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Women’s Health - GGT, IRON & Oxidative Stress

This page is is focused on women's health and how elevated serum measures of both iron and GGT create conditions of oxidative stress favorable for the development and progressive of diseases among females. The scientific studies and review articles described below are drawn from the more than 650 peer-reviewed journal articles available on other library pages of our web site. As discussed on our Why Get Tested page, accurate measures of iron stores and GGT are particularly important since each one is independently predictive of multiple chronic diseases and premature mortality, even when test results are well-within normal laboratory ranges.

The titles of most of the articles listed below are linked to the U.S. National Library of Medicine. Links to Free full text PDFs accompany approximately half of the articles. Library source pages are cited and articles are red-numbered according to their location on the each of the cited pages. Several unnumbered articles appear only on this page.

But first, this important research on changes in iron status that occur over menopause will be of interest to many:

Changes in iron measures over menopause and associations with insulin resistance Insulin Resistance # 13 Free full text

Researchers at the University of Michigan reported the results of this study in 2012. Their "objectives were to examine iron measures in individual women at premenopause and at postmenopause and, secondarily, to determine if any changes contributed to insulin resistance." "In a subset of participants (n=70) in a longitudinal study of menopause, we measured ferritin, transferrin, and soluble transferrin receptor (sTfR) once in the premenopause and once in the postmenopause. We also examined associations between menopausal status and change in iron markers after adjustment for age at menopause, race/ethnicity, and waist circumference. In linear regression models, we examined associations between premenopause iron measures and changes in iron markers over menopause with homeostasis model assessment of insulin resistance (HOMA-IR) changes over menopause, before and after adjustment for age at menopause, race/ethnicity, changes in waist circumference, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) levels." "Women had lower ferritin (p<0.01), higher sTfR:ferritin levels (p<0.01), lower HOMA-IR (p=0.022), and lower glucose (p=0.05) in premenopause compared to postmenopause. After adjustment, lower premenopausal iron levels (sTfR:ferritin levels β=11.0, 95% confidence interval [CI] 0.017-22.0) and larger increases in iron over menopause (changes in sTfR:ferritin β=13.6, 95% CI 0.93-26.3) were associated with larger increases in HOMA-IR." The researchers concluded, "From premenopause to postmenopause, women on average have increases in measures of iron stores. Women who had the greatest changes in iron over menopause (lower measures of premenopausal iron and greater increases in iron measures over the menopause) had the strongest associations between changes in iron and changes in insulin resistance." [Health-e-Iron note: this study highlights the normal increase in iron stores that occurs during menopause. Importantly, in the full paper the authors make special note that "...iron is a modifiable risk factor." Keep this in mind as you read more below and throughout the other pages of this website; maintaining iron levels at premenopausal levels will  likely avert the markedly higher incidence of chronic diseases faced by women following menopause.]

Women’s Health: Cancer

GGT & Oxidative Stress – Female Breast Cancer

Gamma-Glutamyl transferase and breast cancer risk - GGT-Cancer # (1) Free full text

In this 2010 study in the U.K., the oncology researchers stated, "It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT)." The researchers examined data from the Guernsey Cohort Study, which recruited 4,714 women over the age of 32 who attended a cancer research laboratory in Guernsey. Initial baseline measurements, including GGT, were obtained during recruitment. Women with a previous diagnosis of most cancers and women in which new cancers were observed at baseline were excluded from the analysis."GGT was measured in sera (blood serum) from 1,803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer." After adjusting for relevant factors, "there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile(i.e. highest 25% of GGT),the hazard ratio (HR) was 2.17..." [more than a two-fold risk of breast cancer] "When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81..." [nearly a four-fold risk in premenopausal women] "Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of4.90 (95% CI: 1.86, 12.94)."[nearly a five-fold risk] [Healthy-e-Iron note: Tables 4 & 5 from from this study and a graphic derived from the findings are below]

Table 4 Hazard ratio for breast cancer risk in relation to level of serum GGT (adjusted by age, age at first birth/nulliparity, age at menarche, height and weight)

 

Table 5 Breast cancer risk and GGT by menopausal status (adjusted by age, age at first birth/nulliparity, age at menarche, height and weight)


 

 

 

Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer - GGT-Cancer # (11)

This 2011 Brazilian study describes observations of oxidative stress and tissue damage in early and advanced stage breast cancers. "Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages." Early disease was characterized by (among other things) reduced antioxidants (including glutathione) and lipid peroxidation. Advanced disease patients exhibited more pronounced levels of oxidative stress and intense lipid peroxidation. "Plasma iron levels were significantly elevated in AD (advanced disease)." "The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators."


Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy - GGT-Cancer # (13)

This 2011 study "evaluated the oxidative systemic status and hematological profiles of breast cancer patients with advanced ductal infiltrative carcinoma treated with doxorubicin (DOX) or paclitaxel (PTX) within 1 h after chemotherapy." "The results showed that advanced breast cancer diseased (AD) patients without previous chemotherapy presented anemia and high oxidative stress status characterized by elevated levels of lipid peroxidation and nitric oxide, and reduced catalase activity when compared with controls."


Oxidative Stress, Obesity, and Breast Cancer Risk: Results From the Shanghai Women’s Health Study - GGT-Cancer  (12) Free full text

This study was reported in 2009 by researchers at Vanderbilt Epidemiology Center. The study noted that "Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems,leading to oxidative stress and cancer development." "We conducted a nested case-control study within the Shanghai Women's Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F(2t)-IsoP and 15-F(2t)-IsoPM were measured by gas chromatography mass spectrometry for 436 breast cancer cases and 852 individually matched controls." "Urinary excretion of isoprostanes was not significantly different between cases and controls. However,among overweight women,levels of isoprostanes were positively associated with breast cancer risk,which became stronger with increasing body mass index (BMI). Among women with a BMI > or = 29,the odds ratio (OR) increased to 10.27 (95% CI, 2.41 to 43.80) for the highest compared with the lowest tertile of 15-F(2t)-IsoPM (P for trend = .003; P for interaction = .0004)." The researchers concluded, "Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity." [Health-e-Iron note: Figure 2 from this study is below. Also, elevated iron and elevated GGT both correlate with obesity]


 

IRON & Oxidative Stress – Female Breast Cancer 

Iron-binding proteins and C-reactive protein in Nipple Aspirate Fluids: role of Iron-driven inflammation in breast cancer microenvironment?  IRON-Cancer # (4) Free full text

This 2010 study by Italian researchers reports that nipple aspirante fluids in female breast cancer patients contain substantially more iron (ferritin) than in matched healthy controls. Ferritin levels were significantly higher in post-menopausal breast cancer patients than in post-menopausal controls, as well as in pre-menopausal cancer patients when compared to pre-menopausal controls. The researchers concluded, "These data may support the involvement of inflammation and deregulation of iron homeostasis in breast cancer etio-pathogenesis. The significant accumulation of CRP (C-reactive protein) in NAF (Nipple aspirate fluid) in conjunction to the disruption of iron homeostasis may help to identify women at higher breast cancer risk." [Health-e-Iron note; Figure 3 from this study appears below]


Dietary and stored iron as predictors of breast cancer risk: A nested case-control study in Shanghai - IRON-Cancer # (18) Free full text

This 2009 study in China attributed the rapid changes in breast cancer incidence rates in China, at least in part, to dramatically increased meat consumption. Plasma ferritin levels and reported dietary iron intake were compared in 346 women with fibrocystic changes, 248 breast cancer cases and 1,040 controls.Increasing ferritin levels were significantly associated with increasing risk of nonproliferative fibrocystic changes (OR Odds Ratio: 2.51). Similar, but weaker, trends were observed for proliferative changes and for breast cancer. Risk of breast cancer relative to the risk of fibrocystic changes was associated with dietary iron intake in women with nonproliferative fibrocystic changes (OR: 2.63). The researchers concluded, "...this study finds significant associations between iron (stored and dietary) and fibrocystic disease and breast cancer."

 

Does excess iron play a role in breast carcinogenesis? An unresolved hypothesis IRON-Cancer # (19)

In a 2007 review from Albert Einstein College of Medicine in New York, "Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe(3+)) is reduced to ferrous iron (Fe(2+)), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation - three established risk factors for breast cancer." "In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake."

 

Body iron stores and breast cancer risk in female atomic bomb survivors (37)

This 2011 study was conducted in a group of Japanese atom bomb survivors, those with high ferritin (58 ng/mL) versus those with low ferritin (13.2 ng/mL), the high ferritin group experienced a 64% increase breast cancers. The authors concluded, "The results support the hypothesis that elevated body iron stores increase the risk of breast cancer. However, the study was inconclusive regarding the question of whether body iron alters radiation-induced breast cancer risk."

 

Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages 

This was a breast cancer cell study reported in 2013. The investigators, from Penn State University, noted, "Tumor-associated macrophages play a critical role in breast tumor progression; however, it is still unclear what effector molecular mechanisms they employ to impact tumorigenesis. Ferritin is the primary intracellular iron storage protein and is also abundant in circulation. In breast cancer patients, ferritin is detected at higher levels in both serum and tumor lysates, and its increase correlates with poor clinical outcome. In this study, we comprehensively examined the distribution of ferritin in normal and malignant breast tissue at different stages in tumor development. Decreased ferritin expression in cancer cells but increased infiltration of ferritin-rich CD68-positive macrophages was observed with increased tumor histological grade. Interestingly, ferritin stained within the stroma surrounding tumors suggesting local release within the breast. In cell culture, macrophages, but not breast cancer cells, were capable of ferritin secretion, and this secretion was further increased in response to pro-inflammatory cytokines. We next examined the possible functional significance of extracellular ferritin in a breast cancer cell culture model. Ferritin stimulated the proliferation of the epithelial breast cancer cell lines MCF7 and T47D. Moreover, this proliferative effect was independent of the iron content of ferritin and did not increase intracellular iron levels in cancer cells indicating a novel iron-independent function for this protein. Together, these findings suggest that the release of ferritin by infiltrating macrophages in breast tumors may represent an inflammatory effector mechanism by which ferritin directly stimulates tumorigenesis."

 

GGT & Oxidative Stress – Cancer - Female Reproductive System

Prospective Study of the Association of Serumγ-Glutamyltransferase with Cervical Intraepithelial Neoplasia III and Invasive Cervical Cancer GGT-Cancer # (2) Free full text

In 2010 a group of researchers in Austria evaluated the relationship of intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) with GGT. This relationship was studied, "in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. This investigation found that, "during median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001,HR log unit increase 3.45 (1.92-6.19)]. In other words, above low normal GGT of ~ 18/U/L, the risk of Invasive Cervical Cancer increased in direct proportion to other higher GGT levels, including normal high and highly elevated. The researchers concluded, "Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer." [Healthy-e-Iron note: Figure 1 and Table 5 from this study are below]


Figure 1. Kaplan-Meier estimates of cumulative incidence of CIN-III (A) and ICC (B) according to categories of serum GGT, measured at baseline. For the analysis of CIN-III, women with one or more gynecologic examinations during follow-up were included (n = 73,354); for the ICC analyses, all women were included (n = 92,843).

 

Human ovarian tumors express gamma-glutamyl transpeptidase GGT-Cancer # (29)  Free full text

This 1994 study examined GGT expression in primary human ovarian tumors. "GGT was expressed in some epithelial inclusion glands and occasionally in a small subset of stromal cells. Granulosa-stromal cell tumors were largely GGT-negative. In contrast, GGT-positive neoplastic cells were observed in 33 of 45 common epithelial ovarian tumors. None of the patients had been treated with chemotherapy. Some of the tumors had only rare GGT-positive cells, while others consisted almost entirely of GGT-positive cells. "At the time of this "early" study, researchers had not yet determined if  "expression of GGT serves as a marker for identifying neoplasms with enhanced resistance to platinum-based therapy." [Health-e-iron note: more current studies support the opinion that it does]


Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer

This 2013-published study was conducted in Austria. The Investigators reported,":Gamma-glutamyltransferase (GGT) - a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance - is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients.Methods:In this multicenter study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. Results:Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l(-1)) than in patients with BTO (20.01 (12.78) U l(-1), P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1-1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03)." Conclusion: "High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels."


Prognostic significance of gamma-glutamyltransferase in patients with endometrial cancer: a multi-centre trial  - GGT-Cancer # (8) Free full text

The following background was provided in this 2012 study, "GGT, a known marker for apoptotic balance, seems to promote tumour progression, invasion and drug resistance. Recently, high GGT serum levels were shown to be associated with impaired prognosis in patients with cervical cancer." In a muli-center trial in Austria, "Patients were stratified in GGT risk groups, and univariate and multivariable survival analyses were performed. Results: Mean pre-therapeutic serum GGT level was 30.8 (41.5) U l(-1). Elevated and highly elevated serum GGT levels (P=0.03 and P=0.005), tumour stage (P<0.001 and P<0.001), grade (P<0.001 and P=0.02) and age (P<0.001 and P<0.001) were independently associated with progression-free survival in univariate and multivariable survival analyses. The researchers concluded, "Pre-therapeutic serum GGT is a novel and independent prognostic parameter for progression-free survival of patients with endometrial cancer. Stratifying patients into prognostic subgroups could be used for patient counselling and individualised treatment planning."

 

Relevance of gamma-glutamyltransferase--a marker for apoptotic balance--in predicting tumor stage and prognosis in cervical cancer - GGT-Cancer # (10)

In this 2011 study reported by investigators from Memorial Sloan-Kettering Cancer Center, New York, in a multi-center trial, "pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters." "We (further) investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer." The investigators concluded, "High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer."


Lifestyle-related biomarkers and endometrial cancer survival: Elevated gamma-glutamyltransferase as an important risk factor - GGT-Cancer # (40)

This Austrian study was reported in 2013. The researchers noted, "Lifestyle seems to play an important role in endometrial cancer mortality, but it remains unclear which biomarkers are involved. The aim of this study was to assess the extent of the association between lifestyle-related biomarkers and the survival of endometrial cancer patients. Methods: A sub-cohort of 242 endometrial cancer patients, from a population-based study of the more than 90,000 female participants of the Vorarlberg Health Monitoring and Promotion Programme, was followed for a median duration of twelve years. Besides age, tumour staging, and histology, also pre-diagnostic levels of body mass index, blood pressure, triglycerides, total cholesterol, glucose, gamma-glutamyltransferase (GGT), and serum uric acid were analysed in Cox proportional hazards regression models to estimate multivariate mortality risks. Results: During follow-up 89 deaths occurred of which 49 were cancer-related. Survival was associated with age, tumour stage, and histology. Of the biomarkers, log(10)-transformed GGT showed a large effect on cancer-related mortality (HR=3.35, 95% CI 1.12-10.03), whereas the other parameters did not appear with significant effects after adjustment for the other factors. Conclusion: Elevated level of GGT, a lifestyle-related marker, was associated with poor survival among endometrial cancer patients.

 

IRON & Oxidative Stress – Cancer - Female Reproductive System

Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary IRON-Cancer # (30)

In this 2011 review, the authors cover the three roles of redox-active iron in clear cell carcinoma of the ovary carcinogenesis. "This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC (clear cell carcinoma) carcinogenesis."


Risk of carcinoma in women with ovarian endometrioma IRON-Cancer # (31)

This 2011 review updates the knowledge respecting "the three major processes in which iron is implicated in repeated events of hemorrhage and endometriosis in epithelial ovarian carcinoma: 1) increasing oxidative stress promotes DNA methylation; 2) activating anti-apoptotic pathways supports tumor promotion; and 3) aberrant expression of stress signaling pathways contributes to tumor progression."

 

Age-related Accumulation of Non-heme Ferric and Ferrous Iron in Mouse Ovarian Stroma Visualized by sensitive non-heme iron histochemistry - IRON-Cancer # (32)

Published in March, 2012, this study was undertaken to to determine the quantities of non-heme iron accumulated over time in the ovaries of laboratory mice. The author stated, "Intraperitoneal iron overload in adult mice resulted in non-heme iron deposition in the entire stroma and generation of enlarged macrophages, suggesting that excessive iron accumulation induced macrophage morphological changes. The data indicated that non-heme iron accumulation in ovarian stromal tissue may be related to aging of the ovary due to increasing oxidative stress."


GGT, IRON, Oxidative Stress in Women: Cancer & Mortality

Prospective study of the association of gamma-glutamyltransferase with cancer incidence in women - GGT-Cancer # (3) Free full text

In 2008, this team of Austrian investigators noted, "Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored." "...We investigated the association of GGT with overall and site-specific cancer incidence in a population-based cohort of 92,843 Austrian women with 349,674 serial GGT measurements, prospectively followed-up for a median of 13.5 years." "During follow-up, 4,884 incidence cancers were observed.Compared to normal low GGT (<17.99 U/L), cancer risk was elevated for all other GGT categories (p for trend < 0.0001), with adjusted hazard ratios (95% confidence intervals) of 1.06 (0.99-1.13) for GGT levels between 18.00 and 35.99 U/L (normal high),1.12 (1.02-1.22) for GGT levels between 36.00 and 71.99 U/L (elevated) and1.43 (1.28-1.61) for highly elevated GGT (>72.00 U/L). In other words, overall cancer risks increased 6-43% in proportion to increasing GGT measures in women when GGT was above ~ 18/U/L. The researchers concluded, "Our study is the first to demonstrate in a large population-based cohort that high GGT levels significantly increased cancer risk in women." [Healthy-e-Iron note: Figure 1 from this study is below]

FIGURE 1 – Adjusted cumulative overall cancer incidence according to baseline GGT levels among 92,843 female Austrian adults (mean age 41.7 years) in the VHM&PP. Curves were estimated at the average values of covariates using Cox proportional hazards models adjusted for body-mass index, smoking status, occupational status and year at entry into the cohort.

[Health-e-Iron note: a slide presentation from the authors of the above research can be viewed by clicking on this LINK]

 

Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population GGT-Cancer # (16) Free full text

These researchers investigators studied serum markers of liver injury and  "12-year mortality among 14,950 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, who were negative for markers of viral hepatitis B and C. Abnormal ALT was defined as >30 U/L in men or >19 U/L in women, and abnormal GGT as >51 U/L in men or >33 U/L in women. "Only GGT was associated with all-cause mortality, including from liver disease, cancer and diabetes. The researchers concluded, "In the US population, elevated GGT was associated with mortality from all causes, liver disease, cancer, and diabetes, while ALT was associated only with liver disease mortality."

 

Possible role of membrane gamma-glutamyltransferase activity in the facilitation of transferrin-dependent and -independent iron uptake by cancer cells - GGT-Cancer # (22) Free full text

This 2003 reported study in Italy "...aimed at verifying the possibility that GGT-mediated iron reduction may participate in the process of cellular iron uptake." In this laboratory study of four distinct human tumor cell lines, exhibiting different levels of GGT activity, were studied. The uptake of transferrin-bound iron was investigated..." The researchers concluded, "...that membrane GGT can represent a facilitating factor in iron uptake by GGT-expressing cancer cells, thus providing them with a selective growth advantage over clones that do not possess the enzyme." [Healthy-e-Iron note: Figure 1 from this study is below]


Figure 1
Effects of modulation of membrane GGT activity on transferrin-mediated uptake of 55Fe by 4 human cancer cell lines expressing different levels of GGT activity. Data shown are means ± SEM of 2–5 experiments. Panel A: U937 histiocytoma cells (*significantly different from control value, P < 0.05; **significantly different from the "+GSH+gly-gly" value, P < 0.05). Panel B: Me665/2/60 melanoma cells (*significantly different from control value, P < 0.05). Panel C: K562 erythroleukemia cells (**significantly different from the "+GSH+gly-gly" value, P < 0.05). Panel D: Me665/2/21 melanoma cells (differences not statistically significant).

 

Erythrocytes as targets for gamma-glutamyltranspeptidase initiated pro-oxidant reaction - GGT-Cancer # (22) 

This research team in France reviewed stated, "...in recent years, findings from our group and from others showed that GGT-catalysed extracellular metabolism of GSH leads, in the presence of iron, to the generation of reactive oxygen species (ROS). "The objective of the present work is to determine whether the red blood cells are targets for plasma GGT-initiated pro-oxidant reaction" And, "The results obtained demonstrate that the GGT/GSH/iron system oxidises isolated erythrocyte membranes. A significant release of haemoglobin and a decrease of erythrocyte deformability are also observed." The researchers concluded, "GGT-mediated ROS production is able to oxidise erythrocytes and thus disturbs their functions."

 

Iron status and risk of cancers in the SU.VI.MAX cohort -  IRON-Cancer # (42) Free full text

This is a 2005 study of iron status and cancer in a population of "middle-aged adults living in France where iron supplementation and iron-fortified foods are rarely used." In this study more than 10,000 subjects, iron status was measured by serum ferritin.Women with ferritin above 160 ng/mL had an 88% increased risk of cancer.   This association was not found among men. The researchers concluded, "After adjustment for confounding factors, our data do not support a major role of iron status or intake in the risk of cancer in men but suggest a potential deleterious effect of high iron status in women."

 

Body iron stores and mortality due to cancer and ischaemic heart disease: a 17-year follow-up study of elderly men and women IRON-Cancer # (12)

In 1995 researchers who undertook this European study concluded the following, "These results suggest that body iron stores are a risk factor for mortality due to cancer in postmenopausal women. This may be due to accumulation of stored iron among women after menopause."

 

Total mortality by transferrin saturation levels: two general population studies and a metaanalysis -  IRON-Cancer # (14) Free full text

This 2011 Danish population study followed 45,159 men and women for up to 18 years. The researchers reported that compared to transferrin saturation below 50%, for individual with higher transferrin saturation, men experienced 30%, and women 50% increased mortality during the period. [Health-e-Iron note: Figure 2 from study appears below]


Serum iron, copper and zinc concentrations and the risk of cancer mortality in US adults - IRON Cancer #  (43)

This was a 2004 U.S. study of the results from the Second National Health and Nutrition Examination Survey. "For men and women combined, the adjusted RRs (95% confidence intervals, CI) for the four levels were 0.96 (0.57-1.61), 1.00 (reference), 1.12 (0.80-1.58), 1.86 (1.07-3.22) for iron... The authors concluded, "People with higher serum iron, transferrin saturation, or copper concentrations had an increased risk of dying from cancer."

 

Total mortality by transferrin saturation levels: two general population studies and a metaanalysis - IRON-Heart # (26) Free full text

In this 2011 study two Danish populations totaling 45,159 individuals, subjects with transferrin equal to or above 50% were compared to subject with lower transferrin saturation. "Multifactorially adjusted hazard ratios for total mortality for TS≥50% vs <50% were1.4 (95% CI 1.2-1.6; P<0.001)overall, 1.3 (1.1-1.6; P=0.003) in men, and 1.5 (1.1-2.0; P=0.005) in women. Results were similar if the 2 studies were considered separately. A stepwise increased risk of total mortality was observed for stepwise increasing levels of TS (log-rank P<0.0001), with the highest risk conferred by TS≥80% vs TS<20% with a hazard ratio of 2.2 (1.4-3.3; P<0.001). The population-attributable risk for total mortality in the combined studies in individuals with TS≥50% vs <50% was 0.8%. In metaanalysis, the odds ratio for total mortality for TS≥50% vs <50% was 1.3 (1.2-1.5; P<0.001)under the fixed-effects model." The researchers concluded,"Individuals in the general population with TS≥50% vs <50% have an increased risk of premature death." [Health-e-Iron note: Figures 2 & 3 from the study above appear below]



Women’s Health: Gestational Diabetes

Gamma-glutamyltransferase, alanine transaminase and aspartate transaminase levels and the diagnosis of gestational diabetes mellitus - GGT-Diabetes (34)

The objective of this 2012 published study undertaken in Malaysia was "To evaluate gamma-glutamyltransferase (GGT), alanine transaminases (ALT) and aspartate transaminases (AST) levels and prevalent gestational diabetes mellitus (GDM)." "Random plasma glucose, GGT, ALT and AST and the 50-g glucose challenge test were done on antenatal women followed by diagnostic 3-point 75-g oral glucose tolerance test within two weeks. GDM was diagnosed by ADA (2011) criteria." "The risk for GDM was higher for women in the highest GGT quartile band compared to the lowest: RR 1.35 95%CI 1.0-1.8; P=0.04. However, after adjustment for confounders, GGT was no longer associated with GDM. There was no correlation between ALT and AST levels and GDM.

 

Gamma-glutamyltransferase level in pregnancy is an independent risk factor for gestational diabetes mellitus - GGT-Diabetes # (35)

In another gestational diabetes study from Malaysia that was reported in 2008 the reseachers set out "To evaluate the relationship between gamma-glutamyltransferase (GGT) level in pregnant women at oral glucose tolerance test (OGTT) and the diagnosis of gestational diabetes (GDM)." "GGT level correlated positively with the 2-hour glucose level (Spearman's rho = 0.112: P < 0.05). GGT values that were stratified into quartiles demonstrated a significant trend with diagnosis of GDM (chi(2) for trend; P = 0.03). Multivariable logistic regression analysis taking into account maternal age, gestational age at OGTT, body mass index and a positive 50-g glucose challenge test (GCT) indicated that high GGT was an independent risk factor for GDM (adjusted odds ratio [AOR] 2.1 95% CI 1.2-3.8: P = 0.01). In the subset of women identified by a positive GCT, on multivariable logistic regression analysis, only high GGT was an independent risk factor for GDM (AOR 2.3 95% CI 1.3-4.2: P = 0.007)." The researchers concluded, "Raised GGT level is an independent risk factor for GDM in high risk pregnant women undergoing OGTT."

 

Can serum gamma-glutamyltransferase levels be useful at diagnosing gestational diabetes mellitus? - GGT-Diabetes # (36)

In another 2012 similar gestational diabetes study reported in Turkey, "The aim of this study was to evaluate plasma gamma-glutamyltransferase (GGT) in gestational diabetes mellitus (GDM) in pregnant women at oral glucose tolerance test (OGTT) and the diagnosis of GDM and to explore whether this activity is associated with metabolic parameters." "his prospective control study included 37 women with GDM and 42 women with normal glucose tolerance in pregnancy (control group). In the study group (GDM), blood was taken for analyzing 100 g OGTT from women who have abnormal 50 g glucose challenge test (GCT)." "Compared with the controls, the GDM group had significantly higher mean values for serum fasting glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), triglyceride and GGT. Within the GDM group, GGT levels were only negatively correlated with high-density lipoprotein (r = -0.41, p = 0.01). GGT was determined to be an independent metabolic parameter for GDM. The researchers concluded, "The increase at GGT level is an independent risk factor for GDM and identified as high-risk women for diagnosis of GDM."

 

Serum ferritin concentration in gestational diabetes mellitus and risk of subsequent development of early postpartum diabetes mellitus - IRON-Diabetes # (21) Free full text

In this 2010 study from Iran, serum ferritin was measured in 128 pregnant women (64 women with gestational diabetes and 64 age-matched controls). Women with gestational diabetes had higher serum ferritin than controls (112 vs. 65 ng/mL). "Higher iron stores...are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors." The researchers concluded, "Elevated serum ferritin concentrations in mid-pregnancy are associated with an increased risk of GDM independent of C-reactive protein and body mass index. Ferritin levels in GDM cannot be used as an indicator to predict subsequent glucose concentration in early postpartum oral glucose tolerance test."

 

A prospective study of prepregnancy dietary iron intake and risk for gestational diabetes mellitus - IRON-Diabetes # (22) Free full text

This 2011 study was reported by researchers from Division of Epidemiology, Statistics and Prevention at the National Institutes of Health. "The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of diabetes mellitus GDM." "A prospective study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses' Health Study II. A total of 867 incident GDM cases were reported. Pooled logistic regression was used to estimate the relative risk (RR) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors." "Dietary heme iron intake was positively and significantly associated with GDM risk. After adjusting for age, BMI, and other risk factors, RRs (95% CIs) across increasing quintiles of heme iron were 1.0 (reference), 1.11 (0.87-1.43), 1.31 (1.03-1.68), 1.51 (1.17-1.93), and 1.58 (1.21-2.08), respectively (P for linear trend 0.0001). The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 (1.10-1.36). No significant associations were observed between total dietary, nonheme, or supplemental iron intake and GDM risk." The researchers concluded, "These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk."

 

Iron and Oxidative Stress in Pregnancy   Free full text

This 2003-published review states, "Pregnancy, mostly because of the mitochondria-rich placenta, is a condition that favors oxidative stress. Transitional metals, especially iron, which is particularly abundant in the placenta, are important in the production of free radicals. Protective mechanisms against free radical generation and damage increase throughout pregnancy and protect the fetus, which, however, is subjected to a degree of oxidative stress. Oxidative stress peaks by the second trimester of pregnancy, ending what appears to be a vulnerable period for fetal health and gestational progress. Conditions restricted to pregnancy, such as gestational hypertension, insulin resistance and diabetes, exhibit exaggerated indications of free radical damage. Antioxidants as well as avoidance of iron excess ameliorate maternal and early fetal damage. Estimates of gestational iron requirements and of the proportion of iron absorbed from different iron supplemental doses suggest that with present supplementation schemes the intestinal mucosal cells are constantly exposed to unabsorbed iron excess and oxidative stress. Unpublished work carried out in Mexico City with nonanemic women at midpregnancy indicates that 60 mg/d of iron increases the risk of hemoconcentration, low birth weight and premature birth and produces a progressive decline in plasma copper. These risks are not observed in women supplemented with 120 mg iron once or twice per week.

 

Iron status in women with and without gestational diabetes mellitus

 In this study from Iran reported in 2009, the researchers noted, "Gestational diabetes mellitus (GDM) affects approximately 7% of all pregnancies." "Pregnancy, mostly because of the mitochondria-rich placenta, is a condition that favors oxidative stress. A transitional metal, especially iron, which is particularly abundant in the placenta, is important in the production of free radicals." "In this case-control study, 34 women with diagnosed GDM were compared with 34 non-GDM women in the control group at 24-28 weeks of pregnancy in terms of iron status, including ferritin, serum iron, total iron-binding capacity (TIBC), hemoglobin (Hb), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH)." "...concentration of serum ferritin, iron, transferrin saturation and hemoglobin, MCV, and MCH was significantly higher in the GDM group and TIBC was significantly lower in this group (P<.05). No significant association was observed with the other variables including familial history of diabetes and GDM." The researchers concluded, "Our findings indicate an association between increased iron status and GDM. The role of iron excess from iron supplementation in the pathogenesis of GDM needs to be examined."

 

Gestational diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake - IRON-Diabetes # (23) Free full text

This 2011 study was similar to the study directly-above. Researchers in Sweden "investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk." "We conducted a prospective cohort study of 3,158 pregnant women. A food frequency questionnaire was used to assess maternal diet. Multivariable generalized linear regression models were used to derive estimates of relative risks (RRs) and 95% CIs." "Approximately 5.0% of the cohort developed GDM (n=158). Heme iron intake was positively and significantly associated with GDM risk (Ptrend=0.04). After adjusting for confounders,women reporting the highest heme iron intake levels (≥1.52 vs. <0.48 mg per day) experienced a 3.31-fold-increased GDM risk (95% CI 1.02-10.72). In fully adjusted models, we noted that a 1-mg per day increase in heme iron was associated with a 51% increased GDM risk (RR 1.51 [95% CI 0.99-2.36]). Nonheme iron was inversely, though not statistically significantly, associated with GDM risk..." The researchers concluded, "High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk. Associations of GDM risk with dietary nonheme iron intake are less clear..." [Health-e-Iron note: Figure 1 from this study appears below]

 

Gamma glutamyltransferase as a novel marker of coronary artery calcification in women 

The aim of this 2012 study was stated as follows: "Gamma glutamyltransferase (GGT) has attracted great interest as a potential novel marker of cardiovascular risk. However, its association with coronary artery calcification (CAC) score-determined coronary artery atherosclerosis is unknown. This study was designed to assess the association of GGT with CAC score." "Participants, 311 asymptomatic men and 220 asymptomatic women who underwent evaluation of CAC by cardiac computed tomography, were retrospectively investigated. Correlation and logistic regression analysis were used to assess the association of GGT with CAC score and other variables." "Women but not men with higher GGT had a higher incidence of CAC score above 100 and a higher prevalence of metabolic syndrome (P = 0.012 and 0.007, respectively). GGT was positively correlated with C-reactive protein (CRP) in women (r = 0.336, P < 0.001). GGT was independently associated with the incidence of CAC score above 100 in women [odds ratio (OR) 1.228, 95% confidence interval (CI) 1.206-1.252, P = 0.001] but not in men." The researchers concluded, "In asymptomatic women, GGT is independently and positively associated with CAC score and it can be useful as a provisional new risk factor for CAC. Additionally, metabolic syndrome and CRP may be the mediators of the mechanisms by which GGT increases CAC in asymptomatic women."

 

Increased Ferritin Concentrations Correlate with Insulin Resistance in Female Type 2 Diabetic Patients

This 2012 reported study was to access the relationship between ferritin and insulin resistance in different gender and ethnicities...; this study aimed to investigate it using homeostasis model assessment (HOMA-IR), and to explore whether it is gender-specific." "Stratified by gender, a 1-tertile ferritin increase significantly correlated with a 0.241-unit increase in HOMA-IR (beta = 0.241, p = 0.001) in female diabetes, but not in male diabetes (beta = 0.072, p = 0.232), after adjusting for demographic, dietary, clinical and inflammatory factors. The researchers concluded, "Iron overload, which produces elevated levels of ferritin, may augment insulin resistance in female but not in male type 2 diabetes."

 

Serum ferritin: a predictor of early spontaneous preterm delivery

The objective of this 1996-reported study from the Department of Nutrition Sciences, University of Alabama was "To identify biochemical indices for iron and protein nutriture as well as acute-phase reactants as predictors of preterm delivery." "In this nested case-control study, serum samples were obtained at about 24 weeks' gestation from 94 indigent multiparas. These cases were defined based on having a spontaneous delivery of 32 weeks or less (n = 31) with two control groups, one delivering spontaneously at 33-36 weeks (n = 32) and the other delivering spontaneously at 37 weeks or more (n = 31). The concentrations of iron, ferritin, transferrin, transferrin saturation, and transferrin receptor were measured as indices of iron status. The concentrations of acute-phase reactants, including C-reactive protein, alpha-2-macroglobulin, beta-2-microglobulin and ceruloplasmin, were also measured, along with albumin, prealbumin, retinol-binding protein, copper, and zinc." "Serum ferritin concentrations were negatively correlated with gestational age at birth (P = .034). For subjects having serum ferritin levels above the median compared with those below, the odds ratio of having an early spontaneous preterm delivery was 2.99 (95% confidence interval 1.13-7.89). The other indices, including iron status and the acute-phase reactants, were not significantly associated with gestational age at birth." The investigators concluded, "Elevated serum ferritin levels during the second trimester are predictive of early spontaneous preterm delivery, possibly because these reflect an acute-phase reaction to subclinical infections that are closely associated with premature delivery."
 

Polycystic Ovary Syndrome - Iron, GGT and Oxidative Stress

 

Iron metabolism and the polycystic ovary syndrome Insulin Resistance # (14) Free full text

This 2012-published review is from Spain. "The polycystic ovary syndrome (PCOS) is associated with insulin resistance and abnormal glucose tolerance. Iron overload may lead also to insulin resistance and diabetes. Serum ferritin levels are increased in PCOS, especially when glucose tolerance is abnormal, suggesting mild iron overload. Factors contributing to potential iron overload in PCOS include the iron sparing effect of chronic menstrual dysfunction, insulin resistance, and a decrease in hepcidin leading to increased iron absorption. Enhancement of erythropoiesis by androgen excess is unlikely, because soluble transferrin receptor levels are not increased in PCOS. Future venues of research should address the long-term effects of PCOS treatment on iron overload and, conversely, the possible effects of iron lowering strategies on the glucose tolerance of patients with PCOS."

 

Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism  Insulin Resistance # (15) Free full text

The researchers in this 2009 published study noted, "Increased serum ferritin levels and iron stores may be involved in the development of abnormal glucose tolerance in women presenting with obesity and/or polycystic ovary syndrome (PCOS)." "We aimed to study the determinants of serum ferritin levels in premenopausal women among indexes of insulin resistance, adiposity, hyperandrogenism, and genotypes pertaining to inflammation, oxidative stress, and iron metabolism." "A total of 257 premenopausal women, classified depending on the presence or absence of PCOS, obesity, and/or abnormal glucose tolerance, underwent a complete metabolic evaluation, serum ferritin, haptoglobin, and C-reactive protein (CRP) measurements, and genotyping for proinflammatory and prooxidant variants and mutations in the HFE [i.e. Hemochromatosis] gene." "Serum ferritin concentrations were increased in women presenting with PCOS and/or abnormal glucose tolerance, independent of obesity." "A stepwise multivariate linear regression analysis (R²  0.18, P = 0.0001) retained menstrual dysfunction (β =  0.14, P 0.035), free testosterone (β =  0.14, P =  0.052), insulin sensitivity index (β = -  0.12, P = 0.012), the His63Asp [i.e. H63D] variant in HFE (  0.16, P =  0.008), and abnormal glucose tolerance (β = 0.15, P =  0.015) as significant predictors of the logarithm of ferritin levels, whereas CRP, haptoglobin, waist-to-hip ratio, or variants in the TNFα, TNFRSF1B, IL6, IL6ST, IL6Rα, PON1, and HFE Cys282Tyr [i.e. C283Y] mutation exerted no influence." The researchers concluded, "Androgen excess (partly because of hyperandrogenemia and partly because of menstrual dysfunction), insulin resistance, abnormal glucose tolerance, and the HFE His63Asp variant correlate with ferritin levels in premenopausal women." [Health-e-Iron note: Figure #1 from this paper appears below]

 


 

Effect of metformin on serum ferritin level in women with polycystic ovary syndrome  Free Full text

This 2011-reported study was undertaken in Iran.The researchers noted: "Polycystic ovary syndrome (PCOS) is one of the most common diseases among women associated with various inflammatory reactants such as C-reactive protein (CRP) and ferritin. This study aimed to investigate the effect of metformin on probable reduction of serum ferritin in patients with PCOS. This study was conducted on 45 patients with PCOS who had not other systemic diseases and did not take any medications. Weight, waist and hip circumstances (WHR), body mass index (BMI), metabolic indexes, CRP, ferritin and  Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were measured before the study. Metformin (500 mg/tid) tablets were prescribed for three months and then same above parameters were remeasured. Of 45 patients, 19 (42.2%) were overweight and 14 (31.1%) were obese. After drug therapy, there was a significant reduction in waist circumstance and serum ferritin." "Comparison of serum ferritin, hsCRP and HOMA-IR before and after three months treatment with metformin among mentioned above sub-groups of BMI showed a significant difference of HOMA-IR (p=0.04), serum ferritin (p=0.02) in normal BMI group, while there was not significant difference of hsCRP (p=0.4)."  "This reduction was significant only in the lean and overweight groups but not in the obese group." The researchers concluded, "The effect of metformin on reduction of serum ferritin was not significant just in obese group and was not associated with metabolic and anthropometric indexes." [Health-e-Iron note: Tables 1 and 2 from this study are below]


 

Body Iron Stores Are Increased in Overweight and Obese Women With Polycystic Ovary Syndrome   Free full text

This 2005-reported study is from an investigation undertaken in Spain. The authors suggested, "Increased body iron stores are associated with insulin resistance and type 2 diabetes. In conceptual agreement, increased serum ferritin levels are positively associated with the prevalence of the metabolic syndrome in men and adult pre and postmenopausal women and with an increased risk of type 2 diabetes in both men and women. Given that insulin resistance and an increased risk of type 2 diabetes are frequent in patients with polycystic ovary syndrome (PCOS), we hypothesize that body iron stores might be especially increased in these women." "We studied 78 patients with PCOS and 43 non-hyperandrogenic control subjects matched for BMI and degree of obesity." The researchers concluded, "that increased body iron stores, expressed as increased serum ferritin concentrations, are present in overweight and obese women with PCOS but not in lean patients. These increased iron stores might contribute to the insulin resistance and β-cell dysfunction frequently found in PCOS patients, as has been proposed for insulin resistance, the metabolic syndrome, and type 2 diabetes." [Health-e-Iron note: Figure 1 from this study is below]



The effects of 8 months of metformin on circulating GGT and ALT levels in obese women with polycystic ovarian syndrome  

This was a 2008-reported study from the UK. The investigators reported "The prevalence of non-alcoholic fatty liver disease (NAFLD) in polycystic ovarian syndrome (PCOS) is high. Small studies have shown reductions in serum alanine aminotransaminase (ALT) and gamma-glutamyltransaminase (GGT) concentrations, both surrogate liver fat markers, and sometimes improvements in liver histology in individuals with NAFLD treated with metformin." "We performed post hoc data analysis from a trial, involving 82 obese women aged 22-46 years with PCOS." "Sixty-six participants completed the study. Mean weight, serum ALT and GGT decreased from 100.3 to 96.6 kg (p < 0.0001), 29.7 to 25.8 U/l (p = 0.012) and 21.4 to 16.9 U/l (p < 0.0001) respectively. Associations between weight reduction and decreases in serum ALT and GGT were highly significant and independent of change in Homeostasis Model Assessment of Insulin Resistance." The researchers concluded, "Metformin therapy is associated with reductions in surrogate liver fat markers in obese women with PCOS. This adds indirect support for a benefit of metformin in attenuating/reversing liver fat accumulation in PCOS and more generally."

 

Hepcidin levels in diabetes mellitus and polycystic ovary syndrome  Free full text 

The authors of this 2013-reported study undertaken in the U.K. noted, "Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load." "Serum concentrations of the active form of hepcidin (hepcidin-25) and hepcidin:ferritin ratio were evaluated in participants with Type2 diabetes (n=33, control subjects matched for age, gender and BMI, n=33) and participants with polycystic ovary syndrome (n=27, control subjects matched for age and BMI, n=16). To investigate whether any changes observed were associated with insulin resistance rather than insulin deficiency or hyperglycaemia per se, the same measurements were made in participants with Type1 diabetes (n=28, control subjects matched for age, gender and BMI, n=30). Finally, the relationship between homeostasis model assessment of insulin resistance and serum hepcidin:ferritin ratio was explored in overweight or obese participants without diabetes (n=16)." "Participants with Type2 diabetes had significantly lower hepcidin and hepcidin:ferritin ratio than control subjects (P<0.05 and P<0.01, respectively). Participants with polycystic ovary syndrome had a significantly lower hepcidin:ferritin ratio than control subjects (P<0.05). There was no significant difference in hepcidin or hepcidin:ferritin ratio between participants with Type1 diabetes and control subjects (P=0.88 and P=0.94). Serum hepcidin:ferritin ratio inversely correlated with homeostasis model assessment of insulin resistance (r=-0.59, P<0.05). The researchers concluded, "Insulin resistance, but not insulin deficiency or hyperglycaemia per se, is associated with inadequate hepcidin levels. Reduced hepcidin concentrations may cause increased body iron stores in insulin-resistant states."