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Responsivity of pituitary gonadotropes to luteinizing hormone-releasing factor in idiopathic precocious puberty, precocious thelarche, precocious adrenarche, and in patients treated with medroxyprogesterone acetate.

One hundred micrograms synthetic luteinizing hormone-releasing factor (LRF) were administered to 13 girls and 2 boys with idiopathic precocious puberty, 3 girls with precocious thelarche, 2 girls with precocious adrenarche, and 5 children treated with medroxyprogesterone acetate (MPA). Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses were assessed. The mean readily releasable LH rose to a peak of 8.4 plus or minus 1. 8 ng/ml (LER 960) in the children with idiopathic precocious puberty and was significantly greater than in normal prepubertal (1.8 plus or minus 0.14) or pubertal children (4.9 ng/ml) (LER 869) was higher in precocious puberty but not significantly greater than in normal prepubertal (5.3 plus or minus 1.9) or pubertal girls (6.0 plus or minus 1.2). The mean concentration of plasma estradiol rose significantly above resting levels after LRF in the girls with idiopathic precocious puberty. The LH response in girls with precocious the larche was in the prepubertal range. In 4 of 5 children with sexual precocity treated with MPA, the LH release evoked by LRF was diminished.

Child

The child with precocious puberty.

Precocious puberty can be very confusing and frightening to an affected child and his or her family. The following presentation includes the pertinent physiology, psychology, etiology, diagnosis, and treatment of precocious pubertal development. Radioimmunoassays for gonadotropins and several key hormones are now available which enable the clinician to evaluate and follow the patient's condition with confidence and expertise. Three drugs have been proven effective and the most recent one, cyproterone acetate, has produced exciting clinical remissions with virtually no known side effects.

Adolescent

Clinical use of the LH-RH in assessing gonadotropic reserve in children with idiopathic precocious puberty, premature thelarche and premature adrenarche.

Serum LH and FSH were assayed in 31 girls with normal pre puberty, precocious puberty, premature thelarche, and premature adrenarche, aged 2 to 9 years. The effect of synthetic luteinizing hormone-releasing hormone (LH-RH) on serum gonadotropins was evaluated in eleven of them. In all girls with precocious puberty, serum LH was increased up to high levels. The mean releasable LH in two girls with idiopathic precocious puberty was significantly greater than in normal prepubertal or pubertal children. Basal FSH in children with precocious puberty was within the limits of normal prepuberal children, and FSH secretion in response to LH-RH was not significantly greater than in the group of normal prepubertal and pubertal girls. In children with premature thelarche and premature adrenarche, basal levels of LH and FSH, as well as gonadotropin response to LH-RH were in the prepubertal range. These preliminary results show that the LH-RH test might be of clinical value in differenitating abnormal puberal development.

Age Factors

[Hormonal regulation and hormone therapy in childhood and adolescence. Part 2: Therapeutic problems (tall stature, amenorrhea, delayed puberty, oligomenorrhea, precocious puberty, anorexia nervosa, anisomastia, hypermastia, acne etc)].

The most important therapeutic problems of female puberty and adolescence are discussed, including high stature, amenorrhoea, oligomenorrhea, pubertas tarda, anovulation, anorexia, anisomastia, hypermastia. Indications for treatment are given and the possibilities for a prophylactic medicine in this age group are stressed.

Acne Vulgaris

Asymmetric ovarian enlargement in idiopathic precocious puberty.

A patient with precocious puberty is presented in whom the pneumogynogram showed only one enlarged ovary. Because tumor could not be excluded, the patient had exploratory operation six weeks later. Both ovaries and the uterus were enlarged, compatible with the central stimulation seen in idiopathic precocious puberty. Care should be used in interpreting pneumogynograms as evidence of possible ovarian tumor in young girls with precocious puberty who have only modest unilateral ovarian enlargement.

Child

The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty.

8 children with precocious puberty were treated with cyproterone acetate (CPA). During treatment there were no definite clinical signs of depressed adrenocortical function. The plasma cortisol concentrations were grossly depressed and the diurnal cortisol rhythm was abolished. Two months after discontinuation of CPA treatment the adrenocortical function had greatly improved. The lysin-vasopressin stimulation test revealed in one child a normal, in another child an exaggerated ACTH response during CPA therapy. Fasting plasma ACTH concentrations were elevated compared with normal controls, but they were very low compared with patients with Addison's disease. The results suggest that CPA has a twofold effect leading to adrenocortical insufficiency: i.e., inhibition of cortisol secretion by the adrenals themselves and inhibition of ACTH secretion at the hypothalamopitiuitary level.

Adolescent

Effect of cyproterone acetate (CA) on growth and endocrine function in precocious puberty.

16 girls with precocious puberty have been studied. Following low dosage cyproterone acetate (CA) therapy (mean daily dosage 65 mg/m2BSA) a beneficial effect on growth and skeletal maturation was observed. During high dosage therapy (150 mg/m2 per day) endocrinological studies were performed in 10 of these patients. There was no significant difference in HGH levels (insulin- and arginine-test), T3 and TSH values (TRH-test) between patients and controls, T4 concentration was significantly increased. Basal prolactin levels and prolactin response to TRH was definitely elevated. Oral glucose load and arginine infusion resulted in a significantly enhanced insulin release. There was a significant reduction in basal LH levels and an increase in FSH response to LH-RH. Basal and diurnal plasma cortisol values were markedly reduced and the cortisol release due to corticotrophin injection, lysinevasopressin (LVP) injection and insulin-hypoglycemia as well. A definite increase in basal ACTH levels was observed, during LVP- and insulin-hypoglycemia test ACTH concentrations were within or significantly above normal range. In our patients a primary adrenocortical insufficiency due to CA treatment was evident.

Arginine

[Family stress for parents of girls with precocious puberty].

This study addresses whether precocious puberty influences the child-rearing practices of parents. Three patients groups, girls with idiopathic precocious puberty, with premature thelarche and with premature pubarche were studied. These groups were compared with each other, and with reference groups of 'normal' school children and children referred for asthma or referred for behavioural problems. The results showed that the parents of the total group of patients did not experience more family stress and did not appraise their child-rearing situation as being more problematic than that of parents of normal school children, and they had significantly fewer problems than the parents of children referred for asthma of for behavioural problems. Within the group results suggested that parents of girls with premature pubarche experienced more family stress than those of the two other groups. Parents reported specific physical and educational concerns about their daughters. Therefore we recommend that specific attention should be given through a programme of relevant information.

Adaptation, Psychological

A female case of the HCG-producing ectopic pinealoma associated with precocious puberty.

A female case of precocious puberty associated with HCG-producing ectopic pinealoma was reported. The patient, a 5-year-old girl, was referred to the hospital because of headache and choked discs. Physical examination revealed normal physical growth with breast enlargement. Endocrinological study revealed a high plasma HCG concentration of 1192 ng/ml with a normal FSH level. None of HCG, LH and FSH did respond to the LH-RH test. A partial resection of the tumor and an external X-ray irradiation relieved the symptoms and breast enlargement subsided with a remarkable decrease in the plasma HCG level. Histological examination revealed two-cell-pattern pinealoma and electron microscopic findings showed abundant secretory granules in the dark cells. HCG content in the tumor was as high was 400 ng/mg of acetone dried tumor tissue, but no FSH was detectable. Hitherto, all of the reported cases of precocious puberty associated with pineal tumors have been exclusively boys. A normal level of plasma FSH concentration with a somewhat elevated prolactin level might be a contributory factor for the development of precocial sexual development in the present case.

Child, Preschool

[Precocious puberty associated with Silver's syndrome].

Precocious puberty has been reported as an important feature of the Silver-Russell syndrome. The present case refers to a boy entered puberty at the chronological age of 11 years and the bone age of 6 years 6/12. Criteria for precocious puberty in this syndrome are discussed by comparison with previously published cases, and it is concluded that abnormalities in clinical pubertal development are quite unusual in this syndrome.

Bone Diseases, Developmental

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.

Adult

[Teratoma of the 4th ventricle and precocious puberty. Case report].

A case of precocious puberty and diabetes insipidus in a 7 years old boy due to a malignant teratoma in the IVth ventricle is reported. The tumor had grown into the IIIrd and lateral ventricles as found on the necropsy. The original site of the tumor and the possible physiopathological mechanisms for the precocious puberty are discussed.

Cerebral Ventricle Neoplasms

The neuro-radiological examination of endocrine disorders of central origin in the child (precocious puberty, hypopituitarism).

The neuro-radiological findings in 38 cases of precocious puberty of central origin and 9 cases of hypopituitarism (craniopharyngiomas excepted), are reported. The radiological examination consisted of plain films of the skull and pneumo-encephalography. In the 9 cases with hypopituitarism radiological examination was normal in 4 and localised but quite diverse anomalies were discovered in 5. Out of 38 patients presenting with isosexual precocious puberty, 29 were female and 9 male. Out of the 29 girls, neuro-radiological examination was normal in 20 and showed a hypothalamic anomaly in 9. Out of the 9 boys, 8 had a hypothalamic anomaly, and only one examination was normal. In precocious puberty we found 1 ectopic pinealoma and 2 gliomas of the chiasma. In these three cases the clinical context and radiological examination made the diagnosis obvious. Masses were discovered in 7 (3 spongioblastomas and 4 heterotopias). In 2 cases (spongioblastomas) neurological symptoms were present and made an operation mandatory. In 5 cases (1 spongioblastoma, 4 heterotopias) precocious puberty was an isolated finding. It was not possible to make, on a clinical or radiological bases, a distinction between spongioblastoma and heterotopia. As time has passed the role of surgery has changed. Formerly, surgery aimed at excision of the lesion, but with advances in medical treatment surgical intervention is now directed towards biopsy and the histological study of lesions which may be treated by radiotherapy.

Adolescent

Hypothalamo-pituitary-gonadal function in male central precocious puberty.

Eleven boys aged 1-10 years with central precocious puberty were studied. According to the pubertal development six were classified as P2, one as P3 and four as P5. In all cases plasma testosterone levels were definitely elevated (1.7-5.8 ng/ml) when compared with pre-pubertal controls. Peak values after HCG (3 X 1500 units) in four of the boys were in the high adult range. The binding capacity of serum testosterone oestradiol binding globuline (TeBG) ranged between 0.5 and 7.30 microgram/dl. Basal plasma levels of LH and FSH were respectively 2.06 +/- 0.64 and 1.2 +/- 0.25 miu/ml, and peak levels after LHRH (0.1 mg/m2) 13.9 +/- 3.7 and 2.6 +/- 0.43 miu/ml respectively. The data demonstrated a significant increase of plasma testosterone and post LHRH LH peak levels in boys with central precocious puberty when compared with pre-pubertal controls. The patients at stage P2 exhibited high levels of plasma testosterone contrasting with the degree of pubertal maturation, high values of TeBG and low response to LHRH which were in the pre-pubertal range. These findings suggest that the testicular sensitivity to LH increases early in boys with central precocious puberty, while the testosterone responsiveness, both at peripheral and hypothalamic levels, is delayed.

Child

Luteinizing hormone response to clomiphene citrate in central precocious puberty.

OBJECTIVE: The aim of the present study was to determine the LH response to clomiphene citrate administration in children with central precocious puberty and different bone ages to gain insight into the hypothalamic maturation mechanism. PATIENTS AND METHODS: Twelve children with untreated central precocious puberty were studied. Five had central nervous system lesions and seven had idiopathic central precocious puberty. Their chronological and bone ages ranged from 1.7 to 8.8 years and 3.5 to 13.5 years, respectively. Clomiphene citrate (3 mg/kg/day) was administered orally for 7 days. Blood samples were collected on days 0, 6 and 8. LH and FSH were determined by RIA. The results were compared with GnRH responses or with bone age. RESULTS: No increase over basal LH levels was detected in four patients, but increased LH levels were detected in the remaining eight during clomiphene administration. The shift from negative to positive responses was around 8-9 years bone age. The sum of LH responses (days 6 and 8) to clomiphene citrate, and particularly the 8th-day LH levels, were significantly correlated with their respective bone age (r = 0.83). However, the LH responses to GnRH were not significantly correlated with bone age or with LH responses to clomiphene. CONCLUSIONS: This study shows that the LH responsiveness to clomiphene citrate in central precocious puberty increases with skeletal maturation, indicating that the activation of the hypothalamic pubertal mechanism in central precocious puberty may progress in a gradual sequence. These changes in LH response to clomiphene in central precocious puberty mimic those observed with the development of normal puberty, but occur at a much earlier age.

Bone Development

Hypothalamic hamartoma: a source of luteinizing-hormone-releasing factor in precocious puberty.

The presence of a hypothalamic hamartoma and precocious puberty in a 19-month-old boy provided an opportunity to study their relation. Excised tissue had the ultrastructural characteristics of an independent neuroendocrine unit -- i.e., neurons containing neurosecretory granules and blood vessels with fenestrated endothelium and double basement membranes. Immunofluorescence studies using specific antibody to luteinizing-hormone-releasing factor showed antigenicity to the factor in the hamartoma. The testicular-hypothalamic-pituitary axis was tested. Clomiphene unresponsiveness suggested a lack of maturation of central-nervous-system events characteristic of normal puberty. The negative feedback system between gonad and brain was intact but partially resistant to steroid suppression. These studies suggest that hypothalamic hamartomas may cause precocious puberty by autonomous production and release of luteinizing-hormone-releasing factor into vessels that communicate with the pituitary portal blood system.

Brain Neoplasms

The natural history of autonomous gonadal function, adrenarche, and central puberty in gonadotropin-independent precocious puberty.

Gonadotropin-independent precocity (GIP) is a syndrome marked by precocious pubertal development in the absence of pubertal levels of gonadotropins. To investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal maturation in this syndrome, we conducted longitudinal studies spanning up to 10 yr in two such affected individuals. A cross-sectional analysis of adrenal androgen secretion was performed in nine additional patients to assess further the time course of adrenarche in GIP. Serial evaluations revealed progression of secondary sexual characteristics, statural growth, and skeletal maturation, all consistent with ongoing exposure to pubertal gonadal steroid levels. On the other hand, adrenarche (n = 11) and spontaneous and GnRH-stimulated gonadotropin secretion (n = 2) progressed in chronological age-appropriate manners despite long term pubertal levels of gonadal sex steroid secretion. After the development of central puberty, as documented by the appearance of pulsatile gonadotropin secretion, we sought to determine whether the potential for gonadal autonomy persisted. Despite complete pituitary desensitization induced by administration of a GnRH agonist, both patients studied demonstrated an ongoing capacity to secrete pubertal levels of gonadal steroids. Our study suggests that the timing of adrenarche and central puberty in these subjects with GIP was apparently unaltered by prolonged exposure to gonadal steroids. Subsequent to the development of central puberty, pulsatile gonadotropin secretion may override and, thus, mask the underlying defect(s) in adolescents and adults with histories of GIP.

Adrenal Glands