Onset of puberty at eight years of age in girls determines a specific tempo of puberty but does not affect adult height

AIMS: To analyse the effect of early puberty (onset between 7.5 and 8.5 y) on pubertal growth and adult height in girls, and the implications of this effect for the age limit for normal onset of puberty. METHODS: Longitudinal study in Reus (Spain) of 32 girls with early puberty until they reached adult height. Data from these girls were compared with longitudinal data from girls (116) from the same population with normal onset at 10 (n = 37), 11 (n = 47), 12 (n = 19) and 13 (n = 13)y. We analysed height, target height, adult height, pubertal height increase, duration of pubertal growth, age at menarche and time to menarche. RESULTS: The adult height of girls with early puberty (160.9 +/- 5.4cm) was similar to that of girls with onset at later ages (p = not significant). In these girls, puberty lasted 5.4 +/- 0.7 y and the mean growth during puberty was 31.1 +/- 3.5 cm. As the age of onset of puberty increases, the duration of puberty and mean growth during puberty progressively decreased (p < 0.001). Girls with early puberty reached menarche at a mean age of 10.9 +/- 1.0 y, 3.2 +/- 0.9 y after onset of puberty, and this time span was greater than in the other groups. CONCLUSION: Girls with onset of puberty at 8 y show all the compensatory phenomena related to height at onset, pubertal duration and height increase during puberty. These phenomena cause their adult height to be similar to that of girls who begin puberty at the age of 10 to 13 y.     

Sexual precocity: sex incidence and aetiology

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.     

Sexual precocity: sex incidence and aetiology.

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.     

Growth hormone secretory dynamics in children with precocious puberty

We investigated whether an increase in growth hormone secretion contributed to the growth spurt in children with precocious puberty by measuring the 24-hour profile of serum growth hormone in 51 patients with central precocious puberty. Girls with central precocious puberty had significantly greater mean 24-hour levels of growth hormone in comparison with normal prepubertal girls (5.1 +/- 0.5 SEM vs 3.4 +/- 0.3 ng/mL, P less than 0.005). Mean 24-hour growth hormone levels did not differ significantly between boys with central precocious puberty and normal prepubertal boys (4.4 +/- 1.2 vs 3.0 +/- 0.4 ng/mL). Serum somatomedin C levels were significantly correlated with mean 24-hour growth hormone levels in the girls only. Height age advancement (expressed as height age/chronologic age) was significantly correlated with mean 24-hour growth hormone levels in both boys and girls with central precocious puberty. We conclude that spontaneous 24-hour growth hormone secretion in girls with precocious puberty is greater than that of normal prepubertal girls and may mediate at least in part the increased growth rate in this disorder.     

Pharmacodynamics of Aqueous Leuprolide Acetate Stimulation Testing in Girls: Correlation between Clinical Diagnosis and Time of Peak Luteinizing Hormone Level

We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.     

Ovarian function in girls with McCune-Albright syndrome

We measured plasma estradiol levels and ovarian volumes in eight girls with precocious puberty due to McCune-Albright syndrome. Six girls had gonadotropin-independent ovarian estrogen secretion and two girls had pubertal gonadotropin levels. Mean ovarian volume in all patients was significantly greater than in normal prepubertal girls. Mean ovarian volumes of the girls with McCune-Albright syndrome overlapped the range found in girls with idiopathic central precocious puberty or central precocious puberty associated with central nervous system lesions. However, the degree of asymmetry between the right and left ovaries was significantly greater in girls with McCune-Albright syndrome. Asymmetry was due, for the most part, to the presence of large solitary cysts in the larger of the two ovaries. In the six girls with McCune-Albright syndrome and gonadotropin-independent precocious puberty, both mean ovarian volume and the degree of asymmetry between the right and left ovaries were significantly correlated with plasma estradiol. Serum follicle-stimulating hormone bioactivity was increased in two patients but did not vary with ovarian cyst size. Thyroid-stimulating hormone levels were normal but serum prolactin was slightly elevated in one of the six girls with gonadotropin-independent precocious puberty. Fluctuation in the size of unilateral ovarian cysts appears to result in changes in the plasma estradiol level, leading to advancement and spontaneous regression of secondary sexual characteristics and menses in girls with McCune-Albright syndrome. The cause of the cyst formation is unknown but may be related to periodic elevation of as yet undefined serum factors such as follicle-stimulating hormone bioactive substances.     

Constitutional delay of growth and puberty: from presentation to final height

This retrospective study evaluated clinical characteristics of patients with constitutional delay of growth and puberty (CDGP) at presentation, during puberty and at final height. The records of 151 children (105 boys, 46 girls) with CDGP were reviewed and the results were evaluated with respect to findings in healthy Turkish schoolchildren. CDGP was twice as frequent in boys as in girls. Height and weight deficit and short sitting height of the children were evident at presentation and continued up to final height. Mean age of onset of puberty was retarded by 2.5 years in girls and by 3 years in boys. The time between onset of puberty and pubertal growth spurt was shorter in both girls and boys than in the controls. Peak growth velocity was compromised in both girls and boys. Forty-one patients (30 boys, 11 girls) reached final height (FH). Mean FH was shorter than both target height and predicted adult height. The Bayley-Pinneau method was found to be a better predictor of FH than either the Tanner-Whitehouse method or target height. FH also showed correlation with the father's height. There was no effect of testosterone treatment on final height. Height deficit at onset of puberty, shorter duration between onset of puberty and pubertal growth spurt, compromised peak growth velocity and short upper segment due to delayed puberty, are findings which may explain the decreased final height of children with CDGP.     

Estradiol levels and secretory dynamics in normal girls and boys as determined by an ultrasensitive bioassay: a 10 year experience

We utilized an ultrasensitive recombinant cell bioassay to measure serum estradiol in 800 normal children from birth through puberty. 105 children had repeat samples every 4 months as they approached puberty. We measured estradiol levels every hour for 24 hours in 55 children. Estradiol increased with age and pubertal stage in girls and boys, and was higher in girls than boys at each stage. Prepubertal girls have estradiol levels of 1.6 +/- 2.6 pg/ml. Prepubertal boys have estradiol levels of 0.4 + 1.1 pg/ml. Estradiol had a diurnal variation in girls and boys, with the trough occurring 08.00-20.00 h in girls, and 12.00-20.00 h in boys. We confirm that estradiol levels are higher in girls than boys even before physical signs of puberty, and that estradiol increases throughout puberty in girls and boys. This 10-year experience in 800 children shows the range and variability of estradiol by an ultrasensitive bioassay.     

Evaluation of gonadotropin responses to synthetic gonadotropin-releasing hormone in girls with idiopathic hypopituitarism.

We hypothesized that prepubertal girls with gonadotropin deficiency would produce less follicle-stimulating hormone (FSH) in response to synthetic gonadotropin-releasing hormone (GnRH) than would gonadotropin-sufficient children. To test this hypothesis, we performed 103 GnRH tests serially in 21 children who had idiopathic hypopituitarism with growth hormone deficiency. We tried to predict whether puberty would occur in the 17 girls with bone ages of 8 years or less. Of these 17 girls, 4 failed to have spontaneous secondary sexual characteristics by age 16 1/2 years, and 12 had spontaneous complete pubertal development. One girl had incomplete pubertal maturation with partial gonadotropin deficiency; her results were combined with those of the girls who had no spontaneous pubertal development. With increasing bone age, the girls with complete pubertal development had a decrease in the increment of FSH released in response to GnRH, although basal gonadotropin concentrations did not change. For GnRH tests performed at bone ages of 8 years or less, basal luteinizing hormone (LH) values did not differ between girls with complete puberty and those with absent or incomplete puberty. However, basal FSH and the incremental response of LH and FSH to GnRH were greater in those with complete puberty. Only two girls with prepubertal bone ages at the time of testing, who subsequently had complete puberty, had incremental FSH responses to GnRH that were less than 5 IU/L. Individual incremental LH responses to GnRH did not discriminate well between groups. None of the girls with adrenocorticotropic hormone deficiency, either originally or subsequently, had spontaneous puberty, but 4 of 12 girls with thyrotropin deficiency, either originally or subsequently, had complete puberty. We conclude that a significant increase in GnRH-stimulated FSH suggests that spontaneous pubertal development will occur in girls with idiopathic hypopituitarism. However, a low FSH response to GnRH may not be diagnostic of gonadotropin deficiency.     

Increased perinatal intracranial pressure and prediction of early puberty in girls with myelomeningocele

An increased risk of developing precocious puberty has been reported in children with myelomeningocele. In order to evaluate this further and to study factors associated with early or precocious puberty the medical records of all girls with myelomeningocele, born from 1970 onwards (n = 64), who were admitted to our unit were reviewed. Early/precocious puberty (E/PP) was defined as breast development or pubic hair corresponding to Tanner stage 2 before the age of 9.2 years. In 32 out of 62 cases data were sufficient for evaluation of the timing of puberty. Twenty girls had E/PP and 12 girls normal timing of puberty. In the girls who had reached the age of 9.2 years the incidence of E/PP was at least 52%. Girls with E/PP had a higher incidence of hydrocephalus, were treated with intraventricular shunts more often, and had significantly higher frequency of increased intracranial pressure during the perinatal period (p < 0.05, p < 0.01, and p < 0.001, respectively). The group of girls developing E/PP was also more severely disabled with respect to motor and urological function and had more shunt revisions. In conclusion, E/PP in girls with myelomeningocele is strongly associated with increased intracranial pressure particularly during the perinatal period.     

Breast contact thermography for differentiation between premature thelarche and true precocious puberty

Breast contact thermography was used to differentiate between premature thelarche and true precocious puberty. The technique was applied to 10 girls with premature thelarche, 12 with precocious puberty and 105 controls (Tanner B1-5). In controls, the scores attributed to the maturative thermographic signs correlated with breast development stages. In premature thelarche thermographic signs of vascularization were always absent, while in precocious puberty they were always observed, although in some cases unilaterally. The thermographic index (higher total score between the two breasts) ranged from 0 to 3 in girls with premature thelarche and from 4 to 10 in girls with precocious puberty. The thermographic pattern in premature thelarche was similar to that in prepubertal girls and did not progress in two girls who were repeatedly examined. We emphasize the useful role of contact thermography in evaluating pubertal breast development and in differentiating between premature thelarche and true precocious puberty.Abbreviations BCT breast contact thermography - TI thermographic index - B breast development stage - F fundus - N nipple - A areolar zone - V vascular growth pattern     

Cerebral irradiation causes blunted pubertal growth in girls treated for acute leukemia

The improved treatment of childhood leukemia is a major achievement. The late effects of the treatment need further investigation. Growth inhibition has been demonstrated in earlier studies. Growth and the timing of puberty were studied in 179 girls who had been treated for acute lymphoblastic leukemia (ALL) in Denmark, Finland, Norway, and Sweden. The patients were divided into two groups according to mode of CNS prophylaxis: with or without cerebral irradiation. Longitudinal analysis of 103 patients showed no difference in prepubertal growth in irradiated and nonirradiated girls. Growth during puberty was normal in girls without irradiation and below normal in irradiated girls. There was no difference in growth between girls after 24 Gy or 20 Gy of cerebral irradiation. Irradiated girls had a final height which was one SD less than expected before puberty and menarche occurred one year earlier than in the nonirradiated girls. Prophylactic cerebral irradiation is the most important factor for subnormal growth after treatment for ALL. There is no short-term influence on growth but the effects of irradiation become apparent several years after therapy when girls enter puberty somewhat early and have a subnormal pubertal growth. Growth and growth hormone (GH) levels should be evaluated several years after CNS irradiation, and treatment with GH and/or luteinizing hormone releasing hormone (LHRH) analogues may be considered. © 1994 Wiley-Liss, Inc.     

Increased perinatal intracranial pressure and prediction of early puberty in girls with myelomeningocele.

An increased risk of developing precocious puberty has been reported in children with myelomeningocele. In order to evaluate this further and to study factors associated with early or precocious puberty the medical records of all girls with myelomeningocele, born from 1970 onwards (n = 64), who were admitted to our unit were reviewed. Early/precocious puberty (E/PP) was defined as breast development or pubic hair corresponding to Tanner stage 2 before the age of 9.2 years. In 32 out of 62 cases data were sufficient for evaluation of the timing of puberty. Twenty girls had E/PP and 12 girls normal timing of puberty. In the girls who had reached the age of 9.2 years the incidence of E/PP was at least 52%. Girls with E/PP had a higher incidence of hydrocephalus, were treated with intraventricular shunts more often, and had significantly higher frequency of increased intracranial pressure during the perinatal period (p < 0.05, p < 0.01, and p < 0.001, respectively). The group of girls developing E/PP was also more severely disabled with respect to motor and urological function and had more shunt revisions. In conclusion, E/PP in girls with myelomeningocele is strongly associated with increased intracranial pressure particularly during the perinatal period.     

The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy

Between 1979 and 1983, 129 children (95 girls) with precocious puberty were referred to the National Institutes of Health and received treatment for at least 6 months with the long-acting LHRH analogue D-Trp6-Pro9-NEt-LHRH. The majority (107 of 129) of the children had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis in association with hypothalamic hamartomas (24 of 107) or other central nervous system lesions (21 of 107), or idiopathic precocious puberty (62 of 107). Hypothalamic hamartomas or other central nervous system lesions were a frequent cause of central precocious puberty in girls (27 of 87), but idiopathic precocious puberty was still the most frequent diagnosis (63%). Idiopathic precocious puberty was uncommon in boys (6%). The patients with peripheral precocious puberty included six girls with McCune-Albright syndrome and six boys with familial male precocious puberty. These children had peripheral sex steroid secretion in the absence of hypothalamic-pituitary-gonadal axis maturation. The children with combined peripheral and central precocious puberty included nine children with congenital adrenal hyperplasia and one girl with a virilizing adrenal tumor. In the patients with central precocious puberty or combined peripheral and central precocious puberty, LHRHa therapy caused suppression of gonadotropin and sex steroid levels (P less than 0.001), stabilization or regression of secondary sexual characteristics, and decreases in growth rate and in the rate of bone age maturation (P less than 0.005). Patients with peripheral precocious puberty, however, had no significant change in gonadotropin or sex steroid levels, growth rate, or the rate of bone age maturation, and no improvement in secondary sexual characteristics. Thus, LHRHa is an effective treatment of central precocious puberty and combined peripheral and central precocious puberty, but is ineffective in the therapy of peripheral precocious puberty.     

Intellectual function of girls with precocious puberty

The IQ of 52 girls with precocious puberty (mean age 9.5 +/- 2.8 years) was compared with that of 51 normal matched control subjects (mean age 9.7 +/- 2.8 years) and with that of eight girls with fast puberty (onset at normal age but accelerated advancement). Girls with precocious puberty had a significantly higher verbal IQ score than the control subjects but no difference was found in the performance score. The distribution of the verbal IQ score in the girls with precocious puberty was skewed toward the upper side of the theoretical distribution curve. The distribution was two or more times the expected theoretical percentile in the above average area (greater than 110, 56.9% v 25%), and five times more in the very superior area (greater than 130, 10.1% v 2.2%). The girls with fast puberty had the same behavior as the population with normal development. The results are interpreted as possible evidence of an effect of sex hormones on brain development, especially on the left hemisphere, during the prepubertal period.     

Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia.

Early puberty in 28 children (23 girls, five boys) treated for acute lymphoblastic leukaemia (ALL) at a mean age of 4.0 years (range 1.4-7.8) is described. All but one had received prophylactic cranial irradiation (1800-2400 cGy) and three children had received additional cranial or craniospinal irradiation as treatment for relapse of their leukaemia. Mean age for the onset of puberty was 8.8 (SD 0.8) years in the girls and 9.3 (0.8) years in the boys; this is greater than two standard deviations from the mean for normal girls and boys. Five children (three girls, two boys) had precocious puberty. The onset of puberty occurred at greater than two standard deviations from the mean for normal girls and boys in 14(13%) girls and 4(3%) boys treated at less than eight years of age between 1970 and 1985. In a group of 55 girls treated for ALL who had survived in first remission for six years or more from diagnosis, there was a relation between young age at onset of treatment and early menarche. We suggest that premature activation of the hypothalamic-pituitary-gonadal axis occurs as a consequence of hypothalamic dysfunction due to cranial irradiation. Precocious and premature puberty in children treated for ALL may be an important factor in contributing to short stature.     

Delayed puberty

Delayed puberty is common, occurring in 3% of the population. It is seen much more frequently in boys than girls and in the majority of cases is due to constitutional delay in growth and puberty. These individuals do not need significant numbers of investigations and treatment is usually unnecessary. Regular monitoring is indicated to ensure puberty does progress in due course, with reassurance for the child and family that this is a common occurrence. A short course of low dose testosterone or oestrogen may be beneficial in inducing puberty if this is significantly delayed as this can be psychologically difficult. Puberty will usually then proceed spontaneously to completion.All girls with pubertal delay require karyotyping to exclude Turner syndrome. More detailed investigation would be indicated in individuals with any additional features such as: a history of pituitary hormone deficiencies, previous radiotherapy or chemotherapy, evidence of chronic disease, midline or dysmorphic features, learning difficulties, tall stature, gynaecomastia or anosmia, neonatal history of bilateral crypto-orchidism or small penis.For those patients requiring treatment, this involves commencement of low dose testosterone in boys or oestrogen in girls, with slowly increasing doses as puberty progresses.     

Growth in precocious puberty

Growth in precocious puberty is a subject of concern to families and clinicians alike. The definition of precocious puberty and the role of obesity in the age of onset have also been areas of debate since the Lawson Wilkins Society recommended a lowering of the age of onset of precocious puberty in US girls. An understanding of growth patterns in normal children with earlier or later onset of puberty and the variable rate of progression between individuals with central precocious puberty as well as the imprecision in available height prediction methods are important in assessing height outcomes in this condition. In the absence of randomised controlled trials in this area, only qualified conclusions about the effectiveness of interventions can be drawn. In general, it appears that height outcome is not compromised in untreated slowly progressive variants of central precocious puberty. In rapidly progressing central precocious puberty in girls, gonadotrophin releasing hormone agonists (GnRH agonists) appear to increase final height by about 5cm in girls treated before the age of eight, but there is no height benefit in those treated after eight years. Scanly data is available to assess treatment effects in boys. GnRH agonists appear to be relatively safe. The decision to treat central precocious puberty should take into account rate of progression of pubertal changes as well as biochemical markers and may need to address other factors (for example psychosocial and behavioural issues) as well as height outcome.     

Hypothyroidism-associated testicular enlargement: is it a form of precocious puberty or not? A case report

In children with untreated hypothyroidism, the onset of puberty is usually delayed, but gonadotropin-independent precocious puberty may occur in children with severe hypothyroidism of long duration. The association of hypothyroidism, delayed bone age and gonadotropin-independent precocious puberty is defined as Van Wyk Grumbach syndrome (VWGS). VWGS has been described mostly in girls, and only seldom in boys. The manifestation of VWGS in boys is only testicular enlargement without substantial Leydig cell stimulation or testosterone secretion. We report a case of testicular enlargement due to obvious hypothyroidism secondary to autoimmune thyroiditis in a boy who presented with obesity. With this case report, we would like to emphasize that VWGS is not a real gonadotropin- independent precocious puberty in boys as it is in girls. Additionally, we would like to emphasize that delayed bone age is a special discriminating feature for differentiation of VWGS from the other causes of precocious puberty.     

长效促性腺激素释放激素类似物和甲孕酮治疗对真性性早熟女孩预测身高影响的比较

目的观察促性腺激素释放激素类似物（ＧｎＲＨａ）和甲孕酮用于治疗真性性早熟女孩,对其抑制性发育,减慢骨成熟和生长速度,改善成人期预测身高的作用。方法分别使用两种药物治疗两组特发性真性性早熟女孩各９例,时间６～１２个月,观察治疗前后的身高、性发育情况、骨龄、成人期预测身高等,并进行综合比较。结果两组患儿经治疗后,性发育情况大多数得到抑制。甲孕酮治疗组骨龄年增长为１１岁,身高年增长为７６ｃｍ,成人期预测身高治疗前后无改变。长效ＧｎＲＨａ组骨龄年增长为０２岁,身高年增长为５６ｃｍ,成人期预测身高治疗６个月时增长３１ｃｍ,较治疗前明显改善（Ｐ＜００１）,治疗１年时增长６４ｃｍ,较治疗６个月时更为明显（Ｐ＜００５）。结论长效ＧｎＲＨａ与甲孕酮相比较,除可抑制性发育进程外,还可有效减慢骨成熟和生长速度,最终改善成人期预测身高,治疗时间愈长,效果愈明显