theory for ultimate cutting cycle with igf and t3

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    theory for ultimate cutting cycle with igf and t3


    If what i read in the stickies is correct and that igf actually inhibits the loss of glyocogen from the muscle and forces the body to use fat and blood sugar as its primary energy source. Then by supplementing T3 with igf would yeild an expenential fat loss, and the loss of muslce mass would be considerably less if nut completly negated by the effects of IFG. This is just a theory of course. what do u guys think

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    Email page This was a stufy i found on the amercian thyroid assoc site

    Thyroid Hormone Action


    Thyroid hormone stimulates bone growth by increasing the action of insulin-like growth factor-I

    The background of the study. Thyroid hormone is essential for normal bone growth in children, and it stimulates the turnover of bone in adults. In children and adults with hypothyroidism, the production of growth hormone and insulin-like growth factor (IGF)-I, which are needed for normal growth, are decreased, but the decreases may not be sufficient to account for the growth retardation in the children. Bone cells contain receptors for thyroid hormone; therefore thyroid hormone probably has direct effects on bone. This study evaluated the effects of triiodothyronine (T3) on the production of IGF-I, the receptors for IGF-I, and the growth-promoting actions of IGF-I in bone cells in vitro.

    How the study was done. Bone-forming cells (osteoblasts) were grown from pieces of bone obtained at the time of knee or hip joint replacement in six women and five men with osteoarthritis. The cultured cells were characterized as osteoblasts by several biochemical tests.

    The results of the study. Incubation of osteoblasts with T3 for 24 hours did not increase the cellular levels of IGF-I, but did increase the cellular levels of IGF-I receptors. T3 and IGF-I alone stimulated osteoblast proliferation, and the effect of IGF-I was amplified by exposing the cells to T3 before they were exposed to IGF-I.

    The conclusions of the study. In osteoblasts T3 increases IGF-I receptors and increases the ability of IGF-I to stimulate proliferation of the cells. These results help to explain why children with hypothyroidism grow poorly

    The original article. Pepene CE, Kasperk CH, Pfeilschifter J, Borcsok I, Gozariu L, Ziegler R, Seck T. Effects of triiodothyronine on the insulin-like growth factor system in primary human osteoblastic cells in vitro. Bone 2001;29:540-6.
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    another

    Thyroid growth and function are increased in mice in which the growth-promoting substance, insulin-like growth factor-I, and its receptor are expressed in thyroid tissue

    The background of the study. Insulin-like growth factor-I (IGF-I), acting via its receptor on cells, stimulates the growth of many tissues. In this study the gene for IGF-I, the gene for the IGF-I receptor, and both genes, were introduced into thyroid tissue of mice to determine if thyroid growth and function were affected.

    How the study was done. Transgenic mice were produced by injecting portions of the human IGF-I gene or the IGF-I receptor gene into fertilized mouse eggs. Mice carrying each gene were bred together to obtain mice bearing both genes. Expression of the two genes was verified by detection of the gene products in thyroid tissue of these mice, but not in thyroid tissue from normal mice.

    The results of the study. The body weight and behavior of the transgenic mice were similar to that of normal mice. The weight of the thyroid glands and the thyroid function were higher in the mice with both transgenes.

    The conclusions of the study. In mice, insertion of the genes for IGF-I and its receptor in thyroid tissue results in increased thyroid growth and function. Increases in these two substances in thyroid tissue could play a role in the causation of goiter in humans.

    The original article. Clement S, Refetoff S, Robaye B, Dumont JE, Schurmans S. Low TSH requirement and goiter in transgenic mice overexpressing IGF-I and IGF-I receptor in the thyroid gland. Endocrinology 2001;142:5131-9.
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    Thyroid hormones are important for growth and development of many tissues. Altered thyroid
    hormone status causes testicular abnormalities. For instance, juvenile hypothyroidism
    =neonatal

    transient hypothyroidism induces macroorchidism, increases testicular cell number (Sertoli,
    Leydig, and germ cells) and daily sperm production. Triiodothyronine (T3) receptors have been
    identified in sperm, developing germ cells, Sertoli, Leydig, and peritubular cells. T3 stimulates Sertoli
    cell lactate secretion as well as mRNA expression of inhibin-
    a, androgen receptor, IGF-I, and

    IGFBP-4. It also inhibits Sertoli cell mRNA expression of M
    ullerian inhibiting substance (MIS),

    aromatase, estradiol receptor, and androgen binding protein (ABP) and ABP secretion. T3 directly
    increases Leydig cell LH receptor numbers and mRNA levels of steroidogenic enzymes and steroidogenic
    acute regulatory protein. It stimulates basal and LH-induced secretion of progesterone, testosterone,
    and estradiol by Leydig cells. Steroidogenic factor-1 acts as a mediator for T3-induced
    Leydig cell steroidogenesis. Although the role of T3 on sperm, germ, and peritubular cells has not
    yet been completely studied, it is clear that T3 directly regulates Sertoli and Leydig cell functions.
    Further studies are required to elucidate the direct effect of T3 on sperm, germ, and peritubular
    cells.
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    another study part 1


    There are close interrelationships between the multitude of hormones that regulate bone formation and protein biosynthesis in mammalian growth and development. Not only is insulin-like growth factor-I (IGF-I) one of the key mediators of cellular metabolism and proliferation, directly influenced by growth hormone (GH) [<A id=ref_link title=1 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib1">1,<A id=ref_link title=2 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib2">2] but thyroid hormones can also modify plasma IGF-I levels. A direct relationship between circulating levels of thyroid hormones and IGF-I has been reported [<A id=ref_link title=3-5 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib3">3-5]. The tissue availability of IGF-I is also influenced by insulin since insulin and IGF binding protein-1 (IGFBP-1) are inversely regulated.

    Traditional endocrine investigations have typically examined isolated variables. Despite the substantial anecdotal evidence for cross-talk between various endocrine axes, multifactorial approaches to endocrine analysis are less commonly employed. In this work we describe a method for identifying relationships between endocrine markers from a statistical analysis of the correlations between data sets derived from wide-ranging biochemical analyses of serum collected from two human cohorts treated with a recombinant human (rh) IGF-I/IGFBP-3 complex. Administration of this complex in clinical and preclinical studies had previously established its stimulatory effects on bone mass, muscle and other tissues, including a pronounced effect on the circulating level of associated biochemical markers such as collagen type I C-terminal propeptide, CICP [<A id=ref_link title=6-10 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib6">6-10]. Here we examine the possibility that endocrine factors outside the IGF axis are instrumental in modulating the stimulatory responses mediated by the IGF-I/IGFBP-3 complex. For the purposes of this study, circulating levels of CICP were considered to be a surrogate marker for the effects of rhIGF-I/IGFBP-3 complex on collagen synthesis and, by extension, the previously documented anabolic effects of this complex.

    Like most hormone replacement treatments, rhIGF-I/ IGFBP-3 complex produces varying degrees of response from each treated individual and a percentage of treated individuals fails to respond to the treatment altogether. Likewise, a population of individuals diagnosed with a given disorder will generally exhibit widely disparate neuroendocrine profiles. Such disparity is particularly evident in small human study cohorts and might account for some, if not most, of the variability in drug response typically observed in small clinical studies. To improve clinical treatment regimens -- such as those involving IGF-I complex supplementation -- these interrelationships need to be clarified.

    The aim of the current study was to derive a statistical method for identifying -- prior to actual drug administration -- the key endocrine variables controlling an individual's subsequent response to the drug. Since interactions between different biochemical and endocrine subsystems (e.g. between the somatotropic, thyroid and adrenal axes) are complex, we examined a large number of biochemical markers in each patient and attempted to draw correlations between the effect of rhIGF-I/IGFBP-3 administration on each patient's CICP levels by the end of the study. CICP was chosen as the reference response marker since previous studies have shown CICP levels to be biochemical surrogates for the underlying processes of bone remodelling and formation [<A id=ref_link title=11-13 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib11">11-13]. It was not the purpose of this investigation to prove a stimulatory effect of the rhIGF-I/IGFBP-3 on CICP levels per se (since that had previously been demonstrated by others) but rather to measure in each treated individual possible correlations between the basal endocrine profile and the treatment-induced CICP response of that individual.

    The initial results of our statistical analysis indicated that each subject's response to rhIGF-I/IGFBP-3 administration was controlled in part by the individual's thyroid status prior to drug administration. We tested this putative endocrine relationship further in an independent experimental rat model. Undernourished rats were rendered hypothyroid and subsequently treated with rhIGF-I/IGFBP-3 complex for 3 days. Levels of protein synthesis in these animals were compared to those of euthyroid control rats.
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    part 2


    RhIGF-I and rhIGFBP-3 production

    Both rhIGF-I and rhIGFBP-3 were expressed and purified as previously described in detail [<A id=ref_link title=8 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib8">8,<A id=ref_link title=14 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib14">14,<A id=ref_link title=15 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib15">15]. Each protein was produced separately in Escherichia coli and then partially purified prior to complex formation. Following fermentation of E. coli, rhIGF-I was refolded and then purified by ion-exchange chromatography and hydrophobic interaction (HIC columns). IGFBP-3 was purified using a similar protocol. Following purification on HIC columns, the two proteins were mixed together in a 1:1 molar ratio with the complex being further purified by ion-exchange chromatography. Purity of the complex was verified by reversed phase high-performance liquid chromatography (HPLC) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis and was estimated to be > 95%. Bioactivity was monitored using a cell culture assay (proliferation of MG-63 cells). The complex was formulated in a buffered solution, and documented to be sterile and free of endotoxin prior to use.

    <A id=hd_toc title=\"Clinical studies \" href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#toc">Clinical studies

    Two individual clinical trials of rhIGF-I/IGFBP-3 complex ('drug') were performed: The first study ('9602') involved repeated once-daily intravenous administration of rhIGF-I/IGFBP-3 to 15 normal volunteers (male and female), ages 20-53 years, for 6 days. The second trial ('9604') involved continuous subcutaneous infusion of rhIGF-I/IGFBP-3 complex to 12 normal female volunteers, ages 55-70 years, for a period of 7 days. Biochemical profiles representing a variety of endocrine systems were determined on two separate occasions: just prior to first treatment and at the end of the study. Each study cohort was divided into four groups: placebo, low, medium and high dose (0, 0·3, 1·0 and 3·0 mg kg-1 day-1 for study '9602' and 0, 0·5, 1·0 and 2·0 mg kg-1 day-1 for study '9604'). In this study, only the data from the subjects who received rhIGF-I/IGFBP-3 are considered, since the study attempts to correlate basal endocrine status to changes in CICP caused by rhIGF-I/IGFBP-3 administration. It is not an objective of the current study to show statistically significant effects of the treatment on any biochemical parameter by comparing placebo to treatment, although such effects have been documented by others. Approval for these studies was obtained from the local ethical committee and informed consent was obtained from the study subjects.
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    part 3


    Biochemical analyses of clinical samples

    Markers for assay were selected from the somatotrophic axis [IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, acid labile subunit (ALS), growth hormone], thyroid axis [total triiodothyronine (T3), total and free tetraiodothyronine (T4), thyroid stimulating hormone (TSH), thyroglobulin (TG)], adrenal axis [cortisol, aldosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulphate (DHEAS), cortisol-binding globulin (CBG), 17- hydro xyprogesterone (<A id=ref_link title=17 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib17">17-OHP)], gonadal axis [testosterone (T), androstenedione (A4), estradiol (E2), luteinizing hormone (LH), prolactin (PRL), sex-hormone binding globulin (SHBG)], bone markers [CICP, osteocalcin (OC), bone alkaline phosphatase (BAP), intact parathyroid hormone (iPTH), calcitonin] using diagnostic kits purchased from Nichols Institute Diagnostics (San Juan Capistrano, CA, USA) and Diagnostic Systems Laboratories (Webster, TX, USA). Hormones (such as insulin, proinsulin C-peptide, angiotensin) and cytokines (interleukins 1b, 4 and 6, tumour necrosis factor-a and interferon-g) were also analysed, employing kits obtained from Linco Research, Inc. (St Charles, MO, USA), Genzyme Corporation (Framingham, MA, USA), Metra Biosystems (Mountain View, CA, USA) and Diagnostic Products Corporation (Los Angeles, CA, USA).

    In order to minimize the effects of intersubject variability, the biochemical response of each subject was expressed on a relative basis (i.e. for each biochemical marker, the level at the end of the study was expressed as a percentage of the baseline value prior to treatment). The change in CICP levels was used as the 'response' for deriving the formulas. To normalize for treatment effects at different doses of IGF-I/IGFBP-3, the IGF responsiveness of each subject was computed relative to the mean value for the treatment group to which the individual belonged.

    <A id=hd_toc title=\"Animal study \" href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#toc">Animal study

    Female Sprague-Dawley rats (200 g) (B & K Universal, Stockholm, Sweden) were used according to guidelines and regulations issued by the ethical animal committee at Göteborg University. The animals were adapted in four groups of eight with free access to chow and water on a 12-h light: dark cycle for 14 days prior to experimentation. Two groups of animals were then given propylthiouracil (PTU; Sigma, St Louis, MO, USA, 0·1% final concentration) in the drinking water for 10 days to produce hypothyroidism [<A id=ref_link title=16 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib16">16], and remained on PTU treatment during the 6-day experimental period. During the 6-day experimental period access to food in all groups was restricted to 25% of the amount of food consumed by freely fed rats. Food was provided at 10.00 h daily, and consumed within 1 h. Water was provided ad libitum. On day 3 of food restriction all animals were anaesthetized using diethylether and implanted with an osmotic pump (Alzet 1003 D) in the dorsal skin fold of the neck. The pump contained L-[U-14C] phenylalanine (Amersham, UK) (35 nCi g-1 body weight in 100 mL) and was driven by the osmotic pressure between the compartment within the pump and the tissue environment, yielding a flow rate of 1 mL h-1. Between day 3 and day 6 of food restriction the rats received either rhIGF-I/IGFBP-3 complex (5 mg g-1) or saline by twice daily injections in the lateral tail vein. The rats were killed by cervical dislocation 12 h after the final injection.

    <A id=hd_toc title=\"Protein synthesis \" href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#toc">Protein synthesis

    Hind limb muscles (gastrocnemius) were excised and frozen intact in liquid nitrogen until preparation for determination of protein synthesis. Protein synthesis was estimated from incorporation of L-[U-14C]phenylalanine into protein over a 3-day period with constant and continuous isotope delivery. Muscle tissue was homogenized (10% wt/vol) and proteins were isolated and extracted by acid precipitation as previously described [<A id=ref_link title=17 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib17">17]. Incorporation is given as disintegrations per minute per milligram protein. The counting efficiency of radioactivity in muscle protein was above 80% and all tissue samples contained 10-fold more radioactivity than appropriate blank specimens.

    <A id=hd_toc title=\"Biochemical analyses of animal samples \" href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#toc">Biochemical analyses of animal samples

    Blood samples were collected into heparinized syringes by puncture of the heart and were frozen until analyses. Plasma amino acids were analysed by HPLC with a precolumn derivatization method (Waters Associates Liquid Chromatographic System, Milford, MA, USA) [<A id=ref_link title=18 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib18">18]. Blood glucose levels were measured by the GodPap method (Boehringer Mannheim, Germany). Plasma insulin was analysed by radioimmunoassay (Pharmacia Sweden AB, Stockholm, Sweden) and IGF-I was analysed by an IGFBP-blocked IGF-I radioimmunoassay (IGF-R 20, Mediagnost, Tübigen, Germany) with efficient extraction of IGFBP [<A id=ref_link title=19 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib19">19].
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    results part 4


    The effect of rhIGF-I/IGFBP-3 complex administration on the circulating levels of CICP was quantified in each patient in study '9604', and normalized for each dose group (n = 3), as described in the Materials and Methods section. This was considered as the 'response' data set.

    A variety of biochemical markers were measured in each cohort prior to treatment. The values obtained are shown in Tables 1 and 2. These are the 'basal' data sets.

    Pearson correlation coefficients were determined by pairwise comparison of each 'basal' data set with the 'response' data set and a grid of correlation coefficients (Table 3) was generated. The basal markers most closely correlated to the CICP 'response' were osteocalcin, TSH and total T4 (r values indicated by bold type in Table 3).

    We next examined whether ratios between these basal markers might be correlated to response. The highest correlations were observed in the following cases: log TSH: IGF-I ratio, and total T4: IGF-I ratio. By combining these two expressions, the following formula was empirically derived which, when applied to the basal markers of the '9604' cohort, generated a data set in good agreement with the CICP response data set:

    P = {log([TSH] + 1)}*0[tT4]/[IGF-I]

    where P is the predicted effect of the drug on CICP levels, and [TSH], [tT4] and [IGF-I] are the serum concentrations of TSH (IU mL-1), total T4 (ng mL-1) and IGF-I (ng mL-1) just prior to the start of the study. For simplicity, if an assay value fell outside the normal clinical range (TSH 0·5-5·0 IU mL-1; total T4 40-130 ng mL-1; IGF-I 70-440 ng mL-1) for one of these factors, the closest boundary value within the normal range was arbitrarily assigned to it in the computation instead. Less than 5% of all measured values were outside the clinical range.

    Independent validation for this predictive formula was obtained by applying it to a completely independent basal data set obtained by measuring biochemical markers in the '9602' study cohort. Despite substantial differences in the demographics of the two study cohorts (i.e. age and gender) and in the mode of drug administration, the predictive algorithm fits the data set of '9602' equally well as it fits the data set of '9604' (r = 0·78, P < 0·05, see Fig. 1). Baseline serum T4 and TSH also correlated with CICP responses in the '9602' study.

    Experimental support for the hypothesis that thyroid status influences the responsiveness of an individual to systemically administered rhIGF-I/IGFBP-3 complex was further evaluated in an experimental rat model; Propylthiouracil (0·1% in the drinking water for 10 days) induced hypothyrosis as determined by reduced concentrations of T4 in plasma (Fig. 2). Food intake was reduced and body weight was maintained during this 10-day period of propylthiouracil treatment whereas euthyroid rats ate more and gained 12 ± 1% weight (data not shown). Restricting food intake in rats to 25% of that in freely fed controls during a 6-day period caused a significant weight loss in hypo- as well as euthyroid rats. This pattern of weight loss was not altered in response to short-term treatment with rhIGF/IGFBP-3 complex (Fig. 3).

    Blood glucose levels were not altered in response to thyroid status or rhIGF/IGFBP-3 complex provision. Plasma concentrations of insulin were not significantly altered in response to hypothyroidism but were significantly increased following rhIGF/rhIGFBP-3 complex supplementation, compared to rats treated with saline. Plasma concentration of IGF-I was reduced by 43 ± 5% (P < 0·05) in hypothyroid rats compared to euthyroid rats despite equal food consumption for both groups of animals. Treatment with rhIGF-I/IGFBP-3 complex resulted in a 30% (P < 0·05) increase in plasma concentrations of IGF-I in euthyroid as well as hypothyroid rats. Overall plasma concentrations of amino acids were not altered among the study groups. (Table 4).

    Long-term incorporation of [14C]phenylalanine into muscle proteins was similar in euthyroid and hypothyroid rats treated with saline. Protein synthesis was increased by 35 ± 9% (P < 0·05) following treatment with rhIGF/IGFBP-3 complex in euthyroid rats compared to the saline-treated controls. This stimulation of protein synthesis was completely abolished in rats suffering from hypothyroidism (Fig. 4).

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    discussion part 5 and last


    From several studies we have evidence to suggest that rhIGF-I/IGFBP-3 treatment results in improved protein biosynthesis, collagen formation, grip strength, or bone formation [<A id=ref_link title=7-10 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib7">7-10]. Nevertheless, individuals exhibit variable responses to a rhIGF-I/IGFBP-3 treatment regimen and, in order to achieve more consistent results, individual factors of importance for treatment efficacy need to be identified and, if possible, addressed. The present study aimed to define such biochemical markers for rhIGF-I/IGFBP-3 treatment and provides results suggesting that the extent to which an individual responds to rhIGF-I/IGFBP-3 treatment may be largely influenced by the ratio between plasma concentrations of thyroid hormones and IGF-I in that individual prior to treatment.

    We derived this relationship from a statistical analysis of human serum markers, not biased by biological rationale, and subsequently investigated and verified the correlation between thyroid status and response to rhIGF-I/IGFBP-3 treatment in an experimental rat model.

    Previous studies in our laboratory have demonstrated a stimulatory effect of rhIGF-I/IGFBP-3 on protein biosynthesis in skeletal muscle from undernourished rats (rhIGF-I/IGFBP-3 complex, but not free IGF-I, supports muscle protein biosynthesis in rats during semi-starvation [<A id=ref_link title=20 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib20">20]). In the present study this effect of rhIGF-I/IGFBP-3 was abolished in rats rendered hypothyroid by treatment with propylthiouracil. The duration of hypothyroidism in the present study (16 days) therefore seems to be adequate to create alterations in muscle and bone tissue, as has also been described by others [<A id=ref_link title=21 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib21">21]. Understanding the interactions between metabolic signals in the regulation of IGF-I is crucial, since thyroid hormone status exerts an influence on food intake, which, in turn, affects IGF-I levels. Moreover, thyroid hormones may modify circulating IGF-I concentrations either directly or indirectly by preventing GH secretion or modulating GH receptor levels, thus leading to low serum IGF-I concentrations. It is therefore important to emphasize that in the present model, food intake was limited and equal in euthyroid and hypothyroid rats. Therefore, variations of IGF-I levels between euthyroid and hypothyroid animals did not depend on feeding, but could be attributed directly to thyroid status. Not only was plasma concentration of IGFI reduced in the hypothyroid rats but the stimulatory effect of exogenous rhIGF-I/IGFBP-3 supplementation on protein synthesis in skeletal muscle was completely abolished. Such direct cross-talk between thyroid status and IGF responsiveness in peripheral tissue has not been previously demonstrated, although the effects of thyroid hormones on GH action are well known [<A id=ref_link title=22-25 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib22">22-25]. It has been suggested that thyroid hormone might act independently of GH by regulating IGF-I receptor expression or signalling and thus IGF-I effects on target cells. This suggestion is supported by the observation that thyroid hormone up-regulates IGF-I receptors and IGF-I binding in cultured pituitary cells, and increased serum thyroid hormone levels have been shown to increase IGF-I binding to erythrocyte membranes. The possibility that hypothyroidism affects IGF-I receptors specifically at target tissue level (i.e. bone or muscle) can therefore be entertained. Impaired IGF-I receptor synthesis or signalling could potentially explain the impaired response to rhIGF-I/IGFBP-3 supplementation observed in our study.

    In addition, both IGF-I and IGFBP-3 are significantly reduced in response to hypothyroidism and normalized to basal values following thyroid hormone replacement or GH therapy [<A id=ref_link title=26 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib26">26]. In hypothyroid rats this reduced plasma concentration of IGFBP-3 has been shown to be associated with a reduction of IGFBP-3 mRNA levels in liver [<A id=ref_link title=27 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib27">27]. Since the vast majority of IGF-I in plasma circulates bound to IGFBP-3, a reduction of IGFBP-3 in the circulation suggests a more rapid clearance of IGF-I from the circulation. The reduction of plasma levels of IGF-I in hypothyreosis might be further aggravated in this manner.

    Cross-talk between thyroid hormone and the endocrine and paracrine actions of IGF-I provides an attractive hypothesis for the mechanism of changes in tissue mass and differentiation seen in thyroid dysfunction [<A id=ref_link title=28 href="http://web33.epnet.com/citation.asp?tb=1&_ug=sid+AF96 C59C%2D6328%2D4852%2D8CD6%2D58 32DEF6F65B%40sessionmgr5+dbs+a ph+cp+1+5CB5&_us=hd+False+hs+T rue+cst+0%3B1+or+Date+fh+False +ss+SO+sm+ES+sl+0+ri+KAAACB4C0 0106701+dstb+ES+mh+1+frn+11+FF C3&_uso=tg%5#bib28">28] and supports our findings that the stimulatory effect of IGF supplementation on bone and muscle tissue may be influenced by thyroid status, although the exact details of this mechanism remain to be elucidated. Particularly intriguing is the fact that both TSH and T4 levels appear to have a positive effect on the CICP marker in vivo. At the moment we do not have an explanation for this observation.

    In conclusion, we acknowledge that the evidence presented here from clinical studies is purely correlational. The influence of the thyroid axis on IGF action was demonstrated in an experimental rat model instead. Treatment with propylthiouracil completely abolished the stimulatory effects of rhIGF-I/IGFBP-3 on muscle protein synthesis. The interpretation of these results is complicated by the possibility that propylthiouracil, in addition to reducing thyroid hormone levels, might be influencing the test animals in other ways. Nevertheless, it is consistent with a contributory role for the thyroid axis in IGF signalling.

    The relationship between the two endocrine axes is not a simple one. The predictive formula is based on relationships between levels of biochemical markers. Thus, based on raw hormone levels alone, it would not be possible to make predictions. For example, none of the patients in either cohort are (technically) hypothyroid, though some individuals are at the bottom of the clinical range for TSH. There is also substantial variability in the levels of thyroid hormones observed. An improved understanding of the interactions between neuroendocrine systems may facilitate the design of efficient drug regimens in the treatment of diseases such as osteoporosis and muscle wasting.
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    Anyone else got an opinion, sorry about all the post but this has been the only board that has a designated forum for IGF. Someone was trying to tell me that T3 would increase IGF-BP, according to what I've read this is a small case but the overall effect is exponential because T3 activates more IGF receptors and in vivo the effects of IGF are amplified by T3 or pre-use of. Anyway i'm new to this board so I thought I'd contribute.
    Thanks guys
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    cripes! I am gonna have to print that out and use it for reading in the "throne" room. I will have to summon all my powers of concentration
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    Cliff notes please......
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    Good post game, i cant wait for more people to chime in on this.
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    So what would be a good dosage of T3 to go with 33,cg per day of Igf R3 ?
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    I have a more complete profile on the synergistic effects of T3 and IGF-I, its pretty awesome if you like to check it out in the new T3 I made at IBE in addition to these old post.
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