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.     

Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood.

Ovarian transposition in adults has been shown to protect ovarian function in about 60% of cases by reducing ovarian exposure to less than 4 to 7 Gy. We therefore evaluated the effect of ovarian transposition during childhood or adolescence. Eighteen girls had ovarian transposition performed at a mean (+/- SEM) age of 9.4 +/- 1.2 years (range, 1.2 to 16 years). Twelve were prepubertal and six had menstruated at the time of ovarian transposition. The initial abnormalities were Hodgkin disease (5 cases), iliac Ewing sarcoma (3), medulloblastoma (2), ovarian seminoma (1), and vaginal or uterine tumor (7). The irradiation was external in 11 cases and local by vaginal curietherapy in 7 cases. Fifteen girls received chemotherapy. The ovarian transposition was bilateral in 15 patients and unilateral in 3 cases; in the latter the other ovary had been destroyed by the tumor or by abdominal irradiation. Ovaries were placed just below the iliac crest (15 cases) or posterolateral to the uterus (3); thus, the calculated ovarian radiation dose was up to 9.5 Gy. At the time of evaluation (8.6 +/- 0.9 years after ovarian transposition), 16 girls had menstruated and 2 remained amenorrheic because of major lesions of the vagina and uterus caused by the vaginal curietherapy. Basal plasma gonadotropin values were normal. Ovulation was documented in seven cases. Two pregnancies occurred. Complications of ovarian transposition were present in four patients: intestinal occlusion, dyspareunia, functional ovarian cysts, and pelvic adhesions with tubal obstruction. We conclude that ovarian transposition, performed before abdominopelvic irradiation during childhood, can preserve ovarian function. Longer follow-up is required to assess the risk of ovarian dystrophy because of vascular lesions or chemotherapy.     

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.     

Calcified ovarian fibromas in prepubertal girls

Ovarian fibromas in prepubertal girls are rare. We describe two girls aged 8 and 11 years with extensively calcified ovarian fibromas. One patient had a single unilateral fibroma with metaplastic bone formation in the calcified area. The other patient had bilateral nodular fibromas suggesting the possibility of naevoid basal-cell carcinoma syndrome although broader manifestations are lacking at present.     

Ovarian cysts in young girls with hypothyroidism: follow-up and effect of treatment

Ovarian cysts have been reported in girls with longstanding uncompensated primary hypothyroidism. Restoration of euthyroid state has been associated with resolution of these cysts; long-term follow-up of these patients is however lacking. We evaluated the outcome in ten girls with ovarian cysts and hypothyroidism managed at our hospital with special emphasis on subsequent pubertal development and ovarian imaging. Patients were diagnosed at the age of 8.6 +/- 2.3 years (mean +/- SD) with severe uncompensated primary hypothyroidism (TSH levels >100 mIU/l in all; 509.3 +/- 651 mIU/l) and growth retardation (height SDS -4.1 +/- 1.8). Nine girls had vaginal bleeding at diagnosis; five also had thelarche. LH and FSH levels were prepubertal in all patients. Ovarian cysts were bilateral in eight girls (80%); internal septation was noted in six. Thyroxine replacement (4.1 +/- 0.7 microg/kg/day) led to normalization of TSH levels with reversal of pubertal changes and regression of ovarian cysts in all patients 2.2 +/- 1.0 months after treatment. At last follow-up 3.5 +/- 2.6 years after initiation of treatment at the age of 12.0 +/- 2.3 years, all patients had normal ovarian size in ultrasound evaluation with six girls progressing to normal puberty. Our study emphasizes the need to exclude hypothyroidism in young girls with ovarian cysts. Identification of hypothyroidism in these girls obviates the need for extensive investigations.     

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.     

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.     

Functional ovarian hyperandrogenism and polycystic ovary syndrome in prepubertal girls with obesity and/or premature pubarche

AIMS: Functional ovarian hyperandrogenism (FOH) is considered to be a form of polycystic ovary syndrome (PCOS) at adolescence. There are almost no data in the prepubertal period, although one of the earliest manifestations of PCOS is premature pubarche. Prepubertal girls with obesity or insulin resistance are also at risk to develop the full PCOS phenotype after puberty. The aim of this study was to evaluate prepubertal girls with premature pubarche and/or obesity for PCOS or FOH. METHODS: Twenty-seven prepubertal girls with premature pubarche and/or obesity aged >6 years were evaluated. FOH was defined as abnormal ovarian 17OHP response to challenge with GnRH analog of >2 ng/ml after exclusion of adrenal dysfunction. All patients underwent a pelvic ultrasound examination. RESULTS: Sixteen patients had premature pubarche, seven were obese, and four had both premature pubarche and obesity. Eleven of 27 patients (40.7%) showed high (>2 ng/ml) 17OHP response to GnRH challenge. Three patients (11%) with FOH also showed PCO morphology on pelvic ultrasound examination. CONCLUSION: In prepubertal girls who carry risk factors, including genetic polymorphisms and/or particular environmental factors, FOH/PCOS could develop at a high rate.     

The risk of functional ovarian hyperandrogenism and polycystic ovary syndrome in patients with hyperandrogenism

To describe the presence of dysregulations in steroid biosynthesis and the risk of functional ovarian hyperandrogenism (FOH) and polycystic ovary syndrome (PCOS)-like development in children with hyperandrogenism, 28 girls were studied. Adrenal steroidogenic profile was defined by basal and ACTH-stimulated levels of 17OHP, cortisol, DHEAS and androstenedione, and delta precursor/delta product ratios. Ovarian hyperandrogenism was defined by 17OHP response to LHRH stimulation, and pelvic ultrasonography (US) was performed to evaluate ovarian morphology. Basal and ACTH-stimulated hormonal results revealed non-classical 21-hydroxylase deficiency-like status in one patient (3.6%), and 21-hydroxylase deficiency heterozygote carrier-like state in four patients (14.3%), while the other 23 patients (82.1%) had functional adrenal hyperandrogenism (FAH). Among these patients with FAH, 47.83% had FOH; when these patients were evaluated by pelvic US, 30.4% had morphological changes which were not concordant with their age. We suggest that even mild forms of hyperandrogenism must be considered seriously and dysregulations of the steroidogenic pathway and ovarian abnormalities must be evaluated carefully to determine the risk of FOH/PCOS.     

Oophoropexy in children with ovarian torsion.

AIM: Children who have suffered from ovarian torsion may be at increased risk for a repeat event, and after unilateral ovarian loss, the contralateral ovary is at risk for future torsion. Oophoropexy has not been emphasized enough in the literature. We present our experiences with oophoropexy in children. METHODS: The medical records of 10 patients with ovarian torsion, who underwent oophorectomy and contralateral oophoropexy between April 1992 and April 2003, were reviewed retrospectively. The ovary was connected to the peritoneum of the posterior abdominal wall avoiding a disturbance of the tubo-ovarian anatomic relationship. RESULTS: The ages of patients ranged from 5 days to 14 years, with a mean age of 7.7 years. The period from onset of symptoms to hospital admission was ranged from 2 hours to 11 months. Only 1 ovary was salvaged after detorsion and bilateral oophoropexy was performed. In the other patients, the torsion caused necrosis, and oophorectomy or salpingo-oophorectomy and contralateral oophoropexy were carried out. Ovarian torsion occurred in 4 previously normal ovaries, in 5 cystic ovaries, and in 1 ovary containing a mature cystic teratoma. Two out of 10 patients had thrombus formation within the vessels of the twisted ovaries. An embolic phenomenon did not develop in any of the cases. At follow-up, all pubertal girls had normal menstrual periods. CONCLUSIONS: Failure to protect ovaries from subsequent torsions can result in castration, and we performed oophoropexy in both retained detorsed and contralateral ovaries without any postoperative complication. We performed medial oophoropexy to avoid tubo-ovarian disturbance. Oophoropexy is an easy and reversible procedure, and should be done in all cases of ovarian torsion.     

Childhood ovarian juvenile granulosa cell tumor: a retrospective study with 3 cases including clinical features, pathologic results, and therapies

Ovarian juvenile granulosa cell tumor (JGCT) is an extremely rare sex cord-stromal tumor that is most commonly encountered in prepubertal girls and young women. In this study, 3 cases of childhood JGCT are reported. The main causes of hospitalization were abnormal abdominal signs and syndromes. Imaging findings indicated masses with multiple cysts and solid components in the abdominal cavities. Diagnosis was confirmed by histopathology. Tumors were excised completely, and all cases have a good outcome in the follow-up (2 to 13 y) without any adjuvant chemotherapy or radiotherapy. This data suggests that children with JGCT might have a variety of initial clinical manifestations. Pathologic examination especially immunohistochemical staining could help to diagnose JGCT. For children, adjuvant treatment may not be necessary if the tumor can be excised completely in early stage.     

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay

Based on growing evidence that estradiol is produced in small amounts even in the prepubertal ovary, we hypothesized that estradiol levels in girls with Turner's syndrome (TS) are lower than in normal prepubertal girls secondary to the lack of normally functioning ovaries. Estradiol levels in untreated girls with TS have not been previously well defined because of the lack of adequate sensitivity of previously available estradiol assays. We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, or degree of bone age delay. In conclusion, girls with TS have significantly lower estradiol levels than normal age-matched prepubertal girls. This report is consistent with the hypothesis that the lack of normal ovarian function in girls with TS is evident even before puberty.     

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.     

Ovarian torsion

Ovarian torsion is a rare problem in the pediatric age group that must be included in the differential diagnosis of any girl with abdominal pain or a pelvic or abdominal mass. Clinical presentation is nonspecific, and diagnosis is based on a high index of suspicion. Ultrasound scan remains the most useful investigation, but blood flow on Doppler examination does not exclude ovarian torsion. Current recommendations of treatment strongly support ovary conservation, and macroscopic appearance of the ovary is not a reliable indicator of the degree of necrosis and potential for ovary recovery. For children with ovarian torsion, laparoscopic detorsion should be performed with strong consideration of oophoropexy. An underlying ovary lesion such as mature teratoma or functional cyst is found in most cases; however, the risk of cancer in these patients is extremely low. If there is concern of a mass or underlying pathology, then follow-up ultrasound, resolution of edema and interval laparoscopic treatment may be required.     

Ovarian ultrasound assessment in normal children,idiopathic precocious puberty,and during low dose pulsatile gonadotrophin releasing hormone treatment of hypogonadotrophic hypogonadism.

Ultrasound assessment of ovarian volume, follicular size, and uterine growth was undertaken in 40 normal premenarcheal girls aged 6 months to 14 years. Ovarian follicles were detected from 6 months of age and increased in size and number, so that after the age of 8.5 years there was a progressive increase in the incidence of ''megalocystic'' appearance. Eight girls with idiopathic precocious puberty had large megalocystic ovaries which regressed on treatment with gonadotrophin releasing hormone analogue. These findings contrasted with those seen in two prepubertal patients with hypogonadotrophic hypogonadism in whom the natural sequence of ovarian development was greatly accelerated by pulsatile administration of native gonadotrophin releasing hormone.     

Ovarian germ cell tumors in children: a clinical study of 66 patients

BACKGROUND: Ovarian germ cell tumors are rare in childhood. The aim of this study is to review clinical presentation, management, and outcome in a two-center series of girls with ovarian germ cell tumor. PROCEDURE: The records of 66 patients (median age 9 years) with histologically proven ovarian germ cell tumor (either benign or malignant), treated over a 44-year-span, were reviewed. RESULTS: Pain and an abdominal mass were the most frequent symptoms. The tumors were right-sided in 35, left-sided in 28, and bilateral in 3. Most patients (52) were stage I, 4 were stage II, 6 stage III, and 1, with liver metastases, stage IV. Sixteen patients had an emergency operation for tumor torsion. Unilateral salpingo-oophorectomy was the most frequently performed procedure (n = 46), and ovarian-sparing tumorectomy was performed in 9 patients (one bilaterally). Histologically, teratomas were found most frequently (mature: 45, immature: 9), followed by mixed tumors (n = 7), yolk sac tumors (n = 3), dysgerminoma (n = 2), gonadoblastoma (n = 2), and embryonal carcinoma (n = 1). Surgical removal of the tumor with or without the ovary and/or adnex was the sole treatment in 55 patients, chemotherapy was administered in 10 and radiotherapy + chemotherapy in one. Intra-operative spillage of tumoral fluid occurred in six; this did not influence outcome in five. Recurrence was observed in three patients. Two patients, with malignant disease, died. The 64 survivors are now between 8 months and 44 years after treatment. CONCLUSIONS: With a recurrence rate of 4.5% and a mortality rate of 3%, this series confirms the excellent prognosis for girls with ovarian germ cell tumor (GCT).     

Diagnosis of ovarian follicular cysts from birth to puberty: a report of twenty cases

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.     

Ovarian mucinous borderline cystoadenoma, in a premenarchal girl

Ovarian epithelial tumors (cystoadenomas/cystoadenocar-cinomas) are not as common in girls as the germinal tumors (teratomas). Mucinous or serous borderline cystoadenomas (CAdB) with a low malignant potencial, represent 20% of epithelial tumors. As an intermediate type of benign-malignant neoplasia, these tumors are usually giant cystic pelvic masses found in young females, but exceedingly rare before menarche. Stage 1 (tumor limited to the ovary) is the most frequent stage at diagnosis. Bilateral ovarian compromise occurs in 10-15% of patients. Open surgery is preferred to perform a fertility sparing procedure such as oophorectomy, salpingo-oophorectomy or even a tumorectomy in selected cases. The latter requires intraoperative biopsy confirmation of free margins, to prevent recurrence. Prolonged follow up is indicated to detect a recurrence or a contralateral tumor development. Survival is excellent in most of these patients. We present the case of a premenarchal girl with a huge mucinous CAdB.     

Ovarian granulosa cell tumors in childhood

Granulosa cell tumors (GCT) of the ovary are prepubertal in 5% of the patients. In girls less than 20 years old, 80% of GCTs differ from those among adults. These juvenile granulosa cell tumors (JGCTs) are usually benign. GCTs belong to ovarian sex cord-stromal tumors, the more common ovarian tumors being epidermal and germinal. The etiology of GCT remains unknown. Most young children with GCT present with precocious pseudopuberty. Among adolescents GCT often causes menstrual irregularities, virilization, abdominal swelling, and pain. When JGCT is limited to the ovaries the outcome is excellent with only salpingo-oophorectomy. However, more widely spread tumors are difficult to treat and cause mortality. Cisplatin-containing chemotherapy can induce remissions in adult GCTs. Estrogens and peptide hormones, i.e., inhibin, are useful in the follow-up of the patients. The authors describe 3 children with GCT and review current data on this rare tumor from molecular biology to clinical aspects.     

OVARIAN GRANULOSA CELL TUMORS IN CHILDHOOD

Granulosa cell tumors (GCT) of the ovary are prepubertal in 5% of the patients. In girls less than 20 years old, 80% of GCTs differ from those among adults. These juvenile granulosa cell tumors (JGCTs) are usually benign. GCTs belong to ovarian sex cord-stromal tumors, the more common ovarian tumors being epidermal and germinal. The etiology of GCT remains unknown. Most young children with GCT present with precocious pseudopuberty. Among adolescents GCT often causes menstrual irregularities, virilization, abdominal swelling, and pain. When JGCT is limited to the ovaries the outcome is excellent with only salpingo-oophorectomy. However, more widely spread tumors are difficult to treat and cause mortality. Cisplatin-containing chemotherapy can induce remissions in adult GCTs. Estrogens and peptide hormones, i.e., inhibin, are useful in the follow-up of the patients. The authors describe 3 children with GCT and review current data on this rare tumor from molecular biology to clinical aspects.