October 19721 NUTRITION RE V l E WS 2 2'9

The vitamin A concentration in the livers was extremely variable and several livers showed concentrations below 10 pg. per gram, the concentrations of folate and vitamin B, I were similarly extremely variable, and none of the vitamins-measured show any changes in concentration thst could be correlated with gestational age.

The rcsulta of this study of the growth and some aspects of chemical composi- tion of the fetus in this poorly nourished

group are in gencral accord with the observations on the nutritional status of the maternal population reported earlier by Venkatachalam (loc. cit.). They em- phasise the need for more ettention to the antenatal nutrition of these mothers if their-children who suMve are to achieve their full genctic potential. The low reserves of vitamins, especially vita- min A, are particularly vital in this respect because of the relationship be- tween this and resistance to infection.

ORAL CONTRACEPTIVE AGENTS AND VITAMINS

Many women using oml confmceptiw agenfs (OCA) show abnormal tryptophan metabolism. which i s corrected with high doses of pyridoxine. Estrogens can elewte frypfophan oxygenase activity in rats.

Folic acid rcsponsiue megaloblastic anemia may be a rare cucnt associaled wifh the we of OCA. Impaired absorption of diefaty polyglulamyl folic acid in women on OCA has been reporfed.

Oral contraceptive agents are among the most widely used of drugs. Until recently their use was confined to

. women of affluent countries or the well-todo women of developing coun- tries. With increasing emphasis on family planning programs in developing coun- tries, this trend is now changing and increasing numbers of poor and malnour- ished women are also using contraceptive pills.

Oral contraceptive agents have been associated with many clinical side effects of a trivial nature (nausea, vomiting, emotional changes, headaches, facial pig- mentation, and alopecia) 11s well (1s

serious complications like hypertension, thrombocmbolic phenomena, and din- b e t e s mellitus. Most of these complica- tions are also associated with pregnancy, suggesting thcir hormonal origin IR. E. tiodgcs, J. A m . Dickt. A m . 6'3, 212

The biochcmic-nl basis for thrsc! com- plications is not undrrstootl, t h o u ~ h

(1971)l.

several metabolic lesions due to use of ovarian hormones are known. Among these lesions are some that suggest a functional deficiency of vitamin B, and fo lk acid.

Elevated excretion of certain metabo- lites of tryptophan, such as xanthurenic acid and kynurenic acid, following tryptophan load has been observed in pregnant women as well as in women on OCA (Hodges, loc. cit.; D. P. Rose and 1. P. Braidmnn, Am. J. Clin. Nutrition 24, 673 (1971)]. These changes are charac- teristic of functional deficiency of vita- min B,, as manifested by lowered activity of the pyridoxnl phosphate dependent enzyme, kynurcninse. Simi- lnr chnngcs have been observed in healthy women u t the time of ovulation (when cstrogcn nclivity is highest), as comparcd with the postmcnstrual jwriod \It. I t . Ijrown, Itosr, J. hl. Price, and ti. Wolf, Ann. N. Y. Acut!. Sci. 106, 4 4 (196911 . 'I'his sup;gc~sts thnt normal physioloKir.cil variations in liormonc

230 NUTRITION REVIEWS I Vol. 30. No. I0

levels can produce detectable effects on the metabolism of tryptophan. A. L. Luhby et al. [Am. J. Clin. Nutrition 24, 684 (1971)]. however, point out that mid-menstrual cycle changes in the tryptophan load test can often be de- tected only with a higher loading dose ( 5 g.) and not with a lower dose of tryPtQPhan.

Females of some species, like human beings and rats, excrete higher levels of metabolites (after tryptophan load) whereas mice behave differently [J. E. Leklem, Am. J. Clin. Nutrition 24,659 (1971)l. Sex difference in humans can be observed only with a high dose of

The altered tryptophan metabolism in pregnancy has been found to be cor- rected with high doses of pyridoxine (Brown et al., loc. cit.). However, A. Hamfelt and L. Hahn [Clin. Chim. Acta 25, 91 (1969)l observed that for the same level of pyridoxal phosphate in plasma, higher excretion of xanthurenic acid occurred in women during early pregnancy. This suggests that in preg- nancy there is a higher requirement for vitamin &, which leads to functional deficiency of the vitamin.

Depression, mood, and sleep pattern changes observed in significant numbers of women using OCA have been reported to be corrected with 60 mg. of pyri- doxine, but not with 25 mg. The correlation between the dose of pyridox- ine and correction of tryptophan metab- olism was systematically investigated by Luhby et al. Effects of 2, 5, 10, and 20 mg. pyridoxine were evaluated in 34 women, who showed impaired trypto- phan metabolism due to contraceptive pills. (All women do not show this effect.) By regression nnalysis it wnti concluded that 25 mg. of pyridoxine pcr day could correct thc nlmormnlily of tryptophan load tent. Allowing for n safety margin, thc aulhors rccommcnd

tryptophan-

30 rng. pyridoxine per day for women on OCA. In view of the recent findings of D. Sharada and M. S. h j i [Int. J. Vit. Nutrition Res. 42, 43 (1972)] that administration of a high dose of pyridox- ine results in a fall in erythrocyte riboflavin, i t is conceivable that constant use of high doses of pyridoxine along with OCA may precipitate ribonavin deficiency.

The exact mechanism by which estro- genic steroids alter tryptophan metabo- lism is not established. Three possibilities have received support through experi- ments with laboratory a n h l s : 1. Estrogenic steroids elevate the ac-

tivity of the enzyme tryptophan oxygen- ase. This channels greater quantities of tryptophan into the tryptophanniacin pathway, thereby straining the capacity of the pyridoxal phosphate (PLP) de- pendent enzymes of that pathway, es- pecially after a tryptophan load [A. R. Green, M. H. Joseph, and G. Cunon,

man, loc. cit.; M. Brin, Am. J. Clin. Nutrition 24,699 (1971)]. 2. Increased activity of certain PLP

dependent enzymes such as amino trans- ferases decreases availability of the coen- zyme for enzymes of the tryptophan metabolizing pathway (Brin, loc. cit.).

3. Estrogen sulphate e ~ t e ~ formed in the liver inhibit the enzymes kynurenin- ase and kynurenine aminotransferase by competing with pyridoxd phosphate for the binding sites on apoproteins. Experi- mental evidence for this has been ob- tnined by M. Mason and B. Manning [Am. J. Clin. Nutrition 24, 786 (1971); Mnson, J. Ford, and H. L. C. Wu, Ann. N . Y. Acnd. Mcd. Sci. 166,170 (1969)]. However, this possibility cannot explain the higher excretion of N-methyl nico- linnmide by pregnant womcn I Hose, Clin. Sci. 31,206 (1966)j.

Adminhlrntlon of 10 p f l . of nn eslro- genic derivative to inhct fcm:ilc. raLq WIIS

Lancet 1,1288 (1970); ROW and Braid-

Ocfobcr 19721 NUTRITION REVIEWS "1 1

found to elevate tryptophnn oxygenase activity. A higher dose (250 pg.) failed to elicit similar response (Rose and Braidman, loc. cit.). Brin (loc. cit.) studied the effects of estrogens on tryptophan oxygenax and alanine amino t r a n s f e r n (GPT) activities in the livers of ovruiectomizcd and ovariectomized and adrenalectomized female rats. His results suggest that estrogens have a direct effect in elevating the activity of tryptophan oxygenase but the effect on GPT activity is mediated through corti- coskriods.

Accordiig to Green et al. (loc. cit.) elevation of tryptophan oxygenase may result in decreased availability of trypto- phan for serotonin synthesis. Also, the increased demand for PLP for the tryptophan-niacin pathway may reduce availability of the coenzyme for sero- tonin formation, which in turn may be responsible for the behavioral changes. Further, it has been shown that kynurenine and hydroxykynurenine in- hibit uptake of tryptophan by brain [Curzon. Am. J . Clin. Nutrition 24,830 (1971)]. No experimental data on the effects of OCA on serotonin levels are available, but clinical trials have indi- cated that behavioral changes in OCA users may be corrected by pyridoxine [M. J. Baumblatt and F. Wilson, Lancet 1 , 832 (1970)). However. while the metabolic defects are due to the estro- genic component, behavioral changcs have been reportcd to be more frequenl with progestogenic pills (Rose and Brnid- man, loc. cit.).

Cases of folic acid responsive megalo- blastic anemin among women who use controccptive pills hnve been rcportcd [ A . Pnton, Lancet 1, 4 1 8 (19691, R. R . Streiff, Clin. R o y , 17, 345 (19G9); '1'. F. N c c h ~ l r s nnd I,. h l . Snyder, N c w E:ngI. J. hlcd. 282, 858 (1070); J. I.. Rywr, J. J. l:orquc*t, nrid J. I 'c~tilc~, Ac l i i ~ ~ i 1 ~ ~ 1 1 i l l ~ O ~ . 115, (1!171)] . l~ioc.hciniic-al

evidence of folic acid deiiciency (as judged by low serum folate and in- creased FIGLU excretion) has been obtained in women on OCA by A. hl. Shojania, G. 1. Hornady, and P. H. Barnes [Lancet 1 , 1376 (1968); Am. J. Obstet. Cyiiec. 111, 782 (1971)j and more recently by Luhby, N. Shimizu, P. Davis, and J. M. Cooperman [Fcd . Proc. 30, 239 (1971)]. However, many other reports fail to confirm these findings.

Streiff [J. Am. Med. Assn. 214, 105 (1970)] has reported that intestinal absorption of natunlly occurring folate polyglutamate, but not monoglutamate, is impaired in women who use OCA. This might be due to inhibition of intestinal conjugase activity, since mestranol could inhibit this enzyme in vitro [Streiff and B. Greene, Clin. Res. 18, 418 (1970)). However, Streiff feels that this may not lead to folk acid deficiency, since the normal American diet has enough folate to meet the daily requirement even if absorption is re- duced to 50 per cent, and folk acid deficiency due to use of OCA is a rare event. This argument, however, may not be valid for diets of women in poorer countries.

The possibility of a'conelation be- tween thromboembolic disease and folic acid deficiency due to use of OCA has been pointed out by C. E. Butterworth [J. Am. hled. Assn. 214, 137 (197011. Folic acid deficiency may cause accum- ulation of homocystcine in blood, which in turn may produce coagulation dis- order.

Estrogen has h e n shown to f;icililal.t? the conversion of 5 C l i , - F H 4 to FH, , thc coenzynic form of folic acid in ruts (Bovina. Int. J. Vit. Nutrition Rcs. 41, 453 (1971)l. 'I'his m a y mean that dcspitc lowcrcd nl)sorption of dietary folutc, thew niny be I)ellcr utilization of u v i i i l a l h ~ folirtc b y womivi who usc slcw)id a p n t s .