Gonadotropin-Dependent Precocious Puberty: Single-Center Experience From Western India

Objective: To describe the characteristics of gonadotropin-dependent precocious puberty (GDPP) in Indian children. Methods: Clinical profiles of GDPP (n=78, 61 females) and premature thelarche (n=12) from a single center in Western India were retrospectively studied. Results: Pubertal onset was earlier in boys than girls (29 vs 75 months, respectively; P=0.008). The basal luteinizing hormone (LH) was ?0.3 mIU/mL, except 18% of GDPP girls. At 60 minutes after GnRHa-stimulation, all patients (except one girl) had LH ?5 mIU/mL. The GnRHa-stimulated LH/FSH ratio was ?0.34 at 60 minutes in girls with GDPP unlike premature thelarche. Only one girl had an allergic reaction to long-acting GnRH agonist. Among GnRH agonist-treated girls (n=24), the predicted final adult height was -1.67±1.5 SDS, whereas the attained final height was -0.25±1.48 SDS. Conclusion: We establish the safety and efficacy of long acting GnRH agonist therapy in Indian children with GDPP. The 60-minute stimulated serum LH/FSH of ?0.34 differentiated GDPP from premature thelarche.

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Clinical characteristics and etiological analysis of premature pubarche:A report of 55 cases / 中国实用儿科杂志

OBJECTIVE: To analyse the clinical characteristics,aetiology distribution,and metabolic risk parameters of patients with with premature pubarche(PP). METHODS: A retrospective study was performed in 55 patients affected by PP,who received ACTH stimulation test,and the data were evaluated. Among them 17 cases were detected CYP21 A2 gene,and indicators of lipid metabolism of idiopathic premature adrenarche(IPA,15 cases)and idiopathic premature pubarche(IPP,14 cases)were analyzed. RESULTS: The sample included 55 patients with PP(53 female and 2 male),with a mean pubarche age of(7.2±0.9)years for girls and(7±0.8)years for boys. There was an accelerated bone age(BA/CA ratio>1)(1.20 ± 1.5)in girls. A total of 9 patients were classified as non-classic congenital adrenal hyperplasia(NCCAH,16.4%),15 as IPA(27.3%),14 as IPP(25.4%),16 as HPGA function launch(29.1%)and 1 with exaggerated adrenarche(EA,1.8%). There was no significant difference in the diagnostic rate of NCCAH between ACTH stimulation test and CYP21 A2 gene detection(P=0.596). The sex hormone binding protein(SHBP)of IPA was reduced(P=0.007). CONCLUSION: The etiology of premature pubarche-non-classic congenital adrenal hyperplasia(16.4%)is not uncommon. The ACTH stimulation test is useful for the diagnosis of NCCAH,but the sensitivity is not 100%.

Hipertricosis cubital en una paciente con pubarquia precoz: Caso clmico / Hypertrichosis cubiti in a girl with precocious puberty: Case report

La hipertricosis cubital es un aumento localizado de la densidad, longitud y espesor del vello. Es una entidad benigna con muy escasos pacientes descritos en la literatura médica (alrededor de medio centenar). La mitad de los casos descritos asocian otros defectos o malformaciones, y la otra mitad son problemas puramente estéticos. La pubarquia precoz en niñas se define como el inicio del vello púbico antes de los 8 años de edad. Se presenta a una paciente de 6 años con la asociación no descrita previamente de hipertricosis cubital y pubarquia precoz.

Hypertrichosis cubiti is a localized increase in hair density, length and thickness. It is an uncommon and benign entity with very few patients described in the medical literature (more or less than half a hundred). Half of the described patients associate other defects or malformations and the other half are purely aesthetic cases. Early pubarche in girls is defined as the onset of pubic hair before 8 years of age. We present a six-year-old patient with the association not previously described of hypertrichosis cubiti and precocious pubarche.

Implicancias del polimorfismo de repeticiones de glutamina del receptor de andrógenos en la presentación de eventos peripuberales / Implications of androgen receptor gene glutamine repeat polymorphism in the presentation of peripubertal events

Puberty is a period of transition during which girls and boys acquire secondary sexual characteristics and reproductive capacity. The order of appearance of the pubertal traits accounts for a correct or otherwise incorrect activation of the hypothalamic-pituitary-gonadal axis. The growth of the pubic hair before 8 years in girls and 9 years in boys (precocious pubarche, PP) without any other apparent cause has been largely attributed to the early increase of adrenal androgen levels. Also, premature adrenarche (PA) was traditionally considered an extreme within the normal range, however emerging evidence links early androgen excess with the metabolic syndrome. In this context, it has been suggested that an exacerbated clinical manifestation of androgens may be related to greater sensitivity of the androgen receptor (AR). The purpose of this review is to summarize the current knowledge of the contribution of the CAG repeats polymorphisms of AR in the peripubertal manifestations of androgens with special emphasis on precocious pubarche and body composition

Age of Onset of Puberty in Apparently Healthy School Girls from Northern India.

Objective: To determine the age of pubertal onset and menarche in school-going girls, and to assess the impact of obesity on pubertal timing. Design: Cross-sectional Setting: Seven schools across Delhi, India. Participants: 2010 school girls, aged 6-17 years Methods: Anthropometric measurement and pubertal staging was performed for all subjects. Menarche was recorded by ‘status quo’ method. Body mass index was used to define overweight/obesity. Serum gonadotropins and serum estradiol were measured in every sixth participant. Main outcome measure: Age at thelarche and menarche—analyzed for entire cohort and stratified based on body mass index. Results: Median (95% CI) ages of thelarche, pubarche and menarche were 10.8 (10.7-10.9) y, 11.0. y (10.8-11.2) y and 12.4 y (12.2-12.5) y. Overweight/obese girls showed six months earlier onset of thelarche and menarche than those with normal BMI (P<0.05). Serum gonadotropins did not vary significantly in overweight/obese subjects. Conclusion: The study provides the normative data for pubertal growth in Indian girls. Pubertal onset occurs earlier in overweight and obese girls.

Pubertad en adolescentes de áreas rurales y urbanas / Puberty in adolescent of rural and urban areas

Introducción: los factores genéticos determinan un crecimiento potencial, pero el medio ambiente, inhibe o acelera su expresión. Objetivo: determinar el comportamiento según procedencia urbana o rural, de variables relacionadas con el desarrollo puberal: telarquia, pubarquia, menarquia...

Introduction: the genetic factors determine a potential growth, but the environment inhibits and to speed up its expression. Objective: to determine the behavior according the urban or rural origin of the variables related to the pubertal development: telarche, pubarche and menarche. Methods: a correlation and descriptive study was conducted in urban and rural adolescents from the Holguín province...

Gonadothropin-releasing hormone agonist as a treatment of choice for central precocious puberty.

Precocious puberty is defined as pubertal development which occurs too early. The age limit in this term is based on the onset of puberty in normal population. Some points have to be taken into account, such as ethnicity, gender, nutritional conditions, and secular trends. In girls, precocious puberty is defi ned by breast development occured before 8 years old. In boys, precocious puberty is defi ned as gonadarche or pubarche before 9 years of age. The clinical course of precocious puberty varies widely, ranging from alternating, slowly progressive, and rapidly progressive form. The rapidly progressive forms of idiopathic central precocious puberty need to be treated because it may result in early epiphyseal closure and short fi nal height, and also pyschosocial problems in the affected children and the family. The aims of treatment are to arrest physical maturation, prevent early menarche, and also improve adult height combined with normal body proportions. Gonadotropin releasing hormone analogue is the treatment of choice for central precocious puberty. Gonadotropin releasing horomone analogue has suppressive effect on the pituitarygonadal axis, therefore it suppresses LH secretion. This leads to the return of estradiol and testosterone to prepubertal levels. Treatment using gonadotropin releasing horomone analogue is shown to reduce breast size, pubic hair, ovarian and uterine size in girls, and decrease testicular size in boys. Gonadotropin releasing hormone analogue is effective in halting progression of secondary sexual characteristics development, presenting menstrual cycle, slowing bone-age advancement, and also improving final height.

Forma no clàsica de hiperplasia adrenal congénita en la niñez y adolescencia / Non-classic way of congenital adrenal hyperplasia in childhood and adolescence

INTRODUCCIÓN: la hiperplasia adrenal congénita es un trastorno hereditario de la esteroidogénesis suprarrenal, trasmitido por mutaciones genéticas con carácter autosómico recesivo, las cuales afectan las enzimas que intervienen en la biosíntesis del cortisol. La causa la constituye en 90 a 95 por ciento de los casos la deficiencia de la enzima 21 hidroxilasa. OBJETIVO: exponer la experiencia de los autores de este trabajo en la forma no clásica de esta enfermedad. MÉTODOS: se realizó la caracterización de 7 pacientes diagnosticados en la sala de endocrinología pediátrica del Instituto Nacional de Endocrinología, ubicada en el Hospital Pediátrico del Cerro, durante el período 1998-2008. Todos los pacientes pertenecían al sexo femenino. RESULTADOS: los síntomas se iniciaron a una edad promedio de 8,8 años y más de la mitad de los casos presentaron pubarquia precoz. La menarquia se produjo a una edad media de 10,7 años. Se logró el diagnóstico bioquímico al obtenerse valores elevados de 17 hidroxiprogesterona (en condiciones basales). Se emplearon distintas modalidades de tratamiento según la edad de cada paciente y los síntomas predominantes en cada caso. CONCLUSIONES: se corroboró la mayor frecuencia de diagnóstico de esta enfermedad en el sexo femenino, así como la importancia del estudio y el seguimiento ante un paciente con pubarquia precoz(AU)

INTRODUCTION: the congenital adrenal hyperplasia is an inherited disorder of suprarenal esteroidogenesis, transmitted by genetic mutations with a autosomal recessive character affecting the enzymes intervening in cortisol biosynthesis. In the 90 to 95 percent of cases, the cause is a deficiency of Hydroxylase enzyme 21. OBJECTIVE: to show the current paper authors' experience in the non-classic way of this entity. METHODS: we made a characterization of 7 female patients diagnosed in the Children Endocrinology Ward of the National Institute of Endocrinology located in the Children Hospital, Cerro municipality during 1998-2008. RESULTS: symptoms started at a mean age of 8,8 years and more the a half of cases had an early pubarche. Menarche appeared at a mean age of 19,7 years. We made a biochemical diagnosis achieving higher values of 17 hydroxyprogesterone (in basal conditions). Different treatment modalities were used according to each patient and predominant symptoms in each case. CONCLUSIONS: we verified the great frequency of this entity in female sex, as well as the study and follow-up significance in face of a patient presenting early pubarche(AU)

Pubarquia precoz: Experiencia en 173 casos / Precocious pubarche: Experience in 173 cases

Background: Precocious pubarche (PP), defined as the development of sexual pubic hair before 8 years of age in females and before 9 years in males, is usually a benign condition but it can also be the first sign of an underlying disease. Aim: To analyze the etiology andperform a short term follow up in a cohort of patients with PP. Material and methods: A group of 173 patients (158 females) consulted for PP with a mean age of 7.4±0.1 years. These patients were followed between 15 to 60 months. Anthropometric measurements, bone age, serum levels of total testosterone, 17 OH progesterone (17 OHP) and dehydroepiandrosterone sulphate (DHEAS) were evaluated. Results: Mean birth weight and length was 3024.1±50.5 g and 48.5±0.3 cm,respectively. Ten percent of children were small for gestational age at birth. Bone age was accelerated by 1.1±0.01 years. One hundred and twelve patients were classified as having idiopathicPP (64.7%; 105 females), 29 as central precocious puberty (16.8%; only females), 16 as exaggerated adrenarche (EA 9.2%; 13 females) and 16 as non classical adrenal hyperplasia (9.2%; 11 females). Conclusions: PP represents a common and usually benign sign. However, 26% of cases had apathologic underlying condition. Therefore, all children with PP should be evaluated by a pediatric endocrinologist. Low birth weight was not frequent in this cohort and these patients did not show EA

Growth and sex differentiation of children born small for gestational age / 소아과

The incidence of small for gestational age (SGA) births is frequent, accounting for 2.3% to 8% of all live births. Several childhood and adult diseases are related to early postnatal growth and birth size, and 10% of children born SGA may have a short stature throughout postnatal life. Additionally, they may have abnormal growth hormone (GH)-insulin like growth factor axis, HPA axis, and gonadal function. Permanent changes are detrimental in an environment of nutritional abundance, and predispose SGA children to an array of diseases in adolescence and adulthood. Such changes may also cause premature pubarche, adrenarche, and precocious puberty. The varying results from clinical studies necessitate more prospective case control studies. Reproductive tract abnormalities and reproductive dysfunction are related to SGA births. GH treatment is required for SGA infants who do not experience catch-up growth.

Update on the etiology, diagnosis and therapeutic management of sexual precocity: [review]

Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Gonadotropin-dependent precocious puberty (GDPP) results from the premature activation of the hypothalamic-pituitary-gonadal axis and mimics the physiological pubertal development, although at an inadequate chronological age. Hormonal evaluation, mainly through basal and GnRH-stimulated LH levels shows activation of the gonadotropic axis. Gonadotropin-independent precocious puberty (GIPP) is the result of the secretion of sex steroids, independently from the activation of the gonadotropic axis. Several genetic causes, including constitutive activating mutations in the human LH-receptor gene and activating mutations in the Gs protein a-subunit gene are described as the etiology of testotoxicosis and McCune-Albright syndrome, respectively. The differential diagnosis between GDPP and GIPP has direct implications on the therapeutic option. Long-acting gonadotropin-releasing hormone (GnRH) analogs are the treatment of choice in GDPP. The treatment monitoring is carried out by clinical examination, hormonal evaluation measurements and image studies. For treatment of GIPP, drugs that act by blocking the action of sex steroids on their specific receptors (cyproterone, tamoxifen) or through their synthesis (ketoconazole, medroxyprogesterone, aromatase inhibitors) are used. In addition, variants of the normal pubertal development include isolated forms of precocious thelarche, precocious pubarche and precocious menarche. Here, we provide an update on the etiology, diagnosis and management of sexual precocity.

A puberdade precoce é definida como o desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e dos 9 anos nos meninos. A puberdade precoce dependente de gonadotrofinas (PPDG) resulta da ativação prematura do eixo hipotálamo-hipófise-gonadal e mimetiza o desenvolvimento puberal fisiológico, embora em idade cronológica inadequada. A avaliação hormonal, principalmente os valores de LH basal e após estímulo com GnRH exógeno confirmam a ativação do eixo gonadotrófico. A puberdade precoce independente de gonadotrofinas (PPIG) é o resultado da secreção de esteróides sexuais independentemente da ativação do eixo gonadotrófico. Diversas causas genéticas, incluindo mutações ativadoras constitutivas no gene do receptor do LH humano e mutações ativadoras no gene da subunidade a da proteína G representam as etiologias da testotoxicose e da síndrome de McCune Albright, respectivamente. O diagnóstico diferencial entre PPDG e PPIG tem implicação direta na opção terapêutica. Análogos de GnRH de ação prolongada é o tratamento de escolha da PPDG. A monitorização do tratamento da PPDG é realizada pelo exame clínico, avaliação hormonal e exames de imagem. Para o tratamento da PPIG, são usadas drogas que bloqueiam a ação dos esteróides sexuais nos seus receptores específicos (ciproterona, tamoxifeno) ou bloqueiam a sua síntese (cetoconazol, medroxiprogesterona e inibidores da aromatase). Variantes do desenvolvimento puberal normal incluem as formas isoladas de telarca, pubarca e menarca precoces. Nesta revisão, atualizamos a etiologia, o diagnóstico e tratamento da precocidade sexual.

Características clínicas, endocrinas y metabólicas de una población argentina de niñas con pubarca prematura / Clinical, hormonal and metabolic findings in argentinean girls with premature pubarche

La pubarca prematura se ha asociado con alteraciones hormonales y metabólicas. Se estudiaron 40 niñas con pubarca prematura de 7,23 ± 0,29 años (media ± ESM). Se evaluó grado de desarrollo, talla, edad ósea, IMC y peso al nacimiento (PN). Se dosaron andrógenos, gonadotrofinas, lípidos, glucemia e insulina, HOMA e índice glucemia/insulina (G/I) y se compararon con un grupo control normal de 25 niñas. Las pacientes se dividieron según el nivel de sulfato de dehidroepiandrosterona (SDHEA) en dos grupos, Pre A (Pre adrenarca), < 400 ng/ml, n= 17 y Post A (Post adrenarca) < 400 ng/ml , n= 23. El grupo Post A tuvo mayor edad cronológica, edad ósea y grado de vello pubiano que el Pre A, sin diferencias en IMC ni en peso de nacimiento (PN). Insulina y HOMA fueron mayores y G/I menor en Post A que en Pre A y grupo control. Dos niñas en Post A tuvieron franca resistencia a la insulina. 64 % de las niñas en Pre A y 59 % en Post A tuvieron valores elevados o limítrofes de colesterol total (CT). Conclusiones: el grupo Post A presentó menor sensibilidad insulínica y ambos grupos de pacientes tuvieron valores de CT elevados, alteraciones que podrían favorecer el riesgo de futuras complicaciones. Se recomienda el seguimiento a largo plazo de todas las niñas con pubarca prematura.

Precocious pubarche in girls is caused by premature adrenarche in most cases. Less frequently it occurs in absence of biochemical markers of adrenarche being ascribed to increased target tissue sensitivity. Premature pubarche with pronounced adrenarche has been associated with insulin resistance and dyslipemia, especially in girls with history of low birth weight. Most studies have been conducted in hispanic and affrican-american patients. We studied a total of 40 argentinean girls with isolated premature pubarche, aged 7.23 ± 0.29 years (mean ± SEM) at the moment of diagnosis. Grade of sexual development, height, weight, BMI and birth weight (BW) were recorded. Dehidroepiandrosterone sulphate (DHEAS), androstenedione (A), testosterone (T), 17OH progesterone (17 OHP), SHBG, LH, FSH, PRL and estradiol were measured. Total cholesterol (TC), LDL cholesterol (LDL- C), triglycerides (TGC), glucose, insulin, HOMA and fasting glucose/ insulin index (G/I) were evaluated and compared with those in a control group of 25 normal girls. Patients were divided into two groups: Pre A (Pre adrenarche), with DHEAS < 400 ng/ml, and Post A (Post adrenarche), with DHEAS > 400 ng/ml. Post A girls had higher chronological age, bone age advancement and grade of pubic hair development than Pre A girls. No difference was found regarding BMI or BW. Besides higher DHEAS levels, Post A girls showed elevated A and 17OHP levels than Pre A girls (86 ± 8 vs 35 ± 4 ng/dl, p<0. 0001 and 1.1 ± 0.09 vs 0.75 ± 0.07 ng/ml, p< 0.01, respectively). Insulin levels (µUI/ml) were 4.51 ± 0.75 in Pre A, 6.53 ± 1.11 in Post A and 4.05 ± 0.45 in control group. Fasting G/I was 24.07 ± 3.75 in Pre A , 18.4 ± 2.34 in Post A and 25.41 ± 2.31 in controls. HOMA was 0.90 ± 0.12 in Pre A, 1.35 ± 0.22 in Post A and 0.89 ± 0.11 in control group. Post A girls had higher insulin and HOMA and lower G/I than control group girls (p<0.05) while those parameters in Pre A girls were not different than in normal control subjects. Only two patients in Post A group had HOMA and G/I consistent with insulin resistance. TC was higher in Pre A than in control group (182.2 ± 4.9 vs156.7 ± 8.5 mg/dl, p<0.05). According to The National Cholesterol Education Program definition, 64 % of Pre A girls and 59 % of Post A girls had elevated or borderline TC levels. TGC values were not different among Pre A, Post A and control group (81.1 ±7.1, 77.6 ± 6.1 and 71.9 ± 4.7 mg/dl, respectively. Summary and Conclusions: In this cohort of argentinean girls with premature pubarche, we did not find a significant history of intrauterine growth retardation. Patients with biochemical pattern of adrenarche showed clinical signs of androgen exposure (accelerated bone age, more advanced degree of pubic hair development) and a serum profile suggestive of reduced insulin sensitivity compared with those without biochemical adrenarche. Both groups of patients had undesirable total cholesterol levels. These findings support the recommendation of long-term follow-up for all girls with premature pubarche.

Enfoque práctico de la pubarquia precoz

La pubarquia precoz, es considerada una variante normal del desarrollo, sin consecuencias a largo plazo. Recientemente se ha relacionado con alteraciones endocrino-metabólicas en la pre-pubertad y fundamentalmente en la post-pubertad. La pubarquia precoz, hoy por hoy, representa un factor predictivo de disfunción ovárica y/o adrenal y de síndrome metabólico. Este artículo es resultado de una revisión bibliográfica sobre esta entidad, realizado con el objetivo de disponer de las herramientas que nos permitan el diagnostico, la evaluación, el seguimiento y los tratamientos adecuados.

Precocious pubarche was believed to be a normal variant of pubertad developpement, without long-term consequences.Recently premature pubarche has been associated to endocrine-metabolic disturbances in the pre-puberal age and especially after puberty. At present, premature pubarche represent a predictive factor of ovarian and/or adrenal disfunction and Metabolic Syndrome. This article result from a bilbliographic review about this entity, the objective is to dispose of tools to make the adequate diagnosis, approach, treatment and follow-up.