A multicentre randomised controlled trial of an intervention to improve the accuracy of linear growth measurement.

AIMS: To evaluate linear growth assessment and the effect of an intervention on measurement accuracy in primary care practices (PCP) within eight US geographical areas. METHODS: In this multicentre randomised controlled intervention study, paediatric endocrine nurses as site coordinators (SC) visited 55 randomly assigned PCP to evaluate growth assessment of staff performing linear measurements. SC observed 127 measurers assessing a total of 878 children: 307 (baseline), 282 (3 months), and 289 (6 months). Accuracy was determined by SC re-measuring each child with correct technique and equipment. State of the art equipment and a standardised growth training session were provided to the intervention group (IG) following the baseline visit. SC repeated data collection at all PCP at 3 and 6 months. RESULTS: There were no baseline differences between IG and CG equipment, technique, or accuracy; only 30% of measurements were accurate (< or =0.5 cm from SC). Post-intervention, significantly more IG measurements were accurate: IG = 55%, CG = 37% at 3 months; IG = 70%, CG = 34% at 6 months. Odds ratio of accuracy for IG versus CG was 2.1 at 3 months and 4.5 at 6 months. At 6 months, mean difference from the SC measurements was 0.5 cm in IG and 1.1 cm in CG. CONCLUSIONS: In PCP, children are measured inaccurately. Our intervention significantly improved measurement accuracy. Improved accuracy could yield more rapid detection and diagnosis of paediatric growth disorders.

Treatment of familial male precocious puberty with spironolactone and testolactone.

Because the pubertal growth spurt in boys appears to be mediated by both androgens and estrogens, we hypothesized that blockade of both androgen action and estrogen synthesis would normalize the growth of boys with familial male precocious puberty. To test this hypothesis, we studied nine boys (age range, 3.3 to 7.7 years) during treatment with an antiandrogen (spironolactone) or an inhibitor of androgen-to-estrogen conversion (testolactone), followed by treatment with both agents. After six months of observation without treatment, the first four boys received spironolactone for six months, followed by spironolactone and testolactone. The next five boys received testolactone for six months, followed by spironolactone and testolactone. Neither spironolactone nor testolactone, given alone, was satisfactory as a treatment for this condition. However, a combination of spironolactone and testolactone, given for at least six months, restored both the growth rate and the rate of bone maturation to normal prepubertal levels and controlled acne, spontaneous erections, and aggressive behavior. The combined therapy was associated with a significantly lower growth rate than testolactone alone (P less than 0.05) and a significantly lower rate of bone maturation than spironolactone alone (P less than 0.05). No important adverse effects were observed during combined treatment. Six of the nine boys continued to receive the combined therapy for an additional 12 months and maintained normal prepubertal rates of growth and bone maturation. The mean predicted height (+/- SEM) increased progressively during the combined treatment although the difference between the pretreatment and post-treatment predictions was not significant (169.5 +/- 2.8 at the end of treatment vs. 166.2 +/- 4.5 cm before treatment; P = 0.29). We conclude that blockade of both androgen action and estrogen synthesis with the combination of spironolactone and testolactone is an effective short-term treatment for familial male precocious puberty. Further study will be required, however, to assess the long-term outcome in boys who receive this treatment.

Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinizing hormone-releasing hormone.

Premature thelarche is a benign condition that affects young girls. In contrast, central precocious puberty is considered a more serious disorder that causes progressive secondary sexual development, accelerated growth and skeletal maturation, early epiphyseal fusion, and short adult stature. Differentiation between these 2 conditions is important, but may be difficult on clinical grounds, since patients with both disorders may present initially as isolated breast development. To examine the potential usefulness of gonadotropin measurements in distinguishing early central precocious puberty from premature thelarche, we measured basal and LHRH-stimulated plasma gonadotropin levels in 58 girls with idiopathic premature breast development. The girls were divided into six clinically distinct groups, based on the severity of clinical presentation, ranging from isolated breast development (group A) to complete secondary sexual development and accelerated growth and skeletal maturation (group F). The mean basal plasma LH levels and the peak LH response to LHRH stimulation were significantly less in girls with isolated thelarche (group A) than in girls with complete sexual development (group F). The mean basal plasma FSH levels did not differ between these groups, but the peak FSH response to LHRH was greater in girls with isolated thelarche than in girls with complete sexual development. Thus, girls with isolated premature thelarche had a FSH-predominant response to LHRH [mean ratio of peak LH to peak FSH, 0.29 +/- 0.10 (+/- SD)], while girls with complete sexual development had a LH-predominant response (peak LH/FSH, 4.16 +/- 1.80). All girls with isolated thelarche had peak LH/FSH ratios less than 1, and all girls with complete sexual development had a ratio greater than 1. Girls with early or intermediate manifestations of central precocious puberty, who had features of puberty in addition to breast development but lacked all of the features of group F, comprised groups B-E. These girls also had intermediate peak LH/FSH ratios, ranging from 0.29 +/- 0.10 (group B) to 3.35 +/- 2.66 (group E). We conclude that girls with early central precocious puberty frequently have LH and FSH responses to LHRH that are indistinguishable from the FSH-predominant responses of girls with isolated thelarche. These data are consistent with the hypothesis that premature thelarche and central precocious puberty may represent different positions along a continuum of hypothalamic LHRH neuron activation.

Resumption of puberty after long term luteinizing hormone-releasing hormone agonist treatment of central precocious puberty.

To determine whether puberty resumes normally after long term LHRH agonist (LHRHa) treatment, we studied 16 children with central precocious puberty treated with LHRHa (D-Trp6,Pro9,NEt-LHRH) for 1-4 yr (mean, 3.3 yr). Treatment was discontinued at a mean age of 11.6 +/- 1.3 (+/- SD) yr. Plasma hormone levels, growth velocity, rate of bone maturation, and pubertal stage were assessed at the end of treatment and 3 and 12 months later. Basal plasma sex steroid and basal and LHRH-stimulated gonadotropin levels returned to near-pretreatment levels 3 months after discontinuation of therapy and were fully restored to pretreatment levels at 12 months. Growth velocity, which had been 7.8 cm/yr before treatment, was stable after discontinuation of treatment at approximately 2.6 cm/yr. The predicted height, which had increased during treatment (P less than 0.01), remained stable at approximately 5 cm above the pretreatment predicted height. The rate of bone age advancement (delta bone age/delta chronological age) increased gradually from 0.4 at the end of treatment to the normal value of 0.9 12 months posttreatment. Breast and pubic hair pubertal stages, which were stable throughout treatment and were 4.0 +/- 0.8 (+/- SD) and 3.6 +/- 1.0 at the end of treatment, increased to 4.9 +/- 0.2 and 4.5 +/- 1.0. This approximated the normal rate of 1 stage/yr. Menses occurred in 8 of 12 girls within 1 yr after treatment and in an additional 3 by 20 months after treatment. Six of the girls had menstruated before treatment, and all of these menstruated within 14 months after discontinuing therapy. We conclude that gonadotropin and sex steroid secretion and the clinical progression through puberty appear to resume normally after discontinuation of long term LHRHa treatment of central precocious puberty. Long term follow-up will be required, however, to determine whether the improvement in predicted height of these patients will be achieved, and whether adult reproductive function will be normal.

Blood pressure and body size in precocious puberty.

Blood pressure increases with age in normal children. This increase appears to be related to body size. To assess the role of body size as a determinant of blood pressure in precocious puberty, we compared the blood pressure of 81 children with precocious puberty with the blood pressure standards for normal children from the NHLBI Task Force on Blood Pressure Control in Children. Children with precocious puberty had significantly increased blood pressure for chronologic age (p less than 0.05) but generally appropriate blood pressure for height age or weight age. These data are consistent with the hypothesis that increased body size causes the increased blood pressure for chronologic age in children with precocious puberty. Physicians who evaluate such children should assess whether blood pressure is appropriate for height age rather than chronologic age.

Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P less than 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone.

The McCune-Albright syndrome is characterized by café au lait spots, fibrous dysplasia of bones, and sexual precocity. Girls with precocious puberty due to this syndrome have episodic increases in serum estrogen levels together with the formation of large ovarian cysts. The serum gonadotropin levels are typically suppressed, and the precocious puberty has not responded to treatment with long-acting analogues of luteinizing hormone-releasing hormone (LHRH). Encouraged by our initial success in a pilot study of one patient, we have now treated five girls with the McCune-Albright syndrome with the aromatase inhibitor testolactone, which blocks the synthesis of estrogens. Testolactone decreased the levels of circulating estradiol (P less than 0.05) and the ovarian volume (P less than 0.05), and there was a return to pretreatment levels after testolactone was stopped. During treatment, the peak responses of luteinizing hormone and follicle-stimulating hormone to stimulation by LHRH rose above suppressed pretreatment levels--significantly above pretreatment levels for follicle-stimulating hormone (P less than 0.02)--and then returned to pretreatment levels after testolactone was discontinued. Growth rates fell in three patients during treatment but could not be assessed in the other two because of bone deformities. The mean rate of bone maturation decreased and menses stopped in three of the four girls who were menstruating regularly. We conclude that testolactone is an effective treatment of precocious puberty in the McCune-Albright syndrome.

Luteinizing hormone releasing hormone analogue therapy for central precocious puberty. Long-term effect on somatic growth, bone maturation, and predicted height.

The long-acting analogue of luteinizing hormone releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), is effective in the short-term treatment of central precocious puberty. We report the results of two to four years of LHRHa therapy in 27 children with this disorder. Secondary sex characteristics regressed in most patients. Sex steroid levels and basal and LHRH-stimulated gonadotropin levels remained suppressed compared with pretreatment values. Linear growth rates decreased from 11.0 +/- 0.8 (SEM) cm/yr before treatment to 5.7 +/- 0.4 cm/yr at two years of treatment and 3.7 +/- 0.7 cm/yr at four years of treatment. Predicted heights by the Bayley-Pinneau method increased from 156.4 +/- 2.0 cm before treatment to 162.3 +/- 2.3 cm at two years and 163.4 +/- 2.4 cm at three years. Five patients treated for four years had a mean increase in predicted height of 5.5 cm. To date no adverse effects have been observed. However, the ultimate safety of this analogue is not known. We conclude that LHRHa appears to be an effective long-term therapy for central precocious puberty.

Dental development in precocious puberty.

One hundred and one children with precocious puberty were given an oral examination. Dental root development was assessed using panoramic radiographs. All mandibular canines, pre-molars, and molars which could be visualized without apparent distortion were included. The patients were grouped for analysis according to the etiology of their precocity, e.g., McCune-Albright syndrome, familial male, congenital adrenal hyperplasia, central nervous system lesions, and idiopathic precocious puberty. Dental development was significantly retarded relative to their chronological age in patients with idiopathic precocious puberty. However, no significant abnormal dental development was detected in any of the other groups. Individual oral-facial growth and development remain the primary considerations for timing orthodontic treatment.

Behavior problems and social competence in girls with true precocious puberty.

We report a controlled standardized behavioral assessment of 33 girls with true precocious puberty using the Child Behavior Checklist. Although a majority of the girls were reported not to have behavior problems, many were reported to have a dysphoric adjustment to their condition. Twenty-seven percent of the girls with true precocious puberty scored greater than 2 SD above the mean on the Total Behavior Problem scale 10 times the expected prevalence rate. They also scored significantly higher (P less than 0.01) than matched controls on both the internalizing or "overcontrolled symptom" and externalizing or "undercontrolled symptom" scales. Forty-eight percent scored greater than 2 SD above the mean on the Social Withdrawal scale. The high prevalence of reported problem behaviors in this sample may be related directly or indirectly to the precocious maturation mediated by biologic, psychologic, social, and environmental variables. Although elevated levels of sex steroids may directly contribute to increased aggressive and hyperactive behaviors, they may also be modified by social and environmental factors.