Idiopathic True Precocious Puberty Research Articles

Changes in the Predicted Adult Height after Gonadotropin-Releasing Hormone Agonist Treatment in Girls with Idiopathic True Precocious Puberty

Purpose: We evaluated the effects of the timing of treatment initiation with gonadotropin-releasing hormone agonist (GnRHa) on the change in predicted adult height (PAH) in girls with idiopathic true precocious puberty (TPP). Methods: Data for this retrospective study were collected on 104 girls with TPP who were treated with GnRHa for 36 months, between January 2002 and March 2012. Results: The PAH SDS differed before and after treatment in all patients (-1.91 ± 1.47 vs. -1.37 ± 1.17 after 1 year of treatment, -1.96 ± 1.58 vs. -0.48 ± 1.11 after 3 years of treatment) as well as in Group 1 (-2.15 ± 1.54 vs. -1.51 ± 1.20 after 1 year of treatment, -2.09 ± 1.59 vs. -0.55 ± 1.19 after 3 years of treatment) and Group 2 (-1.57 ± 1.34 vs. -1.17 ± 1.12 after 1 year of treatment, -1.50 ± 1.55 vs. -0.21 ± 0.74 after 3 years of treatment). This result could be due to improvement in bone age advancement during the treatment. The difference between mid-parental height SDS and PAH SDS was decreased after GnRHa treatment. However, the means of PAH SDS did not surpass the mid-parental height SDS. Conclusion: GnRHa treatment can preserve growth potential by slowing bone age progression, resulting in short adult height, but it cannot alter the genetic growth potential.

특발성 진성 성조숙증으로 진단된 소아의 원인 및 임상적 분석

Objectives: The purpose of this study is to estimate genetic and environmental factors, which can affect Idiopathic true Precocious puberty, and to evaluate the clinical and endocrinologic characteristics. Methods: Retrospective and Comparative analysis of 76 children (72 girls and 4 boys) has been diagnosed with idiopathic true precocious puberty, and treated with GnRHa from December 2008 to July 2011. Results: 1. The Average chronological age (CA. yr) of children diagnosed with idiopathic true precocious puberty was <TEX>$8.40{\pm}0.81$</TEX> (girls), <TEX>$9.93{\pm}0.12$</TEX> (boys). 2. The Average height & weight percentile (%ile) of the girls diagnosed with idiopathic true precocious puberty was <TEX>$67.38{\pm}22.04$</TEX>, <TEX>$67.69{\pm}23.20$</TEX>. 3. The girls' mothers have diagnosed with idiopathic true precocious puberty, and they were shorter than the average. This shows that mother's small height and idiopathic true precocious puberty are closely related to each other. 4. BMI percentile (%ile) of girls diagnosed with idiopathic true precocious puberty was <TEX>$63.26{\pm}24.86$</TEX>. 23.6% of children were diagnosed with overweight or obesity. This result shows that obesity and idiopathic true precocious puberty are proportionally related. 5. Birth weights (kg) of the children diagnosed with idiopathic true precocious puberty were <TEX>$3.16{\pm}0.43$</TEX> (girls), <TEX>$3.15{\pm}0.38$</TEX> (boys). 8.3% of children were diagnosed with Intrauterine growth retardation. 6. The Average bone ages (BA. yr) of the children diagnosed with idiopathic true precocious puberty were <TEX>$10.51{\pm}0.99$</TEX> (girls), <TEX>$12.10{\pm}0.97$</TEX> (boys). The Average BA-CA was <TEX>$2.11{\pm}0.81$</TEX> (girls), <TEX>$2.00{\pm}0.87$</TEX> (boys). 7. The Average predicted adults' height (PAH. cm) of the children diagnosed with idiopathic true precocious puberty was <TEX>$151.61{\pm}4.00$</TEX> (girls), <TEX>$163.50{\pm}2.15$</TEX> (boys). The Average MPH-PAH was <TEX>$6.84{\pm}4.91$</TEX> (girls), <TEX>$6.00{\pm}5.35$</TEX> (boys). 8. 23.6% of the children treated with GnRHa were co-treated with Growth Hormone. Conclusions: Estimated factors which cause Idiopathic true precocious puberty are mother's small height, obesity, and Intrauterine growth retardation. However, the studies of Oriental Medicine for Idiopathic true precocious puberty were lacking. Further clinical and experimental researches are needed.

The Relationship between Initial Body Mass Index and Body Mass Index after One Year of Gonadotropin-Releasing Hormone Agonist Therapy in Idiopathic True Precocious Puberty Girls

The Relationship between Initial Body Mass Index and Body Mass Index after One Year of Gonadotropin-Releasing Hormone Agonist Therapy in Idiopathic True Precocious Puberty Girls Ju Young Yoon, M.D., Min Jae Kang, M.D., Se Young Kim, M.D., Ji Young Seo, M.D., Sei Won Yang, M.D., Young Ah Lee, M.D., Ji Eun Lee, M.D., Hye Rim Chung, M.D and Choong Ho Shin, M.D. Department of Pediatrics , Seoul National University College of Medicine, Seoul, Department of Pediatrics, Bundang Jesaeng General Hospital, Seongnam, Department of Pediatrics, Eulji University School of Medicine, Seoul, Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea

Clinical research of luterinizi releasing hormone anogist with zhibaidihuang pill treatment for girls idiopathic true precocious puberty

目的 研究达那唑、知柏地黄丸联合治疗女孩特发性性早熟临床疗效.方法29例乳房在B3期以内的女孩特发性性早熟(ICPP)患儿,其中9例单独使用达那唑,12例采用达那唑、知柏地黄丸联合治疗,未治疗作为对照组8例.治疗前后分别进行生长速率、第二性征、骨龄的测定,子宫卵巢成熟度测定以及达必佳(LHRH)激发实验.结果两组患儿在治疗4个疗程后进行疗效对比结果:达那唑组患儿平均身高增速减慢不明显、最终身高的预测值增加不明显(P＞0.05)、第二性征减退、血LH峰值不同程度下降、骨龄无改变;达那唑、知柏地黄丸联合治疗组患儿,平均身高增速减慢、最终身高的预测值增加(P＜0.001);第二性征减退明显减退,骨龄/年龄比值(△BA/△CA)值下降(P＜0.001),提示骨龄增长速度减慢、血LH峰值显著下降(P＜0.001)、子宫卵巢均有不同程度的回缩.结论达那唑、知柏地黄丸联合治疗轻、中度女孩ICPP,可减慢骨骼生长,延缓骨龄成熟,改善最终身高,并且减轻患者的经济负担。

Evaluation of the true precocious puberty rats induced by neonatal administration of Danazol: therapeutic effects of nourishing "Yin"-Removing "Fire" Chinese herb mixture.

BackgroundNourishing "Yin"-Removing "Fire" Chinese Herb Mixture, a traditional herb-based formulation, has been successfully used for the management of idiopathic true precocious puberty (IPP) for more than thirty years. Precocious puberty rat model by neonatal administration of Danazol was used to investigate the effects of the herb mixture on the advanced sexual development of the rats, and the expression of hypothalamic gonadotropin-releasing hormone (GnRH), which is the important regulator for the hypothalamus-pituitary-gonadal axis, particularly at puberty.MethodsFemale Sprague-Dawley rats were divided into five groups: intact normal (N), IPP model (M), vehicle with no IPP (V), IPP model exposed to herb mixture (HM) and IPP model exposed to saline (S). Rats at 5 days of age were given a single subcutaneous injection of 300 microgram of Danazol dissolved in 25 microliter vehicle of propylene glycol-ethanol (1:1, v/v), to establish the precocious puberty model. From the day 15, rats in HM and S groups were continuously fed with either Nourishing "Yin"-Removing "Fire" Chinese Herb Mixture 2 ml or saline 2 ml, until 3 consecutive regular estrous cycles were established. The day of vaginal opening and the day of setup regular estrous cycle of the rats were observed. Blood concentration of estrogen was determined by radioimmunoassay. Immunohistochemistry and RT-PCR analysis were used to explore the expression of GnRH.ResultsThe day of vaginal opening and first estrous showed significant advancement in M compared with N and V (p < 0.05, respectively). The blood estrogen level increased significantly in M compared with those in other groups (about 28 days of age, at the time of vaginal opening in M rats) (p < 0.05, respectively). GnRH cells in rostral medial septum (MS), Broca diagonal band nucleus (DBB) and the medial preoptic area (MPOA), were calculated. The number in M was less than those in N and V (p < 0.05, respectively). The number was significantly higher in HM than that in M (p < 0.05). The GnRH mRNA expression increased significantly in M compared with that in N and V (p < 0.05).ConclusionThe true precocious puberty model by neonatal administration of Danazol in female rats showed augmented expression of hypothalamic GnRH; the Nourishing "Yin"-Removing "Fire" Chinese Herb Mixture down-regulated the increased GnRH expression, and significantly delayed the sexual development of the precocious puberty rat.

Height prognosis of children with true precocious puberty and growth hormone deficiency: Effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.

Preserving adult height potential in girls with idiopathic true precocious puberty

We designed a prospective study of height potential in girls with idiopathic precocious puberty, comparing the presenting features of girls with and without evidence of reduced adult height potential. The 14 girls with impaired adult height prognoses (group 1) were reexamined after treatment with a gonadotropin releasing hormone agonist, nafarelin. The seven girls with the prognosis of unimpaired height (group 2) were followed without therapy. We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 (mean +/- SEM: 1.4 +/- 0.06 vs 1.0 +/- 0.05; p less than 0.005) and by the greater difference between predicted height and target height in group 1. The mean predicted height in group 1 was significantly less than the mean target height (150.7 +/- 2.1 vs 165.4 +/- 3.0 cm; p less than 0.005), whereas the mean predicted and target heights in group 2 were similar (165.4 +/- 3.0 vs 164.3 +/- 2.1 cm). Initial estradiol levels were also greater in group 1 than in group 2 (21.6 vs 10.6 pg/ml; p less than 0.05), although this difference was not sustained during follow-up. In group 1, nafarelin therapy suppressed the pituitary-gonadal axis, and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy, 2 years of treatment slightly improved predicted heights from 150.7 +/- 2.1 to 152.7 +/- 2.0 cm (p less than 0.05). Height predictions also increased without therapy during the 2-year observation period in group 2, from 165.4 +/- 3.0 to 168.7 +/- 4.1 cm (p less than 0.05). Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis, and that height potential is preserved without therapy in those with a good initial height prognosis.

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.

Treatment of true precocious puberty with a potent luteinizing hormone-releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis.

We used the LHRH agonist D-Trp6-Pro6-N-ethylamide LHRH (LHRH-A) to treat 19 children (12 girls and 7 boys) with true precocious puberty. Fourteen patients had idiopathic true precocious puberty, 4 had a hamartoma of the tuber cinereum, and 1 had a hypothalamic astrocytoma. Basal gonadotropin secretion and responses to native LHRH decreased within 1 week of initiation LHRH-A therapy, and sex steroid secretion decreased within 2 weeks to or within the prepubertal range. Ultrasonographic evaluation of the uterus indicated a postmenarchal size and shape in all 11 girls studied before treatment, which reverted to prepubertal size and configuration in 5 girls during LHRH-A therapy. The enlarged ovaries decreased in size and the multiple ovarian follicular cysts regressed. Sexual characteristics ceased advancing or reverted toward the prepubertal state in all patients receiving therapy for 6-36 months. All 5 girls with menarche before therapy had no further menses. Three girls had hot flashes after LHRH-A-induced reduction of the plasma estradiol concentration. Height velocity, SDs above the mean height velocity for age, and SDs above the mean height for age decreased during LHRH-A therapy; the velocity of skeletal maturation decreased after 12 months of LHRH-A therapy and was sustained during continued therapy over 18-36 months. In 4 patients, a subnormal growth rate (less than 4.5 cm/yr) occurred during LHRH-A therapy. Six patients had cutaneous reactions of LHRH-A, but no demonstrable circulating antibodies to LHRH-A. In 2 patients in whom LHRH-A therapy was discontinued because of skin reactions, precocious sexual maturation resumed at the previous rate for the ensuing 6-12 months; subsequently, they were desensitized to LHRH-A, and during a second course of therapy, their secondary sexual development and sex steroid levels again quickly decreased. LHRH-A proved an effective and safe treatment for true precocious puberty in boys as well as girls with central precocious puberty whether of the idiopathic type or secondary to a hamartoma of the tuber cinereum or a hypothalamic neoplasm.

Luteinizing Hormone-Releasing Hormone Analog Treatment of Boys with Hypothalamic Hamartoma and True Precocious Puberty

A long-acting analog of LRH (LRHa) has been shown to suppress pituitary gonadotropin and estradiol secretion to prepubertal levels in girls with idiopathic true precocious puberty. We treated six boys, aged 1-6 yr, with true precocious puberty due to hypothalamic hamartoma for 6-24 months with daily sc injections of LRHa. The patients had enlarged testes (6-25 ml), Tanner stage II-IV pubic hair, facial and axillary hair, increased growth rate, and an advanced bone age. Frequent erections occurred in all patients. Computed tomography of the head showed abnormalities characteristic of hypothalamic hamartoma (0.5-3 cm in diameter) in each boy. Each patient had measurable LH and FSH levels, with pulsed nocturnal secretion, and pubertal LH and FSH responses to LRH. Serum testosterone was in the range for normal adult men (200-600 ng/dl). LRHa significantly decreased basal LH (P less than 0.005) and FSH levels (P less than 0.01), LRH-stimulated gonadotropin levels (P less than 0.005), and serum testosterone levels (P less than 0.005). Testis size decreased significantly (P less than 0.005). Annualized growth velocity (centimeters per yr) decreased significantly compared to the pretreatment growth rate (P less than 0.01). Bone age advancement per yr slowed significantly during the course of LRHa treatment (P less than 0.01). Pubic hair, facial hair, and erections decreased in all patients. LRHa is an effective treatment for boys with precocious puberty associated with hypothalamic hamartoma. Chronic therapy will be required, however, to assess the ultimate effect of LRHa.

Idiopathic Precocious Puberty in the Chimpanzee: A Case Report

A female chimpanzee developed premature sex skin swelling, breast budding, advanced bone age, and moderate estrogen effect of the vaginal cytology. Extensive radiographic and hormonal studies excluded all the known causes of precocious puberty and pseudopuberty, yielding a diagnosis of idiopathic true precocious puberty. To our knowledge this is the first observation of idiopathic true precocious puberty in a chimpanzee.

Daily rhythm of plasma melatonin in normal and precocious puberty.

A previous study of normal humans has shown a decrease in plasma melatonin at the onset of puberty, suggesting that melatonin may act to restrain pubertal onset. We have measured plasma melatonin throughout a 24-h period in normal and constitutionally short males at different pubertal stages and in patients with idiopathic true precocious puberty and familial male isosexual precocity. The 24-h profile of plasma melatonin was similar for the prepubertal, pubertal, and adult males studied, with all subjects having low levels (20-50 pg/ml) during the day and high levels (80-100 pg/ml) at night between 0100-0500 h. The 24-h profiles of the patients with isosexual precocity were similar to the profiles observed throughout normal puberty. These data do not support a role for melatonin in the initiation of normal or precocious puberty in man.

The effect of medroxyprogesterone acetate on gonadotropin secretion in girls with precocious puberty.

Plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) as detected by radioimmunoassay have been found to be present in prepubertal children and show a gradual rise until the onset of puberty. Children with idiopathic true precocious puberty have plasma gonadotropin levels which are appropriate for their advanced degree of sexual development. A potent progestational agent, 6-methyl-17-hydroxyprogesterone acetate or medroxyprogesterone has been used in the treatment of precocious puberty and will suppress its physical manifestations. In this study the effect of medroxyprogesterone on gonadotropin levels was investigated in seven girls with true precocious puberty. Plasma LH values were found to be significant lower in patients receiving this agent than in a group of normal prepubertal girls. FSH values did not differ from the control group. One patient was evaluated prior to treatment and showed decreasing levels of LH after therapy was begun. These data suggest that medroxyprogesterone may act on the pituitary-hypothalamic axis to suppress the pubertal levels of LH.