Quality of life for patients with advanced gastrointestinal cancer randomised to early specialised home-based palliative care: the ALLAN trial.

BACKGROUND: The primary aim of specialised palliative care (SPC) is to improve the quality of life (QoL) for patients with a high symptom burden from a life-threatening disease. This randomised study aimed to assess the QoL impact of early integration of SPC alongside tumour-specific palliative treatment in patients with gastrointestinal (GI) cancers. METHODS: We randomly assigned ambulatory patients with advanced GI cancer to early integration of SPC and palliative tumour-specific treatment or tumour-specific treatment alone. The primary endpoint was QoL assessed at baseline and every sixth week using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. RESULTS: A total of 118 patients were randomised. The difference in total FACT-G score between patients assigned to early integration with SPC and controls was 5.2 points (95% CI: -0.1 to 10.5, p = 0.216), 6.7 points (95% CI: 0.2 to 13.3, p = 0.172), and 13 points (95% CI: 5.7 to 20.2, p = 0.004) at weeks 6, 12, and 24, respectively. CONCLUSIONS: This prospective randomised trial strengthens the argument for early integration of SPC with tumour-specific treatment in patients with advanced GI cancers. We found an improved QoL for patients with advanced GI cancer 24 weeks after randomisation to early integration of home-based SPC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (ref: NCT02246725).

Oral Methadone versus Morphine IR for Patients with Cervical Cancer and Neuropathic Pain: A Prospective Randomised Controlled Trial.

Objectives: In India, cervical cancer is the most common cancer among women and makes up for up to 29% of all registered cancer in females. Cancer-related pain is one of the major distressing symptoms for all cancer patients. Pain is characterised as somatic or neuropathic, and the total pain experience is often mixed. Conventional opioids are the backbone of analgesic treatment but are most often not sufficient in alleviating neuropathic pain, common in cervical cancer. Accumulating evidence of the advantage of methadone compared to conventional opioids, due to agonist action at both µ and q opioid receptors, N-methyl-D-aspartate (NMDA) antagonist activity and the ability to inhibit the reuptake of monoamines has been demonstrated. We hypothesised that, with these properties', methadone might be a good option for the treatment of neuropathic pain in patients with cervical cancer. Material and Methods: Patients with cervical cancer stages ll-lll were enrolled in this randomized controlled trial. A comparison was made between methadone versus immediate release morphine (IR morphine), with increasing doses until pain was controlled. Inclusion-period was from October 3rd to December 31st 2020, and the total patient-study period was 12 weeks. Pain intensity was assessed according to the Numeric Rating Scale (NRS) and Douleur Neuropathique (DN4). The primary objective was to determine whether methadone was clinically superior versus noninferior to morphine as an analgesic for the treatment of cancer related neuropathic pain in women with cervical cancer. Results: A total of 85 women were included; five withdrew and six died during the study period, leaving 74 patients completing the study. All participants showed a reduction in mean values of NRS and DN4 from the time of inclusion and to the end of the study period, for IR morphine and methadone 8.4-2.7 and 8.6-1.5, respectively (P < 0.001). The DN4 score mean reduction for Morphine and Methadone were 6.12-1.37 and 6.05-0, respectively (P < 0.001). Side effects were more common in the group of patients receiving IR morphine compared to the patients treated with methadone. Conclusion: We found that Methadone had a superior analgesic effect with good overall tolerability compared with morphine as a first-line strong opioid for the management of cancer-related neuropathic pain.

Integration of Specialized Palliative Care with Oncological Treatment in Patients with Advanced Pancreatic Cancer.

Introduction: The incidence of pancreatic cancer is around 5 in 100,000, and the 5-year survival is poor. Pancreatic cancer patients have a high disease-specific burden of symptoms, and palliative chemotherapy has varying side effects. The American Society of Clinical Oncology (ASCO) suggests integrating specialized palliative care (SPC) with standard oncological treatment for pancreatic cancer patients at stage ≥III. This study investigated the effects of enrollment into SPC >30 days before death. Materials and Methods: This retrospective study included 170 patients with histopathologically verified pancreatic adenocarcinoma who received palliative chemotherapy at Skåne University Hospital and died between February 1, 2015, and December 31, 2017. Results: Of the 170 patients, 151 were enrolled within the SPC unit; 97 of them for >30 days before death (group A). The remainder (group B) received SPC for ≤30 days before death (n = 54) or not at all (n = 19). Patients in groups A and B lived a median of 73 and 44 days, respectively, after the last palliative chemotherapy treatment (p < 0.001), but did not differ in terms of median overall survival (11.2 months vs. 10.9 months). Death in the hospital occurred in 84% of patients never admitted to SPC and 2% of patients ever admitted to SPC. Conclusion: Enrollment in SPC for longer than 30 days may lower the risk of receiving futile palliative chemotherapy at the end of life, compared with patients enrolled in SPC for 30 days or less before death. Enrollment in SPC lowers the risk of dying in a hospital.

The Introduction and Experiences of Methadone for Treatment of Cancer Pain at a Low-resource Governmental Cancer Center in India.

OBJECTIVES: This study aimed to describe the clinical experience of the health-care professionals (HCPs) responsible for the introduction of methadone, for the treatment of complex cancer pain, at a low-resource hospital in India in a patient-group, burdened by illiteracy, and low socio-economic status. MATERIALS AND METHODS: Ten HCPs: Four medical doctors, four nurses, one pharmacist, and one hospital administrator were interviewed. The interviews are examined using a qualitative conventional content analysis. RESULTS: The interviews showed a confidence amongst the HCPs, responsible for the safe introduction of methadone in a stressful and low-resource surrounding, to patients with cancer pain and the different aspects of methadone, as initiation, titration, and maintenance of treatment. CONCLUSION: Introduction of methadone for cancer pain management is safe and feasible although low resources in a challenging hospital setting and care environment.

Second-line palliative chemotherapy, survival, and prognostic factors in patients with advanced pancreatic cancer.

INTRODUCTION: Pancreatic cancer is a highly lethal disease with a close association between incidence and mortality. First-line (FL) palliative chemotherapy prolongs survival and alleviates cancer-related symptoms. However, the survival benefit of second-line (SL) treatment is uncertain, as studies fail to consistently show prolonged survival for any given SL treatment, and in the absence of prognostic factors patients will receive a futile treatment. The aim of this study was to examine prognostic factors and survival in patients with pancreatic cancer, with special reference to SL therapy. MATERIAL AND METHODS: This retrospective study included all patients with histopathologically verified pancreatic adenocarcinoma who received palliative chemotherapy at Skåne University Hospital and died between 1 Feb 2015 and 31 Dec 2017. RESULTS: During the study period, a total of 170 patients with pancreatic cancer died after receiving palliative chemotherapy. Of these, 72 had received SL treatment after progression on FL treatment. Median overall survival (OS) from the start of SL treatment was 5.0 months (95% CI: 4.0-6.1). Median OS was 2.9 months for patients with performance status 2 at start of SL treatment compared to 5.3 months for patients with performance status 0-1 (p = .03), and 3.5 months (95% CI: 3.0-5.4) in patients with hypoalbuminemia (<36 g/L) at the start of SL therapy compared to 8.0 months (95% CI: 5.3-11.1) for patients with normal albumin levels (p = .009). Weight loss during FL therapy, a doubling of CA 19-9 after FL therapy, and length of progression-free survival during FL treatment were not associated with survival following SL therapy. CONCLUSION: Poor performance status and hypoalbuminemia are negative prognostic factors for survival on SL palliative treatment in patients with advanced pancreatic cancer. Possible gain in survival should be carefully considered before initiating SL chemotherapy.

The Use of Methadone in Pediatric Cancer Pain - A Retrospective Study from a Governmental Cancer Center in India.

BACKGROUND: The management of cancer-related pain relies on access to opioids. When regular opioids are not tolerated, or are insufficient, methadone is an affordable and effective analgesic. AIM: The aim of the project was to describe the pattern of use and clinical experience of methadone in pediatric cancer pain at a governmental cancer hospital in Hyderabad, one of the four Indian cancer centers with permission to prescribe methadone. METHODS: This was a retrospective study of medical records of all children, under the age of 18, who had been prescribed methadone from September 9, 2017, to November 19, 2019. Data on analgesic effect, prior and concomitant analgesic treatment, opioid side effects, and the handling of methadone were analyzed. RESULTS: A total of 11 children were identified and studied. Methadone was introduced mainly when pain was uncontrolled by regular opioids. Initial daily doses ranged from 1 to 15 mg. The duration of treatment ranged from 7 to 307, with a median of 50 days in the nine patients where treatment exceeded one single dosage. Good analgesic effect was reported in 5/9 children, unchanged from previous analgesic treatment in three patients and without any effect in one child. No severe side effects were reported. CONCLUSION: Low-dose methadone in the treatment of pediatric cancer pain at a low-resource cancer center was safe and well tolerated by the patients, with long treatment durations. It was safely managed, administered with single to double daily dosages, hence easy for patients and family to handle, and an affordable treatment option.

The Use of Methadone in Adult Patients with Cancer Pain at a Governmental Cancer Center in India.

BACKGROUND: Management of cancer-related pain relies on the access to opioids. When regular opioids as morphine are not tolerated or are insufficient, adjuvant opioids as methadone are an affordable and effective analgesic. AIM: The aim of the project was to describe the pattern of use and clinical experiences of methadone in patients with cancer-related pain at a low-resource hospital in Hyderabad, one of few Indian cancer centers with permission to prescribe methadone. METHODS: Medical records of all patients who had been prescribed methadone, September 9, 2017 and November 19, 2019 were studied retrospectively. Data on analgesic treatment and opioid side effects were analyzed. RESULTS: A total of 93 adult cancer patients were included in the study. A majority of patients (79%) were prescribed opioid analgesic, mainly morphine, before methadone introduction. The initial daily dose of methadone ranged between 5 and 22.5 years and in the vast majority of the patients 5 mg, divided in two daily administrations. A good analgesic effect, with decreased pain, was reported in 60% of the patients. No severe side effects were reported. CONCLUSIONS: In this study, methadone as a primary opioid was used with a good analgesic effect for cancer pain in a low-resource setting. Indication for methadone was mainly uncontrolled pain with a regular opioid treatment. No severe adverse effects were reported. Further research and prospective studies are needed on methadone treatment in low-resource settings to establish the robust guidelines to support prescribing physicians.

Low-dose Oral Ketamine as a Procedural Analgesia in Pediatric Cancer Patients Undergoing Bone Marrow Aspirations at a Resource-limited Cancer Hospital in India.

AIM: Many pediatric cancer patients undergo repeated bone marrow aspirations (BMAs) for diagnostic and treatment evaluation purposes. Full anesthesia is the standard of care during this procedure in high-income countries. At hospitals with low resources in low/middle-income countries many children undergo these painful procedures without sufficient pain relief. This study aimed to evaluate the usefulness of low-dose oral ketamine as a procedural analgesic in a low-resource pediatric cancer care department. MATERIALS AND METHODS: Pediatric patients, 4-15 years of age, who underwent BMAs between September 31 and November 30, 2018, were invited to participate. The study was designed as a placebo-controlled, single-blinded trial with three trial groups. Group K received 1.0 mg/kg of ketamine and Group KM received 1.0 mg/kg ketamine with an addition of 0.2 mg/kg midazolam, mixed in juice 30 min before procedures. Group P received placebo consisting of plain juice. All three groups also received the hospital's current standard treatment for procedural pain in BMAs. Patients and caregivers assessed the procedural pain, as did the performing doctors. For the patients, Faces Pain Scale - Revised was used and the Numeric Rating Scale-11 for caregivers and doctors. RESULTS: A total of 87 patients were included in the study distributed with 29 in Group K, 29 in Group KM, and 29 in Group P. Seven patients were excluded, one patient denied participation and the remaining did not meet the inclusion criteria. There was no significant difference between the pain reported by the groups. A total of 69% patients in Group KM and 35% in Group K had somnolence reported as a side effect compared to 14% in Group P. CONCLUSION: We found no significant effects on the procedural pain in any of the treatment groups compared to placebo. There were only mild side effects. The doses of ketamine might be insufficient for this painful and stressful procedure.

Prescription of pain medication among older cancer patients with and without an intellectual disability: a national register study.

BACKGROUND: The longevity for people with intellectual disability (ID) has significantly increased in developed countries during the past decades. Consequently, the incidence of cancer is expected to increase in this group. The aim of the present study was to investigate the prescription of pain medication in older cancer patients with intellectual disability (ID) compared to older patients in the general population, surviving or living with a cancer diagnosis. METHODS: This Swedish national registry-based study, included people with ID aged 55 years or older in 2012, and alive at the end of that year (ID cohort, n = 7936). For comparisons, we used a referent cohort, one-to-one matched with the general population by year of birth and sex (gPop cohort, n = 7936). People with at least one diagnosis of cancer during 2002-2012 were identified using the Swedish National Patient Register, resulting in 555 cancer patients with ID and 877 cancer patients from the general population. These two cohorts of cancer patients were compared with respect to prescription of pain medication for the period 2006-2012. Outcome data were aggregated so that each patient was categorized as either having or not having at least one prescription of each investigated drug group during the study period, and relative risks (RRs) for prescription were estimated for prescription in the ID cohort vs the gPop cohort. RESULTS: Cancer patients with ID were less likely than cancer patients in the gPop cohort to have at least one prescription of COX inhibitors (RR 0.61) and weak opioids (RR 0.63). They were, however, more likely to be prescribed paracetamol (RR 1.16), antidepressants (RR 2.09), anxiolytics (RR 2.84), and "other hypnotics, sedatives, and neuroleptics" (RR 1.39). No statistically significant differences between the two cohorts were found for strong opioids, antiepileptics, tricyclic antidepressants, or hypnotics and sedatives. CONCLUSION: In the studied cohort of older people surviving or living with cancer, prescriptions for pain-treatment was less common in patients with ID compared to the general population. These results may suggest that pain is not sufficiently treated among cancer patients with ID, a situation that most likely would compromise the quality of life in this group.

Low-Dose Oral Ketamine for Procedural Analgesia in Pediatric Cancer Patients Undergoing Lumbar Puncture at a Resource-Limited Cancer Hospital in India.

Aim: The aim of this study was to evaluate the therapeutic efficacy and safety profile of orally administered low-dose ketamine for procedural pain management in pediatric cancer patients undergoing lumbar puncture (LP) in a resource-limited hospital setting. Methods: Patients between 4 and 15 years of age, with leukemia, undergoing LP were asked to participate. The study was designed as a two-armed blinded placebo-controlled trial where 0.8 mg/kg (bodyweight) of ketamine mixed in juice was given 30 minutes before the procedure to Group K (ketamine) compared with placebo, only juice, to Group P (placebo). In addition, topical analgesia (EMLA®) was given according to established standard of care. Patients and caregivers assessed the pain using the Wong-Baker Faces Pain Rating Scale. Results: A total number of 52 patients, equally distributed between Group K and Group P, were included in the study. The placebo-controlled group had significantly higher self-reported pain score than the group receiving ketamine (p = 0.046), as well as in caregiver-assessed pain (p = 0.033). Only three incidents of mild adverse effects were reported. Conclusion: Low-dose oral ketamine can be safely administered for procedural analgesia in pediatric cancer patients undergoing LP in a resource-limited hospital setting and have significant pain-reducing effect compared with placebo.

Palliative Sedation via Intraosseous Vascular Access: A Safe and Feasible Way to Obtain a Vascular Access End of Life.

Intraosseous (IO) access is normally reserved for emergencies and critical care conditions when venous cannulation is not possible. Nonetheless, we present a case of IO insertion to a 56-year-old man, tetraplegic for many years due to progressive spinal muscular atrophy and with refractory suffering. The IO access was used for palliative sedation with propofol in a home care setting. The patient died after 11 days of palliative care, of which the last 4 days were with palliative sedation using an IO cannula as a vascular access. No complications were noted from this route of administration. We advocate the use of IO access in the palliative care of terminal ill patients when a venous cannulation is not possible.

Specialized Palliative Care and the Quality of Life for Hospitalized Cancer Patients at a Low-Resource Hospital in India.

AIM: This study aimed to compare the quality of life (QoL) of cancer patients, with an Eastern Cooperative Oncology Group (ECOG) performance of 3-4, in contact with or without contact, with a specialized palliative care unit (PCU) at a low-resource governmental cancer hospital, as well as studying the impact of this contact on the QoL in their caregivers. MATERIALS AND METHODS: Hospitalized patients with an ECOG performance of 3 or 4 and their primary caregiver were asked to participate in this observational study. Patients in contact with the specialized PCU and their closest caregivers formed Group A, while patients and families without this contact formed Group B. Contact was mainly one consultation. The patients were asked to complete the Palliative Care Outcome Scale (POS), and the caregivers were asked to complete the Hospital Anxiety and Depression Scale (HADS) and the distress thermometer (DT). RESULTS: There was no statistically significant difference between the median POS values of the patient groups, neither regarding the total sum nor per any item. There were also no statistically significant differences between the median HADS values and median DT values when comparing the caregivers to Group A and B. CONCLUSION: Consultation with a specialized PCU at this tertiary referral center did not alter the QoL of patients with an ECOG performance of 3-4 nor did it affect the psychological well-being of their caregivers. We argue that monitoring prescribed treatment and follow-up is a necessary component of PC.

Cancer Treatment and End-of-Life Care.

AIM: To study to what extent tumor-specific treatment (chemo- or radiotherapy) was given during the last 30 days in life and to examine how many of the patients were referred to a specialized palliative care unit (PCU), at a low-resource governmental hospital in India. PATIENTS AND METHODS: Medical records of adult cancer patients deceased between April 1 and May 31 in 2016, and pediatric cancer patients deceased between April 1 and September 30 in 2016 were collected. Data regarding gender, age at admission, cancer diagnosis, tumor-specific treatment received, referral to the PCU, and date of death, were sampled. RESULTS: A total of 96 patients (52 adults and 44 pediatric patients) were included in the study. In the last 30 days of life, tumor-specific treatment was given to 39 adult patients and 38 pediatric patients. During the last week in life, 26 adult and 25 pediatric patients, respectively, received tumor-specific treatment. Twenty-six adult and 25 pediatric patients, respectively, were referred to the PCU. End-of-life (EoL) tumor therapy was given to a lesser extent among referred patients. CONCLUSIONS: Eighty percent of the patients were given tumor-specific treatment near EoL. Half of the patients had been referred for specialized palliative care (SPC).

End-of-Life Treatments in Pediatric Patients at a Government Tertiary Cancer Center in India.

AIM: The primary objective of this study was to describe demographics and end-of-life treatments of children with cancer at a government tertiary cancer center in India. METHODS: A retrospective review was undertaken of medical charts of all children younger than 18 years, who died as inpatients while undergoing treatment at the pediatric oncology department between April and September 2016. Data were collected on demographics, diagnosis, treatments, survival, palliative care involvement, and symptoms at end of life. RESULTS: There were 44 pediatric oncology patients who died in the hospital during the study period. The most frequent diagnoses were hematological malignancies (n = 29). Tumor-specific treatment was given to 38/44 (86%) patients in the last 30 days of life, and 13 patients in the last day of life or 1 day before. Of all deaths, 23/44 (52%) occurred within 30 days of admission to the pediatric ward and 34/44 (77%) within 90 days. Of the 44 patients, 25 (57%) were referred to palliative care. The median number of days between referral and death was 14 (0-78) days. Frequent symptoms documented were bleeding (11/44), dyspnea (10/44), pain (7/44), seizures (7/44), and delirium (5/44), with each patient having one or more of these symptoms. Only patients with a palliative care referral received opioid analgesics or benzodiazepines at the end of life. CONCLUSIONS: This study highlights the demographics of suffering, death, and end-of-life care in children with cancer at a government tertiary cancer center in India.

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment.

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.

Effects of morning cortisol replacement on glucose and lipid metabolism in GH-treated subjects.

OBJECTIVE: Insulin resistance is a frequent consequence of GH replacement therapy but patients on GH replacement therapy often also have replacement of other hormone deficiencies which theoretically could modify the metabolic effects of GH. In particular, cortisol replacement if given in supra physiologic doses immediately before the evaluation of insulin sensitivity could influence insulin sensitivity. The aim of this study was thus to evaluate the effect of morning cortisol replacement given prior to a euglycaemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry on glucose and lipid metabolism. METHODS: Ten GH/ACTH-deficient adults received, in a double-blind manner, either cortisol (A) or placebo (B) before the clamp whereas five GH-deficient-ACTH-sufficient adults participated in a control (C) clamp experiment. All subjects received GH replacement therapy. RESULTS: Serum cortisol levels were significantly higher after cortisol than after placebo (324+/-156 vs 132+/-136 mmol/l; P=0.006) and similar to controls (177+/-104 mmol/l). As a measure of the biological effect of cortisol, eosinophil leukocyte counts in peripheral blood decreased (164+/-91 x 10(9)/l vs 216+/-94 x 10(9)/l; P=0.04). Cortisol replacement had no significant effect on insulin-stimulated glucose uptake (11.8+/-1.8 vs 13.2+/-3.9 micromol/kg min), either on glucose oxidation or on glucose storage. There was also no significant effect of cortisol on fasting endogenous glucose production and no effect was seen on serum free fatty acid concentrations. CONCLUSION: Administration of cortisol in the morning before a clamp cannot explain the insulin resistance seen with GH replacement therapy.

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults.

OBJECTIVE: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. METHODS: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88+/-0.13 mg) (B); GH+acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry. RESULTS: GH increased basal free fatty acid (FFA) levels by 74% (P=0.0051) and insulin levels by 93% (P=0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61+/-8.03 vs 12.74+/-5.50 micromol/kg per min (s.d.), P=0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r=-0.638, P<0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35+/-5.65 vs 12.74+/-5.50 micromol/kg per min, P=0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32+/-3.00 vs 5.88+/-2.39 micromol/kg per min, P=0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r=-0.867, P=0.0093) and during insulin-stimulated (r=-0.927, P=0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86+/-5.22 vs 8.67+/-6.65 micromol/kg per min, P=NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99+/-1.98 vs 11.73+/-2.38 micromol/kg per min, P=NS for B vs A and 11.55+/-2.7 vs 10.99+/-1.98 micromol/kg per min, P=NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14+/-8.74 vs 16.61+/-8.03 micromol/kg per min, P=0.0077 for D vs A) and this was again due to enhanced fasting (7.90+/-2.68 vs 5.16+/-2.28 micromol/kg per min, P=0.01 for D vs A) and insulin-stimulated (9.78+/-3.68 vs 7.95+/-2.64 micromol/kg per min, P=0.07 for D vs A) glucose oxidation. CONCLUSION: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.

Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle.

The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 micro g/kg body weight.d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[(3)H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects. GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy. In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.