Evaluation of emotional reactions to oral contraceptive use

CLINICAL

OPINION

This section reports opinion on the handling of clinical situations, i.e., the clinical diagnosis and management of certain disease entities. Papers should range from eight to twenty typed pages, including illustrations, tables, and figures which clarify the author’s management. References are limited to six citations. Mail to Frederick P. Zuspan, M.D., Editor.

Evaluation of emotional reactions to oral contraceptive use FRANCIS

J.

KANE,

JR.,

M.D.

Houston, Texas

A review of available clinical studies indicates that 10 to 40 per cent of oral contraceptiw users may suffer mild to moderate depression syndromes. Clinical and animal data indicate that a variety of mechanisms may be involved, including alterations in folate, pyridoxine, and vitamin BIz metabolism, as well as related effects on biogenic amine metabolism. Interactive effects may result, such as impairment of usual coping mechanisms and psychological defenses by altered central nervous systemfunction. (AM. J. OBSTET~ &NE~OL. 126: 968: 1976.)

SINCE 1968, there has continued to be a lively interest in the evaluation of emotional reactions to oral contraceptive use and the possible mechanisms from which such change might stem. In 1968, Nilsson, Jacobson, and Ingemanson’ reported a prospective study of 168 women at a university hospital in Sweden. A total of 54 pill users were compared with 104 women using other contraceptive means. There were no significant differences between the two groups with reference to choice of contraceptives as regards age, parity, psychologic testing, etc.

depressive symptoms-feelings of depression, sleep disturbance, inferiority feelings, and difficulty in starting work, (3) neurasthenic symptoms-increased fatigability, increased emotional liability and irritability, and (4) weight gain. Lewis and Hoghugh? reported a study from their general practice of 50 patients who were pill users compared to a like number of non-pill users. Clinical assessment by a psychiatrist with use of the Hamilton Rating Scale comprised the examination. Women who were taking oral contraceptives had significantly more clinical depression (two were suicidal) and, as a group, this was confirmed by a significantly higher score on the Hamilton Rating Scale. Patients with a previous history of depression were found to be more inclined to develop depression with the use of oral contraceptive medication. Three of the medication users made paranoid accusations against their husbands. There was a trend toward higher depression scores with longer time periods of

Method and results After 2 to 4 months, pill users had a significant increase (12.5 per cent) in (1) psychiatric morbidity, (2) Rep&t requests: Dr. Francis J. Kane, Jr., Professor of Psychiatry, Baylor College of Medicine, c/o Methodist Hospital, 6516 Bertner, Houston, Texas 77025. 966

Emotional reactions to oral contraceptive use

use and higher dosages of progestin. A similar relationship of depression to higher progestin use was reportecl bp Grant and Pryse-Davies3 in their 1968 study. Cullberg. Gelli. and Jonsson4 reported a study of 99 pill users and 99 controls which showed 14 per cent reported mental or sexual disturbances during the first 6 months but no change of mental symptoms after another 6 months. Petersen,” in a study of 215 patients utilizing psychiatric evaluation inventories and rating scales, reported 46 per cent of his patients showing strong adverse reactions. mostly of the depressed type. He also reported that the gestagen-dominant preparations showed more psychic symptoms. Herzburg and Coppen” studying 150 pill users and 40 controls reported depression in 6 per cent of the pill users and 2 per cent of’ the controls. Grounds, Davies, ant1 Mowbra!,. in a double-blind study with 10 women, over two cvcles using fairly comprehensive psychiatric and psych&gical evaluation, showed that nine of 10 patients were depressed during the first month when taking the pill. whereas the control groups had onI) two of ten patients depressed. In addition. they reported decreased sexual interest in eight of ten patients. In 1971 Silbergeld. Brast. and Noble’ in a double-blind, crossover placebo study four cycles long, involving eight patients, showed very significant tranquilizing effects. Self-rated anxiety was also increased. There have been some reported negative studies. Herzburg, Johnson, and Brown,” in a 1 year study of 218 pill users and 54 IUD users using psychiatric evaluation and rating scales, demonstrated no clear significant dif’ft-rencr hetwecn the groups. Goldziehel and associates,” using a double-blind, crossover method utilizing placebo, reported some increased nervousness in the first treatment cycle with one preparation. They also reported that estrogen-dominant preparations showed psychic symptoms in contrast to gestagen-dominant preparations. Kutner and Brown” in a number of studies have been unable to support a relationship between oral contraception and depression. They found no evidence of’ oral rontraceprives aggravating a depressive history but a history of depression in relation to pregnancy did seem to be related to discontinuance of the drug. The strength of their data lies in the use of objective rating instruments such as the MMPI Depression Scale. a large sampling of’ patients (5,15 1), and its existence as part of a multiphasic health screening. study of 299 women Cullberg ‘* in a double-blind showed that 14 per cent more individuals reported adverse mental changes in the interview ratings of the gcstagen-dominated medication groups then a placebo

969

group. Estrogen-dominated pill groups ~l~owd IX lwr cent more negative reactions than the pi;dx) groups. These differences tvere signific ;II~I al III<- 0.05 Ic~\cf. The mental symptoms were gencr.ally JIIIICI a11tl mostl! of a depressive tiysphoric type. Iu his at:.itl! C:~~llberg-” examined the relationship ol prcmtnxtrltal irritabilitv. and found more tlepressiw rcac,tionh tll,r tl I IIOSC,i\ ithout premenstrual svmptoms. Huffer. Levin, and Awnson” conlpar~~i I6 pa’icnrs who experienced adverse psychologic al s\‘nll)toms 11ith 23 who had none. Of those Tvho had tliflicrlttv, 11 showed depressice reactions and five hacl loss of’wsual interest and pleasure not rclateti 10 tlcprwsicm. All developed these symptoms while on the OI-al c.cmtraccp tive and IOSI them after discontinrc;rrlc-~,. T\\o f;lc tot-5 tended to correspond with the dc\t:lopn~t~r~~ ~~l’ad\c’~w reactions: (1) the use of c-ombined ;I\ c~l)posecf to sequential type of contraceptive pill ~rirl (2) ape of subject. ? here has also been adclitiotlal rcsc;w h into the biologic mechanisms that may produce II~CW* changes. Adclitional evidence has been ga~llcrrtl \vhich sho\\s that oral contracrptives etfect, dirc,ctlv ;i~:d intlircctly. biogenic amine metabolism which i< I bought tc) 1~ important in the biology of del”.‘ssiort---the nlost common clinical condition re~portt’d tn I II\ csstigators. Using purified rat brain synaptowrnc 111cparalions (pinched-off nerve endings), ~Jar~onsk~ \ l)rogrsicr-olw and is slightly decreased hv cstrog-cn. In another clinical study, we” rcportcd on SC”\tan women who were studied on a single-blind basis. TM.O subjects received only a combination oral tr,ntrawpti\c agent while the other five receivetl rlw rnos1 ~~ommonfy used estrogenic hormone, mestranol, f.ol ‘1 ~\ceks tollowed by a ~ornhirlrd-horniorle pill colil:Lining mrstranol and a progestin (either tlot.cth;ntlronc 01 ethynodiol). The first menstrual period in ~hcw phsGtally normal regularly menstruating womt~~i isas used to familiarize the subjects tvith the proc~edIIrcs in testing and to provide baseline data. Derring the lutral phase of- the cycle. they lvere hospitalized on rht Clinical Research Unit of ;he North Carolill~l \lemorial Hospital for a 60 hour period. usualh OII -1 rwrkend. During that period on the Unit, they wcw c-onfined to the Ynit and received a VMA-fi-ee tIiel.onl\. ,ic,li\ity was confined to a walking on the Unit. I’tlev NWP studitad with a number of behavioral-rating tlevic CF..,111subjects on the higher dosage of Ortho-Nctvunl rc.ported dc-

970

Kane

pression, while none of the five women receiving the lower dosage of Ortho-Novum or ethynodiol reported depression as such. Two of these subjects reported anxiety and altered mental functioning with significant changes on the factors of the Clyde Mood Scale supporting these perceived changes. Subjects on the higher dosage of Ortho-Novum showed a decreased level of urinary metabolites during the drug period as compared to the normal luteal phase. After the drug was discontinued, one subject had a decrease in normetanephrine excretion. On the other hand, those taking the lower dose of Ortho-Novum or ethynodiol showed an increase in normetanephrine excretion as the most consistent finding. At both the low and high doses, the vaginal smears were consistent with an estrogen and progestin effect and inhibition of ovulation. The changes described above may be related to functional pyridoxine deficiency. Mason, Ford, and Wu” have examined several vitamin B&ependent enzyme systems in the tryptophan-kynurenine pathway and suggest that estrogen conjugates compete with pyridoxal phosphate for binding sites on several apoenzymes, notably kynureninase and kynurenine transaminase. Since the transaminase is less sensitive to deficiency of pyridoxal phosphate, xanthurenic acid accumulates and its level is used as an index of pyridoxine deficiency. In vie\v of the fact that estrogen has been shown to inhibit 5hydroxytryptophan decarboxylase in vitro, I7 it is not unreasonable to suppose that a similar situation may exist along the indole pathway, reducing levels of tryptamine and serotonin, the synthesis of which is pyridoxine dependent. Since dopa decarboxylase is thought to be the same enzyme as 5-hydroxytryptophan decarboxylase and is also pyridoxine dependent, levels of catecholamines may be similarly affected. It has been shown” that up to 25 mg. of pyridoxine are required daily to correct tryptophan metabolism along the kynurenine pathway in women taking oral contraceptives. As the usual dietary requirement is approximately 2 mg. daily, there seems to be evidence that oral contraceptives markedly interfere with the proper use of, or increase the need for, pyridoxine. In view of the many decarboxylase and transaminase reactions that are pyridoxine dependent, it is unlikely that such a situation would manifest itself with one clinical symptom such as depression, and consideration must be given to the possibility of functional pyridoxine deficiencies being contributory to other side effects of oral contraceptives. An oral COIItraceptive manufactured in Spain, which contains 25 mg. of pyridoxine, is reported to have fewer side effects.lg

December Am. J. Obstet.

15, 1976 Gynerol.

In another study, it was shown’” that 12 women whose glucose tolerance tests had progressively deteriorated while taking steroid contraceptive improved considerably upon receiving 1 month therapy with vitamin B6 while continuing their steroid contraceptive. Another possible contributor to the phenomena observed may relate to alterations in folate metabolism. Shejania, Hernady, and Barnes” have recently reported a significant lowering of plasma folate levels in oral contraceptive users. In their study, 30 per cent of the values of those using contraceptives were below the lowest of the nonusers. Folate deficiency and megaloblastic anemia have recently been reported associated with the use of oral contraceptives. Streifp’ described five women taking oral contraceptives. in whom folate deficiency and megaloblastic anemia developed, who did not respond hematologically to a normal hospital diet but did respond to the oral administration of 250 pg of folic acid daily even though they continued to take oral contraceptives. Two additional patients had a hematologic response following discontinuation of oral contraceptive agents without the need for folic acid supplementation. Folate absorption studies in nine women taking oral contraceptive agents appeared to show a reduction in absorption of folate polyglutamate but not the monoglutamate form. Prior treatment with folic acid abolished the malabsorption of folate polyglutamate. Another contribution to the understanding of this abnormality was reported by da Costa and Rothenberg,‘” who showed the presence of a macromolecular factor with binding determinants for unreduced and partially reduced folates to be present in the leukocytes of patients who were pregnant and those taking oral contraceptives. This binding capacity was reduced by 90 per cent at the end of the pregnancy. Wertalik and associate? have shown a significant reduction of serum vitamin Blf levels in women taking oral contraceptives. This reduction can occur within 5 months and serum levels may fall to values indistinguishable from other forms of vitamin Bi2 deficiencies. In spite of the drastic reduction in serum levels in some women, no anemia or evidence of tissue depletion was detected. They also confirmed the presence of a redurtion of serum folates. The authors were unable to explain this phenomenon since absorption seemed normal, as evidenced by normal Shilling tests in two subjects and an increase in vitamin Blz serum level when a small oral dose was administered. Lowered folic acid levels may interfere with biogenic amine metabolism since folic acid has been shown to be an important cofactor in the rate-limiting step in the biosynthesis of norepinephrine. Reynolds and associates” studied

Volutne Nurnher

I”6 x

serum folate and vitamin Blz levels in 101 patients lvith depressive illness. Subnormal folates were found in 24 per cent and subnormal BIz levels in 0.2 per cent of the patients. Patients with subnormal f’olate levels were found to have significantly higher depressive scores and significantly lower validity scores on the Mark Nyman Temperament Scale on admission and discharge. Vitamin BIZ ” deficiencv has been shown to be important in producing many types of psychological disturbances including depression, confusion. and psychotic pictures. Metabolic studies have also shown alterations in the metabolism of vitamin A and vitamin C as well. A significant increase in plasma levels of vitamin A has been shown in women taking the oral contraceptive pills” when compared with controls studied under similar conditions. None of the pill users have values approaching toxic levels. In another study, Kalesh and associates’” showed that women taking oral contraccptives exhibited significantly lower platelet ascorbic acid levels than controls 2 weeks after both had been placed on a low vitamin C diet. It is of interest that there is one study showing improvement in depressive symptoms in psychiatric patients with the administration of 1 Cm. of ascorbic acid solution per day.“’ The MMPI Depression Scale showed significant improvement at the 1 per cent le\,el of probability in the ascorbic acid group while another rating scale showed significant improvement in the manic clepressive paranoid symptom complexes. Animal studies” ha\,e shown that intraperitoneal administration of ascorbic acid produced a significant decrease in the concentration of dopamine and an increase in norepinephrines in the cerebral hemispheres cerebellum, dyencephalon. mesencephaIon. and medulla oblongata.

REFERENCES

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5.

6.

Nilsson, A., Jacobson. L., and Ingemanson, C. A.: Side ef-fects of an oral contraceptive with particular attention to mental symptoms and sexual adaptation, Acta Obstet. Gvnecol. Stand. 46: 537. 1967. Lewis. 4.. and Hoghughi, M.: An evaluation of depression as a side effect. Br. 1. Psvchiatrv 115: 697. 1969. Grant, E. C. G., and &yse:Davies, J.: Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases, Br. J. Med. 3: 777, 1968. Cullberg, I., Gelli, M., and lonsson, C.-O.: Mental and sexual gdj&tment before and after six months’ use of an oral contracemive. Acta Psvchiatr. Stand. 45: 259, 1969. Petersen, P.: bsvchiatrische und psychologische Aspekte der Familienpl&ung hei oraler‘ Kontra&ption, &org Thieme Overlap. Stuttgart, 1969. Herzburg. B.. and Coipen, A.: Changes in psychological symptoms in women taking oral contraceptives, Br. J. Psychiatry 116: 161. 1970.

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971

Comment The evidence summarized vwulcl sttv~t IO point to the occurrence of mild to motleraic tlc~prcssivc stat~a characterized b! tiredness, letharqv,< sadness. and sometimes accompained b\ a loss of intrrest in st’x. There is also widespread e\-itlrsnce 10, considerable alteration in a variety of biologic systems. especialh those related to biogenic amine metabolis~n. The cx;wt relationship of these altered biologic -VSI~IIIS to ltlc clinical s~tnptoJJlatolo~~ reportt’d rllusI remain speculative, since the t\\o phenomena I~a\e general]\ been studied separately. Further clinical vrudirs inwlving the simultaneous evaluation of ttiew biologic alrtbrations, if’ any. are related to the psychological changes seen. The available evidence ~vould suggest that drugs with a higher dosage of progestin S~CIJJ IO bt* associated with more unclesirabte psychologital side effec,ts. .-\nother variable lvhich ma! make a nrajo~. contribution related to the interaction of pt,rsc,r&y wriahles tvith drugs that affect the central nerwus svstem. It has bee11 demonstrated that in a number tri studies drugs with se&rive effects-which includes thr, progestinscause personality disorganization in p(‘J-sons whose adequate psychological functioning depends up011 ;I high degree of alertness nrlcl ahilit\ IO i)c*rform a( tivity.“’ It is clear that much remain\ to hr wttled in a definitive way as to the contribution of;l~l\’ (lr all of the abole factors in the genesis of’ the psvcholo,gicat changes which seem to occur in ahout IO per (‘cnt of the patients who take oral contratcpti~~:~.

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with different gestagemestrogen combinations-a double blind comparison with a placebo, Acta Psychiatr. Stand. Suppl. 236: 1972. Huffer, V., Levin, L., and Aronson, H.: Oral contraceptives-depression and frigidity, J. Nerv. Ment. Dis. 151: 1, 35, 1970. Janowsky, D. S., and Davis, J. M.: Progesterone-estrogen effects on uptake and release of norepinephrine by synaptosomes, Life Sci 9: 525, 1970. Kane, F. J.. Lipton, M., Krall, 0.: Psychoendocrine study of oral contraceptive agents, Am. J. Psychiatry 127: 85, 1970. Mason, M., Ford, J., and Wu, H. L. C.: Effects of steroid and non-steroid metabolites on enzyme conformation and pyridoxal phosphate binding, Proc. N. Y. Acad. Sci. 166: 170, 1969. Mason, J., and Schirchi, L.: Inhibition of B6 enzymes by free and conjugated estrogens, Fed. Proc. 20: 200, 196 1. Luhby, A. L., Davis, P., Murphy, M., Gordon, M., Brin, M., and Spiegel, H.: Letters: Pyridoxines and oral contraceptives, Lancet 2: 1083, 1970. Otte, J.: Letter: Oral contraceptive and depression, Lancet 2: 498, 1969. Spellacy, W. N., Buhi, W. C., and Birk, S. A.: The effects of vitamin B6 on carbohydrate metabolism in women taking steroid contraceptives-Preliminary report, Contraception 6: 4, 265, 1972. Shejania, A. M., Hernady, G., and Barnes, P. H.: Oral contraceptives and serum-folate levels, Lancet 1: 6, 1376, 1968. Streiff, R. R.: Megaloblastic anemia due to folylconjugase inhibition by oral contraceptive agents, J. A. M. A.

23. Da Costa, M. and Rothenberg, S. P.: Appearance of JOlate binder in leukocytes and serum of women who are pregnant or taking oral contraceptives, J. Lab. Clin. Med. 83: 2, 207, 1974. 24. Wertalik, A., Metz, E. N., Lobuglio, A. F.. and Bolcerzak. S. P.: Decreased serum B12 levels with oral contraceptive use, J. A. M. A. 221: 12, 1371, 1972. 25. Reynolds, E. H., Preece, J. M., Bailey, J., and Coppen: F late deficiency in depressive illness, Br. .J. Psychiatry 117: 287, 1970. 26. Reynolds, E. H., Mimer, G., Matthews. D. M., and Chanarin, I.: Anticonvulsant therapy folic acid and vitamin B12 metabolism and mental symptoms, Epilepsia 7: 260, 1966. 27. Gal, I., Parkinson, C., and Craft, I.: Effects of oral contraceptives on human plasma Vitamin A levels, Br. Med. I. 2: 436, 1971. 28. Kale&, V., et al.: Effect of estrogen-containing oral contraceptives on platelet and plasma ascorbic acid concentrations, Contraception 4: 3, 183, 1971. 29. Mimer, G.: Ascorbic acid in chronic psychiatric patients-a controlled trial, Br. J. Psychiatry 109: 294, 1963. 30. Izquierdo, J. A., Jofre. I. J., and Acevedo. C.: The effect of ascorbic acid on the cerebral and adrenal catecholamine content in the male rat, J. Pharm. Pharmacol. 20: 210, 1968. 31. Klerman, G. L.. DiMascio. A., Greenblatt, M., and Rinkel. M.: The influence of specific personality patterns on the reactions of phrenotropic agents, it! Masserman. J., Editor: Biological psychiatry. New York. 1959, Grune‘g Stratton, Inc., pp. 224-24?.