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Growth hormone deficiency
Published in Nadia Barghouthi, Jessica Perini, Endocrine Diseases in Pregnancy and the Postpartum Period, 2021
Patients with Laron syndrome (a condition caused by a genetic abnormality of the GHR in which there is complete insensitivity to GH) have smaller gonads and genitalia as well as delayed onset of puberty.8,9 The role of GH at conception is not clear given that normal ovulation and fertility can be observed in individuals with Laron syndrome and other causes of GH resistance.8
Endocrine and Metabolic Side Effects
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Ayse Serap Karadag, Emin Ozlu, Bodo C. Melnik
Phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires a specific protein 1 (SP1)-binding site in the POMC promoter. FoxO1 binds to STAT3 and prevents STAT3 from interacting with the SP1-POMC promoter complex, and consequently inhibits STAT3-mediated leptin action (67,68). Isotretinoin-induced nuclear FoxO1 may thus impair POMC expression, explaining reduced expression of ACTH in acne patients. FoxO1 suppresses the expression of hepatic GH receptor (GHR) (69), which plays a key role for the hepatic synthesis of IGF-1 (69,70). GHR-knockout pigs that lack GHR exhibited markedly reduced serum IGF-1 levels and reduced IGFBP3 activity (70). This animal model mimics the endocrine deviations observed in IGF-1-deficient patients with Laron syndrome (71), who do not develop acne when untreated (72). FoxO1 also suppresses PPAR-γ (73), which mediates hepatic secretion of IGF-1 (74). Isotretinoin via upregulation of FoxO1 in acne suppresses the hypothalamus-pituitary system at various levels.
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Growth hormone circulates with the blood bound to growth hormone-binding proteins (GHBPs).600,601 Two circulating GHBPs have been characterized, one of high affinity and the other of low affinity, and both are specific for GH. The high affinity GHBP corresponds to the extracellular portion of the hepatic GH receptor, whereas the low affinity does not appear to be related to this receptor. Approximately half of the circulating GH is complexed to the high affinity GHBP. The GHBPs protect GH from degradation and prolong the biological persistence of the hormone in vivo. The levels of GHBPs are low in the fetus and neonate, rise rapidly after birth, and stay constant through adult life. The endowment of GHBPs may be relatively fixed for a given individual and may play a pivotal role in somatic growth, determining growth rate and height potential.602 Certain forms of short stature resistant to GH (pygmies, Laron dwarfism) may have absent or decreased GHPB levels in plasma. However, some cases of Laron syndrome associated with insensitivity to GH are due to mutations in the GH receptor, which lead to defective expression of the receptor on the cell surface.603
Ocular Disorders in Turkish Children with Sensorineural Hearıng Loss: A Cross-Sectional Study and Literature Review
Published in Seminars in Ophthalmology, 2018
Pinar Altiaylik Ozer, Emrah Utku Kabatas, Gokce Tasdemir Ertugrul, Bengi Ece Kurtul, Umut Kaygusuz, Selmin Karatayli Ozgursoy
A genetically defined syndromic cause of SNHL was detected in 26 patients (23.6%) of our study. All of these cases were reported to have a congenital type of SNHL, and all were bilateral except for a case of Struge Weber syndrome with unilateral SNHL. All cases with syndromic SNHL had an ocular abnormality. Usher syndrome was the most common syndrome observed among our cases (seven cases, 6%). Since the retina and cochlea share the same embryologic origin during embryogenesis, oculoauditory syndromes like Usher syndrome have already been studied in many previous studies and were listed in the literature as common syndromes associated with ocular abnormalities.7,21 Although rare, sensorineural hearing loss is also reported as a feature of Pendred and Laron syndromes.22,23 Ocular findings in Pendred syndrome have not been previously studied in the literature, so we have little knowledge about the associated eye findings in these cases. In our study, there was only one case of congenital SNHL with the diagnosis of Pendred syndrome. This patient had a refractive accommodative type of esotropia as the only ocular finding. Laron syndrome is a syndrome of primary growth hormone receptor insensitivity, which is reported to be associated with some ocular abnormalities like pseudopapilledema and congenital disc abnormalities in addition to congenital SNHL.24 We had two patients with Laron syndrome, who both had strabismus, with no other documented ocular abnormalities.
Investigational IGF1R inhibitors in early stage clinical trials for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2019
Haim Werner, Rive Sarfstein, Ilan Bruchim
As alluded to above, during malignant transformation, a primitive pattern of IGF1R expression is established, leading to enhanced IGF1R levels. A similar developmental trend is exhibited by IGF2, which is produced by most cancer cells and constitutes the main oncogenic ligand in tumors (IGF1 is often produced by stromal cells). These early observations led to the dogma that IGF1R overexpression is a critical requisite for establishment of a malignant phenotype [59]. The appeal of this stance stemmed from the fact that high IGF1R levels and signaling are regarded as key events, indispensable in order for the cell to adopt proliferative/oncogenic pathways. It is important, however, to realize that this paradigm is not necessarily true in every type of cancer. Thus, whereas IGF1R overexpression is a common feature of most pediatric tumors, often associated with recurrent chromosomal translocations, and other solid tumors such as brain and renal cancers, the situation in epithelial tumors, which are more widespread in adults (e.g. breast, prostate), is more complex [33,60]. These early analyses relied on the conception that IGF1R overexpression, per definition, must reflect the existence of a cancerous phenotype. It is clear today that this belief is, at best, an oversimplification. Thus, IGF1 binding and IGF1R mRNA levels are markedly enhanced in erythrocytes and lymphocytes, respectively, of Laron syndrome patients, a congenital type of IGF1 deficiency shown to be associated with protection from cancer development [61,62]. In addition, certain growth factors were shown to increase IGF1R expression without evidence of malignancy [63,64]. Combined, data support the view that enhanced IGF1R concentrations do not necessarily reflect the existence of cancer.