The role of estrogen in bone growth and maturation during childhood and adolescence

Twenty years ago it was believed that pubertal growth was stimulated by testicular androgen in boys and by adrenal androgen in girls. Estrogen, which was used to inhibit growth in excessively tall girls, was not thought to have growth-promoting effects. We hypothesized that estrogen has a biphasic effect on epiphyseal growth, with maximal stimulation at low levels. We showed that the administration of low doses of estrogen, corresponding to a serum estradiol level of about 4 pg/ml (15 pmol/l) caused more than a 60% increase over the prepubertal growth rate in both boys and girls. To test the hypothesis that estrogen is the principal mediator of the pubertal growth spurt in boys, we administered the aromatase inhibitor, testolactone, to boys with familial male-limited precocious puberty. Testolactone produced near normalization of both growth velocity and bone maturation, despite levels of serum testosterone that remained within the adult male range. The observation that low levels of estrogen stimulate growth and bone maturation suggested that estrogen might explain the more rapid epiphyseal maturation of prepubertal girls compared to boys. To determine whether prepubertal girls have higher estrogen levels than prepubertal boys, we developed an ultrasensitive recombinant cell bioassay for estrogen with a sensitivity of 0.02 pg/ml (0.07 pmol/l) estradiol equivalents. Prepubertal girls had approximately eight-fold higher levels of serum estradiol than did prepubertal boys (0.6 ± 0.6 pg/ml (SD) (2.2 ± 2.2 pmol/l) vs 0.08 ± 0.2 pg/ml (0.29 ± 0.73 pmol/l), P < 0.05). We concluded that the pubertal growth spurt of both sexes is driven primarily by estrogen, and that the more rapid epiphyseal maturation of prepubertal girls (vs boys) may be explained by their higher estradiol levels.     

Effect of puberty on the relationship between bone markers of turnover and bone mineral density in Turner's syndrome

It has been suggested that the appropriate timing of puberty is necessary for normal bone mineral acquisition which may not be achieved amongst patients with Turner's syndrome (TS). The aim of this study was to assess bone mineral density (BMD) and bone turnover in 34 patients with TS (age range 2.2-39.0 years). The areal BMD (aBMD) was determined by dual-energy X-ray absorptiometry, and the volumetric BMD was calculated. Blood and second voided urine samples were taken the morning after an overnight fast for evaluation of the biochemical markers of bone turnover: bone-specific alkaline phosphatase (BAP) and N-telopeptides of type I collagen (NTX), respectively. Both were determined by enzyme-linked immunosorbent assay. The patients were divided into three groups: group 1 (n = 13; prepubertal; age range 2.2-19.0 years), group 2 (n = 10; teenagers; age range 12.4-19.0 years), and group 3 (n = 11; adults; chronological age >20 years). They were also grouped by breast development according to Tanner stage into B1 (n = 12), B2-3 (n = 9), and B4-5 (n = 13). The aBMD was significantly lower in group 1 and was higher at Tanner stages 4 and 5 as compared with patients at Tanner stage 1. The bone turnover markers were significantly higher in group 1 (NTX: p = 0.002; BAP: p = 0.0005) and declined, as puberty progressed. A negative correlation was observed between aBMD and biochemical bone markers at the lumbar spine (NTX: r = -0.54, p = 0.05; BAP: r = -0.44, p = 0.01) and in the whole body (NTX: r = -0.60, p = 0.0008; BAP: r = -0.19, p = 0.002). We conclude that the negative relationships between aBMD and biochemical markers suggest a high bone turnover, mainly in prepubertal patients and that the results observed in relation to aBMD and puberty are imputed to the delayed puberty which occurs amongst TS patients.     

Sex hormone-binding globulin and thyroxine-binding globulin levels in premature thelarche

Premature thelarche is defined as the isolated development of breast tissue in girls less than 8 years of age. Although breast development is an estrogen-dependent process, these girls do not have elevated serum estrogen levels, and the hormonal basis for their condition is unclear. We studied the levels of two estrogen-dependent transport proteins, sex hormone-binding globulin (SHBG) and thyroxine-binding globulin (TBG), in order to determine if there was evidence for a more subtle estrogen effect in girls with premature thelarche. SHBG levels in girls with premature thelarche were not significantly different from those of prepubertal girls of the same ages and were significantly lower than those in girls undergoing pubertal development at the appropriate age (P less than 0.05) and in normal women (P less than 0.001). There was no statistically significant difference in TBG levels between the girls with premature thelarche and prepubertal controls. There was also no significant difference in TBG levels between prepubertal girls and girls in early puberty. In contrast, women had TBG levels that were significantly lower than those in all girls studied. We conclude that the estrogen exposure (whether endogenous or exogenous) of girls with premature thelarche is less than that of girls in early true puberty and similar to that of other prepubertal girls. Further, changes in serum TBG are not as sensitive an indicator of estrogen effect as is breast development or changes in SHBG. This study also suggests that large amounts of exogenous estrogens are not an element in the development of premature thelarche.     

Resolution of apparent growth hormone-dependent growth failure during puberty: a case report

A prepubertal boy with apparent growth hormone (GH)-dependent growth failure displayed a marked increase in growth velocity, normal GH responses to arginine/insulin infusion and a fourfold increase in spontaneous 24-hour GH secretion following the onset of normal puberty. The case supports earlier observations of a transient form of GH insufficiency in some short prepubertal children, but represents the first evidence that puberty restores spontaneous as well as stimulated GH secretion in such patients.     

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turner's syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turner's syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.     

Volumetric bone mineral density in young women with Turner's syndrome treated with estrogens or estrogens plus growth hormone

To explore the effects of estrogen replacement therapy (ERT) and recombinant growth hormone (GH) treatment on bone mineral density (BMD) in Turner's syndrome, we assessed volumetric BMD (vBMD), which is less dependent on body and bone sizes, in these patients at final height. The areal BMD (aBMD) was measured in 26 young women with Turner's syndrome (age range 17.5-25.0 years) by dual-energy X-ray absorptiometry, and vBMD was calculated. Patients were subdivided as group 1 (n = 12; ERT alone) and group 2 (n = 14; GH + ERT). Years of estrogen exposure were not different between the groups (group 1: 6. 4 +/- 1.5 years; group 2: 5.3 +/- 1.7 years); in group 2, GH therapy was 5.3 +/- 1.4 years. Final heights were significantly higher in group 2 than in group 1 (148.1 +/- 3.0 vs. 142.0 +/- 2.8 cm; p < 0. 0001) as well as aBMD (1.073 +/- 0.118 vs. 0.968 +/- 0.122 g/cm(2); p < 0.04). vBMD was higher in group 2 but not significantly different from group 1 (0.374 +/- 0.030 vs. 0.358 +/- 0.027 g/cm(3); p = 0.169). aBMD was reduced with respect to the normative values in both groups (group 1: -1.97 +/- 1.04 SDS, p < 0.0001 vs. 0; group 2: -0.93 +/- 1.01 SDS, p < 0.005 vs. 0), whereas vBMD was not (group 1: -0.07 +/- 0.79 SDS; group 2: 0.42 +/- 0.82 SDS). Our data suggest that: in Turner's syndrome GH administration improves final height and aBMD, but it does not significantly increase vBMD; aBMD reduction in Turner's syndrome is likely due to the impaired growth and reduced bone size; Turner's patients on ERT from adolescence show vBMD values in the normal range in young adulthood.     

Blunted pubertal growth after leukemia: a new pattern of growth hormone insufficiency

Growth, age at menarche and spontaneous GH secretion were studied in girls after treatment for acute lymphoblastic leukemia (ALL). These girls had normal prepubertal growth but subnormal pubertal growth. Mean final height was 1 SD less than expected before puberty. The average age at menarche was significantly lower than the normal mean for Swedish girls. The mean 24-hour GH secretion was severely blunted and there was no increase during puberty. We suggest that girls treated for ALL, including CNS irradiation, have a relative GH insufficiency which becomes clinically obvious only when the girls cannot respond to the increased demands for GH in puberty.     

Cardiac performance in Turner's syndrome patients on growth hormone therapy.

OBJECTIVES: To investigate possible cardiac morphofunctional alterations observed in 26 Turner's syndrome (TS) patients on prolonged high-dose growth hormone (GH) therapy. STUDY DESIGN: We examined 26 TS subjects treated with rhGH (1 U/kg/week) for a mean period of 4.9 years (range 1-7.8) and 37 age-, weight- and height-matched healthy girls. Left ventricular volume, mass, systolic function, cardiac index, systemic vascular resistance and diastolic function were evaluated by two-dimensional and Doppler echocardiography. RESULTS: Heart rate and systolic blood pressure (BP) were higher in TS patients than in controls, while diastolic BP was lower. Left ventricular volumes, ejection fraction, mass index, M/V ratio and cardiac index did not differ significantly; systemic vascular resistance was slightly decreased. Left ventricular fractional shortening and mean velocity of circumferential shortening were slightly increased while end-systolic meridional stress was decreased in TS. Contractile state was normal in TS. Diastolic function assessment showed a shortening of isovolumetric relaxation and diastolic filling times with an increased atrial contribution and a normal pulmonary venous flow. CONCLUSION: Cardiac morphology in TS patients on GH therapy is similar to controls. The observed changes in left ventricular systolic and diastolic function should be interpreted as an adaptation to the higher heart rate and reduced peripheral vascular resistance induced by GH therapy.     

Psychosocial functioning after discontinuation of long-term growth hormone treatment in girls with Turner syndrome

It is common practice in the case of Turner syndrome (TS) to treat short stature with GH treatment and to induce puberty with estrogens at an age as close to normal puberty as possible. This approach in most cases leads to a height in the normal range in childhood, adolescence, and adulthood in TS. Little data is available, however, on its effect on psychosocial functioning. In the present study, we evaluated psychosocial functioning in a group of 50 women with TS, after reaching final height in two multicenter GH trials. Thirty-six girls participated in a randomized dose-response study from mean (SEM) age 6.8 (0.4) years, and 14 girls participated in a frequency-response study from age 13.2 (0.4) years. After discontinuation of long-term GH treatment, these 50 girls were evaluated for psychosocial functioning at a mean age of 18.8 (0.3) years. GH was given in a dosage of 4 IU/m2/day (approximately 0.045 mg/kg/day), 6 IU/m2/day, or 8 IU/m2/day. After a mean GH treatment duration of 7.1 (0.4) years, mean final height (ref. normal girls) was FH1.2 (0.2) SD score. Behavioral problem scores (Achenbach) of the TS women were comparable to normal Dutch peers. Although self-perception (Harter total scale: p < 0.01), and bodily attitude (Baardman: p < 0.05) was significantly less positive than for their normal Dutch peers, we found no evidence of depression. TS women rated their family functioning higher than their Dutch peers (p < 0.0001), and had a slightly different coping pattern. These results show that even after reaching a height in most cases within the normal range and puberty induction at a pubertal age, some women with TS still experience psychosocial problems. It is likely, however, that GH and estrogen treatment improved psychosocial functioning. Long-term follow-up of these GH-treated patients will allow an evaluation of their life achievements.     

Sex‐Specific Fat Distribution Is Not Linear Across Pubertal Groups in a Multiethnic Study

Objective: To investigate sexual dimorphism and race differences in fat distribution (android/gynoid) before and during puberty. Research Methods and Procedures: Fat distribution was measured by skinfold thickness and DXA in healthy African‐American, Asian, and white subjects (n = 920), divided into pre‐, early, and late pubertal groups. Results: Gynoid fat masses adjusted for covariates were lower in late pubertal compared with prepubertal boys, but were not consistently greater in late pubertal compared with prepubertal girls. Progression of sex‐specific fat distribution with increasing maturation was present in Asians only. Among African‐American and white subjects, early pubertal boys had greater gynoid fat mass compared with the prepubertal group, whereas early pubertal girls had less gynoid fat mass compared with the prepubertal group. Sexual dimorphism in fat distribution was present in all pubertal groups, except among whites at early puberty. Among girls, Asians had lower gynoid fat than whites and African Americans in all pubertal groups. Among boys, Asians had less gynoid fat by DXA in early puberty and late puberty. Discussion: Comparison among races demonstrated differences in sexual dimorphism and sex‐specific fat distribution with progression in pubertal group. However, in all race groups, the fat distribution of late pubertal boys was more “male” or “android” than prepubertal boys, but late pubertal girls did not differ consistently from prepubertal girls. These findings suggested that the greater sexual dimorphism of fat distribution in late puberty compared with prepuberty may be attributable to larger changes in boys with smaller changes in girls.     

Prenatal melatonin influences developmental changes of tachykinins in response to estradiol benzoate

The developmental changes of hypothalamic, pituitary, striatum and pineal gland tachykinin concentrations, as well as the response to estradiol-benzoate (EB) administration, were studied in offspring of control and melatonin (MEL) treated mother rats. Female rats were studied throughout different phases of the sexual development: infantile, prepubertal and pubertal periods, in the four following groups; control-offspring+vehicle; control-offspring+EB; MEL-offspring+vehicle; MEL-offspring+EB. Hypothalamic NKA in control-offspring+ vehicle was significantly increased only at 27 days of age and in control-offspring+EB at 27 days of age and during the infantile period. Hypothalamic SP levels increased similarly in control-offspring+EB during the infantile period but the EB influence was more pronounced with significantly increased concentrations at 32 days of age. Prenatal melatonin treatment produced major alterations in these patterns of postnatal development. In MEL-offspring+EB tachykinins concentrations in the hypothalamus during infantile and prepubertal periods did not increase, however at 37 days of age, they showed significantly higher values than in control-offspring+EB groups. The developmental pattern of pituitary NKA and SP concentrations in both; control-offspring+vehicle and control-offspring+EB groups, showed similar values from the infantile period to puberty, indicating that NKA and SP concentrations remained at similar levels independently of the sexual stage, only at 27 days of age in control-offspring+EB significantly increased values were found as compared to MEL-offspring+EB. Prenatal melatonin did not produce marked modifications, only significantly lower NKA and SP concentrations in MEL-offspring+EB group were observed at 25 days of age in comparison to control-offspring+EB group. Striatal NKA and SP concentrations showed a similar developmental pattern. In control-offspring, EB treatment produced NKA and SP decreased concentrations at the infantile period than in control-offspring+vehicle and significantly increased concentrations during the prepubertal period, then during the pubertal period NKA and SP concentrations decreased in control-group+EB. However, prenatal melatonin treatment reduced the levels of striatal NKA and SP during the prepubertal period after EB treatment and delayed until pubertal period the increase previously observed in control group during the prepubertal period. In MEL-offspring+vehicle group striatal concentrations of both tachykinins remained at low levels from infantile period until pubertal period. Prenatal melatonin and EB did not produce major alterations in SP pineal concentrations throughout sexual development. Plasma estradiol concentrations were significantly higher in the groups that received EB treatment than in those that received vehicle during prepubertal and juvenile periods in control-offspring+EB group and during the pubertal period in MEL-offspring+EB group. These data indicate that prenatal MEL treatment may influence NKA and SP developmental pattern from the infantile period until adulthood in the female rat.     

Cross-sectional growth study in patients with Turner's syndrome

The body height, weight and growth velocity were investigated in 416 patients with Turner's syndrome whose age ranged from 3 to 17 years. They were all prepubertal at the time of the present study. The chromosomal analysis revealed 45, X monosomy in 148 cases, mosaicism in 208 cases, and nonmosaic structural abnormalities of X chromosome in 60 cases. There were no significant differences in height, growth velocity and weight between the patients with the 45, X karyotype and those with other chromosomal variants at any age. Combined mean heights at 3, 10 and 17 years of age were 86.0 +/- 3.5 (m +/- SD), 116.7 +/- 5.8 and 136.8 +/- 4.8 cm, respectively. These values were below -2.0 SD of normal Japanese girls. The growth velocity was 6.0 +/- 0.5 cm/year at 4 years of age, but decreased gradually and was 1.6 +/- 0.7 cm/year at 17 years of age. The degree of overweight was within +/- 10% of ideal body weight for height between the ages of 3 and 8, 10-20% between the ages of 9 and 10, and 20-30% above the age of 11 years.     

Growth curves of children with Down syndrome.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight. These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.     

Gonadotropin pulsatile secretion in girls with premature menarche

Five prepubertal girls (2.3-8.1 years old) were studied for isolated or recurrent vaginal bleeding in the absence of other signs of precocious puberty (premature menarche). Four of these girls with recurrent vaginal bleeding were studied for pulsatile gonadotropin secretory patterns. During sleep 3 girls showed luteinizing hormone (LH) pulses with low amplitude and a pubertal pattern of frequency whereas follicle-stimulating hormone (FSH) increased without demonstrable episodic secretion. Luteinizing hormone-releasing hormone (LHRH) tests demonstrated that FSH responses are greater than the LH responses, as in prepuberty. In 3 cases estradiol levels had augmented above normal prepubertal range. The menses spontaneously stopped during the follow-up. A reevaluation of the gonadotropin pattern, having the menses stopped for 6 months, in one of the girls with pulsatile LH secretion showed an apulsatile prepubertal LH pattern. Also estradiol levels returned to prepubertal range. A follow-up of 10-66 months of these patients did not show any growth and bone acceleration or signs of precocious puberty. Our data suggest that in premature menarche a partial and transient activation of hypothalamo-pituitary axis could be present. Premature menarche seems to be a benign and self-limiting condition and one of the girls had a normal onset of puberty during follow-up.     

Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience

BACKGROUND: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied. PATIENTS/METHODS: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5-0.7 IU/kg/week (0.17-0.23 mg/kg/week) from the mean +/- SD age of 11.9 +/- 3.1 years during 5.1 +/- 2.1 years. RESULTS: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was -0.7 +/- 1.1 SDS, being 170.4 +/- 7.2 cm in boys and 158.0 +/- 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 +/- 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 +/- 7.0 cm vs. 27.5 +/- 6.6 cm (p < 0.005); girls: 9.6 +/- 7.4 cm vs. 22.2 +/- 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty. CONCLUSIONS: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5-0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty.     

Growth failure in early life: an important manifestation of Turner syndrome

The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from -0.68 at birth to -1.60 at 1 year, -1.80 at 2 years and -1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.     

GH assessment and three years' hGH therapy in girls with Turner syndrome.

Fifteen girls with Turner syndrome (TS) were submitted to GH secretion assessment before undergoing hGH therapy. In the first 9 months, hGH was given at a dose of 0.5 IU/kg/week s.c. daily; afterward, the dose was increased to 1 IU/kg/week s.c. daily. The girls were prepubertal, with a mean (SD) chronological age (CA) of 12.5 (2.6) years, and a mean (SD) bone age of 10.5 (1.8) years. A clonidine stimulation test, 1-29 GHRH test and GH spontaneous nocturnal secretion assessment were performed in all patients. Results showed a variable pattern of GH secretion in 10 patients, in only 2 did we find all values definitely normal, and in 3 we found a total GH deficiency. Height velocity, expressed as standard deviation scores (SDS) for CA according to Turner references, during the first year of treatment increased significantly: 0.36 (1.15) -3.30 (2.87) (p < 0.001), and the increment remained quite unchanged during both the second and third years: 3.16 (2.96) and 2.55 (3.87), respectively (n.s.). Height, expressed in SDS for CA for Turner references, increased significantly throughout the whole period of treatment and reached the highest value at the end of the third year of therapy. GH secretion parameters poorly correlated with pretreatment auxological data or response to treatment. Our long-term study confirms that in TS GH measurement is not useful in indicating hGH therapy or in predicting the response.     

Effect of recombinant human growth hormone on urinary 15N-nitrogen balance in girls with Turner syndrome as compared to children with growth hormone deficiency

15N-nitrogen balances before and on human growth hormone (hGH) were studied in 13 girls with Turner syndrome (TS) aged 4.4-16 (median 13.2) years (45,X0 or equivalent, no X0/XX mosaicism, no estrogen replacement). The results were compared with those reported from 9 patients with growth hormone deficiency (GHD). The TS patients received subcutaneous hGH doses of 2 x 3 (group A, n = 6), 3 x 2 (group B, n = 3), or 2 x 6 (group C, n = 4) IU/m2 on consecutive days. The mean 15N dose given to the patients of groups A and C was higher (13.6 mg/kg) than that given to those of group B (2.7 mg/kg). The lower hGH doses in the first two groups induced small positive mean 15N balance changes (+0.6 +/- 0.6 mg/kg 15N, group A; +0.03 mg/kg, group B). The higher hGH dose in group C caused a more marked mean balance change (+3.0 mg/kg 15N) comparable to that in GHD patients (+3.2 mg/kg). Individual variation of response, however, was larger in patients with TS than in those with GHD. With low and high hGH doses, there were responders and nonresponders. It is concluded from this pilot study in a small number of cases that 15N balance studies might be potentially useful to choose the appropriate hGH dose for long-term treatment in TS patients.     

Diagnostic utility of a low-dose gonadotropin-releasing hormone test in the context of puberty disorders

OBJECTIVES: The 10-microg gonadotropin-releasing hormone (GnRH) test assesses pituitary gonadotroph responsiveness, whereas the 100-microg dose assesses maximal secretory capacity. Our aims were to establish normative data for the low-dose test in children and to evaluate the test in diagnosing common pubertal disorders. METHODS: We retrospectively classified 107 children who underwent 10-microg GnRH tests into normal prepubertal (20 boys, 10 girls), normal early pubertal (10 boys, 16 girls), constitutional delay of puberty (CDP, 13 prepubertal boys >12 years), hypogonadotropic hypogonadism (HH, 5 prepubertal boys >12 years), central precocious puberty (CPP, 19 girls) or premature thelarche/variant (13 girls). RESULTS: Peak LH response was higher in prepubertal boys >12 years compared with younger boys (p < 0.01) but showed no further change in early puberty. CDP boys had LH responses similar to prepubertal boys >12 years. HH boys showed an absent LH response which diagnosed HH with 100% sensitivity and 96% specificity. Thelarche girls had LH:FSH peak ratios lower than normal prepubertal (p = 0.001), pubertal (p < 0.05) or CPP (p = 0.001) girls. CONCLUSIONS: We have established normative values for the low-dose GnRH test in children. The test successfully differentiated HH from CDP in boys, and contributed to the differential diagnosis of CPP and premature thelarche in girls.