Pediatric oncofertility care in limited versus optimum resource settings: results from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a secondary report to elucidate the diverse spectrum of oncofertility practices for childhood cancer around the globe, we present and discuss the comparisons of oncofertility practices for childhood cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia, and Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the USA, Europe, Australia, and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered in case of childhood cancer as well as their degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for childhood cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings for ovarian and testicular tissue cryopreservation; (2) frequent utilization of gonadal shielding, fractionation of anticancer therapy, oophoropexy, and GnRH analogs; (3) promising utilization of oocyte in vitro maturation (IVM); and (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, in vitro spermatogenesis, and stem cells reproductive technology as they are still in preclinical or early clinical research settings. CONCLUSIONS: Based on Repro-Can-OPEN Study Part I & II, we presented a plausible oncofertility best practice model to help optimize care for children with cancer in various resource settings. Special ethical concerns should be considered when offering advanced and innovative oncofertility options to children.

Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study.

PURPOSE: The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. METHODS: Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. RESULTS: Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD <3), surgical excision of any organ of the genital tract (RR = 1.63, 95 % CI 1.20-2.21), testicular radiation ≥4 Gy (RR = 1.99, 95 % CI 1.52-2.61), and exposure to bleomycin (RR = 1.55, 95 % CI 1.20-2.01). CONCLUSION: Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Preservation of growth hormone secretion in response to growth hormone-releasing peptide-2 during prednisone therapy.

Children who require long-term glucocorticoid treatment often demonstrate poor growth. Growth hormone (GH) secretion is decreased during glucocorticoid treatment, and this decrease may be due to a relative excess of the hypothalamic hormone somatostatin (SRIF). GH-releasing peptide-2 (GHRP-2) is a GH secretagogue that acts via multiple mechanisms at multiple sites. One of its proposed mechanisms is the ability to bypass SRIF blockade of GH secretion. We measured the ability of GHRP-2 to release GH before and during prednisone therapy (20 mg orally three times daily for 4 days). The degree of preservation of GH secretion and the pattern of GH release in response to GHRP-2 were compared with those observed in response to arginine, a known SRIF inhibitor. GH release in response to GHRP-2 and arginine was measured in the same eight subjects before and during prednisone therapy. Before prednisone, peak GH levels in response to arginine and GHRP-2 were 8.8 +/- 2.8 and 80.8 +/- 21.2 microg/L. During prednisone therapy, the peak GH level in response to arginine and to GHRP-2 was 20.1 +/- 8.3 and 71.3 +/- 18.4 microg/L, respectively. The difference in peak values before and after prednisone was not significant. The time to the peak GH level during prednisone therapy occurred sooner for both arginine and GHRP-2. The pattern of GH release to arginine and to GHRP-2 was not identical, and the mean area under the curve for GH release to GHRP-2 decreased significantly with steroid treatment (P = .04), suggesting that GHRP-2 acts by mechanisms additional to the removal of SRIF inhibition. GHRP-2 elicited a 10-fold greater GH response than arginine at baseline, and the GH response was threefold greater versus arginine even in the face of prednisone therapy. GH release occurred earlier for both arginine and GHRP-2 during steroid treatment. We propose that this may suggest an increased storage phenomenon due to the blockade of GH secretion by glucocorticoids and then a sudden release with SRIF inhibition. If GHRP-2 can indeed counteract the inhibitory effect of glucocorticoids on GH secretion, then a new form of therapy may be available to support growth in children who must receive long-term steroid treatment.

Systematic approach for detection of endocrine disorders in children treated for brain tumors.

Endocrine dysfunction can be challenging to diagnose in children treated for brain tumors. Treatments are available for hormonal replacement and when necessary, hormonal suppression. Without these endocrine treatment regimens, life can be unnecessarily difficult or unpleasant. An endocrine survey can be used to screen at-risk neuro-oncology patients once or twice a year to facilitate the recognition of endocrine dysfunction. It is hoped that through the use of a routine screening program, physicians will be able to diagnose and begin treatment of endocrine problems in a time-efficient manner.

Predictors of change in insulin sensitivity during glucocorticoid treatment.

Glucocorticoid induced alterations in carbohydrate metabolism can result in hyperglycemia. We evaluated changes in carbohydrate metabolism produced by four days of prednisone (20 mg PO TID) measuring insulin sensitivity, basal glucose, basal insulin and first phase insulin release (FPIR). We correlated these measures of carbohydrate metabolism with changes in free fatty acids and lactate levels both of which have been reported to be possible mediators of insulin sensitivity. Insulin sensitivity decreased by 64% (p = 0.002), basal insulin levels increased 50% (p = 0.026), FPIR tripled (p = 0.064) while fasting glucose levels increased significantly but remained normal. Basal FFAs levels increased (p = 0.045) while lactate levels did not change significantly, and neither predicted changes in SI. Basal levels of SI and FPIR were found to be independent predictors of change in insulin sensitivity and together explained 83% of the change in insulin sensitivity produced by short term treatment with prednisone.

Decreased reverse T3 levels in neonates with central hypothyroidism.

Concern arises when a sick infant is found to have a low serum T4, normal thyroid hormone binding, and a nonelevated thyroid-stimulating hormone. Hypothyroxinemia in this situation can result from either euthyroid sick syndrome or central hypothyroidism. To help distinguish between these diagnostic possibilities, we have measured reverse T3 and other thyroid function chemistries in six neonates who have central hypothyroidism in association with hypopituitarism. We found that these infants all had reverse T3 levels that were much lower than reported normal levels for premature and term neonates. This finding suggests that low reverse T3 levels can help to distinguish infants with central hypothyroidism from sick and well infants who tend to have relatively elevated reverse T3 levels.

Optic nerve hypoplasia: absence of posterior pituitary bright signal on magnetic resonance imaging correlates with diabetes insipidus.

PURPOSE: Magnetic resonance imaging has been used to examine children with optic nerve hypoplasia for pituitary abnormalities who may be at risk for anterior pituitary hormonal deficiencies. We correlated the sellar and optic pathway anatomic findings on magnetic resonance imaging in children with optic nerve hypoplasia with findings from their endocrinologic and ophthalmologic examinations to determine whether magnetic resonance imaging findings predict anterior and posterior pituitary dysfunction. METHODS: A retrospective review identified five children with optic nerve hypoplasia and endocrinopathy who also underwent high resolution volumetric magnetic resonance imaging. RESULTS: All children had severe bilateral optic nerve hypoplasia and anterior pituitary hormone deficiencies. Three children had no recognizable intrasellar or ectopic posterior pituitary bright spot on magnetic resonance imaging; all had clinical evidence of diabetes insipidus. Two patients with a recognizable but ectopic posterior pituitary did not have diabetes insipidus. CONCLUSION: Children with optic nerve hypoplasia and no recognizable posterior lobe of the pituitary gland on magnetic resonance imaging are at risk for both anterior and posterior pituitary dysfunction, whereas those with a posterior lobe on magnetic resonance imaging appear to have intact posterior pituitary function.

Isolated magnesium malabsorption in a 10-year-old boy.

Isolated magnesium malabsorption (congenital hypomagnesemia) has been reported in approximately 30 patients worldwide. Patients typically present by 6 months of age with convulsions and diarrhea. We report an unusual case of isolated magnesium malabsorption in an older boy with no diarrhea.

Characterization of a noncontiguous gene deletion of the growth hormone receptor in Laron's syndrome.

Noncontiguous deletion of the GH receptor (GHR) gene has been described as a molecular defect causing Laron's syndrome (LS). The abnormal allele (GHR Del-3,5,6) lacks exons 3, 5, and 6. Exon 4 is retained on variant-sized restriction fragments. We studied DNA from 10 additional LS subjects of Jewish-oriental origin and found this allele in 3 samples. All subjects with this complex deletion allele were from Iran or Iraq and were not clinically distinguishable from other individuals with LS. Multiple restriction enzyme digests and Southern blotting with GHR exon 4-specific probes demonstrated that the allele retains genomic material for at least 9.8 kilobases 5' and 1.8 kilobases 3' to exon 4. Reverse transcription of mRNA, polymerase chain reaction amplification, and cDNA sequencing showed that exon 4 is syntenic and colinear with the other GHR exons. Normal splice sites were used, but the predicted protein was severely truncated due to a frameshift and a premature stop codon in exon 7. The premature stop codon terminated the protein after amino acid 53 and led to loss of the transmembrane and intracellular portions of the receptor. This mutant GHR gene results clinically in severe GH insensitivity.

Effect of hypersomatostatinemia on growth hormone secretion in cystic fibrosis patients with diabetes.

We have recently shown that hypersomatostatinemia is a feature of cystic fibrosis (CF) when these patients have CF-associated pancreatogenic diabetes mellitus (CFDM). To address the possibility that patients with CFDM might have suppressed pituitary growth hormone (GH) release as a result of increased plasma somatostatin, GH secretion in 8 CFDM patients and 8 normal male controls was studied using a standard arginine infusion stimulus. Concentrations of the GH-dependent peptides, insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) were also measured. We found that mean GH concentrations in the CFDM group were significantly increased (p < 0.05) rather than decreased at the 30-min (12.3 +/- 3.6 vs. 3.8 +/- 1.9 ng/ml), 45-min (15.4 +/- 2.9 vs. 6.1 +/- 2.3 ng/ml) and 60-min (13.2 +/- 2.3 vs. 6.2 +/- 2.2 ng/ml) time points of study. Mean GH area under the curve (633 +/- 128 vs. 249 +/- 107 ng/ml) was also significantly greater (p < 0.05) in the CFDM group. Despite higher GH levels in the CFDM patients, their IGF-I and IGFBP-3 concentrations were low. We conclude that plasma somatostatin elevations in the CFDM group are not of sufficient magnitude to suppress pituitary GH release. Decreased levels of growth mediating peptides in the relatively malnourished CF subjects suggest a pattern of malnutrition-induced GH resistance which may contribute to poor weight and height gain.

Preservation of somatostatin secretion in cystic fibrosis patients with diabetes.

Immunohistochemical studies of pancreatic tissue from patients with cystic fibrosis associated with diabetes mellitus (CFDM) show increased numbers of somatostatin secreting delta cells. To look for a possible functional correlate to this finding basal and arginine stimulated plasma somatostatin and serum C peptide concentrations in eight insulin treated patients with cystic fibrosis and eight normal male controls were measured. Mean basal somatostatin concentrations were not different in the two groups. Mean peak somatostatin concentrations were significantly higher in the group with CFDM: 11.60 pmol/l v 7.14 pmol/l in controls. Mean peak C peptide concentrations were significantly lower in the group with cystic fibrosis: 0.89 nmol/l v 4.27 nmol/l in controls. This observation provides a physiological correlate to the pathological finding of increased somatostatin content in pancreatic tissue from patients with CFDM. Selective preservation of somatostatin secretion in patients with cystic fibrosis may further complicate pancreatic endocrine insufficiencies through paracrine inhibition of insulin and glucagon secretion.

Genetics of growth hormone gene expression.

The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)

Double vagina, cardiac, pulmonary, and other genital malformations with 46,XY karyotype.

We have studied two unrelated genetic males with a novel constellation of genital, cardiac, and pulmonary malformations. The genital abnormalities consisted of a true double vagina, retention of Müllerian structures, and undervirilization of the external genitalia. Both infants had complex cyanotic congenital heart defects, hypoplastic right lungs, anomalous pulmonary venous return, and abnormalities of the diaphragm. One patient had rhabdomyomatous dysplasia of the lungs. The cause of this malformation pattern is unknown. There was no family history of similar defects, no consanguinity, no known exposure to teratogens, and no chromosome abnormality. The retention of Müllerian structures and undervirilization of male genitalia in these cases could be the result of failure in production of adequate amounts of testosterone and Müllerian inhibitory factor at appropriate times in gestation. Because the developing human vagina is at no stage a duplicate structure, a double vagina cannot be the result of arrested genital differentiation. The unusual occurrence of a true double vagina should lead to careful pulmonary and cardiac evaluation.

Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism.

Laron-type dwarfism is an autosomal recessive genetic disorder that is characterized by high levels of growth hormone and low levels of insulin-like growth factor I in the circulation. Several lines of evidence suggest that this disease is caused by a defect in the growth hormone receptor. In order to analyze the receptor gene in patients with Laron-type dwarfism and with other growth disorders, we have first determined the gene structure in normal individuals. There are nine exons that encode the receptor and several additional exons in the 5' untranslated region. The coding exons span at least 87 kilobase pairs of chromosome 5. Characterization of the growth hormone receptor gene from nine patients with Laron-type dwarfism shows that two individuals have a deletion of a large portion of the extracellular, hormone binding domain of the receptor gene. Interestingly, this deletion includes nonconsecutive exons, suggesting that an unusual rearrangement may have occurred. Thus, we provide direct evidence that Laron-type dwarfism can result from a defect in the structural gene for the growth hormone receptor.