The Chocolate Coated Pill

From a dissertation on the side effects of Oral Contraceptives, read before the Society on Friday, 2nd December,


THE CHOCOLATE CO ATED PILL
Roger H. Smith, B.Sc.
From a dissertation on the side effects of Oral Contraceptives, read before the Society on Friday, 2nd December, 1966 T he great increase in the world birth rate that is presently taking place, and which increases the population by 165,000 people per day, has been estimated to double the total human population by the turn of the century.T h e problems set by such a rise in numbers is not confined to the East or to the " under developed" countries of Africa, but is calcul ated to increase the population of Britain by 50% in those same thirty-odd years.
Clearly, something has to be done to check this growth which far outstrips the foreseeable increase in food resources, and even more clearly the answer is birth control, in one way or another.In Britain at present the control is largely by two methods, the oral contra ceptive and the intrauterine device (IU D ), so that in 1965 over 500,000 women in this country were taking one or other form of pill at some time, and 400,000 took pills over a 12 month period without a break.But at the same time, the Pill has come in for much adverse criticism for its possible or actual side effects in both the lay and the scientific press, and as a result, there has grown suspicion and fear in many women and not a few doctors whose job it is to prescribe the Pill.

THE PILLS
In Britain the main drugs in use are com bined progestin/oestrogen preparations, taken between days five and twenty-five of the menstrual cycle.N ine such preparations are approved by the Council for the Investigation of Fertility Control (C IF C ), the research branch of the F P A .This paper will consider the evidence regarding the side effects of this type of pill alone.
Another type of Pill has recently been developed and marketed, known as the Sequential Therapy type, where pure progestin is given between clays 5-20 followed by five days of combined pills.But a certain failure rate does not allow as much confidence in these as in the combined forms, and for this reason only the combined form will be considered.

POSSIBLE SIDE EFFECTS
There are well established side effects to the Pill, such as initial nausea and vomiting in some women, but there are other effects not so well established, like liver damage, increased risk of thrombo-embolic disease, weight gain and other metabolic changes; this paper seeks to correlate the evidence available regarding these doubtful effects.

WEIGHT CAIN
It has been said that the weight gain during oral contraceptive therapy presents no problem.It was a man who said it, and not a woman, and it was in a m edical rather than a philoso phical context that it was said.W h en we talk about a weight gain we m ust consider the age group and sex of the subjects involved, and here we are dealing w ith wom en between the ages o f 16 and 50, the very people to whom any weight gain seems im portant.So that, far from presenting no problem , w eight gain could prove to be a deciding factor to any wom an consid ering w hether to take the P ill for th e first tim e, or w hether to continue taking it having once started therapy.B efore w e pass this off as of m inor im portance, we should at least exam ine the incidence and extent of w eight gains dur ing therapy, and investigate the cause and nature of the gain.
In a recent study, the C .I .F .C .found that treatm ent w ith A novlar is associated w ith a high incidence o f w eight gain; of 156 patients studied, 4 6 % p ut on m ore than 3lbs, and 22% gained m ore than 7 lbs.Liggins, using larger doses o f A novlar in th e treatm ent of dysfunc tional uterine bleeding, found general increases of w eight o f up to g lbs., and one case of a gain of 20 lbs., all over sim ilar periods o f tim e. B u t W isem an has found that treatm ent with com pounds other than A novlar, such as Conovid or O vulen, give equivocal results, weight gains over 3 lbs.being m atched by a sim ilar incidence of w eight loss greater than 3 lbs.W h ile com paring their actions in a different context, Jackson found that A novlar had a predom inately progesterone-like influence on th e reproductive organs but C o n ovid gave a m ore oestrogenic picture.T h u s, in those w om en on A novlar there was a dorm ant, hypo plastic endom etrium , w ith thick, scanty cervical m ucus, w hile w om en on C on ovid had cornified vaginal epithelium and proliferative endom e trium .
It is conceivable that w eight gain in A novlar therapy, then, is the expression of progcsteronelike properties of its progestin, N orethisterone, while the progestin of C onovid , or of O vulen, having less progesterone-like activity and m ore oestrogenic properties, would not be expected to stim ulate a gain in w eight.Such a hypothesis is supported b y evidence which suggests that Progesterone itself is an anabolic agent.
D ew ar has shown conclusively that the m ain tenance of the w eight gain o f pregnancy in m ice is dependent upon circulating Progest erone; furtherm ore, Progesterone adm inistered to m ale and non-pregnant fem ale m ice pro duced w eight gain, and this gain was uninfluenced by coincident oestrogen adm inis tration.Such gains were associated with increased appetite, and were the " m an ifest ations" o f th e accum ulation of body fat and body water, regardless of diet.O n unrestricted diets there were also increases in body protein.
D uring hum an pregnancy, the m other's w eight gain is associated w ith rising blood Progesterone levels; not all of this w eight gain is due to increased body water for there is a considerable increase in body nitrogen.T h e w eight gain of oral contraceptive therapy would likew ise seem to be anabolic, at least in part, for the fall in w eight w hich follow s the cessation o f therapy in such cases is slow, spread over several weeks or m onths, and its rate of fall is not affected to any significant degree b y th e application of diuretics.
T h ese lines o f evidence suggest that pro gesterone-like therapy, including som e oral contraceptives, can be expected to carry w ith it the possibility o f w eight gain of an anabolic nature.B u t a further factor m ay act in addition to anabolic influence, per se.; that is, increased appetite.T h e increased appetite m ight be seen as part of the anabolic effect, b ut it m ight be preferable to think of it rather as a m ani festation of the general " new lease of life " so w idely reported by patients introduced to oral contraception.If this is so, then dieting m ay often be a necessary accom panim ent of therapy.

F ig . 2
T h e effect on appetite would also help explain why other studies, such as that by Flow ers, have found w eight gains w ith O vulen and other products other than A novlar; indeed, one wom an out of 200 on O vulen gained 20 lbs. in three m onths.
T h e conclusion, then, m ust be that weight gain can be a m edical problem , and hence wom en or oral contraceptive therapy should be followed up; and usually the problem is a psychological one to th e patient, w hich m ight call for advice.In order to give advice where it is needed we m ust be presented w ith more hard facts from large scale studies of weight and appetite in treated wom en, and, where gains occur, of the nature o f this gain.

BLOOD COAGULABILITY
M uch has been m ade of the assertion that synthetic steroids m ight increase blood coagul ability.W h ile reporting in the m edical journals has stim ulated a proper study of the problem , the reaction to the advertising in th e news papers has bred a fear of oral contraceptives in m any wom en.T w o lines o f study have been pursued : (1) a large scale statistical com parison o f the incidence of throm bo-em bolic disease in wom en taking oral contraceptives and those of the same age-group not under going therapy.
(2) haem atological investigations in the treated and non-treated groups.
(1) Haematology Behind the word " coagulability" there are two prim ary processes of rem arkably sim ilar com plexity, coagulation and fibrinolysis.E ach com prises of a system of precursors and activ ators; each depends upon successive steps of activation; in each there is a num ber of negative systems tending to antagonise the various activation steps and products.T h e two pro cesses are currently thought to be in dynam ic equilibrium in the circulating blood, pivoting round the fibrin m olecule: the one process form s the clot, the other destroys it.A n y change in blood coagulability is the result of an upset of this norm al equilibrium .In assess ing the effect of an increased activity of any one part o f either system, one m ust consider whether there is not also a change in the activity of a factor or factors in the opposing system.In any event, the interpretation of such a rise within its own system is a very difficult task.
T h e only factor which has consistently been shown to change is factor V I I of th e coagul ation system; its blood concentration increases.N o other coagulating factor has been dem on strated to change in any reproducible m anner.Factor V I I also increases in pregnancy, and is increased in patients with recent D V T (" D eep Venous T hrom bosis" ), but only in these latter cases has there been dem onstrated a shortening of the heparin clotting tim e.If an increase in factor V I I , per se, is contributory to greater clotting tendencies, such increases as have been shown still cannot be said to constitute satis factory evidence for increased coagulability.T h ere is neither any inform ation regarding the state of the fibrinolytic system during therapy, nor of any influence that th e synthetic steroids m ight have on the antithrom bin and other systems.T h e only inform ation that can safely be accepted as evidence either way is that showing change in clotting or bleeding times.Pincus, in his classical trials using C onovid, did find shortening of bleeding and clotting times, but using 10 m g doses rather than th e 5 m g used

You already know
Lyndiol 2.5 to be the ora! contraceptive with the lowest incidence of side-effects, the most reasonable price-to-patient and the dosage scheme most likely to ensure patient reliability But did you also know that Lyndiol 2.5 is

Organon
Agencies of the U .S. G overnm ent have carried out large scale statistical surveys, and have concluded that " there is no increase in the incidence o f throm botic disease in women taking oral contraceptives com pared w ith the incidence in non-pregnant wom en of the same age group w ho are not treated" .
T h ere have been m any isolated reports of throm bo-em bolic disease in treated 'wom en, but it is im portant to consider that a certain incidence is in any case expected in wom en of th is age group, w hether or not they are taking th e pill.It is the view of the D u n lo p C o m m ittee that the incidence in treated women is indeed just that expected on this basis; but the C o m m ittee is nevertheless urging that all throm bo-em bolic incidents in treated women should be reported.H owever, by the tim e statistical analysis is possible and is available, it is likely th at the present form o f pill w ill be obsolete.
HEPATOXICITY M an y drugs have been shown to be toxic to th e liver, a fact that should not be surprising, fo r the liver is the m ain site of drug detoxic ation and excretion, and it is the first port of call for oral drugs once absorbed into the blood.C h olestatic jaundice of a non-sensitive type has been shown to develop in relation to therapy w ith the general group of steroids alkylated at the C -17 position, to which group belong m ost o f the progestins presently used in oral con traceptive preparations.T h e general rule is th at the C -17 alkylated steroids cause liver dam age if given often enough and in sufficient am ounts, so that the problem here is w hether the am ounts o f these com pounds in the various pills constitute a risk o f hepatoxicity.
M any studies have been carried out attem pt ing to determ ine just this one sim ple fact, only to find that the answer is not so sim ple.T h ere seems to be no com m on plan to the studies, each one having em ployed a different drug or com bination of drugs on different groups o f wom en in d ifferent countries and using different criteria for liver damage.B u t, com plicated as this m ight seem, it is possible to draw certain conclusions on th e subject, and to see certain general trends.
Scandinavian workers have been able to dem onstrate quite widespread liver damage in treated wom en, while elsewhere the conclusion has been that there is no danger of associated hepatoxicity during normal contraceptive therapy.In Finlan d, abnorm ally raised serum transaminase levels were found b y E isalo et al in all of seven post-menopausal w om en treated, and by Palva and M ustala in five.E isalo gave one or two tabs, per day o f L yn d io l; Palva used A novlar.Eisalo was later able to reproduce his results in a num ber of cyclical wom en between the ages o f 17 -52 using V o lid an as well as L ynd iol or Lynestranol.
O ther isolated reports have com e from Scandinavia, so that it has been suggested that the apparent high incidence o f liver damage there m ight be connected w ith the fact that viral hepatitis takes an unusually virulent form in this geographical area.H owever, B orglin in Sweden has not been able to dem onstrate hepatoxicity in patients on L yndiol.
In a British report on liver dam age, b y Aascher and C uth bert, five post-menopausal w om en had been treated w ith A novlar; their ages were between 62 -80.Stoll in A ustralia produced liver dam age in treating breast cancer with 6 tabs per day of L yn d io l, equal to 30 m g lynestranol + 0.9 m g m estranol; clearly this represents an abnorm ally m assive dose, b u t it docs serve to illustrate that these are potentially very dangerous drugs.T h u s there would seem to be tw o im portant factors in the aetiology of liver damage in treated w om en; one a possible post-menopausal predisposition to drug induced intra-hepatic cholestasis, and the other the possible predis position due to previous liver disease.A third possibility has been suggested, that Scandin avian wom en, and post-menopausal wom en in general, share som e com m on enzym e deficiency.
M ore reassuring are the results of a large scale study, b y T yle r in L os Angeles, which covers eight years o f observation.T y le r reports a general incidence of abnorm al liver function, but in each case the changes have been of the order expected in norm al pregnancy; it seems fair to conclude that these changes, due to a variety o f preparation, m ight not be patho logical but attributable rather to the pseudopregnant state.M o re specifically, he studied 6,500 cycles in 435 wom en on O rthonovin over a period o f 3 years, during which tim e he found no abnorm ality which could cause alarm, and certainly no indication in any patient that the pill should be discontinued by reason of liver damage.Sw yer and L ittle working in B ritain have failed to dem onstrate any liver m alfunction in a group of 12 wom en treated for a m inim um period of 3 years.Sim ilarly, workers in other parts of the world outside Scandinavia have failed to find evidence o f liver damage in norm al treatm ent.T h u s, apart from incidences in post-meno pausal wom en, or where large doses of drugs have been used, the only reports of hepatic dysfunction have com e from Scandinavia, and from Finlan d in particular.T h e pill would therefore seem to be safe as a contraceptive except for the one exception o f wom en w ith a history of liver disease.CONCLUSION H aving investigated the three problem s of weight gain, throm bo-em bolic disease and liver damage, it is apparent that there is little in the way o f definite scientifically based conclusion to be m ade.W h ile the scanty evidence avail able at present allows o f reasonable generalis ation, it also calls for m ore investigation.A nother tw enty years of study could clarify the im plications of therapy, b u t b y that tim e the present form of the pill will have been super seded.
N ot every wom an taking the pill is destined to becom e obese and yellow , w ith m assive D V T ; it would b e unrealistic to think so.B u t it would be equally ill-inform ed to ignore the real risks.H ow ever, the risks that seem to operate are greatly outweighed by the trem endous social the therapeutic advantages of oral contraceptive therapy.Dewar.Q.J. Ex. Physiol., 1957, 15, 216-229. Dewar. Q. J. Ex. Physiol., 1964, 49, 151. Egeberg and Owren. B.M.J., 1963, i, 220. Thomson and Poller. B.M.J., 1965, i, 1586. Food and Drugs Administration, 1963.Final Report on Enavid.
Press Releases of the Committee on Safety of Drugs.

DIAGNOSTIC PROBLEM (fro m page 3 1 )
Diagnosis : A drenocortical hyperfunction.Confirm ed by the finding of an elevated cortisol secretion rate together with high levels of urinary 17-hydroxycorticosteroids. In addition the diurnal varia tion of plasma 17-hydroxycorticosteroids was found to be absent although the absolute values were just w ithin the upper range o f normal.
T o determ ine the site o f th e underlying pathological lesion, the full range o f available tests was carried out.Space precludes their discussion here, but in the event the m ost telling evidence was provided b y a presacral aerogram w hich disclosed the presence o f an abnorm ally enlarged right adrenal gland.R ig h t adrenalectom y was carried out with the removal of a 28 G .cortical adenom a. Som e difficulty was subsequently experienced in discontinuing exogenous steriod therapy, but otherwise the patient m ade an excellent recovery with resolu tion of all presenting com plaints together with restoration o f blood pressure to norm al levels.
Laboratories Limited Newhouse • Motherwell • Lanarkshire in m ore m odern therapy.N o such results were foun d in the studies o f Egeberg or o f T h o m p son whose work is referred to above.

Fig
Fig. 4. Abnormal results of liver function tests (Eisalo et al 1965) , Mears: "Recent Advances in Ovar ian and Synthetic Steroids and the control of ovarian function" .Sidney Symposium, 1964.ed.Shearman.