Control of ovulation time and cycle length with clomiphene citrate

Control of ovulation time and cycle length with clomiphene citrate J.

G.

BOUTSELIS,

N.

VORYS,

J.

C.

ULLERY,

M.D.

M.D. M.D.

Columbu,s. Ohio A significant segment of our population is strongly motivated to practice the rhythm method of family planning. Clomiphene citrate, 50 mg. daily for 5 days beginning on the fifth day of the menstrual cycle was administered to 120 patients. Ap@oximately 98 per cent of the patients exhibited a predictable ouulatory pattern not exceeding n 3 day r:ariation in ovulation, makin.g the rhythm method of fnmily phning morn effeclir~e in preventing conception. -

C: L 0 M I P H E N E citrate is a new orally administered nonsteroid compound effective for the induction of ovulation in anovulatory women.“. 7-9, 13. 15, IF, II, 21 Successful clomi-

are highly rnotivatcd and wish to practice some form of the so-called “rhythm method” as a means of spacing or limiting the nu~rrber of children in their family. Our results in the former group of patients will bc published in a separate report. Thereftnr, th( present study concerns only those paticrlts who wish to avoid conception for \xriahle periods of time using the rhythm mcrhocl of family planning.

phene citrate therapy can result in ovulation and menstruation in a manner which simulates the normal cycle. As a result fertility potential is enhanced and symptoms due to irregular or prolonged anovulatory cycles niay be alleviated. Although many reports have appeared in reccntlitcrature concerning clomiphene citrate and its ability to induce ovulation,3-5, ‘-@, “’ I:) is, 1i-21 virtually no attention has been directed toward its effect on the consistently ovulating and menstruating patient. At this point, reference is made to two groups of patients. The first group are those patients who are infertile or subfertile who reveal no apparent cause for their infertility following a complete dia,gnostic work-up. Variation in ovulation time may be a factor contributing to the infertility of this group. Reference is also ma.de to a second group of patients who

Material

and

methods

The patients participating in this study are a cgrOLlJ3 of highly motivated women with a sincere interest of wishing to space ot limit the number of children in their families. 13~ cause of their religious beliefs, some tylje of the rhythm method is the only means by which this objective might be accnmplishcd. After a thorough indoctrination ix1 therurometer rhythm, coitus was sqggested only during the luteal phase of the cycle, beginning with the third postovulatory day. ff it became difficult for each couple to adhere to this period of prolonged abstinence, thcrr c‘clitus was also sqgested during the immediate postmenstrual phase for a period of 3 ~1ays. Patients selected for this study were those between 20 and 40 years of age who had maintained basal body temperature: grqhs for a. rninirnum of 6 months preceding climi-

From the Department of Obstetrics and Gynecology, 7‘ha Ohio State Uniuersity College of Medicine. The authors wish to acknowledge their indebtedness to The Wm. S. Merrell Co. for supplying the clomiphene citrotv for this ;rrr,e~tigation.

949

950

Boutselis,

Vorys,

and

Aplil 1, 1967 Am. J. Obst. & Gynec.

Ullery

60I BEFORE &SJ DURlNG

CLOMID CLOMlD

THERAPY THERAPY

8

DAYS Fig.

1. Variation

of ovulation

0

before

and

VARIATION

1.6% IaLL IO

OF OVULATION

during

clomiphene

2

3

1

1.6% m 9

therapy

(120

4

patients).

5+

DAYS VARIATION OF OVULATION Fig.

2. Variation

of ovulation

following

the

phene therapy. The possibility of multiple pregnancies and side reactions was explained and accepted by all patients. Patients excluded from this study were those women who exhibited more than one anovulatory cycle during the 6 months before clomiphene therapy; those currently on hormone therapy other than thyroid; subfertile patients; those with unexplained pelvic pain; and those patients with clinically detectable pelvic pathology.

last

dose

of clomiphene

(120

patients).

During the early part of our study, clomiphene citrate was administered in daily doses of 50 to 100 mg. for 5 days beginning on the fifth day of the menstrual cycle. It soon became apparent that the desired effects could be obtained with a daily dose of 50 a 50 mg. daily dose was used mg. ; therefore throughout the study. Basal body temperature graphs were maintained throughout clomiphene therapy as an indicator od ovulation. In the majority of instances, patients

Clomiphene

were given office appointments on a monthly basis when certain maximum data might be obtained. This included cervical mucus testin%, vaginal cytoloCgy, endometrial biopsies for histologic and enzynle histochemistry e\,aluation, and pelvic examination to detect the presence of ovarian enlargement.

ovulation

Results age distribution and parity of clomcitrate-treated patients was not surlwisinq. The peak age distribution was bet.wern 26 arid 28 and the average patient parity was 3. ‘I‘hc~ most important aspect o’f this study W.IS tch see what effect clomiphere citrate had on tbc ti?rz~ at which ovulation occurred. This rna,y be expressed better as the variation of ovulation in days during each succeeding menstrual cycle for a 6 month period of tilrle. Fur e.xample, if a patient exhibited an ovulatory pattern between day 14 and day 16 of her C-yclc, thrn this patient was dcs&gnated as liaving a variation in o\,ulation oi 2 days. As noted in Figs. 1 and 2, in the rlomil~t~ene-treated patients, there was a considrrablr improvcmcnt in the consistency which o\.ltlation occltrred within a 2 or 3

25% I@4

30 1

5-6

5-7

6-6

6

OVULATION

Fig. 3. Day of ovulation

following

6-9

DAYS

6-10

AFTER

inducticr

Q51

day variation period, With thr vxceptil )n tri one patient, there were no unrxpectrd r*arl) or late ovulations which, whcm thq ~1%) occur, expose the patient to a t,‘rratw j)osnGphene cjtratc and on one occasion 0~5 tiic‘ tenth day, thrll this patient would by JI~~N Cal in tllat group of patients who okxlatetl lwtween the sixth and tenth day aftt%r the% !.~sI administcr~cl dose of clorniphen~ i, ( :lo,!!ici : Although tile distribution of o\.lIlatc>r) {x11terns in 120 patichnts app’ears to tr:l\-c> ix 1~.itk range, as notrcl in Fi;q:-. 3, it sl~ould ht, (‘r)lphasiyecl tllat tbacll patient r~sp~:n~l~‘~i 111 a fairly consistent mann~~r. ‘Uris irlrlwr!atrt observation is rrot illustratt~cl in Pi:2 Ii tr1(1 is better shc~wn iit Fiq. t.

‘I’he phench

0

for

7

LAST

DOSE

the last dose of clmniphcwe

OF

CLOMIPHENE

i 120 patients).

952

Boutselis,

Vorys,

and

April 1, 1967 Am. J. Obst. & Gynec.

Ullery

This increase of cycle length was attributed primarily to an increase in the follicular phase of the menstrual cycle. Fig. 7 represents a fairly typical example of a patient’s basal body temperature graphs before and during clomiphene therapy. Because it was not practical to illustrate 12 cycles for presentation purposes, only the

If we accept the normal corpus lutein phase as 14 days, then clomiphene citrate therapy increased the luteal phase of the menstrual cycle by nearly one day (Fig. 5). Similarly, if we accept the normal menstrual cycle length as being 28 days, then clomiphene citratctreated patients exhibit a 2 day increase in the cycle length (Fig. 6).

5

6

7

0

9

IO

II

OVULATION DAY AFTER LAST DOSE OF CLOMIPHENE Fig. 4. Seven hundred and twenty ovulations in 120 clomiphene-treated patients.

CORPUS Fig.

5. Duration

of corpus

lutewn

phase

LUTEUM

PHASE (DAYS)

in 720 Clomid-treated

menstrual

cycles

in 120 patients

12

Clomiphene

for ovulation

induct1~1~

100

I .6% J#2ma27

1.6% 0 ^ 26

2s

29

LENGTH Fig, 6. Menstrual

99.0

cycle

I 2I,,

4

length

OF

MENSTRUAL

in 120 Clornid-treated

/ 6, , 8, , IO, , 12, 1,,14

31

30

16,

patients

DAY OF CYCLE ( 18I1 20,,I 22 I 24I,

32

CYCLE (720

26,I

28I,

33

34

35

(DAYS) menstrual

30v

1 32I,

cycles),

34I

I 36I 8138 I140 I

98.6

97.8 974 970

NO

990

,I

986

-

98.2 97.8

r -

97.4

-

OF

oF.z~990 97.0

III

9

I % % I ,I

MENSTRUAL PERIODS 28-35 DAYS OVULATION DAY VARIES FROM 14 to 23 I I I l I c I I I, q I1 I I < IT I I I I1 I I I I r 1 t

xxxxxx 1 / I

~~~~~~~~~~111-1 1 1 1 1 1 CLOMID 50 mgm. DAILY

97.0 -

Fig. 7. Basal body

1 1 1 1 7 CLOMID 50 mgm. DAILY temperature

chart.

953

954

Boutselis,

Vorys,

Fig.

NO SIDE

April 1, 1967 Am. J. Obst. & Gynec.

Ullery

8.

72.5%

REACTIONS

ABDOMINAL

COMPLAINTS

VASOMOTOR OVARIAN

PHENOMENA ENLARGEMENT

NAUSEA

+ VOMITING

HEAVIER

MENSES

URINARY

SYMPTOMS

VISION HAIR

and

DISTURBANCES LOSS

OTHER

SYMPTOMS

TOTAL

SIDE

215%

REACTIONS

I

I 0

I 4

therapy

( 120 patients).

NO. OF SIDE Fig.

9. Side

effects

during

Clomid

I 6

I a

REACTIONS

I IO

Clomiphene

sixth

cycle

of the control

period

and

the first

two cycles during clomiphene therapy are shown for illustrative purposes. Fig. 8 illustrates the histologic changes of an cndometrial biopsy taken on the third postcn~ulatory day of a clomiphenc citratctreated patient. Note the well-preserved enclometrial glands with subnuclear vacuoles. ‘I’htxre is no pseudostratification of gland cells. Gland and stromal mitoscs are absent. V1’h~* vaginal srncar of this patient exhibited fairI) typical progestalional cytologic ePTects. All side reactions encountered (Fig. 9 i M’(‘lT gencralh~ mild and transient. In no CZlS(b was therapy administered specifically for side c.ffects. It was not surprising that all complaints of abdominal pain were associated with the time of ovulation and may he compared in severity with ovulatory pain in tire untreated patient. The vasomotor phenomena were described as hot flashes and. in all probabilityz were related to the antiestros:.enic t.ffec.t of the compound. ( )varian rnlargement was rarely detected by bin~anual examination. This does not imply tllat ovarian enlargrment might not have been pr-esvnt in more than three patients during the course of clomiphene therapy. If UT arc to detect a more exact incidence of ovarian rvsts durin,~ clomiphene therapy, we should employ other diagnostic nlethocls such as culdoscopy or laparotomy, which would be impractical for our present objectives. Comment Patients desiring to space or limit the numof children in their family without the methods must rely 11se of rontraceptive basically on some form of the rhythm method. ‘The rhythm method, as practiced currently by the average patient, has been 1~~s because of many interthan satisfactory related reasons, including irregular ovulatory patterns eshibitcd by these patients. Although test tape’, ’ and chloride the r,rw glucose spot test”’ ma)- challengethe superiority of tile basal body temperature method in detecting ovulation, they ofTrr no assistance in regulatin~g the time at which ovulation occurs during the menstrual cycle. I)er

for ovulation

inductio!

955

Glomiphene citrate has been shown t:o IX% effective in the induction of ovrllalic rn in anovulatory patients,“, 4. 5, r-n. f 1. 13 Ii ?I tlo\Trever no reports ha\-e appeared in thy litcl,ature concerning its use in normal paGents and its ability to control cyclr lengtll and the time of ovulation. Our preiimin~zli~ r)hser\,atiuris’ in this latter category. whir,ti included 96 patients, were first present& !wfort, the New England Obstetric ant1 Gvnccologic Society in Boston on Oct. 27. 1%i. ‘l?h(b presenl report includes an additic+~l 24 patients, a total of 120 patients. Tiefore clori~iphcnc citrate thcrall!. oi control period of basal body temperatur-c IWO~ din,g. it \4sas surprising to notr that or 11 t)nc’ patient ovulated on the samt~ da)- c111rinq each of her menstrual cycles. ?‘his MYXI~~ sceln 1.0 indicate that the ovlIlator\ II)(TJI~nism of most patients itivol\Gng the iiypothalamic-pituitary-o\rarian axis has irlli,insic peculiarities which prevent rrpeatt-d i~~~rl(~(.t timing in the phenomenon oi ovulation. At least this would serm to be the cxmclus~c~~~ if we are to ac.ccp1 a relatively crudr indicalol. of ovulation as the basal body ~CIII~XY ;~fl~rc, method. Since menstrual cyc~le IfLllgti t ~3) be controlled M it11 precision by tlrt. tr~;~~lation suppressing compounds, it is rc~asorr;+bic~ to assume that clomiphcnc citrate- may !~.ILI‘ a beneficial cKect in rcgulatin~ tllc ovtii.3toq ~llecl~anisrn and. indirectly, tht. riicrlklr ti;d cycle lenpth. tri the present study, o~i~lation tiriic control cvithin a 3 day variation ili tn IIlation \\-a~ notrtl in 1 I8 (98.3 pt‘~’ u’I~! 1 ol clonliphrnc citr.atc*-trcaatrd patirnts. I‘O~ r~>at~d to 29 ( 24 per c‘rnt ! of patients prior to I ~0!11iphene citratr thwapy. Owllaticxl ST+ irltrol Lvithiri 2 days was rioted in 11 I! i !I”,. ; /)<‘Icent 1 of c,lorniphene citrate 4rratc.d ~‘3 I iCnts. conlparcd to 19 (15.8 per cent’ of’ l,aiicnts prior to clomiphen~~ ritratca therap-. Mot (L imt~~ml~~ol portant tliari ;L 2 or 3 da); variatioil in the time oi ovulation wirlr c,lonlij~hcnc* citrate thtarapy is the absrnce of ~~nesl~~~~d earl)- or late ovl~lations. Most pl1ysiciarls (‘IIgaged in tha rhythm method of farr&: plansec‘n prvpnanq. rrstilt I’S III :llc ninz havr kvll(xr~ unexpected eal-1) or late ox,ulation coital frequent)\vas bas~cl 01~ p)ast [!ibrfor-

956

Boutselis,

Vorys,

and

Apil 1, 1967 Am. J. Obst. & Gynec.

Ullery

mance of basal body temperature recordings. Exceptions to this are the group of patients who limit intercourse to the postovulatory phase of the cycle. Therefore, the majority of patients would be contented with the rhythm method if they could be given reasonable assurance that untimely ovulations would not occur. This assurance and confidence may be given to patients with clomiphene citrate therapy. It should be emphasized that, in spite of the apparent efficacy of clomiphene citrate to regulate ovulation time, it does not induce a stereotype patient response as noted with the ovulatory suppression compounds. Rather, each patient under clomiphene therapy exhibits a fairly consistent ovulatory response which may differ significantly from that of another patient. Therefore, any patient desiring to space or limit her family number by this method of ovulation time control should be treated on an individual basis until her ovulatory pattern is stabilized. The duration of clomiphene citrate therapy for these patients has not been determined at the present time; however, it is planned that therapy should be continued for a minimum of one year. Basal body temperature recordings should be continued during this one year period. Thereafter, several options may be exercised. One group of patients may continue clomiphene citrate therapy without basal body temperature recording, while the second group of patients discontinues drug therapy but maintains their basal body temperature charts. These tentative plans have a twofold objective. First, it will demonstrate whether the clomiphene citrate regulated ovulatory pattern can be maintained after therapy has been discontinued. Second, if ovulation time can be controlled by clomiphene citrate, then can the rhythm method be practiced effectively without the aid of basal body temperature recording, which is considered tedious by most patients. The increased duration of the corpus lutein phase in the majority of patients indicates a

beneficial response to clomiphene citrate therapy. This factor represents indirect evidence that clomiphene citrate stimulates, rather than depresses, pituitary gonadotropin secretions. When clomiphene citrate is administered during the postovulatory phase, the corpus lutein phase of the cycle may be prolonged by more than 2 days, as noted in several of our infertility patients with a short luteal phase. Clomiphene citrate exhibited a remarkable ability to control the menstrual cycle length. This observation may indicate that clomiphene citrate would be effective in various types of dysfunctional uterine bleeding which occur with a disturbance in ovulation timing, an inadequate luteal phase or in anovulatory dysfunctional uterine bleeding. Since the present investigation introduces the use of a nonsteroid compound to perfect the practice of the rhythm method in the area of family planning, it is mandato’ry that certain precautions be taken to rule out any adverse reactions which may interfere with the possibility of fertilization and implantation. The authors feel that these precautions have been taken, when we consider the voluminous reports which have appeared in the literature during the past 5 years and summarized by Johnson and ass0ciates.l” Obviously, Huhner tests could not be performed during the present study; however, the authors of this report have performed Huhner tests in many infertile patients and a significant number of conceptions have occurred, indicating that clomiphene citrate, when administered from the fifth to the ninth day of the cycle, would have no adverse effects on the cervical mucus at ovulation time. During the present study, cervical mucus at ovulation time, postovulatory vaginal cytology, and endometrial biopsies for histologic and enzyme histochemistry compared favorably with normal patients not on clomiphene citrate therapy. These findings will be published in a later report, when more comprehensive studies are completed.

REFERENCES

1. Birnberg, C. H., et al.: 194, 1963.

Obst.

& Gynec.

21:

2. Bout&is, J. G.: Control of Ovulation Time and Cycle Length in 96 Normal Patients

Clomiphene

3. 4. 5. 6. 7. 8. 9. IO.

With Clam. uph me Citrate, presented to the New England Obstetric and Gynecologic Society, Boston, Oct. 27, 1965. Unpublished data. Charles, D., et al.: J. Obst. & Gynaec. Brit. Chmm. 71: 6G. 1964. Charles, D., e; al.: AM. J. OBST. & GYNEC. 86: 913, 1963. Dickey,.R. P., et al.: Fertil. & Steril. 16: 485, 1965. Doyle, J. B.; Pt al.: J. A. M. A. 172: 1744, 1960. Greenblatt. R. B., et al.: J. A. M. A. 178: 101. 1961. (;reenblatt, R. B., et al.: Aar. J. OBST. & <:YNEG 84: 900. 1962. Greenblatt; R. %.: Fertil. & Steril. 12: 402, 1961. Johnson, J. E., Jr., ct al.: Clinical Experience With Clomid, presented at the Thirteenth Annual Meeting of the Pacific Coast Fertility Society, Las Vegas, Oct. 29, 1965.

for

11. Kistner, R. W.: 380, 1965. 12. McSweenev. D. & Gyncc.

13. Naville, 290.

ovulation

in&x-tic,-~

957

(\M. J. OHST. & i;\xb

(. 92:

1.. and Sbarra.

4. 1

Ollst.

‘iiS: 201, ‘1965.

A.

H.,

et al.:

Fertil.

& Stewii

15:

1964

14. Riley, G. M., and Evans, ‘I’. &Y,: .%>I. J. OHS-I. & GYXEC. 89: 97, 1964. 15. Rev. S.. et al.: Fertil. & Steril. 14: 575. i96;;. 16. Smith, ‘0. W., Smith, G. V., and Ki:;tIwr. R, W.: 1. .4. M. A. 184: 878, 1963. A. L., and Janovski. N 4 17. Soutl&, .1 .A M. A. 181: 443, 1962. 18. Thompson, R. J., and Mellin~cr. R. (. : ,X~I J. OBST. & CYNFC. In prc-ss. 19. Vorys, N., et al.: Anr. J. OH.ST. Sr s :t 1’1:~: 88: 425. 1964. 20. Wall. J. A., et al.: ,4&f. J. 0~s~. & (;\-\L.<: 88: 1072. 1964. 21. Whitelaw, J. M.. ct al.: Fcrtii. ?+ Stencil 14: 3.55. 1963.