SA MEDICAL JOURNAL 29 AUGUST 1981 347

The effectoestrogens

of clomiphene andon cervical mucus

conjugated

Results

Patienrs were started on clomiphene citrate 50 mg/d; this dosewas doubled if ovulation, as judged by the basal bodytemperature chart and a rise in serum progesterone levels duringthe luteal phase, was not achieved. The clomiphene was takenfrom day 5 to day 9 of the cycle, counted from the start ofmenstruation. Conjugated oestrogens 2,5 mg/d for 7 daysbeginning on day 10 of the cycle were added ifmucus productionhad been poor during the preceding cycle. .

Patients attended the clinic from day 13 to day 16, as well asonce between day 24 and day 26 for determination of the serumprogesterone level. During the mid--cycle visits, cervical muc~swas aspirated, and blood was taken for serum oestradioldeterminations. Patients kept a basal body temperature chartand noted·the length of the cycles accurately.

A cervical score was calculated, taking into consideration thecolour of the cervix, the presence of a cervical mucus tongue(receptaculum cervicis), the quantity, translucency, viscosityand spinnbarkeit of the mucus, and whether it formed a fernpattern on drying. Values were allocated for all these parameters.according to a scale ranging from 0 to 3, with a maximum score of21 (Table 11).

Oestradiol assay was performed with radio-immunoassay kitssupplied by Internation eIS, Immeuble P3, 2 rue Stephenson,78181 St Quentin Yvelines, CCdex, France. All statisticalcomparisons between groups were performed by the one-wayanalysis of variance. 14

J. V. VAN DER MERWE

Summary

The analysis of 157 menstrual cycles in 50 patientson ovulation-inducing regimens showed that inrestoring ovulation clomiphene citrate inhibitedcervical mucus production and causedhypersecretion of oestradiol. The inhibitory effectwas inversely proportional to serum oestradiollevels, and the addition of conjugated oestrogens'did not"rectify the inhibitory effect, increase plasmaoestradiol levels or increase cycle length. Doublingthe clomiphene dosage made no significantdifference to any of the parameters examined. Themechanism of this inhibitory effect is still obscure.

S. Air. med. J., 60, 347 (1ga1).

Oomiphene citrate is the agent most widely used in theinduction of ovulation. Although specifically indicated in thecase of the anovulatory patient1 with an intact reproductivecentre 2 and normal blood oestrogen levels, 1- 3 it is often arbi­trarily used in conditions such as luteal phase defects4,5 and whenprecise timing of ovulation is important, for example in thepatient who requires artificial insemination.6

One of the side-effects of this form of induction ofovulation isinhibition of cervical mucus production;7,8 this is not universallyaccepted,9,1O but is often said to be one explanation for thedichotomy between pregnancies achieved and ovulatory cycles, I1

The inhibition of cervical mucus production is thought to be dueto the anti-oestrogenic effect of clomiphene on the cells whichsecrete cervical mucus,12 A logical solution, widely practised; isto prescribe oestrogens for 5 - 7 days after clomiphene tocounteract this effect. 1,12 This has been shown not to affectovulation. 13 Conjugated oestrogens are often used for thispurpose. 12

This paper deals with the inhibitory effect of clomiphenecitrate on cervical mucus production and the value ofconjugatedoestrogens in restoring this production.

TABLE I. PATIENT GROUPS

Group No,I Control group

11 Clomiphene 50 mgIII Clomiphene 100 mgIV Clomiphene 50 and 100 mg plus 2,5 mg

conjugated oestrogens

No, of cycles505117

39157

Patients and methods

A retrospective analysis was made of the records of 50 patients(32 with anovulation, 12 with oligo-ovulation and 6 with lutealphase defects) on an ovulation-inducing regimen. A total of 157cycles was analysed and divided into the groups shown in Table1. The patients' initial cycles, before they had received anytreatment, served as the control group.

Gynaecological Endocrinology and Infertility Unit,Department of Obstetrics and Gynaecology, TygerbergHospital, Parowvallei, CPJ. V. VAN DER MERWE, M,MED, (0, & G,), f,C.O.G. (S,A,), M,D., Head(Present appointment: Professor and Head, Department ofObstetrics and Gynaecology, University of Pretoria.)

Date received: 14 October·198O.Reprint requestS to: Professor J. V. van der Merwe, Dept of Obstetrics and Gynaecology,University of Pretoria, 0002 RSA.

From Fig. 1 it can be seen that there was significant inhibition ofcervical mucus production in the patients on clomiphene (P <0,0001). This was true for the total cervical score as well as forferning, spinnbarkeit and the presence of a receptaculum cervicis(Fig. 2), There were no significant differences between thegroups receiving different doses of clomiphene. The sameinhibitory effect was present in the group receiving conjugatedoestrogens (P < 0,0001), with no statistically significantimprovement when compared with the groups receivingclomiphene alone.

Blood oestradiol levels (Fig. 3) were significantly higher (P<0,0001) in the clomiphene groups (11, III and IV), with nosignificant differences between the group receiving 50 mgclomiphene and that receiving 100 mg or between these gtoupsand the group which also received oestrogen, Furthermore, ifpatients treated with clomiphene were divided into groupsaccording to their blood oestradiol levels an inverse relationshipto cervical mucus production was noted (Fig. 4).

348 SA MEDIESE TYDSKRIF 29 AUGUSTUS 1981

TABLE 11. CERVICAL SCORING SYSTEM

Score

Colour of mucusMucus tongue(receptaculum cervicis)Quantity

Translucency

ViscositySpinnbarkeitFerning

oPaleNo mucus

No mucus

No mucus

No mucusNilNil

Pale pinkSecretion confined toborders of external osSmall amount on glassslideOpaque

Thick, gelatinous mucus1-4 cmLinear ferning withpatchy distribution

2PinkMucus forming tongueon posterior cervical lipMucus covers '/4 of slidesurfaceSlightly opaque - be­coming translucentBecomes viscous5-7 cmLinear ferning withside-branches in areason slide

3HyperaemicMucus secretion reachingvaginal epitheliumMucus covers 1/2 or moreof slide surfaceClear translucent mucus

Watery (like white of egg);;, 8 cmComplete feming on largestporfion of slide, with well­developed side-branches

n mGroups

I

500

1,5 10~ 2,25

E"'.~1,25

l~ 2,00.~ 6

~ ~ 1.00"-

~~"u 1,75

£1,75

1,50'\

~\( !::~.. 1 I '"~ ~ ~ ~ ",\

J n m I!l n m llI: I n m I!lGroups

Fig. 2. Representation of observations of feming pattern, spinnbarkeit andreceptaculum cervicis. The number of observations, mean and standarderror are shown.

Fig. 3. Representation of serum oestradiol levels in the four groups. Thenumber of observations, mean and standard error are shown.

2000

....0E 1500Q.

0.-"C

I IT ID N 0~

1000-Groups V)

Cl)

0

15

Cl)~

ou

CJ)

ou:>~

Cl)

U

As would have been expected, serum progesterone levelsduring the late luteal phase (Table Ill) were significantly greaterin the treated groups than in the control group (P< 0,001), withno statistically significant differences between the differenttreatment groups. There were no significant differences in cycleduration (Table IV) between the different groups.

Fig. 1. Representation ofthe cervical score in the four groups. The numberof observations, mean and standard error for each group are shown.

Comment

Several interesting points emerge from this study. In restoringovulation, clomiphene citrate: (a) inhibits cervical mucus

-

Fig. 4. Representation of the inverse relationship between serumoestradiol levels and cervical score if treatment cycles are arbitrarilydivided into three groups, depending on serum oestradiol levels (group A- oestradiol < 1000 pmoVI; group B-1 000 - 2000 pmoVI; group C ­>2000 pmolfl). The number of observations, mean and standard error areshown. The cervical score differed significanUy (P < 0,02).

2500

......0EQ.

0 1500=~-enCl.>

0

SOO

A 8Groups

c

14

12 ~:>~

Cl.>L>

10

SA MEDICAL JOURNAL 29 AUGUST 1981 349

production (the total cervical score as well as its individualcomponenrs being affected); and (b) causes hypersecretion ofoestradiol, with an inverse relationship between serum oestradiollevels and cervical mucus production.

The inhibitory effect of clomiphene on cervical mucusproduction may be explained by a prolonged anti-()estrogeneffect on the endocervical glands or perhaps an excessiveproduction of androgens, as seen during the clomiphene­induced ovulation. 15 However, patienrs with elevated bloodandrogen levels due to the polycystic ovary syndrome, as well asthose being given gonadotrophins to induce ovulation, resultingin increased follicular apparatus steroid secretion, have beenfound to produce sufficient cervical mucus. It therefore seemsthat despite increased oestradiol levels the inhibition ofcervicalmucus production in patients on clomiphene is due to acontinuing anti-()estrogenic effect on the cervical glands.

No statistically significant differences as regards any of theparameters examined existed between the group receivingclomiphene 50 mg and that receiving 100 mg. Although theanalysis was not specifically designed to compare serumprogesterone levels on a time-related basis, there are nosignificant differences in either serum oestradiol or progesteronelevels between the lower and higher clomiphene dosage groupsin this study. It therefore does not seem necessary to increase theclomiphene dosage to stimulate further hormone production bythe follicular apparatus in those patients who ovulate onclomiphene 50 mg.

The addition of conjugated oestrogens to the treatmentregimen did not neutralize the inhibitory effect ofclomiphene onthe cervical mucus, nor did it serve to increase plasma oestradiolvalues or increase cycle length. It is therefore pointless toprescribe conj ugated oestrogens to rectify the inhibi tory effect ofclomiphene in a particular patient.

TABLE IV. CYCLE DURATION IN DAYS

TABLE Ill. SERUM PROGESTERONE LEVELS (nmol/I)

Group No. No. of observations Mean ± SEI 47 9,92 ± 1,1111 50 18,29 ± 1,65III 17 21,34 ± 2,96IV 39 23,49 ± 2,35

Group No.r

11IIIIV

No. of observations50511739

Mean ± SE28,63 ± 0,5728,55 ± 0,8229,76 ± 0,5929,14 ± 0,41

The author wishes to express his thanks to Dr C. Vivier, PrincipalMedical Superintendent of Tygerberg Hospital, for permission to

publish.

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2. Taymor, M. L. (1979): Clin. Obstet. Gynec., 22, 145.3. Lapez-Gamez, G., Martinez-Zurita, F., Bedolla-Tovar, N. ec al. (1978):

Ferti!. and Steri!., 29, 2!6.4. Quagliarello, J. and Weiss, G. (1979): Ibid., 31,373.5. Echt, C. R., Romberger, F. T. and Goodman, J. A. (1969): Ibid., 20,564.6. Rajan, R. (1978): J. Indian med. Ass., 71, 33.7. Lamb, E. J. and Guderian, A. M. (1966): Obstet. and Gynec., 28, sos.8. Graff, M. (1972): Ferti!. and Steril., 22,209.9. Editorial (1976): Obstet. gynec. Surv., 31,739.

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258-298. Ames, Iowa: Iowa State University Press.15. Marshal!, J. R. (1978): Clin. Obstet. Gynec., 21, 147.