Undernutrition and Pubertal Timing in Female Survivors of Medulloblastoma and Other Embryonal Tumors.

CONTEXT: Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. OBJECTIVE: To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. DESIGN, SETTING, AND PATIENTS: Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children's Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. MAIN OUTCOME MEASURES: Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. RESULTS: The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (ß = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. CONCLUSIONS: Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

Long-term effects of treatment of central precocious puberty with gonadotropin-releasing hormone analogs every three months.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) analogs represent the treatment of choice in patients with central precocious puberty (CPP). Recently, GnRH analogs that can be administered every 3 months have been developed and appear to be as safe and effective as one-monthly formulations. However, there are limited data regarding its long term safety and efficacy profile. We aimed to evaluate the long-term safety and efficacy treatment of CPP with GnRH analogs every 3 months. METHODS: We prospectively studied all patients who were diagnosed with CPP in our center between January 2015 and December 2019. All patients were treated with intramuscular leuprolide acetate 11.25 mg every 3 months. RESULTS: Twenty-four patients with CPP were included in the study. Mean follow-up was 3.1 years. Height gain ranged between 4 and 6 cm. Bone mineral density (BMD) was not affected. Body mass index (BMI) increased in all subjects but none was obese at the end of follow-up. CONCLUSIONS: Treatment of patients with CPP with GnRH analogs every 3 months induces substantial increases in height and does not affect BMI or BMD. Therefore, it represents an attractive option for these young patients.

Pubertal Development: What's Normal/What's Not.

Onset of puberty, as defined by breast stage 2, appears to be starting at younger ages since the 1940s. There is an ongoing controversy regarding what is normative, as well as what is normal, and the evaluation that is deemed necessary for girls maturing before 8 years of age. There are potential implications of earlier pubertal timing, including psychosocial consequences during adolescence, as well as longer term risks, such as breast cancer and cardiometabolic risks. There are additional consequences derived from slower pubertal tempo, for age of menarche has not decreased as much as age of breast development; these include longer interval between sexual initiation and intentional childbearing, as well as a broadened window of susceptibility to endocrine-related cancers.

Girls with Premature Thelarche Younger than 3 Years of Age May Have Stimulated Luteinizing Hormone Greater than 10 IU/L

Objective: Premature thelarche (PT) is defined as isolated breast development in girls before eight years of age. Gonadotropin-releasing hormone (GnRH) stimulation test is sometimes used to distinguish between PT and central precocious puberty (CPP), although the interpretation of the test at early ages is challenging. The objective of this study was to determine the follicle stimulating hormone (FSH) and luteinizing hormone (LH) responses to GnRH stimulation in girls with PT below 3 years of age. Methods: A standardized GnRH stimulation test, bone age and pelvic ultrasound were evaluated and those without pubertal progression after a minimum of one-year follow up were included in the study. Results: On GnRH stimulation test, the median (range) baseline LH was 0.29 (0.10-0.74) IU/L, baseline FSH was 4.96 (3.18-7.05) mIU/mL, and the peak median LH was 5.75 (3.31-8.58) IU/L with the peak mean±standard deviation FSH was 40.38±20.37 mIU/mL. Among the patients, 33.3% (n=10) had baseline LH >0.3 IU/L, 67% (n=20) had peak LH >5 IU/l and 16.6% (n=5) >10 IU/L. The mean peak LH/FSH ratio was 0.17±0.09 and was ≤0.43 in all participants. Conclusion: Although consensus statements usually define baseline LH >0.3-0.5 IU/L, peak LH >5 IU/L, and LH/FSH ratios >0.66-1.0 as diagnostic cut-offs for CPP, in children below 3 years of age, the baseline and peak LH values may be similar to pubertal values, possibly due to mini-puberty. A dominant FSH response on GnRH stimulation test is more valuable than the peak LH response in the diagnosis of PT.

Effect of gonadotropin-releasing hormone analog on ovarian reserve in children with central precocious puberty.

BACKGROUND: Gonadotropin-releasing hormone analog (GnRHa) is the mainstream treatment for central precocious puberty (CPP). However, its effect on the ovarian reserve in CPP girls remains unclear. This study was designed to analyze the changes of ovarian reserve in CPP girls during and after GnRHa therapy, with an attempt to achieve the early prediction of the effect of GnRHa treatment on the reproductive function of CPP girls, eliminate the concerns of girls and their parents on the potential toxicities of GnRHa treatment, and improve the patients' adherence to treatment. METHODS: The clinical data of 383 CPP girls who had been treated with GnRHa for more than half a year in our hospital within the past 10 years were retrospectively analyzed. The serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), FSH/LH, estradiol (E2), and anti-Müllerian hormone (AMH) levels, as well as uterine and ovarian volumes, were measured before treatment, at various time points during treatment, and after menarche or resumption of menses (ROM) after treatment discontinuation. RESULTS: GnRHa treatment had similar effects on uterine/ovarian volumes, LH, FSH, and E2: these indicators were significantly inhibited during the treatment (compared with the pre-treatment levels), gradually returned normal after drug withdrawal, and became significantly higher than the pre-treatment levels after menarche or ROM (both P<0.05 for LH and FSH levels and P>0.05 for E2 and uterine/ovarian volumes). AMH level transiently decreased 6 months after GnRHa treatment (2.70±1.76 vs. 3.56±2.21, t=3.227, P=0.001); however, the AMH levels after 12, 18, and 24 months of treatment were similar to the pre-treatment level (P>0.05). The FSH/LH ratio significantly increased after 12 months of treatment compared with the pre-treatment (P<0.05), and the FSH/LH ratio after menarche or ROM was significantly lower than the pre-treatment value (1.34±0.66 vs. 5.69± 6.85, t=3.068, P=0.006). When FSH/LH and FSH level were used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was higher than at pre-treatment (FSH/LH ratio: 100% vs. 46%, χ2=27.586, P<0.05; FSH level: 100% vs. 99%, P>0.05). When AMH level was used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was slightly lower than at pre-treatment (87% vs. 93%, P>0.05). CONCLUSIONS: The ovarian reserve of CPP girls is somehow inhibited during GnRHa treatment but is gradually restored after drug discontinuation. Thus, GnRHa treatment does not affect ovarian reserve in CPP children after the treatment stops.

Does the risk of arterial hypertension increase in the course of triptorelin treatment?

BACKGROUND: Gonadotropin-releasing hormone agonists (GnRH-a) are common treatment options for central precocious puberty (CPP) in childhood. GnRH-a treatment is useful and has a good safety profile, with minimal adverse effects and no severe long-term consequences. The common side effects in children are menopause-like symptoms and local adverse events at the injection site. CASE PRESENTATION: We present the case of a girl with CPP who developed arterial hypertension from treatment with GnRH-a (triptorelin). Comprehensive diagnostic studies ruled out other causes for her hypertension and its complications. After therapy was interrupted, her blood pressure remained within normal limits for age. Consequently, we hypothesize that the hypertension presented by our patient was related to triptorelin treatment. CONCLUSIONS: Although the etiology of this adverse event is not known and only some hypotheses can be made, clinicians should be aware that arterial hypertension might appear during triptorelin treatment in childhood with CPP. Therefore, they should routinely monitor the arterial blood pressure of patients under treatment.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

The diagnosis of androgenetic alopecia in children: Considerations of pathophysiological plausibility.

Androgenetic alopecia (AGA), one of the most common causes of hair loss in men and women, is an infrequent cause of alopecia in children. In AGA, patients generally start noticing hair thinning after the onset of puberty due to progressive miniaturisation of the hair follicle which leads to vellus transformation of terminal hair. However, the occurrence of prepubertal AGA has rarely been reported in the literature. The pathophysiology of AGA is tightly linked to androgen hormones; prepubertal children do not usually produce significant amounts of adrenal or gonadal androgens. When it does occur, an underlying abnormality should be suspected. Secondary causes of AGA must be excluded when evaluating a patient before the appearance of puberty. Premature puberty, polycystic ovarian syndrome and other causes of hyperandrogenism can present with hair loss in an androgenetic pattern. This article reviews the normal physiology of androgen hormones and their role in the pathophysiology of childhood AGA.

Prevalence of Premature Thelarche at 18 Months of Age: A Population- and Hospital-Based Study of Prevalence and Incidence in Girls Born at Northern Älvsborg County Hospital in Sweden.

OBJECTIVE: The aim of this work was to investigate the prevalence of premature thelarche (PT) in 18-month-old girls, and the incidence of clinically evaluated PT for girls aged 18-36 months. METHODS: In the prevalence substudy, a prospective population-based cohort of 3,140 girls born at Northern Älvsborg county hospital (NÄL) in Trollhättan, Sweden, was followed for 2 years. Girls with breast development at the 18-month health check were referred to one pediatric center in NÄL for evaluation. All girls with PT were included and followed for clinical outcome and 17ß-estradiol. The prospective incidence substudy covered 8 years in a 10-year period and included all girls aged 18-36 months born at NÄL who were clinically evaluated for PT. RESULTS: The prevalence of PT at 18 months in our cohort was 1.6/1,000. The 5 girls with PT no longer showed symptoms at the follow-up 3-6 months later. The incidence was 1.1/1,000 for girls aged 18-36 months and 1.0/1,000 for girls aged 18-30 months who were clinically evaluated for their PT. CONCLUSION: This is the first prospective population-based study of PT and it shows a prevalence of PT at age 18 months of 1.6/1,000. The incidence of clinically evaluated PT was 1.1/1,000. Our result is in line with other studies reporting the incidence of PT from medical records (0.4-40/1,000). The outcome of PT in our study, as in the other studies, is that the great majority of girls show only benign symptoms.

Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus.

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.

Gynecologic and reproductive outcomes in fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. METHODS: Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. RESULTS: Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35 years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. CONCLUSIONS: Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population.

The Beneficial Effect of Combined GH/GnRHa Therapy in Increasing Adult Height Outcome in Children With ISS.

CONTEXT: Management of GH-treated children with idiopathic short stature (ISS) with early puberty and adolescents in midpuberty at initiation of treatment is challenging. OBJECTIVE: To assess the effect of combined GH/GnRHa therapy during puberty on achieved adult height (AHt) in these children with ISS and to determine whether outcome depended on sex and pubertal status at initiation of GH therapy. DESIGN: Retrospective, single-center observational study from 2003-2018. SETTING: Tertiary endocrine center. PATIENTS: One hundred ninety-two GH-treated children with ISS; 58 of 192 were treated by GH/GnRHa during puberty; 31 of 58 were prepubertal (19 girls) and 27 of 58 pubertal (19 girls) at initiation of GH. MAIN OUTCOME MEASURES: AHt, gain-in-height standard deviation score (SDS), AHt vs predicted adult height (PAHt), AHt vs target height (THt). RESULTS: Most boys and girls attained AHt SDS within the normal range (-0.73 ± 0.60 and -0.85 ± 0.65, respectively). Treatment modality, pubertal status, and sex were tested for their joint effect on growth outcome measures. Combined GH/GnRHa therapy increased AHt vs PAHt (P < 0.001) and AHt vs THt (P = 0.035). Prepubertal status at onset of GH treatment increased AHt (P = 0.049), gain-in-height SDS (P < 0.001), AHt vs PAHt (P < 0.001), and AHt vs THt (P = 0.042). Female sex increased AHt vs PAHt (P < 0.001). CONCLUSIONS: Our study demonstrated a beneficial effect of combined GH/GnRHa therapy in increasing AHt outcome in children with ISS with early/normal puberty and in adolescents naïve to GH treatment who are in midpuberty at initiation of therapy. This effect was more pronounced in the prepubertal group and in girls. Prospective randomized controlled trials are needed to assess whether GnRHa can increase AHt in GH-treated children with ISS.

Central precocious puberty, functional and tumor-related.

Precocious puberty is defined as the appearance of secondary sex characteristics before 8 years of age in girls and before 9 years of age in boys. Central precocious puberty (CPP) is diagnosed when activation of the hypothalamic-pituitary axis is identified. It is a rare disease with a clear female predominance. A background of international adoption increases its risk, with other environmental factors such as endocrine disruptors also being associated with CPP. The causes of CPP are heterogeneous, with alterations of the CNS being of special interest. Physical injuries of the CNS are more frequent in boys, while idiopathic etiology is more prevalent among girls. However, in the last decade the number of idiopathic cases has diminished thanks to the discovery of mutations in different genes, including KISS1, KISS1R, MKRN3, and DLK1 that cause CPP. For the diagnosis of CPP, hormone studies are needed in addition to the clinical data regarding signs of pubertal onset. For this purpose, the GnRH test continues to be the gold standard. Imaging analyses, such as bone age and brain MRI, are also very useful. Furthermore, genetic testing must be incorporated in the diagnosis of CPP, especially in familial cases. Early puberty has been related to various consequences in the medium and long term such as behavioral problems, breast cancer, obesity, and metabolic comorbidities. However, there are few studies that have exclusively analyzed patients with CPP. GnRH analogs are the most frequent treatment election with the main objective being to improve adult height. Currently, there are new formulations that are being investigated.

Being Reproductive.

Women's reproductive health maintenance begins in the early years of growth and development. Routine care is the basis for early detection of menstrual dysfunction and delays or acceleration of physical development. Patients and their families may not address menstruation concerns because of the sensitive nature of the topic, the patient's self-conscious attitudes, and the parent's apprehension. Providers should be able to provide early detection of menstrual abnormalities, which may uncover underlying health concerns and structural abnormalities. Early intervention and treatment may accelerate or decelerate physical growth, preserve fertility, and promote healthy behaviors with decreased psychological stress for patients and families.

Phenotypic testicular abnormalities and pubertal development in boys with McCune-Albright syndrome.

Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune-Albright syndrome (MAS). On the basis of such analysis, we concluded that:1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP.

A mathematical model for predicting the adult height of girls with idiopathic central precocious puberty: A European validation.

BACKGROUND: A previous single-center study established a mathematical model for predicting the adult height (AH) in girls with idiopathic central precocious puberty (CPP). OBJECTIVE: To perform internal and external validations by comparing the actual AH to the calculated AH established by this model and to update it. METHODS: The original formula, calculated AH (cm) = 2.21 (height at initial evaluation, SD) + 2.32 (target height, SD) - 1.83 (luteinizing hormone/follicle-stimulating hormone peaks ratio) + 159.68, was established in a sample of 134 girls (group 4) and was applied to additional girls with CPP seen in the same center (group 1, n = 35), in Germany (group 2, n = 43) and in the Netherlands (group 3, n = 72). This formula has been updated based on these extended data, and both versions are available at the following location: http://www.kamick.org/lemaire/med/girls-cpp15.html. RESULTS: Despite the differences among the 4 groups in terms of their characteristics at the initial evaluation and the percentages of patients treated with the gonadotropin-releasing hormone analogue, they have similar calculated and actual AHs. The actual AHs are 162.2±7.0, 163.0±7.6, 162.4±7.7 and 162.1±5.6 cm in groups 1 to 4, respectively. They are highly correlated with the AHs calculated by the formula established in the original group (group 4), with R at 0.84, 0.67 and 0.69 in groups 1 to 3, respectively. When the actual AHs and the AHs predicted by the Bayley and Pinneau method are compared, the R is 0.76, 0.51 and 0.64 in groups 1 to 3, respectively. The absolute differences between actual AHs and the calculated AHs are greater than 1 SD (5.6 cm) in 15%, 35% and 28% of the patients in groups 1 to 3, respectively. CONCLUSION: This study validates and updates the previously established formula for predicting AH in girls with CPP. This updated formula can help clinicians to make treatment decisions.

Comparison of two bone markers with growth evolution in 74 girls with central precocious puberty.

BACKGROUND: The bone markers bone alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen crosslinks (CTX) are correlated with growth rate during normal puberty. The objective of this study was to evaluate the relationship between the serum concentrations of BAP and CTX and growth evolution in girls with idiopathic central precocious puberty (CPP) to help predict adult height. METHODS: A retrospective single-center study was conducted in 74 girls with CPP for whom a serum sample at initial evaluation was available to retrospectively measure BAP and CTX concentrations; 66.2% of them were untreated. RESULTS: The serum BAP concentrations showed significant positive correlations with height in standard deviations (SDS) at the initial evaluation (n = 62; r = 0.31; p = 0.015) and with the difference between bone and chronological ages (n = 61; r = 0.39; p = 0.002). BAP was also positively correlated with adult height as measured in both cm and SDS in untreated patients (n = 19; r = 0.58; p = 0.009). The serum CTX concentrations showed significant positive correlations with growth rate the year before the initial evaluation as measured in both cm and SDS (n = 65; r = 0.34; p = 0.006). CONCLUSIONS: This study revealed significant correlations of serum BAP and CTX concentrations with growth evolution in girls with CPP. The high positive correlation between serum BAP and adult height in untreated girls suggests that BAP can possibly be used to optimize models of adult height prediction in girls with CPP.