Long-Term Endocrine and Metabolic Consequences of Cancer Treatment: A Systematic Review.

The number of patients surviving ≥5 years after initial cancer diagnosis has significantly increased during the last decades due to considerable improvements in the treatment of many cancer entities. A negative consequence of this is that the emergence of long-term sequelae and endocrine disorders account for a high proportion of these. These late effects can occur decades after cancer treatment and affect up to 50% of childhood cancer survivors. Multiple predisposing factors for endocrine late effects have been identified, including radiation, sex, and age at the time of diagnosis. A systematic literature search has been conducted using the PubMed database to offer a detailed overview of the spectrum of late endocrine disorders following oncological treatment. Most data are based on late effects of treatment in former childhood cancer patients for whom specific guidelines and recommendations already exist, whereas current knowledge concerning late effects in adult-onset cancer survivors is much less clear. Endocrine sequelae of cancer therapy include functional alterations in hypothalamic-pituitary, thyroid, parathyroid, adrenal, and gonadal regulation as well as bone and metabolic complications. Surgery, radiotherapy, chemotherapy, and immunotherapy all contribute to these sequelae. Following irradiation, endocrine organs such as the thyroid are also at risk for subsequent malignancies. Although diagnosis and management of functional and neoplastic long-term consequences of cancer therapy are comparable to other causes of endocrine disorders, cancer survivors need individually structured follow-up care in specialized surveillance centers to improve care for this rapidly growing group of patients.

NORMAL TISSUE REACTIONS TO CHRONIC RADIATION EXPOSURE IN MAN.

This paper presents an overview of radiobiological dependences governing the occurrence of tissue (organ) reactions that determine the outcomes of chronic exposure to low-LET ionizing radiation (IR) in humans. The mechanisms involved in the development of tissue reactions (TRs) to long-term exposures to IR and radioadaptation are considered. The overview describes the reactions of the haematopoietic, immune, nervous, reproductive and endocrine systems, lungs, skin and crystalline lens to chronic radiation exposure, which are of fundamental importance in view of radiation protection. It is shown that the individual's physiological tissue (organ) reserve, and also that induced by radiation exposure at low-dose rates are of great significance in the context of TR development.

Treatment outcomes, growth height, and neuroendocrine functions in patients with intracranial germ cell tumors treated with chemoradiation therapy.

PURPOSE: We carried out a retrospective review of patients receiving chemoradiation therapy (CRT) for intracranial germ cell tumor (GCT) using a lower dose than those previously reported. To identify an optimal GCT treatment strategy, we evaluated treatment outcomes, growth height, and neuroendocrine functions. METHODS AND MATERIALS: Twenty-two patients with GCT, including 4 patients with nongerminomatous GCT (NGGCT) were treated with CRT. The median age at initial diagnosis was 11.5 years (range, 6-19 years). Seventeen patients initially received whole brain irradiation (median dose, 19.8 Gy), and 5 patients, including 4 with NGGCT, received craniospinal irradiation (median dose, 30.6 Gy). The median radiation doses delivered to the primary site were 36 Gy for pure germinoma and 45 Gy for NGGCT. Seventeen patients had tumors adjacent to the hypothalamic-pituitary axis (HPA), and 5 had tumors away from the HPA. RESULTS: The median follow-up time was 72 months (range, 18-203 months). The rates of both disease-free survival and overall survival were 100%. The standard deviation scores (SDSs) of final heights recorded at the last assessment tended to be lower than those at initial diagnosis. Even in all 5 patients with tumors located away from the HPA, final height SDSs decreased (p = 0.018). In 16 patients with tumors adjacent to the HPA, 8 showed metabolic changes suggestive of hypothalamic obesity and/or growth hormone deficiency, and 13 had other pituitary hormone deficiencies. In contrast, 4 of 5 patients with tumors away from the HPA did not show any neuroendocrine dysfunctions except for a tendency to short stature. CONCLUSIONS: CRT for GCT using limited radiation doses resulted in excellent treatment outcomes. Even after limited radiation doses, insufficient growth height was often observed that was independent of tumor location. Our study suggests that close follow-up of neuroendocrine functions, including growth hormone, is essential for all patients with GCT.

Pituitary hormone dysfunction after proton beam radiation therapy in children with brain tumors.

OBJECTIVE: To characterize endocrine dysfunction in pediatric patients with brain tumors who received proton beam (PB) radiation therapy and to compare those treated with PB radiotherapy only versus combined conventional and PB irradiation. METHODS: A retrospective review of medical records of patients ≤18 years of age who received PB radiation therapy for a brain tumor between 2000 and 2008 was performed. Variables analyzed included patient demographics, tumor type, therapeutic modalities, radiation doses, and types and timing of endocrine dysfunction. RESULTS: Thirty-eight patients were identified, of whom 31 (19 boys and 12 girls; mean age, 11.9 ± 3.3 years) had undergone endocrine evaluation. Of these patients, 19 received PB radiotherapy only and 12 received conventional plus PB irradiation. Before irradiation, a cranial surgical procedure was performed in 28 study subjects, and 22 received chemotherapy. The mean duration of follow-up after radiation therapy was 1.8 ± 0.8 years. Nine patients (47%) in the PB only group and 4 (33%) in the conventional plus PB group developed endocrine dysfunction (no significant difference) after cranial irradiation. Children with endocrine sequelae treated with PB irradiation alone received fewer cobalt gray equivalents than those treated with conventional plus PB irradiation (5,384 ± 268 versus 5,775 ± 226, respectively; P<.02), and pituitary hormone deficiencies were detected later during follow-up in those who received PB radiotherapy only versus conventional plus PB irradiation (1.17 ± 0.4 years versus 0.33 ± 0.11 year, respectively; P<.01). CONCLUSION: A high rate of endocrine sequelae was seen in our study. Children with brain tumors treated with conventional plus PB irradiation developed endocrine dysfunction faster and received a higher radiation dose than those receiving PB radiotherapy only. Prior surgical treatment and chemotherapy were additional risk factors. Large prospective studies are needed to evaluate further the incidence of endocrine sequelae after PB irradiation in children.

Spectral modulation attenuates molecular, endocrine, and neurobehavioral disruption induced by nocturnal light exposure.

The human eye serves distinctly dual roles in image forming (IF) and non-image-forming (NIF) responses when exposed to light. Whereas IF responses mediate vision, the NIF responses affect various molecular, neuroendocrine, and neurobehavioral variables. NIF responses can have acute and circadian phase-shifting effects on physiological variables. Both the acute and phase-shifting effects induced by photic stimuli demonstrate short-wavelength sensitivity peaking ≈450-480 nm. In the current study, we examined the molecular, neuroendocrine, and neurobehavioral effects of completely filtering (0% transmission) all short wavelengths <480 nm and all short wavelengths <460 nm or partially filtering (~30% transmission) <480 nm from polychromatic white light exposure between 2000 and 0800 in healthy individuals. Filtering short wavelengths <480 nm prevented nocturnal light-induced suppression of melatonin secretion, increased cortisol secretion, and disrupted peripheral clock gene expression. Furthermore, subjective alertness, mood, and errors on an objective vigilance task were significantly less impaired at 0800 by filtering wavelengths <480 nm compared with unfiltered nocturnal light exposure. These changes were not associated with significantly increased sleepiness or fatigue compared with unfiltered light exposure. The changes in molecular, endocrine, and neurobehavioral processes were not significantly improved by completely filtering <460 nm or partially filtering <480 nm compared with unfiltered nocturnal light exposure. Repeated light-dark cycle alterations as in rotating nightshifts can disrupt circadian rhythms and induce health disorders. The current data suggest that spectral modulation may provide an effective method of regulating the effects of light on physiological processes.

[Comparative morphological analysis of peripheral endocrine glands in small mammals inhabiting areas with high levels of radioactive pollutants and exposed to chronic irradiation in laboratory experiments].

The comparative study of cellular-tissue reactions in endocrine organs (thyroid and suprarenal glands, ovary) of rodents exposed to radiation in natural conditions (Radium station in Komi Republic and 30-km zone of Chernobyl APP) and experimental conditions modeling the chronic exposure has been conducted. There is evidence that chronic irradiation in low doses causes morphological disorders in different levels of structural organization (cellular-tissue, organism and population levels). The experimental results showed that observed variations in thyroid, suprarenal glands and ovary by morphometric parameters reflect the natural changes in their functional activity (within the physiological limits). These changes are directed at the homeostasis maintenance in changed conditions and have a compensatory and adaptation character. The effects of low dose radiation influence with combination of other agents may be amplified at the cellular-tissue reactions level. In comparison with experimental results, the natural conditions (high level of radioactivity with alpha- and beta-emitters, high natural radionuclides, toxic elements and extreme climatic factors) induce more expressed changes as a significant increasing of chromosomal and genes mutations in cells, destructive processes in organs of endocrine system and disorders of reproductive functions.

Effects of therapy with [177Lu-DOTA 0,Tyr 3]octreotate on endocrine function.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. METHODS: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. RESULTS: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 +/- 16 to 25 +/- 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 +/- 0.5 to 22.7 +/- 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (15.0 +/- 0.9 to 10.6 +/- 1.0 nmol/l, p < 0.05 and 61.8 +/- 8.7 to 33.2 +/- 3.7 nmol, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 +/- 0.6 to 7.7 +/- 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 +/- 5.6 to 62.4 +/- 7.7 IU/l, p < 0.05) and LH (26.8 +/- 2.1 to 21.1 +/- 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT(4)) levels decreased (17.7 +/- 0.4 to 15.6 +/- 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T(3)) levels did not change. Reverse triiodothyronine (rT(3)) levels decreased (0.38 +/- 0.03 to 0.30 +/- 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA(1c) levels (> 6.5%). CONCLUSION: In men (177)Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA(1c). Therefore, PRRT with (177)Lu-octreotate can be regarded as a safe treatment modality with respect to short- and long-term endocrine function.

[Tissue reactions under chronic exposure to ionizing radiation].

The overview presents an outline of the radiobiological mechanisms governing the origin of tissue reactions manifested by a number of systems influencing the course and the outcomes of chronic exposure of man. The issues under consideration include the key mechanisms of tissue reactions and adaptation in response to a long-term and fractionated exposure to ionizing radiation. The response of the hemopoietic, of immune, of genital, of endocrine, of respiratory systems and of the skin to chronic radiation is described. The development of a new approach to threshold dose estimation for chronic exposure effects is discussed.

Long-term endocrine sequelae of childhood cancer.

PURPOSE OF REVIEW: To update knowledge related to the long-term endocrine sequelae of childhood cancer. RECENT FINDINGS: Endocrine deficiencies are common after cranial irradiation, chemotherapy and specific tumors. These deficiencies include growth hormone, thyrotropin, adrenocorticotropin and gonadotropin deficiencies, primary hypothyroidism, gonadal failure and obesity. Recent studies highlight the impact of radiation on the development of endocrine sequelae. Risks for obesity after childhood tumors include hypothalamic injury, with inactivity and daytime sleepiness. About 6% of adult female survivors of childhood cancer develop persistent ovarian failure. Risks for ovarian damage include ovarian irradiation and alkylating agents. Appropriate fertility-preservation options should be offered. Offspring of women who had uterine irradiation as children are more likely to be born preterm or have low birth weight. Secondary neoplasia or relapse should be considered when treating endocrine deficiencies in cancer survivors. Risk of secondary neoplasia is increased following radiation exposure and certain malignancies. Treatment with growth hormone does not increase cancer recurrence, but survivors may have a 2-fold risk of developing a secondary solid tumor, most commonly a meningioma. SUMMARY: Standardized, multidisciplinary long-term surveillance is important in childhood cancer survivors to identify and treat endocrine and other late effects of cancer and its therapy.

The effects of electromagnetic fields from power lines on avian reproductive biology and physiology: a review.

Electrical power lines are ubiquitous in the developed world and in urban areas of the developing world. All electrical currents, including those running through power lines, generate electric and magnetic fields (EMFs). Electrical power lines, towers,and distribution poles are used by birds for perching, hunting, and nesting. Therefore, many bird species, like humans, are exposed to EMFs throughout their lives. EMFs have been implicated in adversely affecting multiple facets of human health,including increasing the risks of life-threatening illnesses such as leukemia, brain cancer, amyotrophic lateral sclerosis, clinical depression, suicide, and Alzheimer's disease. A great deal of research and controversy exists as to whether or not exposure to EMFs affects the cellular, endocrine, immune, and reproductive systems of vertebrates. Laboratory work has used mice, rats, and chickens as models for this EMF research in an effort to understand better the possible implications of EMF exposure for humans. However, EMF exposure of wild birds may also provide insight into the impacts of EMFs on human health. This review focuses on research examining the effects of EMFs on birds; most studies indicate that EMF exposure of birds generally changes, but not always consistently in effect or in direction, their behavior, reproductive success, growth and development, physiology and endocrinology, and oxidative stress under EMF conditions. Some of this work has involved birds under aviary conditions, while other research has focused on free-ranging birds exposed to EMFs. Finally, a number of future research directions are discussed that may help to provide a better understanding of EMF effects on vertebrate health and conservation.

Growth and puberty after treatment for acute lymphoblastic leukemia.

UNLABELLED: Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment. PATIENTS AND METHOD: The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy), and group C underwent chemotherapy plus radiotherapy (24 Gy). Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging. RESULTS: Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau) between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy). The final predicted height (Bayley-Pinneau) was significantly less (P = 0.0071) in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis. CONCLUSION: Radiotherapy was been responsible for late side effects, especially related to growth and puberty.

Growth and puberty after treatment for acute lymphoblastic leukemia

Nos últimos 20 anos, após o tratamento de pacientes portadores de leucemia linfoblástica aguda, com quimioterapia e radioterapia, houve melhora na taxa de sobrevivência e cura em torno de 70 por cento. Crianças portadoras da doença foram envolvidas em protocolos de tratamento internacionais que visavam melhorar a sobrevida e minimizar os graves e irreversíveis efeitos tardios. A nossa unidade utiliza o protocolo internacional GBTLI LLA-85 e 90, com as drogas metrotexate, citosina, arabinoside, dexametasona e radioterapia .Entretanto, estes tratamentos podem causar insuficiências gonadais e prejuízo no crescimento. PACIENTES E MÉTODO: Os autores analisaram 20 crianças fora de terapia a fim de determinar o papel das várias doses de radioterapia sobre alterações endocrinológicas. Foram divididos em três grupos baseados na profilaxia do sistema nervoso central: o grupo A foi submetido à quimioterapia, o grupo B à quimioterapia mias radioterapia (18Gy) e o grupo C à quimioterapia mais radioterapia (24 Gy). Foram avaliadas as concentrações séricas de LH, FSH, GH e testosterona. Os estudos de imagem incluiram idade óssea, ultrassonografia pélvica, escrotal e ressonância nuclear magnética do crânio. RESULTADOS: Houve diferenças significativas nas respostas do hormônio de crescimento e prejuízo na estatura final (Bayley-Pinneau) entre os dois grupos irradiados e o grupo que não foi irradiado, mas não houve diferenças quando se compararam as doses de radiação utilizadas (18 ou 24 Gy). A previsão da altura final (Bayley-Pinneau) foi menor (p= 0,0071) nos dois grupos tratados com radioterapia. Duas meninas apresentaram puberdade precoce e um menino teve atraso puberal associado a calcificação do epidídimo. CONCLUSÃO: A radioterapia é responsável por efeitos colaterais especialmente quanto ao crescimento e puberdade.

Radiofrequency (RF) effects on blood cells, cardiac, endocrine, and immunological functions.

Effects of radiofrequency electromagnetic fields (RFEMF) on the pituitary adrenocortical (ACTH), growth (GH), and thyroid (TSH) hormones have been extensively studied, and there is coherent research on reproductive hormones (FSH and LH). Those effects which have been identified are clearly caused by heating. The exposure thresholds for these effects in living mammals, including primates, have been established. There is limited evidence that indicates no interaction between RFEMF and the pineal gland or an effect on prolactin from the pituitary gland. Studies of RFEMF exposed blood cells have shown that changes or damage do not occur unless the cells are heated. White cells (leukocytes) are much more sensitive than red cells (erythrocytes) but white cell effects remain consistent with normal physiological responses to systemic temperature fluctuation. Lifetime studies of RFEMF exposed animals show no cumulative adverse effects in their endocrine, hematological, or immune systems. Cardiovascular tissue is not directly affected adversely in the absence of significant RFEMF heating or electric currents. The regulation of blood pressure is not influenced by ultra high frequency (UHF) RFEMF at levels commonly encountered in the use of mobile communication devices.

Effect of heavy ions on neuro-endocrine regulations.

During American and Russian short and long-term space flights neuroimmune dysregulations have been observed in man and rats for up to three months after the return. During Extra-Vehicular Activity, radiation exposure risk is greater to elicit short and/or long-term deleterious effects on the functional capacity of the neuroimmune system. In order to assess the effects of high LET events on neuroimmune networks, our preliminary ground-based study was to investigate brain inflammatory responses in mouse after low dose radiation exposure with high LET particles (12C, 95MeV/u, 42 mGy). Plasma corticosterone levels were rapidly (6 hours) increased by two-fold, then decreased 24 hours post-irradiation. At 3 days plasma corticosterone and ACTH concentrations were also two- to three-fold increased. Plasma ACTH levels were still elevated up to seven days to two months. Furthermore immune functions are under current assessment. The results of this study should allow a greater understanding of the effects of high LET particles on neuroimmune system.

ELF-EMF, endocrine disruptors, light: what if we apply triage to research?

Triage in medicine is an effective means to maximize health benefits of limited resources. This paper suggests to use triage principles as a means to identify biomedical and epidemiological research priorities. The author applies the following questions to three putative problems which receive different research and funding attention: (a) Does a suspected exposure render many humans at risk? (b) Is a disease frequent, difficult to treat and expensive? and (c) Is a causal link between (a) and (b) biologically plausible? On the basis of answers to (a), (b), and (c) it is concluded that ELF-EMF and childhood leukaemia would not qualify for further urgent investigations and that endocrine disruptors and to-be-identified end-points would not qualify for urgent investigations. Provided that answers to the outlined triage questions can be considered as a practical guide to urgent research investigations, the suggestive link between light, endocrine systems and hormone-dependent cancers should become a higher priority research focus.

[The correction of immunoendocrine disorders in patients with hyperplastic processes in the endometrium]. / Korrektsiia immunoéndokrinnykh narushenii u bol'nykh s giperplasticheskimi protsessami v éndometrii.

Effects were studied of extremely high-frequency electromagnetic radiation (EHF EMR) on indices for the immune and endocrine systems in a series of 48 patients presenting with hyperplastic processes in endometrium. EHF EMR-related normalization of values for the above systems was found out to take place together with a return of correlations back to normal, which fact makes it possible to use this modality as an immunocorrective factor.

[Effects of low-intensity laser irradiation on hormonal responsiveness of patients with pulmonary tuberculosis]. / Vliianie nizkointensivnogo lazernogo izlucheniia na gormonal'nuiu reaktivnost' bol'nykh tuberkulezom legkikh.

To examine the impact of low-intensive laser radiation (LILR) on endocrine function in patients with pulmonary tuberculosis, the time course of blood levels of thyroid hormones, cortisol, and insulin was studied in 117 patients of whom 64 received complex treatment by using LILR. Pulmonary tuberculosis was ascertained to be characterized by a marked hormonal imbalance, including impaired metabolism of thyroid hormones, hypercorticism, altered pancreatic incretion, which negatively affects the efficiency of antituberculosis therapy. Intravenous and epicutaneous therapy promotes recovery of endocrine responsiveness and enhances the efficiency of treatment in patients with pulmonary tuberculosis.

[Late effects of chemo- and radiotherapy in two children treated for acute lymphoblastic leukemia]. / Odlegle skutki chemio- i radioterapii u dwojga dzieci z rozpoznaniem ostrej bialaczki limfoblastycznej.

UNLABELLED: The endocrinological disorders are known sequelae of cancer therapy. The aim of our study was to evaluate the effects of chemo- and radiotherapy on growth and auxiological parameters in children treated for acute lymphoblastic leukaemia (ALL) since 1984 to 1996. We studied growth, pubertal development and endocrine functions in 32 patients who were treated for ALL. Two of them had endocrine abnormalities. Both took a different course of disease and treatment because of local relapse in uterus (the girl) and in testis (the boy). All patients received cranial preventive radiotherapy but two of them also received: abdominal irradiation (the girl) and direct testicular irradiation (the boy) with total doses 24 Gy. The girl had clinical and biochemical symptoms of primary thyroid failure, growth hormone deficiency and hypergonadotropic hypogonadism recognized after 8 years following the completion of therapy. The boy had biochemical symptoms of hypogonadism with low serum testosterone concentration responses to stimulation with human gonadotropin after 4 years of remission. CONCLUSION: We suggest that clinical and biochemical assessment of endocrinological functions including growth, pubertal development, thyroid function should be performed at regular intervals following chemotherapy and radiotherapy in patients with acute lymphoblastic leukaemia and another carcinomas.

[The effect of low-intensity infrared laser therapy on the endocrine function of patients with climacteric disorders]. / Vliianie nizkointensivnoi infrakrasnoi lazerterapii na éndokrinnuiu funktsiiu patsientov s klimaktericheskimi narusheniiami.

The authors examined males and females aged 40-65 with menopausal disorders. Low-intensive infrared laser therapy produced a response both in males and females in menopause as evidenced by normalization of FSH, LH levels and elevation of sex steroid hormones.