Ovarian tissue cryostorage and grafting: an option to preserve fertility in pediatric patients with malignancies

Fertility preservation in childhood cancer has become an important area of investigation due to increasing survival rates after cancer therapy. For these patients with an increased risk of infertility and premature ovarian failure, cryopreservation of ovarian tissue is a promising tool to preserve at least part of the reproductive potential. In recent years significant improvements have been achieved in this area, and 2 live births after autografting of frozen-thawed ovarian tissue have been reported. However, further research is needed to assess the clinical effectiveness of ovarian cryopreservation, to optimize the technique, and to limit the risk of reintroducing cancer cells in the patient with the graft.     

Feasibility of ovarian tissue cryopreservation for prepubertal females with cancer

BACKGROUND: Loss of fertility is one of the long-term adverse effects of high-dose chemotherapy or total body irradiation for cancer, even in children. Ovarian tissue cryopreservation (OTC) may make it possible for survivors of childhood cancer to have children. We evaluated the feasibility of this technique for prepubertal girls. METHODS: Between September 2000 and February 2005, 49 prepubertal girls were referred to the Reproductive Biology Unit for OTC before sterilizing treatment. RESULTS: One ovary each was collected from 47 patients, by laparoscopy in 24 patients and laporotomy in the others. In 16 cases, the ovary was harvested during laparotomy to resect a residual abdominal tumor. No complications occurred after operations. Ovarian tissue was frozen by a slow-cooling protocol, using DMSO and sucrose as cryoprotectants. An mean of 17.6 +/- 6.5 ovarian tissue fragments was cryopreserved per patient. Follicle concentration was evaluated histologically for 46 patients and a strong correlation was found between age and follicular density. None of the cases had visible ovarian tumor components. Ovarian cryopreservation was not carried out for two patients. CONCLUSION: The cryopreservation of ovarian tissue could be systematically offered even to prepubertal girls at risk of sterility due to gonadotoxic treatment.     

Should ovarian cryopreservation be offered to girls with cancer

Current therapy of childhood cancer makes long-term survival a realistic outcome for most patients. However, some treatment regimens entail a significant risk of infertility. No established method for preservation of female fertility is currently available. Ovarian cryopreservation is an experimental technology that is being offered with increasing frequency to women undergoing cancer therapy. It has not yet been reported in children and adolescent girls. The aim of this review is to stimulate discussion on the possibility of performing ovarian cryopreservation in pre-menarcheal girls in advance of therapies that may induce ovarian failure. We present a multi-disciplinary discussion of the risks and benefits associated with the procedure and propose guidelines for its implementation. We propose that all girls about to receive treatment that has a high risk for infertility be offered consultation about the possibility of ovarian cryopreservation.     

Ovarian tissue cryopreservation: a practical option?

Strategies to preserve fertility in young women undergoing potentially curative chemotherapy for malignant disease have been extremely limited. This limitation stems from the complex physiology of the human oocyte and the difficulties encountered in attempting to cryopreserve both developing and mature oocytes in sufficient quantities. Although in vitro fertilization and embryo cryopreservation can be used in those young women with a partner, this technique is unsuitable for the vast majority of patients and offers only a small chance of a pregnancy. Advances in cryobiology coupled with encouraging results in laboratory animals have prompted research into the storage of ovarian cortical tissue, which in young women is rich in primordial follicles. This tissue can be grafted back into the host, theoretically restoring the possibility of normal fertility. Primordial follicles contain oocytes at their least differentiated stage and appear to be relatively resistant to the combined insults of cryopreservation and the subsequent grafting procedure. Interest in this technique has been fuelled by its successful application in large domestic animals, such that ovarian tissue banking is being rapidly adopted into clinical practice before there is any hard evidence of its efficacy in humans.     

Anthropomorphic measurements and event-free survival in patients with favorable histology Wilms tumor: a report from the Children's Oncology Group

There are several methods of fertility preservation available for female patients facing infertility following gonadotoxic treatment of cancer or systemic disease. Embryos, oocytes or ovarian tissue can be cryopreserved and stored until the time when the patient is cured of her main disease and is expecting parenthood. The individual's choice depends on the nature and stage of the main disease, expected treatment, their condition, and age and existence of the partner. It is important to inform all such women about the options, and together with them, choose the most appropriate ones. It is often possible to save ovarian tissue even though the first chemotherapy courses have been undergone, but many more follicles can be stored before cancer treatment. Pediatr Blood Cancer 2009;53:254–260. © 2009 Wiley‐Liss, Inc.     

Preserving female fertility following cancer treatment: Current options and future possibilities

Children and women of reproductive age are increasingly surviving cancer diagnoses, and therefore long‐term quality‐of‐life issues are of greater importance at the time of diagnosis. Cancer therapies including radiation and chemotherapy can be detrimental to fertility, and therefore many patients are motivated to preserve fertility prior to cancer treatment. The only highly successful method in preserving fertility to date is embryo cryopreservation, which may not be appropriate for some patients due to age, delay in treatment, cancer type and stage, as well as availability of an acceptable sperm donor. Alternative methods including oocyte cryopreservation and ovarian tissue banking may also preserve fertility while providing additional flexibility to patients. In vitro ovarian follicle maturation following tissue banking is one potential approach that would not require a delay in cancer therapy for ovarian stimulation, would not require an immediate sperm donor, and does not carry the risk of reintroducing malignant cells following tissue transplantation. In vitro follicle culture systems have resulted in successful live births in the mouse. However, many challenges must be addressed in translating the system to the human. This review summarizes current approaches to fertility preservation and discusses recent developments and future challenges in developing a human in vitro follicle culture system. Pediatr Blood Cancer 2009;53:289–295. © 2009 Wiley‐Liss, Inc.     

Fertility preservation in children and adolescents with cancer

With excellent survival rates for individuals diagnosed with cancer during childhood or adolescence an awareness of quality of life, including fertility preservation is essential. Chemotherapeutic regimens that include alkylating agents and radiation treatments directed at the gonads or pituitary, including total body irradiation are particularly gonadotoxic. Assessment of potential for gonadotoxicity and appropriateness of fertility preservation techniques prior to the start of cancer directed therapies in every individual pediatric patient is crucial for limiting this late effect of therapy. Sperm banking for postpubertal males prior to the initiation of gonadotoxic therapy should be considered standard of care. Postpubertal females receiving highly gonadotoxic therapy that places them at risk of acute ovarian failure should consider embryo or oocyte cryopreservation prior to the initiation of therapy. Oocyte cryopreservation, as well as cryopreservation of gonadal tissue, whether ovarian or testicular, remain experimental and as such should be offered as part of a research protocol. Females who receive treatment that deplete their ovarian reserve should be evaluated for the development of premature menopause following their treatment. Embryo or oocyte cryopreservation post therapy may offer females at risk of premature menopause the opportunity to preserve their reproductive window. Further research clarifying gonadotoxicity of contemporary treatment regimens and improving interventions to preserve fertility are necessary to prevent infertility as a long term adverse effect of cancer treatment. The establishment of programs that streamline access to current fertility preservation techniques will assist in ensuring that all eligible patients can avail themselves of current options.     

Orthotopic ovarian transplant--review and three surgical techniques

Transplantation of organs is a rapidly expanding faculty of medicine. While the solid organ transplantation has grown by leaps and bounds, ovarian transplantation is still in its infancy. Although recent interest has been generated for preservation of fertility in cancer therapy patients, other indications have emerged. Ovarian dysgenesis with missing normal ovarian complement and premature ovarian failure has come in the forefront. Three cases of orthotopic ovarian transplant with different surgical techniques have been described along with a brief overview.     

Ovarian tissue cryopreservation: a practical option?

Strategies to preserve fertility in young women undergoing potentially curative chemotherapy for malignant disease have been extremely limited. This limitation stems from the complex physiology of the human oocyte and the difficulties encountered in attempting to cryopreserve both developing and mature oocytes in sufficient quantities. Although in vitro fertilization and embryo cryopreservation can be used in those young women with a partner, this technique is unsuitable for the vast majority of patients and offers only a small chance of a pregnancy. Advances in cryobiology coupled with encouraging results in laboratory animals have prompted research into the storage of ovarian cortical tissue, which in young women is rich in primordial follicles. This tissue can be grafted back into the host, theoretically restoring the possibility of normal fertility. Primordial follicles contain oocytes at their least differentiated stage and appear to be relatively resistant to the combined insults of cryopreservation and the subsequent grafting procedure. Interest in this technique has been fuelled by its successful application in large domestic animals, such that ovarian tissue banking is being rapidly adopted into clinical practice before there is any hard evidence of its efficacy in humans.     

Reproductive technologies 1998: options available for the cancer patient.

Recent advances in the field of reproduction have potentially opened opportunities for the preservation of the reproductive potential of young cancer patients with good long-term prognosis for survival. In the postpubertal male, cryopreservation of ejaculated sperm is both feasible and potentially successful. Semen parameters at the time of procurement are of minor significance; intracytoplasmic sperm injection (ICSI) can bypass sperm concentration and motility problems and can lead to successful fertilization. For the prepubertal male there are no clinically applicable options insofar as extraction and cryopreservation of postmeiotic sperm cells (mature spermatozoa or round spermatids) is not feasible. To date, efforts for culture of testicular tissue and in vitro maturation of male germ cells have not been successful. In both pre- and postpubertal females, cryopreservation of ovarian cortical tissue or enzymatically extracted follicles and the in vitro maturation of preantral follicles are of potential clinical use, but, to date, these approaches have been successful only in laboratory animals. An additional option available to the postpubertal female is the stimulation of ovaries with exogenous gonadotropins and retrieval of mature oocytes for cryopreservation. The recent application of ICSI in previously cryopreserved human mature oocytes has improved fertilization rates and has resulted in live births. Unfortunately, a shortcoming of this approach is the limited number of oocytes that can be harvested after stimulation of the ovaries. Further, all these approaches potentially harbor the risk of the cryopreservation of malignant cells with their subsequent reintroduction in the patient at a later date. This is a more realistic concern for patients suffering from hematologic or gonadal tumors. Finally, even though cryopreservation of embryos has been successfully used for many years, this option is not available to the pediatric and adolescent patient. It should not be forgotten that, even if the patients' own gametes are not available in the future, donor sperm and eggs provide the option for offspring and can give the opportunity to the females to carry a pregnancy as long as their uterus has not been affected by the cancer treatment. Given the rapid progress we are witnessing in the field of reproductive medicine, it is probable that in the very near future most of the options described and newer ones will be clinically available.     

Diminished ovarian reserve in adolescent cancer survivors treated with heavy metal chemotherapy

The extent to which heavy metal chemotherapy results in treatment-related ovarian damage is controversial. Anti-Mullerian hormone (AMH) levels measured more than 1 year after cancer therapy completion were abstracted from the medical records of 39 female survivors of childhood cancer aged 11 years and older, whose only gonadotoxic exposure was heavy metal chemotherapy. One-fifth of survivors who received cisplatin had AMH levels indicative of diminished ovarian reserve at last measurement. There was an observed clustering of low AMH in patients diagnosed in the peripubertal age range (i.e., 10–12 years). These findings may support a small, but present, risk of gonadal damage after heavy metal chemotherapy.     

Fertility preservation medicine: A new field in the care of young cancer survivors

Treatment modalities for numerous oncological and non‐oncological conditions result in gonadal insufficiency and infertility. Furthermore, pelvic‐abdominal radiation may result in uterine damage resulting in poor reproductive outcomes such as preterm birth, low birth weight, and spontaneous abortion in adult survivors of childhood cancers. In response to the recognition of the impact of cancer treatments on fertility, several fertility preservation techniques have been developed. In prepubertal children, fertility preservation options are usually limited to ovarian cryopreservation because of sexual immaturity, but oocyte freezing can be performed in adolescent children. Two prospective randomized studies showed no benefit of gonadal suppression with GnRH analogs to preserve gonadal function and thus this treatment should not be recommended. For adult survivors of childhood cancer who experienced reproductive failure, third party reproduction techniques are highly successful. Pediatr Blood Cancer 2009;53:267–273. © 2009 Wiley‐Liss, Inc.     

Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer

Increasingly young people survive cancer in childhood and as a result complications of its treatment are becoming more common and important. Premature ovarian failure is recognized as a complication of radiotherapy to a field that includes the pelvis and alkylating‐agent‐based chemotherapy. Young pre‐pubertal girls are not protected from the effects of gonadal toxic therapy. A young woman, successfully treated for cancer during childhood, may experience regular periods in the presence of a significantly reduced ovarian reserve. There is, however, no reliable measure of ovarian reserve available for the individual woman. Assessment of ovarian function relies on the use of surrogate markers such as follicle stimulating hormone, inhibin‐B, and anti‐mullerian hormone as well as ultrasound assessment of ovarian volume and antral follicle count. We discuss the physiology of normal ovarian function, the effects of cancer treatments on ovarian function and the techniques for evaluation of ovarian reserve in survivors of childhood cancer. Pediatr Blood Cancer 2009;53:296–302. © 2009 Wiley‐Liss, Inc.     

Impact of ovarian transposition before pelvic irradiation on ovarian function among long‐term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study

1 Background

We reviewed the effect of ovarian transposition (OT) on ovarian function among long‐term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy.

2 Procedure

Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients.

3 Results

Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25–60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1–207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m² (HR = 11.2, 95% CI = 3.4–36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2–1.9; P = 0.41).

4 Conclusions

OT did not appear to modify risk of POI in this historic cohort of long‐term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at‐risk patients whenever feasible.     

Endocrinology and metabolism after premature pubarche in girls

The prevalence of functional ovarian hyperandrogenism, hyperinsulinism and dyslipidaemia is increased in adolescent girls with a history of premature pubarche, defined as the appearance of pubic hair before the age of 8 years. The ovarian hyperandrogenism is characterized by clinical signs of androgen excess and an exaggerated ovarian 17-hydroxyprogesterone response to gonadotrophin-releasing hormone aganist stimulation. The hyperinsulinism and dyslipidaemia are detectable before and during pubertal development, and they are commonly accompanied by low serum levels of insulin-like growth factor binding protein-1 ( IGEBP-1 ) and sex hormone binding globulin, and by an increased prevalence of anovulation from late adolescence onwards. In girls, premature pubarche, hyperinsulinism, low serum levels of IGFBP-1 dyslipidaemia, anovulation and hyperandrogenism (or various combinations of these conditions) have been related to reduced fetal growth, indicating that these constellations or sequences may have a prenatal origin. These findings suggest that premature pubarche in girls should no longer be regarded as meaely a normal variant of development, but rather as a childhood marker pointing to an increased risk of a polyendocrine-metabolic disorder of prenatal origin.     

Tumor lysis syndrome after combination chemotherapy for ovarian cancer

Tumor lysis syndrome is infrequently encountered following the treatment of solid tumors. A 47-year-old woman developed this syndrome after receiving combination chemotherapy for ovarian cancer. The levels of serum lactate dehydrogenase, uric acid, phosphate, and creatinine increased, whereas the serum calcium level decreased. These metabolic abnormalities were treated successfully using a combination of vigorous intravenous hydration, parenteral bicarbonate to keep urinary pH > 7, furosemide, and allopurinol. This unusual and easily treatable complication should be anticipated in patients with rapidly growing ovarian cancer undergoing aggressive treatment. © 1993 Wiley-Liss, Inc.     

Diagnosis of Ovarian Follicular Cysts from Birth to Puberty: A Report of Twenty Cases

ABSTRACT. Twenty girls aged 1 day to 17 years have been studied for ovarian follicular cysts. Clinical features leading to the discovery of the follicular cyst were different in prepubertal girls and in girls whose cyst was discovered during puberty. Before seven years of age, four girls presented a precocious pseudopuberty where breast development was in contrast with very low pituitary gonadotropin levels; two girls in this age group were diagnosed after complaining about abdominal pain. In two cases the diagnosis was prenatal during routine ultrasonography of the mother. After ten years of age, abnormal menses (5 cases) or acute abdominal pain (5 cases) were the main clinical features. In only one case the cyst presented as an abdominal mass. Follow-up of the 20 patients showed: spontaneous disappearance of the cyst within 3 to 32 weeks in 9 cases; ovariectomy in 8 cases, due to a torsion of a large cyst (over 55 mm) in 7 children and because of the fear of a possible tumor in one; limited resection of the cyst in 4 cases. By systematic ultrasonography, discovery of an ovarian cyst as defined by a non-echogenic area over 20 mm may occur relatively often in young girls. Spontaneous disappearance is frequent when the cyst is small (under 55 mm). Torsion of large cysts remains the major complication.     

Le syndrome de Turner : quoi de neuf dans la prise en charge ?

Turner syndrome is a rare genetic disorder, affecting approximately one in 2500 live-born female, due to total or partial absence of the X chromosome. Typical clinical features are short stature and premature ovarian failure and less constantly phenotypic particularities such as congenital malformations, acquired cardiovascular, otological (hearing impairment), autoimmune and metabolic pathologies. The phenotype is highly variable with slight or even normal phenotype. Several studies have shown that growth hormone treatment improves adult height. The possibility of pregnancies after oocyte donation highlights the high risk of these pregnancies requiring a careful follow-up, especially in terms of cardiovascular issues. Although the quality of life seems similar to the normal population, the presence of cardiovascular and otological diseases, and delayed feminisation are associated with an impaired quality of life. Early diagnosis and regular screening for potentials associated complications are essential in the medical follow-up of these patients. The recent publication of recommendations should lead to an optimization and harmonisation of the medical practices and follow-up from paediatric age to adulthood, a lowering morbidity and self-esteem improvement. The interest of ovarian cryopreservation at an early age in these patients is under investigation.     

Endometrial carcinoma after Hodgkin disease in childhood

A 34-year-old patient developed metastatic endometrial carcinoma after Hodgkin disease in childhood. She had ovarian failure after abdominal irradiation and chemotherapy for Hodgkin disease, and received exogenous estrogens, a treatment implicated in the development of endometrial cancer in menopausal women. Young women on replacement estrogens for ovarian failure after cancer therapy may also have increased risk of endometrial carcinoma and should be examined periodically.     

Novel heterozygous mutation in the PTEN gene associated with ovarian germ cell tumor complicated by growing teratoma syndrome and overgrowth in a two‐year‐old female

Growing teratoma syndrome (GTS) is a condition in which mature teratoma with negative tumor markers arises at the site of a treated malignant germ cell tumor. Pathogenic variants in PTEN have been reported to cause autosomal dominant cancer predisposition syndromes and are associated with germ cell tumors. We report the association of a novel heterozygous pathogenic variant in PTEN and very early onset ovarian germ cell tumor complicated by GTS as well as overgrowth syndrome. This marks the youngest reported patient to have developed GTS following treatment of her primary malignant ovarian germ cell tumor.