THE EFFECTS OF PENICILLIN ADMINISTRATIONON MENSTRUAL AND OTHER SEXUAL

CYCLE FUNCTIONS- BY

A. E. W. McLACHLAN and DONALD D. BROWNVenereal Diseases Medical Officers, City and County of Bristol

Since penicillin became available for thetreatment of bacterial infections, the non-toxicity of the drug has been the subject ofuniversal emphasis. Nevertheless, a numberof toxic sequels, chiefly of minor importance,have been reported. These were more frequentin the early days of penicillin therapy, havegradually become less common, and wereprobably correctly ascribed, in the majorityof cases, to the impurities unavoidably presentin the commercially processed drug. Thestandard of purity attained by the time thatpenicillin became available for the treatmentof gonorrhoea and syphilis in the civilianclinics of this country has made untowarddrug-sequele extremely rare, in our experience,with the exception of those related to themenstrual function.

Early in our series of cases, alterations inthe normal menstrual cycle of non-pregnantpatients were observed, notably the onset ofpremature menstrual periods, lengthenedperiods, increased loss, and premenstrual or

trual dysmenorrhaea, and, in the case ofiant women, the occurrence of uterineos in relation to penicillin administration.rst these were presumed to be due to)cal pathological conditions present or torxheimer-like reaction.te frequency of menstrual sequele, how-seemed to indicate that the drug or somerity was the cause. That this was indeed

th- _ase was proved by the occurrence ofsi- tr phenomena in uninfected control cases,

a healthy volunteer, the other two beingmild cases of trichomonatous vaginitis whosetreatment had been completed. These 3patients were particularly chosen for their

B

previous constancy in menstrual cycle, loss,and dysmenorrhoea. The results of theadministration of 150,000 Oxford units ofpenicillin, given in 5 doses each of 30,000 unitsat 3-hourly intervals, are shown graphicallyin Figs. 1, 2, 3. In one of the patients men-struation occurred 7 days before the expecteddate: in the other two the periods weredelayed by 7 and 10 days respectively. Theduration of menstrual flow was increased by2 to 3 days in all 3 patients. Loss was increasedin all instances, and clots were also increasedin the 2 cases in which they normally occurred.Premenstrual dysmenorrhoea was increased inone, abolished in one, and instituted in thethird. Menstrual dysmenorrheea, severe inone patient, occurred for the first time in all3 patients and persisted throughout the period.In these cases the subsequent periods werenormal in all respects. This experimentindicated that menstrual irregularities couldbe instituted by the penicillin available, andit was decided to investigate the subjectfurther.

Examination of the literature has revealedfew observations on the menstrual sequelsof penicillin administration. Leavitt (1945)states: " The effect of penicillin in inducingpremature menstruation or in prolongingmenstruation already started has been thesubject of comment by several of the doctorscontributing to the Bulletin of the RapidTreatment Centres." Unfortunately we havenot been able to obtain access to this publica-tion. In his personal series of cases, Leavittfound that 8 out of 21 pregnant patientstreated with penicillin manifested symptomsof 'uterine activity-uterine cramps, bleeding,

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PENICILLIN ADMINISTRATION AND SEXUAL CYCLE

or both. Of these 8 patients, 2 evacuatedthe contents of the uterus. He consideredthat the action of the penicillin on the uterusmight be due to some impurity, as 7 of these8 cases had been treated with the same batchof the drug. Lentz and others (1944) noted2 cases of threatened abortion followingpenicillin treatment for syphilis in pregnantwomen. Mascall (1945) stated that almostall his patients complained of premenstrualpain or uterine pain; menorrhagia was amarked symptom, and if the period wasnearly due its onset was expedited. In 2 casesof early pregnancy there had been abortion.He believed that these side-effects were due,not to the penicillin, but to some associatedimpurities. Walker (1945) had also notedsimilar menstrual phenomena.

Speiser and others (1946) did not observeany menstrual abnormality following penicillintherapy attributable to the drug. In only 1

instance in 100 cases of early syphilis treatedwith penicillin was there any alteration fromthe usual cycle. He suggested that someassociated pathological process may haveaccounted for the intermnenstrual bleedingnoted by other workers. (This, in view of ourrecent observations with pure penicillin, may

be a reflex of the purity of the drug used bySpeiser and others.)

Personal ObservationsThe immediate and later sexual-cycle side-

effects of penicillin administration have beenstudied in an unselected series of 216 non-pregnant women observed, except where other-wise indicated, for a mnimum of 4 post-therapeutic menstrual cycles, in 32 pregnantwomen treated at varying stages of gestation,and in 16 women whose treatment commencedduring the puerperium. Sodium and calciumsalts of varying batches and of differentmanufacture have been employed in aqueoussolution, or in beeswax-arachis-oil or beeswax-ethyl-oleate emulsion. There has been insuffi-cient evidence to indicate that any individualbatch of drug or vehicle was more-or less-provocative of reactions than the others. Onthe other hand it is apparent from con-sideration of the graphs that, while thesequele were minimal in patients treated with100,000 Oxford units (Figs. 7 to 10), these areof essentially similar character to thoseoccurring in the higher dosage groups (Figs.11 to 21). The distribution of cases, schemesof penicillin treatment, and incidence ofuterine sequelk are indicated in Table I.

TABLE I

PENICILLIN DOSAGE AND INCIDENCE OF UTERINE SEQUELRF

Total dosage 100,000 150,000 200,000 300,000 2,400,000 2,400,000of penicillin units units units units units units

5 x 20,000 5 x 30,000 40,000 units single doseDetailsof* units units 3-hourly 300,000 TotalaDmiitratison 3-hourly 3-hourly single dose single dose for 71 days units dailyadministration (aqueous (aqueous (emulsion) (emulsion) (aqueous for 8 daysan s u solution) solution) calcium calcium solution) (emulsion)

sodium sodium sodium calciumand calcium and calcium

0I . 0 a 0 I . V. 0100 aI&8z I6~z I6 I Ca~1

Non-pregnant . 8 6 75-0 42 -40 195-2 46 34 73-9 4 4 100 96 94 97- 10 10 100 2061188 91P3Pregnant.. . - -! - 6 1 16-7 6 1 16-7 ------ 20 12 60 - 32 14 438

Puerperal . -.__| .- 4 2 50-0 - - - - - 12 10 833|- -I- 16 12 75 0Amenorrhcea:Physiological

(no causeascertained) 4 4 100 - - 2 2 1 - - . 6 6 100

Pubertal .. 2 2 1 - - 2 2 100Menopausal - _ 2 2 1 - _ 2 2 100

Normal controls 3 100 _ - 1 3 3100

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TABLE 11

PENICILLIN DOSAGE AND MENSTRUAL PERIODS AFFECTED

Penicillin: Number Number Post-penicillin menstrual periods affecteddosage in of of patients _ __ _ __

Oxford units patients affected 1 1, 2 1, 2, 3 1, 2, 3,4

100,000 8 6 2 4 - -150,000 42 40 30 4 4 2200,000 46 34 20 10 4 -300,000 4 4 2 2

2,400,000 106 104 64 24 4 |. 12

Total 206 188 118 44 12 14

Percentage 100 91[3 57 3 21-4 5-8 6-8

MENSTRUAL FUNCTION SEQUELIEMenistrual Periods.-Analysis of the menstrual

periods affected in the various groups of patients(Table II) indicates that, in the vast majority,the sequelh have been related to the first 2 post-penicillin cycles although in some cases the thirdand fourth cycles may also be affected. Thereis again a striking similarity in the pattern of resultsin the various groups independent of time-dosagefactors.The chief symptomatic changes in relation to

the menstrual function are shown in Table III.Approximately 60% of the patients show changesin cycle, in duration of period, and in menstrualloss.

Menstrual Cycle.-The cycle was lengthened in27-2% of cases, the average increase being 9 to11 days (limits, 2 to 41 days); it was shortenedin 32.7% of cases, the average being 10 to 11 days(limits, 2 to 20 days). In the remaining 40-1%the cycles were unaffected.

Menstrual Flow.-The duration of menstrualflow was lengthened in 44-5% of cases, the averageincrease being 5 to 6 days (lirmits, 1 to 22 days)beyond the patient's normal; it was shortenedin 11 7%, the average being 2 days. The remaining43-8% were unaffected.

Menstrual Loss.-This was increased in 56-1%of cases, the increase in the majority being" marked," but in 10% being extremely heavy.Loss was decreased in 2 5% of cases, while theremaining 41 4% were un-affected. The occurrenceof menstrual clotting for the first tirne was notedby 12.1% of patients.

Dysmenorrhawa.-Perhaps the most strikingfeature of penicillin therapy has been the institutionof premenstrual or menstrual dysmenorrhcea inapproximately one-third of the cycles, while, on

the other hand, some 10% of patients normallysuffering dysmenorrhcea experienced temporaryor permanent relief. Premenstrual pain commonlyoccurred 2 days before the onset of flow, beingof moderate severity in the majority of cases.Exceptionally, the associated abdominal pain andtenderness were hyperacute and were highlysuggestive of an " acute abdomen." There were,however, no associated temperature, pulse rate,or respiratory increases, and the pain usuallyabated with the onset of menstrual flow. Menstrualpain, while usually of moderate degree in thoseaffected, was occasionally of the utmost severity.

Mittelschmertz Phenomenon.-T h e m i t t e 1-schmertz phenomenon was noted in 8 patients, 6of whom had had 2,400,000 units of penicillin forthe treatment of early syphilis, the remainint 2receiving 200,000 units for the treatment ofgonorrhea. None of these patients had previouslyexperienced this phenomenon, nor has it recurred.One other patient complained of intermenstrualbleeding; she noted a scanty 1-day loss, recurringevery third day for 2 menstrual cycles and com-mencing 3 days after the cessation of the firstpost-penicillin period (Fig. 26).

At the start of this investigation, an attemptwas made to determine by graphical recordswhether a general pattern of results could berelated to the time in the menstrual cycle atwhich penicillin was exhibited. It soonbecame apparent that the seque-e -alterationsin cycle, in loss, and in the occurrence ofdysmenorrhoea, etc.-were unpredictable forany given patient. That, however, the sequelkeare of individual idiosyncratic pattern isshown in 5 of our cases by the recurrenceof similar phenomena in the same patient onrepeated administration of penicillin (Fig. 6).

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PENICILLIN ADMINISTRATION AND SEXUAL CYCLE

TABLE III -

POST-PENICILLIN MENSTRUAL SEQUELk3

Penicillin dosage in Oxford units Total Per cent.

100,000 150,000 200,000 300,000 2-4 mil.

No. of menstrualperiods involved 12 60 64 6 182 324 100

Menstrual cycle: .Lengthened .. 2 18 12 0 56 88 27-2Shortened 2 28 22 0 54 106 32-7Unaffected 8 14 30 6 72 130 40-1

Duration ofperiod:Lengthened .. 6 26 22 6 84 144 44-5Shortened ".2 2 34 38 11 7Unaffected 6 32 40 64 142 43-8

Menstrual loss:Increased 10 46 30 4 92 182 56-1Decreased - 4 - 4 8 2 5Unaffected 2 10 34 2 86 134 41P4

Clots:Increased . - 12 2 _ 6 20 6-1Decreased - 2 - - 4 6 1.9

-Instituted .. 12 6 22 40 12-4Abolished .. 2 2 0-6Unaffected 12 34 54 6 150 256 79 0

Dysmenorrhaea:Premenstrual

Increased . 6 - 2 6 14 4.3Decreased .. 2 - 2 0-6Instituted . - 6 4 20 30 9.3Abolished .. 2 2 2 12 18 5.5Unaffected .. 12 44 58 2 144 260 80-3

MenstrualIncreased .. - 6 6 1.9Decreased - 2 2 4 1-2Instituted . 20 6 4 36 66 20-4Abolished .. 4 - 8 12 3-6Unaffected . 12 28 58 2 136- 236 72-9

PHYSIOLOGICAL AMENORRHCEAIn 3 cases of physiological amenorrhcea, varying

in duration from 8 to 15 weeks and for which nocause could be determined, 100,000 units ofpenicillin (for gonorrhoea) restored normal men-strual function. In the fourth case (of 3 months'duration) a heavy period occurred 1 week after100,000 units of penicillin; some 30 days later640,000 units of penicillin were administered in2 days for a relapse manifested by arthritis; thistreatment was again followed by one heavy period,and subsequently by normal cycles (Figs. 4, 5). Inthe other 2 cases ofapproximately similar durations,courses of 2,400,000 units for sero-negative primaryand sero-positive syphilis were followed by the

same result. In 2 cases of pubertal amenorrhoeaof 4 and 6 months' duration respectively, occurringin patients of 14 and 14j years of age who werethe subjects of congenital and acquired syphilisand who were treated with 2,400,000 units ofpenicillin, menstruation was re-established for2 complete menstrual cycles: further follow upof these cases proved impracticable because oftheir transfer elsewhere (Fig. 22).

MENOPAUSEIn 2 patients at the menopause, penicillin tem-

porarily restored the menstrual function. In 1patient, aged 51, in whom no menstrual loss hadbeen noted for 9 months, a 1-day flow occurred

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BRITISH JOURNAL OF VENEREAL DISEASES

on the third day of a 74-day (2,400,000 unit)course of penicillin. This was followed 22 dayslater by a 4-day period of moderately heavy loss.No further menstruation was noted. The otherpatient, aged 45, had been increasingly irregularfor about a year, the last menstrual losses being86 and 129 days respectively before the com-mencement of a 2,400,000 unit course of penicillinfor late syphilis. Seven days after completion ofpenicillin therapy a normal 6-day menstrual losswas experienced. This was followed by a 3-dayloss 40 days later, since when the menses haveceased completely (Figs. 23 and 24).

PREGNANCY

Of 32 cases of pregnancy treated with penicillin(Table IV), 12 experienced uterine cramps. Ofthis number 3 showed, in addition, uterine hemor-rhage. Cramps occurred most commonly on thefirst day, usually after the second or third injection

of penicillin, and consisted of a series of 1 to 3moderately vigorous uterine contractions, followedby a sequence variable in number and graduallydecreasing in amplitude. The contractions lastedover a period varying from a few minutes up to2 to 3 hours. Recurrence of the pains was unusual.Bleeding was in no case of serious import, andvaried from a slight staining of the linen to markedsoiling of a sanitary pad.Labour occurred in 5 patients, 3 between the

seventh and ninth months of gestation, and theremaining 2 at " term." In the 3 patients of thefirst group (seventh to ninth month) labour painsfollowed " penicillin cramps " without any initialhiemorrhage. In 1 patient (7 months pregnant,in whom asymptomatic early syphilis was detectedby routine ante-natal serological tests) the uterinecramps, of very moderate severity, began on thefirst day of penicillin treatment, passed off in1 hours, and were followed after an interval of

LE IV

PENICILLIN DOSAGE AND INCIDENCE OF UTERINE SEQUELA3 IN PREGNANCY

Uterine sequelaeDosage ofMonth penicillin Number Uterine cramps Bleeding * Labour Day ofonset of

nancy |units) patients No. of | No. of No. of commencementnancy ord -atent_afete_ ptint affected_ patieeqents(roaffe afce paften aff ected affected of injections)

150,000 2 1 50 1 50 - 5

0-3 200,000 2 - -

2,400,000 2 - - - - - --

150,000 - - - - - - --

4-6 200,000 4 - _

2,400,000 6 2 33-3 1 16-7 - 1,4

150,000 4 1 25 1 25

7-9 200,000 -

2,400,000 10 7 70 1 10 3 30 1,1,2,3,4,6,8

150,000 - - - I -Term t

200,000 - - -

2,400;000 2 2 100 - 2 100 1,8

32 13 40-6 4 12-5 5 15-6 -

* Bleeding was associated with uterine cramps and these cases are included in this group.t Patients whose treatment began within 24 hours of the&calculated date of confinement.

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PENICILLIN ADMINISTRATION AND SEXUAL CYCLE

4 hours by labour pains. A macerated feetus wasexpelled some 10 hours later. In this case for4 or 5 days before the onset of labour foetalmovements had not been felt nor the feetal heartsounds detected, and the appearance of thefoetus was consistent with death at that time.The second patient was suffering from late

congenital syphilis, also detected by ante-natalserological tests. Uterine cramps of moderateseverity began 2 hours after completion of the7i days' course of treatment and persisted for8 to 10 hours. Labour, which began the folIowingday, resulted in a healthy 7 months' infant.

In the third patient, 8 months pregnant and thesubject of untreated late secondary syphilis, foetalmovements ceased on the third day of penicillintreatment and the faetal heart sounds could nolonger be heard. Uterine cramps occurred onthe third and fourth days but were of very mildcharacter. Apart from this, the course of peni-cillin was completed uneventfully. Thirty-six hourslater labour commenced and resulted in the birthof a small macerated feetus.

The role of penicillin in causing labourmust be regarded as doubtful in the first andthird cases, because of the feetal death dueto syphilis, but it cannot be ignored as aprobable precipitant of labour in the secondcase. In the 2 cases at " term " i.e. within48 hours of calculated date, labour com-menced in 1 following uterine cramps conse-quent on the second penicillin injection, andin the other following cramps occurring onthe last day of the course of treatment. Fromthese cases at term no conclusions can bedrawn. It seems, however, permissible tosuggest that the sequele of pepicillin treatmentin pregnancy are more likely to occur withthe higher dosages and in the more advancedstages of pregnancy.

PUERPEIJUMOf 16 patients whose penicillin treatment began

early in the puerperium, 12 showed some altera-tion in the lochia. Four patients were treatedwith 150,000 units. Of these, 2, treated on thefifth and eleventh days respectively, were unaffec-ted; 1 (fourth day), showed a marked-increasein lochia rubra, persisting for 36 hours, whichthen rapidly diminished and became serous;1 (eleventh day) showed a rapid diminution inlochia alba which had completely ceased at thetermination of the 12-hours' penicillin administra-tion. No further visible loss was reported.Twelve patients were treated with 2,400,000

units. Two were completely unaffected. Three,

after penicillin commencing on the fourth, fifth,and eighth days of the puerperium respectively,showed a marked increase in loss, temporary innature, and in no case persisting after the termina-tion of the penicillin course or altering the normalsequence of lochial changes. Six (third, fourth,fourth, sixth, seventh, and tenth days respectively)experienced marked decrease of lochial flowwithout alteration of the total duration. In1 patient (sixth day) however, the lochia ceasedccompletely within 12 hours of the commencementof the penicillin course and did not become-re-established.

LACTATIONDuring the puerperium it was noted that

changes in lactation occurred in relation to,penicillin therapy. Of the 4 patients treated with150,000 units, 2 were unaffected, 1 showed a-temporary decrease of secretion for 48 hours afterpenicillin administration, while 1, after a pro-gressive diminution in secretion, became " dry '"after 5 days in spite of all efforts to restore thefunction. Of the 12 patients treated with 2,400,000-units, 2 showed no lactatory changes, and &experienced a temporary decrease limited to theduration of penicillin administration. In 2 cases,however, lactation completely ceased and couldnot be re-established. Two of the 3 patientsexhibiting failure of lactation had, in previouspregnancies, successfully breast-fed their infants.

The vagary of lochial alterations does notappear to depend upon the dosage or pointin the puerperium at which the penicillintherapy was commenced. Similarly the stageof disease had no bearing; the 4 cases ofgonorrhcea (150,000 units) were all uncompli-cated, while analysis of the syphilis groupshows no significant variations in sequels inthe early, late, and late congenital stages.The numbers of cases observed are, however,so small that only the most tentative conclu-sions can be drawn.

In regard to lactation, however, a moreconstant sequel is seen in the depression ofthe function in 75 per cent. of the patientsobserved, the criterion of " decrease" beingthe necessity for the institution of supplemen-tary feeding. Of those affected, 25 per cent.permanently ceased to lactate. Apart fromthe penicillin no extraneous factors could beelicited, and it seems not unreasonable toconclude that the drug was the inhibitingagent. No constant relationship was notedbetween the occurrence or type of lochialsequels and the diminution of lactation.

BRITISH JOURNAL OF VENEREAL DISEASES

Our observations on patients treated later inthe puerperium or during the normal lactationpenod are few, numbering only 3 cases, and arenot included in Table I. In 1 case a course of2,400,000 units, begun on the twenty-fourth dayafter delivery for late asymptomatic syphilis,resiflted in a marked decrease of lactation duringthe 7i days of treatment, and supplementaryfeeding had to be instituted. This measure becameunnecessary within 48 hours of the terminationof penicillin injections. In a second case of latecongenital syphilis, treated from the twenty-eighthday as an out patient with daily injections ofpenicillin in oil-wax emulsion, no lactatory changeswere reported. One-day menstrual losses, however,occurred on the thirty-third, forty-first, and forty-eighth days; no local cause could be detected,and no further losses were reported. In the thirdpatient (late syphilis, 2,400,000 units in oil-waxemulsion) treatment was begun at the fifty-seventhday; no lactatory changes were reported, but anormal-duration heavy menstrual period withmarked, unaccustomed premenstrual pain,occurred17 days after completion of drug therapy; in thiscase menstruation continued at normal intervalswithout change in lactation (Fig. 25).

Summary and ConclusionsMenstrual cycle sequele were found to

occur in 91'3 per cent. of 206 non-pregnantfemale patients treated with penicillin invarying time-dosage schedules. The principalchanges noted were alteration (lengthening orshortening) of the cycle and duration offlow, and the institution of premenstrual ormenstrual dysmenorrhoea, occasionally of theutmost severity.

Uterine bleeding and/or cramps occurredin 43-8 per cent. of 32 women at varyingstages of pregnancy who were undergoingpenicillin therapy; in 1 of these cases it isprobable that this form of treatment precipi-tated the onset of labour at the seventhmonth.

Alterations in the lochia were observed in

75 per cent. of 16 women treated during thefirst fortnight of the puerperium; increasedloss during the period of drug-therapy wasseen in 4, decrease in 7, and complete ablationin 1.

Lactation was diminished in 75 per cent.of 16 cases. While this decrease was usuallylimited to the injection period and normalfunction was subsequently rapidly regained,permanent cessation of- lactation occurred in25 per cent. of those affected.

Restoration of normal menstrual functionwas noted in 1 patient treated late in the puer-perium, a normal cycle becoming establishedwithout interference with lactation.

Reactions to penicillin cannot be forecast.They appear to result from individual idio-syncracy, as is evidenced by the recurrence ofa similar pattern of sequels on re-exhibitionof the drug.

It is believed that these phenomena arecaused by the penicillin available to us or tothe impurities inseparable from the processof manufacture. That the latter hypothesis isthe case is suggested by the decreasing fre-quency in recent months of such reactions,despite greatly increased penicillin dosage, andby the absence of sequale in 2 patients treatedwith pure penicillin.

We desire to express our thanks to the nursingstaff of Q Ward, Southmead Hospital, whoseco-operation has made the collection of dataeasier, and to the Medical Officer of Health ofBristol for permission to publish these observations.

REFERENCESLeavitt, H. M. (1945). J. vener. Dis. Inf., 26, 150.Lentz, J. W., Ingraham, N. R., Beerman, H., and

Stokes, J. H. (1944). J. Amer. med. Ass.,126, 408.

Mascall, W. N. (1945). Brit. J. vener. Dis., 21, 157.Speiser, D. M., and Thomas, E. W. (1946).

J. vener. Dis. Inf., 27, 20.Walker; B. (1945). Brit. J. vener. Dis., 21, 157.

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