transforming-growth-factor-alpha and Puberty--Precocious

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

Topics: Child; Child, Preschool; Comorbidity; Drug Resistant Epilepsy; Endocrine System Diseases; Epilepsies, Partial; Female; gamma-Aminobutyric Acid; Gonadotropin-Releasing Hormone; Hamartoma; Hormones, Ectopic; Humans; Hypothalamic Diseases; Hypothalamus; Infant; Male; Nerve Net; Puberty, Precocious; Transforming Growth Factor alpha

In mammals and humans, reproductive capacity is attained at puberty as the end-point of a complex series of developmental and neuroendocrine events that lead to true sexual maturity. As for humans, sexual precocity looks like a pathologic status. While for some animals, sexual precocity may be a valuable quantitative character. For some species, the character of sexual precocity was developed in the evolutionary process and stably transmitted to future generations. Sexual precocity is a complex character determined by polygenes. This review introduced the association between KiSS-1, GPR54, LHR, FSHR, CYP, ER, TGFa, IGF-, GNAS1, HSD3B2, SHBG, VDR genes and sexual precocity in mammals.

Topics: Animals; Gene Expression Regulation, Developmental; GTP-Binding Protein alpha Subunits, Gs; Humans; Progesterone Reductase; Puberty, Precocious; Receptors, Estrogen; Receptors, FSH; Receptors, G-Protein-Coupled; Sexual Maturation; Transforming Growth Factor alpha

Precocious puberty is a significant child health problem, especially in girls, because 95% of cases are idiopathic. Our earlier studies demonstrated that low-dose levels of manganese (Mn) caused precocious puberty via stimulating the secretion of luteinizing hormone-releasing hormone (LHRH). Because glial-neuronal communications are important for the activation of LHRH secretion at puberty, we investigated the effects of prepubertal Mn exposure on specific glial-derived puberty-related genes known to affect neuronal LHRH release. Animals were supplemented with MnCl(2) (10 mg/kg) or saline by gastric gavage from day 12 until day 22 or day 29, then decapitated, and brains removed. The site of LHRH release is the medial basal hypothalamus (MBH), and tissues from this area were analyzed by real-time PCR for transforming growth factor α (TGFα), insulin-like growth factor-1 (IGF-1), and cyclooxygenase-2 (COX-2) messenger RNA levels. Protein levels for IGF-1 receptor (IGF-1R) were measured by Western blot analysis. LHRH gene expression was measured in the preoptic area/anteroventral periventricular (POA/AVPV) region. In the MBH, at 22 days, IGF-1 gene expression was increased (p < 0.05) with a concomitant increase (p < 0.05) in IGF-1R protein expression. Mn also increased (p < 0.01) COX-2 gene expression. At 29 days, the upregulation of IGF-1 (p < 0.05) and COX-2 (p < 0.05) continued in the MBH. At this time, we observed increased (p < 0.05) LHRH gene expression in the POA/AVPV. Additionally, Mn stimulated prostaglandin E(2) and LHRH release from 29-day-old median eminences incubated in vitro. These results demonstrate that Mn, through the upregulation of IGF-1 and COX-2, may promote maturational events and glial-neuronal communications facilitating the increased neurosecretory activity, including that of LHRH, resulting in precocious pubertal development.

Topics: Animals; Cyclooxygenase 2; Female; Gene Expression Regulation, Developmental; Hypothalamus; In Vitro Techniques; Insulin-Like Growth Factor I; Luteinizing Hormone; Manganese; Median Eminence; Preoptic Area; Puberty, Precocious; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1; RNA, Messenger; Transforming Growth Factor alpha; Up-Regulation

Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor alpha (TGFalpha), and GRM1A, which encodes the type 1 metabotropic glutamate receptor alpha isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.. Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFalpha, KISS1, GPR54, and GRM1A.. Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFalpha, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.. Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.

Topics: Adolescent; Child; Child, Preschool; Female; Gene Expression; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Infant; Kisspeptins; Male; Puberty, Precocious; Radiography; Receptors, LHRH; Seizures; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Hypothalamic hamartomas (HHs) are congenital lesions composed of neurons and astroglia. Frequently, HHs cause central precocious puberty (CPP) and/or gelastic seizures. Because HHs might express genes similar to those required for the initiation of normal puberty, we used cDNA arrays to compare the gene expression profile of an HH associated with CPP with three HHs not accompanied by sexual precocity.. Global changes in gene expression were detected using Affymetrix arrays. The results were confirmed by semiquantitative PCR, which also served to examine the expression of selected genes in the hypothalamus of female monkeys undergoing puberty.. All HHs were associated with seizures. Ten genes whose expression was increased in the HH with CPP were identified. They encode proteins involved in three key cellular processes: transcriptional regulation, cell-cell signaling, and cell adhesiveness. They include IA-1 and MEF2A, two transcription factors required for neuronal development; mGluR1 and VILIP-1, which encode proteins involved in neuronal communication, and TSG-6 that encodes a protein involved in cell adhesiveness. Of these, expression of mGluR1 also increases in the female monkey hypothalamus at puberty.. Increased expression of these genes in HHs may be relevant to the ability of some HHs to induce sexual precocity.

Topics: Adolescent; Adult; Animals; Cell Adhesion Molecules; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Profiling; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Kisspeptins; Macaca mulatta; Male; Oligonucleotide Array Sequence Analysis; Puberty, Precocious; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Metabotropic Glutamate; Repressor Proteins; Sexual Maturation; Transforming Growth Factor alpha; Tumor Suppressor Proteins

Activation of LH-releasing hormone (LHRH) secretion, essential for the initiation of puberty, is brought about by the interaction of neurotransmitters and astroglia-derived substances. One of these substances, transforming growth factor alpha (TGFalpha), has been implicated as a facilitatory component of the glia-to-neuron signaling process controlling the onset of female puberty in rodents and nonhuman primates. Hypothalamic hamartomas (HH) are tumors frequently associated with precocious puberty in humans. The detection of LHRH-containing neurons in some hamartomas has led to the concept that hamartomas advance puberty because they contain an ectopic LHRH pulse generator. Examination of two HH associated with female sexual precocity revealed that neither tumor had LHRH neurons, but both contained astroglial cells expressing TGFalpha and its receptor. Thus, some HH may induce precocious puberty, not by secreting LHRH, but via the production of trophic factors--such as TGFalpha--able to activate the normal LHRH neuronal network in the patient's hypothalamus.

Topics: Astrocytes; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hamartoma; Human Growth Hormone; Humans; Hypothalamic Diseases; Immunohistochemistry; Infant; Luteinizing Hormone; Magnetic Resonance Imaging; Neurons; Puberty, Precocious; Transforming Growth Factor alpha

Precocious puberty of cerebral origin is a poorly understood disorder of human sexual development, brought about by the premature activation of those neurons that produce luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling sexual maturation. An increased production of transforming growth factor alpha (TGF alpha) in the hypothalamus has been implicated in the mechanism underlying both normal and precocious puberty. We have now used two gene delivery systems to target TGF alpha overexpression near LHRH neurons in immature female rats. Fibroblasts infected with a retroviral construct in which expression of the human TGF alpha gene is constitutively driven by the phosphoglycerate kinase promoter, or transfected with a plasmid in which TGF alpha expression is controlled by an inducible metallothionein promoter, were transplanted into several regions of the hypothalamus. When the cells were in contact with LHRH nerve terminals or in the vicinity of LHRH perikarya, sexual maturation was accelerated. These results suggest that precocious puberty of cerebral origin may result from a focal disorder of TGF alpha production within the confines of the LHRH neuron microenvironment.

Topics: 3T3 Cells; Animals; Female; Gene Transfer Techniques; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Mice; Neurosecretory Systems; Phosphoglycerate Kinase; Plasmids; Promoter Regions, Genetic; Puberty, Precocious; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Retroviridae; Sexual Maturation; Transfection; Transforming Growth Factor alpha

It has long been known that lesions of the hypothalamus lead to female sexual precocity. While an increased production of luteinizing hormone-releasing hormone (LHRH), the neurohormone that controls sexual development, appears to mediate the advancement of puberty induced by these lesions, little is known about the mechanism(s) by which hypothalamic injury activates LHRH secretion. Since brain lesions result in accumulation of neurotrophic/mitogenic activities in the injured area, we tested the hypothesis that transforming growth factor alpha (TGF-alpha), a mitogenic polypeptide recently shown to stimulate LHRH release, is produced in response to hypothalamic injury and mediates the effect of the lesion on puberty. Radiofrequency lesions of the preoptic area-anterior hypothalamic area (POA-AHA) of 22-day-old female rats resulted in precocious puberty within 7 days after the operation. RNA blot hybridization revealed that lesion-induced puberty was preceded by an increase in TGF-alpha mRNA levels in the POA-AHA. Epidermal growth factor (EGF) mRNA was undetectable in both intact and lesioned hypothalami. TGF-alpha mRNA levels, quantitated by RNase protection assays, were 3.5-fold greater in lesioned animals approaching puberty than in age-matched controls. Immunohistochemical studies, utilizing single- and double-staining procedures, demonstrated the presence of TGF-alpha precursor-like immunoreactivity in reactive astrocytes surrounding the lesion site. Hybridization histochemistry showed increased TGF-alpha mRNA expression in cells of the same area, further implicating reactive astrocytes as a site of TGF-alpha synthesis. The actions of TGF-alpha are mediated by its interaction with EGF receptors. Continuous infusion of RG-50864, an inhibitor of EGF receptor kinase activity, at the site of injury prevented the advancement of puberty induced by the lesion. These results suggest that TGF-alpha acting via EGF-like receptors contributes to the acceleration of puberty induced by anterior hypothalamic lesions. They also indicate that activation of TGF-alpha gene expression in glial cells is a component of the hypothalamic response to injury.

Topics: Animals; Antisense Elements (Genetics); Blotting, Northern; Catechols; ErbB Receptors; Female; Gene Expression; Hypothalamus; Nitriles; Nucleic Acid Hybridization; Protein-Tyrosine Kinases; Puberty, Precocious; Rats; Rats, Inbred Strains; RNA, Messenger; Transforming Growth Factor alpha; Tyrphostins