Gonadotropin-suppressive therapy in girls with early and fast puberty affects the pace of puberty but not total pubertal growth or final height.

Early and fast puberty (EFP) in girls, defined as pubertal onset at age 8-9 yr, with an accelerated course, may cause compromised final height (FHt) and psychosocial distress. Treatment with a gonadotropin-suppressive agent is controversial, because the improvement in FHt is equivocal and there may be risk of obesity. We analyzed the data of 126 girls with EFP: 63 treated with GnRH analog (GnRHA) since Tanner stage 3, for 2-4 yr; and 63 untreated. Age at onset of puberty; accelerated time of transition from Tanner stage 2 to 3 (<1.3 yr); and clinical, hormonal and sonographic findings were similar in the 2 groups. The girls given GnRHA treatment had a significantly prolonged pubertal course, compared with the accelerated course in the untreated girls (4.7 +/- 0.4 vs. 2.45 +/- 0.4 yr, P < 0.001). After therapy, they reached Tanner stages 4 and 5 and FHt at a significantly older age than the untreated group (P < 0.001), and their menarche was delayed (12.8 +/- 0.6 vs. 10.8 +/- 0.5 yr, P < 0.001). However, the different pace of puberty in the 2 groups did not change the total pubertal growth and the bone maturation rate. The Ht gain from Tanner stage 3 to 4 (10.4 +/- 2.7 vs. 11.2 +/- 3.1 cm) and from Tanner stage 4 to FHt (8.2 +/- 2.7 vs. 8.8 +/- 3.6 cm) was similar in the treated and untreated girls, as were absolute Ht and bone age at each pubertal stage. The weight gain of the treated girls was more pronounced during treatment (P = 0.0016), but it was arrested after discontinuation of therapy; and by the time FHt was reached, the body mass index was similar in the 2 groups. The treated and untreated girls achieved a similar mean FHt, which was not significantly different from their respective mean target Ht (THt). Individual analysis revealed that 70% of the treated girls and 67% of the untreated girls attained their THt range (THt +/- 0.5 SD) or surpassed it. In conclusion, treatment with GnRHA affected only the pace of EFP. The similar Ht gain and bone maturation rate at each pubertal stage in the treated and untreated girls may suggest that the total pubertal growth is not dependent on pubertal duration and pace and is probably determined already at the onset of the normal pubertal development. The treatment did not compromise the FHt and did not cause long-lasting obesity. Therefore, GnRHA therapy may be suggested for use in girls who have psychosocial difficulties in coping with EFP.

Sexual precocity in boys: accelerated versus slowly progressive puberty gonadotropin-suppressive therapy and final height.

The indication for GnRH analog treatment in boys with central sexual precocity is based mainly on the age of onset of puberty. Our aim was to determine whether the rate of pubertal progression should also be taken into consideration. Included in the study were 81 boys with central sexual precocity: 27 with true precocious puberty (onset at <9 yr) and 54 with early puberty (onset at 9-10.5 yr). At the time of analysis, all had completed puberty, and 66 (22 central precocious puberty, 44 early puberty) had achieved final height. Progression of puberty (Tanner stage 2 to 3) was accelerated (0.5-1.32 yr) in 42 boys (16 central precocious puberty, 26 early puberty) and slow (1.7-2.9 yr) in 39 (11 central precocious puberty, 28 early puberty). The boys with accelerated puberty had significantly elevated T levels (central precocious puberty and early puberty, P < 0.001), faster growth rate (change in height SD score/duration: central precocious puberty, P < 0.05; early puberty, P < 0.01), and faster bone maturation rate (change in bone age/duration: central precocious puberty, P < 0.05; early puberty, P < 0.001). All 42 boys with accelerated puberty were treated with GnRH analog for 2.3-4.2 yr; the duration to completion of puberty and the height gain after therapy was discontinued were similar for the boys with central precocious puberty and early puberty. The 39 boys with slow puberty received no treatment and had a prolonged course of puberty (central precocious puberty, 5.05 +/- 0.3 yr; early puberty, 4.72 +/- 0.77 yr; average normal, 3.5 yr). The final height achieved in the 35 (11 central precocious puberty, 24 early puberty) untreated boys was within the range of their respective target height. The 31 (11 central precocious puberty, 20 early puberty) treated boys also achieved their genetic target height. Predictions based on the Bayley-Pinneau method at Tanner stage 3 for all boys and at discontinuation of therapy for treated boys overestimated the achieved final height (P < 0.001). In conclusion, boys with sexual precocity, whether central precocious puberty or early puberty, may have either accelerated or slow pubertal development. The decision to institute suppressive therapy should be based also on the rate of pubertal progression. Treatment should be offered only to those (either central precocious puberty or early puberty) with accelerated growth and bone maturation rates and rapid increase in T levels. Suppression therapy apparently converts accelerated puberty into nonsustained slow puberty and probably prevents compromised final height.

Longitudinal analysis of growth over the first 3 years of life in Turner's syndrome.

OBJECTIVE: To evaluate longitudinal growth in Turner's syndrome (TS) over the first 3 years of life. METHODS: Growth of 47 patients with TS was compared with that of 40 age-matched control girls by using an analysis according to the Infancy-Childhood-Puberty and bi-exponential models. RESULTS: A mean of 1.2 SDs were lost before birth and a total of 3.0 SDs were lost by age 3 years. According to the Infancy-Childhood-Puberty model, intrauterine growth retardation contributed -1.24 SDs, a 5-month delay in childhood growth spurt contributed -0.96 SDs, and slow childhood growth contributed an additional -0.8 SDs by age 3 years. The bi-exponential analysis disclosed a quasi-linear first exponent and a confining second exponent, which merged at age 18 months in control subjects and 24 months in patients with TS. The first exponent confers an average annual growth rate of 8.4 cm/y in control subjects and 6.7 cm/y in patients with TS. CONCLUSIONS: Intrauterine growth retardation and the initial 3 years of life contribute most of the deficit in the final height of patients with TS. These data provide a reference of standards for longitudinal growth in patients with TS at age 3 months to 3 years.

Experience with cyproterone acetate in the treatment of precocious puberty.

The authors review their experience (1967-present) in the use of cyproterone acetate (CPA) in precocious puberty. CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg b.i.d. (70-100 mg/d). After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial stimulatory effect of the GnRHa as well as an adjunct drug in case of very active adrenarche causing advanced bone age during GnRHa treatment. The final heights of girls treated with CPA and girls treated with D-Trp6-LHRH were found comparable: 157.8+/-5.1 cm vs 159.6+/-6.3 cm, respectively. The main adverse effects were occasional fatigue due to partial adrenal insufficiency with CPA and gynecomastia in a few boys. Liver function tests were normal in all patients with the exception of one boy with severe hypothalamic disease, including precocious puberty, who developed liver cirrhosis 3 years after stopping CPA following 5 years treatment. Other indications for CPA treatment during childhood and adolescence, such as fast puberty, congenital adrenal hyperplasia and acne, are also mentioned.

Delayed growth and puberty in patients with Gaucher disease type 1: natural history and effect of splenectomy and/or enzyme replacement therapy.

BACKGROUND: Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation. OBJECTIVE: To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy. METHODS: We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy. RESULTS: Deceleration of growth at age 3-5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34 +/- 0.42 at age 0-3 years to -1.93 +/- 0.95 (P < 0.01) at age 7-10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height-standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty. CONCLUSIONS: Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty.

Cirrhosis in a child with hypothalamic syndrome and central precocious puberty treated with cyproterone acetate.

UNLABELLED: Before the advent of gonadotropin-releasing-hormone analogues, cyproterone acetate (CPA) had been widely prescribed for the treatment of precocious puberty. Although it is usually well tolerated, liver toxicity has been recognized as a complication of its long-term use. We report the occurrence of cirrhosis in a 10-year-old boy with hypothalamic syndrome and precocious puberty who was treated with CPA for over 50 months. Despite discontinuation of the medication, the liver disease progressed. The patient died of sepsis and multiorgan failure at the age of 14 years. This is the first paediatric report of substantial liver damage and liver toxicity progressing to cirrhosis associated with CPA treatment. CONCLUSION: Prolonged cyproterone acetate treatment may induce cirrhosis. Monitoring of liver function both during treatment and for several months after discontinuation of therapy is recommended.

Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the Bayley-Pinneau method.

This study was designed to determine the benefit of therapy on final height (FHt) in girls with central precocious puberty (CPP). A total of 102 patients were evaluated--28 untreated, 26 treated with cyproterone acetate (CyA), and 48 treated with GnRH analogue (GnRHA)-and their achieved FHt was compared to the respective target height (THt). Of the untreated girls, half (14/28) had a slow course of puberty and reached THt +/- 0.5 SD (FHt 160.2 +/- 7.1, THt 159.5 +/- 6.6 cm); the other half (14/28) had an accelerated course of puberty with a FHt well below THt (FHt 150.8 +/- 4.3, THt, 159.2 +/- 5.9 cm) and in most cases (14/28) below the height-SDS of both parents. The treated girls (both regimens) reached THt above (CyA group: FHt 157.8 +/- 5.1, THt 156.8 +/- 5.1 cm; GnRHA group: 159.6 +/- 6.3, THt 157.7 +/- 5.7 cm). We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years. Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used, regardless of the advanced bone age of the patients.

Early polycystic ovary-like syndrome in girls with central precocious puberty and exaggerated adrenal response.

Exaggerated adrenal response (ExAR), i.e. hypersecretion of both 17-hydroxypregnenolone (170HPreg) and 17-hydroxyprogesterone(17OHP) in response to adrenocorticotropic hormone (ACTH) stimulation, is frequently found in women with polycystic ovary (PCO) syndrome who had precocious adrenarche. In an earlier study we found an abnormal adrenal response in girls with idiopathic true central precocious puberty (CPP) at early stages of puberty. On follow-up it was noted that a significant number of girls with CPP develop PCO-like syndrome at a relatively young age. The aim of the present study was to determine if there is an association between ExAR and early PCO in girls with a history of CPP. Included were 49 girls with a history of CPP, 34 of whom were treated with gonadotropin-releasing hormone (GnRH) analog. All 49 were evaluated at full maturity, at ages 12.5-14 years, 0.5-4 years after menarche or resumption of menses. Of the 49 girls, 20 had at least 3/4 clinical signs of PCO (irregular menses, hirsutism, acne and obesity) and were defined as PCO-like+, whereas 29 did not fulfil the criteria and were considered PCO-like-. Girls with a definite enzyme deficiency were excluded from the study. All participants underwent a combined iv ACTH-GnRH test at early follicular phase. The PCO-like+ girls all revealed ExAR, i.e. an elevated stimulated 17OHPreg of 63.4 +/- 9.6 nmol/l (normal 28.6 +/- 9.2 nmol/l) and a normal stimulated 17OHPreg/17OHP ratio of 7.1 +/- 1.8 (normal 6.2 +/- 2.7), whereas all the PCO-like- had a normal adrenal response (30.0 +/- 8.7 and 5.3 +/- 2.0 nmol/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

High prevalence of abnormal adrenal response in girls with central precocious puberty at early pubertal stages.

Abnormal adrenal response is often observed in girls with precocious adrenarche (1). We studied the adrenal response in 112 girls with idiopathic true central precocious puberty (CPP) at early stages of puberty compared to that in 21 girls with normal puberty (controls). The aims of this study were to determine the prevalence of abnormal adrenal response at early stages of puberty, the possible correlation of abnormal adrenal response with pubertal signs at onset of puberty and with plasma androgen levels, and a possible association with the activity of the hypothalamic-pituitary-gonadal (HPG) axis. All participants underwent a combined i.v. adrenocorticotropic hormone (ACTH)-gonadotropin-releasing hormone (GnRH) test at Tanner stage 2-3: 62 of the CPP girls before and 50 during treatment with GnRH analog. The stimulated levels of 17-hydroxypregnenolone (17OHPreg) and the stimulated 17OHPreg/17-hydroxyprogesterone ratio were analyzed and compared to previously reported norms. The result revealed three patterns of adrenal response: normal (17OHPreg < or = 24 nmol/l and 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 17/21 (80.9%) controls; exaggerated (17OHPreg > 24 nmol/l, 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 3/21 (14.3%) controls; and non-classical 3 beta-hydroxysteroid dehydrogenase deficiency (17OHPreg > 24 nmol/l and 17OHPreg/17OHP ratio > 7) in 12/112 (10.8%) CPP patients and 1/21 (4.8%) controls. The clinical features at onset of puberty were comparable in all girls with the CPP in spite of the different adrenal response patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Final height of girls with Turner's syndrome: correlation with karyotype and parental height.

Final height of 75 adults with Turner's syndrome (45 Israeli, 30 Italian), never treated with GH, was examined to see if a relationship with karyotype patterns and parental height existed. Patients were divided into five groups according to their chromosome pattern, as follows: group A = 45, X karyotype (34 patients); group B = mosaicism (11 with karyotype 45,X/46,XX and 7 with karyotype 45,X/46,XY); group C = deletion of all or part of Xp (19 patients); subgroup C1 = 6 with complete deletion of Xp; subgroup C2 = 9 with mosaicism 45,X/46,X,i(Xq); subgroup C3 = 4 with 45,X/46,X,ring(X); group D = deletion of Xq (4 patients); pure gonadal dysgenesis (PGD) group = 9 patients with pure 46,XX gonadal dysgenesis. No statistical difference was noted between the mean height of the two national populations studied (Italian 142.2 +/- 5.7 and Israeli 143.0 +/- 7.2 cm). The mean heights of group D (148.9 cm; range 147-166.2) and the PGD group (156.0 cm; 141-171.5) were found to be significantly higher than those observed in groups A, B and C (p < 0.03, p < 0.02 and p < 0.02, respectively), even though gonadal distinction existed in all five groups. Subgroup C1, where a deletion of the entire Xp segment [46,X,i(Xq)] was present, was found to be the shortest group (median height 134.5; range 131.9-138 cm).(ABSTRACT TRUNCATED AT 250 WORDS)

Central precocious puberty: evaluation by neuroimaging.

To evaluate the incidence of abnormal intracranial findings in children with central precocious puberty, 62 children (51 girls, 11 boys) were examined by computerized tomography and/or magnetic resonance imaging (MRI) of the brain. Forty-four had normal examinations; 18 (11 girls, 7 boys) showed intracranial pathologies, including hamartoma of the tuber cinereum (8 cases), parenchymal loss (3 cases), hypothalamic-chiasmatic lesions (2 cases), lesions of the corpus callosum (2 cases), suprasellar cyst (1 case), and pineal cyst and mesiotemporal sclerosis (1 case each). Based on the correlation between the clinical and the imaging results of this series, the authors recommend MRI as the imaging method of choice in the investigation of precocious puberty.

Hearing impairment in idiopathic hypoparathyroidism and pseudohypoparathyroidism.

Sensorineural hearing impairment is a lesser known feature of hypoparathyroidism. The hearing of 20 patients with idiopathic hypoparathyroidism was investigated by pure-tone audiometry. Bilateral sensorineural hearing loss was found in three (15%). Sensorineural hearing loss is considered to be associated with a prolonged low calcium level in the inner ear fluid and is a possible complication of hypoparathyroidism.

GH and GHBP activity and not IGF-1 and its receptor activity express growth velocity reduction during treatment of central precocious puberty by a superactive GNRH analogue.

We studied six patients with central precocious puberty (CPP) (five girls and one boy, aged 9-14.4 years) before and after 5 and 12 months of treatment with GnRH-A (D-TRP-6-LHRH-depo, DECAPEPTYL Ferring, Sweden), and 14 age-matched prepubertal children serving as controls. GnRH suppressed gonadal sex hormone secretion and arrested the gonadarche development. Growth velocity decreased from 9.8 +/- 1.6 (mean +/- SD) to 4.6 +/- 1.0 cm/year after 1 year of treatment. Basal serum IGF-1 levels of the CPP patients were 35.4 +/- 2.8 nmol/l, which was significantly higher than that of the controls (18.8 +/- 1.9, P = 0.00007). After GnRH-A there was a slight but significant increase in serum IGF-1 levels from 35.4 +/- 2.8 (mean +/- SE) to 40.3 +/- 2.1 nmol/l after 5 months (mean difference of 4.9 +/- 1.7, P = 0.02), reversing to 35.6 +/- 2.8 nmol/l after 12 months. The number of high affinity IGF-1 binding sites on erythrocytes (RBC) in the controls was 3.3 +/- 0.3 sites/cell, similar to that found in the patients before treatment. Following therapy, the number of the binding sites decreased from 4.0 +/- 0.8 (mean +/- SE) to 2.5 +/- 0.6 sites/cell after 5 months (mean difference of -1.4 +/- 0.5, P = 0.01), to 2.7 +/- 0.7 sites/cell after 12 months. Basal levels of plasma GH in the CPP patients were 7.1 +/- 1.3 ng/ml, significantly higher than those of the controls (1.2 +/- 0.2, P = 0.00001). Treatment decreased plasma GH in patients from 7.1 +/- 1.3 to 1.3 +/- 0.3 ng/ml after 5 months (mean difference of -5.8 +/- 1.3, P = 0.003) and to 2.7 +/- 1.5 ng/ml after 12 months. The GH binding protein (GHBP) activity in the controls was 76.2 +/- 6.2% relative specific binding, similar to that of the patients before therapy. The mean basal GHBP activity of the patients increased from 75.5 +/- 7.3 to 101 +/- 6.4% (mean difference of 25.5 +/- 9.7, P = 0.01) after 5 months and to 90.1 +/- 5.6% after 12 months of treatment. In conclusion, plasma GH and its receptor activity are a better indicator of the GnRH-A effect on growth than IGF-1 and its receptor activity.

Social, educational and vocational status of 48 young adult females with gonadal dysgenesis.

OBJECTIVE: The purpose of this study was to evaluate the educational, vocational and social function of young adults with gonadal dysgenesis. DESIGN: Forty-eight female patients with gonadal dysgenesis (17, 45XO; 26, 45XO/46XX or other mosaics; and five pure gonadal dysgenesis) followed by our multidisciplinary team from childhood, were re-evaluated in adult age. RESULTS: Mean age +/- SD at diagnosis was 11.4 +/- 5.0 years and mean age at the time of survey was 29.6 +/- 6.3 years. The mean final height for the patients was 145.5 +/- 8.3 cm (range 134-170 cm). Mean verbal IQ (WISC-R) for the 39 subjects tested was 101.4 +/- 20.7 and mean performance IQ was 86.8 +/- 17.7. No difference in verbal IQ levels was found between the various karyotype groups. Twenty-five had an academic education. All were employed except for one housewife; 37 work in white collar professions. A significant correlation was found between verbal IQ and education (P = 0.005) and between verbal IQ and profession (P = 0.005). Twenty-three served in the army. Fourteen are married: three have an adopted child and two a child born after in vitro fertilization (IVF); others are waiting for IVF or adoption. Five patients had some form of psychiatric problem that required psychiatric or psychological treatment in the past (two had transitory anorexia nervosa and three behavioural problems). Sixty-three per cent reported having wide and satisfactory social relations but limited to female friends. CONCLUSION: Positive adjustment in the professional area and fair adjustment in the social area were not related to physical stigmata or to any other independent variable tested, but rather to intellectual ability and a high degree of achievement motivation.

New findings in a patient with Dubowitz syndrome: velopharyngeal insufficiency and hypoparathyroidism.

We report on a boy with Dubowitz syndrome and hypoparathyroidism from which he recovered, only to redevelop it at 6 years. He also had a submucous cleft palate and cineradiographic studies showed velopharyngeal insufficiency. Although a submucous cleft palate is a well-known manifestation of Dubowitz syndrome, velopharyngeal insufficiency has not been previously described.

Pubertal development, growth and final height in girls with sexual precocity after therapy with the GnRH analogue D-TRP-6-LHRH. A report on 15 girls, followed after cessation of gonadotrophin suppressive therapy.

Since 1980 15 girls with sexual precocity who were treated with the superactive GnRH-analogue D-TRP-6-LHRH for 1-5 2/12 years were followed for 1 to 5 6/12 years after discontinuation of therapy. Reactivation of puberty became noticeable 2-4 months and growth velocity increased 4-10 months after treatment was stopped. Menarche (or re-mensis) appeared after 3-9 months in 12/15 girls and after 2 6/12 years in 1. At termination of therapy the predicted final height had improved in 6/8 patients. In the 8/15 patients who had reached their final height at the time of study, the achieved final height was practically equal to the post-treatment prediction in 3/8, above it in 4/8 and below it (but equal to the pretreatment prediction) in 1 patients only who was insufficiently treated. It was found that in patients who had started treatment at an earlier bone age, the benefit as concerned final height was greater and was better evaluated by taking into consideration their genetic growth potential.