Oral contraceptives ULF
LARSSON-COHN,
Link6ping,
and vitamins: A review
M.D.
Sweden
The literature is reviewed.
concerning the infiuence of estrogen-containing oral The appearance of an elevated plasma concentration
contraceptives of vitamin
on vitamins A is probably
without clinical importance, while there seems to be a clear connection between disturbances of vitamin B, metabolism and mental symptoms. Low levels of folic acid and vitamin B,, have also been noted. Despite this, it is very rare that hematologic abnormalities develop during hormonal contraception. A reduced concentration of vitamin C in plasma and blood corpuscles
has
been
reported.
The
clinical
significance
of these
A
Gal and associate? first reported that combination-type oral conceptives were associated with a significant increase of the plasma level of vitamin A. At Days 3 to 5 of the menstrual cycle, the mean concentration per 100 ml. of plasma was 40 pg in a control group and 91 pg in the users of the contraceptives. At cycle Days 18 to 21, the corresponding values were 50 and 77 pg, respectively. None of the subjects had values approaching toxic levels (300 pg per 100 ml.) . Based on the fact that very high From the Department Gynecology, University Received
for
publication
Relvised
May
1, 1974.
Accepted Reprint Department University
May
of Obstetrics Hospital. February
is unknown.
doses of vitamin A given to pregnant laboratory animals may induce fetal malformations,2 the authors were somewhat worried that in women conceiving immediately after discontinuing oral contraceptive treatment even a moderate increase could have a possible adverse effect on reproduction. Briggs and colleagues” have verified that combination-type oral conceptives may elevate the level of vitamin A (the mean plasma concentrations of 88 control and 48 treated subjects were 38 and 73 pg per 100 ml., respectively), while medroxyprogesterone acetate* had the opposite effect. Vitamin A exists in plasma mainly bound to beta lipoproteins. As this lipid fraction is raised during treatment with estrogen-containing oral contraceptives+ B it was believed that the increased plasma level of vitamin A was secondary to alterations of the plasma lipids. It was estimated that the increase was about equal to what would be obtained by a daily oral dose of 900 pg, e.g., roughly what is considered to be the normal daily requirement. This was compared to the fact that ‘during pregnancy it is common to give 3,000 pg or more per day. Despite this, no report linking such treatment with fetal abnormalities has appeared. The authors concluded that they did not see any support for the suggestion that the increase in the plasma concentration of vitamin A would constitute a possible teratogenic hazard.
IN RECENT YEARS, a number of articles have been published describing alterations of vitamin status in users of estrogen-containing oral contraceptives. A great number of commercially available oral contraceptives have been employed in the various studies. In most reports, the results obtained from subjects using different brands of oral contraceptives were pooled, making it impossible to determine whether any specific oral contraceptive was more prone to induce biochemical changes than any of the others. The estrogenic component of the drugs was between 0.05 and 0.15 mg. of ethinyl estradiol or mestranol. This paper is a review of some of the more important articles covering this topic.
Vitamin
alterations
and
Vitamin B, (pyridoxinel The relationship between oral contraceptives and vitamin B,, metabolism has received a certain
7, 1974.
6, 1974.
requests: Dr. Ulf Larsson-Cohn, of Obstetrics Hospital, 581
and Gynecology, 85 LinkBping, Sweden.
*Depo-Provera, The Upjohn Kalamazoo, Michigan 49001. 84
Co.,
7171
Portage
Rd.,
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amount of attention in recent years. The reasons are that there seems to be a clear link between disturbances in some pyridoxine-dependent enzyme systems and symptoms of mental depression and that large doses of the vitamin have been reported to be able to more or less normalize the situation. Low availability of pyridoxine induces deficiency of pyridoxine phosphate which is part of several coenzymes needed for the tryptophan-nicotinic acid cycle. Tryptophan is an amino acid which, besides its importance for the synthesis of proteins, also is needed for production of nicotinic acid in the body. This is shown by the fact that symptoms similar to those of pellagra may appear in some inborn errors of metabolism concerning the trytophan-nicotinic acid cycle. Some steps in this cycle are particularly sensitive to lack of pyridoxine phosphate.” If a sufficient amount of vitamin B,; is not available, all tryptophan that has entered the metabolic cycle cannot proceed to nicotinic acid but will be excreted in the urine as easily detected intermediary metabolites. Therefore a functional deficiency of vitamin B,; is usually diagnosed by an oral tryptophan load.’ In 1966, Rose” reported that after a tryptophan load women receiving combination-type oral contraceptives showed increased urinary excretion of xanthuric acid which is one of the metabolites that may be measured when this load test is employed. Later there was a series of papers confirming that this type of contraceptive drugs may induce a functional vitamin B,; deficiency.“, !‘-*’ It has also been shown that it is possible to demonstrate abnormal metabolites in the urine even without a tryptophan load.” A review concerning trytophan metabolism in health and disease was recently published.” It seems to be the estrogenic component of combined oral contraceptives that induces the changes’” while synthetic testosterone-derived progestins may have the opposite effect.“, I’; According to one report,‘? ethynodiol diacetate and lynestrenol are more anti-estro,genic in this respect than norethindrone. It is noteworthy that steroidal and nonsteroidal estrogens seem to have a similar effect on tryptophan metabolism.” The physiologic mechanism causing these changes is not clearly understood; probably several factors are of importance. In the liver of the intact rat, estrogens and pregnancy increase the activity of tryptophan oxygenase, while activity is reduced but
Oral
contraceptives
and
vitamins
85
not completely inhibited in adrenalectomized animals, suggesting that the effect is largely mediated through the adrenals. lb: Because of this enzyme induction, increased amounts of tryptophan are shunted into the tryptophan-nicotinic acid cycle, raising the requirements for pyridoxine phosphate to such a level that available pyridoxine will be insufficient. It has been shown that women treated with estrogens may have an increased activity of glutamic oxalacetic transaminase in the erythrocytes,13, Iv and animal studies have demonstrated raised activity of liver glutamic pyruvic transaminase18, 2o and tryosine aminotransferase.20 These observations suggest that accelerated synthesis of pyridoxine phosphate-dependent enzymes other than tryptophan oxygenase may accelerate the pyridoxine deficiency. It is also possible that estrogenic metabolites may compete with pyridoxine phosphate for binding sites at the protein part of some apoenzymes of importance for the metabolic cycle.?’ Tryptophan is a precursor of serotonin. Mentally depressed patients may have reduced concentrations of serotonir? and tryptophar? in the cerebrospinal fluid. It has also been reported that some depressed individuals who committed suicide had a low concentration of serotonin in the brain.*’ These observations support the theory that a low level of brain serotonin may induce depression.“” Tryptophan potentiates the antidepressive effect of monoaminooxidase inhibitors”‘-“!’ and is also antidepressive by itself.“~ “‘I It is the only amino acid which is partly bound to plasma proteins and only free tryptophan can pass into the brain. While the total concentration of tryptophan was equal in control subjects and in patients with depression, the level of free tryptophan was significantly lower in the depressed subjects.‘” Most clinically effective antirheumatic drugs such as aspirin and indomethacin raise the concentration of free tryptophan in vitro.“2 This effect is not seen after administration of drugs without anti-inflammatory potency.‘:’ The percentage of free tryptophan in plasma of patients treated with antirheumatic drugs has been reported to be significantly higher than in control subjects.“’ It is known that both lithium and salicylic acid increase the level of tryptophan in the braina and that treatment with antirheumatic drugs may have a beneficial effect on mental depression.:“’ Aylward and Maddock”: recently reported that patients treated with such drugs
86
Larsson-Cohn
had elevated free tryptophan in the plasma and that there was a positive correlation between the concentration of free tryptophan, the improvement of rheumatic symptoms, and the “depressive scores” of the patients. It is evident that all these observations support the theory that the brain concentration of tryptophan is of importance in the development of depression. There are several possible ways for raised activity in the tryptophan-nicotinic acid cycle to affect the production of serotonin. The most obvious explanation is that the increased rate of metabolism induces a lack of tryptophan and/or pyridoxine, both essential for the synthesis of serotonin. It could also be that some of the tryptophan metabolites appearing during pyridoxine deficiency may reduce the transport of tryptophan over the blood-brain barrier.“” Although some authors have been unable to find any significant difference in the frequency of mental symptoms between oral contraceptive users and control subjects,3”t 40 many studies indicate that there is an elevated frequency of depression during hormonal contraception.41-4” Baumblatt and Winston44 found that large doses of tryptophan had a beneficial effect on depressive patients receiving oral contraceptives. Adams and co-workerP investigated tryptophan metabolism in 22 depressed oral contraceptive users in whom there was believed to be a connection between the contraceptive treatment and the mental symptoms. The vitamin B, status was determined before the medication and after 2 and 4 months of a double-blind crossover trial with a placebo or pyridoxine, 40 mg. daily. After 2 months, there was a crossover from placebo to pyridoxine and vice versa. The participants completed a Black self-rating depression questionnaire every second week. Before the onset of treatment, 18 of the women had abnormal excretion of tryptophan metabolites, although only 11 of them were considered to have an absolute pyridoxine deficiency. All subjects with a diagnosis of absolute pyridoxine deficiency had improvement in the symptoms of depression following treatment with the high doses of the vitamin (the normal daily requirement is considered to be 2 mg.), while those with a relative or no lack of pyridoxine did not respond to the treatment. The placebo had no effect. There did not seem to be any correlation between duration of treatment and degree of pyridoxine deficiency. However, in an earlier investigation from the same
January 1. 1973 .4m J. Obstrt. Gynecnl
laboratory, it was reported that women who had used oral contraceptives for 6 months had a higher excretion of abnormal tryptophan metabolites than those who had received the tablets for 3 months only.“6 The progestogen component of the pill does not seem to be of importance for the development of depression. This assumption was supported by Rose and AdamP who found that a mini-pill, with 0.5 mg. of megestrol acetate, did not affect tryptophan metabolism and by Wolf and associates17 who reported that 5 mg. daily of norethindrone given to male subjects for up to 19 weeks did not affect tryptophan metabolism. It seems likely that treatment with progestogens alone does not affect the metabolism of vitamin B,. In a series of studies summarized by Kotake and Murakami,47 it has been shown that xanthuric acid has a tendency for binding to insulin. In the dog and the rabbit, this xanthuric acid-insulin complex had a hypoglycemic effect that was about half as strong as that of an equivalent amount of insulin. Spellacy and colleagueP who administered 100 mg. of pyridoxine daily for one month to 12 users of combined oral contraceptives who had shown a progressive deterioration of oral glucose tolerance found that the vitamin medication significantly improved the carbohydrate tolerance. However, it should be pointed out that 8 of the 12 women still showed abnormal carbohydrate tolerance. Despite this, it may be that vitamin B, deficiency could be of some importance in the appearance of reduced carbohydrate tolerance during combined oral contraceptive treatment. Luhby and co-workersl” tried to determine the amount of pyridoxine that should be given to oral contraceptive consumers with signs of abnormal tryptophan metabolism in order to correct the situation. They found that 2 mg. daily, e.g., the normal daily requirement, was sufficient in only 1 of 10 subjects while 20 mg. restored normal metabolism in 7 of 8 women. From these data, it was concluded that 25 mg. should be a sufficient dose. However, in order to be on the safe side, a daily dose of 30 mg. was recommended. As pointed out by Adams and associates,4” however, there may be potential risks by administering high doses of this vitamin. Women ingesting combined oral contraceptives have low levels of some amino acids,lgg 49* 5o probably as a result of a catabolic effect of elevated aminotransferase activity. This could be caused by raised glucocorticoid action
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induced by the estrogen treatment. It is possible that this undesired effect could be accelerated by high doses of vitamin B,. The mechanism for this effect could be as follows: By definition, a coenzyme activates a latent apoenzyme. However, it has been shown in both the rat51 and man13 that a coenzyme, when existing in abundance, may accelerate the synthesis of the apoenzyme itself. A raised breakdown of amino acids must probably be considered as a negative side effect, especially in regions with low protein intake. Therefore, it is yet not established if women using combined oral contraceptives should routinely be given vitamin B,, and it is evident that there is still much research to be done in this field. The problem is particularly relevant in discussions about the effects of oral contraceptives in undernourished or malnourished women. Folic
acid
and
vitamin
B,z
Low levels of folic acid are not uncommon in pregnancy. Some possible reasons that have been suggested are parasitization by the fetus,“2l 53 reduced folate absorption,52 and/or altered folate metabo1ism.54’ 55 A low concentration of folic acid has been found during treatment with combined and there have been a few oral contraceptives,56-58 reports of megaloblastic anemia during this type of contraceptive medication.5g-61 On the other hand, several authors62-66 have not been able to find any significant changes in folate metabolism during hormonal contraceptive treatment. Shojania and associates57 reported that oral contraceptive users had a parallel lowering of the folic acid content of the erythrocytes and an increase of the urinary excretion of formimino-glutamic acid simultaneously with the reduction of the plasma level of folic acid. The investigation was performed in Winnipeg, Ontario, Canada, an area which is characterized by very long, cold winters and very short summers with the consequence that consumption of vegetables and fruit is small. Therefore, it was assumed that many subjects had a low folic acid intake which would partly explain why the results were at variance with those of some previous reports. Folic acid appears in the food mainly as a polyglutamate which is believed to be metabolized to a monoglutamate by a folate conjugase in the jejunal mucosa.G7 The postabsorptive folic acid concentration in women receiving oral contraceptives was considerably lower after ingestion of a polyglutamate
contraceptives
and
vitamins
87
than when a monoglutamate was given.60t ‘* The difference was believed to be caused by the hormonal steroids which reduced the activity of the folate conjugase. Stephans and colleaguesGg found that the plasma folic acid concentrations of women receiving oral contraceptives did not differ from those of control subjects. However, they observed that the oral contraceptive users showed a lower mean rise of folic acid after an oral loading with pteroylpolyglutamate than the control subjects. When the women were saturated with polyglutamate before the load test, no difference was found. The oral contraceptive treatment did not inhibit the folate conjugase activity in human or guinea pig jejunal mucosa in vitro. It was speculated that the lower postabsorptive concentration of folic acid after polyglutamate could have been because of an increased plasma clearance of absorbed folate. Briggs and Briggs, 70 from Zambia, have reported that combined oral contraceptives (but not DepoProvera) reduced the plasma concentration of vitaThe vitamin levels of European control min B,,. subjects were significantly higher than those observed in African control subjects or European women receiving oral contraceptives, while the latter group showed plasma concentrations that were about equal to those of African control subjects. Many of the African women receiving oral contraceptives were considered to have dangerously low serum vitamin B,, levels. It is likely that the differences among races were caused by variations in the nutritional standards. In a recent study, Wertalik and co-workers”’ measured the concentrations of vitamin B,, and folic acid in one control group, one group of pregnant women receiving iron tablets combined with folic acid and cyanocobalamin, and one group of women using combined oral contraceptives. The mean vitamin B,, concentrations of the pregnant women and of the oral contraceptive users were significantly lower than those of the control group. Fifty per cent of the women receiving the contraceptives had subnormal serum values (below 200 ppg per milliliter), and in 3 subjects the concentration was under 100 ppg per milliliter, which was considered to indicate a clear deficiency of the vitamin. Four women provided blood samples before treatment and after 2 to 5 months of oral contraceptive medication. All of them showed a reduction of the vitamin B,, level; despite the very limited material, the
88
Larsson-Cohn
difference was significant at the 0.1 per cent level. The folate levels in this group did not change during this period. A previous observation’l of a raised serum unsaturated B12 binding capacity could not be confirmed, and the vitamin B,, concentration in the erythrocytes was within the normal range. The mean hematocrit value and the neutrophil lobe average did not differ among the three groups. The plasma folic acid concentrations of the total group of contraceptive users were significantly lower than those of the control group (p < 0.01) ; in 6 cases (30 per cent), the concentrations were below the range of normal for the laboratory. Four of these subjects also had subnormal vitamin B,, concentrations. It is difficult to explain the mechanism behind these seemingly contradictory observations. As there were no signs of anemia, no evident alteration of the binding capacity of the serum, and normal vitamin B,, levels in the erythrocytes, the authors believed that the oral contraceptive in some way increased the tissue avidity for vitamin Br?, resulting in a redistribution of the vitamin. It is interesting that in a recent study’” a very slight but statistically significant difference was observed between a number of “red blood cell parameters” (hemoglobin, hematocrit, red blood cell count, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration) of 1,100 oral contraceptive users and 1,600 control subjects. The alterations were considered to be consistent with a folic acid and vitamin B,, deficiency, and the differences were most obvious in women who had used the pill for more than 5 years. The socioeconomic status of the subjects was high. It is possible that if changes of the hematologic values become evident during oral contraceptive treatment there must usually exist some additional factor, e.g., malnutrition or intercurrent disease, or that very large groups of subjects must be studied. This also agrees with the cited investigation from where low plasma folic acid concentraWinnipeg,“s tions were found in women supposed to have a low folic acid intake. Well-controlled studies of the effects of the oral contraceptive treatment on the folic acid/vitamin B12 status of populations with inadequate nutritional standards would be of great interest. Vitamin
C (ascorbic
acid)
That the ascorbic acid concentration is higher than in menT3 suggests that
in women female sex
hormones may be of importance for the blood level of this vitamin. Studies of the plasma vitamin C variation during the menstrual cycle have been conflicting.7” The number of reports on the effects of combined oral contraceptives on ascorbic acid concentrations is very limited. In one study concerning 2 control subjects and 4 women receiving combined oral contraceptives, the latter, in general, showed the lowest plasma levels of the vitamin, and there seemed to be a certain tendency for the concentration to be inversely related to the duration of treatment.74 The control women had the highest level at midcycle, e.g., during the period of raised estrogen production, while those receiving oral contraceptives tended to show the maximum level during the weeks they were off the “pill.” Oral load tests indicated that the tablets did not cause increased urinary excretion of the vitamin. In fact, Harris and co-workers7” recently showed that women using combined oral contraceptives excreted about half as much ascorbic acid in the urine as did control subjects. In a short communication, Briggs and Briggs7” have reported that the vitamin C concentration in leukocytes and thrombocytes was lower in users of combined oral contraceptives than in control subjects, in pregnant women, and in women treated intramuscularly with Depo-Provera. The same authorsi later compared the plasma and leukocyte levels of ascorbic acid in one control group, one unspecified group of geriatric patients, and one group of postmenopausal women treated with conjugated estrogens, with the same parameters in women using combined oral contraceptives, mini-pills, or Depo-Provera. The geriatric patients and the subjects treated with estrogens, e.g., postclimacteric women and those using combined oral contraceptives, had lower concentrations than those found in the other groups. After administration of ascorbic acid, 5 mg. daily for 2 weeks, this difference disappeared. It was believed that the estrogens increased the rate of metabolism of the vitamin. A similar conclusion was drawn by Harris and colleagues.‘” Kalesh and co-workers.7X who determined the levels of vitamin C in plasma and thrombocytes in control subjects and in women using combined oral contraceptives, reported that after 2 weeks of low vitamin C intake the concentrations were lower in the contraceptive users. It was speculated that a reduced vitamin C level may alter the electrical potential of the thrombocytes which could contribute to the development of thromboembolic disease. HOW-
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ever, the interpretation of the results was somewhat complicated by the fact that the difference between the 2 groups disappeared after another week of reduced ascorbic acid intake. Estrogens elevate plasma ceruloplasmin.7s As this copper-containing protein has ascorbic acid-oxidase C activity,sOv R1 it is possible that the low vitamin concentration may be secondary to increased ceruloplasmin activity. While Rivers and Devine74 found plasma levels that were well within normal limits, Briggs and Briggs76 reported that many women using combined oral contraceptives develop low levels of vitamin C. They speculated that some of the side effects during contraceptive treatment could be caused by such a deficiency. However, no scientific proof for this hypothesis seems to have been published. Conclusions Based on the data presented in this review, the following conclusions may be drawn. 1. Women using combined oral contraceptives tend to have raised plasma concentrations of vitamin A. Available evidence indicates that this increase is not harmful. 2. Disturbance of the vitamin B, metabolism is not uncommon during treatment with estrogen-containing oral contraceptives. There are strong indica-
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and
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tions that in some cases this can induce mental depression and that administration of large doses of the vitamin may normalize the situation. 3. In one report, an oral contraceptive-induced low level of vitamin B, has been linked to the occurrence of reduced carbohydrate tolerance, However, the evidence hitherto presented is insufficient to permit any conclusion to be drawn from this observation. 4. The plasma concentration of vitamin B,, and/or folic acid may be reduced during prolonged treatment with estrogen-containing oral contraceptives. Although, in general, these changes seem to be without clinical significance, it cannot be excluded that hematologic alterations may appear in some subjects with low nutritional standards. 5. Treatment with combined oral contraceptives may reduce the concentration of vitamin C in plasma, leukocytes, and thrombocytes. The significance of these observations is unknown. 6. As it seems that the estrogenic component of combined oral contraceptives induces the biochemical alterations which have been described in this review, it may be that a more widespread use of estrogen-free mini-pills or the new brands of contraceptives with an estrogen content of only 0.02 to 0.03 mg. may be beneficial in this respect.
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56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.
72. 73. 74. 75. 76. 77. 78. 79. 80. 81.
Luhby, A. L., Shim& N., Davis, P., and Cooperman, J. M.: Fed. Proc. 30: 239 1971. Shojania, A. M., Hornady, G. J., and Barnes, P. Ii.: AM. J. OBSTET. GYNECOL. 111: 782, 1971. Wertalik, L. F., Metz, E. N., LoBuglio, A. F., and Balcerzak, S. P.: J. A. M. A. 221: 1371, 1972. Paton, A.: Lancet 1: 418, 1969. Streiff, R. R.: J. A. M. A. 214: 40, 1970. Flury, R., and Angehrn, W.: Schweiz. Med. Wochenschr. 102: 1628, 1972. Spray, G. H. : Lancet 2: 110, 1968. McLean, F. H., Heine, M. W., Held, B., and Streiff, R. R.: AM. J. OBSTET. GYNECOL. 104: 745, 1969. Maniego-Bautista, L. P., and Bazzano, G.: J. Lab. Clin. Med. 74: 988, 1969. Cast&, 0. M., and Rossi, R. R.: J. Obstet. Gynaecol. Br. Commonw. 77: 548, 1970. Pritchard, J. A.. Scott, D. F., and Whalley, P. J.: AM. J. OBSTET. GYNECOL. 109: 341, 1971. Bernstein, L. A., Gutstein, S., Weiner, S., and Efron, F.: Am. J. Med. 48: 570, 1970. Necheles, T. F., and Snyder, L. M.: N. Engl. J. Med. 282: 858, 1970. Stephans, M. E. M., Craft, I., Peters, T. J., and Hoffbrand, A. V. : Clin. Sci. 42: 405, 1972. Briggs, M., and Briggs, M.: Lancet 2: 1037, 1972. Bianchine, J. R., Bonnlander, B., Macaraeg, P. V. J., Hersey, R., Bianchine, J. W., and McIntyre, P. A.: J. Clin. Endocrinol. Metab. 29: 1425, 1969. Fisch. I. R.. and Freedman. S. H.: Clin. Pharmac-l Ther. 14: 245, 1973. Dodds, M. I~.: J. Am. Diet. Assoc. 54: 32, 1969. Rivers, J. M., and Devine, M. M.: Am. J. Clin. Nutr. 25: 684. 1972. Harris, A. B., Hartley, J., and Moor, A.: Lancet 2: 201, 1973. Briggs, M., and Briggs, M.: Nature 238: 277, 1972. Briggs, M., and Briggs, M.: Lancet 1: 998, 1973. Kalesh, A. G., Mallikarjuneswara, U. R., and Clemetson, C. A. B.: Contraception 4: 183, 1971. Schenker, J. G., Jungreis, E., and Polishuk, W. Z.: Int. J. Fertil. 17: 28, 1972. Holmberg, C. G., and Laurel], C. B.: Acta Chem. Stand. 2: 550, 1948. Osaki, S., McDermott, J. A., and Frieden, E.: J. Biof. Chem. 239: 3570, 1964. ,“a.
LARSSON-COHN,
Link6ping,
and vitamins: A review
M.D.
Sweden
The literature is reviewed.
concerning the infiuence of estrogen-containing oral The appearance of an elevated plasma concentration
contraceptives of vitamin
on vitamins A is probably
without clinical importance, while there seems to be a clear connection between disturbances of vitamin B, metabolism and mental symptoms. Low levels of folic acid and vitamin B,, have also been noted. Despite this, it is very rare that hematologic abnormalities develop during hormonal contraception. A reduced concentration of vitamin C in plasma and blood corpuscles
has
been
reported.
The
clinical
significance
of these
A
Gal and associate? first reported that combination-type oral conceptives were associated with a significant increase of the plasma level of vitamin A. At Days 3 to 5 of the menstrual cycle, the mean concentration per 100 ml. of plasma was 40 pg in a control group and 91 pg in the users of the contraceptives. At cycle Days 18 to 21, the corresponding values were 50 and 77 pg, respectively. None of the subjects had values approaching toxic levels (300 pg per 100 ml.) . Based on the fact that very high From the Department Gynecology, University Received
for
publication
Relvised
May
1, 1974.
Accepted Reprint Department University
May
of Obstetrics Hospital. February
is unknown.
doses of vitamin A given to pregnant laboratory animals may induce fetal malformations,2 the authors were somewhat worried that in women conceiving immediately after discontinuing oral contraceptive treatment even a moderate increase could have a possible adverse effect on reproduction. Briggs and colleagues” have verified that combination-type oral conceptives may elevate the level of vitamin A (the mean plasma concentrations of 88 control and 48 treated subjects were 38 and 73 pg per 100 ml., respectively), while medroxyprogesterone acetate* had the opposite effect. Vitamin A exists in plasma mainly bound to beta lipoproteins. As this lipid fraction is raised during treatment with estrogen-containing oral contraceptives+ B it was believed that the increased plasma level of vitamin A was secondary to alterations of the plasma lipids. It was estimated that the increase was about equal to what would be obtained by a daily oral dose of 900 pg, e.g., roughly what is considered to be the normal daily requirement. This was compared to the fact that ‘during pregnancy it is common to give 3,000 pg or more per day. Despite this, no report linking such treatment with fetal abnormalities has appeared. The authors concluded that they did not see any support for the suggestion that the increase in the plasma concentration of vitamin A would constitute a possible teratogenic hazard.
IN RECENT YEARS, a number of articles have been published describing alterations of vitamin status in users of estrogen-containing oral contraceptives. A great number of commercially available oral contraceptives have been employed in the various studies. In most reports, the results obtained from subjects using different brands of oral contraceptives were pooled, making it impossible to determine whether any specific oral contraceptive was more prone to induce biochemical changes than any of the others. The estrogenic component of the drugs was between 0.05 and 0.15 mg. of ethinyl estradiol or mestranol. This paper is a review of some of the more important articles covering this topic.
Vitamin
alterations
and
Vitamin B, (pyridoxinel The relationship between oral contraceptives and vitamin B,, metabolism has received a certain
7, 1974.
6, 1974.
requests: Dr. Ulf Larsson-Cohn, of Obstetrics Hospital, 581
and Gynecology, 85 LinkBping, Sweden.
*Depo-Provera, The Upjohn Kalamazoo, Michigan 49001. 84
Co.,
7171
Portage
Rd.,
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121 1
amount of attention in recent years. The reasons are that there seems to be a clear link between disturbances in some pyridoxine-dependent enzyme systems and symptoms of mental depression and that large doses of the vitamin have been reported to be able to more or less normalize the situation. Low availability of pyridoxine induces deficiency of pyridoxine phosphate which is part of several coenzymes needed for the tryptophan-nicotinic acid cycle. Tryptophan is an amino acid which, besides its importance for the synthesis of proteins, also is needed for production of nicotinic acid in the body. This is shown by the fact that symptoms similar to those of pellagra may appear in some inborn errors of metabolism concerning the trytophan-nicotinic acid cycle. Some steps in this cycle are particularly sensitive to lack of pyridoxine phosphate.” If a sufficient amount of vitamin B,; is not available, all tryptophan that has entered the metabolic cycle cannot proceed to nicotinic acid but will be excreted in the urine as easily detected intermediary metabolites. Therefore a functional deficiency of vitamin B,; is usually diagnosed by an oral tryptophan load.’ In 1966, Rose” reported that after a tryptophan load women receiving combination-type oral contraceptives showed increased urinary excretion of xanthuric acid which is one of the metabolites that may be measured when this load test is employed. Later there was a series of papers confirming that this type of contraceptive drugs may induce a functional vitamin B,; deficiency.“, !‘-*’ It has also been shown that it is possible to demonstrate abnormal metabolites in the urine even without a tryptophan load.” A review concerning trytophan metabolism in health and disease was recently published.” It seems to be the estrogenic component of combined oral contraceptives that induces the changes’” while synthetic testosterone-derived progestins may have the opposite effect.“, I’; According to one report,‘? ethynodiol diacetate and lynestrenol are more anti-estro,genic in this respect than norethindrone. It is noteworthy that steroidal and nonsteroidal estrogens seem to have a similar effect on tryptophan metabolism.” The physiologic mechanism causing these changes is not clearly understood; probably several factors are of importance. In the liver of the intact rat, estrogens and pregnancy increase the activity of tryptophan oxygenase, while activity is reduced but
Oral
contraceptives
and
vitamins
85
not completely inhibited in adrenalectomized animals, suggesting that the effect is largely mediated through the adrenals. lb: Because of this enzyme induction, increased amounts of tryptophan are shunted into the tryptophan-nicotinic acid cycle, raising the requirements for pyridoxine phosphate to such a level that available pyridoxine will be insufficient. It has been shown that women treated with estrogens may have an increased activity of glutamic oxalacetic transaminase in the erythrocytes,13, Iv and animal studies have demonstrated raised activity of liver glutamic pyruvic transaminase18, 2o and tryosine aminotransferase.20 These observations suggest that accelerated synthesis of pyridoxine phosphate-dependent enzymes other than tryptophan oxygenase may accelerate the pyridoxine deficiency. It is also possible that estrogenic metabolites may compete with pyridoxine phosphate for binding sites at the protein part of some apoenzymes of importance for the metabolic cycle.?’ Tryptophan is a precursor of serotonin. Mentally depressed patients may have reduced concentrations of serotonir? and tryptophar? in the cerebrospinal fluid. It has also been reported that some depressed individuals who committed suicide had a low concentration of serotonin in the brain.*’ These observations support the theory that a low level of brain serotonin may induce depression.“” Tryptophan potentiates the antidepressive effect of monoaminooxidase inhibitors”‘-“!’ and is also antidepressive by itself.“~ “‘I It is the only amino acid which is partly bound to plasma proteins and only free tryptophan can pass into the brain. While the total concentration of tryptophan was equal in control subjects and in patients with depression, the level of free tryptophan was significantly lower in the depressed subjects.‘” Most clinically effective antirheumatic drugs such as aspirin and indomethacin raise the concentration of free tryptophan in vitro.“2 This effect is not seen after administration of drugs without anti-inflammatory potency.‘:’ The percentage of free tryptophan in plasma of patients treated with antirheumatic drugs has been reported to be significantly higher than in control subjects.“’ It is known that both lithium and salicylic acid increase the level of tryptophan in the braina and that treatment with antirheumatic drugs may have a beneficial effect on mental depression.:“’ Aylward and Maddock”: recently reported that patients treated with such drugs
86
Larsson-Cohn
had elevated free tryptophan in the plasma and that there was a positive correlation between the concentration of free tryptophan, the improvement of rheumatic symptoms, and the “depressive scores” of the patients. It is evident that all these observations support the theory that the brain concentration of tryptophan is of importance in the development of depression. There are several possible ways for raised activity in the tryptophan-nicotinic acid cycle to affect the production of serotonin. The most obvious explanation is that the increased rate of metabolism induces a lack of tryptophan and/or pyridoxine, both essential for the synthesis of serotonin. It could also be that some of the tryptophan metabolites appearing during pyridoxine deficiency may reduce the transport of tryptophan over the blood-brain barrier.“” Although some authors have been unable to find any significant difference in the frequency of mental symptoms between oral contraceptive users and control subjects,3”t 40 many studies indicate that there is an elevated frequency of depression during hormonal contraception.41-4” Baumblatt and Winston44 found that large doses of tryptophan had a beneficial effect on depressive patients receiving oral contraceptives. Adams and co-workerP investigated tryptophan metabolism in 22 depressed oral contraceptive users in whom there was believed to be a connection between the contraceptive treatment and the mental symptoms. The vitamin B, status was determined before the medication and after 2 and 4 months of a double-blind crossover trial with a placebo or pyridoxine, 40 mg. daily. After 2 months, there was a crossover from placebo to pyridoxine and vice versa. The participants completed a Black self-rating depression questionnaire every second week. Before the onset of treatment, 18 of the women had abnormal excretion of tryptophan metabolites, although only 11 of them were considered to have an absolute pyridoxine deficiency. All subjects with a diagnosis of absolute pyridoxine deficiency had improvement in the symptoms of depression following treatment with the high doses of the vitamin (the normal daily requirement is considered to be 2 mg.), while those with a relative or no lack of pyridoxine did not respond to the treatment. The placebo had no effect. There did not seem to be any correlation between duration of treatment and degree of pyridoxine deficiency. However, in an earlier investigation from the same
January 1. 1973 .4m J. Obstrt. Gynecnl
laboratory, it was reported that women who had used oral contraceptives for 6 months had a higher excretion of abnormal tryptophan metabolites than those who had received the tablets for 3 months only.“6 The progestogen component of the pill does not seem to be of importance for the development of depression. This assumption was supported by Rose and AdamP who found that a mini-pill, with 0.5 mg. of megestrol acetate, did not affect tryptophan metabolism and by Wolf and associates17 who reported that 5 mg. daily of norethindrone given to male subjects for up to 19 weeks did not affect tryptophan metabolism. It seems likely that treatment with progestogens alone does not affect the metabolism of vitamin B,. In a series of studies summarized by Kotake and Murakami,47 it has been shown that xanthuric acid has a tendency for binding to insulin. In the dog and the rabbit, this xanthuric acid-insulin complex had a hypoglycemic effect that was about half as strong as that of an equivalent amount of insulin. Spellacy and colleagueP who administered 100 mg. of pyridoxine daily for one month to 12 users of combined oral contraceptives who had shown a progressive deterioration of oral glucose tolerance found that the vitamin medication significantly improved the carbohydrate tolerance. However, it should be pointed out that 8 of the 12 women still showed abnormal carbohydrate tolerance. Despite this, it may be that vitamin B, deficiency could be of some importance in the appearance of reduced carbohydrate tolerance during combined oral contraceptive treatment. Luhby and co-workersl” tried to determine the amount of pyridoxine that should be given to oral contraceptive consumers with signs of abnormal tryptophan metabolism in order to correct the situation. They found that 2 mg. daily, e.g., the normal daily requirement, was sufficient in only 1 of 10 subjects while 20 mg. restored normal metabolism in 7 of 8 women. From these data, it was concluded that 25 mg. should be a sufficient dose. However, in order to be on the safe side, a daily dose of 30 mg. was recommended. As pointed out by Adams and associates,4” however, there may be potential risks by administering high doses of this vitamin. Women ingesting combined oral contraceptives have low levels of some amino acids,lgg 49* 5o probably as a result of a catabolic effect of elevated aminotransferase activity. This could be caused by raised glucocorticoid action
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induced by the estrogen treatment. It is possible that this undesired effect could be accelerated by high doses of vitamin B,. The mechanism for this effect could be as follows: By definition, a coenzyme activates a latent apoenzyme. However, it has been shown in both the rat51 and man13 that a coenzyme, when existing in abundance, may accelerate the synthesis of the apoenzyme itself. A raised breakdown of amino acids must probably be considered as a negative side effect, especially in regions with low protein intake. Therefore, it is yet not established if women using combined oral contraceptives should routinely be given vitamin B,, and it is evident that there is still much research to be done in this field. The problem is particularly relevant in discussions about the effects of oral contraceptives in undernourished or malnourished women. Folic
acid
and
vitamin
B,z
Low levels of folic acid are not uncommon in pregnancy. Some possible reasons that have been suggested are parasitization by the fetus,“2l 53 reduced folate absorption,52 and/or altered folate metabo1ism.54’ 55 A low concentration of folic acid has been found during treatment with combined and there have been a few oral contraceptives,56-58 reports of megaloblastic anemia during this type of contraceptive medication.5g-61 On the other hand, several authors62-66 have not been able to find any significant changes in folate metabolism during hormonal contraceptive treatment. Shojania and associates57 reported that oral contraceptive users had a parallel lowering of the folic acid content of the erythrocytes and an increase of the urinary excretion of formimino-glutamic acid simultaneously with the reduction of the plasma level of folic acid. The investigation was performed in Winnipeg, Ontario, Canada, an area which is characterized by very long, cold winters and very short summers with the consequence that consumption of vegetables and fruit is small. Therefore, it was assumed that many subjects had a low folic acid intake which would partly explain why the results were at variance with those of some previous reports. Folic acid appears in the food mainly as a polyglutamate which is believed to be metabolized to a monoglutamate by a folate conjugase in the jejunal mucosa.G7 The postabsorptive folic acid concentration in women receiving oral contraceptives was considerably lower after ingestion of a polyglutamate
contraceptives
and
vitamins
87
than when a monoglutamate was given.60t ‘* The difference was believed to be caused by the hormonal steroids which reduced the activity of the folate conjugase. Stephans and colleaguesGg found that the plasma folic acid concentrations of women receiving oral contraceptives did not differ from those of control subjects. However, they observed that the oral contraceptive users showed a lower mean rise of folic acid after an oral loading with pteroylpolyglutamate than the control subjects. When the women were saturated with polyglutamate before the load test, no difference was found. The oral contraceptive treatment did not inhibit the folate conjugase activity in human or guinea pig jejunal mucosa in vitro. It was speculated that the lower postabsorptive concentration of folic acid after polyglutamate could have been because of an increased plasma clearance of absorbed folate. Briggs and Briggs, 70 from Zambia, have reported that combined oral contraceptives (but not DepoProvera) reduced the plasma concentration of vitaThe vitamin levels of European control min B,,. subjects were significantly higher than those observed in African control subjects or European women receiving oral contraceptives, while the latter group showed plasma concentrations that were about equal to those of African control subjects. Many of the African women receiving oral contraceptives were considered to have dangerously low serum vitamin B,, levels. It is likely that the differences among races were caused by variations in the nutritional standards. In a recent study, Wertalik and co-workers”’ measured the concentrations of vitamin B,, and folic acid in one control group, one group of pregnant women receiving iron tablets combined with folic acid and cyanocobalamin, and one group of women using combined oral contraceptives. The mean vitamin B,, concentrations of the pregnant women and of the oral contraceptive users were significantly lower than those of the control group. Fifty per cent of the women receiving the contraceptives had subnormal serum values (below 200 ppg per milliliter), and in 3 subjects the concentration was under 100 ppg per milliliter, which was considered to indicate a clear deficiency of the vitamin. Four women provided blood samples before treatment and after 2 to 5 months of oral contraceptive medication. All of them showed a reduction of the vitamin B,, level; despite the very limited material, the
88
Larsson-Cohn
difference was significant at the 0.1 per cent level. The folate levels in this group did not change during this period. A previous observation’l of a raised serum unsaturated B12 binding capacity could not be confirmed, and the vitamin B,, concentration in the erythrocytes was within the normal range. The mean hematocrit value and the neutrophil lobe average did not differ among the three groups. The plasma folic acid concentrations of the total group of contraceptive users were significantly lower than those of the control group (p < 0.01) ; in 6 cases (30 per cent), the concentrations were below the range of normal for the laboratory. Four of these subjects also had subnormal vitamin B,, concentrations. It is difficult to explain the mechanism behind these seemingly contradictory observations. As there were no signs of anemia, no evident alteration of the binding capacity of the serum, and normal vitamin B,, levels in the erythrocytes, the authors believed that the oral contraceptive in some way increased the tissue avidity for vitamin Br?, resulting in a redistribution of the vitamin. It is interesting that in a recent study’” a very slight but statistically significant difference was observed between a number of “red blood cell parameters” (hemoglobin, hematocrit, red blood cell count, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration) of 1,100 oral contraceptive users and 1,600 control subjects. The alterations were considered to be consistent with a folic acid and vitamin B,, deficiency, and the differences were most obvious in women who had used the pill for more than 5 years. The socioeconomic status of the subjects was high. It is possible that if changes of the hematologic values become evident during oral contraceptive treatment there must usually exist some additional factor, e.g., malnutrition or intercurrent disease, or that very large groups of subjects must be studied. This also agrees with the cited investigation from where low plasma folic acid concentraWinnipeg,“s tions were found in women supposed to have a low folic acid intake. Well-controlled studies of the effects of the oral contraceptive treatment on the folic acid/vitamin B12 status of populations with inadequate nutritional standards would be of great interest. Vitamin
C (ascorbic
acid)
That the ascorbic acid concentration is higher than in menT3 suggests that
in women female sex
hormones may be of importance for the blood level of this vitamin. Studies of the plasma vitamin C variation during the menstrual cycle have been conflicting.7” The number of reports on the effects of combined oral contraceptives on ascorbic acid concentrations is very limited. In one study concerning 2 control subjects and 4 women receiving combined oral contraceptives, the latter, in general, showed the lowest plasma levels of the vitamin, and there seemed to be a certain tendency for the concentration to be inversely related to the duration of treatment.74 The control women had the highest level at midcycle, e.g., during the period of raised estrogen production, while those receiving oral contraceptives tended to show the maximum level during the weeks they were off the “pill.” Oral load tests indicated that the tablets did not cause increased urinary excretion of the vitamin. In fact, Harris and co-workers7” recently showed that women using combined oral contraceptives excreted about half as much ascorbic acid in the urine as did control subjects. In a short communication, Briggs and Briggs7” have reported that the vitamin C concentration in leukocytes and thrombocytes was lower in users of combined oral contraceptives than in control subjects, in pregnant women, and in women treated intramuscularly with Depo-Provera. The same authorsi later compared the plasma and leukocyte levels of ascorbic acid in one control group, one unspecified group of geriatric patients, and one group of postmenopausal women treated with conjugated estrogens, with the same parameters in women using combined oral contraceptives, mini-pills, or Depo-Provera. The geriatric patients and the subjects treated with estrogens, e.g., postclimacteric women and those using combined oral contraceptives, had lower concentrations than those found in the other groups. After administration of ascorbic acid, 5 mg. daily for 2 weeks, this difference disappeared. It was believed that the estrogens increased the rate of metabolism of the vitamin. A similar conclusion was drawn by Harris and colleagues.‘” Kalesh and co-workers.7X who determined the levels of vitamin C in plasma and thrombocytes in control subjects and in women using combined oral contraceptives, reported that after 2 weeks of low vitamin C intake the concentrations were lower in the contraceptive users. It was speculated that a reduced vitamin C level may alter the electrical potential of the thrombocytes which could contribute to the development of thromboembolic disease. HOW-
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Oral
ever, the interpretation of the results was somewhat complicated by the fact that the difference between the 2 groups disappeared after another week of reduced ascorbic acid intake. Estrogens elevate plasma ceruloplasmin.7s As this copper-containing protein has ascorbic acid-oxidase C activity,sOv R1 it is possible that the low vitamin concentration may be secondary to increased ceruloplasmin activity. While Rivers and Devine74 found plasma levels that were well within normal limits, Briggs and Briggs76 reported that many women using combined oral contraceptives develop low levels of vitamin C. They speculated that some of the side effects during contraceptive treatment could be caused by such a deficiency. However, no scientific proof for this hypothesis seems to have been published. Conclusions Based on the data presented in this review, the following conclusions may be drawn. 1. Women using combined oral contraceptives tend to have raised plasma concentrations of vitamin A. Available evidence indicates that this increase is not harmful. 2. Disturbance of the vitamin B, metabolism is not uncommon during treatment with estrogen-containing oral contraceptives. There are strong indica-
REFERENCES 1.
Gal, I., Parkinson,
2.
436, 1971. Moore, T.:
3.
In Sebrell, W. H., and Harris, R. S., editors: The Vitamins, New York, 1967, Academic Press. Inc.. D. 280. Brig&, M.; ‘B&&s, M., and Bennum, M.: Contraception
4. 5. 6. 7. a.
9. 10.
11. 12. 13.
C., and Craft, I.: Br. Med. J. 2:
6: 275.
Murphy, M., and Spiegel, H.: Am. J. Clin. Nutr. 24: 684, 1971. Price, S. A., Rose, D. P., and Toseland, P. A.: Am. J. Clin. Nutr. 25: 494, 1972. Rose, D. P., Adams, P. W., and Strong, R.: J. Obstet. Gynaecol. Br. Commonw. 80: 82, 1973. Rose, D. P., Strong, R., Folkard, J., and Adams, P. W.: Am. J. Clin. Nutr. 26: 48, 1973.
and
vitamins
89
tions that in some cases this can induce mental depression and that administration of large doses of the vitamin may normalize the situation. 3. In one report, an oral contraceptive-induced low level of vitamin B, has been linked to the occurrence of reduced carbohydrate tolerance, However, the evidence hitherto presented is insufficient to permit any conclusion to be drawn from this observation. 4. The plasma concentration of vitamin B,, and/or folic acid may be reduced during prolonged treatment with estrogen-containing oral contraceptives. Although, in general, these changes seem to be without clinical significance, it cannot be excluded that hematologic alterations may appear in some subjects with low nutritional standards. 5. Treatment with combined oral contraceptives may reduce the concentration of vitamin C in plasma, leukocytes, and thrombocytes. The significance of these observations is unknown. 6. As it seems that the estrogenic component of combined oral contraceptives induces the biochemical alterations which have been described in this review, it may be that a more widespread use of estrogen-free mini-pills or the new brands of contraceptives with an estrogen content of only 0.02 to 0.03 mg. may be beneficial in this respect.
14. 15. 16. 17. ia.
1972.
Aurell, M.; Cramer, K., and Rybo, G.: Lancet 1: 291, 1966. Rijssner, S., Larsson-Cohn, U., Carlsson, L. A., and Boberg, J.: Acta Med. &and. 190: 301, 1971. Rose, D. P., Strong, R., Adams, P. W., and Harding, P. E.: Clin. Sci. 42: 465, 1972. Greenberg, L. D., Bohr, D. M., McGrath, H., and Rinehart, J. F.: Arch. Biochem. 21: 237, 1949. Rose, D. P.: Clin. Chem. Acta 18: 221, 1966. Price, J. M., Thornton, M. J., and Mueller, L. M.: Am. 1. Clin. Nutr. 20: 452. 1967. Luhb;, A. L., Brin, M.1 Gordon, M., Davis, P.,
contraceptives
19. 20. 21. 22.
Rose, D. P.: J. Clin. Pathol. 25: 17, 1972. Rose, D. P., and Braidman, I. P.: Am. J. Clin. Nutr. 24: 673, 1971. McGinty, F., and Rose, D. P.: Life Sci. 8: 1193, 1969. Wolf, H., Brown, R. R., Price, J. M., and Madsen, P. 0.: J. Clin. Endocrinol. Metab. 31: 397, 1970. Braidman, I. P., and Rose, D. P.: Endocrinology 82: 1250, 1971. Aly, H. E., Donald, E. A., and Simpson, M. H. W.: Am. J. Clin. Nutr. 24: 297, 1971. Brin, M. : Am. J. Clin. Nutr. 24: 699, 1971. Mason, M., Ford, J., and Wu, H. L. C.: Ann. N. Y. Acad. Sci. 166: 170, 1969. Aschcroft, G. W., Crawford, T. B. B., Eccleston, D.,
Sharman, 23. 24. 25. 26.
D. F. MacDoughall,
E. J., Stanton,
J. B.,
and Binns, J. K. : Lancet 2: 1049, 1966. Coppen, A., Brooksbank, B. W. L., and Peet, M.: Lancet 1: 1393, 1972. Shaw, D. M., Cramps, F. E., and Eccleston, E.: Br. J. Psychiatry 113: 1407, 1967. Coppen, A. J.: J. Psychiatr. Res. 9: 163, 1972. Coppen, A., Shaw, D. M., and Farrell, J. P.: Lancet
1: 79, 1963. 27.
28. 29.
Pare, C. M. B.: Lancet 2: 527, 1963. Glassman, A. H., and Platman, S. R.: Res. 7: 63, 1970. Ayuso-Gutierrez, J. L., and Lopez-Ibor Int. Pharmacopsychiatry 6: 92, 1971.
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J. J.:
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