Treatment of central precocious puberty

doi:10.1053/beem.2002.0188

Best Practice & Research Clinical Endocrinology & Metabolism

Volume 16, Issue 1, March 2002, Pages 165-189

https://doi.org/10.1053/beem.2002.0188 Get rights and content

Abstract

This chapter describes several aspects of the management of treatment in girls and boys with central precocious puberty. Although there is some controversy about the indication for gonadotrophin releasing hormone (GnRH) agonist treatment in the literature, a list of clear indications is presented and monitoring requirements for treatment are discussed with reference to the pertinent literature. The development of clinical, psychological, hormonal, sonographical and auxological parameters that can be expected during GnRH agonist treatment is described in detail. In view of the scant evidence-based knowledge, we review the final outcome of patients treated with GnRH agonists with respect to reversibility of hormonal suppression, reproductive function, final height and side effects.

The data published so far show that GnRH agonist treatment using the modern depot preparations is not only convenient but also safe, with relatively minor side effects. The outcome in terms of final height is favourable in the majority of patients.

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Cited by (62)

Daily GnRH agonist treatment effectively delayed puberty in female rats without long-term effects on sexual behavior or estrous cyclicity
2022, Physiology and Behavior
Citation Excerpt :
Administration of GnRH agonists during the early stages of puberty can allow patients to express their experienced gender more easily until they reach an age when gender-affirming hormone treatment can be prescribed [16]. Although GnRH agonists have been used safely and successfully in children and adolescents to treat precocious puberty [17–19] and endometriosis [11, 12], few studies have measured lasting outcomes after treatment had been terminated [19, 20]. In one study, young women (15–22 years old) with endometriosis received a depot injection of a GnRH agonist every 3 months for a year.
The present study examined the long-term effects of suppressing puberty with a GnRH agonist on reproductive physiology and behavior in female rats. We have recently reported that administration of the GnRH agonist leuprolide acetate (25 µg/kg) daily between postnatal day (PD) 25–50 delayed puberty and disrupted the development of copulatory behavior and sexual motivation in male rats. However, pilot data from our lab suggest that this low dose of leuprolide acetate (25 µg/kg) was not high enough to significantly delay puberty in female rats. Therefore, we injected female Long-Evans rats with leuprolide acetate at a higher dose (50 µg/kg) or 0.9% sterile saline, daily , starting on PD 25 and ending on PD 50. Vaginal opening was monitored daily starting on PD 30 for signs of pubertal onset and first estrous cycle. In addition, we measured estrous cyclicity starting approximately 2 weeks after the last injection of leuprolide (∼PD 64). Immediately after monitoring estrous cyclicity, the female rats were mated on their first day in behavioral estrus using the partner-preference paradigm, with and without physical contact (PD 95–110). We found that this dose of leuprolide (50 µg/kg) significantly delayed puberty; however, neither estrous cyclicity nor sexual motivation was significantly affected by periadolescent exposure to leuprolide. Together with our findings in male rats, these results add to our understanding of the developmental effects of chemically suppressing puberty in rats.
Daily GnRH agonist treatment delays the development of reproductive physiology and behavior in male rats
2021, Hormones and Behavior
Citation Excerpt :
Pubertal suppression has been shown to relieve the distress associated with experiencing physical signs of puberty (Cohen-Kettenis and van Goozen, 1998; de Vries et al., 2011). Although GnRH agonists have been deemed safe to treat conditions such as precocious puberty (Clemons et al., 1993; Massart et al., 2009; Partsch and Sippell, 2002), few studies have measured the lasting consequences once puberty was permitted to progress (Lee et al., 2016; Partsch and Sippell, 2002). For example, adult male patients who received GnRH agonist treatment for central precocious puberty were found to have normal lumbar and volumetric bone mineral density (BMD) after reaching adult height (Bertelloni and Mul, 2008; van der Sluis et al., 2002).
The present study was designed to examine the effects of suppressing pubertal onset with leuprolide acetate, a gonadotropin releasing hormone (GnRH) agonist. Starting on postnatal day (PD) 25, male Long-Evans rats were injected daily with either leuprolide acetate (25 μg/kg dissolved in 0.9% sterile physiological saline; n = 13) or sterile physiological saline (1.0 ml/kg 0.9% NaCl; n = 14) for a total of 25 days. Males were monitored daily for signs of puberty (i.e., preputial separation). On the last day of leuprolide treatment (PD 50), half of each treatment group was injected with 10.0 μg of estradiol benzoate (EB) daily for three consecutive days (PD 50–52) and 1.0 mg of progesterone (P) on the 4th day (PD 53), whereas the other half of each treatment group received oil injections. Four hours after P injections, all subjects were given the opportunity to interact with a gonadally-intact male and a sexually receptive female rat (i.e., a partner-preference test with and without physical contact). Copulatory behavior and sexual motivation were measured. Hormone injections and mating tests were repeated weekly for a total of 3 consecutive weeks. Results showed that leuprolide delayed puberty as well as the development of copulatory behavior and the expression of sexual motivation. By the last test, the leuprolide-treated subjects showed signs of catching up, however, many continued to be delayed. Estradiol and progesterone mildly feminized male physiology (e.g., decreased testes weight and serum testosterone) and behavior (e.g., increased lordosis), but did not interact with leuprolide treatment.
The clinical spectrum of childhood narcolepsy
2018, Sleep Medicine Reviews
Citation Excerpt :
To achieve a complete pituitary-gonadal suppression the recommended dosage of triptorelin is 75–100 mg/kg body weight/4 wk and a dose of 90/mg/kg body weight for leuprolin. In Europe the recommended starting dose is 3.75 mg for body weight >20 kg and 1.875 mg for a body weight <20 kg [194]. Once started, the effects of therapy must be evaluated by a follow-up every 6 mo.
Narcolepsy type 1 is a life-long, severe, multifaceted disease often arising in childhood or adolescence. Beyond the classical symptoms (excessive daytime sleepiness, cataplexy, hallucinations, sleep paralysis and nocturnal fragmented sleep), metabolic, endocrinological, psychiatric and psychosocial aspects must be considered. Despite the increased awareness after H1N1 pandemic influenza and vaccination, narcolepsy is still misdiagnosed and unrecognized. The peculiar presentation of symptoms in narcoleptic children could in part explain the misdiagnoses. Excessive daytime sleepiness presenting as chronic drowsiness or irritability could be stigmatized as laziness or misinterpreted as behavior or inattention disorder. The persistent hypotonia and the complex hyperkinetic movements that characterize cataplexy close to the onset, could be misdiagnosed as a movement disorder or as other neurologic conditions. The consequent therapeutic delay could turn into dramatic consequences. The narcolepsy onset, indeed, is associated with abrupt weight gain and sometimes with precocious puberty that require a prompt recognition and treatment to avoid auxological and metabolic complications. Moreover, narcoleptic children could have behavioral and psychiatric disorders ranging from mood to psychotic ones that need ad hoc management. Accordingly, spreading the awareness outside the sleep specialist community is necessary in order to reduce the diagnostic delay and to obtain prompt and multidisciplinary management.
Gonadotrophin-independent precocious puberty; female and male
2018, Encyclopedia of Endocrine Diseases
GnRH-independent precocious puberty (GIPP) is defined as pubertal signs at an age younger than the reference range mostly caused by autonomous secretion of sex steroids by the gonads or the adrenal gland. The etiology of GIPP may vary by the gender of the child and is categorized into either congenital/genetic or acquired disorders. The main symptoms in girls are breast development and vaginal discharge or bleeding and in boys early pubic hair development, an enlarged penis, with rapid growth, tall stature. Laboratory studies will reveal elevated levels of sex steroids and suppressed levels of gonadotropins. Depending on the etiology treatment may require a medical (anti-androgens, anti-estrogens, and aromatase inhibitors) or a surgical approach. In this article the clinical presentation, diagnostic procedures and treatment options are summarized.
Chapter 1 - Female Genital Tract Development and Disorders of Childhood
2018, Diagnostic Gynecologic and Obstetric Pathology
Female reproductive tract development is a complex process intricately tied to the patterning of the male (Wolffian) reproductive tract and renal anlage. Development starts from undifferentiated mesoderm known as the genital ridge, with germ cells migrating to this location from the yolk sac. The müllerian duct begins as an invagination of the coelomic epithelium at the top of the genital ridge and elongates by active cell proliferation using the Wolffian duct as a guide. Many genes have been linked to female reproductive tract development, but only a few have been directly implicated by animal knockout models; this is because the simplex female reproductive tract pattern (i.e., one with a single cervix and uterus, with two separate fallopian tubes) is limited to humans and other primates. Most recently, genomic sequencing has identified more genes, mostly transcription factors and extracellular signaling molecules, and mutations in those genes, associated with malformations of the female reproductive tract. The most common congenital abnormality of the human female genital tract occurs when the paired müllerian ducts fail to fuse or the subsequent septum fails to resorb, yielding a spectrum of uterine anomalies, including uterus didelphys and bicornuate uterus. External female genital tract development requires both the absence of a key male determining factor (SRY) and presence of its antagonist (WNT4). Virilization of genetically female fetuses is due to excessive androgens from congenital adrenal hyperplasia or maternal blood.
Advanced bone age as an indicator facilitates the diagnosis of precocious puberty
2018, Jornal de Pediatria
Diagnosis of central precocious puberty has always been challenging in clinical practice. As an important method in the diagnosis of central precocious puberty, luteinizing hormone-releasing hormone stimulation test is complex and time-consuming. In many cases, clinical traits are inconsistent with luteinizing hormone-releasing hormone stimulation test results, therefore not reliable for diagnosis. In this study, the authors intended to find an indicator that predicts the results of the luteinizing hormone-releasing hormone stimulation test among subjects with early pubertal signs.
Cases of 382 girls with early breast development before 8 years old and luteinizing hormone-releasing hormone stimulation test before 9 years old were included and underwent follow-up tests. Patients with peak luteinizing hormone level ≥5 IU/L were considered positive in the luteinizing hormone-releasing hormone stimulation test. Anthropometric data, body mass index, bone age evaluation, blood hormones levels of luteinizing hormone, estradiol, follicle-stimulating hormone, and uterine and ovarian volumes were analyzed.
Subjects with positive results in the initial test demonstrated early bone maturation, accelerated growth, and elevated basal blood luteinizing hormone, estradiol, and follicle-stimulating hormone levels, when compared with subjects with negative results in the initial test. Subjects with positive results in the follow-up test presented a more advanced bone age and more accelerated linear growth, when compared with subjects with negative results in the follow-up test.
According to the statistical analysis, advanced bone age is the most effective predictor of the result of luteinizing hormone-releasing hormone stimulation test.
O diagnóstico da puberdade precoce central sempre foi complicado na prática clínica. Como um importante método no diagnóstico de puberdade precoce central, o teste de estimulação do hormônio liberador do hormônio luteinizante é complexo e demorado. Em muitos casos, as características clínicas são incompatíveis com os resultados do teste de estimulação do hormônio liberador do hormônio luteinizante e, assim, não são confiáveis para o diagnóstico. Neste estudo, visamos constatar um indicador que previsse os resultados do teste de estimulação do hormônio liberador do hormônio luteinizante entre indivíduos com sinais puberais precoces.
Foram incluídos casos de 382 meninas com desenvolvimento precoce das mamas antes dos 8 anos de idade e teste de estimulação do hormônio liberador do hormônio luteinizante antes dos 9 anos e elas foram submetidas a testes de acompanhamento. Os resultados das pacientes com nível máximo de hormônio luteinizante ≥ 5 IU/L foram consideradas positivos no teste de estimulação do hormônio liberador do hormônio luteinizante. Foi feita uma análise dos dados antropométricos, do índice de massa corporal, da avaliação da idade óssea, dos níveis sanguíneos de hormônio luteinizante, volumes uterinos e ovarianos de estradiol (E2) e do hormônio folículo-estimulante.
Os indivíduos com resultado positive no teste inicial demonstraram maturação precoce do osso, crescimento acelerado e níveis sanguíneos elevados de hormônio luteinizante, estradiol e hormônio folículo-estimulante, em comparação aos indivíduos com resultados negativos no teste inicial. Os indivíduos com resultados positivos no teste de acompanhamento apresentaram um maior avanço na idade óssea e crescimento linear mais acelerado, em comparação aos indivíduos com resultados negativos no teste de acompanhamento.
De acordo com a análise estatística, a idade óssea avançada é o indicador mais efetivo do resultado do teste de estimulação do hormônio liberador do hormônio luteinizante.

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Regular ArticleTreatment of central precocious puberty

Abstract

Pediatric Neurology

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Lancet

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Puberty: Ontogeny, neuroendocrinology, physiology, and disorders

Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society

Pediatrics

Pubertal development in Swiss girls

Helvetica Paediatrica Acta

Variations in the pattern of pubertal changes in girls

Archives of Disease in Childhood

Sexual maturation in East German girls

Acta Paediatrica

Continuing positive secular growth change in the Netherlands 1955-1997

Pediatric Research

Pubertal development in Swiss boys

Helvetica Paediatrica Acta

Variations in the pattern of pubertal changes in boys

Archives of Disease in Childhood

Sexual maturation in East German boys

Acta Paediatrica

Precocious puberty

For puberty that comes too soon, new treatment highly effective

Journal of the American Medical Association

Advances in the treatment of precocious puberty

Advances in Pediatrics

Sexual precocity: sex incidence and aetiology

Archives of Disease in Childhood

Etiology and age incidence of precocious puberty in girls: a multicentric study

Journal of Pediatric Endocrinology and Metabolism

Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty

Journal of Pediatric Endocrinology and Metabolism

Isosexual precocious puberty in girls

Acta Paediatrica Scandinavica

Treatment of progressive central precocious puberty with leuprorelin depot

Monatsschrift Kinderheilkunde

Idiopathic isosexual central precocious puberty: magnetic resonance findings in 30 patients

British Journal of Radiology

Central precocious puberty: clinical and imaging aspects

Journal of Pediatric Endocrinology and Metabolism

Luteinizing hormone-releasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty

Journal of Clinical Endocrinology and Metabolism

Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin-releasing hormone agonist depot

Archives of Disease in Childhood

The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history

Journal of Clinical Endocrinology and Metabolism

Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: a longitudinal study

Pediatrics

Neurofibromatosis type 1 and precocious puberty

Journal of Pediatric Endocrinology and Metabolism

True precocious puberty: a long-term complication in children with shunted non-tumoral hydrocephalus

Helvetica Paediatrica Acta

Accelerated pubertal development in patients with shunted hydrocephalus

Archives of Disease in Childhood

Precocious puberty in myelomeningocele patients

Journal of Pediatric Orthopaedics

Growth and pubertal development in patients with meningomyelocele: a retrospective analysis

Acta Paediatrica

Precocious puberty after hypothalamic and pituitary irradiation in young children

New England Journal of Medicine

Cranial irradiation and early puberty

Journal of Clinical Endocrinology and Metabolism

Early puberty in Williams syndrome

Clinical Dysmorphology

Precocious puberty

Precocious Sexual Development, A Clinical Study of 100 Children

Modifying the outcome of complete precocious puberty. To treat or not to treat

Spontaneously regressive central precocious puberty in girls. Impact on therapeutic indications in precocious puberty

Annales de Pédiatrie

Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20 untreated patients

Journal of Clinical Endocrinology and Metabolism

Self-remitting or transient precocious puberty

Regular Article
Treatment of central precocious puberty