Abnormalities in Copper Status Associated with an Elevated Risk of Parkinson's Phenotype Development.

In the last 15 years, among the many reasons given for the development of idiopathic forms of Parkinson's disease (PD), copper imbalance has been identified as a factor, and PD is often referred to as a copper-mediated disorder. More than 640 papers have been devoted to the relationship between PD and copper status in the blood, which include the following markers: total copper concentration, enzymatic ceruloplasmin (Cp) concentration, Cp protein level, and non-ceruloplasmin copper level. Most studies measure only one of these markers. Therefore, the existence of a correlation between copper status and the development of PD is still debated. Based on data from the published literature, meta-analysis, and our own research, it is clear that there is a connection between the development of PD symptoms and the number of copper atoms, which are weakly associated with the ceruloplasmin molecule. In this work, the link between the risk of developing PD and various inborn errors related to copper metabolism, leading to decreased levels of oxidase ceruloplasmin in the circulation and cerebrospinal fluid, is discussed.

Establishment and Validation of Prognostic Nomograms Based on Serum Copper Level for Patients With Early-Stage Triple-Negative Breast Cancer.

Background: Altered copper levels have been observed in several cancers, but studies on the relationship between serum copper and early-stage triple-negative breast cancer (TNBC) remain scare. We sought to establish a predictive model incorporating serum copper levels for individualized survival predictions. Methods: We retrospectively analyzed clinicopathological information and baseline peripheric blood samples of patients diagnosed with early-stage TNBC between September 2005 and October 2016 at Sun Yat-sen University Cancer Center. The optimal cut-off point of serum copper level was determined using maximally selected log-rank statistics. Kaplan-Meier curves were used to estimate survival probabilities. Independent prognostic indicators associated with survival were identified using multivariate Cox regression analysis, and subsequently, prognostic nomograms were established to predict individualized disease-free survival (DFS) and overall survival (OS). The nomograms were validated in a separate cohort of 86 patients from the original randomized clinical trial SYSUCC-001 (SYSUCC-001 cohort). Results: 350 patients were eligible in this study, including 264 in the training cohort and 86 in the SYSUCC-001 cohort. An optimal cut-off value of 21.3 µmol/L of serum copper was determined to maximally divide patients into low- and high-copper groups. After a median follow-up of 87.1 months, patients with high copper levels had significantly worse DFS (p = 0.002) and OS (p < 0.001) than those with low copper levels in the training cohort. Multivariate Cox regression analysis revealed that serum copper level was an independent factor for DFS and OS. Further, prognostic models based on serum copper were established for individualized predictions. These models showed excellent discrimination [C-index for DFS: 0.689, 95% confidence interval (CI): 0.621-0.757; C-index for OS: 0.728, 95% CI: 0.654-0.802] and predictive calibration, and were validated in the SYSUCC-001 cohort. Conclusion: Serum copper level is a potential predictive biomarker for patients with early-stage TNBC. Predictive nomograms based on serum copper might be served as a practical tool for individualized prognostication.

Clinical significance of the ratio of serum copper to zinc in patients with inflammatory bowel disease / 中华消化杂志

Objective:To explore the serum levels of copper and zinc and the application value of the ratio in assessing disease activity in patients with inflammatory bowel disease (IBD).Methods:From March 2019 to April 2020, 200 patients with IBD hospitalized at the Department of Gastroenterology of the First Affiliated Hospital of Anhui Medical University were selected by prospective random direct sampling method, including 100 patients with Crohn′s disease (CD) and 100 patients with ulcerative colitis (UC). The Crohn′s disease activity index (CDAI) and the modified Mayo score were used to evaluate the disease activity of CD patients and UC patients. In the same period 100 healthy individuals in the routine physical examination were selected as healthy control group. The serum levels of copper and zinc of the healthy control group, the CD group and the UC group were determined by atomic absorption spectrometry. The levels and the ratio of serum copper to zinc of three groups were compared. The ratio of serum copper to zinc of CD patients and UC patients with different disease activity were compared. The correlation between the ratio of serum copper to zinc and IBD activity indexes were analyzed, which included fecal calprotectin (FC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), CDAI and Mayo score. Receiver operating characteristic curve was drawn to analyze the value of the ratio of serum copper to zinc, CRP and ESR in predicting disease activity of patients with IBD. Independent sample t test, least significant difference- t test and Pearson correlation analysis were performed for statistical analysis. Results:The serum copper levels and the ratio of serum copper to zinc of the CD group and the UC group were both higher than that of the healthy control group, however the serum zinc levels were lower than that of the healthy control group ( (32.27±7.69) and (29.80±9.68) mol/L vs. (20.16±6.67) mol/L; 2.81±1.57 and 2.29±1.09 vs. 0.68±0.36; (14.64±7.11) and (15.65±8.17) mol/L vs. (34.29±16.40) mol/L), and the differences were statistically significant ( t=2.81, 5.87, 1.47, 7.21, 1.73 and 2.56, all P<0.05). Among CD patients, the the ratio of serum copper to zinc of patients at remission stage (29 cases), mild activity stage (23 cases), moderate activity stage (30 cases) and severe activity stage (18 cases) was 2.61±1.43, 2.75±1.35, 3.15±2.37 and 4.17±1.77, respectively, and the ratios of serum copper to zinc of patients at mild activity stage, moderate activity stage and severe activity stage were all higher than that of patients at the remission stage, and the differences were statistically significant ( t=3.41, 7.92 and 5.84, all P<0.05). There were statistically significant differences in the ratios of serum copper to zinc between patients at mild activity stage and moderate activity stage, severe activity stage, and between patients at moderate activity stage and severe activity stage ( t=5.82, 6.23 and 3.45, all P<0.05). Among UC patients, the ratio of serum copper to zinc of patients at remission stage (10 cases), mild activity stage (30 cases), moderate activity stage (45 cases) and severe activity stage (15 cases) was 1.52±0.44, 1.74±0.58, 2.38±0.83 and 3.80±1.19, respectively, the ratio of serum copper to zinc of patients at moderate activity stage was higher than that of patients at remission stage and mild activity stage, and the ratio of serum copper to zinc of patients at severe activity stage was higher than those of patients at remission stage, mild activity stage and moderate activity stage, and the differences were statistically significant ( t=7.92, 5.83, 3.21, 9.54 and 2.83, all P<0.05). There was no statistically significant difference in serum copper to zinc ratio between patients at remission and at mild activity stage ( P>0.05). The ratio of serum copper to zinc of CD patients was positively correlated with FC and CRP ( r=0.697 and 0.586, P=0.014 and 0.001), however was not correlated with ESR or CDAI score (both P>0.05). The ratio of serum copper to zinc of UC patients was positively correlated with FC, ESR and Mayo score ( r=0.488, 0.452 and 0.331, P=0.001, P<0.01 and P=0.041), however was not correlated with CRP ( P>0.05). The cut-off value of the ratio of serum copper to zinc, CRP and ESR for the diagnosis of CD activity was 1.76, 8 mg/L and 20 mm/1 h, respectively. Among them, ESR was the most effective in the diagnosis of CD activity with an area under the curve (AUC) value of 0.830, and to the sensitivity and specificity was 69.0% and 86.2%, respectively. The cut-off value of the ratio of serum copper to zinc, CRP and ESR for the diagnosis of UC activity was 1.63, 8 mg/L and 20 mm/1 h, respectively; among which the the ratio of serum copper to zinc had the highest efficacy in the diagnosis of UC activity, with an AUC value of 0.862, sensitivity and specificity of 73.0% and 90.9%, respectively. Conclusion:The the ratio of serum copper to zinc is correlated with the disease activity of IBD, which may become a new auxiliary indicator for the evaluation of disease activity.

Zinc and copper nutriture of women taking oral contraceptive agents.

A cross-sectional and follow-up study of young women taking oral contraceptive agents revealed a marked increase in serum copper levels. This increase was significant after the taking of oral contraceptive agents for 3 months. No significant effect of oral contraceptive agents on serum zinc and hair levels or copper were observed. There was no correlation between duration of oral contraceptive agent therapy and zinc or copper concentrations in serum or hair. Serum and hair concentration of zinc or copper were also not significantly correlated.

PIP: It is well known that OC (oral contraception) may provoke changes in metal metabolism. This study examines the effects of OC use in serum and hair level of both zinc and copper. The study involved a control group of 24 women, aged 18-20, who had never been on OC; a cross-sectional experimental group of 33 women, aged 18-23, who had been using combined OC for at least 3 months; a follow-up experimental group of 12 women, aged 18-22, who were about to start OC treatment for the first time, and who were examined again at 3 and at 6 months. Blood samples and hair samples were collected and analyzed with the Vir and Love method. Mean serum copper concentration was significantly higher in OC users; hair copper values were also higher, but the difference was not a significant one. Mean serum zinc levels were slightly lower, and hair zinc levels slightly higher in OC users; differences between users and nonusers, however, were not significant. No significant correlation was found between duration of OC treatment and serum and hair metal values. In the follow-up experimental group mean serum copper level increased at 3 months of OC treatment, and mean hair copper values decreased; there were no significant differences at 3 and at 6 months. Mean serum zinc concentration and mean hair zinc concentration also decreased in the control group, but the decline was not significant. No significant correlation was found between serum and hair concentration of zinc or copper in the control or in the experimental group. These findings are consistent with others reported in the published literature. The biological significance of the rise in serum copper levels, and of the slight alteration in serum zinc level after OC use is still not known.

Effects of oral contraceptive agents on copper and zinc balance in young women.

Young adult women were selected from a group of volunteers on the basis of present and past use of oral contraceptive agents. Subjects were either those who had never used oral contraceptives or those who had used an agent for a minimum of two menstrual cycles. All subjects were fed diets that provided 2.02 to 2.11 mg of copper and 9.15 to 9.10 mg of zinc daily in an 18-day controlled metabolic study. Both oral contraceptive users and nonusers were in negative zinc balance and zinc excretion as not different (P > 0.05) for the groups. Oral contraceptives did not alter (P > 0.05) the metabolic balance of copper; the mean copper retention values were -0.16 mg/day for the nonusers and -0.13 mg/day for the users of oral contraceptives. As anticipated from reports in the literature, the plasma copper levels were higher (P < 0.01) in the oral contraceptive group, but the levels of zinc were not different. Although blood levels of zinc and copper are usually changed with the use of oral contraceptives, the retention of the two nutrients appears not to be affected.

PIP: Young adult women were selected from a group of volunteers on the basis of present and past use of (OCs) oral contraceptives. Subjects were either those who had never used OCs or those who had used an agent for a minimum of 2 menstrual cycles. All subjects were fed diets which provided 2.02-2.11 mg of copper and 9.15-9.10 mg of zinc daily in an 18-day controlled metabolic study. Both OC users and nonusers were in negative zinc balance and zinc excretion was not different (P 0.05) for the groups. OCs did not alter the metabolic balance of copper (P 0.05); the mean copper retention values were -0.16 mg/day for the nonusers and -0.13 mg/day for OC users. As anticipated from reports in the literature, the plasma copper levels were higher (P 0.01) in the OC group, but the levels of zinc were not different. Although blood levels of zinc and copper are usually changed with the use of OCs, the retention of the 2 nutrients appears not to be affected.

Absorption of stable isotopes of iron, copper, and zinc during oral contraceptives use.

The absorption of iron, copper, and zinc was determined in 22 women 19 to 25 years of age from the difference between intake and fecal output of the stable isotopes 58Fe, 65Cu, and 70Zn, as measured by neutron activation analysis. Of the 22 women, 14 were using oral contraceptive agents, and the other eight were not. Absorption in the group using oral contraceptive agents did not differ significantly from the group not using oral contraceptive agents. The overall iron absorption averaged 14%, copper 57%, and zinc 38%.

PIP: Absorption of iron, copper, and zinc was determined in 22 women (19-25 years old) from the difference between intake (regulated by testers) and fecal output of the stable isotopes Fe-58, Cu-65, and Zn-70, as measured by neutron activation analysis. Of the 22, 14 were using oral contraceptives (OCs) (1 sequential and the rest combined), and 8 were not. Absorption values did not differ significantly between the OC users and the nonusers. These data suggest that stable isotopes of elements offer promise as a means of measuring mineral absorption without the undesirable aspects of feeding radioactive materials to humans. Disadvantages include difficulty obtaining hardward, expense of radioactive isotopes, and requirement for additional radiochemical separations for zinc, and possibly other minerals.

Influence of mineral intake and use of oral contraceptives before pregnancy on the mineral content of human colostrum and of more mature milk.

PIP: The effects of mineral intake and long-term oral contraceptive use before pregnancy on the mineral content of milk of healthy lactating women were evaluated in a study of 52 volunteers ages 18-31. Subjects reporting previous oral contraceptive use had significantly lower levels of copper in serum, perhaps reflecting reduced copper stores resulting from prolonged estrogen exposure, but concomitant changes in copper levels in their milk were not noted. Serum calcium and magnesium levels were not significantly affected by prior pill use. Pill use had no significant effect on concentrations of calcium, magnesium, zinc, copper, or iron in colostrum at day 3 or more mature milk at day 14 of lactation, while mean manganese levels were significantly lower at both times for previous oral contraceptive users (but still exceeded manganese levels recommended for infants). Mineral and vitamin supplementation significantly improved the levels of zinc and iron intake, but did not appreciably alter the mineral content of milk. Higher levels of zinc were found in colostrum compared to day 14 milk, while manganese concentrations increased significantly during the 1st 2 weeks of lactation. Calcium, magnesium, iron and copper levels did not change significantly as lactation progressed. Levels of calcium, magnesium, zinc, copper, and manganese in colostrum were significantly positively correlated with the mineral concentration on day 14. No significant diurnal or daily variation was observed in the levels of calcium, magnesium, or zinc content in milk during 2 24-hour periods.^ieng

Interactions between growth and nutrient status in school-age children of urban Bangladesh.

The relationship between biochemical, anthropometric, and sociodemographic indexes was investigated in 242 children aged 5-12 y from five schools in Dhaka City, Bangladesh. As height-for-age increased so too did the mean serum concentrations of hemoglobin, protein, vitamin A, and zinc; serum copper concentrations were highest in the shortest group. Serum copper concentrations were highest in those with the lowest serum vitamin A concentrations. By multiple regression analysis, family income, age, weight-for-age, hemoglobin, and serum copper were strongly related to serum vitamin A. For every unit change in serum vitamin A there was a 4.92 unit change in hemoglobin, when all the other factors were taken into account. This study shows that there is a complex interaction between concentrations of biochemical indexes of nutritional status and other anthropometric, biochemical, and sociodemographic variables.

PIP: Between February and March 1990, health workers interviewed and took anthropometric measurements and blood samples from 242 children 5-12 years old, attending 3 primary schools in affluent areas and 2 primary schools in poorer areas around a university campus in Dhaka, Bangladesh. Researchers wanted to study the interaction between anthropometric and biochemical measures of nutritional status in seemingly healthy school children. As the height-for-age increased, so did the mean serum levels of protein, hemoglobin, and vitamin A (p = 0.001 for protein and 0.01 for hemoglobin and vitamin A). The rising trends were strongest for hemoglobin and vitamin A. Children in the group with the highest serum vitamin A level ( 1.05 mcmol/L) had significantly higher hemoglobin levels than did those with lower vitamin A levels (adjusted, 138.9 g/L vs. 133.8 g/L for 0.7-1.07 mcmol/L and 132.8 g/L for 0.7 mcmol/L; p = 0.002). For every unit change in vitamin A, a 4.92 unit change in hemoglobin existed. Children who had the lowest serum vitamin A levels had the highest serum copper levels (22.8 mcmol/L vs. 22.3 mcmol/L middle vitamin A group and 19.8 mcmol/L highest vitamin A group; p = 0.05). Multiple regression analysis showed that family income, age, weight-for-age, and hemoglobin and serum copper levels were significantly associated with serum vitamin A levels. These findings reveal that short children who were light for their age had lower serum vitamin A and hemoglobin levels and higher serum copper levels than their taller and heavier counterparts. They demonstrate a complex interaction between serum levels of biochemical indexes of nutritional status and other anthropometric, biochemical, and sociodemographic variables.

Oral contraceptives and ascorbic acid.

Plasma, leukocyte, and platelet ascorbic acid levels are decreased in women ingesting oral contraceptive steroids. Studies have shown that it is the estrogenic component of the oral contraceptive agents that is associated with the decresased ascorbic acid concentrations. Urinary excretion of ascorbic acid does not appear to be increased by the steroids. Although serum levels of copper are increased by estrogens and oral contraceptives, ascorbic acid catabolism does not appear to be increased (unpublished). Our preliminary data on tissue uptake of ascorbic acid suggest that changes in tissue distribution are one possible answer for the observed effects of the steroids on blood levels of ascorbic acid.

PIP: Plasma, leukocyte and platelet ascorbic acid levels have been shown to decrease in in women using oral contraceptives (OC). Supplemental ascorbic acid therapy ranging from 50-200 mg/day showed no difference between the values for supplemented and nonsupplemented OC use. Measurement of plasma ascorbic acid after supplementation with 500 mg ascorbic acid/day for 14 days showed that adequate supplementation to reach tissue saturation and maximum fasting plasma levels occurred in control subjects but not in OC users. Other studies indicated that when women were maintained for 75 days on high ascorbic acid intake, the plasma levels in OC users were lower than in controls. Studies in humans and animals suggest that the estrogen in OCs cause decreased plasma and tissue levels of ascorbic acid. Women taking oral progestin (.35 mg daily norethisterone) and depot progestin (150 mg medroxyprogesterone acetate im every 3 months) had similar leukocyte plasma and platelet levels of ascorbic acid to controls. 625 mg daily of conjugated estrogens showed lower plasma and leukocyte levels than controls. Whereas increase of urinary excretion of ascorbic acid during OC therapy has not been shown, an increase in serum copper levels has been shown under OC use and estrogen influence. It is suggested that an increased catabolism of ascorbic acid accounts for the decreased plasma and tissue levels in humans and animals with estrogen or OC steroids. Other unconfirmed or disputed suggestions include decreased absorption, changes in tissue distribution and decreased levels of reducing compounds. Tissue uptake patterns in steroid-treated animals appear altered suggesting that changes in tissue distribution may be associated with observed changes in ascorbic acid blood levels in OC users.

Elevations in serum copper, erythrocytic copper, and ceruloplasmin concentrations in smokers.

Previous investigators have reported significant elevations of serum copper and ceruloplasmin levels in lymphoma patients and subjects using estrogen, but have not taken into account the smoking habits of these populations. In order to determine whether smoking had any effect on these variables, the authors examined five groups for serum and erythrocytic copper and ceruloplasmin levels: 40 healthy subjects, 14 users of oral contraceptives, 25 smokers, 14 nonsmoking pretreatment lymphoma patients, and eight treated lymphoma patients. Significant elevations of serum copper and ceruloplasmin in pretreatment lymphoma patients, treated patients, and estrogen users were found, confirming previous reports. In addition, all groups had elevations of erythrocytic copper compared with the healthy subjects. Also, significant elevations of serum copper (P less than .0053) and ceruloplasmin (P less than .0001) were found in smoking relative to nonsmoking subjects. No correlation between duration of smoking and these elevations was found.

PIP: Levels of serum and erythrocytic copper and ceruloplasmin are compared among groups of smoking and nonsmoking individuals, some of whom have taken oral contraceptives 97 subjects were studied. 40 were healthy subjects who were nonsmokers, and 4 users of oral contraceptives, 25 smokers, and 4 nonsmoking pretreatment lymphoma patients, and 8 patients under treatment for lymphoma were also studied. There were elevations of serum copper and ceruloplasmin activity for all 5 groups. By Student's t test, there were elevations of serum copper, erythrocytic copper, and ceruloplasmin in all 4 groups compared with healthy nonsmoking subjects at least at the P.01 level,; it was P.05 for erythrocytic copper smokers. Significant correlations of linear relationship between serum copper and ceruloplasmin were noted for all populations except smokers. No correlation was apparent between duration of smoking, or frequency of usage and elevations of serum copper, erythrocytic copper, or ceruloplasmin.

Zinc and copper concentrations in leucocytes and erythrocytes in healthy adults and the effect of oral contraceptives.

The content of zinc and copper of whole blood, plasma, erythrocytes and white cells, has been measured in normal controls. The concentrations of zinc and copper in leucocytes are about seven and ten times respectively higher than those in erythrocytes. Women taking oral contraceptives showed significant increases in the concentrations of copper in plasma and whole blood but not in leucocytes or erythrocytes. Oral contraceptives did not alter the concentration of zinc in any of the fractions or in whole blood. These data provide a baseline for the assessment of the body status of zinc and copper in various disease states in which deficiencies may be present.

PIP: The content of zinc and copper of whole blood, plasma, erythrocytes, and white cells has been measured in normal controls. The concentrations of zinc and copper in leucocytes are about 7 and 10 times respectively higher than those in erythrocytes. Women taking oral contraceptives (OCs) showed significant increases in the concentrations of plasma in copper and whole blood but not in leucocytes or erythrocytes. OCs did not alter the concentration of zinc in any of the fractions or in whole blood. These data provide a baseline for the assessment of the body status of zinc and copper in various disease states in which deficiencies may be present.

Oral contraceptives and serum copper concentration.

PIP: Serum copper concentrations were determined by atomic absorption spectroscopy in 502 women (average age 23.8 years) using oral steroid contraceptives. Mean serum copper level in these women increased substantially (primarily during second or third cycle of treatment), corresponding to levels obtained during the second trimester of pregnancy. An average of 207 g/100 ml was found compared to an average of 129 g/100 ml in normal non-contracepting women. 6.5% of the cases experienced an increase in serum copper beyond the normal range, indicating possible liver dysfunction. Following cessation of oral contraceptives, serum copper level returned to the normal range within 4-6 weeks. The composition and type (combined or sequential) of steroid pills, and duration of treatment made no difference in serum copper levels. Knowledge of serum copper levels may help in selecting suitable subjects for oral contraceptive preparations and deciding when to cease medication in order to prevent early hepatic damage.^ieng

Serum copper in long-term users of copper intrauterine devices.

A study was undertaken to determine whether long-term use of a copper intrauterine device (IUD) was associated with any alteration in the serum copper levels and thereby whether absorption of copper from the device in utero could result in copper toxicity. Serial estimations in copper IUD wearers showed that there was no alteration in serum copper levels for a period of up to 24 months. The mean range and frequency distribution of serum copper levels in long-term copper IUD wearers was similar to that seen in the normal population. There was no difference in the mean 24-hour urinary copper excretion between the control group and the copper IUD wearers. Data suggest that the copper released from a copper IUD may not be readily absorbed from the uterine fluid. This hypothesis needs verification.

PIP: This study was performed to determine whether long-term use of copper IUDs was associated with any alteration in serum copper levels in users. These studies had both cross-sectional and longitudinal components, with the cross-sectional aspect covering 148 controls and 202 women who used either the Lippes loop (n=95) or the copper T 200 (n=107) for 6-48 months. The longitudinal aspect was carried out in 7 women not using any form of contraception and in 17 women who had had a copper IUD inserted; serial copper levels in serum were measured every 3 months for 24 months. The aim was to ascertain any danger of copper toxicity with copper-medicated IUD use. Serial estimations in copper IUD wearers showed that there was no alteration in serum copper levels for up to 24 months. The mean range and frequency distribution of serum copper levels in long-term copper IUD wearers were similar to those seen in the normal (control) population. In addition, there was no difference in the mean 24-hour urinary copper excretion between the control group and copper IUD users. The results verified the first hypothesis of the researchers, that copper released from a copper IUD is not readily absorbed.

The effect of intrauterine devices containing zinc and copper on their levels in serum.

Serum levels of copper and zinc were determined in 11 health women in whom Latex Leaf intrauterine devices (IUDs) containing copper and zinc had been inserted. Patients with low levels of serum copper or zinc before insertion usually had increased levels of either of these metals while using the device, but they did not exceed the upper limits of normal values. When the group was considered as a whole, the serum levels of zinc showed a slight tendency to increase with duration of IUD use, whereas there was no statistical difference between the serum levels of copper before and after insertion of the IUD.

PIP: Serum levels of copper and zinc were measured in 111 healthy women in whom Latex Leaf IUDs containing copper and zinc had been inserted. The women ranged from 21 to 41 years of age. Months of use ranged from 1 to 23 with an average of 14.6. The 1st blood sample was obtained before insertion and the 2nd from 1 to 19 months after insertion. Mean level of serum copper in the 1st sample was 1.42 mcg/ml. Age and parity had no effect; a slight tendency for higher levels was observed only in multigravidas. There were no significant changes in mean copper levels even when the levels were correlated with duration of usage. Mean serum zinc level before insertion was 1.1 mcg/ml with no correlation to age, gravidity, or parity. The 2nd sample showed a slight increase, 109% + or -3.25% standard error p .005. This increase correlated with the time the device was in situ. In general, patients with low levels of serum copper or zinc before insertion usually had increased levels after use but these levels did not exceed the upper limits of normal values. This may be due to an initially low level of the copper fraction bound to serum albumin and indicates the existence of some equilibrium between free and bound metal in the system.

Serum copper and zinc in hormonal contraceptive users.

There has been a growing awareness of possible alterations in the trace element profiles of hormonal contraceptive users and their consequences. A study of serum copper and zinc levels in users of combined estrogen-progestogen contraceptives and in users of injectable progestogen was undertaken. Use of combined estrogen-progestogen contraceptives resulted in a significant decrease in serum zinc levels within 3 days and an increase in serum copper levels within 10 days. In users of combined estrogen-progestogen contraceptives the magnitude and time of occurrence of the decrease in zinc levels and the increase in copper levels was unaltered by chemical composition, dosage, route of administration, and duration of use beyond 3 months. With injectable progestogen (norethindrone enanthate, 20 mg/month), a significant decrease in serum zinc levels occurred within 24 hours after injection. Serum copper levels were not altered. With injectable progestogen, the type of drug, the dosage, and the duration of use beyond the 1st month had no effect on the magnitude of the decrease in serum zinc levels.

PIP: Changes in serum copper and zinc levels were evaluated in Indian (India) women classified as undernourished who use various forms of hormonal contraception, including combination formulations of 30 and 50 mcg ethinylestradiol; injectable combined dihydroprogesterone acetophenide and estradiol enanthate; intravaginal rings of combined d-norgestrel and estradiol; and progestin-only injectable formulations. Serum zinc levels decreased within 3 days and serum copper increased within 10 days in women using combination estrogen/progesterone contraceptives. These alterations were not affected by route of administration, dose levels, chemical composition of the 2 components, or duration of use beyond 3 months. Women using the progestin-only injectable formulation containing norethindrone enanthate (20 mg/month) showed a significant decrease in serum zinc levels within 24 hours of injection. Serum copper levels in progestin-only injectable users were unaltered, however. Again, the type of progestin injected, the dosage, and the duration of use beyond the first month had no effect on the magnitude of the decrease in serum zinc levels.

A progressive rise in serum copper levels in women taking oral contraceptives: a potential hazard?

PIP: 123 healthy Jewish women (18-22 years) were divided into OC (oral contraceptives) users (n=75), and controls (n=48). All women were on a similar diet. The OC users were divided into 3 groups (1, 2 and 3) based on the OC preparations they were taking. Venous blood samples were collected; serum copper levels were measured using atomic absorption spectrophotometry (Parker et al.'s method). Serum copper levels did not correlate with time of menstrual cycle for each group, and for all groups considered together. Mean serum copper level in the control group, 120 ug/100 ml +/- 15 SD (standard deviation), was significantly lower than the serum copper level of all contraceptive groups considered together. Of the 3 groups, group 3 (those taking Neogynon) showed a steady and progressive rise in serum copper level. The mechanism of action of the rise of serum copper and ceruplasmin levels following OC intake is not clear. Hypercupremia may be due to excessive absorption of copper by the intestines, to a shift of copper from tissue to blood compartment, or to both. Chronic copper intoxication could result from hypercupremia associated with chronic OC use. Studies of Wilson's disease show that severe damage could result from excessive copper deposition in various tissues. Further research should be done to determine the potential hazards of chronic copper intoxication, particularly in patients taking Neogynon.^ieng

Effect of oral contraceptive agents on vitamin and mineral requirements.

Oral contraceptive agents alter the metabolism of some nutrients, which could affect nutritional requirements. The effects of oral contraceptives on pyridoxine, folacin, thiamin, riboflavin, vitamin A, ascorbic acid, zinc, and copper as determined by studies done in the last five years are reviewed. Evidence for actual nutritional deficiencies due to the use of oral contraceptives is still insufficient, and more research is needed. Supplements are advised only for those women in whom other factors, such as disease, impair nutritional adequacy.

PIP: Metabolic changes caused by oral contraceptives (OCs) in terms of the vitamins pyridoxine, folacin, thiamin, riboflavin, ascorbic acid, and A and the minerals zinc and copper are discussed. Pyroxidine in the form of coenzyme pyridoxal phosphate is involved in conversion of tryptophan to niacin, and tryptophan load tests have shown that certain metabolites of B6 have increased secretion when OCs are used. Folic acid deficiency has been found in some OC users. As with pyroxidine and folacin, OC users may require supplementation of thiamin as well. When riboflavin deficiency is preexistent, OCs exacerbate the condition (this effect may be race-dependent). Vitamin A, in contrast to the B vitamins, increases in the plasma of women taking OCs, perhaps due to greater mobilization of the vitamin by the liver. OC users generally show significantly lower leukocyte and platelet levels of ascorbic acid, and supplementation may be necessary. Zinc levels generally decrease, whereas copper levels in serum significantly increase in association with OC use. At present, supplements of vitamins and minerals are recommended only for high-risk groups.

Effect of oral contraceptive progestins on serum copper concentration.

OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

PIP: High serum copper concentration--a well-known effect of oral contraceptive (OC) use--has been linked to increased mortality from cardiovascular disease. The influence of OCs containing newer progestins has not been investigated, however. This concern was addressed in a 1987-88 cross-sectional epidemiologic study of 610 nonpregnant, nonlactating West German women 18-44 years of age. 195 women (32.1%) were current OC users, but only 152 of these women were able to cite the name of the formulation they were taking. In 70% of cases, the OC contained less than 45 mcg of ethylestradiol (median dose, 32.4 mcg). The most common progestin components were desogestrel (41%) and levonorgestrel (30%). Mean serum copper concentration was higher among users of all types of OCs than among non-users, but this concentration varied more strongly according to the OC's progestin compound than its estrogen content. The greatest increase in serum copper (55% compared with non-users) was recorded in users of OCs containing anti-androgen progestins, followed by desogestrel (46%), norethisterone/lynestrenol (42%), and levonorgestrel (34%). The increase in serum copper was more pronounced in women taking OCs containing 45 mcg or less of ethylestradiol than in users of OCs with a high estrogen dose. In the regression models, the different progestin compounds alone explained 28% of the total variance in serum copper concentration. Further investigation of OC-induced increases in serum copper concentration and their impact on cardiovascular risk are warranted.

Effect of family size and income on the biochemical indices of urban school children of Bangladesh.

The relationship between family size and income and the biochemical indices of 242 children (aged from 5 to 12 years) from five schools in Dhaka City, Bangladesh, was investigated. Socio-economic data were collected by questionnaire and blood samples were drawn by visiting each school on a prefixed date. Mean levels of all measures, except for serum zinc, fell within the normal range. Older boys, but not girls (10-12 years of age) had statistically significantly higher haemoglobin, serum protein and serum vitamin A levels compared with those of the younger boys (5-9 years of age). The children were divided into three family size groups (small, up to 4 members; medium, 5-7 members; and large, 8 or more) to investigate the effect of family size on the biochemical data. The children from smaller families showed significantly higher levels of haemoglobin and serum vitamin A compared with the children from large families. For serum protein, copper and zinc, there was no statistically significant difference between the children of different family size groups. To analyse the effect of family income, children were divided into three income groups (low, up to taka 2000; medium, taka 2001-4500; and high, 4501 or more). The children from the low family income group had significantly lower serum protein (7.5 g/100 ml) and haemoglobin (13.4 g/100 ml) levels compared with those of the children from the high family income group (for protein, 7.7 g/100 ml and haemoglobin, 14.1 g/100 ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrites and L-citrulline levels in copper intrauterine device users.

The mechanism of copper in limiting intrauterine infections in intrauterine device (Cu IUD) users is poorly understood. Copper ions may enhance the release of reactive oxygen radicals, which in turn decrease the release of reactive nitrogen intermediates (RNI). RNI are known to have bactericidal effect. The present study compares the levels of RNI prior to Cu-T insertion and at different post-insertion intervals up to 12 weeks. The decrease in RNI was evident by one week and continued until 12 weeks. Therefore, the bactericidal effect of copper in IUD is via reactive oxygen intermediates. The superoxide anion inactivates this active intermediate nitric oxide. Therefore, excess of superoxide radical will markedly shorten the half-life of nitric oxide but will not prevent its conversion to nitrites and nitrates.

PIP: Copper ions may enhance the release of reactive oxygen radicals that decrease the release of reactive nitrogen intermediates (RNIs), known to have a bactericidal effect. The capability of the Copper-T IUD to generate RNIs was investigated in women seeking IUD insertion at a family planning clinic in Chandigarh, India. A significant decrease in nitric oxide levels was recorded from pre-insertion to 1 week post-insertion. Moreover, the values at 4 weeks' post-insertion were significantly lower than those at 1 week, and the 12 weeks' post-insertion level was lower than that recorded at 4 weeks. Uterine aspirate L-citrulline levels at 1 week post-insertion were significantly lower than pre-insertion levels; again, values at 4 and 12 weeks post-insertion were significantly less than those of the receding levels. There was no significant difference in levels of nitrites or serum L-citrulline before and after IUD insertion. Although the exact mechanism of the decrease in RNI levels at the local site after IUD insertion is unknown, it appears related to the sterile intrauterine milieu. At the peak of copper release, the inflammatory cells are activated to release reactive oxygen radicals. Copper potentiates the effect of superoxide dismutase, which influences the half-life of nitric oxide, but does not prevent its conversion to nitrites and nitrates.