Oral contraceptives and ascorbic acid

Transcription

1 Oral contraceptives and ascorbic Jen y M. Rivers,2 Ph.D. ABSTRACF Plasma, heukocyte, and platelet ascorbic 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 decreased ascorbic concentrations. Urinary excretion of ascorbic does not appear to be increased by the steroids. Although serum levels of copper are increased by estrogens and oral contraceptives, ascorbic catabolism does not appear to be increased (unpublished). Our preliminary data on tissue uptake of ascorbic suggest that changes in tissue distribution are one possible answer for the observed effects of the steroids on blood levels of ascorbic. Am. J. Clin. Nutr. 28: , Most of the reported studies are in agreement that ascorbic levels are reduced in plasma, leukocytes and platelets of women ingesting oral contraceptive agents (OCA), either sequentially or in combination (Table 1). McLeroy and Schendel (1) studied 126 women, 6 controls and 6 who had taken oral contraceptives for at least 1 year. The two groups were matched on the basis of age and body weight. The mean ascorbic intake, as calculated from -day dietary intake records, was 86 ± 5 mg and 8 ± 8 mg for the experimental and control groups, respectively. The group taking OCA had significantly lower leukocyte ascorbic levels than controls. Briggs and Briggs (2) studied 1 untreated control women and 9 who were taking steroid contraceptives. The ascorbic concentration in both leukocytes and platelets was significantly lower in women taking the oral contraceptives than in controls. The groups were matched on the basis of age but their estimated dietary intake of ascorbic was not reported. In another study reported by Briggs and Briggs (), mean ascorbic levels in leukocytes and plasma were lower in 1 9 women taking the OCA than in 16 untreated controls. Rivers and Devine () studied plasma levels in women taking OCA and 2 controls over two and one-half menstrual cycles. The women were ingesting 150 mg of ascorbic daily and were given 00 mg of ascorbic on the days that blood samples were drawn. Plasma levels in the control subjects showed a cyclic pattern, being highest at the time of ovulation. This cyclic pattern was not observed in the subjects ingesting oral contraceptives. The mean plasma level for all phases of the cycle was also less than in control subjects (Table 1). The difference between plasma total ascorbic and reduced ascorbic was similar for both groups. This suggests that if dehydroascorbic is increased by oral contraceptives, it is taken up rapidly by tissues. Kalesh et al. (5) reported comparable plasma and platelet ascorbic values for OCA and non-oca users, prior to initiating a depletion study (Table 1). The sample size in this study was small which may account for the difference between their results and that of others (1 -) who have studied subjects whose intake of ascorbic was not controlled. Briggs and Briggs also measured leukocyte and platelet ascorbic levels in women before and after 1-2 months of treatment with oral contraceptives (2). A summary of the results (Table 2) shows that short-term treatment with OCA was associated with decreased levels of ascorbic. Kalesh et al. (5) studied depletion of reduced ascorbic in platelets and plasma of women instructed to adhere to a diet containing mg of ascorbic. An initial blood sample was obtained and the women were given 0 mg of ascorbic daily for 1 week prior to the -week depletion period. After weeks of depletion, women taking OCA had plasma and platelet levels similar to controls (Table ). The From the Division of Nutritional Sciences, Cornell University, Ithaca, New York 185. Professor. 550 The American Journal of Clinical Nutrition 28: MAY 1975, pp Printed in U.S.A.

2 ORAL CONTRACEPTIVES AND ASCORBIC ACID 551 TABLE 1 Relationship between ingestion of oral contraceptive agents and ascorbic concentrations in heukocytes, plasma and platelets OCA N N Ref Leukocyte ascorbic mg/0 g ± ± 6.6 (1) ALg/l08 cells 1 9 ± ± 22 (2) g/l0e cells 16 5 ± ± 16 () Platelet ascorbic mg/g wet weight Plasma ascorbic mg/loomh 16 2 TABLE 2 Leukocyte and platelet ascorbic before and after treatment with oral contraceptive agents Group Subj, N Ascor bic Leukocyte, Platelet, ig/8 cells mg/g tissue pre post pre post OCA (Ref 2) ± ± ± ± authors attribute significance to the lower platelet values found after 1 and 2 weeks of depletion in the oral contraceptive users but this appears questionable due to the small sample size, and the variability that occurs in leukocyte values in the same subject from 1 week to the next when subjected to a low ascorbic intake (6). Whether or not ascorbic supplementation can restore blood levels of the vitamin in OCA users to control levels is less well documented (Table ). In the study by McLeroy and Schendel (1) some women were taking ascorbic supplements ranging from mg/day. subjects taking a supplement had higher leukocyte levels than nonsupplemented, but no difference was found between the values for supplemented and ± ± ± ± (2) (5) () (5) () nonsupplemented oral contraceptive users. Briggs and Briggs () measured plasma ascorbic before and after supplementation with 500 mg ascorbic /day for 1 days. Since the mean plasma level (0. mg/loo ml) in OCA users before supplementation was above that indicative of any significant leukocyte depletion, the supplementation should have been adequate to reach tissue saturation and maximum fasting plasma levels. This appeared to be true in control subjects but not in OCA users. Studies in our laboratory () showed that when women were maintained for 75 days on high intakes of ascorbic, the plasma levels in OCA users were lower than in controls. The increase in plasma total ascorbic and ascorbic hours after ingesting 00 mg oral doses of the vitamin (Table 5) was less in OCA users than in controls. The data, although scant, suggest that supplementation with ascorbic will increase plasma and leukocyte levels of the vitamin but not to the same extent as in control subjects. It appears that the quantity of dietary ascorbic required to maintain a certain plasma, leukocyte, or platelet ascorbic level in women on oral contraceptive steroids may be greater than in control subjects. Both human and animal studies suggest that it is the estrogenic component in the OCA that causes decreased plasma and tissue levels of ascorbic. Briggs and Briggs (2, ) studied

3 552 RIVERS TABLE Ascorbic depletion of plasma and platelets in women taking oral contraceptive agents and ingesting an estimated mg ascorbic /day Depletion Initial 1 Weeks 2 Plasma 0.8 ± ± ± ± 0.1 mg/l00 ml OCA 0.92 ± ± ± ± 0.1 Platelets.9 ± ± ± ± 6.8 mg/bog OCA.7± ± ± ±.07 (Ref 5). TABLE Effect of vitamin C supplementation OCA N j N ± SD Ref Leukocyte ascorbic, mg/0 g Supplemented#{176} ± b9. ± 6.1 (1) Not supplemented ± ± 7.0 (1) Plasma ascorbic, mg/0 ml Before supplement ± ± 0.0 () After supphement 1.6 ± ± 0. 1 () a mg/day. b soo mg/day per 1 days. TABLE 5 Increase in plasma ascorbic and total ascorbic after 00 mg dose Total ascorbic Ascorbic mg/0 ml OCA (Ref ). ascorbic levels in women using oral and depot progestins and also in postmenopausal women receiving estrogen therapy. A summary of these results is given in Table 6. Women taking the oral progestin (05 mg daily norethisterone) and depot progestin (1 50 mg medroxyprogesterone acetate i.m. every months) had leukocyte, plasma and platelet levels of ascorbic similar to the controls. Women taking 625 mg daily of conjugated estrogens had lower plasma and leukocyte levels than controls. Clemetson (7) measured reduced ascorbic in liver, adrenal, spleen, and plasma of guinea pigs injected intramuscularly with 0.5 mg of estradiol valerate weekly for 6 weeks (Table 7). He observed lower levels in tissues of the estrogen injected animals except for the spleen. In additional work from the same laboratory (8), guinea pigs injected with 50 pg daily of ethinyl estradiol--methyl ether (mestranol) for 2 weeks (except in one experiment injection was not given during weekends) showed decreased concentrations of reduced ascorbic in adrenal gland, plasma and blood vessels (Table 8). The reason for the observed depression of plasma and blood cell ascorbic in OCA users is not known. However, it does not appear to be due to increased urinary excretion of ascorbic (). Measurements of urinary ascorbic following ingestion of 00 mg of ascorbic in subjects maintained on high intakes revealed no differences between control and experimental subjects (Table 9). The report of decreased urinary excretion of reduced ascorbic in women taking oral contraceptives (9) is questionable, since ascorbic was determined in 0-00 ml of urine by the 2,6-dichiorophenolindophenol method. Because of the relatively high concentration of reducing compounds in urine, values obtained by this method are usually higher than values for total ascorbic as determined by the 2,-dinitrophenylhydrazine method. The data were expressed as concentration which is not valid since there is not a linear relationship between urine volume and the amount of ascorbic excreted. If urinary excretion of ascorbic is contributing to the decreased plasma and tissue levels of ascorbic in women using oral contraceptives, changes in urinary excretion should be evident during a normal menstrual

4 ORAL CONTRACEPTIVES AND ASCORBIC ACID 55 TABLE 6 Effect of progestin and estrogen on leukocyte, platelet and plasma ascorbic levels Oral progestagen Depot progestagen Estrogen therapy Ref Leukocytes,sg/8 cells 5± 12 6± 11 8± 17 20± 9 () Plasma, mg/0 ml 0.9 ± ± ± ± 0.2 () Platelets, mg/g wet weight 0.26 ± ± 0.1 (2) TABLE 7 Reduced ascorbic in plasma and tissues of guinea pigs following estradiol valerate injections Liver, mg/0 g Adrenal, mg/bog Spleen,mg/lOOg Plasma, mg/0 ml (Ref 7). Estrogen N N 1.5 ± ± ± TABLE 8 Reduced ascorbic in plasma and tissues of guinea pigs following ethinyl estradiol--methyl ether injections Adrenal,mg/lOOg Plasma,mg/lOOml Bloodvessel,mg/lOOg Mestranoh 19.9 ±. 17. ± ± N Mean N Mean l 2.17 b L.51 (Ref 8). a Values obtained by calculation of the published results. b Number of pooled samples. TABLE 9 Urinary excretion of ascorbic following a 00-mg dose Total asc orbic mg/ hours mg/2 hours OCA (Ref ). cycle. The available information is contradictory. Some workers have reported a sharp decrease in urinary excretion at the time of ovulation (), others a sharp increase (1 1), and still others have reported no significant changes (, 12). Serum levels of copper have been shown to increase in women ingesting oral contraceptives (7, 8, 1) and under estrogen influence (8, 1, 1 5). Ceruloplasmin has ascorbic oxidase activity (1 6) and several investigators (1 -, 5, 8) have suggested that an increased catabolism of ascorbic may account for the decreased plasma and tissue levels in humans and animals treated with estrogen or oral contraceptive steroids. Other suggestions include decreased absorption (1), changes in tissue distribution (1, ), and decreased levels of reducing compounds such as reduced glutathione (8). Presently, none of these suggestions have been confirmed or disputed. We are currently studying the catabolism and tissue uptake of ascorbic in rats and guinea pigs given ethynylestradiol, norgestrel, a mixture of ethynylestradiol and norgestrel, and progesterone. The preliminary data suggest that the steroids have no effect on the rate of ascorbic breakdown. Recovery of 1 C from C-L-1-ascorbic in carbon dioxide, urine and feces in the steroid-treated animals was similar to controls. Tissue uptake patterns do appear to be altered by the steroids which suggests that the observed changes in blood levels of ascorbic in oral contraceptive users may be due to changes in tissue distribution. References 1. McLEROY, V. J., AND H. E. SCHENDEL. Influence of oral contraceptives on ascorbic concentrations in healthy, sexually mature women. Am. J. Chin. Nuts. 26: 191, BRIGGS, M., AND M. BRIGGS. Vitamin C requirements and oral contraceptives. Nature 28: 277, BRIGGS, M., AND M. BRIGGS. Vitamin C and colds. Lancet b : 998, RIVERS, J. M., AND M. M. DEVINE. Plasma

5 55 RIVERS ascorbic concentrations and oral contraceptives. Am. J. Chin. Nuts. 25: 68, KALESH, D. G., V. R. MALLIKARJUNESWARA AND C. A. B. CLEMETSON. Effect of estrogen containing oral contraceptives on platelet and plasma ascorbic concentrations. Contraception : 18, RIVERS, J. M., E. D. HUANG AND M. L. DODDS. Human metabolism of L-ascorbic and erythorbic. J. Nutr. 81: 16, CLEMETSON, C. A. B. Ceruloplasmin and green plasma. Lancet 2: 7, SAROJA, N., V. R. MALLIKARJUNESWARA AND C. A. B. CLEMETSON. The effect of estrogens on ascorbic in the plasma and blood vessels of guinea pigs. Contraception : 269, HARRIS, A. B., J. HARTLEY AND A. MOOR. Reduced ascorbic- excretion and oral contraceptives. Lancet 2: 201, PAESCHKE, K. D., AND H. W. VASTERLING. Photometrischer Askorbinsaueretest zur Bestimmung der Ovulation, Verglichen mit andren Methoden der Ovulations-terminbestimmung. Zentr. Gynaekol. 2: 817, LOH, H. S., AND C. W. M. WILSON. Relationship of human ascorbic- metabolism to ovulation. Lancet 1: 1, HAUCK, H. H. Plasma levels and urinary excretion of ascorbic in women during the menstrual cycle. J. Nutr. : 51 1, ELGEE, N. J. Medical aspects of oral contraceptives. Ann. Intern. Med. 72: 09, VON STUDNITZ, W., AND D. BEREZIN. Studies on serum copper during pregnancy, the menstrual cycle, and after administration of estrogens. Acts Endocrinol. 27: 25, RUSS, E. M., AND J. RAYMUNT. Influence of estrogens on total copper and ceruhoplasmin. Proc. Soc. Expth. Biol. 92: 65, OSAKI, S., J. A. McDERMOTT AND E. FRIEDEN. Proof for the ascorbate oxidase activity of ceruloplasmin. J. Bioh. Chem. 29: 570, 196.