Vorzeitige und verzögerte Pubertät beim Mädchen

In sexual precocity, premature thelarche and premature pubarche have to be distinguished from pathological forms of precocious puberty. The latter has to subdivided into central precocious puberty and precocious pseudopuberty. Delayed puberty is mostly due to a constitutional delay of puberty which will later result in normal pubertal development. However, pathological forms of delayed puberty have to be considered which result either centrally from disorders of the hypothalamus and the pituitary or peripherally from the ovaries. The diagnostic work-up of the different forms is an essential prerequisite for therapy which can encompass pharmacological suppression and induction of pubertal development.     

Clinical expression of precocious pubertal development in girls

The paediatric endocrinologist is frequently asked whether pubertal development in a girl is normal, early or too early (precocious). This review will cover all clinical expression of premature development of puberty: central precocious puberty (neurogenic, secondary, and idiopathic) where treatment with GnRHa is considered, early puberty, partial puberty or pubertal variants and peripheral or pseudo precocious puberty related to an antonomous hypersecretion of estrogens by the ovaries. A special attention should be paid also to the role of environmental disruptors in the development of peripheral precocious puberty. GnRHa treatment should be considered only when evidence of central activation of the gonadotropic axis is proved by the LHRH-test.     

Recent advances in the management of sexual precocity in girls.

Sexual precocity has important psychosocial implications for the prematurely developing child, as well as being associated in some cases with significant pathology. Conscientious evaluation and initiation of effective therapy can have a significant impact on improving long-term outcome. The differentiation between complete sexual precocity with activation of the hypothalamic-pituitary axis and incomplete sexual precocity without activation of the central reproductive system is of paramount importance. In incomplete sexual precocity, the sex steroids are of exogenous, adrenal, or gonadal origin. Premature adrenarche presents with the early development of pubic hair only and must be distinguished from adrenal hyperplasia or an androgen-secreting neoplasm, which may be associated with accelerated growth, advanced bone age, and virilization. When incomplete sexual precocity involves the ovary, ovarian tumors must be considered. Other causes of incomplete sexual precocity include hypothyroidism and gonadotropin-independent precocity such as McCune-Albright syndrome. Complete sexual precocity or precocious puberty of central origin is diagnosed in girls by gonadotropin-releasing hormone challenge yielding a stimulated luteinizing hormone peak greater than 15 IU/L. Radiologic evaluation of the central axis is necessary. Treatment of precocious puberty relies on the use of potent agonists of gonadotropin-releasing hormone that reversibly suppress the prematurely activated pituitary. Depot preparations are efficacious. Early initiation and careful monitoring of treatment can reduce physical signs of development, improve the likelihood for normal adult height, and postpone normal pubertal progression to a more appropriate age.     

Disorders of pubertal development

Puberty is the period of life during which reproductive capability is acquired. It is characterized clinically by the acquisition of secondary sexual characteristics associated with a growth spurt, and on average takes 3-4 years. Early maturation is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys. Delayed puberty is defined when there are no signs of puberty at the age of 13.4 years in girls and 14 years in boys (2 SD above the mean of chronological age for the onset of puberty). There are many forms of premature sexual maturation: gonadotrophin-dependent (central, or 'idiopathic' or 'true' precocious puberty) and gonadotrophin-independent precocious puberty (McCune-Albright syndrome in girls, testotoxicosis in boys); isolated premature thelarche (in the forms of classical, atypical and variant); premature adrenarche (characterized by the production of significant quantities of androgens between 5 and 8 years of age); premature menarche. The differential diagnosis of delayed puberty is between constitutional delay of growth and puberty, pubertal delay secondary to chronic disease and hypogonadotrophic hypogonadism.     

Update on pubertal development.

This review provides updated information relating to the timing of pubertal onset from a large study of girls seen in pediatric practices. In addition, new studies investigating the relationship of the hormone leptin to the onset of puberty are discussed, as well as new information on the neuroendocrine control of pubertal regulation. A provocative study documenting poor mental health, more behavior problems, and lower IQ in children with premature adrenarche when compared with controls raises the question of whether psychological stress triggers premature adrenarche or whether the early increase in adrenal hormone secretion causes psychosocial problems. Finally, significant advances in the management of central precocious puberty in girls have been made over the past year.     

Precocious Puberty: Changing Trends in Diagnosis and Treatment

Objective: the complications of precocious puberty may include premature menarche, shortened adult height due to accelerated bane maturation, and psychological distress. With advances in molecular biology and medical imaging techniques, and with a decade and a half of experience with the use of gonadotrophin-releasing hormone (GnRH) agonist analogue therapy to suppress central precocious puberty, the diagnosis and treatment of sexual precocity has been greatly refined. This paper discusses the recent advances in diagnostic and therapeutic interventions for central precocious puberty in girls, with emphasis on the following outcomes: final adult height, ovarian function, and psychological sequelae.Methods: we reviewed the literature on the diagnosis and therapy of precocious puberty. Data were abstracted from reports that included outcome measures of final adult height, ovarian/menstrual function or psychological assessments in treated and untreated female patients.Results: most reports demonstrate increased final adult height in women treated with GnRH analogues when compared to reports of untreated patients or those treated with cyproterone acetate or medroxyprogesterone acetate. This effect appears to be most marked in patients with extremely precocious pubertal onset, before age five to six years. Menarche occurs within two years of treatment cessation in nearly all patients. Limited data exist regarding the psychological consequences of sexual precocity or its treatment.Conclusion: GnRH analogues have become the treatment of choice for girls with central precocious puberty. Their ability to suppress chronically the central activation of the hypothalamic-pituitary-ovarian axis represents a major advance, and results in the slowing of bone maturation and the reversible delay of menarche and the progression of secondary sexual characteristics.     

不同初治年龄对先天性肾上腺皮质增生症患儿发育的影响

目的了解不同初治年龄对先天性肾上腺皮质增生症(CAH)患儿身高、骨龄、性早熟等方面的影响。 方法将1982~2004年在上海新华医院和上海市儿科医学研究所内分泌、遗传代谢病专科诊治的32例CAH患儿(年龄：女≥8岁，男≥9岁)，按初治年龄分为≤3岁组(14例)和>3岁组(18例)，观察两组间末次复诊时骨龄与身高龄之差、性早熟例数及男女患儿发生性早熟的不同。 结果14例初治年龄≤3岁患儿末次复诊时骨龄与身高龄之差\[(30±20)岁\]与18例>3岁组\[(46±16)岁\]比较差异有显著性(P<005)，初治年龄>3岁组发生真性性早熟(9例)与≤3岁组(2例)比较差异有显著性(χ2=4453，P<005)。男性患儿发生真性性早熟(9例)与女性患儿(2例)比较差异有显著性(χ2=4794，P<005)。 结论CAH患儿≤3岁得到诊治者其预测终身高较>3岁方诊治者明显改善，其性早熟发生率明显减少，男性CAH患儿较女性CAH患儿更易发生性早熟。     

The role of sonography in pediatric gynecology

Sonography has a major role in the evaluation of children with gynecologic disorders. The size, consistency, and origin of pelvic masses and the status of the internal genitalia can be evaluated. Sonography is useful in evaluation of children with precocious puberty because it can demonstrate adult-size ovaries in true precocious puberty, which distinguishes this from premature thelarche and adrenarche. Specific causes of precocious sexual development such as adrenal and ovarian tumors and cysts also can be diagnosed.     

The rise in adrenal androgen biosynthesis: adrenarche

Adrenarche is characterized by the increase in adrenal androgen production, namely dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs around 6 years of age. These steroids are secreted by the zona reticularis (ZR) of the adrenal gland. This is associated with pubarche or the increase in androgen-dependent hair growth at the time of puberty. The increase in adrenal androgen production can be explained by the increase in the expression of DHEA-synthesizing steroidogenic enzymes in the ZR. Adrenarche is an event independent of gonadarche and is found only in humans and select nonhuman primates. Although numerous prenatal and postnatal factors are important in the onset of adrenarche, a specific adrenal cortical androgen-stimulating hormone has not been identified. Evidence also exists for a role for adrenarche in behavior, skeletal maturation, and postpubertal well-being. Adrenarche is influenced by sex and race, and some of this variation may be related to the insulin and insulin-like growth factor (IGF) signaling pathways. In addition, children with premature and exaggerated adrenarche may be predisposed to certain diseases later in life.     

The clinical evaluation and treatment of female precocious puberty

One in 180 American girls has precocious puberty. Accordingly, as a primary care physician, the obstetrician/gynecologist must be knowledgeable about the clinical evaluation and management of this disorder. Pubertal precocity has numerous causes and may be classified broadly as being central or peripheral in etiology. A meticulous history and physical examination, the judicious choice and interpretation of laboratory tests, and the selective use of radiological studies are the cornerstones of the evaluation. The initial approach should focus on identifying life-threatening tumors of the brain, adrenal gland, or ovary. The management goals include reducing the gonadotropin secretion and sex steroid effects and maximizing the eventual adult height. Because the child and her parents are frequently extremely distressed, the treating physician’s sensitivity and reassurance are paramount. The obstetrician/gynecologist, as both primary care physician and consultant, is in an ideal position to investigate, diagnose, and treat female precocious puberty.     

Disturbances of puberty

The initiation and progress of puberty requires progressive pulsatile stimulation of the pituitary by GnRH and of the gonads by LH and FSH. Gonadal maturation continues throughout childhood and is not confined to puberty. We have discussed the events of normal puberty and emphasized the consonance of the acquisition of different components of sexual maturation, including growth acceleration. Departure from this consonance is a sign of abnormality. The method by which constitutional delay of growth and puberty can be distinguished from gonadotrophin deficiency has been discussed as well as the treatment options for both conditions. We have emphasized the significance of pulsatile gonadotrophin secretion and how the development of a multicystic ovarian morphology on ultrasound can be used as a non-invasive assessment of gonadotrophin pulsatility in girls. Pulsatile GnRH therapy mimics normal puberty. The converse of suppressing the clinical signs of central precocious puberty can be achieved by abolishing gonadotrophin pulsatility with GnRH analogue therapy. We now recognize qualitative pulse abnormalities of gonadotrophin secretion which occur in isolated premature thelarche and in some cases of delayed puberty. Although clinical assessment remains the key to the diagnosis of disorders of puberty, studies of gonadotrophin pulsatility have aided our understanding and treatment of these conditions.     

中国城市儿童性早熟现状的调查研究

目的对国内城市儿童性早熟现状进行调查,为制定有效的预防策略,并推动儿童性早熟的临床规范化和个性化治疗提供理论依据。方法 2014年3月至12月在全国范围内开展"中国城市儿童性早熟现状调研"活动。调研共收集来自全国10余省市的2 687份问卷,其中1 714份问卷纳入统计分析。结果调查人群大多分布在全国10个主要省市,包括北京、上海、重庆、江苏、湖北等;调查患儿以女童为主,其男女比例约1∶16。诊断为中枢性性早熟的患者占75.79%(1 299/1 714);调查中初次诊断为中枢性性早熟患者占88.91%(1 524/1 714)。调查患者的骨龄为(10.00±1.77)岁,高于实际年龄(8.29±1.60)岁,差异有统计学意义(P0.001);初次诊断为CPP的患者的骨龄为(10.11±1.70)岁,高于实际年龄(8.35±1.57)岁,差异均有统计学意义(P0.001)。结论国内城市儿童性早熟就诊患者的年龄偏大,为防止患者就诊时已错过最佳的干预和治疗时机,应引起对疾病筛查的高度重视,做到早发现、早诊断和早治疗。     

Pubertas praecox und Pubertas tarda bei Mädchen

Puberty can be considered as a phase in the continuum of the development of gonadal function and the ontogeny of the hypothalamus-pituitary-gonadal system to attainment of full sexual maturation and fertility. Although the sequence of changes is reasonably constant, the start of puberty and duration of its course are very variable. A useful definition of precocious puberty in girls is the presence of signs of sexual maturation, and delayed puberty is defined as a lack of physical manifestations of sexual maturation in girls at a chronologic age that is 2.5 standard deviations below or above the mean age at onset of puberty. The ages of 8 years and 13.5 years in girls serve as practical guidelines to determine the need for evaluation. Diagnostics and therapy for precocious and delayed puberty are summarized in this article.     

Hypothalamic hamartoma and precocious puberty: report of a case.

Hypothalamic hamartoma is reported to be associated with precocious puberty. Here, the authors present a seven-year-old girl whose onset of puberty occurred at the age of two. Under the impression of idiopathic precocious puberty, cyproterone acetate was initially tried. Since the effect of her medication was not satisfactory, it was discontinued at the age of five years and 11 months. However, rapid advance of bone age and vaginal spotting recurred after the withdrawal of treatment. She was re-evaluated at the age of six, and a magnetic resonance image (MRI) study of the head revealed a hypothalamic hamartoma. At that time, a long-acting analog of luteinizing hormone-releasing hormone (LHRHa), leuprolide acetate, was prescribed. Her secondary sex characteristics regressed and her hypothalamic-pituitary-gonad axis was suppressed after treatment. The clinical presentation, mechanism and treatment of precocious puberty caused by hypothalamic hamartomas are fully discussed in this report.     

Diagnosis and management of precocious puberty in atypical presentations of McCune-Albright syndrome: a case series review

BackgroundMcCune-Albright syndrome is a rare syndrome, classically defined as the triad of precocious puberty, fibrous dysplasia of bone, and café au lait lesions. Partial or atypical presentations of McCune-Albright syndrome, with only one or two of the classic symptoms, have been described in the literature and remain particularly challenging due to lack of diagnostic phenotype. In these patients, the utility of analysis of mutations in the gene of the α subunit of the stimulatory G-protein is limited and so the diagnosis is often based on clinical judgment. Three atypical cases of suspected McCune-Albright syndrome with gonadotropin-independent precocious puberty are presented.CasesCase #1: A 5-year-old female presented with painlesss vaginal bleeding and was found to have café au lait lesions. She was diagnosed with gonadotropin independent precocious puberty with eventual progression to gonadotropin dependent precocious puberty which was successfully treated with both letrozole and gonadotropin-releasing hormone agonist therapy. Case #2: A 3-year-old female presented with painless vaginal bleeding and was found to have café au lait lesions. She was diagnosed with gonadotropin independent precocious puberty and was successfully treated with letrozole. Case #3: A 5-year-old female presented with fibrous dysplasia and was found to have evidence of uterine and ovarian enlargement on ultrasound. She was diagnosed with gonadotropin-independent precocious puberty and was successfully treated with letrozole.Summary and ConclusionAlthough different in presentation, all three atypical cases of suspected McCune-Albright syndrome with gonadotropin-independent precocious puberty were successfully treated with aromatase inhibitors. This small case series shows the utility and efficacy of aromatase inhibitors in the setting of atypical cases of suspected MAS with gonadotropin-independent precocious puberty.     

Endokrinologie der weiblichen Adoleszenz

Puberty is a central turning point in every young person’s life. It signals the transition from childhood to sexually mature and fertile adulthood and encompasses profound physical, emotional and social changes. At the beginning of this yearlong process lies the activation of two pivotal hormonal axes (gonadarche, adrenarche) which entails the characteristic physical changes (thelarche, menarche, pubarche). Preceded by short peaks of activity during fetal development and immediately after birth, it is the third period of active pulsatile GnRH release in humans and occurs after years of hormonal inactivity during infancy. Mature GnRH release from the hypothalamus results in activation of downstream endocrine organs such as the pituitary gland and the ovary. Regulation of this process occurs at various levels and includes neuronal, genetic and metabolic factors which still have not been fully understood. However, it is known that the hormonal processes underlying puberty are very vulnerable and can easily be disturbed at any stage of development leading to precocious activation or prolonged inhibition and thus to abnormal pubertal maturation, a severe condition which requires effective and specific treatment in order to avoid long-term damage.     

Nonclassic adrenal hyperplasia

Among 297 women with nonclassic adrenal hyperplasia (NCAH), premature pubarche was the most common complaint in girls (87%), and the frequency of hirsutism increased progressively with age from adolescence (50%) to adulthood (70%). The frequency of spontaneous miscarriages was high in NCAH patients (20%), but it decreased significantly after treatment.     

Do Most 7- to 8-Year-Old Girls with Early Puberty Require Extensive Investigation and Treatment?

Study ObjectiveTo investigate the etiology, progression, and treatment of precocious puberty in 7- to 8-year-old girls with breast development. Additionally, we evaluated the value of diagnostic tests in differentiating rapidly progressive precocious puberty (RP-PP) and slowly progressive precocious puberty (SP-PP) in these girls.DesignAmbispective cohort study.SettingSingle-center, pediatric endocrinology unit.ParticipantsGirls with breast development between the ages of 7 and 8 years and assessed between July 2016 and July 2018.InterventionsCollected of clinical data and followed-up for 2 to 3 years. Girls were divided into RP-PP and SP-PP groups.Main Outcome MeasuresDescribed the etiology, rate of progression of puberty, and proportion intervened and compared the results of auxiliary examinations between the groups.ResultsA total of 212 girls were enrolled, of which 211 (99.53%) were diagnosed with central precocious puberty (CPP) and 1 with peripheral precocious puberty (PPP). Hypophysis magnetic resonance imaging revealed that none had pathological brain lesions requiring surgical intervention. A total of 95 girls (44.81%) developed RP-PP, and 117 girls (55.19%) developed SP-PP. A total of 31 girls (14.62%) with RP-PP received treatment due to deteriorated predicting adult height. As compared with the SP-PP group, the RP-PP group showed more advanced bone age (BA), a higher level of basal luteinizing hormone (LH), and larger ovarian volume and uterine volumes. Receiver operating characteristic analyses revealed that BA was the best at identifying girls with RP-PP.ConclusionThe majority of girls with breast development between the ages of 7-8 years do not need treatment. BA is a useful preliminary test for identifying girls with RP-PP who are more likely to require treatment.     

Nocturnal melatonin levels are unaltered by ovarian suppression in girls with central precocious puberty

Girls with central precocious puberty were utilized as a model in which to study the melatonin secretory response to ovarian suppression. Eight girls with central precocious puberty documented by clinical and endocrine characteristics, including sleep-entrained augmentation of luteinizing hormone (LH) pulsatility, were investigated. Nocturnal (6:00 P.M. to 9:00 A.M.) plasma melatonin levels were measured hourly by a sensitive and specific radioimmunoassay before and after gonadotropin-ovarian downregulation with gonadotropin-releasing hormone (GnRH)-agonist. Although nocturnal melatonin elevations varied widely between girls, patterns within the same individual were remarkably reproducible and unaltered before and after treatment. Although estrogens have been shown to modulate melatonin synthesis and secretion, in this model, reduction of estrogen levels was not associated with alterations in plasma melatonin concentrations.