Isosexual Precocious Puberty Research Articles

Etiology and Clinical Features of Isosexual Precocious Puberty in Taiwanese Girls: Twenty-Three Years’ Experience in National Taiwan University Hospital

The aim of this study was to elucidate the etiology and clinical features of Taiwanese girls with isosexual precocious puberty. 460 girls with precocious puberty were enrolled in this study. 284 of them had a GnRH test and 179 girls with gonadotropin-dependent precocious puberty (GDPP) underwent brain MRI. Our results showed 7% of these 460 girls had gonadotropin-independent precocious puberty (GIPP). The other 93% patients had GDPP and 96% of them were idiopathic. Functional ovarian cyst and hypothalamic hamartoma were leading causes of GIPP and organic GDPP, respectively. The presence of undetectable basal serum FSH and LH levels had a specificity of 95% in girls with GIPP. Among girls with GDPP, those aged < 5 years had a higher percentage of detected CNS lesions than older girls (8% vs 3%). Girls with organic CNS lesions also had more advanced bone age SDS (6.9 +/- 3.3 vs 3.3 +/- 1.9), larger uterine volume (13.8 +/- 12.1 vs 6.6 +/- 8.1 cm3), higher basal serum estradiol (33.5 +/- 17.1 vs 26.8 +/- 18.2 pg/ml), and higher peak LH level after GnRH stimulation (45.2 +/- 36.2 vs 25.8 +/- 27.3 U/l) than those with idiopathic GDPP. In conclusion, GIPP is uncommon in Taiwanese girls with precocious puberty. Functional ovarian cyst and hypothalamic hamartoma are leading causes of GIPP and organic GDPP, respectively. The presence of neurological deficit, younger age at onset of puberty, presence of menstruation, rapid advance of bone age, markedly enlarged uterus, high serum estradiol, and high peak LH level after GnRH stimulation are suggestive of organic GDPP.

Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls

In 1960 Van Wyk and Grumbach described a syndrome of juvenile hypothyroidism, precocious puberty and ovarian enlargement. These findings undergo complete regression with thyroid hormone replacement therapy. This diagnosis can be made on the basis of imaging findings and thyroid function analysis, avoiding surgery. To relate the distinctive clinical and imaging features and putative pathophysiological mechanism of a series of patients with Van Wyk and Grumbach syndrome (VWGS). Patients with VWGS diagnosed at two large children's hospitals over a 6-year period beginning in 1999 were retrospectively reviewed. A literature review was also conducted. Five female patients were diagnosed with cystic ovarian enlargement and hypothyroidism at ages ranging from 9 to 17 years. Isosexual precocious puberty was found in prepubescent patients. Associated findings included delayed bone age, ascites, and pleural and pericardial effusions. Ovarian cyst involution occurred following treatment of the hypothyroidism. The association of primary hypothyroidism with cystic ovarian enlargement and precocious puberty is important to recognize. In the absence of suspected ovarian torsion, surgery is unnecessary, as cyst regression occurs after appropriate thyroid hormone replacement. Noncompliance with hormone replacement therapy should be considered when cystic ovarian enlargement is noted in patients with a history of hypothyroidism.

Primary hypothyroidism with precocious puberty and bilateral cystic ovaries

It is a general observation that children with hypothyroidism have delayed sexual maturation and delayed puberty. However, longstanding untreated hypothyroidism could be associated with isosexual precocious puberty. Here we report a nine year old girl with longstanding untreated hypothyroidism presenting with precocious puberty and bilateral multicystic ovaries, which promptly responded to thyroid hormone replacement.

Feminizing Adrenal Adenoma Presenting As Isosexual Precocious Puberty

Feminizing Adrenal Adenoma Presenting As Isosexual Precocious Puberty

Enucleation for Prepubertal Leydig Cell Tumor

Leydig cell tumors in children are rare, comprising only 4% to 9% of all primary testis tumors in prepubertal males. Almost all of these boys present with isosexual precocious pseudopuberty associated with increased testosterone, low gonadotropin levels and a testis mass. We present our experience with testis sparing enucleation of Leydig cell tumor in prepubertal boys. Two patients presented with isosexual precocious puberty at ages 6 and 9 years. Each patient had a well circumscribed, painless testicular mass, increased serum testosterone (101 and 444 ng/dl [normal 0 to 25]), normal gonadotropins and negative alpha-fetoprotein levels. Both patients underwent successful enucleation of the testis mass following proper testis oncological surgical principles. Both patients had normalization of the serum testosterone following enucleation of the Leydig cell tumor. At 9 and 44 months of followup they have maintained normal ipsilateral testicular volume compared to the contralateral gonad, and 1 patient entered puberty spontaneously at 1 year postoperatively. Neither patient suffered any morbidity, and both have presumably benefited from preservation of the involved gonad with preserved testicular volume. Prepubertal boys with isosexual precocious pseudopuberty, an isolated testis mass, increased testosterone and low or normal gonadotropin levels can reliably be diagnosed with Leydig cell tumors. Based on the ability to establish the diagnosis preoperatively and the universal benign behavior of unilateral, prepubertal Leydig cell tumor, we believe these patients are best treated with testis sparing enucleation of the tumor. In view of the high likelihood that this tumor in prepubertal boys is benign, a transscrotal surgical approach should be considered.

Female precocious puberty, obesity and polycystic‐like ovaries

To evaluate the characteristics of obese girls with gonadotropin releasing hormone-dependent precocious puberty with and without polycystic-like ovaries. Forty-seven overweight (> 75(th) centile of the Italian reference data) girls with a diagnosis of isosexual precocious puberty underwent auxological analysis, hormonal assay and utero-ovarian sonographic and Doppler evaluation. On the basis of sonography the patients were subdivided into two groups, girls presenting normal ovaries (Group I; n = 31) and those with polycystic-like ovaries (Group II; n = 16). The mean body weight was significantly higher (P = 0.003) in Group II than it was in Group I. In addition, the patients with polycystic-like ovaries fell within our definition of superobese (> or = 97(th) centile of the Italian reference data) in 44% of cases. The uterine and ovarian volumes were significantly greater in Group II compared with Group I patients. The Doppler evaluation showed intraparenchymal ovarian vascularization and low downstream impedance to flow in all patients in Group II. Girls with precocious puberty and polycystic ovaries, compared with those without polycystic ovaries, have a higher incidence of body weight exceeding the 85(th) centile of the Italian reference data (obesity).

SEXUAL PRECOCITY: A HISTORICAL PERSPECTIVE AND UPDATE

Puberty is the interval in the life cycle during which the child becomes an adult. It is heralded by physical changes such as acceleration of linear growth and appearance of secondary sexual characteristics, capped by attainment of reproductive capability, and orchestrated by increases in the secretion of hypothalamic, pituitary, and gonadal hormones. This article discusses selected historical and contemporary aspects of isosexual precocious puberty, i.e., the development of sexual characteristics prior to the usual age of pubertal onset.

Suprasellar Arachnoidal Cyst as a Cause of Precocious Puberty - Report of Three Patients and Literature Overview

The authors present three boys--3 years old, 5.8 years old and 10.4 years old--who were diagnosed with isosexual precocious puberty (IPP) triggered by a rare developmental disorder of suprasellar arachnoid cyst (SAC) accompanied by corpus callosum and fornix dysgenesis as well as anterior commissura magna agenesis (patient 1) and empty sella (patients 2, 3). The reason for diagnostic management recommendation was a rapid progression of IPP signs over one year (patients 1, 2) or 6 months (patient 3) prior to hospitalization, these signs having been present but less intense since infancy (patient 1), 4th year of life (patient 2) and approximately 8 years of age (patient 3). Neurological signs (spastic paresis in patient 1, postural tremor in patient 2 and head bobbing and behavioral changes in patient 3), as well as slowly progressing increased head circumference were observed since neonatal period (patient 1), 1 year old (patient 2) and approximately 4 years old (patient 3). None of the patients manifested hypophyseal-hypothalamic axis dysfunction other than IPP prior to and after surgical management. Shunt implantation resulted in gradual resolution of neurological signs in all patients and in patient 3 also in partial normalization of serum testosterone levels and growth rate. Regression of IPP in patients 1 and 2 was achieved by administration of a long-acting GnRH analogue. Our observations are in accord with data reported by other investigators and confirm the often slow, insidious development of subsequent SAC signs, the type and intensity of which differ from patient to patient. We suggest that some of the neuroanatomical anomalies coexisting with SAC may have a common genesis, or they could under certain conditions be an additional trigger for IPP and possibly other hypothalamopituitary dysfunction.

Precocious puberty: clinical and endocrine profile and factors indicating neurogenic precocity in Indian children.

The objective of this study was to evaluate the clinical and endocrine profile of patients with precocious puberty followed up in a tertiary care hospital. Records of 140 patients (114 girls, 26 boys) with precocious puberty were reviewed. Clinical features including age of onset, stage of pubertal development, presenting symptoms, features suggestive of CNS involvement and family history were analyzed. Endocrine investigations included basal and GnRH-stimulated levels of LH and FSH as well as 17OHP, DHEA, hCG and thyroid profile. Abdominal and pelvic ultrasonography and CNS imaging were correlated with clinical features. Girls outnumbered boys in this series (4.4:1). Neurogenic central isosexual precocious puberty (CIPP) was more common in boys (10 out of 18, 55.6%) than girls (16 out of 77, 20.8%). The most common cause of neurogenic CIPP was hypothalamic hamartoma present in five girls and four boys. Other causes of neurogenic CIPP included neurotuberculosis, pituitary adenoma, hydrocephalus, post radiotherapy, CNS tumors and malformations. Peripheral precocious puberty (PPP) was secondary to adrenal causes in boys and ovarian cysts in girls. Benign variants of precocious puberty, such as premature thelarche and premature adrenarche, were present in 23 and six girls, respectively. Hypothyroidism was present in four girls and McCune-Albright syndrome in one girl. Girls with neurogenic CIPP had a lower age of onset as compared to idiopathic CIPP (3.6 +/- 2.7 years vs 5.4 +/- 2.5 years, p = 0.014). The lowest age of onset was seen in girls with hypothalamic hamartoma (1.6 +/- 0.9 years). Forty-seven girls with CIPP (seven neurogenic and 40 idiopathic) presented after the age of 6 years. Features of CNS involvement, in the form of seizures, mental retardation, raised intracranial tension or focal neurological deficits, were present in seven girls (43.8%) and four boys (40%), and gelastic seizures were present in three children. Girls with CIPP had greater bone age advancement (3.4 +/- 1.5 years) and negative height standard deviation for bone age (-2.7 +/- 1.5) than those with PPP (1.9 +/- 1.6 years and -1.3 +/- 1.3) and premature thelarche (0.4 +/- 0.4 years and -0.8 +/- 0.8). Patients with neurogenic CIPP had significantly higher levels of baseline and GnRH-stimulated levels of LH and FSH and LH:FSH ratio than those with idiopathic CIPP. Occurrence of neurogenic CIPP in seven girls with an age of onset after 6 years emphasizes the need for CNS imaging in these girls contrary to the current recommendations. The fact that 65.6% cases of idiopathic CIPP presented after the age of 6 years raises the possibility that these patients may be physiological variants of normal puberty. Pointers to neurogenic CIPP included early age of onset in girls, clinical features of CNS involvement, and elevated basal and stimulated LH levels and LH:FSH ratio.

Aromatase P450 Expression in a Feminizing Adrenal Adenoma Presenting as Isosexual Precocious Puberty

Aromatase P450 Expression in a Feminizing Adrenal Adenoma Presenting as Isosexual Precocious Puberty

Molecular defects causing ovarian dysfunction.

The functions of the hypothalamic-pituitary-ovarian and -adrenal axes are intertwined, and molecular defects in either axis may cause ovarian dysfunction. Advances in molecular genetics have allowed new insights into the pathophysiology of ovarian disorders. Specific gene mutations causing delayed puberty and/or ovarian failure, and heterosexual or isosexual precocious puberty have recently been described. The molecular insights gained into ovarian dysfunction have already led to rational therapies for some of these conditions.

Mutation analysis of the follicle-stimulating hormone receptor gene in girls with gonadotropin-independent precocious puberty resulting from autonomous cystic ovaries

Objective: To search for germline activating mutations of the FSH receptor in girls with gonadotropin-independent precocious puberty. Design: Molecular studies in human tissue. Setting: Four girls with polycystic ovaries and gonadotropin-independent isosexual precocious puberty without clinical and molecular features of McCune-Albright syndrome. Intervention(s): Peripheral blood was used for DNA extraction. The α-subunit of the Gs gene and the entire exon 10 of FSH receptor gene were amplified by polymerase chain reaction (PCR). Gs-α mutations characteristic of McCune-Albright syndrome were excluded by denaturating gradient gel electrophoresis (DGGE) and allele-specific PCR. Exon 10 of the FSH receptor gene was analyzed by DGGE and direct sequencing. Main Outcome Measure(s): Results of DGGE and direct sequencing. Result(s): No germline activating mutations were detected in exon 10 of our patients. Instead, two previously described polymorphisms were found, leading to the substitution of alanine for threonine at position 307 and of serine for asparagine at position 680 of the FSH receptor molecule. Conclusion(s): Germline activating mutations were not found in exon 10 of the FSHR gene in any of our patients. Further studies, preferably in ovarian tissue, will be required to exclude the presence of somatic activating mutations of the FSH receptor in these patients.

A 7 Year Old Female with Isosexual Precocious Puberty and a Feminizing Adrenal Tumor

A 7 Year Old Female with Isosexual Precocious Puberty and a Feminizing Adrenal Tumor

A Novel Luteinizing Hormone Receptor Mutation in a Patient with Familial Male-Limited Precocious Puberty: Effect of the Size of a Critical Amino Acid on Receptor Activity

Familial male-limited precocious puberty (FMPP) is a form of luteinizing hormone-releasing hormone (LHRH)-independent isosexual precocious puberty caused by gain-of-function mutations of the luteinizing hormone/chorionic gonadotropin receptor (hLHR). The most common mutation is 1733 A>G, which causes substitution of Asp-578 by Gly. In this study, a male infant presented at the age of 20 months with accelerated sexual development was analyzed for the presence of activating mutations of the hLHR. Analysis of exon 11 of the hLHR gene by genomic polymerase chain reaction (PCR), asymmetric PCR, and dideoxy sequencing identified a single base substitution, 1734 T>A, which led to the replacement of Asp-578 by Glu. The same mutation was found in the mother. Expression of the mutated hLHR in HEK 293 cells demonstrated elevated basal levels of intracellular cAMP in the transfected cells confirming the constitutive activating nature of the mutated hLHR. A possible genotype-phenotype relationship of the hLHR mutations was examined by a comparison of thein vitroactivities of the hLHRs carrying the Asp578Gly, Asp578Tyr, Asp578Trp, and Asp578Glu mutations in HEK 293 cells. A positive correlation between the size of the substituting amino acid and the basal level of intracellular cAMP of cells expressing the mutated receptor was demonstrated.

Sertoli Cell Tumor Causing Precocious Puberty in a Girl with Peutz-Jeghers Syndrome

Distinctive ovarian and cervical tumors are associated with Peutz-Jeghers syndrome (PJS). The most common gynecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules (SCTAT). Other kinds of ovarian tumors have been rarely reported in association of PJS, including Sertoli cell tumors. We report a case of a 4.5-year-old girl with PJS who presented with isosexual precocious puberty (IPP) due to ovarian lipid-rich Sertoli cell tumor. In addition to estrinizing effect of the tumor, the patient had decidual reaction secondary to tumor-derived progesterone secretion. The literature on gonadal tumors in PJS is reviewed, including one previous report of ovarian lipid-rich Sertoli cell tumor associated with this syndrome.

Aromatase expression in human germinomas with possible biological effects.

Gonadal aromatase expression has been demonstrated in human Leydig, granulosa, and thecal cells, but never in human germ cells. In an attempt to explain the unique occurrence of isosexual precocious puberty in a young girl with a hCG-secreting suprasellar germinoma, we demonstrated the presence of aromatase expression in the germ cell component of this tumor. Immunohistochemical staining for P450-aromatase and hCG using a peroxidase-labeled streptaviden-biotin technique was performed on tumor specimens from the above patient and from four other subjects with central nervous system germinoma. Cytoplasmic aromatase staining was present in the germinoma cells of four of five cases of central nervous system germinoma studied. Staining was absent in the lymphocytic element within the tumor and in negative control tissues. The demonstration of aromatase activity in the malignant element of human germinomas indicates that aromatase expression can occur in human germ cells after malignant transformation. This parallels the finding that the transformation of Sertoli cells to sex cord tumor with annular tubules in Peutz Jeghers syndrome is associated with the induction of marked aromatase expression and systemic estrogen effect. We propose that tumor aromatase played a similar role in the unique occurrence of isosexual precocity in a girl with a suprasellar germinoma.

Isosexual precocious puberty: Granulosa cell tumor of the ovary in a 3.5-year-old girl

A case of a 37/12-year-old infant with isosexual precocious puberty due to a granulosa cell tumor is presented, followed by a brief discussion of causes, diagnosis, and management of precocious puberty.

Monitoring of girls undergoing medical therapy for isosexual precocious puberty.

We evaluated the use of sonography in monitoring the efficacy of suppressive therapy with a gonadotropin releasing hormone analogue in girls being treated for isosexual precocious puberty. Ten girls 5 to 9 years of age underwent serial sonography and hormonal stimulation tests on the same day. Sonographic trends of decreasing ovarian volume and uterine length indicated early suppression even when absolute values were above threshold. Changes in ovarian volume were the most sensitive predictor of pituitary-gonadal suppression. Sonography is a sensitive and accurate method of monitoring medical therapy; ovarian volume and analysis of interval change are the most sensitive barometers of change.

Usefulness of ovarian volume and cysts in female isosexual precocious puberty

The real-time pelvic sonograms of 32 girls under 8 years old with true isosexual precocity (23 cases), pseudosexual precocity (four cases), premature adrenarche (four cases), and an undetermined problem (one case) were evaluated retrospectively for ovarian volume and presence and size of cysts. Sonographic findings were compared to those of 181 age-matched controls to determine the best sonographic indicator of precocious puberty. Ovarian volume was 4.6 cm3 in girls with true isosexual precocity, 4.1 cm3 in girls with pseudosexual precocity, and less than 1 cm3 in the other patients as well as in the control population. Ovarian enlargement was bilateral in true precocity and unilateral in pseudosexual precocity. Of the 181 subjects in the control group, 96 (53%) had ovarian cysts, almost all of which were small (less than 9 mm in diameter). Ovarian cysts occurred in 22 of 32 patients (69%) with precocity. The cysts generally were smaller than 9 mm in true isosexual precocity and larger than 9 mm in pseudosexual precocity. In conclusion, small ovarian cysts are not specific to precocious puberty and its various subtypes. Bilateral ovarian enlargement appears to be a reliable indicator of true isosexual puberty, whereas unilateral ovarian enlargement in combination with macrocysts is suggestive of pseudosexual precocity.

Hypothalamic Hamartoma: A Report of 2 Cases

Two patients with hypothalamic hamartoma presented with isosexual precocious puberty. LHRH challenge showed a pubertal LH response in both cases. Serum FSH responses to LHRH were pubertal in case 1, but prepubertal for case 2. Computed tomography revealed isodense noncontrast-enhancing retrosellar mass lesions in both cases. The tumors were composed of mature neurons and neuroglial tissue. Electron microscopy of the lesions failed to demonstrate dense core (neurosecretory) granules in either case. Subtotal removal of the harmartomas resulted in decreased LH responsiveness to LHRH in both cases. Serum FSH responsiveness to LHRH was not significantly suppressed postoperatively in case 1, and FSH responsiveness to LHRH in case 2 showed exaggerated levels, more typical of very young prepubertal girls. Postoperative magnetic resonance imaging (MRI) scans of both patients are also presented.