1023

evidence with extreme care in each case before attributingeven a possible association with oral contraceptives. For

example, if extensive atheromatous narrowing of thecarotid artery in the neck is found in a woman who hasbeen taking contraceptives for only two cycles it would bedifficult to implicate the oral contraceptive as a cause ofthe atheroma; on the other hand it might be postulatedthat an added coagulation factor had precipitated theocclusion.This investigation was supported by a grant from the Scottish

Hospital Endowments Research Trust. Mr. J. Sloan Robertson andMr. A. Paterson kindly gave us access to patients under their care.Requests for reprints should be addressed to W. B. J., Institute of

Neurological Sciences, Killearn Hospital, Glasgow.

REFERENCES

Adams, J. H., Graham, D. I. (1967) Unpublished.Baines G. F. (1965) Br. med. J. i, 189.Bickerstaff, E. R., Holmes, J. M. (1967) ibid. i, 726.Bonnar, J., McNichol, G. P., Douglas, A. S. (1967) in Modern Trends in

Obstetrics (edited by R. J. Kellar). London (in the press).Bradford, D. E. (1967) Lancet, i, 679.Brakman, P., Astrup, T. (1964) ibid. ii, 10.Cahal, D. A. (1965) ibid. ii, 1013.Carroll, J. D., Leak, D., Lee, H. A. (1966) Q. Jl Med. 25, 347.Ehtishamuddin, M. (1965) Br. med. J. i, 921.Food and Drug Administration (1966) Report on the Oral Contraceptives by

by Advisory Committee on Obstetrics and Gynæcology. U.S. Govern-ment Printing Office.

Heasman, M. A., Lipworth, L. (1966) Accuracy of Certification of Cause ofDeath. H.M. Stationery Office.

Illis, L., Kocen, R. S., McDonald, W. I., Mondkar, V. P. (1965) Br. med. J.ii, 1164.

Intercontinental Medical Statistics Ltd. (1967) Personal communication.Jennett, W. B., Angel, F., Cross, J. N. (1967) Unpublished.Lancet (1966) ii, 96.Lorentz, I. T. (1962) Br. med. J. ii, 1191.Nevin, N. C., Elmes, P. C., Weaver, J. A. (1965) ibid. i, 1586.Stewart-Wallace, A. M. (1964) ibid. ii, 1528.Walsh, F. B., Clark, D. B., Thompson, R. S., Nicholson, D. H. (1965)

Archs Ophthal., N. Y. 74, 628.Wynn, V., Doar, J. W. N., Mills, G. L. (1966) Lancet, ii, 720.Zilkha, K. J. (1964) Br. med. J. ii, 1132.

VASOMOTOR-REFLEX RESPONSE IN

IDIOPATHIC AND HORMONE-

DEPENDENT MIGRAINE

J. M. HOCKADAYM.D. Cantab, M.R.C.P.

A. L. MACMILLANB.M., B.Sc. Oxon., M.R.C.P.

RESEARCH ASSISTANTS

C. W. M. WHITTYD.M. Oxon., F.R.C.P.

CONSULTANT NEUROLOGIST

DEPARTMENT OF NEUROLOGY, UNITED OXFORD HOSPITALS

Summary To investigate possible vasomotor abnor-malities in migraine, and any effect on

them of oestrogen and progestogen activity, reflex vaso-dilatation in the hand in response to brief radiant heatingof the trunk was investigated in five males and five femaleswith spontaneous migraine, in five women with migraineprecipitated by an oral-contraceptive regimen, and insix male and nine female migraine-free controls. None ofthe participants had had any preparation containing ergot.No significant differences in response were found betweenmigraine and non-migraine subjects; between males andfemales; between women at various stages of theirnatural menstrual cycles; or between women on and offan oral œstrogen/progestogen contraceptive. Restinghand blood-flow was significantly increased in women

taking oral contraceptives. Local vascular changes, whichthis increase represents, may form the basis for any

effect that an oral-contraceptive regimen may have onmigraine.

Introduction

IT is generally accepted that the headache of migraineis caused by painful vasodilatation of extracranial blood-vessels. Extreme variability of calibre in these vesselshas been observed in a number of migraine patients,especially during the 72 hours before an attack (Wolff1963). Some of the premonitory and associated featuresof an attack indicate that there may also be a more

generalised disturbance of vasomotor function. Struc-tural changes in systemic blood-vessels have been des-cribed occasionally in association with migraine. Redischand Pelzer (1943) observed dilatation and blurring ofoutline of nail-bed capillaries during a migraine attack,and Hauptmann (1946) described " immature capillarypatterns " in the nail folds of migraine subjects. Grant

(1965) has demonstrated abnormal endometrial arterioledevelopment in women liable to migraine. On thefunctional side also, Appenzeller et al. (1963) reportedthat reflex vasodilatation of blood-vessels in the skin ofthe hand in response to radiant heating of the trunk wasdefective in eight of ten migraine subjects. However,Elkind et al. (1965) found no differences in resting forearmskin blood-flows between controls and patients with

migraine, either during an attack or in headache-free

periods.Kerslake and Cooper (1950) established that the peri-

pheral vasodilatation which occurs in the hand in responseto radiant heating of the trunk is a nervous reflex fromcutaneous receptors. The presence of a normal reflex is,therefore, regarded as a test of the integrity of certainautonomic pathways. The reflex is absent in some patientswith cervical-cord or brain-stem lesions whose peripheralpathways are known to be intact (Appenzeller andSchnieden 1963, Johnson and Spalding 1964), thus indi-cating a central pathway passing at least to the lowerbrain-stem. The reflex is absent under conditions of lowskin or central body temperature: Cooper et al. (1964)established threshold levels below which the response isnot consistently obtained-skin temperature 33°C (91-6°F)and central body temperature 36-8°C (98’4OF). Macmillanand Hockaday (1966) found the response to be suppressedby the intravenous administration of a small dose of

ergotamine tartrate.Unless temperature and the administration of ergota-

mine are controlled, they may affect observations of thesort made by Appenzeller et al. (1963). Macmillan and

Hockaday (1966) measured the reflex vasodilatation

response in eight control and eight migraine subjects, underknown conditions of skin and central temperature, usingonly people who had never received any ergot preparation.Under standard conditions of temperature they found nosignificant difference in the magnitude of the reflex

response between the control and the migraine subjectsand suggested that the absence of the response in themigraine subjects noted by Appenzeller et al. (1963) wasrelated to previous therapy with ergot preparations.Any demonstration of unequivocal abnormality of vaso-

motor control in migraine is of importance to the under-standing of its pathophysiology. We have therefore usedthis established vasodilatation response as a yardstick ofpossible differences between normal and migraine subjectsin their response to hormonal variables considered toaffect migraine. It is commonly observed that somepatients may be free from attacks during pregnancy, and

T2

1024

therapy with parenteral or oral progestogens may reduceor abolish attacks (Lundberg 1965). In contrast, somewomen experience attacks only at certain phases of thenormal menstrual cycle, or when on an oral-contraceptive(oestrogen and progestogen) regimen. In the last situation

Whitty, Hockaday, and Whitty (1966) suggested that oneeffective stimulus may be the withdrawal of exogenousprogestogens.We have investigated the reflex vasodilatation response

in women at known stages of the natural menstrual cycleand when on an oral contraceptive (oestrogen/progestogen)regimen. We have also established that under thresholdconditions (Cooper et al. 1964) the response is the same inmales and females and have confirmed the earlier observa-tion of Macmillan and Hockaday (1966) that the responseis similar in migraine and non-migraine subjects of bothsexes. We report our findings here.

Subjects and Plan of InvestigationsTo determine if the response was affected by level of pro-

gesterone activity we tested women with migraine at timesin an oral-contraceptive regimen when progesterone activitywas likely to be high and at others when it was low. We alsotested non-migrainous women at times of high and low pro-gesterone activity in their natural cycle. Since progesteroneactivity may be relatively higher at all times in those on anoral contraceptive, all observations made in the females ona contraceptive regimen were compared with those made onhealthy females with a natural cycle.To confirm a previous observation that the response was the

same in migraine and non-migraine subjects we examinedfemale and male patients with migraine and subjects (femaleand male) without it. Finally, to determine whether the

response was the same in males and females we comparedresults from females with those from males (including migraineand non-migraine subjects).

All subjects investigated were entirely healthy, apart fromtheir migraine. None was receiving medication of any kind(except the five women who, as stated, were on oral-contracep-tive regimens), and none had ever received preparationscontaining ergot. Nineteen females and eleven males were

investigated as follows:Five women with hormone-dependent migraine-i.e., with

migraine occurring only after starting on an oral-contraceptiveregimen (three) or being much increased by such a regimen(two). All were investigated both while taking the contracep-tive pill and during the days off.Ten subjects (five male, five female), with spontaneous

migraine, who were otherwise unselected new patients attend-ing the neurological outpatient department.

Six male and nine female subjects without migraine and (withone exception) without a family history of migraine. Threeof the women were investigated on two occasions some weeksapart, and one was investigated three times.

Criteria for diagnosing migraine were that the patientshould have recurring, throbbing headaches, besides two ofthe following five features: unilateral headache, associatednausea with or without vomiting, visual or other sensory aura,cyclical vomiting in childhood, family history of migraine.

In seven of the women (twelve examinations) sufficientinformation was available for us to assess the probable phase ofthe natural menstrual cycle at which the reflex was tested.Oestrogen and progesterone levels during the normal cyclevary considerably. Loraine and Bell (1963) measuredhormone excretion during the normal menstrual cycle, andfound that excretion levels of pregnanediol rose in the lutealphase to be highest between the 21st and 28th days of thecycle, while pregnanetriol excretion started to rise at thetime of the mid-cycle oestrogen peak, reaching a peak on the23rd and 24th days of the cycle, oestrogen excretion showed amid-cycle, and a luteal-phase peak. Using these measure-ments as a guide, we have assigned our subjects to " low " or

TABLE I-MEAN RESTING HAND BLOOD-FLOW (ORAL TEMPERATUREø 36-8°C, SKIN TEMPERATURE 33°C)

Women in whom all observations were at subthreshold temperatures areexcluded.

" high " hormone (progesterone) activity states according towhether they were tested before or after mid-cycle.

In each of the five women receiving the oral contraceptives,the regimen was similar, comprising 21 days on medication,and 7 days off. All were investigated twice, at the end of theperiod off medication, and late in the period on medication.The preparations used were: Gynovlar ’ (norethisteroneacetate 3-0 mg., ethinyl oestradiol 0-05 mg.), ’ Orthonovin’(norethisterone 2-0 mg., mestranol 0-1 mg.), and ’Ovulen’(ethynodiol diacetate 1-0 mg., mestranol 0-1 mg.).Method

Hand blood-flow was measured by venous occlusion

plethysmography: skin temperature by a thermocouple attachedto the anterior chest wall with adhesive tape, and oral tem-perature with a clinical thermometer under the tongue.The subjects lay on a comfortable couch with a radiant-heat

cradle over the upper trunk. Hand blood-flow was recordedfor 1 minute, and the average flow over this period is called theresting hand blood-flow. The radiant-heat cradle was thenswitched on for 2 minutes; the average hand-blood flow duringthe last 90 seconds of this 2-minute period was used to measurethe reflex response. The reflex response is expressed as theincrease in flow over the resting flow, and as the percentageincrease. In nearly all subjects the response was measuredfive or more times, the subjects resting for at least 4 minutesafter the heat cradle was switched off before the response was

again measured.Results

First the mean resting hand blood-flow, and the meanreflex response was calculated for each individual.Because of the known suppressive effect of low skin andcentral body temperatures on the reflex, this mean

response was calculated, firstly, using all measurements,and, secondly, using only those measurements made whenthe skin and central body temperatures were at or abovethreshold levels-33°C and 36-8°C respectively (Cooperet al. 1964). From these values, the mean, and the stan-dard deviation (S.D.) of the mean, were then calculated ineach group we wished to compare. Both sets of results are

presented here, but only the results obtained at thresholdtemperatures are detailed in tables and 11.The significance of the response for each individual was

tested at the 5% level, and if this arbitrarily chosen levelwas met, the response was said to be positive.

In the following comparisons there was no difference inthe initial oral temperatures in the groups being compared.The resting hand blood-flows were also similar except inthose comparisons involving the five women on oral con-traceptives when they were taking the pill: their mean handblood-flow was 18-93 ml. (:t:l0.19) per 100 ml. hand perminute (all results) and 18-51 ml. (±10-61) per 100 ml.hand per minute (including only threshold temperatureresults). In the fourteen women with natural menstrualcycles the mean resting flow was 8-15 (±4-77) (all results)and 8-81 ml. (±5-01) per 100 ml. hand per minute(including only threshold temperature results). The

1025

TABLE II-MEAN REFLEX INCREASE IN HAND BLOOD-FLOW (ORAL -TEMPERATURE 36’8°C, SKIN TEMPERATURE 33°C)

differences between the two groups are significant at the1% level (all results) and 2% level (threshold temperatureresults) (table i). The variability in resting blood-flows inthe five women on oral-contraceptive regimens when theywere examined while off medication was such that it isnot possible to use them for comparison with othergroups.

Effect of Progesterone ActivityTo elicit any change in the reflex related to hormone

state the results obtained in women when progesteroneactivity was considered to be high were compared withthose obtained when it was considered to be low.

First, this comparison was made in five women receivingoral contraceptives. Measurements had been taken at a

stage in the cycle when artificially administered progesto-gen levels were considered to be high (i.e., in

" mid " or" end " cycle) and at a stage in the cycle when progestogenlevels were lowest (i.e., all observations made at least 4

days after the end of the period on the pill. The numbersof women showing a positive response-expressed both asan increase in hand blood-flow and as the percentageincrease, and including all results or only results obtainedat threshold temperatures-were not significantly different(chi-squared test). The magnitudes of the mean reflexresponses, expressed as the rise in hand blood-flow, werealso similar (for all results, 0-80 >p> 0-70; for resultsobtained when threshold-temperature requirements weremet, 0-99 > p > 0-98, table 11).Second, this comparison was made in women with

natural menstrual cycles, comparing results obtained beforemid-cycle with those obtained after mid-cycle. Seven

investigations were carried out (in six women) after mid-cycle, and five (in three women) before mid-cycle. The

frequency of positive responses before and after mid-cyclewere again similar (chi-squared test). The significance ofthe difference between the size of mean reflex response inthe two groups was tested, and it never reached the 5%level (for all results 0-50 > p > 0-40; for results at thresholdtemperatures, 0-10> p > 0-05, table 11).Effect of Oral-contraceptive RegimenTo determine whether the reflex was altered (irrespec-

tive of the stage of the cycle) in women receiving oral con-traceptives, the results in the five women on such regimenswere compared with those obtained in the nine migraine-free women with natural menstrual cycles. Again, the twosets of results obtained in the women on contraceptiveswere used. The number of women with natural cyclesshowing a positive response was not significantly different

Subjects in whom all observations were at subthreshold temperature are excluded.

from the number in the group of women on contraceptiveregimens (whether " on " or " off " the pill) (chi-squaredtest). There was no significant difference between themagnitude of the mean response obtained in the groupwith natural menstrual cycles and that in the group onoral contraceptives during the " off" phase (for all results,0-20 >p> 0-10; and for results obtained when threshold-temperature requirements were met, 0-50 > p > 0-40, tableII). Similarly there was no significant difference when thecomparison was made using the figures obtained in thegroup on contraceptive regimens during the " on "

phase (for all results, 0-30 > p > 0-20, and for threshold-temperature results, 0-50 > p > 0-40, table 11).

Effect of MigraineTo confirm that the response was the same in those with

and without migraine, the results in fifteen subjects (sixmale, nine female) without migraine were compared withthose in ten subjects (five male, five female) with spon-taneous migraine. The numbers showing a positiveresponse, expressed as an increase in flow, and as a per-centage rise, and including all results or only thresholdtemperature results, were similar in each group (chi-squared test). When all results were included, the magni-tude of the mean increase in flow in the migraine-freegroup exceeded that in the migraine group (0-02 > p > 0-01),but when results obtained at threshold temperatureswere compared, there was no significant difference be-tween the two groups (0-20 > P> 0-10, table 11).

Effect of SexTo determine whether the response was the same in

males and females, results in eleven men (five with mig-raine, six without) were compared with those in fourteenwomen (five with migraine and nine without). The num-bers of subjects showing a positive response were againsimilar in the two groups. The magnitude of the meanreflex response in the female group exceeded that in themale group (0-05 > p > 0-025) when all results were in-cluded, but when the results obtained only when thresholdtemperature requirements were met were compared, therewas no significant difference between the two groups(0-30 > p > 0-20, table 11).

Discussion and Conclusion

The results confirm the earlier observation that there isno demonstrable abnormality of reflex vasodilatation inthe hand in response to reflex heating of the trunk (Mac-millan and Hockaday 1966) in an unselected group ofmigraine subjects, when compared with a group of healthy

1026

migraine-free subjects under certain controlled conditions.Variables such as oral temperature, skin temperature, and

resting hand blood-flows, were similar in the two groups,and none of the participants had ever been treated withergot derivatives. No subjects had any neurologicaldeficit which might affect the reflex pathway, and skin andcentral body temperature levels were monitored so thatobservations made at subthreshold temperature levelscould be excluded.

We conclude that under these conditions migrainesubjects, at any rate between attacks, have a normal

response. An earlier report of its absence (Appenzelleret al. 1963) may be related to the treatment of thesepatients with ergot derivatives, or to their investigationunder temperature conditions when the reflex is knownto be suppressed.The results were regrouped to determine whether the

magnitude of the reflex response differed according to sex.The females were aged from 18 to 39, and all had normalmenstrual cycles; the males were aged from 17 to 40.When results obtained at or above threshold temperatureswere compared, there was no apparent difference in thereflex response between the sexes.

The reflex response was normal in the small group ofwomen taking oral oestrogen/progestogen compoundsirrespective of the stage of the contraceptive cycle, whenthey were compared with a group of migraine free womenwith natural cycles. Further, it was not possible to

demonstrate that the reflex response was altered in relationto a particular stage of the artificial cycle. There was nosignificant difference, either in the number of women

showing a positive response, or in the magnitude of theresponse, whether they were tested at a time of highprogesterone activity, or when this activity was lowest.Similarly, when women with natural menstrual cycleswere tested at high or low progesterone activity stages ofthe cycle, no difference in the response was found.

However, the rate of hand blood-flow at rest was higherin the five women on oral contraceptive regimens whenthey were tested while receiving medication than it was inwomen with natural menstrual cycles. These resultsaccord with the findings of Goodrich and Wood (1964),who showed an increased forearm blood-flow in the thirdtrimester of pregnancy, and during therapy with oral

oestrogen/progestogen contraceptives (stage of cycle notstated), and with the demonstration of increased venousdistensibility in pregnancy (McCausland et al. 1961) andin the progestational phase of the menstrual cycle(McCausland et al. 1963). Although the number of sub-jects examined is small, our findings suggest that peri-pheral vasomotor function is altered in women receivingoral oestrogen/progestogen preparations. Since reflex

response is not reduced, this could well be due to changesin peripheral vessels, and myogenic rather than neurogenicin nature.

The magnitude of the reflex response is neither enhancednor suppressed by natural or artificially induced variationsin progestogen activity. The apparent precipitation denovo, or the enhancement, of vascular headaches, includ-ing migraine, in women taking oral contraceptives (Grant1965) is not accompanied by a reflex abnormality of vaso-motor function as measured by this response, but may berelated to a change in peripheral vasomotor function asshown by a high resting blood-flow in such women.We thank Dr. J. M. K. Spalding for helpful advice; Miss J. Aspden

for secretarial help; the Medical Research Council and the NationalFund for Research into Poliomyelitis and Other Crippling Diseasesfor grants to J. M. H. and A. L. M., respectively.

Requests for reprints should be sent to J. M. H., Department ofNeurology, Churchill Hospital, Oxford.

REFERENCES

Appenzeller, O., Davison, K., Marshall J. (1963) J. Neurol. Neurosurg.Psychiat. 26, 447.

— Schnieden, H. (1963) Clin. Sci. 25, 413.Cooper, K. E., Johnson, R. H., Spalding, J. M. K. (1964) J. Physiol., Lond.

174, 46.Elkind, A. H., Friedman, A. P., Grossman, J. (1964) Neurology, Minneap.

14, 24.Goodrich, S. M., Wood, J. E. (1964) Am. J. Obstet. Gynec. 90, 740.Grant, E. C. G. (1965) Lancet, i, 1143.Hauptmann, A. (1946) Archs Neurol. Psychiat., Chicago, 56, 631.Johnson, R. H., Spalding, J. M. K. (1964) J. Physiol., Lond. 171, 14p.Kerslake, D. McK., Cooper, K. E. (1950) Clin. Sci. 9, 31.Loraine, J. A., Bell, E. T. (1963) Lancet, i, 1340.Lundberg, P. O. (1965) Excerpta med. int. Congr. Ser. 94, 167.McCausland, A. M., Holmes, F., Trotter, A. D. Jr. (1963) Am. J. Obstet.

Gynec. 86, 640.— Hyman, O., Winsor, T., Trotter, A. Jr. (1961) ibid. 81, 472.

Macmillan, A. L., Hockaday, J. M. (1966) Proceedings 4th European Con-ference on Microcirculation, Cambridge; p. 87.

Redisch, W., Pelzer, R. H. (1943) Am. Heart J. 26, 598.Whitty, C. W. M., Hockaday, J. M., Whitty, M. M. (1966) Lancet, i, 856.Wolff, H. G. (1963) Headache and other Head Pain; p. 277. New York.

INFLUENCE OF ENVIRONMENTAL FACTORS

ON FŒTAL GROWTH IN MAN

PETER GRUENWALDM.D. Vienna

ASSOCIATE PATHOLOGIST, SINAI HOSPITAL OF BALTIMORE; ASSOCIATEPROFESSOR OF PATHOLOGY, JOHNS HOPKINS UNIVERSITY, BALTIMORE,

MARYLAND, U.S.A.

HATAO FUNAKAWAM.D. Hokkaido, M.P.H.

CHIEF, DIVISION OF CHILD HEALTH, INSTITUTE OF PUBLIC HEALTH,MINATO-KU TOKYO, JAPAN

SIGERU MITANIM.D. Tokyo

DIRECTOR, MATERNITY HOSPITAL OF THE RED CROSS OF JAPAN,SHIBUYA-KU, TOKYO, JAPAN

TOSHIO NISHIMURA

M.D. KyotoPROFESSOR AND CHAIRMAN, DEPARTMENT OF OBSTETRICS AND

GYNECOLOGY, SCHOOL OF MEDICINE, KYOTO UNIVERSITY, KYOTO, JAPAN

SHIGEKI TAKEUCHI

M.D. TokyoDIRECTOR, METROPOLITAN TSUKIJI MATERNITY HOSPITAL, CHUO-KU,

TOKYO, JAPAN

Summary It would be important to ascertainwhether the increase in average birth-

weight after improvement of economic and health condi-tions is due to increasing length of gestation or betterfœtal growth. Hospital records of three large Japaneseobstetric services were used to obtain information on

birthweight in relation to gestational age during a 20-yearperiod in which not only recovery from war-time depriva-tion took place, but also increase in mean birthweightover pre-war levels. Duration of pregnancy was not

increased, but fœtal growth curves showed a strikingincrease of weight for gestational age during the later partof the third trimester of pregnancy. This attests to the

prominent influence of socioeconomic factors on fœtalgrowth. The curves are consistent with the hypothesisthat differences in average birthweight of populationgroups are due to variations in the time at which growth