Exposure to non-persistent pesticides and puberty timing: a systematic review of the epidemiological evidence.

BACKGROUND: Numerous modern non-persistent pesticides have demonstrated estrogenic/anti-androgenic activity and have been classified as endocrine-disrupting chemicals (EDCs). Processes involved in puberty development are vulnerable to EDCs, such as compounds that interfere with the metabolism or activity of sex steroids. OBJECTIVE: To conduct a systematic review of epidemiological studies on the relationship between early-life exposure to non-persistent pesticides and puberty timing and/or sexual maturation in girls and boys. METHODS: A systematic search was carried out using MEDLINE and SCOPUS databases, including original articles published up to November 2020. RESULTS: Thirteen studies were selected after excluding non-original and non-human studies. Exposure to different types of pesticides has been associated with altered puberty timing in girls and/or boys in eight studies. In utero exposure to atrazine has been related to earlier age of menarche in girls; exposure to organophosphate (OP) pesticides has been related to delayed sexual development in boys and girls; childhood pyrethroid exposure has been associated with pubertal delay in girls and pubertal advancement in boys; and prenatal/childhood exposure to multiple pesticides has been linked to earlier puberty onset in girls and pubertal delay in boys. CONCLUSIONS: Most of the reviewed studies describe a relationship between pesticide exposure and changes in the age of puberty onset or sex hormone levels, although the quality of the evidence is generally low. Further well-designed longitudinal studies are warranted on specific classes of pesticides and on possible interactions between different types of compounds.

Growth hormone deficiency and other endocrinopathies after childhood brain tumors: results from a close follow-up in a cohort of 242 patients.

PURPOSE: Brain tumors are the most common solid tumor in children. The prevalence of survivors from these cancers has been increasing, presenting endocrine sequelae in more than 40% of the cases. Our aim was to characterize the endocrinopathies diagnosed in this population, exploring the outcomes of growth hormone treatment. METHODS: We have performed a retrospective analysis of the survivors that were followed-up through a close protocol at our endocrine late-effects clinic. RESULTS: 242 survivors, followed during 6.4 (0-23.4) years, were considered. The median age at tumor diagnosis was 6.7 (0-18) years and pilocytic astrocytoma was the most frequent neoplasm (33.5%). The prevalence of endocrinopathies was of 71.5%, with growth hormone deficiency being the most frequent (52.9%). An indirect correlation between the age at the beginning of somatropin and growth velocity in the first year of treatment was observed. Those treated with craniospinal radiotherapy presented a smaller final upper/lower segments ratio comparing with those that only received cranial radiotherapy. However, their final height was not compromised when compared to their family height target. We found pubertal delay in 12%; accelerated/precocious puberty in 13.2%; central and primary hypogonadism in 21.9% and 3.3%, respectively; primary and central hypothyroidism in 23.6% and 14.5%, respectively; thyroid nodules in 7.4%; ACTH deficiency in 10.3% and diabetes insipidus in 12%. CONCLUSION: This study reveals a higher prevalence of endocrinopathies in brain tumors survivors and explores the influence of craniospinal irradiation in the adult body proportions. It reinforces the importance of routine follow-up among survivors.

Long-term implications of structured transition of adolescents with inflammatory bowel disease into adult health care: a retrospective study.

BACKGROUND: We aimed to evaluate the long-term clinical and socioeconomic outcome of structured transition care in adolescents with inflammatory bowel disease (IBD). METHODS: We compared the clinical long-term course of 24 patients with and 11 patients without structured transition care within 24 months before and 24 months after transfer from paediatric to adult health care. Socio-economic parameters and quality of life were assessed by IBD Questionnaire (IBDQ-32) and additional items. Treatment costs were calculated for medication, surgery and hospitalisation. RESULTS: The percentage of transfer group patients with an IBD-related intestinal complication was higher compared to the transition group (64% vs. 21%, p = 0.022). We also found a tendency towards a higher number of IBD-related surgery in the transfer group compared to the transition group (46% vs. 13%, p = 0.077). Transfer group patients received higher mean cumulated doses of radiation compared with the transition group (4.2 ± 5.3 mSv vs. 0.01 ± 0.01 mSv, p = 0.036). Delayed puberty was only noted in the transfer group (27%, p = 0.025). Mean expenditures for surgeries and hospitalisation tended to be lower in the transition group compared to transfer group patients (744 ± 630€ vs. 2,691 ± 4,150€, p = 0.050). Sexual life satisfaction was significantly higher (p = 0.023) and rates of loose bowel movements tended to be lower (p = 0.053) in the transition group. CONCLUSIONS: Structured transition of adolescents with IBD from paediatric into adult health care can lead to important clinical and economic benefits.

Trends in the use of puberty blockers among transgender children in the United States.

BACKGROUND: The objective of the study was to identify national trends in the utilization of histrelin acetate implants among transgender children in the United States. METHODS: We analyzed demographic, diagnostic and treatment data from 2004 to 2016 on the use of histrelin acetate reported to the Pediatric Health Information System (PHIS) to determine the temporal trends in its use for transgender-related billing diagnoses, e.g. "gender identity disorder". Demographic and payer status data on this patient population were also collected. RESULTS: Between 2004 and 2016, the annual number of implants placed for a transgender-related diagnosis increased from 0 to 63. The average age for placement was 14 years. Compared to natal females, natal males were more likely to receive implants (57 vs. 46) and more likely to have implants placed at an older age (62% of natal males vs. 50% of natal females were ≥;13 years; p<0.04). The majority of children were White non-Hispanic (White: 60, minority: 21). When compared to the distribution of patients treated for precocious puberty (White: 1428, minority: 1421), White non-Hispanic patients were more likely to be treated with a histrelin acetate implant for a transgender-related diagnosis than minority patients (p<0.001). This disparity was present even among minority patients with commercial insurance (p<0.001). CONCLUSIONS: Utilization of histrelin acetate implants among transgender children has increased dramatically. Compared to natal females, natal males are more likely to receive implants and also more likely to receive implants at an older age. Treated transgender patients are more likely to be White when compared to the larger cohort of patients being treated with histrelin acetate for central precocious puberty (CPP), thus identifying a potential racial disparity in access to medically appropriate transgender care.

Maternal fish oil supplementation during lactation is associated with reduced height at 13 years of age and higher blood pressure in boys only.

Dietary long-chain n-3 PUFA (n-3 LCPUFA) in infancy may have long-term effects on lifestyle disease risk. The present follow-up study investigated whether maternal fish oil (FO) supplementation during lactation affected growth and blood pressure in adolescents and whether the effects differed between boys and girls. Mother-infant pairs (n 103) completed a randomised controlled trial with FO (1·5 g/d n-3 LCPUFA) or olive oil (OO) supplements during the first 4 months of lactation; forty-seven mother-infant pairs with high fish intake were followed-up for 4 months as the reference group. We also followed-up 100 children with assessment of growth, blood pressure, diet by FFQ and physical activity by 7-d accelerometry at 13·5 (sd 0·4) years of age. Dried whole-blood fatty acid composition was analysed in a subgroup (n 49). At 13 years of age, whole-blood n-3 LCPUFA, diet, physical activity and body composition did not differ between the three groups. The children from the FO group were 3·4 (95 % CI 0·2, 6·6) cm shorter (P=0·035) than those from the OO group, and tended to have less advanced puberty (P=0·068), which explained the difference in height. There was a sex-specific effect on diastolic blood pressure (P sex×group=0·020), which was driven by a 3·9 (95 % CI 0·2, 7·5) mmHg higher diastolic blood pressure in the FO compared with the OO group among boys only (P=0·041). Our results indicate that early n-3 LCPUFA intake may reduce height in early adolescence due to a delay in pubertal maturation and increase blood pressure specifically in boys, thereby tending to counteract existing sex differences.

Pathological fractures in paediatric patients with inflammatory bowel disease.

UNLABELLED: Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. CONCLUSION: Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

Antimüllerian hormone as a measure of reproductive function in female childhood cancer survivors.

OBJECTIVE: To evaluate the utility of measuring antimüllerian hormone (AMH) in childhood cancer survivors to assess ovarian reserve, pubertal status, and fertility potential. DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENT(S): Fifty-three female childhood cancer survivors, median age 13.9 years (range: 9-25 years) recruited at least 1 year from completion of cancer therapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum AMH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol measurements, pubertal/menstrual history and Tanner staging, with risk of gonadotoxicity classified as low or high based on chemotherapy agent and pelvic/abdominal radiation. RESULT(S): Thirty-one of the 53 patients (58%) in the cohort had diminished ovarian reserve (DOR) detected by an AMH value <1 ng/mL. We detected DOR by a FSH value of >12 IU/mL in 17 patients (32%). The patients exposed to high-risk chemotherapy or pelvic radiation were at statistically significantly higher risk for DOR as measured by their AMH level. The AMH level was also statistically significantly lower in the patients who had delayed puberty. CONCLUSION(S): Using the serum gonadotropins level to screen childhood cancer survivors for ovarian failure is a suboptimal method. The AMH value identified the patients at risk for delayed puberty and those who could benefit from fertility preservation counseling, which makes AMH perhaps the optimal screening tool for assessing ovarian reserve in this population.

[Budget impact of growth hormone treatment during the transition phase between childhood and adulthood]. / Impacto presupuestario de la utilización de hormona de crecimiento de la edad pediátrica a la adulta.

OBJECTIVE: To estimate the budget impact of somatrophin (Genotonorm) use in growth hormone deficiency (GHD) patients during the transition between childhood and adulthood. METHOD: A budget impact model was designed under the Spanish National Health System with a 5-year time horizon. Calculations of susceptible patients were based on disease prevalence (0.02%) applied to Spanish population. From total GHD cases, 60% was considered persistent and treatment candidates. An expert panel assumed that 20% of candidates would reject the treatment and 8% would withdraw therapy annually. Considered costs included: therapy costs, diagnosis (test and medical visit) and follow-up cost. RESULTS: There would be 49, 93, 132, 186 and 199 patients undergoing treatment each year (2010-2014). The total impact of Genotonorm use during the transition phase would be €367,691, €655,430, €1044,874, €1334,059, and €1594,670 for years 1 to 5. The average annual cost per patient would be €7506, €7059, €7903, €7960, €7995. CONCLUSIONS: GHD treatment during the transition phase in Spain poses an annual average layout of €7684/patient.

Impact of inflammatory bowel disease on pubertal growth.

BACKGROUND: Puberty is thought to be commonly affected in adolescents with inflammatory bowel disease (IBD). AIMS: To determine the impact of Crohn's disease (CD) and ulcerative colitis (UC) on the pubertal growth spurt. METHODS: Retrospective study of 30 boys with CD (CD-M), 11 girls with CD (CD-F), 14 boys with UC (UC-M) and 12 girls with UC (UC-F). Pubertal growth was assessed by calculating peak height velocity SDS (PHV SDS), height SDS at diagnosis (Ht(Diag)) and height SDS at PHV (Ht(PHV)) and age at PHV (Age(PHV)). Systemic markers of disease activity were also collected. RESULTS: Altered parameters of pubertal growth were observed in the CD groups compared to the normal population: in the CD-M group, median Ht(Diag) was -0.56 (p = 0.001) and median Age(PHV) was 14.45 years (p = 0.004), and in the CD-F group, median Ht(Diag) was -1.14 (p = 0.007) and Ht(PHV) was -0.79 (p = 0.039). Individually, 8/30 CD-M cases had one or more parameter affected: 2 boys had Ht(Diag )<-2, 3 boys had Ht(PHV) <-2, 2 boys had an Age(PHV) >2 years above population mean, and 2 boys had a PHV SDS <-2. In the whole group, Age(PHV) showed an association with erythrocyte sedimentation rate (r = 0.4; p = 0.005) and an inverse association with BMI (r = 0.4; p = 0.001). CONCLUSION: Disorders of pubertal growth are more likely to occur in CD and, particularly, in boys.

Association between lead and cadmium and reproductive hormones in peripubertal U.S. girls.

BACKGROUND: Lead (Pb) and cadmium (Cd) are known reproductive toxicants thought to disrupt hormone production throughout sensitive developmental windows, although this has not been previously examined in nationally representative peripubertal children. OBJECTIVES: We examined the association between blood Pb and urinary Cd concentrations and the reproductive hormones inhibin B and luteinizing hormone (LH) in girls 6-11 years of age who participated in the cross-sectional Third National Health and Nutrition Examination Survey (NHANES III) (1988-1994). METHODS: Pb (micrograms per deciliter) was measured in whole blood, and Cd was measured in urine (nanograms per milliliter). Inhibin B (picograms per milliliter) and LH (milli-International units per milliliter) were measured in residual sera for 705 girls. Survey logistic regression was used to estimate associations with pubertal onset based on inhibin B concentration > 35 pg/mL or LH concentration > 0.4 mIU/mL, and multinomial logistic regression was used to estimate the association between Pb and increasing categories of hormone concentrations. RESULTS: High Pb (≥ 5 µg/dL) was inversely associated with inhibin B > 35 pg/mL [odds ratio (OR) = 0.26; 95% confidence interval (CI), 0.11-0.60; compared with Pb < 1 µg/dL]. At 10 and 11 years of age, girls with low Pb (< 1 µg/dL) had significantly higher inhibin B than did girls with moderate (1-4.99 µg/dL) or high Pb (≥ 5 µg/dL). In the subsample of 260 girls with levels of inhibin B above the level of detection and using survey regression modeling, inhibin B levels were lower among girls with both high Pb and high Cd (ß= -0.52; 95% CI, -0.09 to -1.04) than among girls with high Pb alone (ß= -0.35; 95% CI, -0.13 to -0.57), relative to girls with low Pb and low Cd. CONCLUSIONS: Higher Pb was inversely associated with inhibin B, a marker of follicular development, and estimated effects suggestive of pubertal delays appeared to be stronger in the context of higher Cd concentrations. These data underscore the importance of Pb and Cd as reproductive toxicants for young girls.

High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study.

CONTEXT: Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited. OBJECTIVE: Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation. STUDY DESIGN AND PATIENTS: The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed. RESULTS: None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus. CONCLUSIONS: Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.

Gender-related psychological and behavioural correlates of pubertal timing in a national sample of Swiss adolescents.

The potential consequences of early and late puberty on the psychological and behavioural development of the adolescent are not well known. This paper presents focused analyses from the Swiss SMASH study, a self-administered questionnaire survey conducted among a representative sample of 7488 adolescents from 16 to 20 years old. Data from participants reporting early or late timing of puberty were compared with those reporting average timing of maturation. Early maturing girls reported a higher rate of dissatisfaction with body image (OR=1.32) and functional symptoms (OR=1.52) and reported engaging in sexual activity more often (OR=1.93). Early maturing boys reported engaging in exploratory behaviours (sexual intercourse, legal and illegal substance use) at a significantly higher rate (OR varying between 1.4 and 1.99). Both early and late maturing boys reported higher rates of dysfunctional eating patterns (OR=1.59 and 1.38, respectively), victimisation (OR=1.61 and 1.37, respectively) and depressive symptoms (OR=2.11 and 1.53, respectively). Clinicians should take into account the pubertal stage of their patients and provide them, as well as their parents, with appropriate counselling in the field of mental health and health behaviour.

Craniopharyngioma: presentation and endocrine sequelae in 36 children.

We studied the clinical presentation by age of 36 children with craniopharyngioma, and outcome by height and body mass index (BMI). Presenting symptoms included headache (51.4%), vomiting (31%), visual disturbances (22.9%), polyuria and/or polydipsia (17.1%), delayed puberty (19.4%), short stature (13.8%), and precocious puberty (2.7%). Growth deceleration was overlooked, as was diabetes insipidus (actual rate, 52% for both). Delayed puberty was observed in all patients of appropriate age. Mean height standard deviation score (SDS) at admission was significantly lower than mean target height SDS (p = 0.004), while mean final height SDS was similar (p = 0.14). BMI SDS at last follow-up was similar to mean parental BMI SDS. We conclude that although endocrinopathies are present in most patients with craniopharyngioma, they are rarely the reason for referral. While affected prepubertal children have non-endocrine complaints, most adolescents are referred because of delayed puberty. Diabetes insipidus may be more prevalent in craniopharyngioma than previously reported. When patients with hypothalamic obesity are excluded, mean BMI SDS remains within normal range and is influenced mostly by parental BMI SDS.

Late effects in survivors of infant leukemia.

Little is known about the incidence of and risk factor for late effects of infant leukemia. We evaluated 19 children with acute lymphoblastic leukemia and 15 with acute myeloid leukemia who were diagnosed at age 12 months or younger and have survived for more than 5 years after the diagnosis (median length of follow-up, 13 years; range, 5.7-29 years). Ten patients received chemotherapy alone (group A), 17 received chemotherapy and CNS-directed radiation therapy (CRT) (group B), and seven received chemotherapy, CRT and bone marrow transplantation (group C). The most frequently observed late sequelae included problems in growth (66% of survivors), learning (50%), hypothyroidism (15%), and pubertal development (12%). Cataract, cardiac and hearing abnormalities occurred in 6% of patients. Only eight patients (24%) survive without late effects. In comparison to patients in group A, patients in groups B and C had a higher incidence of having at least one late complication (P = 0.009), a greater decrease in height Z score at 5 years after diagnosis (P = 0.023), and a higher incidence of academic difficulties (P = 0.004). The estimated odds of academic difficulties increased by 18% (P = 0.032) for each month younger in age at the time of CRT. These results indicate that late sequelae are common in longterm survivors of infant leukemia and are often related to CRT and the patient's age at the time of CRT.

Late effects of treatment for germ cell tumors during childhood and adolescence.

PURPOSE: To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence. PATIENTS AND METHODS: Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988, 73 are long-term survivors (continuously disease-free for > or =5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median, 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n = 13), and selected cases of ovarian or sacrococcygeal tumors (n = 2), and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomycin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated. RESULTS: More than two-thirds of long-term survivors (n = 50) had at least 1 complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (41% of survivors), endocrine (42%), cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%), genitourinary tract (23%), pulmonary (19%), and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT. CONCLUSIONS: A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.