• Proceedings of the Korean Society of Developmental Biology Conference
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• 2003.10a
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• pp.83-83
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• 2003

The lutropin/choriogonadotropin receptor (LHR) is a member of the rhodopsin-like subfamily of G protein coupled receptor (GPCRs), that has been shown to mediate the internalization of its two naturally occurring agonist, lutropin and choriogonadotropin (CG). The clustered agonist-receptor complex is internalized by a dynamin-dependent pathway and traverses the endosomal compartment without agonist dissociation Dissociation of the agonist-receptor complex occurs in the lysosomes, where both the agonist and receptor are degrade. Recently, constitutively activating mutations of the receptor have been identified that are associated with familial male-precocious puberty (FMPP). A FMPP is a form of sexual precocious puberty in boys in which testosterone levels are elevated independent of changes in luteinizing hormone-releasing hormone and serum luteinizing hormone levels, We have now analyzed two naturally occurring, constitutively active mutants of the human LHR. These mutations were introduced into the rat LHR (rLHR) and are designated L435R and D556Y. Cells expressing rLHR-D556Y bind human choriogonadotropin (hCG) with normal affinity, exhibit a 25-fold increase in basal cAMP and respond to hCG with a normal increase in cAMP accumulation. Cells expressing rLHR-L435R also bind hCG with normal affinity, exhibit a 47-fold increase in basal cAMP, and do not respond to hCG with a further increase in cAMP accumulation. This mutation enhances the internalization of the free and agonist-occupied receptors ~2- and ~17- fold, respectively We conclude that the state of activation of the rLHR can modulate its basal and/or agonist-stimulated internalization. Since the internalization of hCG is involved in the termination of hCG actions, we suggest that the lack of responsiveness detected in cells expressing rLHR-L435R is due to the fast rate of internalization of the bound hCG. The finding that membranes expressing rLHR-L435R respond to hCG with an increase in adenylyl cyclase activity supports this suggestion. Autonomous Leydig cell activity in FMPP is caused by a constitutively activating LH/CGR.

• Clinical and Experimental Pediatrics
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• v.53 no.7
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• pp.759-765
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• 2010

Purpose: This study evaluated the clinical manifestations of and risk factors for pituitary insufficiency in children and adolescents with Rathke's cleft cysts. Methods: Forty-four patients with Rathke's cleft cysts younger than 19 years who visited Seoul National University Children's Hospital between January 1995 and September 2009 were enrolled. Rathke's cleft cysts were confirmed histologically through an operation in 15 patients and by brain magnetic resonance imaging (MRI) in 29 patients. The clinical, hormonal, and imaging features were reviewed retrospectively. Results: The clinical presentation of symptomatic patients was as follows: headache (65%), endocrinopathy (61%), and visual disturbance (19%). Endocrinopathy included central precocious puberty (18%), diabetes insipidus (14%), general weakness (11%), and decreased growth velocity (7%). After surgery, hyperprolactinemia resolved in all patients, but growth hormone insufficiency, hypothyroidism, and diabetes insipidus did not improve. Pituitary insufficiency except gonadotropin abnormality correlated significantly with severe headache, visual disturbance, general weakness, and cystic size. Suprasellar extension of cysts and high signals in the T2-weighted image on brain MRI were related to hypothyroidism, hypocortisolism, and diabetes insipidus. Multivariable linear regression analysis showed that only general weakness was a risk factor for pituitary insufficiency ($R^2$=0.549). Conclusion: General weakness is a risk factor for pituitary insufficiency in patients with Rathke's cleft cysts. When a patient with a Rathke's cleft cyst complains of general weakness, the clinician should evaluate pituitary function and consider surgical treatment.

• Clinical and Experimental Pediatrics
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• v.52 no.12
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• pp.1370-1376
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• 2009

Purpose:Treatment of precocity with gonadotropin releasing hormone analogue (GnRHa) might theoretically exert a detrimental effect on the bone mass during pubertal development. We investigated the short-term changes in bone mineral density (BMD) during GnRHa treatment and the enhancement in the changes with the co-administration of GnRHa and human growth hormone (hGH). Methods:Forty girls with precocious or early puberty who were using GnRHa for more than 1 year were enrolled. Of them, 14 concurrently received hGH. Lumbar bone mineral density was measured before and after the treatment, and bone mineral density-standard deviation scores (BMD-SDSs) were compared according to chronologic age (CA) and bone age (BA), as well as according to the administration of GnRHa alone (Group I) or the co-administration of hGH and GnRHa (Group II). Results:BMDs before and after treatment were in the normal range according to CA but were significantly lower according to BA (P<0.05). During treatment, BMD-SDSs did not change according to CA but significantly increased according to BA (P<0.05). BMD-SDSs in group I did not change during treatment according to CA or BA, while those in group II increased significantly according to BA (P<0.05), but not according to CA. Conclusion:Lumbar BMD was adequate according to CA at initial manifestation of precocity but was lower if compared to BA, that is, BMD did not increase with BA. Because co-treatment with hGH significantly increased BMD-SDSs according to BA, hGH co-treatment could be considered during GnRHa therapy.

• Clinical and Experimental Pediatrics
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• v.49 no.3
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• pp.305-311
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• 2006

Purpose : GnRH analogues(GnRHa) are used to treat central precocious puberty(CPP). However, in some patients, the GV decrease is so remarkable that it impairs predicted adult height(PAH); and there fore, the addition of growth hormone(GH) is suggested. We analysed the growth changes during two years and final adult height(FAH) in girls with idiopathic CPP treated with combined therapy, compared with those of girls treated with GnRHa alone. Methods : For the analysis, we classified the patients, who was treated for longer than two years, into three groups depending on the initial PAH and combination of GH; PAH_L, treated with GnRHa and PAH less than midparental height(MPH) - 5 cm. PAH_H, treated with GnRHa and PAH greater than MPH - 5 cm. GnRHa＋GH, combined GH treatment, regardless of PAH before treatment. We analysed the GV and PAH change during the first two years and FAH. Results : In PAH_L, the PAH(SDS) at first year of therapy was significantly increased to $153.5{\pm}6.5cm(-1.4{\pm}1.3)$ from $149.7{\pm}6.4cm(-2.1{\pm}1.3)$ before treatment(P=0.004). In PAH_H, there was no significant increase in PAH during the two years of treatment. During the first year of combination of GH and GnRHa, GV and PAH increased significantly. We observed significant increases in FAH, comparing to the initial PAH in the PAH_L and GnRHa＋GH groups. The height gains(FAH - initial PAH) were significantly higher in the PAH_L and GnRHa＋GH groups than that in the PAH_H group. Conclusion : This study suggests the FAH and height gains are improved in patients, whose predicted adult height before treatment was shorter than those with higher predicted adult height, with the treatment of GnRHa alone or in combination with GH. GH could not improve the final adult height, but compensated the growth in patients whose growth velocity was decelerated by GnRHa alone.

• Development and Reproduction
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• v.10 no.1
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• pp.55-61
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• 2006

There is growing concern that dietary soy intake is associated with protection of breast cancer. However, questions persist on the potential adverse effects of the main soy constituent genistein(GS) on female reproductive physiology. In this study, we examined whether prepubertal exposure to GS affected on the onset of puberty and the associated reproductive parameters such as hormone receptor expressions in female rats. GS(100mg/kg/day) was administrated daily from postnatal day 25(PND 25) to the day when the first vaginal opening(VO) was observed, and the animals were sacrificed on the day after VO occurred. Gross anatomy and tissue weight were compared to test the GS's effect on the cell proliferation. Furthermore, histological studies were performed to assess the structural alterations in tissues. Specific radioimmunoassay(RIA) were carried out to measure serum LH levels. To determine the transcriptional changes in progesterone receptors(PR), total RNAs were extracted from ovary and uterus and were applied to semi-quantitative reverse transcription polymerase chain reaction(RT-PCR). As a results, advanced VO was shown in the GS group(PND $31.2{\pm}0.6$) compared to the vehicle group (PND $35.3{\pm}0.7$). GS treatment significantly increased wet weight of ovaries and uteri compared to the vehicle group. Increased serum LH levels were also shown in the GS group. Graafian follicles and corpora lutea(CL) were observed only in the ovaries from GS treated animals. Similarly, hypertrophy of luminal and glandular uterine epithelium were found only in the GS group. Collectively, these effects were probably due to the estrogenic effects of GS. In the semi-quantitative RT-PCR studies, the transcriptional activities of PR in both ovary and uterus from GS-treated group were significantly higher than those from the vehicle group. The present studies demonstrated that acute exposure to GS, at levels comparable to the ranges of human exposure, during the critical period of prepubertal stage activates the reproductive system resulting precocious puberty in immature female rats.

• Advances in pediatric surgery
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• v.1 no.2
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• pp.115-121
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• 1995

We reviewed 45 cases of ovarian tumors treated at Seoul National University Children's Hospital from 1983 to 1993. Forty-five patients were operated upon for 52 ovarian tumors. The most common pathologic diagnosis was mature teratoma. The next were functional cyst, the tumors of epithelial cell origin, and those of stromal origin in order of frequency. Six patients(13%) had malignant tumor. There were one malignant teratoma, two dysgerminomas, one endodermal sinus tumor, and two granulosa cell tumors. Four cases were diagnosed as torsion of ovarian cyst preoperatively, and emergency exploratory laparotomy were performed. There were three cases of ovarian tumors associated with precocious puberty. The most widely used diagnostic tool was ultrasonography. In the treatment of these 45 patients, unilateral oophorectomy was done in 38 cases, unilateral oophorectomy with wedge resection of contralateral ovary was done in 5 cases, unilateral oophorectomy with contralateral simple cystectomy was done in one case and total abdominal hysterectomy with bilateral salpingooophorectomy was done in one case. Of the six cases of malignancy, five patients are alive 2 to 6 years after operation and one case was lost to be followed up.

• Journal of Pharmaceutical Investigation
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• v.39 no.1
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• pp.37-41
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• 2009

The purpose of this study was to compare the efficacy of Lorelin Depot $Injection^{(R)}$ (Dongkook Pharm. Co., LTD) with Lucrin Depot $Injection^{(R)}$ (Abbott) by measuring serum testosterone level in rats. Leuprorelin (leuprolide acetate), which is an active compound for the two formulations, is an LHRH analogue that is used for the treatment of a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. Lorelin Depot $Injection^{(R)}$ is a micro-encapsulated formulation to suppress testosterone level by releasing leuprorelin continuously for four weeks with a single subcutaneous injection. The comparison study of the efficacy was performed during four weeks, and serum testosterone levels were monitored in the two formulations. The mean serum testosterone levels from the formulations were decreased to that of the castrate range (50 ng/dL or less) after three days after the initial depot injection, and the concentration were remained throughout four weeks' period. There were no significant differences in the $AUC_{0-3day}$ of testosterone and testosterone levels at 3, 7, 14, 21 and 28 days between the two formulations. These results indicate that the two formulations, Lorelin Depot $Injection^{(R)}$ and Lucrin Depot $Injection^{(R)}$, are bioequivalent in terms of the serum testosterone level in rats.

• The Journal of Pediatrics of Korean Medicine
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• v.25 no.1
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• pp.119-127
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• 2011

Objectives: The purpose of this study is to evaluate the parents' awareness on the oriental medical treatment and their expectation on children's growth. Methods: The survey was conducted on 78 Health Kids Fair visitors, and 87 children's height and weight were measured in this study. Results: 1. Compare to other treatment, 62.82% of the parents responded that herbal medicine is relatively effective in treating weakness, followed by 'Allergic disease'(46.15%) 'Growth disturbance'(26.92%) 'Obesity'(26.92%) 'Respiratory disease'(26.92%) 'Digestive disease'(19.23%) 'Precocious puberty'(8.97%) 'Neurologic & psychologic disease'(6.41%) 'Urogenital disease'(3.85%). 2. Parents recognize that 'Oriental medicine have an effect on children's height mostly'(25.64%) 'Oriental medicine have an effect on children's height partially'(64.10%) 'Oriental medicine have no effect on children's height'(10.26%) 25.64% of the parents responded that herbal medicine would be helpful in increasing height, 64.10% of the parents said they would be helpful to the certain extent, and 10.26% said they would not play any roles. 3. Expected average weight, height, and BMI score for the boys were 71.8kg, 179.6cm and 22.10. For the girls, however, they were 53.4kg, 168.7, and 18.74. 4. Survey on parents' awareness on benefits of different treatments for challenged growth, Herbal medicine'(48.72%) 'Acupuncture'(7.69%), 'Moxibustion'(3.85%), 'Electronic acupuncture and Aqua acupuncture'(1.28%), 'Massage on acupuncture point'(19.23%), 'Consultation of eating habits'(61.54%), 'Consultation of exercise'(47.44%) were measured. Conclusions: Considering the collected results, we realized that the parents' expected height on their children was, in fact, higher than the standard height. In addition, for treatments for their children's growth improvement, parents expected that 'Herbal madicine' 'Massage on acupuncture point' 'Consultation of eating habits' 'Consultation of exercise would be beneficial.

• Journal of Genetic Medicine
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• v.13 no.1
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• pp.41-45
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• 2016

Marfan syndrome (MFS) is an inherited connective tissue disorder with a mutation in the fibrillin-1 (FBN1) gene. Fibrillin is a major building block of microfibrils, which constitute the structural component of the connective tissues. A 10-year-old girl visited our hospital with the chief complaint of precocious puberty. According to her medical history, she had a pulmonary wedge resection for a pneumothorax at 9 years of age. There was no family history of MFS. Mid parental height was 161.5 cm. The patient's height was 162 cm (>97th percentile), and her weight was 40 kg (75th-90th percentile). At the time of initial presentation, her bone age was approximately 11 years. From the ophthalmologic examination, there were no abnormal findings except myopia. There was no wrist sign. At the age of 14 years, she revisited the hospital with the chief complaint of scoliosis. Her height and weight were 170 cm and 50 kg, respectively, and she had arachnodactyly and wrist sign. We performed an echocardiograph and a test for the FBN1 gene mutation with direct sequencing of 65 coding exons, suspecting MFS. There were no cardiac abnormalities including mitral valve prolapse. A cytosine residue deletion in exon 7 (c.660delC) was detected. This is a novel mutation causing a frameshift in protein synthesis and predicted to create a premature stop codon. We report the case of a patient with MFS with a novel FBN1 gene missense mutation and a history of pneumothorax at a young age without cardiac abnormalities during her teenage years.

• Proceedings of the KSAR Conference
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• 2001.03a
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• pp.39-39
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• 2001

Effects of Barodon$^{(R)}$ on body growth, histological changes in seminiferous tubules of testes and serum level of testosterone and FSH were examined in juvenile rats from 5 to 38 wks of age. All rats supplied feed and Barodon-added water(0, 0.1, 0.15, 0.3 and 1.0%) available ad libitum. DNA distribution of testicular cells from control rats obtained by flow cytometry was characterized by 4 peaks representing I : elongated, II round spermatids(1N), III: a variety of 2N cells and IV: 4N cells. Frequencies of 4 testicular cell types were calculated using cumulative DNA frequency distributions. Body growth from 18wk of age was significantly accelerated in rats supplied water with 0.15% Barodon compared to other groups. Testes weights tended to be greater in 0.15% Barodon-treated rats than in control, without significant difference. Diameter of seminiferous tubules advanced in 0.15-0.3% Barodon till 26 wk of age, but there was not significant different. Proportion of spermatids in seminiferous tubules was 48.4% at 6wk of age(round: 81.2% and elongated: 18.8% as proportion of total spermatids) and frequency of spermatids was higher in 0.3% Barodon group(57.1%) than in control(44.0%), but there was no significant difference. Serum testosterone of all groups significantly elevated at 18wk of age and level in 0.15% Barodon group was greatly higher than in others. Serum FSH at 10wks was greatly higher in 0.1-0.3% Barodon groups compared to control, but there were no significant differences. It is concluded that 0.15-0.3% Barodon treatment tended to induce precocious puberty in rats.