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Special Articles

SOME MEDICAL ASPECTS OF

ORAL CONTRACEPTIVES

Lord BRAIND.M. Oxon., Hon. LL.D., D.C.L., D.Sc., F.R.C.P., F.R.S.

PRESIDENT, FAMILY PLANNING ASSOCIATION

A. S. PARKESC.B.E., M.A., Sc.D. Cantab., D.Sc., Ph.D., F.R.S.

MARY MARSHALL PROFESSOR OF THE PHYSIOLOGY OF REPRODUCTION,UNIVERSITY OF CAMBRIDGE

P. M. F. BISHOPD.M. Oxon., F.R.C.P.

ENDOCRINOLOGIST, GUY’S HOSPITAL, CHELSEA HOSPITAL FOR WOMENAND DEPARTMENT OF OBSTETRICS AND GYNÆCOLOGY,

POSTGRADUATE MEDICAL SCHOOL, LONDON

MODE OF ACTION

WHEN the pituitary gonadotrophins were discoveredmore than thirty-five years ago, it was realised that theremust be some controlling mechanism to prevent bothunder- and over-stimulation of the gonads. This provedto depend on the fact that, whereas subnormal amounts ofthe gonadal hormones in the circulating blood stimulatepituitary activity, excessive amounts depress it, thus

creating a " feedback " or reciprocating mechanism. The

pituitary-depressing, and thence gonad-depressing, activityis exerted by exogenous gonad hormones and it is not

sex-specific. Thus androgens are effective in females andoestrogens and progesterone in males.

It was shown that the administration of cestrogens earlyin the menstrual cycle suppressed ovulation in women, andthis discovery was used in the treatment of spasmodicdysmenorrhoea, which does not occur in the absence ofovulation. This use of oestrogen, however, was not

developed for contraceptive purposes. Androgens, thoughat one time used for certain purposes in women, could notbe administered indefinitely because of masculinisingeffects. Progesterone, though free from the disadvantagesof both’ oestrogens and androgens, was inactive whenadministered by the mouth.

Here, if we except the preparation of a weak orallyactive. progestagen, ethisterone, about 1937, the situationrested until the early 1950s, when biological analogues ofprogesterone with high activity by mouth were prepared.John Rock and Gregory Pincus saw and seized the oppor-tunity presented, and after extensive animal experiments,in which high ovulation-inhibiting activity was shown to bea property of the new progestagens, oral contraception,based on the suppression of ovulation by orally activeprogestagens with a small mixture of oestrogen, came intoexistence.The principle involved, therefore, in the use of oral

progestagens to suppress ovulation in women is certainlyphysiological. Even the long-term suppression of ovula-tion by these means has a physiological counterpart in thatthe ovulation-producing activity of the human pituitarygland is suppressed for a year or more during pregnancyand lactation. Moreover, a rapid succession of pregnancies-associated with ovulation, say, only once a year-iscertainly compatible with the normal functioning of thereproductive machinery. Oral contraception in its presentform is therefore far more physiological than, for example,the introduction of chemical spermicides into the vagina.The essential feature of the technique is the need to

suppress ovulation, and not merely to postpone it; and forthis purpose daily medication from days 5 to 25 of the

menstrual cycle is necessary. In spite of the need to con-sume twenty pills to a set schedule during each cycle, themethod has proved remarkably acceptable and effective.And the effects of the exogenous progestagen on theendometrium and cervical mucus are probably supple-mentary anti-fertility factors, which will prevent concep-tion even in the event of a breakthrough ovulation.The endometrial effect may be important because

implantation of a fertilised egg depends on -appropriatepriming of the endometrium before, and for some daysafter, ovulation-a state of affairs not likely to be foundafter exposure for two weeks or more to exogenousprogestagens. The cervical-mucus reaction is also ofconsiderable interest since it was at one time thought tohave possibilities as an independent contraceptive factor.During the follicular phase of the normal cycle the mucuswhich plugs the cervix becomes thin and runny, and by thetime of ovulation it is easily penetrated by spermatozoa.After ovulation, during the luteal phase, it becomes thickand tacky, and resistant to the passage of spermatozoa.This change is brought about by progesterone and can besimulated when it would not otherwise occur by theadministration of progestagen. It is hard to avoid theconclusion that this reaction is a factor in the defence

against conception provided by oral progestagens.SIDE-EFFECTS

Some women experience one or more side-effects, suchas nausea, headache, tenderness and swelling of the breasts,premenstrual swelling, depression, abdominal cramp,lethargy, increased vaginal discharge, water retention,changes in weight, and loss of libido, and some womenhave breakthrough bleeding. In the majority of casesthese side-effects, if any occur at all, develop only duringthe first and possibly second and third cycles of hormoneadministration, though some, such as increase in weightand loss of libido, may persist. Should a woman find theseside-effects intolerable, she will have to abandon this formof contraception. Some women develop a lesion similar tothat known as

" congenital " cervical erosion, which,however, is reversible, and in any case not serious, thoughit may possibly be regarded as another indication foradopting some other method of contraception. There are

other, desirable or " positive ", side-effects-e.g., a senseof wellbeing; freedom from anxiety; relief of dysmenor-rhoea, premenstrual tension, vaginal discharge, seborrhoea,and acne; and increased pleasure in sexual intercourse,which some people remark upon with gratitude.

RISKS OF CARCINOGENESIS

Perhaps the greatest fear in the minds of both the laypublic and their medical advisers is that these compoundsmay induce cancer. It should be remembered that both

oestrogens and progestagens have been in therapeutic usefor a very long time and have not, so far as is known-andthere have been retrospective follow-up studies-givenrise to any serious complications or permanent damage.For instance, by 1933 there were already eight commercialpreparations of cestrogen on the British market, andKaufmann (1933) had succeeded in inducing menstrualbleeding from a fully secretory endometrium in a castratewoman by,giving injections of oestradiol benzoate followedby progesterone. As early as 1936 doubts were beingexpressed as to the possible carcinogenic role of oestrogens(Hunt 1936) and justification for these doubts was beingemphatically denied (Parkes, Bishop, and Dodds 1936),who made the following statement: " It is our opinion thatit would be a great disservice to practical therapeutics if the

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use of sex hormones were to be in any way restricted onaccount of unsubstantiated speculation." Stilboestrol was

synthesised in 1938 (Dodds, Goldberg, Lawson, andRobinson 1938) and was immediately submitted to clinicaltrial (Bishop, Boycott, and Zuckerman 1939, Wintertonand MacGregor 1939). This substance proved to be ahighly potent oestrogen which was cheap enough to

administer in enormous doses and for many years. Thou-sands of women, rightly or wrongly, were given large dosesof stilbcestrol, without, as far as is known, any ill effects.The risks of carcinogenesis, however, were thoroughly

investigated. Aided by a grant from the British EmpireCancer Campaign, Dr. Moira Murray and one of us(Bishop) followed up 530 patients who had attended clinicsat Guy’s Hospital, the Chelsea Hospital for Women, or thedepartment of obstetrics and gynxcology at HammersmithHospital, or had been seen in private practice, who hadreceived oestrogen therapy either continuously or in inter-rupted courses for at least six months and, in many cases,for several years after 1938 when stilboestrol first becameavailable. They found that only 2 patients had developedcancer, one of the breast and another of the body of theuterus. Other similar follow-up studies have been carriedout, and Bishop (1960) collected the combined results offive such studies, including the one just mentioned, whichshowed that out of 1979 patients followed up, only 6 haddeveloped cancer-3 of the cervix, 2 of the body of theuterus, and 1 of the breast. The impression, which somepeople have, that there are many reports of cancer of thebreast or uterus following oestrogen therapy is unfounded.A search of the literature, as provide4by Excerpta Medica(Section of Endocrinology) for a period of ten years up to1954, provided only 5 reports of carcinoma of the breastand 6 of carcinoma of the uterus. Between 1954 and 1960there was 1 further report.

It has been pointed out that granulosa-cell tumours havedeveloped in the ovaries of some mice given oral contra-ceptives for long periods. Lipschiitz et al. (1963) foundthat four out of eighteen mice implanted with pellets of19-nor-progesterone for such long periods as 395 or 402days were seen at necropsy to have developed unilateralgranulosa-cell tumours. It seems unlikely that this obser-vation is significant in the present context, and it is doubt-ful whether it is directly applicable to man. Mouse tissuesare notoriously unstable and ovarian tumours in this

species have also been caused by radiation and section ofthe ovary. In neither case have the observations on miceled to the abandonment of the analogous clinical procedure.On the other hand, there is evidence that progesteronederivatives actually arrest the progress of endometrialcancer and lead to regression of metastases in women.There are already a number of reports in support of this,for example, that of Kennedy (1963). 27 patients who hadpreviously been treated for endometrial cancer by irradiationor surgery were given injections of 17-;x-hydroxy-proges-terone, and 8 showed objective regression of the tumours.

All volunteers in the trials instituted by the Council forthe Investigation of Fertility Control have routine Papani-colaou smears before embarking on oral contraceptives,and subsequently at six-monthly intervals. Of 1900

women given this initial test, 6 had early invasivecarcinoma-in-situ and 5 showed suspicious smears thatreverted to normal. (3 are awaiting surgery and confirma-tion of the diagnosis: 1 has had a hysterectomy but thecondition proved to be non-malignant.) The 6 withcarcinoma were not admitted to the oral contraceptive

trials. Of the women who had a negative smear beforecommencing oral contraceptives, only 1 has developed apositive smear during the course of the trial, which nowcovers more than 20,000 cycles and in some cases extendsover more than five years.

Synthetic oestrogens and-progestagens have thus been inuse now for nearly thirty years. They were administeredto women for therapeutic purposes long before they wereadopted as oral contraceptives, for which purpose theyhave now been used for over eight years. For the whole ofthis time, doctors have been alert to the possibility that theymight cause cancer, but there is no evidence that they do.CAN ORAL CONTRACEPTIVES PERMANENTLY DAMAGE THE

PITUITARY OR THE OVARIES ?For many years it has been orthodox teaching that sex

hormones inhibit the release of gonadotrophins through asuppressive action of the hypothalamus on the anteriorlobe of the pituitary. Recently, Loraine et al. (1963), usingthe method of estimation of urinary gonadotrophins(H.P.G.) of Loraine and J. B. Brown (1959), have madeobservations which might be held to support a direct actionon the ovary; but for technical reasons their interpretationof these experiments is doubtful, and P. S. Brown et al.(1964) obtained different results. So far there have beenfew opportunities of studying the histology of the pituitaryin such human subjects, but up to the present no adversechanges have been found. It would not be surprising ifsome histological changes were to be discovered, correlatedwith the change of pituitary function induced by the drugs,but it would not necessarily follow that these were

permanent.Something perhaps may be inferred about pituitary

activity from what is known about the function of theovaries. Many women have now taken oral contraceptivesfor long periods, and when medication has been stoppedovulation has taken place in the next one or two cycles. Infact, there is evidence that after the discontinuance of oralcontraceptives the immediate likelihood of conception issomewhat greater than normal.So far, then, after more than eight years of use there is

no evidence that either pituitary or ovarian function is

permanently affected by oral contraceptives. Such fearsare purely speculative, and for that reason they can beneither proved nor rebutted.The report of the Medical Research Council for

1962-1963 contains the following statement:" A number of investigators have expressed concern about

the possible long-term endocrinological effects of oral pro-gestagens and suggested that, when administered over monthsor years, such compounds may prove harmful because oftheir potential ability to alter hormonal inter-relationshipsor to interfere with the endocrine environment necessary forfertilization and implantation of the ovum."

Quoting the observations of Loraine et al. (1963), thereport concludes:

" The results obtained in these women and in a number ofothers investigated in a similar manner suggests that long-termtherapy with oral contraceptive agents has no lasting deleteriouseffects on pituitary and ovarian function. Obviously furtherstudies are required before definite conclusions can be drawn."

SUBSEQUENT FERTILITYIt may surprise some readers to learn that oestrogen and

progesterone were used in the treatment of unexplainedinfertility (Mulligan et al. 1952) before they were used asoral contraceptives. The hope was that, by inhibitingpituitary and ovarian activity for three or more cycles, itmight be possible to get a rebound effect in which the

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pituitary-gonadal axis would act more efficiently; andTyler and Olsen (1958) found that up to 15% of suchpatients became pregnant within the two succeeding cyclesafter discontinuing treatment. This empirical therapy isemployed in many fertility clinics in this type of case.A considerable amount of information is now available

about the rate at which women conceive after discontinuingoral contraception because they want to become pregnant.To take one example, of 85 such women in trials conductedby the Council for the Investigation of Fertility Control80% conceived within two months. Much is also knownabout the rate at which, and the extent to which, pituitaryand ovarian activity return to normal or indeed show arebound effect following cessation of oral contraception.The first cycle tends to be prolonged, but all the variousmeans of assessing ovarian activity-endometrial biopsy,vaginal cytology, basal-temperature records, and estimatesof urinary oestrogen and pregnanediol-indicate immediate

, resumption of endogenous pituitary-ovarian activity evenafter many cycles of oral contraception.

ANDROGENICITY AND CONGENITAL DEFORMITIES

The 19-nor-testosterone progestagens have a degree ofandrogenic activity; but in the dosage given, in the inter-rupted courses prescribed, no virilisation has occurred involunteers in oral contraceptive trials, except for the

development or mild exacerbation of acne in a few cases.The question whether a female foetus would be mascu-linised if these compounds were administered to a womanfor contraceptive purposes when in fact she was in theearly stages of pregnancy hardly arises since this is veryunlikely to happen. But these compounds have been usedin high dosage over long periods during pregnancy toprevent miscarriage in women with a history of habitualabortion, and the incidence of fcetal masculinisation hasbeen very small. Furthermord, the fact that oestrogens andprogestagens and combinations of these hormones havebeen administered in enormous doses throughout preg-nancy to prevent not only abortion but toxsemia, and tosalvage the infants of diabetic mothers, disposes of thepossibility of congenital anomalies such as resulted fromthe administration of thalidomide. These hormones are

drugs which have now been used for twenty-five years.DELAY IN THE MENOPAUSE

It has recently been suggested that these preparationsmay be employed beneficially to prolong menstrual life.Ever since oestrogens became available over 30 years ago,they have been prescribed to relieve the tiresome symptomsof the menopause, but not to postpone its onset. Whatsome people fear, however, is that by constant inhibition ofovulation-i.e., the rupture of a mature Graafian follicle-the normal rate of follicle atresia will be slowed, and thatwomen who have for many years relied on oral contracep-tives will inadvertently conceive in their fifties or laterwhen they finally abandon this form of contraception. Theevidence is that the process of follicle atresia is not pri-marily based on the rupture of one of the mature folliclesin each cycle but occurs constantly and independently ofthis event. Of course if a woman is slavishly using oralcontraceptives well into her forties or fifties, she will getartificial withdrawal bleeding instead of natural periods,and thus may not know when she has actually reached herphysiological menopause. The use every now and againof some other contraceptive device, however, will revealwhether or not she has any natural periods.

LACTATION

The effect of oral contraceptives on lactation is not yet

certain, but there is a strong feeling that they diminishlactation in a significant proportion of cases (Dr. EdrisRice-Wray puts it at about 30%, though in the early daysshe was using her cestrogen-progestagen mixtures in whatare now considered to be relatively high doses). Breast-

feeding is important in those areas of the world wherenutritive standards are not high, but these are just theareas in which oral contraception in the early postpartumperiod is all-important-where women have no periods,only pregnancies. The International Planned ParenthoodFederation recognises that this is a most important prob-lem and is collecting as much information on it as possible.

THROMBOSIS AND EMBOLISM

Some years ago, attention was drawn to the occurrenceof venous thrombosis in women taking oral contraceptives.The course of subsequent investigations and discussionsillustrates how difficult it may be to decide whether some-thing which happens to a woman taking the " pill

" is theresult of taking the " pill ".A conference of experts convened in Chicago in 1962

came to the conclusion that the clinical and statisticalevidence showed no relationship between’ Enavid’, in thecircumstances in which it had been used, and venousthrombosis. Three articles in the British Medical 7ournal(1963, 1964) give references to what is known about therelationship between clotting and pregnancy, which tosome extent the administration of oral contraceptivessimulates. The second article concludes that so far thereis no firm evidence that the incidence of thrombosis in

patients on oral contraceptives exceeds the normal expecta-tion and adds that " any misgivings could be resolved onlyby a prospective study of thrombo-embolism in normalwomen and, concurrently, women on the pill’ ". Thisraises the practical question whether a previous attack ofvenous thrombosis is a contraindication to the administra-tion of oral contraceptives. In such cases the risk, if any,must be balanced against the risk that in the absence oforal contraceptives pregnancy may occur, and carry withit the danger of further thrombosis.

ORAL CONTRACEPTIVES AND LIVER FUNCTION

Because hepatic dysfunction and jaundice may occur insubjects treated with some oral anabolic steroids (Drill1963), Eisalo et al. (1964) administered oral contraceptivesto 7 postmenopausal women for twenty-eight days. Theyreported evidence of hepatic dysfunction as judged byelevation of serum-transaminase levels. In 2 of their

patients the progestagen component of the drug waswithout effect, and in 1 out of 3 patients treated with theoestrogen component changes in hepatic function similarto those produced by the whole drug were observed. Thismay indicate that only the oestrogen component was

responsible for the effect. The ages of the patients treated inthis series ranged from 52 to 80 and the number studiedwas small. In a larger number of younger women given asimilar drug, Swaab (1964) found no such changes inS.G.O.T., but the rises in s.G.o.T. in postmenopausalpatients has been confirmed by Palva and Mustala (1964).The significance of the observations of Eisalo et al. inrelation to the use of oral contraceptives in general isuncertain. More information is needed.

THE FAMILY PLANNING ASSOCIATION AND ORAL

CONTRACEPTIVES

Alarmist statements about the dangers of oral contra-ceptives have been made in the press and elsewhere; forexample, it has been said that " if women take drugs of thiskind-for social rather than for therapeutic reasons, they are

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taking part in a mass experiment-call them guinea pigs ifyou like " (Gerrard 1964), a statement freely quoted in thelay press. It seems desirable, therefore, to put on recordthe attitude of the Family Planning Association to the useof oral contraceptives.

Their use in a trial under the auspices of the Council forthe Investigation of Fertility Control was first consideredby the medical advisory council of the Family PlanningAssociation in 1960. The possibility of carcinogenesisand of long-term effects on the pituitary were discussed,and the committee approved the proposed trial. Thecommittee’s conclusions and the evidence’ which led tothem were published in The Lancet (1960). ,

Nearly eighteen months later, in October, 1961, themedical advisory council reviewed the situation, at a

meeting at which Sir Charles Dodds attended by invitationin order that the council might hear his views. It came tothe conclusion that progestagen/oestrogen oral contra-

ceptives might be offered as an alternative method inF.P.A. clinics, provided they were administered to suitablecases under strict medical supervision by medical stafftrained in the method. It was also agreed that furtherclosely studied trials be continued in order to watch theeffects of long-term administration.The medical advisory council of the Association kept the

subject under review, and at a meeting in July, 1962, itdrew attention to the need for research into the long-termeffects of oral contraceptives on a scale which was beyondits own powers. It offered its opinion that since oralcontraceptives were now available through the NationalHealth Service, the Medical Research Council shouldaccept responsibility for investigating their possibleill effects. " Meanwhile, though extensive use of oralcontraceptives in the past has not been shown to have anypermanent ill-effects, the responsibility for prescribingthem rests, as in all prescribing, on the individual doctors,who should realise the present limitations of our know-

ledge." One of us, in the House of Lords on June 6, 1962,had appealed to the Government to accept responsibility forinvestigating the long-term effects of oral contraceptives,and not long afterwards the Medical Research Council setup a committee on steroid sex hormones which includesthis subject in its scope. And since the beginning of thisyear, the safety of new drugs has had to be considered bythe committee on Safety of Drugs.

Finally, the Family Planning Association has done itsbest to make sure that all doctors at its clinics where oral

contraceptives are prescribed are experienced in their use.A handbook on the subject is issued to them and kept upto date by means of circulars. The last of these, issuedthis year, said:

" Routine examination before prescribing these pills shouldinclude routine gynecological examination (bimanual and

speculum with PAP smear when possible) and breast examina-tion ... It is advisable to take a careful history of gynxcologicalcomplaints, menstrual cycle patterns, etc., and also a history ofprevious troubles which might be aggravated by oral contra-ceptives, allergic disorders, convulsive disorders, liver trouble,thrombo-embolic phenomena, etc."It added that:

" The contra-indications listed in the Handbook on Oral

Contraception for F.P.A. doctors are relative and not absolutecontra-indications, and doctors should use their own judgementalong the lines suggested."There is still much to be learnt about the complex neuro-

endocrine interrelationships which underlie the effective-ness of the types of oral contraceptive we have been

considering. Whether their use is justifiable is a matter forindividual decision. But in general their supposed hazardsmust be balanced against the known consequences of usingineffective contraceptive methods or none at all-namely,oppressive pregnancies, unwanted children, back-street

abortions, and overpopulatiori.SUMMARY

The mode of action of oral contraceptives is discussed,and their side-effects are described.

Before they were adopted as oral contraceptives, syn-thetic oestrogens and progestagens were in use for manyyears, being administered for long periods to women fortherapeutic purposes. There is no evidence that, whenused as oral contraceptives, they cause neoplasms inwomen.

Again, there is no evidence that oral contraceptivespermanently affect the pituitary or the ovaries nor thatthey impair subsequent fertility. Their use as prescribedis not known to carry any risk of androgenicity or con-genital deformities, and there is no reason to suppose thatthey delay the menopause.They may interfere with lactation, and further informa-

tion is being sought about this.The risks of thrombosis, embolism, and interference

with liver function require further investigation. If theserisks exist it should be possible to discover how they ariseand to take precautions against them.The Family Planning Association was responsible for

the initial trials of oral contraceptives in this country andhas done its best to ensure that the doctors at its clinicshave up-to-date knowledge of the subject and of theprecautions required in their use.

REFERENCES

Bishop, P. M. F. (1960) Clin. Obstet. Gynec. 3, 1109.— Boycott, M., Zuckerman, S. (1939) Lancet, i, 5.

British Medical Journal (1963) ii, 489, 550.— (1964) ii, 1089.

Brown, P. S., Wells, M., Cunningham, F. J. (1964) Lancet, ii, 446.Dodds, E. C., Goldberg, L., Lawson, W., Robinson, R. (1938) Nature, Lond.

141, 247.Drill, V. A. (1963) Ann. N.Y. Acad. Sci. 104, 858.Eisalo, A., Järvinen, T. A., Luukkainen, T. (1964) Brit. med. J. ii, 426.Gerrard, E. A. (1964) ibid. p. 207.Hunt, E. (1936) Lancet, ii, 1302.Kaufmann, C. (1933) Klin. Wschr. 12, 1557.Kennedy, B. J. (1963) J. Amer. med. Ass. 184, 758.Lancet (1960) ii, 256.Lipschutz, A., Iglesias, R., Salinas, S. (1963) J. Reprod. Fertil. 6, 99.Loraine, J. A., Bell, E. T., Harkness, R. A., Mears, E., Jackson, M. C. N.

(1963) Lancet, ii, 902.— Brown, J. B. (1959) J. Endocrin. 18, 77.

Mulligan, W. J., Horne, H. W., Rock, J. (1952) Fertil. and Steril. 3, 328.Palva, I. P., Mustala, O. O. (1964) Brit. med. J. ii, 688.Parkes, A. S., Bishop, P. M. F., Dodds, E. C. (1936) Lancet, i, 1366.Swaab, L. I. (1964) Brit. med. J. ii, 755.Tyler, E. T., Olson, H. J. (1958) Ann. N. Y. Acad. Sci. 71, 708.Winterton, W. R., MacGregor, T. N. (1939) Brit. med. J. i, 10.

MEDICAL CARE OF HOSPITAL STAFF

I. M. BROWNM.B. Aberd.

PHYSICIAN-SUPERINTENDENT,ST. MARY’S HOSPITAL, EASTBOURNE, SUSSEX

THE old saw about the cobbler’s traditional neglect ofhis family’s footwear can be aptly applied to the hospital’scare of its staff. At the start of the National HealthService, many hospitals had a health service for nurses,for whom tuberculosis was a recognised hazard; but littleattention was given to other staff. Although nurses maywell be exposed to greater risks of cross-infection, thereseems no reason why the same pattern of health care shouldnot be offered to others working in the hospital service-who indeed collectively outnumber the nurses.

In 1948 a health service was started at Eastbourne,