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.     

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: 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.     

Diagnostik und Therapie des klassischen adrenogenitalen Syndroms

Congenital adrenal hyperplasia (CAH) encompasses a group of hereditary diseases. The severity of the causative mutation determines the clinical picture. The most common form is 21-hydroxylase deficiency which can be detected within the first days of life due to the established newborn screening in Germany and can be treated early. Untreated CAH accounts for virilization of girls, a precocious puberty in girls and boys with accelerated bone age followed by a short stature. Additional life-threatening salt-wasting crises occur in cases of classical salt-wasting CAH. The treatment of the classical CAH includes a lifelong drug therapy, which involves treatment with corticosteroids and also mineral corticoids in the presence of salt-wasting. Treatment is controlled by clinical and laboratory parameters whereby treatment as well as over-treatment must be avoided by individualized therapy. Both women and men with classical CAH show impaired fertility. In addition to a hormonal therapy which must be optimized, undesirable effects of excess androgen are causative for impaired fertility in women and men.     

The long term outcome of feminizing genital surgery for congenital adrenal hyperplasia: anatomical, functional and cosmetic outcomes, psychosexual development, and satisfaction in adult female patients

BACKGROUND: There are only a few reports analyzing the long term outcome of feminizing surgery in females with congenital adrenal hyperplasia (CAH). Such analysis is crucial to evaluate the treatment and to make necessary adjustments. STUDY OBJECTIVES: To evaluate the adult outcome after feminizing surgery in adult females with salt wasting CAH. DESIGN: Retrospective observational followup investigation. SETTING: Outpatient clinic of a University Medical Center, in 2002. PARTICIPANTS: Eight patients (born 1973-1983) who underwent feminizing surgery in infancy by the same procedure and the same pediatric surgeon in our center, and 19 healthy female controls (for visual analog scales). METHODS: (a) Study of patients' records (n=8); (b) Systematic evaluation of the current situation (n=6): uroflowmetry, a written questionnaire to screen for psychopathology (Youth Adult Self Report, YASR), structured gynecologic examination and a structured psychosexual interview, including scoring on visual analog scales. RESULTS:(a) The first surgery (age 0.1-3.7 yr) consisted of clitoris reduction and vaginoplasty (single-stage) in 7 patients and clitoris reduction only in one patient. The latter patient had vaginoplasty in puberty. In puberty, 6 of the 7 patients with an initial single-stage procedure required re-vaginoplasty. All 6 patients who participated in this systematic evaluation had undergone (re-) vaginoplasty in puberty; (b) 2 of the 6 patients experienced some urinary incontinence, and in one of them, the uroflowmetry result was abnormal. The YASR showed no psychopathology, except for 1 patient with a slightly elevated externalizing score. Gynecologic examination (n=5) revealed vaginal strictures in 3 patients (1 severe, 2 mild). The 2 patients without vaginal strictures had coitus regularly. In the interview, 2 patients called themselves bisexual, the other 4 heterosexual. None of the patients had homosexual contacts. Sexual developmental milestones (romantic interest, falling in love, kissing and petting, coitus) had been reached by all, except for 1 patient who did not have coitus yet. In the patient group, satisfaction with height, body hair, and external genitalia and sexual fantasies and interest, measured with visual analog scales, was not different compared to the control group, except for satisfaction with total body appearance, which was significantly lower in the patients. CONCLUSION: Despite the poor outcome of the initial single-stage surgery in infancy and the inevitable re-operation in puberty, the adult outcome in our study population seems more positive than the findings in the few previous reports, especially with respect to sexual development and activity.     

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.     

Delay of diagnosis of growth hormone deficiency in Taiwan.

In view of the importance of early detection of growth hormone deficiency, the height and age at the first pediatric endocrinologic clinic visit of 45 patients with growth hormone (GH) deficiency between January 1988 to December 1989 were retrospectively analyzed. Twenty-three patients with idiopathic GH deficiency had a median age of 13 years (range, from 3.8 to 29.9 years) at their first visit and a median height standard deviation score (SDS) of -3.87 (-2.14 to -7.93). Nineteen children with hypothalamopituitary tumors at their first visit, at a median of 2.17 years (0.42 to 7.83 years) after diagnosis of the tumor, had a median height SDS of -3.15 (-0.58 to -4.70). Three children with GH deficiency secondary to cranial irradiation at their first visit, at 8.17 years (1.33 to 10 years) after treatment for their malignancy, had a height SDS of -3.15 (-2.13 to -3.72). It is well known that the earlier the replacement therapy is begun in such patients, the better the prognosis is for final adult height. Regular height measurement and routine screening for shortness at school entry may overcome this delay in diagnosis. In addition, patients who have received cranial irradiation or had hypothalamopituitary tumors should be regularly measured and studied if their height velocities become subnormal. Physicians dealing with children should keep the possibility of growth hormone deficiency in mind when examining a short child.     

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。     

Anterior mediastinal immature teratoma with precocious puberty in a child with Klinefelter syndrome.

ABSTRACT: Klinefelter syndrome occurs in approximately 1 in 1000 males. A 4-year-old boy presented with precocious puberty and an anterior mediastinal mass. Serum alpha-fetoprotein and human chorionic gonadotropin levels were mildly increased. Computed tomography revealed a germ cell tumor (GCT) of the mediastinum. Complete resection of the tumor was performed. Histologic analysis revealed an immature teratoma. Males with Klinefelter syndrome develop GCTs at a rate 50 times higher than unaffected males. This case report calls attention to the need to rule out Klinefelter syndrome in boys who present with precocious puberty and a mediastinal GCT.     

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.     

Anthropometric and intellectual evaluation of individuals with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare, multifaceted genetic disorder resulting from the absence of normally active paternally expressed genes from the 15q11-q13 chromosome region. Due to a lack of anthropometric and intellectual data in Taiwan, we attempted these evaluations. Twenty patients (14 males/6 females) aged 7-23 years with molecularly confirmed PWS were enrolled with parental consent. Their mean height standard deviation score (SDS) was -1.26 +/- 1.89 (from -4.3 to +2.16); mean weight SDS was +1.77 +/- 2.00 (from -0.44 to +5.89); mean body mass index SDS was +3.84 +/- 10.54 (from -0.08 to +10.48); and mean body fat tissue SDS was 39.4 +/- 10.54% (14.7-57.8%) by an InBody 3.0 analyzer. All were hypogonadal. Nine of them had once been given growth hormone therapy, and were taller and slimmer than the rest. Their intelligence tests showed full intelligence quotient = 52.0 +/- 7.6; verbal intelligence quotient = 55.9 +/- 8.77; performance intelligence quotient = 53.2 +/- 9.0. Chronic health status revealed that diabetes was prevalent among the older population. Their IQ was in the range of those with moderate retardation.     

Final height in girls with slowly progressive untreated central precocious puberty

A group of six girls with slowly progressive idiopathic precocious puberty (IPP) and a good initial height prognosis was followed without treatment. At first observation the girls had a bone age advance over chronological age of no more than 18 months, a Δheight age (ΔHA):Δbone age (ΔBA) ratio higher than 0.9 and height prognosis was unimpaired after 6 months. During the first two years of follow-up the girls maintained an acceptable height potential. The ΔHA:ΔBA ratio remained constant at greater than 0.9. Predicted height showed a slight increase or decrease (± 4 cm). The girls were reevaluated after the age of14 years and followed-up until they reached their final height (FH). The mean FH(155.4±2.8 cm) was below the mean target height (159.3 ± 4.2 cm) by 3.9 cm (range -2.1 to -6.7 cm); this difference was not statistically significant. The FH was more than 5 cm below the target height in only one case; this girl had the most precocious onset of puberty, at 6 years of age. In three cases FH was between the 3rd and 10th centiles. These three girls had a target height below 158 cm (< 25th centile). Girls with slowly progressive IPP and a good initial height prognosis preserved height potential with an acceptable final height without therapy.     

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.     

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)     

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.     

Disorders of ovarian function in childhood and adolescence: evolving needs of the growing child. An endocrine perspective

Over the past 15 years there have been changes in the care of children and adolescents paralleling increased longevity of those with chronic illnesses and increased survival after childhood cancer and organ transplantation. A broad understanding of holistic management and long-term risks is required. Optimisation of pubertal progress and normalisation of bone and hormonal health by the end of puberty will reduce the impact of later adult bone loss in chronic disease conditions. Psychosocial issues related to both precocious and delayed puberty can have profound effects on family function.     

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.     

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。