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.     

The effects of gonadotropin releasing hormone analogue therapy on girls with gonadotropin-dependent precocious puberty.

BACKGROUND/PURPOSE: It has been reported that gonadotropin releasing hormone analogue (GnRHa) therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. The purpose of this study was to evaluate the effect of GnRHa on the adult height of girls with gonadotropin-dependent precocious puberty and the adverse effects of such therapy. METHODS: Between 1989 and 2006, 11 girls with gonadotropin-dependent precocious puberty who had been treated with GnRHa and reached their adult height were enrolled in the present study. Follow-up studies of bone age, pelvic sonography and GnRH test were done regularly during the period of treatment. All patients had bone mineral density examined at least 2 years after completion of GnRHa therapy. RESULTS: GnRHa therapy was initiated at the age of 8.0 +/- 1.5 years. The predicted adult height immediately before GnRHa therapy was 146.7 +/- 4.8 cm (-2.3 +/- 0.9 standard deviation [SD]). The duration of GnRHa therapy was 4.7 +/- 1.8 years. The adult height of the patients was 156.3 +/- 4.3 cm (-0.6 +/- 0.8 SD), which is similar to their target height of 157.0 +/- 4.5 cm (-0.5 +/- 0.8 SD). The uterine sizes and gonadotropin responses to GnRH stimulation were well suppressed during treatment. Menstruation resumed 9.2 +/- 5.9 months after the discontinuation of treatment in these patients. Forty-five percent of patients had lumbar bone mineral density less than 1 SD below that of normal young Taiwanese adults in the Taipei region. CONCLUSION: GnRHa therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. However, 45% of patients had decreased bone accretion during therapy.     

促性腺激素释放激素类似物（曲普瑞林）治疗女童特发性中枢性性早熟23例疗效观察

目的观察促性腺激素释放激素类似物（曲普瑞林）治疗女童特发性中枢性性早熟（ICPP）的临床疗效。方法应用曲普瑞林治疗23例ICPP女童6个月,观察治疗前后第二性征、子宫、卵巢、骨龄（BA）、血清雌二醇（E2）、促性腺激素释放激素（GnRH）激发试验激素水平、预测成人终身高的变化及药物副反应。结果治疗后患儿乳房、子宫、卵巢体积均有缩小,E2、促黄体生成激素（LH）、卵泡刺激素（FSH）峰值均显著降低,骨龄成熟延迟,骨龄/实际生活年龄（BA/CA）值下降,预测成人终身高治疗前为（155.5±0.81）cm,治疗后为（157.0±0.81）cm,较治疗前有改善,差异具有统计学意义（P〈0.01）。结论曲普瑞林治疗ICPP能够抑制性腺轴及性腺发育,延缓BA成熟,最终对改善成人终身高有意义。     

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.     

Comparison of the Clinical and Anthropometric Features of Treated and Untreated Girls with Borderline Early Puberty

Study ObjectiveRisks associated with precocious puberty might be observed in the rapidly progressive form of borderline early puberty (BEP). Differentiating the rate of progression is important for deciding treatment with gonadotropin-releasing hormone analogue (GnRHa). The aim was to examine the treatment characteristics and effect of treatment on predicted adult height (PAH).DesignRetrospective observational study.SettingSingle-center, a pediatric endocrinology unit.ParticipantsA total of 135 girls, pubertal findings starting between 7-10 years of age.InterventionsData were collected via chart review. Patient groups were defined as treated with GnRHa (n = 63) or untreated (n = 72) girls.Main Outcome MeasuresReferral characteristics and anthropometric and pubertal findings of the patients with BEP, effect of treatment on PAH, and final height of the groups were compared.ResultsThe mean (±SD) age of the patients at admission and for the first appearence of pubertal findings was 8.8 ± 1.0 and 8.0 ± 0.8 years, respectively. Target height and PAH-target height values at admission were similar. At initiation of treatment, PAH of the treated girls (157.8 ± 7.2 cm) were significantly lower compared with untreated girls (160.7 ± 6.5 cm). The age at menarche of patients in the treated and untreated groups were 12.3 ± 1.0 and 11.3 ± 1.1 years, respectively. The final height of the groups were similar (157.1 ± 6.6 vs 157.0 ± 5.9 cm; P = .922) despite a lower PAH of the treated group.ConclusionGnRHa treatment resulted in an increase in PAH and normalized the age of menarche in patients with BEP. In selected girls with rapidly progressive BEP, GnRHa treatment may be considered.     

Insight: prolonged vaginal bleeding during central precocious puberty therapy with a long-acting gonadotropin-releasing hormone agonist: a proposed mechanism and management plan

We have previously described our data collected after administration of gonadotropin releasing hormone-agonist (GnRH-a) to delay sexual maturation, in premenarchal girls suffering from idiopathic central precocious puberty.¹ We have explained the recurrent episodes of bleeding due to discontinuation of the estrogen support of the proliferative and stable endometrium. The recognition in recent years of the extra-pituitary functions of GnRH-a, the ability of GnRH to stimulate prostaglandin production and the known role of prostaglandins in irregular vaginal bleeding prompted us to seek alternative explanations to our data.We suggest considering a potential clinical use of combination therapies of GnRH agonists and prostanoid receptor antagonists to treat central precocious puberty.     

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。     

Precocious puberty: a comprehensive review of literature

CONTEXT: Precocious puberty currently affects 1 in 5,000 children and is 10 times more common in girls. Statistics indicate that girls in the United States are maturing at an earlier age than they did 30 years ago and the number of girls with diagnosed precocious puberty (the appearance of secondary sex characteristics before 8 years of age or the onset of menarche before age 9) is on the rise. A summary of the growing body of literature on this topic is necessary to inform nurses and other health care providers of the current trends and incidence of precocious puberty to better meet the physical and psychosocial needs of these girls and their families. METHODS: EBSCOhost Research Databases that included CINAHL Plus, Health Source: Nursing Edition, MEDLINE, PsycINFO, and Women's Studies International were searched for journal articles published in the past 10 years (1997-2006) that explicitly examined precocious puberty in females and proposed theories to describe the phenomenon. Search terms included precocious puberty, sexual maturation, menarche, and secondary sex characteristics. These terms were searched individually and in combination with proximate determinants such as endocrine disruptors, environmental toxins, phthalates, stress, skin care, genetics, age, ethnicity, obesity, and assisted reproduction. The search yielded 947 articles addressing this issue. RESULTS: Eighty-two studies or case reports met the criteria for inclusion in this literature review that captured six attributable causes of early sexual maturation in female children. These included genetic, ethnic, and pediatric obesity, as well as environmental toxins that disrupt endocrine function (chemicals, toxins, plasticizers, infant feeding methods, skin and hair products, assisted reproductive technologies), psychosocial stress, and early exposure to a sexualized society. The robustness of the reports varied and few of the studies were widely generalizable but did offer suggestions for assessment and nursing care. CONCLUSIONS: Precocious puberty has health and social implications that are complex and influenced by multiple factors. Further research is needed to expand and elucidate theoretical relationships between the early development of secondary sex characteristics in young girls and the proposed causative factors.     

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.     

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.     

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.     

32例性早熟临床分析

目的　分析女性真性性早熟 (ICPP)患者的临床特点、探讨该病的诊断、治疗方法。方法　对1984年以来的 32例ICPP患者进行回顾性分析。结果　绝大多数ICPP患儿在月经来潮前都有不同程度的乳房发育、阴道分泌物增加等早期征象 ;而且身高也大多超出同龄人。结论　应重视ICPP患儿的早期临床征象 ,对疑似者尽早行GnRH兴奋试验。促性腺激素释放激素的衍生物 (GnRH -A)治疗ICPP ,不仅疗效显著 ,而且可明显改善患者的身高。     

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.     

Adrenarche, pubertal development, age at menarche and final height of full-term, born small for gestational age (SGA) girls.

Children born small for gestational age (SGA) may present advanced bone maturation in childhood and reduced final height. The objectives of the study were to evaluate adrenarche, pubertal development, age at menarche and final height in full-term born-SGA girls. Twenty-four girls (12 born-SGA and 12 matched controls) were evaluated at 6-7.5 years of age for clinical signs of puberty and dehydroepiandrosterone sulfate (DHEAS) levels, as a marker of adrenarche. Thirty-eight girls (19 born-SGA and 19 matched controls) were evaluated at 17.5-18.5 years of age to assess final height, sexual maturation and age at menarche. SGA girls had a mean final height (160.1 cm vs 165.8 cm, p < 0.01) and mean weight (52.1 kg vs 56.5 kg, p < 0.05) significantly lower than controls. Controls had a mean final height significantly higher than their mean target height. Sexual maturation was at stage 5 of Tanner's staging in SGA girls and control subjects. SGA girls had a slightly anticipated puberty (9.9 vs 10.4 years for initial breast development) and a lower age at menarche (11.9 vs 12.3 years). At 6-7.5 years of age, SGA females and controls did not show any difference for clinical signs of puberty; however, DHEAS levels (0.75 + 0.18 microgram/ml vs 0.57 + 0.22 microgram/ml, p < 0.05) were significantly higher in SGA girls than in control subjects. We concluded that full-term born-SGA females have impaired final height and weight in adolescence but substantially normal sexual maturation and age at menarche. Increased DHEAS levels before puberty in born-SGA girls may predispose to increased bone maturation in childhood with a reduced final height. In our population a progressive increment in final stature is evident.     

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。     

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.     

Adrenarche,pubertal development,age at menarche and final height of full-term,born small for gestational age (SGA) girls

Children born small for gestational age (SGA) may present advanced bone maturation in childhood and reduced final height. The objectives of the study were to evaluate adrenarche ,pubertal development ,age at menarche and final height in full-term born-SGA girls. Twenty-four girls (12 born-SGA and 12 matched controls) were evaluated at 6-7.5 years of age for clinical signs of puberty and dehydroepiandrosterone sulfate (DHEAS) levels ,as a marker of adrenarche. Thirty-eight girls (19 born-SGA and 19 matched controls) were evaluated at 17.5-18.5 years of age to assess final height ,sexual maturation and age at menarche. SGA girls had a mean final height (160.1 cm vs 165.8 cm ,p < 0.01) and mean weight (52.1 kg vs 56.5 kg ,p < 0.05) significantly lower than controls. Controls had a mean final height significantly higher than their mean target height. Sexual maturation was at stage 5 of Tanner's staging in SGA girls and control subjects. SGA girls had a slightly anticipated puberty (9.9 vs 10.4 years for initial breast development) and a lower age at menarche (11.9 vs 12.3 years). At 6-7.5 years of age ,SGA females and controls did not show any difference for clinical signs of puberty; however, DHEAS levels (0.75 + 0.18μg/ml vs 0.57 + 0.22μg/ml ,p < 0.05) were significantly higher in SGA girls than in control subjects. We concluded that full-term born-SGA females have impaired final height and weight in adolescence but substantially normal sexual maturation and age at menarche. Increased DHEAS levels before puberty in born-SGA girls may predispose to increased bone maturation in childhood with a reduced final height. In our population a progressive increment in final stature is evident.     

Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs

Investigations have proved the clinical importance of hypothalmic gonadotropin-releasing hormone (GnRH) and its agonistic and antagonistic analogs. A pulsatile pattern of stimulation of specific receptors in the anterior pituitary gonadotrope has been shown to activate pituitary-gonadal function; continuous administration inhibits it. Clinical research has shown promising results in the induction of ovulation using the pulsatile pattern of GnRH administration in patients with hypogonadotropic amenorrhea. Attempts to use GnRH and its agonists to activate the pituitary-gonadal system in patients with idiopathic delayed puberty has proved logistically impractical because of the duration of treatment required to achieve sexual maturation. Treatment of cryptorchidism by intranasal administration 6 times daily for 4 weeks resulted in complete descent in 38% of the 48 boys and partial descent in 28%. For GnRH nonresponders, sequential treatment with human chorionic gonadotropin produced an 86.2% success rate. Because of the ability of GnRH agonists to reversibly suppress the pituitary-gonadal axis without side effects, it can be used in diseases mediated by gonadal steroids. Successful halting of precocious puberty through the administration of GnRH to suppress the nocturnal release of gonadotropin has been demonstrated. Unlike treatment with progestational agents, no side effects are discerned. Continuous administration of GnRH agonist in patients with endometriosis reduces ovarian estrogens and androgens to castration levels, mimicking an ovariectomy. This castration effect highlights the potential use of GnRH agonists in the treatment of metastatic breast cancer. The use of GnRH agonists for the treatment of androgen-dependent prostatic carcinoma has induced clinical improvement with nonmetastatic stage 3 disease and pain relief in metastic stage D disease. In polycystic ovary syndrome, administration of GnRH agonist shows promising results. As a potential contraceptive, GnRH agonists have not yet demonstrated practical advantages. The actions under study include: ovulation inhibition, luteolysis induction, induction of luteal phase defect and reduction of testosterone production. Numerous antagonistic analogs of GnRH have been synthesized and have shown some potential contraceptive effects in animal studies.     

Pediatric and adolescent gynecologic endocrinology.

Best described as a transformation from the infantile state to an accentuated dimorphic adult state, puberty is a sequence of events characterized by the secretion of gonadal hormones leading to the development of secondary sexual characteristics, gametogenesis, and reproductive function. In girls, the first signs of puberty may be evident at age 8, with the process largely completed by age 16; in boys, puberty commonly begins between ages 10 and 12 and is largely completed by age 18. Adrenarche, the secretion of adrenal androgens, starts between ages 6 and 8 and is clinically accompanied by pubarche. Premature pubarche should be diagnosed as either typical or atypical. In atypical premature pubarche, corticotropin testing is recommended to determine nonclassical adrenal enzyme deficiency of steroidogenesis. Children with either type of premature pubarche should be under continued follow-up throughout puberty. The trigger of the onset of puberty is still unknown. The presence of gonadotropin activity and possible circadian rhythm in the prepubertal years allows for new understanding in possible triggering mechanisms of puberty. Precocious puberty, which is associated with significant psychologic implications and possible pathology, must be categorized as complete precocious puberty with activation of the hypothalamic-pituitary axis or incomplete precocious puberty without activation of the central axis as effective therapies are so different. The categorization does not yield diagnoses, as there are multiple etiologies within each category. The treatment of central precocious puberty with gonadotropin-releasing hormone agonists will postpone pubertal progression to a more appropriate age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Precocious puberty

Precocious puberty is an early sexual maturation before the age of 8 in case of girls and 9 in boys. There are two types: isosexual precocious puberty--characteristic are appropriate for the child's genetic and gonadal sex; and heterosexual precocious puberty--sexual characteristic are inappropriate for the genetic sex (feminizing syndrome in boys or virilizing syndrome in girls). Precocious puberty is an important problem in childhood gynecology pediatrics, endocrinology and psychology.