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Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society.

In 1997 a study from the Pediatric Research in Office Settings network, based on pubertal staging of >17,000 girls between 3 and 12 years of age, indicated that breast and pubic hair development are occurring significantly earlier than suggested by our current guidelines, especially in African-American girls. In response to this article, the Lawson Wilkins Pediatric Endocrine Society undertook a comprehensive review of this topic. The primary conclusions of this review are: 1. The current recommendation that breast development before age 8 is precocious is based on outdated studies. Until 1997, no data were available on pubertal staging in US girls that could have documented a trend to earlier maturation. 2. The 1997 study indicates that stage 2 of breast and pubic hair development is being achieved ~1 year earlier in white girls and 2 years earlier in African-American girls than previous studies have shown. 3. Concerns that girls with moderately precocious puberty will be significantly short adults are overstated; most have adult height within the normal range. 4. Therapy with gonadotropin-releasing hormone agonists has not been proven to have a substantial effect on adult height in most girls whose puberty starts between 6 and 8 years of age. 5. New guidelines propose that girls with either breast development or pubic hair should be evaluated if this occurs before age 7 in white girls and before age 6 in African-American girls. No changes in the current guidelines for evaluating boys (signs of puberty at younger than 9 years) can be made at this time.normal puberty, breast development, pubic hair.

Age of Onset↗

Early puberty-menarche after precocious pubarche: relation to prenatal growth.

OBJECTIVE: Girls with precocious pubarche (PP; pubic hair at <8 years of age) as a result of an early or amplified adrenarche (high dehydroepiandrosterone-sulfate [DHEAS]) tend to be hyperinsulinemic, in particular when born with low birth weight (LBW). The objective of this study was to assess the interrelationship among prenatal growth, PP, the timing of puberty-menarche, and adult stature. METHODS: We studied 187 PP girls longitudinally: (1) at birth, (2) in prepuberty, (3) at onset of puberty, (4) at menarche, and (5) on reaching adult stature. This PP cohort was divided into subgroups of higher birth weight (>0 SD), intermediate birth weight (0 to -2 SD), and lower birth weight (less than -2 SD). RESULTS: At the time of PP diagnosis, age, bone age, and BMI were similar across birth weight subgroups; circulating sex hormone-binding globulin and body height were reduced in PP girls with lower birth weight, and these remained so throughout pubertal development. Onset of puberty occurred earlier in PP girls with lower birth weight; so did menarche. Adult height differed by an average of 6.5 cm (approximately 1 SD) between the upper and lower birth weight subgroups; this difference was essentially achieved before puberty and even before PP. Menarche before age 12.0 years was twofold more prevalent in PP girls than in control subjects. Among PP girls, age at menarche was advanced by 8 to 10 months in lower versus higher birth weight girls. Menarche before age 12.0 years was threefold more prevalent among LBW-PP girls than in control subjects (approximately 75% vs approximately 25%). CONCLUSIONS: The link between prenatal growth restraint and early menarche is herewith extended to PP girls. In particular LBW-PP girls may become a target group for interventions directed toward normalization of pubertal onset and progression.

17-alpha-Hydroxyprogesterone↗

New concepts of the growth spurt of puberty.

The timing of the growth spurt of normal children does not affect their final height attainment. Growth rate during the growth acceleration of puberty correlates with changes in GH, and not sex steroid, secretion. GH secretion during puberty is pulse amplitude, and not frequency, modulated. In both central precocious puberty and normal puberty suppressed with a GnRH analogue, the rate of epiphyseal maturation is decreased as are GH pulse amplitude and growth, but with no influence on final height.

Adolescent↗

Hamartoma of CNS associated with precocious puberty.

A male infant had precocious puberty and hamartoma of the CNS. Signs of puberty appeared and progressed from 6 months of age. A computed tomographic scan disclosed an interpedunculary tumor. A craniotomy was successfully performed at 11/2 years of age, and 90% of the tumor was removed. Histologically, the tissue was identified as a hypothalamic hamartoma. Pubertal development stopped. The patient is now 4 years 9 months old and well. Review of medical literature covering a span of 47 years showed 50 cases of hamartomas in or near the hypothalamus confirmed by surgical exploration or autopsy. The male-female ratio of hamartomas with precocious puberty derived from these data is 2:1. Convulsions, mental retardation, or behavioral disorders were present in 48% of the cases; 36% had precocious puberty.

Brain Neoplasms↗

Diagnostic value of testosterone therapy in boys with delayed puberty.

A brief course of testosterone injections is known to be an effective treatment for boys with constitutional delayed puberty. In this study, data from seven boys at least 14 years old who received testosterone enanthate (100 mg intramuscularly monthly for four months) were analyzed to see if linear and testicular growth responses could be useful diagnostically in excluding growth hormone deficiency (GHD) and isolated gonadotropin deficiency, two conditions that are often difficult to distinguish from constitutional delayed puberty. During four months of testosterone therapy, growth rate increased from 4.0 +/- 1.0 cm/y to 10.7 +/- 2.3 cm/y, and was greater than 8 cm/y in all patients. Since testosterone-induced stimulation of linear growth is largely GH-mediated, the large increase in growth rate in all boys is considered indicative of GH sufficiency. Testis length, which did not increase during testosterone therapy, increased by 0.6 to 0.8 cm in every patient (from 2.7 +/- 0.3 cm to 3.4 +/- 0.4 cm) over the following four months, indicating normal gonadotropin secretion and normal pubertal progression; in contrast, the increase in serum testosterone concentrations after discontinuation of testosterone treatment was more variable. It is concluded that the growth response to a four-month course of testosterone is helpful in excluding GHD in boys with delayed puberty, and an additional four months of follow-up is sufficient to document the onset of puberty, thereby eliminating the possibility of isolated gonadotropin deficiency.

Adolescent↗

Laboratory monitoring of children with precocious puberty.

It is necessary not only to perform laboratory tests for the correct diagnosis of children with precocious puberty, but also to monitor laboratory tests to ensure adequacy of therapy. Careful laboratory testing is a requisite in the differentiation of central from peripheral precocious puberty. It is also required to determine whether the patient who presents with early physical changes of pubertal development with peripheral precocious puberty has evidence of pubertal hormonal secretion. The most useful single test is gonadotropin-releasing hormone (gonadorelin) stimulation of luteinizing hormone release. The same stimulation test is also indicated to verify the adequacy of suppression of gonadotropin secretion among patients with central precocious puberty who are being treated with gonadotropin-releasing hormone analogue. It is necessary to know which gonadotropin assay is being used and the range of normal levels to correctly interpret the tests.

Child↗

Paraneoplasic precocious puberty. Report of a new case with hepatoblastoma and review of the literature.

A new case of precocious puberty secondary to production of human chorionic gonadotropin (HCG) by an hepatoblastoma was studied in an 8-month-old infant. A review was made of the 35 cases of paraneoplasic precocious puberty previously reported in the literature. The most frequent cause is hepatoblastoma, which was responsible for 18 cases. There are nine reports of mediastinal teratoma, six of which were observed in patients with Klinefelter Syndrome. In another six cases, the paraneoplasic syndrome was attributed to intracranial tumoration, and two of these patients showed teratoma with areas of choriocarcinoma, whereas germinoma was suspected for clinical reasons in another three. Lastly, one case of presacral teratoma and one of retroperitoneal carcinoma were reported. The differential characteristics of paraneoplasic precocious puberty are: almost exclusive occurrence in males, because of tumoral production of HCG, moderate or absent increase of testicle size, hyperplasia of Leydig's cells without spermatogenesis, and rapidly progressive signs of puberty.

Carcinoma, Hepatocellular↗

Serum T4, T3 and TBG concentrations during puberty in males.

Measurements of serum thyroxine (T4), thyroxine binding globulin (TBG), and triiodothyronine (T3), using RIA, were conducted in healthy Israeli boys, 149 children from the age 8 years were divided into five groups according to Tanner's puberty stages. The correlation with Tanner's staging showed a significant decrease in T4 and TBG concentrations during puberty. However, T3 decreased only toward the last stage of puberty (between P4 to P5). Our data indicate that during puberty in male subjects the decrease in TBG plays a significant role in the decrease of thyroid hormone concentrations.

Adolescent↗

Studies of gonadotrophin pulsatility and pelvic ultrasound examinations distinguish between isolated premature thelarche and central precocious puberty.

We have studied the pulsatile secretion of gonadotrophins at night and made ovarian ultrasound examinations in three girls with central precocious puberty and three with isolated premature thelarche. The three girls with precocious puberty had well-defined pulsatile secretion of LH and FSH with LH predominating, as would be expected in normal puberty. Pulsatile secretion of gonadotrophins was also seen in girls with premature thelarche but the pattern was reversed. In girls with precocious puberty, large "multicystic" ovaries and large uteri were seen on ultrasound examination, whereas girls with isolated premature thelarche had small uteri and ovaries with less than four "cysts" up to 15 mm in diameter. These data provide the key to understanding the aetiology of isolated premature thelarche.

Breast↗

Mean 24-hour growth hormone and testosterone concentrations in relation to pubertal growth spurt in boys with normal or delayed puberty.

The mean growth hormone concentration during 24-hour period in 7 boys of short familial stature and a growth rate of 3.2-5.4 cm/year was between 1.0 and 4.6 ng/ml serum. In 7 boys with pubertal growth spurt and familial tallness (growth rate 7.2-11.0 cm/year) it varied from 0.97 to 4.4 ng/ml and in 6 boys with constitutional delay of puberty (a growth rate of 4.2-5.2 cm/year prior to puberty) from 1.3 to 4.3 ng/ml. No correlation was found between the 24-hour mean growth hormone concentration and the mean 24-hour testosterone concentration in serum or the growth rate, but a correlation was found between testosterone and the growth rate. It is concluded that the growth spurt in puberty is not due to a change in growth hormone concentration but rather to the increase of androgen production in puberty.

Adolescent↗

Influence of puberty on lipids and lipoprotein profile in children with type 1 diabetes mellitus.

In order to assess whether or not the lipoprotein profile worsens throughout puberty in children with type 1 diabetes mellitus and if this change is related to dietary compliance, we studied 46 (20 female, 26 male) children. At the beginning of the study, the mean age (+/- SD) was 10.9 +/- 1.1 years; all the children studied had reached a pubertal stage of P1, G1. The mean duration of diabetes (+/- SD) was 4.9 +/- 1.8 years. The diet and the lipoprotein profile of diabetic children were analysed at the beginning of the study and after 6 years. The quality of metabolic control of subjects studied had not changed significantly at the end of the study (haemoglobin HbA1c 7.6% +/- 2.1% vs 7.9% +/- 2.0%; NS). After puberty, the diabetic patients received more energy from carbohydrate and less from lipids. Total serum cholesterol and triglycerides and levels of low-density lipoproteins were significantly higher and of high-density lipoproteins lower in the diabetic patients after puberty than before (4.47 +/- 0.7 mmol/l vs 5.99 +/- 0.6, P < 0.01; 0.90 +/- 0.02 mmol/l vs 1.45 +/- 0.03, P < 0.01; 2.2 +/- 0.3 mmol/l vs 2.8 +/- 0.5, P < 0.01; 1.5 +/- 0.2 vs 1.1 +/- 0.2, P < 0.01, respectively). These results suggest a detrimental effect of puberty on lipoproteins; probably, dietary compliance plays a role in this worsening. Dietary education should be intensified during adolescence in order to present these changes.

Child↗

The neuro-radiological examination of endocrine disorders of central origin in the child (precocious puberty, hypopituitarism).

The neuro-radiological findings in 38 cases of precocious puberty of central origin and 9 cases of hypopituitarism (craniopharyngiomas excepted), are reported. The radiological examination consisted of plain films of the skull and pneumo-encephalography. In the 9 cases with hypopituitarism radiological examination was normal in 4 and localised but quite diverse anomalies were discovered in 5. Out of 38 patients presenting with isosexual precocious puberty, 29 were female and 9 male. Out of the 29 girls, neuro-radiological examination was normal in 20 and showed a hypothalamic anomaly in 9. Out of the 9 boys, 8 had a hypothalamic anomaly, and only one examination was normal. In precocious puberty we found 1 ectopic pinealoma and 2 gliomas of the chiasma. In these three cases the clinical context and radiological examination made the diagnosis obvious. Masses were discovered in 7 (3 spongioblastomas and 4 heterotopias). In 2 cases (spongioblastomas) neurological symptoms were present and made an operation mandatory. In 5 cases (1 spongioblastoma, 4 heterotopias) precocious puberty was an isolated finding. It was not possible to make, on a clinical or radiological bases, a distinction between spongioblastoma and heterotopia. As time has passed the role of surgery has changed. Formerly, surgery aimed at excision of the lesion, but with advances in medical treatment surgical intervention is now directed towards biopsy and the histological study of lesions which may be treated by radiotherapy.

Adolescent↗

Pelvic ultrasonography: early differentiation between isolated premature thelarche and central precocious puberty.

We examined 55 girls with isolated premature thelarche between the ages of 0.3 and 7.4 years (group A), 20 children with central precocious puberty between 2.1 and 7.7 years of age and 101 age-matched controls. The children with precocious puberty were divided according to distribution of pubic hair into group B (Tanner stages PH1, B2-3; n = 11), representing an early stage of the disorder, and group C (stages PH2-3, B3-4; n = 9), representing an advanced stage. Uterine and ovarian volumes were measured sonographically, peak serum levels of luteinizing hormone and follicle-stimulating hormone were determined after intravenous administration of luteinizing hormone-releasing hormone. The mean uterine and ovarian volumes were significantly greater in children with precocious puberty than in controls (group B: uterine volume: 3.8 +/- 2.0 ml vs 0.9 +/- 0.3 ml for controls, P < 0.001; ovarian volume: 2.2 +/- 1.3 ml vs 0.6 +/- 0.2 ml for controls, P < 0.01; group C: uterine volume: 8.0 +/- 4.4 ml vs 1.0 +/- 0.3 ml for controls, P < 0.01; ovarian volume; 2.6 +/- 1.3 ml vs 0.4 +/- 0.1 ml, P < 0.01). No significant differences were found between children with premature thelarche and the control group. As a diagnostic method for the early detection of central precocious puberty, ultrasound measurement of uterine volume had a sensitivity and specificity of 100% (cut-off value, 1.8 ml), while ultrasound determination of ovarian volume had a sensitivity of 82% and a specificity of 95% (cut-off value, 1.2 ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

Linear growth in patients with Turner syndrome: influence of spontaneous puberty and parental height.

Growth data on 100 patients with Turner syndrome are reported. Seventeen had spontaneous puberty. Between the ages 11 and 13 years, height and height velocity were higher in these girls than in those with induced puberty. Final adult height, however, was not different. Patients disomic for Xp chromosome were taller than the monosomic ones, and the majority of them had spontaneous puberty. Significant positive correlations were found between height of Turner syndrome patients and corrected mid parental height, mother's height and father's height from the age of 6 years. It is concluded that in patients with Turner syndrome spontaneous puberty and parental height should be accounted for in the evaluation of linear growth.

Adolescent↗

Puberty onset in Northern Italy: a random sample of 3597 Italian children.

Entering puberty is one of the most important milestones in life. Studies from around the world have shown that age of pubertal changes onset can vary with race and ethnicity, environmental conditions, geographical location and nutrition. In the last century, the onset of puberty progressively shifted back towards younger ages in several European countries, with a levelling off in the last decades. The aim of our study was to describe the prevalence of secondary sexual characteristics in a group of children living in Northern Italy comparing them with the percentile values published by Tanner in 1976. We enrolled 3496 children drawn from public schools and evaluated height, weight and pubertal stages. The analysis of our data evidenced that the 50th percentile age of puberty onset in both sexes decreased by about 1 yr compared to data published by Tanner. Mean body mass index (BMI) z-score was significantly higher (p = 0.01) in pubertal than in pre-pubertal girls, on the contrary it was higher (p = 0.005) in pre-pubertal than in pubertal boys. In conclusion, our study found that girls and boys of our region are beginning pubertal development about 1 yr earlier than Tanner's British population. Taking into consideration the 3rd percentile age for Tanner's breast stage 2 in girls and testicular volume (TV) of 4 ml in boys, the current internationally used cut-off age for precocious puberty, i.e. 8 yr for girls and 9 yr for boys, can be maintained in our population.

Age Factors↗

Growth hormone deficiency throughout puberty.

Growth during puberty does not appear to be the major determinate of final height in isolated GH deficient patients. Early diagnosis and commencement of therapy are probably the most important factors, as reflected by the correlation between final height and height at the onset of puberty. The cost effectiveness of increasing the dose of GH during puberty does not appear to represent any advantage from the data presently available. Indeed, such an approach may have a deleterious effect on final height by shortening the duration of pubertal maturation. Further prospective studies are required to demonstrate the effectiveness of manipulating the onset and duration of puberty using gonadotrophin releasing hormone analogues on final height in isolated GH deficiency.

Adolescent↗

Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty.

OBJECTIVE: The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. MATERIALS AND METHODS: Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. RESULTS: All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. CONCLUSION: Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape.

Antineoplastic Agents, Hormonal↗

Final height and puberty in 40 patients after antileukaemic treatment during childhood.

UNLABELLED: Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2-3 years with intensive maintenance therapy blunted growth resulted in a significant loss of -1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI. CONCLUSIONS: (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied.

Adolescent↗