Central precocious puberty: from physiopathological mechanisms to treatment

JOURNAL OF BIOLOGICAL REGULATORS & HOMEOSTATIC AGENTS

Vol. 28, no. 3, 0-0 (2014)

EDITORIAL

CENTRAL PRECOCIOUS PUBERTY: FROM PHYSIOPATHOLOGICAL MECHANISMS TO TREATMENT V. CHIRICO1 , A. LACQUANITI2,3, V. SALPIETRO1, M. BUEMI2, C. SALPIETRO1 and T. ARRIGO1 Department of Pediatric Sciences, University of Messina, Messina, Italy; 2Department of Internal Medicine, University of Messina, Messina, Italy; 3Department of Internal Medicine, Mediterranean Institute for Transplantation and Advanced Specialized Therapies, ISMETT, University of Pittsburgh Medical Center, Palermo, Italy 1

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Received June 10, 2013 – Accepted July 28, 2014

Puberty is a complex, coordinated biological process with multiple levels of regulations. The timing of puberty varies greatly in children and it is influenced by environmental, endocrine and genetic factors. Precocious puberty (PP) is an important issue, affecting between 1 in 5.000-10.000 children. The physiopathological mechanism is still unknown. From an etiological point of view, PP may be subdivided into gonadotropin-releasing hormone (GnRH) -dependent and independent causes. GnRH-dependent PP, often called central precocious puberty (CPP), is based on hypothalamic-pituitary-gonadal axis activation associated with progressive pubertal development, accelerated growth rate and advancement of skeletal age. Conversely, peripheral precocious puberty (PPP) is related to sex steroid exposure, independently of hypothalamic–pituitary–gonadal (HPG) axis activation. Kisspeptins play a central role in the modulation of GnRH secretion with peripheral factors that influence the timing of puberty, such as adipokines and endocrine disrupting chemicals. Moreover, PP could be related to genetic disorders, involving pivotal genes of the HPG axis. The standard test used to verify HPG activity is the gonadotropin response to administered GnRH analogs. We describe the physiopathological mechanisms of PP and its clinical implications, analysing diagnostic flow-chart and new potential biomarkers that could reveal PP. An update of the current literature was also carried out regarding the recent novelty for treatment.

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Precocious puberty (PP) affects between 1 in 5.000-10.000 children, with health and psychosocial consequences, in relation to peers and reduced final height (1). Furthermore, this condition has been associated with long-term adverse outcomes, such as an increased risk of adult obesity, type 2 diabetes and breast cancer (2). A debate among pediatric endocrinologists concerning the necessity of revision of the age limit for what is considered PP requiring further diagnostic

evaluation is still open due to the decline in the lower age limit of normality at pubertal onset (3). Establishing the diagnosis of PP requires documenting pubertal physical findings and measuring luteinizing hormone (LH) concentration, which is the key biochemical assessment of pubertal status. When these first level tests are suggestive of PP, a stimulation test with gonadotropin-releasing hormone (GnRH) should be performed to assess the degree of activation of the hypothalamic–pituitary–

Key words: precocious puberty, obesity, GnRH analogue, biomarkers, kisspeptin, endocrine disrupting chemicals Mailing address: Prof. Carmelo Salpietro, Department of Pediatrics, University Hospital “G. Martino”, Via Consolare Valeria, 1 98100 Messina, Italy Tel.: +39 0902213114 Fax: +39 090.2213115 e-mail: [email protected]

0393-974X (2014)

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Copyright © by BIOLIFE, s.a.s. This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.

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gonadal (HPG) axis. Moreover, these analyses, associated with radiological assessments, allow the clinicians to distinguish between central and peripheral forms of PP. In recent years, potential new peptides have been evaluated, such as inhibin and kisspeptin. This editorial focuses on pathophysiological mechanisms underlying PP and new available biomarkers. Moreover, an update of the current literature on recent novelties for the treatment of PP has been carried out. MECHANISMS AND RISK FACTORS Normal pubertal development is caused by the increasing pulsatile activity of the GnRH pulse generator

which leads to the maturation of LH and follicle stimulating hormone (FSH) secretion and subsequently to the maturation of gonads and their activity. For the initiation of puberty, a functioning GnRH neuronal network and pulsatile GnRH secretion are critical prerequisites. Two mechanisms are responsible for the central control of pulsatile GnRH secretion: a tonic inhibitory restraint and excitatory inputs to GnRH neurons. Novel regulators of GnRH secretion have been found to be essential for normal pubertal development. In particular, a G-protein-coupled receptor gene called GPR54 and a family of neuropeptides encoded by the Kiss1 gene named kisspeptins, play a key role in the physiological mechanisms of puberty (4). A number of clinical conditions offer clues regarding the influence on environmental factors, such as nutrition and body size, on puberty. In particular, a relationship between body mass index and timing of pubertal onset in

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Fig. 1. GnRH neurons, which receive trans-synaptic and glial inputs, release GnRH to the hypophysial portal blood system, starting the pulsatile secretion of gonadotropins, LH and FSH, that stimulate the maturation and regulate the function of the gonads. Estradiol and testosterone, secreted by gonads, exert a negative feedback to hypothalamus and pituitary to regulate GnRH secretion. The same action is determined by inhibin B, which negatively regulates FSH and LH secretion. The hypothalamus-pituitary-gonad axis is influenced by peripheral regulators. In particular, high levels of adipokines, such as leptin, often observed in obese children, promotes the GnRH release through kisspeptin neurons stimulation. Similarly, endocrine disrupting chemicals could represent important triggers to puberty beginning. The lack of inhibitors of GnRH system, as observed in genetic disorders involving kisspeptin, its receptor or the makorin ring finger 3 gene, represent another mechanism of precocious puberty. GnRH: gonadotropin-releasing hormone; LH: Luteinizing Hormone; FSH: Follicle Stimulating Hormone

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girls has been revealed (5, 6). A central role is played by the adipose tissue which is responsible for an amplified androgen conversion to estrogens, through an aromatase action and an increased insulin resistance, leading to enhanced bioavailability of sex steroids. The link between peripheral adipose tissues and central nervous system is based on adipokines and gastrointestinal peptides, such as leptin, which communicate the energy store status and the adequate starting time for the energy-intensive process of pubertal development. However, there are other important determinants of puberty. Recent studies support the hypothesis that certain stressful psychosocial factors in infancy and childhood may lead to earlier pubertal maturation (7). Moreover, exposure to endocrine disrupting chemicals (EDCs), such as pythoestrogens, are other possible candidates that may influence the endogenous endocrine milieu, and therefore potentially affect maturation of the reproductive system. A wide variety of synthetic EDCs has been recognized by environmental agencies, including pesticides, pollutants and substances used in plastic manufacturing, whereas natural EDCs could be found in several nutrients. They influence puberty through their estrogenic, antiestrogenic, androgenic, anti-androgenic effects or through their direct effects on GnRH. In fact, it was demonstrated that EDCs may act in the brain by stimulating hypothalamic neurons, thereby releasing kisspeptin and causing earlier onset of puberty (8). Moreover, central PP has also been associated to genetic factors. Several genes have been identified in the complex network of inhibitory, stimulatory, and permissive neuroendocrine factors involved in the control of puberty onset. Mutations in the gene encoding kisspeptin-1 (KISS1) and in the gene encoding its receptor (KISS1R) have been associated with central precocious puberty (9). It was demonstrated that the deficiency of the makorin ring finger 3 (MKRN3) gene, located on long arm of chromosome 15, causes familial central PP in humans (10). Fig. 1 summarizes the main mechanisms involved in the physiopathological process of the central precocious puberty.

of the differences in differential diagnosis and the fundamentally treatment options. A CPP is defined as organic when it is associated with a lesion of the central nervous system (hamartoma, hydrocephalus, infection) (11, 12), whereas an idiopathic form is diagnosed when the neuroradiological evaluation shows no lesion. The frequency of organic and idiopathic CPP varies according to the subject’s sex; idiopathic CPP rarely occurs in boys, but accounts for 70–80% of CPP cases in girls. On the other hand, a PPP is due to an increase of sex steroids with no evidence of activation of the hypothalamic-pituitarygonadal (HPG) axis. It could be secondary to either genetic disorders or very heterogeneous acquired diseases, such as adrenal, gonadal and surrenal tumor, congenital adrenal hyperplasia (13). Table I highlights differential characteristics between the two forms of PP.

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Clinical evaluation PP is classically defined as the development of secondary sexual characteristics before the age of 8 years in girls (presenting with Tanner stage B2) and before 9 years in boys (Tanner G2 and/or testicular volume ≥ 4 ml) (14). In addition to pubic hair, the clinical evaluation of male genital and female breast development is the standard method to monitor pubertal development, since it identifies the progression of secondary sexual characteristics (15). The method proposed by Marshall and Tanner is the most commonly used for this purpose, describing the main changes in external sexual characteristics that occur during the period before (stage 1) and after puberty (stage 5) (16). Furthermore, the onset of puberty is accompanied by an acceleration of linear growth and bone maturation. As a result, bone age will always be advanced compared to chronological age and statural age of the child, with premature closure of the epiphyseal cartilage of conjugation.

PRECOCIOUS PUBERTY ASSESSMENT A combination of clinical signs, bone age, pelvic echography in girls, and hormonal data are required to diagnose PP and make a judgment concerning progression and prognosis. It is important to differentiate between central PP (CPP) and peripheral types of PP (PPP) because

Laboratory tests Timely diagnosis and careful clinical assessment remains pivotal to successful PP management. To demonstrate the early activation of HPG axis in children with pubertal development, the gold standard for laboratory confirmation of CPP is the maximal

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Table I. Etiological classification of precocious puberty.

Table I. Etiological classification of precocious puberty. Gonadotropin dependent (Central PP) CNS Lesions

• Hypothalamic hamartoma • Tumours: optic glioma, germ cell tumour, astrocytoma • Congenital malformations: arachnoid cyst, hydrocephalus, neural tube defect • Acquired: head trauma, cranial irradiation, infection, perinatal asphyxia Non-CNS Lesion

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• Idiopathic • Activating KISS1 gene and GPR54 • Endocrine disruptor exposure; excess endogenous steroids (e.g. CAH) Gonadotropin independent (Peripheral PP) Male

Female

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Congenital

Activating LH receptor mutation (testotoxicosis) Congenital Adrenal hyperplasia DAX1 gene mutation Acquired

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Congenital

GNAs gene activating somatic mutation (McCune–Albright syndrome)

Acquired

Leydig cell tumour, granulosa cell tumour Ovarian Cyst / Tumor hCG secreting tumours Surrenal Tumor Exogenous sex steroids Exogenous sex steroids Long-standing, untreated primary hypothyroidism

PP: precocious puberty; CNS: central nervous system; KISS1: Kisspeptin-1;GPR54: G protein-

coupled receptor CAH:nervous Congenital Adrenal Hyperplasia; LH: luteinizing hormone; hCG: receptor 54; PP: precocious puberty; CNS:54; central system; KISS1: Kisspeptin-1;GPR54: G protein-coupled human chorionic gonadotropin CAH: Congenital Adrenal Hyperplasia; LH: luteinizing hormone; hCG: human chorionic gonadotropin

LH level after GnRH stimulation. However, this test is inconvenient for patients and labor-intensive for clinicians as well as being expensive to carry out. Hence, there has been an effort to find measures that can substitute or simplify this method. Even though the basal concentration of LH and the subcutaneous GnRH analogue stimulation test are suggested as alternatives, none of these are sufficient to substitute as a gold standard.

GnRH agonist stimulation test The key endocrine investigation is to determine LH and FSH response to acute GnRH stimulation in order to distinguish between central and non-

central (peripheral) forms of PP. For decades, GnRH testing has been the standard dynamic test to assess pubertal disorders in children. More recently, leuprolide acetate (LA) stimulation test and other GnRH agonists (GnRHa) have been employed. A potential advantage of GnRHa versus GnRH is that the former compounds elicit prolonged stimulation 16 of gonadotropin secretion and these hormones, in turn, stimulate sex hormone secretion by the gonads. However, despite substantial evidence indicating that a single stimulated gonadotropin sample is informative, many centres continue to obtain multiple samples during LA stimulation test, leading to longer test duration, higher costs, and greater

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inconvenience to patients (17). Inhibin B levels In the past decade, measurements of serum inhibin, produced by granulosa cells in small antral follicles under the influence of FSH, and anti-Mullerian hormone have provided useful tools for clinical investigation in gonadal disorders, including pubertal development diseases. It was revealed that, in girls with CPP, inhibin B levels were in accordance with the clinical stage of maturation, whereas in boys with delayed puberty. Furthermore, inhibin B levels were very low in congenital defects of the gonadotropin-releasing hormone-FSH-testis axis, but they were normal or intermediate in constitutional delayed puberty (18). Determining inhibin B levels together with FSH levels is a considerable help for diagnosing disorders of pubertal development, but further studies are needed.

neurons to modulate GnRH secretion. Kisspeptin levels were significantly higher in girls with CPP than in pre-pubertal girls, and were positively correlated with FSH and LH peak levels after GnRH stimulation, demonstrating that it could serve as a marker for diagnosis and follow-up of CPP and representing a valuable parameter for monitoring treatment efficacy (19).

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Kisspeptin levels Kisspeptins act directly and indirectly on GnRH

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Table II. Diagnostic tools to detect precocious Table II. Diagnostic tools to detect puberty. precocious puberty.

Clinical history

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Metabolomic approach A metabolomic approach was also assessed to identify metabolite urinary markers in PP subjects. Jia detected an altered urinary metabolic signature in PP girls, revealing several key metabolic systems involvement, such as up-regulated catecholamine and serotonin metabolic pathways (20). Moreover, Jang demonstrated that urine metabolomics provided several potential metabolic clues for PP mechanism, revealing abnormal metabolism of amino acid, especially aromatic amino acid, with a close correlation with CPP pathogenesis (21). These urinary metabolite markers could

Clinical Assessment

Laboratory tests

Precocious Puberty

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Family history (suggest a genetic condition) Prior CNS insults (trauma, radiation, meningitis, tumors) Psychological evaluation (disruptive behaviour, male aggression, emotionally labile, depression) Features of puberty (present or not, duration, progression rate) Height and weight Secondary sex characteristics Bone maturation Café-au-lait spots, goiter, bone deformity

LH and FSH levels  GnRH stimulation test  Hormonal evaluation (estradiol, prolactin, hCG, hCG/testosterone)  Inhibin and kisspeptin levels Radiological exams  X-ray (evaluating bone age)  Pelvic ultrasound for internal genitalia / ovaries  Ultrasound or CT adrenals  MRI/CT hypothalamus or pituitary glands CNS: central nervous system; LH: Luteinizing Hormone; FSH: Follicle Stimulating Hormone; CNS: central nervous system; LH: Luteinizing Hormone; FSH: Follicle Stimulating Hormone; GnRH: gonadotropinGnRH: gonadotropin-releasing hormone; hCG: human tomography; chorionic gonadotropin; computed releasing hormone; hCG: human chorionic gonadotropin; CT: computed MRI: magnetic CT: resonance imaging tomography; MRI: magnetic resonance imaging 

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Table III. Management and outcomes of precocious puberty therapy. Table III. Management and outcomes of precocious puberty therapy. Indications to treat children with precocious puberty  Clear diagnostic criteria for precocious puberty  Pubertal LH level after GnRH stimulation and LH/FSH ratio after GnRH stimulation above diagnostic limit  Rapid pubertal development (progression from one pubertal stage to the next ina markedly shorter period of time than normal)  Abnormal height potential (final height prediction < 3rd centile or < target height range or height for bone age < -2 SD)  Loss of height potential during follow up ( bone age more than  statural age)  Psychological / behaviour reasons related to precocious development of secondary sex characteristics Outcomes of precocious puberty therapy       

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Prevention of psychological and social alterations Regression of sexual characters Block of sexual maturation Slow bone maturation Improvement of definitive stature Prevention of early initiation of sexual life Risk prevention of sexual abuse Choices available for the treatment of precocious puberty

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Dosing

Advantage

Rapid Acting

Monthly Depot

3-mo Depot

12-mo Implant

3-4 times daily or every day Quick on/off

Every 28 days

Every 90 days

Every year

Dosing and efficacy well studied

Fewer injections and fewer compliance concerns Painful injections

No injections needed

Disadvantage

Multiple daily Painful injections Surgical doses needed and suboptimal procedure for with poor compliance insertion and compliance removal GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone hormone

provide a potential alternative diagnostic and stratification approach for the clinical management of PP, but further studies are needed to confirm these preliminary data. Instrumental methods Different studies evaluated the role of pelvic sonography in the diagnosis of PP in girls, highlighting that an increase in uterine and ovarian measurements could represent an early and sensitive

sign of PP (22) Thus, pelvic ultrasound, a non invasive, inexpensive and reliable tool, may give a complementary indication to the GnRH test for the distinction between isolated premature thelarche and early-stage PP. Brain MRI is always indicated for boys with isolated CPP, to search for a lesion, but its usefulness 18 for girls is debated. The age of children may represent a valid cut off, considering that girls with PP development of central origin before 8 years of age

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should continue to be examined by a brain MRI. Also BMI, advanced bone age, LH and FSH peaks, have been proposed as factors which may identify girls at high risk of organic CPP (23). Table II summarizes clinical, laboratoristic and radiological tests required to obtain a correct diagnosis of CPP. PRECOCIOUS PUBERTY TREATMENT GnRHa therapy GnRHa therapy is the only choice of treatment in patients with PP. The main aim of PP treatment is to minimise any loss of final adult height, prevent the progression of secondary sexual characteristics and promote psychological well-being. However, GnRHa therapy is not indicated for every patient with PP because there is not always evidence of pubertal responsiveness to GnRH or any apparent impairment of height potential or significantly advanced bone age (24). Several preparations of GnRHa are currently available, including leuprorelin, triptorelin and goserelin, which are available as monthly and threemonthly depot preparations. Although GnRHa treatment has a proven track record in terms of efficacy and safety for the treatment of CPP, the requirement for intermittent injections is inherently unpopular in a pediatric population. Thus, the histrelin implant represents a potentially appealing and novel mode of delivery, resulting in a continuous diffusion (25). Table III synthesizes the available therapeutic choices to treat central precocious puberty.

systemic randomized controlled trials analysing the effects of long-acting GnRHa therapy on FH. The FH increment, with respect to predicted height, can range from 3 to 10 cm, although realistically, a height gain of 4–6 cm is usual after at least 3–4 years of GnRHa treatment in girls with CPP. Arrigo et al. underlined that height gain from GnRHa therapy onset until FH attainment is generally rather limited (on average 2.9 cm) in girls with idiopathic CPP. FH is also significantly conditioned by both target height and treatment duration (27). Outcome data for FH are even less established for boys in whom the incidence of PP is lower than in girls. An analysis of FH from 11 studies showed a remarkably varied mean height gain of 1.8 to 15.0 cm (28)

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Body mass index Many of the past studies concerning the auxological effect of treatment with GnRHa in CPP have focused on final height outcomes, and less attention has been paid to the body weight changes. Published data have demonstrated an increase in BMI during treatment with GnRHa, (29) whereas other reports suggested a reduction of BMI under gonadotropin-suppressive therapy or a weight excess not significantly related to GnRH agonist treatment (30).

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Effects of GnRHa treatment More than 20 years of experience with GnRHa treatment in CPP has provided important data on outcome regarding final height (FH), body mass index (BMI), bone mineral density (BMD) and reproduction.

Final height Significant impairment of FH in untreated CPP has dominated the rationale for intervening with GnRHa treatment. The use of a long-acting GnRHa can initially induce gonadotropin secretion followed by pituitary desensitization and suppression of puberty. By this mechanism, GnRHa contributes to higher adult height (26). However, there are no

Bone mineral density The effect of GnRHa therapy for PP on BMD is unclear and data are controversial. Girls with PP have lower BMD for chronological age and increased bone reasorption markers, with an improvement observed during the first year of therapy with GnRHa (31) On the other hand, Hong et al. demonstrated that threeyear treatment with GnRHa in CPP patients did not impair bone maturation (32).

Reproductive potential and ovulatory dysfunction There are no adverse effects in the longer term to reproductive potential, with a reactivation of gonadal function after treatment cessation. Moreover, no increased risk of ovulatory dysfunction associated with hirsutism or polycystic ovary syndrome has been observed (24). Side effects GnRH agonists are generally well tolerated in

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children and adolescents. In patients with a history of local reaction to GnRH, particularly those with a history of atopy, it may be appropriate to perform skin testing before proceeding with therapy. Systemic hypersensitivity reactions to GnRHa are a rare but important side effect of therapy. GnRHa are synthetic analogues of GnRH that inhibit FSH and LH hormone and have histamine- releasing activity. Local hypersensitivity to depot leuprolide injection, consisting of erythema and, less commonly, sterile abscess, occurs in up to 5% of children who receive this agent. Antibody formation against the GnRH agonist peptides has been a postulated cause for sterile abscess formation (33).

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CONCLUSIONS

kisspeptins and GPR54 in the neuroendocrine regulation of reproduction. Annu Rev Physiol 2008; 70:213-38. Biro FM, Greenspan LC, Galvez MP. Puberty in Girls of the 21st Century J Pediatr Adolesc Gynecol 2012; 25:289-94. Chirico V, Cannavò S, Lacquaniti A, et al. Prolactin in obese children: a bridge between inflammation and metabolic-endocrine dysfunction. Clin Endocrinol (Oxf) 2013; 79:537-44. Bogaert AF. Age at puberty and father absence in a national probability sample. J Adolesc 2005; 28:5416. Losa-Ward SM1, Todd KL, McCaffrey KA, Tsutsui K, Patisaul HB. Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A. Biol Reprod 2012; 87:28. Silveira LG, Noel SD, Silveira-Neto AP, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010; 95:2276-80. Abreu AP, Dauber A, Macedo DB, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 2013; 368:2467-75. Salpietro V, Mankad K, Kinali M, et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27:107-15. Salpietro V, Polizzi A, Bertè LF, et al. Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis. Neuro Endocrinol Lett 2012; 33:569-73. Trivin C, Couto-Silva AC, Sainte-Rose C, Chemaitilly W, Kalifa C, Doz F, Zerah M, Brauner R. Presentation and evolution of organic central precocious puberty according to the type of CNS lesion. Clin Endocrinol (Oxf) 2006; 65:239-45. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009; 123:e752-62 Tinggaard J1, Mieritz MG, Sørensen K, Mouritsen A, Hagen CP, Aksglaede L, Wohlfahrt-Veje C, Juul A. The physiology and timing of male puberty. Curr Opin Endocrinol Diabetes Obes 2012; 19:197-203.

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The key endocrine investigation is to determine the LH and FSH response to acute GnRH stimulation. Ultrasound examination could serve as a complementary tool and, consequently, for the early initiation of appropriate treatment. The treatment goals are prevention of early menarche and early sexual activity, the halting or regression of secondary sex characteristics, normalization of height velocity and deceleration of bone maturation. Precocious puberty can be a troubling time for children and their parents, but fortunately there is medical treatment to stop further physical pubertal development, and there are several forms of support strategies available.

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