transferred in total, the clinical pregnancy rate is therefore 14%. Whereas most of the pregnancies from around the world have been achieved with ovarian tissue transplanted within the ovary or its immediate surroundings, we have had more success with grafting tissue within the anterior abdominal wall at the laparoscopic port sites. Stoop and colleagues suggest that this technique has come of age and can potentially be used in healthy women wishing to preserve fertility for non-medical reasons. While this might prove to be the case in the future, the effi ciency of this technique in the present needs optimisation. The fi rst step towards this goal is to gain an accurate representation of worldwide clinical outcomes, with individual centres accurately reporting their results. Notably, the International Society for Fertility Preservation’s plans to compile these data into a worldwide database are underway, which will help to address this issue.

A short report on current fertility preservation strategies for boys

Advances in cancer treatment have led to improved long‐term survival after childhood cancer, but often at a price of impaired future fertility. Fertility preservation (FP) in male children and early adolescents poses unique challenges as efficacy is unproven.

Fertility in premenopausal women post autologous stem cell transplant with BEAM conditioning.

There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non‐Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1–3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17–33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20–40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17–30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes.

Setting up a fertility preservation programme

With improved survival rates from cancer, young people can expect to lead a normal life, including having their own children. However, cancer or other serious disease itself, and more often its treatment, often leads to a significant reduction in fertility or premature gonadal insufficiency. There is increasing acknowledgement for the importance of fertility preservation (FP) options to be discussed and offered to young people whose fertility is at risk, ideally before the gonadotoxic therapy begins. FP options currently include oocyte, embryo and ovarian tissue cryopreservation; ovarian protection during chemotherapy and semen, sperm and testicular tissue cryopreservation. A multidisciplinary team consisting of committed and enthusiastic doctors, scientists, nurses, counsellors, administrators and researchers is required to provide a holistic FP service with rapid response capacity for acute consultation and procedures and a robust system for long-term follow-up. This speciality is developing rapidly with exciting scientific advances that have relevance for the whole spectrum of reproductive medicine.