Late Effects after Allogeneic Hematopoietic Cell Transplantation Among Children and Adolescents with Non-Malignant Disorders: A Report from the Center for International Blood and Marrow Transplant Research (CIBMTR)

Introduction: Allogeneic hematopoietic cell transplantation (HSCT) is a curative treatment option for children and adolescents with non-malignant disorders. Continued advances in HSCT have led to a growing population of long-term survivors. For these survivors, late occurring chronic health conditions or so-called "late effects" remain a challenge. We examined the cumulative incidence of selected late effects at 5- and 10-years post-HSCT in pediatric and adolescent patients transplanted for non-malignant diseases. Methods: A retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database was performed. Eligible patients (1 - 20 years) underwent HSCT between 1995 and 2012 for treatment of non-malignant disorders including marrow failure, red cell disorders, and immunodeficiencies (Table). Late effects evaluated were: avascular necrosis (AVN), cataracts, diabetes, growth hormone deficiency, hypothyroidism, gonadal dysfunction, renal failure requiring dialysis, and neurologic events (stroke and seizure). The cumulative incidence of each late effect was calculated at 5-years and 10-years from date of first report post-HSCT. Results: Median follow up was 94.1 months. A total of 5,858 patients from 230 centers were included. Median age at HSCT was 5.5 years. The majority (65%) of the patients were White race/ethnicity and 9% were Black, 60% were male. Diagnoses included: Marrow failure disorders, hemoglobinopathies, immunodeficiencies and immune-dysregulation syndromes (Table). The majority (62%) of the cohort received myeloablative conditioning (MAC), and a minority (16%) received total body irradiation (TBI). Among all patients, 19% had chronic graft-versus-host-disease (GVHD). Cumulative incidence estimates at 5- and 10-years post-HSCT are presented in the Table. One-third (28%) of patients had at least one late effect. Cumulative incidence estimates at 10 years included stroke/seizures (11.2%), renal failure (7.7%), growth hormone deficiency/disturbance (7.6%), gonadal dysfunction (4.2%), hypothyroidism (4.1%), cataracts (2.9%), and AVN (1.4%). For AVN, renal failure, and stroke or seizures, incidence was stable between 5 and 10 years. For endocrine-associated late effects, incidence increased over time, nearly doubling from 5 to 10 years (Table). Across the cohort, the probability of growth hormone deficiency increased from 3.7% at 5-years, to 6.5% at 10-years. Similarly, hypothyroidism increased from 2.7% at 5-years, to 4.5% at 10 years. The cumulative incidence of treatment-associated diabetes was 3.1%, with most cases occurring in the first-year post-transplant. Finally, the probability of cataracts at 10 years was 2.9%, which was double the incidence at 5 years. Conclusions Among children and adolescents undergoing HSCT for non-malignant diseases, cumulative incidence of late effects was overall low, and did not exceed 12% at 10 years. The timing of late effect development differed, with the cumulative incidence of AVN, diabetes, renal failure, and seizure/stroke staying fairly stable after 5-years. Diabetes occurred most frequently in the first year, which may be a reflection of steroids or other medications to manage graft-versus-host-disease during the early-post transplant period. In contrast, the incidence of endocrine-associated late effects including growth disturbance, hypothyroidism, gonadal dysfunction and cataracts nearly doubled between 5 and 10-years post-transplant. Findings from this work further emphasize the need for long-term follow-up and screening for late effects, particularly diabetes, renal disease and neurologic symptoms early post-transplant, and cataracts and endocrinopathies over time. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Schoemans: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: personal fees , Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants and personal fees; Gilead: Other: travel grants; CIBMTR: Consultancy, Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees; BHS: Membership on an entity's Board of Directors or advisory committees, Other: travel grants and personal fees , Research Funding; Jazz Pharmaceuticals: Other: personal fees; Takeda: Other: personal fees. Phelan: Amgen Pharmaceuticals: Research Funding.

Biochemical criteria for the development mechanisms of various reproduction disorders in dairy cows

Ventsova I, Safonov V. 2021. Biochemical criteria for the development mechanisms of various reproduction disorders in dairy cows. Biodiversitas 22: 4997-5002. The article presents the evaluation of peroxide, antioxidant, and hormonal conditions of high-producing red-and-white dairy cows in the physiological and pathological course of pregnancy and the postpartum period. The blood concentration of malonic dialdehyde, stable nitric oxide metabolites, S-nitrosothiols, vitamins E and C, carotin, gonadal, corticosteroid, and thyroid hormones, as well as activity of GPx, GR, SOD, catalase, and ceruloplasmin, were estimated to define major disorder-provoking factors. Analysis of the data shows that ketosis-gestosis syndrome during pregnancy, postpartum metritis, and gonadal dysfunction occur mainly because of oxidative stress in the context of unbalanced peroxide responses and antioxidant protection. Levels of malonic dialdehyde compared to healthy animals increased by 42.3%, 75%, 56.6%, respectively, as also enzyme activities of GR by 26%, 68.1%, 30.1% and catalase by 17.3%, 45.1%, and 23.9%, correspondingly. The endocrine status indicators in the animals with ketosis-gestosis syndrome changed as follows: progesterone levels were 29.5% lower in cows, 17?-estradiol and cortisol were 20.8% and 14.7% lower, respectively. In animals with inflammatory uterine diseases and depressing reproductive glands, progesterone level was 2 and 3 times lower than in healthy animals, the content of cortisol was 17.6% and 25.1% lower, and testosterone decreased by 21.4% and 75.1%, respectively.

Repercussions of Stress during Pregnancy and Beyond

Stress, anxiety and depression are the disorders of brain but these affect even unborn child (foetuses). Various phobias affect expecting mothers. All these happen due to stress hormone Cortisol which is secreted during stress. This along with cortisol and other stress hormones lead to endocrine disorders like Graves’ disease, gonadal dysfunction, psychosexual dwarfism and obesity. Stress can also alter the clinical status of many preexisting endocrine disorders such as precipitation of adrenal crisis and thyroid storm. Stress during pregnancy changes hormonal milieu which affect the fetal environment and results in inflammatory conditions that have implications for maternal and infant health.

Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study

Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.

Galactosaemia occurring in association with primary ovarian insufficiency, Addison’s disease and chronic myeloid leukaemia

Classic galactosaemia is the most severe type, inherited in an autosomal recessive fashion and normally detected on newborn screening. It is caused by an inability to digest galactose due to a deficiency of galactose-1-phosphate uridyltransferase (GALT), resulting in an intolerance of feeds in the neonatal period, failure to thrive, hypoglycaemia, jaundice, cataracts, hepatomegaly, vomiting, diarrhoea, developmental delay and an increased risk of Escherichia coli sepsis. The long-term sequelae of this disorder include cognitive impairment, neurological symptoms, such as ataxia, nutritional deficiencies, such as calcium and vitamin D, and gonadal dysfunction. We report here a case of a 34-year-old woman with classic galactosaemia diagnosed in adulthood, developing primary ovarian insufficiency and osteoporosis as well as primary adrenal insufficiency and chronic myeloid leukaemia, which are two associations not seen in current literature. Further studies are needed to determine if an association exists between these diseases.

Investigation of Gonadal Function, Puberty, and their relationship to Serum Ferritin in Male patients with β-Thalassemia major in Syria

Objectives: Endocrine disorders continue to affect the health of thalassemia patients, foremost of which is hypogonadism being the most frequent endocrine complication that involves 70-80% of beta-thalassemia major (β-TM) patients. Actually, the role of iron overload in endocrine complications is well known. Our study goals were to investigate gonadal function, assess pubertal status among Syrian male patients with β-TM and correlate hormonal panel with serum ferritin as the marker of iron overload. Methods: 56 β-TM regularly transfused male patients were enrolled in this study, they were 21.91±5.01 years old. FSH, LH, Total Testosterone, and Serum Ferritin were measured for all patients, 52 of them undergone pubertal status evaluation. Results: Results showed that 60.7% of patients suffered from hypogonadism, which was hypogonadotropic hypogonadism in 97.06% of them. Delayed puberty was seen in 7.7% of the patients, while arrested puberty was found in 82.69% of them. All patients had iron overload and 92.86% of them suffered from severe iron elevation. Both gonadal and pubertal status were independent of the serum ferritin levels (P=0.73), (P=0.81) respectively. There was significant positive correlation between FSH: LH (r=0.584, P=0.0001), FSH: Testosterone (r=0.562, P=0.0001), LH: Testosterone (r=0.746, P=0.0001), MCHC: Testosterone (r=0.292, P=0.038), and BMI: Hb (r=0.351, P=0.009). Conclusions: Our findings indicated that hypogonadism, arrested puberty and severe iron overload were highly prevalent among male patients with β-TM. Patients with better gonadal reserve have higher BMI than those with gonadal dysfunction. We suggest that hypogonadism in β-TM patients is not directly related to serum ferritin levels; other potential factors (such as chronic anemia, hypoxia, and genetic predisposition) may contribute. Also we suggest that adequate blood transfusion and appropriate iron chelation, along with regular evaluation for gonadal status and timely intervention can improve the management of aforementioned complications, thus ameliorating patients’ quality of life.

Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011)

PURPOSE The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) in early responders on the basis of a positron emission tomography (PET)–driven strategy was safe and minimized toxicity compared with standard 6 BEACOPPescalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old. METHODS Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up. RESULTS A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPPescalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004). CONCLUSION Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.

A study of the prevalence of gonadal dysfunction and its association with increasing disease severity in patients diagnosed with chronic kidney disease at a tertiary care center in Kolkata, West Bengal

Background: Hypergonadotropic hypogonadism is a well described hormonal derangement associated with chronic kidney disease, also known as uremic hypogonadism. The objective of this study was to assess the prevalence of gonadal dysfunction associated with chronic kidney disease and to study the co-relation of gonadal dysfunction with disease severity.Methods: In this cross-sectional observational study, 50 patients with diagnosed chronic kidney disease were included during the one-year period from May 2015 to April 2016. The clinical and biochemical parameters related to gonadal dysfunction were evaluated in these cases.Results: Out of the 28 male CKD patients, 19 (68%) patients had Serum Testosterone values less than 90 ng/dl, 18 (64%) patients had a serum leutinizing hormone (LH) level greater than 9 mIU/ml and 19 (68%) patients had a serum follicle stimulating hormone (FSH) level greater than 13 mIU/ml. Out of 22 female CKD patients, 14 (64%) patients had serum estradiol value less than 50 pg/ml, 12 (54%) patients had Serum LH level greater than 80 mIU/ml and 20 (91%) patients had a S. FSH level greater than 26 mIU/ml. Out of a total of 50 patients in this study, 34 patients showed evidence of gonadal dysfunction, the majority of them belonging to stage 5 CKD.Conclusions: Out of the 34 patients showing gonadal dysfunction, 5 (15%) patients were in stage 3 CKD, 11 (32%) patient were in stage 4 CKD and 18 (53%) were in stage 5 CKD. It may be proposed that gonadal dysfunction is very common in CKD patients and the frequency of sexual dysfunction increases as the renal function deteriorates.