ABSTRACT
IGF-1, a high potent mitogenic factor with a dual function is believed to participate with female steroids and other growth factors to prepare endometrium receptivity for successful embryo implantation and further development. Stromal cells forms the functional receptive layer of endometrium structure. Analysis of the conditioned/defined medium of pure cultured human endometrial stromal cells have revealed that stromal cells in a monolayer culture secrete and produce three different types of proteins in a varying amounts. These proteins exhibit a high specificity as well as a high binding affinity for the radiolabeled IGF-1 peptide. The molecular weights of these proteins have been determined by SDS-Page electrophoresis after cross-linking with the radiolegand IGF-1 and then detected with autoradiography. By comparison to the migration of high molecular weights protein markers, these proteins have been identified to correspond to the IGFBP-1 (31 KDa), IGFBP-2 (36 KDa) and IGFBP-3 (45 KDa). The secretion of these binding proteins (IGFBP-1, -2, -3) by endometrial stromal cells may support the view of their biological importance in controlling the delivery and bioavailability of the high mitogen IGF-1 peptide to their nominative type-1 IGF-receptor on cell surface, thereby modulating its action. It seems likely that these IGFBPs may play a key role in switching on/off IGF-1 peptide action , thereby avoiding the uncontrolled proliferation effect of the IGF-1 that favor endometrium cancer development.
ABSTRACT
The growth hormone-insulin-like growth factor-insulin-like growth factor binding protein (GH-IGF-IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF-IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH-IGF-IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.
Subject(s)
Child , Humans , Axis, Cervical Vertebra , Carrier Proteins , Diabetic Nephropathies , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor Binding Proteins , Insulin-Like Growth Factor I , Kidney , Kidney Diseases , Proteins , Proteinuria , Renal Insufficiency, Chronic , Signal Transduction , SomatostatinABSTRACT
O tratamento do hipogonadismo hipogonadotrófico na mulher adulta com hipopituitarismo inclui diversas alternativas terapêuticas de estrógenos e progestágenos, sendo a via oral a de menor custo e a de maior comodidade à paciente. A rota estrogênica oral, entretanto, exerce marcada influência sobre o eixo hormônio de crescimento/fator de crescimento insulina-símile número 1 (GH/IGF-1) nessas mulheres. O tratamento com estrógenos orais, concomitante ao uso de GH em pacientes com hipopituitarismo, antagoniza as ações biológicas do GH e agrava as anormalidades de composição corporal e o metabolismo em geral. Presume-se que o estrógeno oral iniba a secreção/produção de IGF-1 por meio de efeito de primeira passagem hepática, causando aumento da secreção de GH por intermédio de inibição do feedback negativo de IGF-1 em mulheres normais. Isso é demonstrado clinicamente por redução da massa magra, aumento da massa gorda, perfil lipídico aterogênico e prejuízo do bem-estar psicológico. Alguns estudos apontam que os progestágenos com ação androgênica revertem o efeito de diminuição dos níveis séricos de IGF-1 induzida pelos estrógenos orais. Os progestágenos neutros não apresentam esse efeito, porém, quanto maior a potência androgênica, maior será a reversão do efeito de diminuição de IGF-1. Na presente revisão da literatura, serão abordados os aspectos clínicos da reposição com estrógenos e progestágenos nas mulheres com hipopituitarismo, suas interações nas outras deficiências hormonais, bem como o impacto do uso de estrógenos sobre as ações metabólicas do GH.
Treatment of hypogonadotropic hypogonadism in adult women with hypopituitarism can include a wide range of estrogen and progestogen treatment alternatives and oral administration is the route of least cost and greatest patient comfort. The oral estrogen route has a major impact on the growth hormone-insulin-like growth factor I (GH/IGF-1) axis. Oral estrogen therapy, when given concurrently with GH to patients with hypopituitarism, antagonizes the biological effects of GH treatment and aggravates the abnormalities of body composition and the metabolism in general. It is presumed that oral estrogen suppresses the secretion/production of IGF-1 by a hepatic first-pass mechanism, resulting in increased GH secretion by means of suppressing the IGF-1 negative feedback that is present in healthy women. This is clinically manifested in reduced lean body mass, increased fat mass, an atherogenic lipid profile and damage to psychological well-being. Some studies have indicated that progestogens with androgenic actions reverse the effect of reduced serum IGF-1 levels that is induced by the oral estrogens. Neutral progestogens do not exert this effect, however the stronger the androgenic potentialis, the more the effect of reduced IGF-1 will be reversed. This bibliographical review will deal with the clinical aspects of estrogen and progestogen replacement in women with hypopituitarism, their interactions with other hormone deficiencies and the impact of estrogen treatment on the metabolic actions of GH.
Subject(s)
Female , Humans , Estrogen Replacement Therapy , Estrogens/therapeutic use , Human Growth Hormone/metabolism , Hypopituitarism/drug therapy , Progestins/therapeutic use , Body Composition/drug effects , Hypopituitarism/metabolism , Insulin-Like Growth Factor Binding Proteins/metabolism , Insulin-Like Growth Factor I/metabolismABSTRACT
PURPOSE: The purpose of this study was to demonstrate the hypothesis that tussue IGFBP-2,-3, and -4 levels would differ between colon cancer tissue and adjacent normal tissue and to determine whether these factors could affect the clinicopathologic characteristics such as age, tumor stage, differentiation, serosal invasion, and CEA in patients with colon cancer. METHODS: This study group consisted of 102 patients with colorectal cancer who under went operations between January 2004 and December 2006. Postoperative colon cancer specimens and adjacent normal colon tissues were obtained immediately. Histopathologic examinations were made by on pathologist for each specimen. The gene expressions of IGFBP-2,-3,-4 in cancer and normal tissues were measured using a reverse transcriptase-polymerase chain reaction (RT-PCR). In additional, the various clinic-opathologic factors were evaluated for both tissues by comparing the IGFBP-2, -3, -4 expression densities. RESULTS: No significant difference was found in the expression of IGFBP-3, -4 between colon cancer and normal colon tissues. A statistically significant expression of IGFBP-2 was detected in the cancer specimens compared with the normal colon tissues. IGFBP-3 was significantly associated with pathologic N stage. CONCLUSIONS: This is a rare report comparing colon cancer with normal colon tissue for IGFBP expression by means of a systemical evaluation of colon cancer patients. Our data suggest that IGFBP-2 may be intimately associated with malignant phenotypes, and may confer some growth advantage on tumor cells, which means that IGFBP-2 shows a high sensitivity for colorectal cancer. Interestingly, IGFBP-3 was strongly associated with the pathologic N stage. We think further studies are needed to understand this phenomenon.
Subject(s)
Humans , Colon , Colonic Neoplasms , Colorectal Neoplasms , Gene Expression , Imidazoles , Insulin-Like Growth Factor Binding Protein 2 , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor Binding Proteins , Nitro Compounds , PhenotypeABSTRACT
Acute renal failure(ARF) usually has more than one cause and almost always includes an ischemic or nephrotoxic component to varying degrees. Regeneration and repair appear to be modulated by circulating and locally produced growth factors including insulin-like growth factors(IGFs). This study examined the change of serum and renal IGF-IGFBP axis in uremic rat by using IGF-I radioimmunoassay, Western ligand blot, immunohistochemical study and Northern blot analysis. Sera and kidney samples were obtained before and after 1, 3, 5, 7, 10 and 14 days of 45 minutes bilateral renal pedicle clamping. The results were as follows. 1) Following bilateral renal pedicle clamping, rats lost their weight, reaching a maximum after 3 days of ischemic injury. On day 10 uremic rats were still below their starting weights. 2) Following acute ischemic renal injury, serum creatinine rose, reaching a maximum after 3 days. By the 10th day serum creatinine levels had fallen to normal values. 3) Serum IGF-I concentration after 1 day following ischemic injury was significantly decreased compared to preischemic value. However the decreased level was returned to normal value after 3 days of ischemic injury. 4) The alteration of serum IGFBP profiles was observed in uremic rat. The 37-45 kDa sized IGFBP (probably IGFBP-3) was increased after 3 days of ischemic renal injury and continued until 10 days of ischemic injury. Another 28 kDa sized IGFBP also increased after 3 days of ischemic injury. 5) In preischemic kidney, immunoreactive IGF-I were primarily present in cortical tubule. However, IGF-I was markedly decreased on day 3 uremic rat. 6) IGFBP-3 and -7 mRNA in uremic kidney were temporally decreased on day 1 but increased to normal or higher levels after 3 days of ischemic renal injury. IGFBP-1 and -4 mRNA were markedly increased after 1 day and maintained high levels until 5 days(IGFBP-1) and 14 days(IGFBP-4) of ischemic renal injury. These findings suggest that IGF-IGFBP axis may involve in the pathogenesis or the recovery from acute renal failure.
Subject(s)
Animals , Rats , Acute Kidney Injury , Axis, Cervical Vertebra , Blotting, Northern , Constriction , Creatinine , Insulin-Like Growth Factor Binding Protein 1 , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor Binding Proteins , Insulin-Like Growth Factor I , Intercellular Signaling Peptides and Proteins , Kidney , Radioimmunoassay , Reference Values , Regeneration , RNA, Messenger , Weights and MeasuresABSTRACT
Se revisan los Factores Insulinoides de Crecimiento, también denominados "Factores de Crecimiento Similares a la Insulina", sobre los cuales se dispone de abundante información. Se sintetizan conocimientos recientes sobre dichos factores con énfasis en los siguientes aspectos: estructura bioquímica, concentraciones y sus cambios en los líquidos biológicos, proteínas fijadoras, receptores, mecanismos de acción y efectos biológicos
This review summarizes recent knowledge concerning Insulin.like growth factors I and II, with emphasis on their biochemical structure, concentrations, binding proteins, receptors, mechanisms of action, biological effects, and alterations of their concentrations in biological fluids