Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.

INTRODUCTION: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment. OBJECTIVE: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity. METHODS: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time. RESULTS: A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes. CONCLUSIONS: No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.

Various LED Wavelengths Affected Myofiber Development and Satellite Cell Proliferation of Chick Embryos via the IGF-1 Signaling Pathway.

An effect of monochromatic light illumination on muscle mass has been discovered in chickens; however, its effect on the development of embryonic muscle remains unclear. Our previous studies demonstrated that monochromatic green light promoted satellite cell proliferation and muscle growth in posthatching broilers. In this study, we investigated the effects and mechanisms of monochromatic light exposure on muscle development in late embryogenesis. Seven hundred and fifty fertile broiler eggs were randomly assigned to blue (B-group), green (G-group), red (R-group), white (W-group) lights or darkness (D-group) throughout the incubation period. The muscle weight and fiber size were highest in the G-group compared to the other groups during embryonic days (E) 17 to E20. The proliferation of satellite cells isolated from the G-group was highest, and in vivo green light remarkably increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in skeletal muscle. Meanwhile, plasma IGF-1 was higher (15.5-16.2%) in the G-group than that in D- and R-groups, and the satellite cells isolated from the G-group had a more sensitive response to IGF-1. These findings demonstrate green monochromatic photobiomodulation promoted the muscle growth and satellite cell proliferation was related to the IGF-1 signaling pathway in late embryogenesis.

In-ovo monochromatic green light photostimulation enhances embryonic somatotropic axis activity.

Previous studies demonstrated that in ovo photostimulation with monochromatic green light increases body weight and accelerates muscle development in broilers. The mechanism in which in ovo photostimulation accelerates growth and muscle development is not clearly understood. The objective of the current study was to define development of the somatotropic axis in the broiler embryo associated with in ovo green light photostimulation. Two-hundred-forty fertile broiler eggs were divided into 2 groups. The first group was incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W\m2 at shell level, and the second group was incubated under dark conditions and served as control. In ovo green light photostimulation increased plasma growth hormone (GH) and prolactin (PRL) levels, as well as hypothalamic growth hormone releasing hormone (GHRH), liver growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-1) mRNA levels. The in ovo photostimulation did not, however, increase embryo's body weight, breast muscle weight, or liver weight. The results of this study suggest that stimulation with monochromatic green light during incubation increases somatotropic axis expression, as well as plasma prolactin levels, during embryonic development.

Low-level laser irradiation affects the release of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and receptor of IGF-I (IGFBP3) from osteoblasts.

OBJECTIVE: It was the aim of the present study to evaluate whether the laser irradiation of osteoblasts could enhance the release of growth factors including basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and receptor of IGF-I (IGFBP3). BACKGROUND DATA: Low-level laser therapy (LLLT) has been shown to have biostimulatory effects on various cell types by enhancing production of some cytokines and growth factors. MATERIALS AND METHODS: Human mesenchymal stem cells (MSCs) were seeded in osteogenic medium and differentiated into osteoblasts. Three groups were formed: in the first group (single dose group), osteoblasts were irradiated with laser (685 nm, 25 mW, 14.3 mW/cm(2), 140 sec, 2 J/cm(2)) for one time; and in the second group, energy at the same dose was applied for 2 consecutive days (double dose group). The third group was not irradiated with laser and served as the control group. Proliferation, viability, bFGF, IGF-I, and IGFBP3 levels were compared between groups. RESULTS: Both of the irradiated groups revealed higher proliferation, viability, bFGF, IGF-I, and IGFBP3 expressions than did the nonirradiated control group. There was increase in bFGF and IGF-I expressions and decrease in IGFBP3 in the double dose group compared to single dose group. CONCLUSIONS: The results of the present study indicate that LLLT increases the proliferation of osteoblast cells and stimulates the release of bFGF, IGF-I, and IGFBP3 from these cells. The biostimulatory effect of LLLT may be related to the enhanced production of the growth factors.

The effect of the prenatal and post-natal long-term exposure to 50 Hz electric field on growth, pubertal development and IGF-1 levels in female Wistar rats.

To investigate prenatal and post-natal effects of extremely low frequency (ELF) electric field (EF) on growth and pubertal development, pregnant Wistar rats were randomly distributed among three groups. The pregnant rats of the prenatal group were exposed to 24-hour EF at 50 Hz EF 10 kV/min during pregnancy and their subsequent randomly selected female pups continued to be exposed until puberty. The post-natal group was unexposed to EF during pregnancy, but randomly selected female pups from this group were exposed to EF between delivery and puberty at the same doses and duration as the prenatal group. The third group was a sham-exposed group. The mean birth weight and weight gain of the pups during study period were found significantly reduced in prenatal group than post-natal and sham-exposed groups (p < 0.001). No difference could be found among the three groups for body weight at puberty (p > 0.05). The mean age at vaginal opening and estrous were significantly higher at prenatal group than post-natal and sham-exposed groups (p < 0.001). Serum insulin-like growth hormone-1 (IGF-1) levels were found significantly reduced in prenatal exposure group compared with the other two groups (p < 0.001). There was no difference for birth weight, weight gain, the mean age at vaginal opening and estrous and IGF-1 levels between post-natal and sham-exposed groups (p > 0.05). There was also no difference for FSH, LH and E2 levels at puberty among the three groups (p > 0.05). Histological examination revealed that both the prenatal and post-natal groups had the evidence of tissue damage on hypothalamus, pituitary gland and ovaries. In conclusion, early beginning of prenatal exposure of rats to 24 hours 50 Hz EF at 10 kV/m until puberty without magnetic field (MF) resulted in growth restriction, delayed puberty and reduced IGF-1 levels in female Wistar rats. These effects probably associated with direct toxic effects of EF on target organs. Post-natal exposure to EF at similar doses and duration seems to be less harmful on target organs. Post-natal exposure to EF at similar doses and duration seems to be less harmful.

Effect of gamma-sterilization process on PLGA microspheres loaded with insulin-like growth factor-I (IGF-I).

The influence of gamma-sterilization on the physicochemical properties of a controlled release formulation for the insulin-like growth factor-I (IGF-I) was investigated in this study. Recombinant human insulin-like growth factor-I (rhIGF-I) was efficiently entrapped in poly (D,L-lactide-co-glycolide) (PLGA) microspheres by water-in-oil-in-water (W/O/W) solvent evaporation technique. Microspheres were irradiated at a dose of 25kGy and evaluated by means of scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The stability of the released protein was investigated by circular dichroism (CD) and sodium dodecyl sulfate polyacrilamide gel electrophoresis (SDS-PAGE). No difference was noticed in microsphere size and morphology before and after irradiation. Drug loading remains essentially the same after the sterilization process. However, rhIGF-I aggregation was detected by electrophoresis. In addition, subtle changes in DSC pattern were noticed for irradiated microspheres. In vitro drug release from irradiated microspheres was also affected, showing an increased burst effect. From this results it can be concluded that gamma-sterilization process causes changes in the properties of rhIGF-I loaded microspheres.

Efficacy of radiotherapy in normalizing serum IGF-I, acid-labile subunit (ALS) and IGFBP-3 levels in acromegaly.

OBJECTIVE: Radiotherapy (RT) has been used for many years in order to complete the cure of unsuccessfully operated acromegalic patients. Several studies have shown its efficacy in normalizing GH levels, while reports about IGF-I normalization are conflicting. Moreover, data regarding other markers of disease activity, such as IGFBP-3 and acid-labile subunit (ALS), i.e. the other two components of the circulating 150 kDa complex, are lacking. DESIGN: Retrospective study. PATIENTS AND MEASUREMENTS: Sixty-seven acromegalic patients (20 males and 47 females, aged 40 +/- 6 years) who underwent postoperative RT (in fractionated doses for a total of 40-75 Gy) were followed-up for 11 +/- 6 years (range: 1-26 years, median: 10 years). Serum GH and IGF-I levels off medical therapy were measured in all patients; ALS and IGFBP-3 were measured in 11 patients with normalization of IGF-I concentrations. Computed tomography or nuclear magnetic resonance imaging periodically assessed possible development of pituitary deficiency along with imaging of the hypothalamic-pituitary region. RESULTS: Forty-one out of 67 patients (58%) achieved GH levels < 2.5 microg/l by 1-15 years after RT (mean 8 +/- 6) and 37/67 patients (55%) had normal or low IGF-I levels 1-26 years after RT (mean: 12 +/- 6), a normalization of both parameters being seen in 37 patients. GH < 2.5 microg/l and normal IGF-I levels were achieved in 17/26 (65%) patients followed-up for at least 15 years. ALS and IGFBP-3 concentrations paralleled IGF-I levels in all patients studied. With respect to secondary pituitary insufficiency, acquired ACTH deficiency was found in 25 patients, TSH deficiency in 20, gonadotropin deficiency in 23 and GH deficiency in seven. In total, two cases of meningioma and one pineal tumour, possibly related to RT, were seen 9-22 years after RT. CONCLUSIONS: RT is an effective, although slow-acting, therapeutic tool for acromegaly, with 'safe' GH levels and normal IGF-I concentrations being achieved in 65% of patients after 15 years. IGF-I levels normalize more slowly than GH levels. Radiotherapy is able to normalize the concentration of all three components of the circulating 150 kDa complex. Checks for loss of pituitary function and appearance of second brain tumours must be carried out life-long.

Oxidation of human insulin-like growth factor I in formulation studies. 3. Factorial experiments of the effects of ferric ions, EDTA, and visible light on methionine oxidation and covalent aggregation in aqueous solution.

The influence of ferric ions, EDTA, and visible light on the oxidation of methionine and the covalent reducible and nonreducible dimerization in human Insulin-like Growth Factor I (hIGF-I) in aqueous (1 mM) phosphate buffer solution were studied. A reduced factorial experiment with two levels of each factor was used. Regression models for the three responses were constructed with partial least square (PLS) analysis. The hIGF-I variants were quantified by reversed-phase high-performance liquid chromatography (RP-HPLC), gel filtration, and reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The formation of the hIGF-I variants in aqueous solution at pH 6.1 exhibited different dependencies on the variables studied. The oxidation of methionine was affected mainly by visible light and the combination of 10 ppm ferric ions and 20 ppm EDTA, whereas ferric ions alone had no significant effect. The covalent dimerization of hIGF-I was correlated to visible light and ferric ions. The interaction effects of ferric ions with either visible light or EDTA were also significant on the dimerization rates. Both reducible and nonreducible soluble covalent dimers were formed, with the reducible dimer being the most prominent. The oxidation of methionine 59 in hIGF-I is catalyzed by light and by ferric ions in combination with EDTA. The covalent dimerization of hIGF-I is mainly affected by light and by ferric ions. Both reducible and nonreducible dimerization increased by oxidative conditions. Human IGF-I appears to dimerize covalently by both disulfide scrambling and by a radical-promoted nondisulfide pathway. EDTA is necessary for ferric ions to be active in the oxidation of methionine in hIGF-I but not for the covalent dimerization.

Effects of low-dose cranial radiation on growth hormone secretory dynamics and hypothalamic-pituitary function.

Spontaneous growth hormone (GH) secretory dynamics and hypothalamic-pituitary function were studied in 16 long-term survivors of acute lymphoblastic leukemia who were aged 9 to 15 1/2 years and had been treated with prophylactic central nervous system radiation and combined chemotherapy. At the time of study, the mean height was -1.5 SD score below the mean, less than genetic potential, and significantly less than the mean pretreatment height of -0.25 SD score. Height velocity was subnormal for age and sexual stage in all patients. Two patients had compensated hypothyroidism, and four had evidence of gonadal failure. In 11 patients, the peak GH level after two provocative tests was below 10 micrograms/L, which was consistent with GH deficiency. In ten of 13 patients tested, spontaneous GH secretion determined by a 24-hour GH concentration (GHC), GH pulse amplitude, frequency of GH pulses greater than or equal to 5 micrograms/L, and GH peak during wake and sleep hours was significantly less than in normal height controls. Although in three pubertal patients the 24-hour GHC was within normal limits, the GHC during sleep hours, GH pulse amplitude during 24 hours and sleep hours, and peak GH during wake hours were significantly less than in normal height controls. In all pubertal and in two of the prepubertal patients, the somatomedin C (SmC) level was significantly less than in controls. The 24-hour GHC correlated well with the GHC during sleep, peak-stimulated GH level, gonadal steroid level, and the SmC level, but not with height velocity, dose of radiation, or age at radiation. A significant increase in height velocity and the SmC level was noted in all patients treated with GH. These results indicate that GH deficiency occurs after 18 to 24 Gy of cranial radiation and that the puberty-associated growth spurt may mask the decline in height velocity owing to GH deficiency. In some patients treated with cranial radiation, a subtle dysregulation in spontaneous GH secretion may exist despite a normal GH response to provocative testing.