Eliza B. Geer

Gender differences in insulin resistance, body composition, and energy balance

BACKGROUND Men and women differ substantially in regard to degrees of insulin resistance, body composition, and energy balance. Adipose tissue distribution, in particular the presence of elevated visceral and hepatic adiposity, plays a central role in the development of insulin resistance and obesity-related complications. OBJECTIVE This review summarizes published data on gender differences in insulin resistance, body composition, and energy balance, to provide insight into novel gender-specific avenues of research as well as gender-tailored treatments of insulin resistance, visceral adiposity, and obesity. METHODS English-language articles were identified from searches of the PubMed database through November 2008, and by reviewing the references cited in these reports. Searches included combinations of the following terms: gender, sex, insulin resistance, body composition, energy balance, and hepatic adipose tissue. RESULTS For a given body mass index, men were reported to have more lean mass, women to have higher adiposity. Men were also found to have more visceral and hepatic adipose tissue, whereas women had more peripheral or subcutaneous adipose tissue. These differences, as well as differences in sex hormones and adipokines, may contribute to a more insulin-sensitive environment in women than in men. When normalized to kilograms of lean body mass, men and women had similar resting energy expenditure, but physical energy expenditure was more closely related to percent body fat in men than in women. CONCLUSION Greater amounts of visceral and hepatic adipose tissue, in conjunction with the lack of a possible protective effect of estrogen, may be related to higher insulin resistance in men compared with women.

Predictors of Mortality and Long-term Outcomes in Treated Cushing's Disease: A Study of 346 Patients

CONTEXT Active Cushings disease (CD) confers a 4-fold increase in mortality and is associated with significant morbidities. Although excess mortality risk may persist even after CD treatment, predictors of risk in treated CD are not well understood. OBJECTIVE To identify predictors of mortality, cardiovascular (CV) disease, and recurrence after long-term follow-up among patients with treated CD. DESIGN, SETTING, AND PATIENTS A retrospective chart review was conducted to evaluate patients with CD who underwent transsphenoidal adenectomy with a single surgeon. OUTCOME MEASURES Patients were categorized based on disease response after initial treatment. Cox proportional hazard models identified predictors of mortality, recurrence, and CV outcomes in the overall cohort and each subgroup. RESULTS Three hundred forty-six subjects were included. Mean age was 39.9 years, and mean duration of follow-up was 6.3 years (range, 1 mo to 30 y). Duration of exposure to excess glucocorticoids, estimated by duration of symptoms before diagnosis until remission was achieved by any means, was 40.0 months. Multivariate analyses demonstrated that duration of glucocorticoid exposure elevated the risk of death (P = .038), as did older age at diagnosis (P = 0.0001) and preoperative ACTH concentration (P = .007). Among patients who achieved remission, depression increased the hazard of death (P < .01). Male sex, age at diagnosis, diabetes, and depression elevated the risk of CV disease (P < .05). CONCLUSION Long-term follow-up of a large cohort of treated patients with CD identified several novel predictors of mortality. These data illustrate the importance of early recognition and treatment of CD. Long-term follow-up, with management of persistent comorbidities, is needed even after successful treatment of CD.

Mechanisms of Glucocorticoid-Induced Insulin Resistance: Focus on Adipose Tissue Function and Lipid Metabolism

Glucocorticoids (GCs) are critical in the regulation of the stress response, inflammation and energy homeostasis. Excessive GC exposure results in whole-body insulin resistance, obesity, cardiovascular disease, and ultimately decreased survival, despite their potent anti-inflammatory effects. This apparent paradox may be explained by the complex actions of GCs on adipose tissue functionality. The wide prevalence of oral GC therapy makes their adverse systemic effects an important yet incompletely understood clinical problem. This article reviews the mechanisms by which supraphysiologic GC exposure promotes insulin resistance, focusing in particular on the effects on adipose tissue function and lipid metabolism.

Lower Visceral and Subcutaneous but Higher Intermuscular Adipose Tissue Depots in Patients with Growth Hormone and Insulin-Like Growth Factor I Excess Due to Acromegaly

CONTEXT GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. OBJECTIVES Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. DESIGN, SETTING, AND PATIENTS We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. OUTCOME MEASURES Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. RESULTS VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. CONCLUSIONS VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

Body Composition and Cardiovascular Risk Markers after Remission of Cushing's Disease: A Prospective Study Using Whole-Body MRI

CONTEXT Cushings Disease (CD) alters fat distribution, muscle mass, adipokine profile, and cardiovascular risk factors. It is not known whether remission entirely reverses these changes. OBJECTIVES Our objective was to determine whether the adverse body composition and cardiovascular risk profile in CD change after remission. DESIGN, SETTING, AND PATIENTS Fourteen CD patients were studied prospectively: before surgery (active disease) and again postoperatively 6 months after discontinuing oral glucocorticoids (remission). Whole-body magnetic resonance imaging was used to examine lean and fat tissue distributions. OUTCOME MEASURES Body composition (skeletal muscle and fat in the visceral, bone marrow, sc, and inter-muscular compartments) and cardiovascular risk factors (serum insulin, glucose, leptin, high-molecular-weight adiponectin, C-reactive protein, and lipid profile) were measured in active CD and remission (mean 20 months after surgery). RESULTS Remission decreased visceral, pelvic bone marrow, sc (including trunk and limb sc), and total fat; waist circumference; and weight (P < 0.05). Remission altered fat distribution, resulting in decreased visceral/total fat (P = 0.04) and visceral fat/skeletal muscle ratios (P = 0.006). Remission decreased the absolute muscle mass (P = 0.015). Cardiovascular risk factors changed: insulin resistance, leptin, and total cholesterol decreased (P < 0.05), but adiponectin, C-reactive protein, and other lipid measures did not change. CONCLUSIONS CD remission reduced nearly all fat depots and reverted fat to a distribution more consistent with favorable cardiovascular risk but decreased skeletal muscle. Remission improved some but not all cardiovascular risk markers. Remission from CD dramatically improves body composition abnormalities but may still be associated with persistent cardiovascular risk.

MRI assessment of lean and adipose tissue distribution in female patients with Cushing's disease.

Objective  Chronic hypercortisolemia due to Cushing’s disease (CD) results in abnormal adipose tissue (AT) distribution. Whole‐body magnetic resonance imaging (MRI) was used to examine lean and AT distribution in female patients with CD to further understand the role of glucocorticoid excess in the development of abnormal AT distribution and obesity.

Skeletal Muscle Mass in Acromegaly Assessed by Magnetic Resonance Imaging and Dual-Photon X-Ray Absorptiometry

CONTEXT GH and IGF-I are nitrogen retaining and anabolic, but the impact of long-term exposure to supraphysiological GH and IGF-I, either from endogenous overproduction in acromegaly or exogenous sources, on skeletal muscle (SM) mass is not clear. OBJECTIVES The objectives of the study were to assess SM mass by whole-body magnetic resonance imaging (MRI) in acromegaly and test the hypothesis that dual-energy x-ray absorptiometry (DXA) lean tissue mass-derived estimates of SM accurately estimate true SM mass. DESIGN, SETTING, AND PATIENTS The design was a cross-sectional study in 27 acromegaly patients compared with predicted models developed in 315 nonacromegaly subjects and to matched controls. OUTCOME MEASURES Mass of SM from whole-body MRI and lean tissue from DXA were measured. RESULTS SM mass did not differ from predicted or control values in active acromegaly: 31.75 +/- 8.6 kg (acromegaly) vs. 33.06 +/- 8.9 kg (predicted); SM was 95.6 +/- 12.8% of predicted (range 66.7-122%) (P = 0.088). Lean tissue mass (DXA) was higher in acromegaly than controls: 65.91 +/- 15.2 vs. 58.73 +/- 13.5 kg (P < 0.0001). The difference between lean tissue mass (DXA) and SM in acromegaly patients was higher than that in controls (P < 0.0001) consistent with an enlarged non-SM lean compartment in acromegaly. SM mass predicted by DXA correlated highly with SM mass by MRI (r = 0.97, P < 0.0001). SM (MRI) to SM (DXA predicted) ratio was 1.018 (range 0.896-1.159), indicating high agreement of these measures of SM. CONCLUSIONS SM mass in active acromegaly patients did not differ from predicted values. SM mass estimated from DXA agreed highly with SM by MRI, supporting the validity of the DXA model in assessing SM in acromegaly and other disorders of GH/IGF-I secretion.

Prospective Study of Surgical Treatment of Acromegaly: Effects on Ghrelin, Weight, Adiposity, and Markers of CV Risk

CONTEXT Although epidemiological studies have found that GH and IGF-1 normalization reduce the excess mortality of active acromegaly to expected rates, cross-sectional data report some cardiovascular (CV) risk markers to be less favorable in remission than active acromegaly. OBJECTIVE The objective of the study was to test the hypothesis that remission of acromegaly after surgical therapy increases weight and adiposity and some CV risk markers and these changes are paralleled by a rise in ghrelin. DESIGN Forty-two adults with untreated, active acromegaly were studied prospectively. Changes in outcome measures from before to after surgery were assessed in 26 subjects achieving remission (normal IGF-1) and 16 with persistent active acromegaly (elevated IGF-1) after surgery. SETTING The study was conducted at tertiary referral centers for pituitary tumors. MAIN OUTCOME MEASURES Endocrine, metabolic, and CV risk parameters, anthropometrics, and body composition by dual-energy X-ray absorptiometry were measured. RESULTS Remission increased total ghrelin, body weight, waist circumference, C-reactive protein, homocysteine, high-density lipoprotein, and leptin and reduced systolic blood pressure, homeostasis model assessment score, triglycerides, and lipoprotein (a) by 6 months and for 32 ± 4 months after surgery. The ghrelin rise correlated with the fall in the levels of GH, IGF-1, and insulin and insulin resistance. Weight, waist circumference, and ghrelin did not increase significantly in the persistent active acromegaly group. Total body fat, trunk fat, and perentage total body fat increased by 1 year after surgery in 15 remission subjects: the increase in body fat correlated with the rise in total ghrelin. CONCLUSIONS Although most markers of CV risk improve with acromegaly remission after surgery, some markers and adiposity increase and are paralleled by a rise in total ghrelin, suggesting that these changes may be related. Understanding the mechanisms and long-term implications of the changes that accompany treatment of acromegaly is important to optimizing management because some aspects of the postoperative profile associate with the increased metabolic and CV risk in other populations.

Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial

BACKGROUND Cushings disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushings disease. METHODS In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushings disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushings syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0 × ULN and 2·0-5·0 × ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. FINDINGS Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. INTERPRETATION Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushings disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushings disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. FUNDING Novartis Pharma AG.

The Impact of Traumatic Brain Injury on Pituitary Function

It is paramount that clinicians who care for patients with traumatic brain injury (TBI) at any point in time, including neurosurgeons, rehabilitation physicians, internists, neurologists, and endocrinologists, are aware of the prevalence of posttraumatic hypopituitarism and its impacts on acute and long-term recovery. This article reviews the natural history, pathophysiology, and presenting features of hypopituitarism occurring after TBI. Proposed methodologies for screening, diagnosis, and initiation of treatment are discussed, as well as the effect of hormone replacement therapy on clinical outcomes.