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Induction of ovulation with cisclomiphene
Induction of ovulation with cisclomiphene J.
VAN
ET.
CAMPENHOUT,
BORREMAN,
H.
WYMAN,
PH.D.
A.
ANTAKI,
M.D.
Montreal,
Quebec,
M.D.,
F.R.C.S.(C)
M.D.
Canada
Thirty-seven infertile patients with ovulatory defects have been treated with cisclomiphene at dosages varying from 10 to 140 mg. per day. The over-ail ouulatory rate was 78.1 per cent with a pregnancy rate of 51.3 per cent. The results of our investigation with cisclomiphene are presented in detail and are compared with our previous experience with clomiphene. It seems that the ovulatory rate is similar for the two compounds but that the Pregnancy rate is much higher with cisclomiphene. The dosage of 10 mg. of cisclomi#hene is effective but might have to be increased according to the patient’s response. It appears that 10 and 20 mg. of cisclomiphene, respectively, are as effective as 50 and 100 mg. of clomiphene citrate
0 NE o F THE most recent advances in the treatment of infertility due to anovulation has been the introduction of clomiphene citrate. Clomiphene citrate is a mixture of isomers in approximately a 1: 1 ratio of cisclomiphene and transclomiphene. Nearly all the data reported in the literature concern the use of the mixture, and it is only recently that the individual isomers have become available for clinical trials. Preliminary studies seem to indicate that cisclomiphene* is more potent than the transisomer as well as the isomeric mixture for the induction of ovulation in the woman.‘-3 The purpose of this communication is to
report the results of cisclomiphene in the management of ovulatory defects in infertile patients and to compare the results of this study with our previous experience with the use of clomiphene citrate. Material
Presented at the Twenty-eighth Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada, Quebec City, Quebec, Canada, June 15-18, 1972.
Montreal
24, Quebec,
methods
Sixty-three women between the ages of 20 and 36 were selected from among those attending our Infertility Clinic. All patients included in this study were thoroughly investigated in order to exclude possible pituitary, thyroid, or adrenal disease. Furthermore, each was assessed with respect to endogenous estrogen production by means of vaginal cytology, examination of the cervical mucus, and endometrial biopsy ; plasma concentrations of estradiol were measured by radioimmunoassay in most patients. The diagnosis of anovulation in 61 patients was made on the basis of monophasic basal body temperature and serial vaginal cytologies and endometrial biopsies; all of these patients were anovulatory for at least one year. The diagnosis of an inadequate luteal phase in 2 patients was based upon repeated endometrial biopsies on the first day of menses and upon hyperthermic plateaus
From the Infertility Center, Department of Obstetrics and Gynecology, and the Endocrine Research Laboratories, Department of Medicine, Notre Dame Hospital, University of Montreal.
Reprint requests: Dr. J, Van Campenhout, 1560 Sherbrooke
and
St., E.,
Canada.
*Cisclomiphene citrate was supplied by the Wm. S. Merrell Company, Canada.
321
322
Von
Compenhout
Table I. Clinical
February 1. 1973 Am. J. Obstet. Gynrcol.
et al
diagnoses Cisclomiphene
Clomiphene
17 (45.9%)
15 (57.6%)
13 (35.1%)
8 (30.7%)
Diagnosis Polycystic sclerotic ovaries Anovulatory oligomenorrhea Secondary amenorrhea Argonz-Del Castillo Oversuppression syndrome Postpartum Chiari-Frommel Hypothalamic Short luteal phase Anovulatory cycles Total No. of patients
2 1 1 1 1
2 3:
(100%)
26(100%)
of less than 10 days for a period of at least one year. Furthermore, all patients had been investigated to rule out other factors which might be contributing to the infertility. The husbands had normal semen analysis. The clinical diagnoses in the instances of patients selected for treatment with either clomiphene or cisclomiphene are given in Table I. The majority of patients had polycystic sclerotic ovaries or anovulatory oligomenorrhea. According to the diagnosis, the percentage of each type of disorder is approximately the same in the 2 groups treated with either clomiphene or cisclomiphene. The total number of patients who received clomiphene was 26, and 37 patients received cisclomiphene. Among these patients, 10 have been treated with the 2 compounds. There were totals of 129 treatments with cisclomiphene and 93 treatments with clomiphene. In all instances, medication was given for 5 days starting on the fifth day of spontaneous menses or induced withdrawal bleeding. The distribution of patients according to the dosage of cisclomiphene administered is shown in Fig. 1. Twenty-nine patients were started at the 10 mg. dosage, while 7 received initially 20 mg. daily and 1 patient received 40 mg. daily. Four patients responded transitorily to 10 mg. and were subsequently treated with 20 mg.; 11 patients who did not respond at a first treatment with 10 mg. received 20 mg. at the second treatment.
Thus, 22 patients received the 20 mg. dosage. If the response was not satisfactory, the next dosage was increased by 10 or 20 mg. Clomiphene was initially given in a dosage of 50 mg. to 19 patients and 100 mg. to 7 patients. If the response was inadequate, the dosage was progressively increased to 100, 150, and 200 mg. All patients were seen regularly during treatment. A postcoital test was performed 6 to 11 days after drug administration, and an endometrial biopsy was performed the first day of menstrual bleeding. Basal body temperature was continuously recorded. The cycle was considered ovulatory when followed by pregnancy or when endometrial biopsy disclosed a fully secretory differentiation with a hyperthermic plateau of 12 to 14 days. Results
Response to cisclomiphene. Results
according to dosage in 37 patients treated with cisclomiphene are shown in Fig. 1. Among the 29 patients treated with 10 mg., 16 (55 per cent) ovulated and 8 (28 per cent) became pregnant. Among the 22 patients who received 20 mg., 9 (41 per cent) ovulated and 3 (13.6 per cent) became pregnant. Eight pregnancies followed a dosage varying from 30 to 60 mg. Three patients were treated with a dosage varying from 80 to 140 mg., and none of them ovulated. Of the 37 patients (Table II) receiving cisclomiphene for 129 courses of treatment, 29 ovulated (78.1 per cent) and 19 became pregnant (51.3 per cent), with 85 (65.8 per cent) of the 129 treatments resulting in ovulation following the therapy. Table III lists the details of the 19 women who became pregnant following cisclomiphene administration. Of those 19 patients, there were only 2 abortions to date. Nine had an uneventful single pregnancy and were delivered at term of clinically normal children. Eight pregnancies are progressing well. Two pregnancies occurred during the first cycles off the drug and are not included in our results. As shown in Table IV, the ovulatory response to cisclomiphene varied markedly in
Volunle Number
115 3
Ovulation
induction
with
cisclomiphene
323
NUMBER OF PATIENTS I
Fig.
Table II. Summary
1. Results
according
of response to clomiphene No. of patients
Clomiphene, Cisclomiphene,
to dosage
50 to 200 mg. 10 to 140 mg.
26 37
in patients
k@!
No OF PATIENTS
m
No
=
No OF PREGNANCIES
treated
with
OF OVUl.ATlNG
PATIENTS
cisclomiphene.
and cisclomiphene
Treatments 93 129
relation to the adequacy of endogenous estrogens. When endogenous estrogens were assessed as poor or absent, 27.6 per cent ovulatory responses were obtained. When the endogenous estrogen secretion was estimated as good, 65.2 per cent of the responses were ovulatory. Although it must be kept in mind that the numbers are small, it seems that this difference in ovulatory response in relation to the adequacy of endogenous estrogens is encountered at the 10 to 20 mg. dosage level as well as at the 30 to 60 mg. dosage level. When the dose of cisclomiphene is raised to 60 mg. and over, ovulation does not seem to be induced in either group. The abundance and spinnbarkheit of the endocervical mucus was evaluated at the time of the postcoital test in 31 patients during 70 treatments after administration of amounts of cisclomiphene varying between 10 and 80 mg. per day. In each instance, the mucus was abundant with a spinnbarkheit of
Ovulatory cycles 57 (61%) 85 (65.8%)
Ovulating patients 18 (69.2%) 29 (78.1%)
over 10 cm. and numerous ozoa were present.
Pregnan&s 7 (27.0%) 19 (51.3%)
motile
spermat-
Comparative effectiveness of clomiphene and cisclomiphene. The over-all ovulation and pregnancy rates obtained with clomiphene were 69.2 and 27 per cent, respectively, whereas 78.1 and 51.3 per cent were obtained in the cisclomiphene group (Table II). The percentages of ovulating patients and of ovulatory cycles are only slightly higher in the group of women treated with cisclomiphene over those treated with clomiphene. The incidence of pregnancies, however, is significantly higher in the group treated with cisclomiphene (5 1.3 per cent) than in the group receiving clomiphene (27 per cent) . It should be noted that the mean number of treatments per patient was 3.3 for the clomiphene group and 3.4 for the cisclomiphene-treated group. Furthermore, 7 pregnancies resulted from 57 ovulatory cycles in-
324
Van
Campenhout
February 1, 1973 Am. J. Obstet. Gynecol.
et al
Table III. Pregnancies
during
cisclomiphene
Patient
Diagnosis
P. M. F. R. L. M.
Polycystic sclerotic ovaries Polycystic sclerotic ovaries Polycystic sclerotic ovaries Polycystic sclerotic ovaries Anovulatory oligomenorrhea Anovulatory oligomenorrhea Anovulatory cycles Short luteal phase Polycystic sclerotic ovaries Polycystic sclerotic ovaries Anovulatory oligomenorrhea Polycystic sclerotic ovaries Anovulatory oligomenorrhea Polycystic sclerotic ovaries Anovulatory oligomenorrhea Anovulatory cycles Short luteal phase Polycystic sclerotic ovaries Oversuppression syndrome
ii: G. D. D. P. V. B. R. F. D. N. M. T. S. G.
y. 0. J. P. s. J. G. M. G. L. L. P. T. T. R.
Table IV. Ovulatory
treatment 1
Dosage
Cycle
10 10 10 10 10 10 10 10 20 20 20 30 30 40 40 40 40 60 60
response to cisclomiphene
Outcome
1 12 6 1 5 1 2 1
Delivered at term Delivered at term Progressing well (4 months) Delivered at term Delivered at term Progressing well (2 months) Progressing well (5 months) Progressing well (8 months) Delivered at term Delivered at term Delivered at term Progressing well (6 weeks) Progressing well (2 months) Abortion (3 % months) Progressing well (9 months) Progressing well (6 weeks) Abortion (3 months) Delivered at term Delivered at term
: 1 3 4 I 1 3 1 1 2
related
to adequacy
of endogenous
estrogens Endogenous
estrogens
Good
Poor
or absent
Dosage cisclomiphene
of
10 to 30 to
20 60
68 20
44(64.7%) 16 (80%)
15 13
4 (26.6%) 4 (30.8%)
80 Total to 140
924
6:(65.2%)
291
i (27.6%)
(mg.)
No.
of cycles
Ovulations
duced by clomiphene, which represents an incidence of pregnancies of 12.2 per cent, whereas 19 pregnancies were obtained from 85 ovulatory cycles induced by cisclomiphene, which represents an incidence of pregnancies of 22.3 per cent. Moreover, if we consider only the pregnant patients, the mean number of ovulatory cycles which were necessary to obtain the pregnancy was 3.3 for the clomiphene group and 2.6 for the cisclomiphene group. Although these data are based on a restricted number of patients, it seems nevertheless that cisclomiphene is much more effective than clomiphene in regard to the pregnancy rate. If we compare the ovulatory response to the first course of therapy, at various dosages, it appears that dosages of 10 and 20 mg. of cisclomiphene, respectively, are as effective as the doses of 50 and 100 mg. of clomiphene (Table V) .
No.
of cycles
Ovulations
Table VI compares the responses of 10 patients treated successively with both medications; the first 8 patients received initially the isomeric mixture, and the last 2 patients were treated first with cisclomiphene. Four of the subjects did not respond to either clomiphene or cisclomiphene. Three women ovulated after clomiphene treatment (50 or 100 mg.) but became pregnant following 10 mg. courses of cisclomiphene. The remaining 3 patients exhibited a variety of reto 50 and 100 mg. sponses : not responding of clomiphene but ovulating after 40 mg. of cisclomiphene (L. S. ) , becoming pregnant with clomiphene therapy and not ovulating with the cis-isomer (P. L.) , or, as in the case of V. P., ovulating with 50 mg. clomiphene treatments and responding initially to a 10 mg. course of cisclomiphene followed by no response to 10 and 20 mg. dosages and then responding when the dosage of cisclomiphene
Volume Number
Ovulation
115 3
Table V. Response to first course of clomiphene
induction
and cisclomiphene
No.
50 100
Table VI. Comparison and with
cisclomiphene
325
therapy Cisclomiphene
Clomiphene Dosape
(w)
with
Dosape fmiJ 10 20
Ovulation
of patients
17 15
8 (47%) 7 (46.5%)
of ovulating
responses in 10 patients
No.
patients
of
Ovulation
29 22
treated
with
16 (55%) 9 (41%)
clomiphene
cisclomiphene -..Clomiphene Dosage Cm.1 50 100 200
Patient D. A.
No. of treatments 1 1 1
F. R. G. E.+
100 50
5 1
L.
P. M. P. R. S. H. v. P.
50 100 50 100 50 50
1 1 :
B. J.
100
1
P. L.
100
1
s.
“Pregnant
with
human
Ovulation -
5 6
menopausal
Cisclomiphene
gonadotropin
Pregnancy
+
+ + +
-
+ plus
+ human
was increased to 40 mg. These results indicate that a variety of responses can occur in patients being treated with clomiphene and its cis-isomer; Patient V. P. is particularly illustrative in this regard. Comment Few clinical studies concerning the effectiveness of cisclomiphene in the induction of ovulation have been reported to date. Charles and associates,’ administering cisclomiphene at 75 mg. daily dosages to 51 patients, obtained 8 pregnancies or a pregnancy rate of 15 per cent. No pregnancies occurred in the group reported by Murthy and co11eagues,5 but their study was limited to 13 patients. MacLeod and co-worker?’ 3 observed an ovulatory response of 78 per cent and a pregnancy rate of 50 per cent in patients treated
chorionic
Dosage (mg.1 10 30 50 100 10 10 30 50 20 40 10 20 10 10 10 20 40 10 20 10 20
No. of treatments 1 1 1 1 12 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Ovulation
Pregnancy
+ + + + + +
i
. * + _-.
-
gonadotropin.
with 20 mg. of cisclomiphene. In our present study in which the dosage was individualized, the ovulatory rate was 78.1 per cent with an over-all pregnancy rate of 51.3 per cent. If we exclude the 2 cases with short luteal phases which might represent anovulatory cycles with luteinization of follicles or ovulatory cycles with inadequate luteal function, the pregnancy rate is 48 per cent. It should be noted that, contrary to MacLeod and coworkers, we increased our dosage beyond 20 mg. ; 8 pregnancies, which represent 40 per cent of the total number of pregnancies obtained in this study, resulted from dosages of cisclomiphene of 30 to 60 mg. per day. In our experience, cisclomiphene has been shown to be as effective as clomiphene in the management of anovulation. Although the ovulatory response following treatment with
326
Van
Campenhout
February 1, 1973 Am. J. Obstet. Gynecol.
et al.
both compounds is approximately similar, the over-all pregnancy rate is higher following the administration of cisclomiphene than with clomiphene. Charles and associates’ and MacLeod and co-workers29 3 have also observed a higher incidence of pregnancy with cisclomiphene, the latter authors attributing their results to patient selection. The discrepancy between the relatively high rate of ovulation induced by clomiphene and the low pregnancy rate, as noted in our study, has been repeatedly reported.6l 7 MacGregor and associates,6 reviewing the clinical experience with clomiphene citrate, noted that since the initiation of clinical research with this drug the over-all ovulatory response has remained remarkably constant at about 70 per cent, while the over-all pregnancy rate was 31 per cent. This discrepancy has been attributed to the luteinization of developing follicles without ovulation,7 to abnormal corpus luteum function8 and to ovum entrapment.8 It is possible that with the use of cisclomiphene the occurrence of these abnormal ovarian responses may be reduced. Furthermore, an antiestrogenic effect of clomiphene citrate on the cervical mucus has been noted in many clinical studies.g-14 This local factor might interfere with conception and also explain to some extent the discrepancy between the ovulation and pregnancy rates. Contrary to the findings of Charles and associates,l an inhibitory effect of cisclomiphene on the abundance and spinnbarkheit of the endocervical mucus has not been observed in our present study. With regard to dosages, it appears from our study and from the data of MacLeod and co-worker? that 10 mg. of cisclomiphene
would elicit an equivalent ovulatory response to 50 mg. of clomiphene and that 20 mg. of cisclomiphene would equal 100 mg. of clomiphene in the induction of ovulation. As observed for clomiphene,” the ovulatory response to cisclomiphene varied markedly in relation to the adequacy of endogenous estrogen. Patients in whom the estrogen assessment was considered good generally responded well, whatever the dosages of cisclomiphene administered. If we consider the patients who became pregnant more than 6 months before the end of the present study, we note an abortion rate of 15.3 per cent. All delivered pregnancies were single, and no ovarian hyperstimulation syndrome was observed. Only 5 patients of the 37 (13.5 per cent) treated with cisclomiphene reported side effects; these 5 complained of mild vasomotor hot flushes. It seems thus that there is no contraindication to increase the dosage, provided it is adjusted to the individual response and progressively increased. In conclusion, although the data presented are based on a restricted number of patients and the homogeneity of the two groups of patients treated with cisclomiphene and with the isomeric mixture, respectively, is difficult to ascertain, it seems, nevertheless, that cisclomiphene is as effective as clomiphene in regard to apparent ovulation rate but has the decided advantage of being much more effective in terms of pregnancy rate. From our experience, it would seem worthwhile to increase progressively the dosage of cisclomiphene at least to 60 mg., the treatment being individualized according to the patient’s response.
REFERENCES
1. Charles, D., Klein, T., Lunn, S. T., and Lorraine, J. A.: J. Obstet. Gynaecol. Br. Commonw. 76: 1100, 1969. 2. MacLeod, S. Cl., Mitton, D. M., and Tupper, W. R. Cl.: AM. J. OBSTET. GYNECOL. 108: 814, 1970. 3. MacLeod, S. C., Mitton, D. M., and Parker, A. S.: Ann. R. COB. Physicians Surg. Can. 4: 52, 1971.
4.
Hotchkiss, J., Atkinson, L. E., and Knobil, E.: Endocrinology 89: 177, 1971. 5. Murthy, Y. S., Parekh, M. C., and Arronet, G. H.: Int. J. Fe&l. 16: 66, 1971. 6. MacGregor, A. H., Johnson, J. E., and Bund, C. A.: Fertil. Steril. 19: 616, 1968. 7. Van Hall, E. V., and Mastboom, J. L.: AM. J. OBSTET. GYNECOL. 103: 165, 1969. 8. Jones, G. S., Maffezzoli, R. D., Strott, C. A.,
Volume Numhrr
115 3
Ross,
Ovulation
G. T.,
and Kaplan, G.: AM. J. OBSTET. 1970. Van Campenhout, J., Simard, R., and Leduc, B.: Fertil. Steril. 19: 700, 1968. Graff, G.: Fertil. Steril. 22: 209, 1971. Cohen, M. R., and Perez-Pelaez, M.: Fertil. Steril. 16: 141, 1965. Figueroa-Casas, P. R., Archangeli, 0. A., GYNECOL.
9. 10. 1 I. 12.
induction
with
cisclomiphene
327
Gowland, C. M., Bodano, A. R., Berli, and Bonofiglio, E. C.: AM. J. OBSTET.
108: 847,
COL.
13. 14.
106:
R. R., GYNE-
828, 1970.
Shirai, E., Iizuka, R., and Notake, Steril. 23: 331, 1972. Lamb, E. J., and Guderian, A. Gynecol. 28: 505, 1966.
Y.: M.:
Fertil. Qhstet.
VAN
ET.
CAMPENHOUT,
BORREMAN,
H.
WYMAN,
PH.D.
A.
ANTAKI,
M.D.
Montreal,
Quebec,
M.D.,
F.R.C.S.(C)
M.D.
Canada
Thirty-seven infertile patients with ovulatory defects have been treated with cisclomiphene at dosages varying from 10 to 140 mg. per day. The over-ail ouulatory rate was 78.1 per cent with a pregnancy rate of 51.3 per cent. The results of our investigation with cisclomiphene are presented in detail and are compared with our previous experience with clomiphene. It seems that the ovulatory rate is similar for the two compounds but that the Pregnancy rate is much higher with cisclomiphene. The dosage of 10 mg. of cisclomi#hene is effective but might have to be increased according to the patient’s response. It appears that 10 and 20 mg. of cisclomiphene, respectively, are as effective as 50 and 100 mg. of clomiphene citrate
0 NE o F THE most recent advances in the treatment of infertility due to anovulation has been the introduction of clomiphene citrate. Clomiphene citrate is a mixture of isomers in approximately a 1: 1 ratio of cisclomiphene and transclomiphene. Nearly all the data reported in the literature concern the use of the mixture, and it is only recently that the individual isomers have become available for clinical trials. Preliminary studies seem to indicate that cisclomiphene* is more potent than the transisomer as well as the isomeric mixture for the induction of ovulation in the woman.‘-3 The purpose of this communication is to
report the results of cisclomiphene in the management of ovulatory defects in infertile patients and to compare the results of this study with our previous experience with the use of clomiphene citrate. Material
Presented at the Twenty-eighth Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada, Quebec City, Quebec, Canada, June 15-18, 1972.
Montreal
24, Quebec,
methods
Sixty-three women between the ages of 20 and 36 were selected from among those attending our Infertility Clinic. All patients included in this study were thoroughly investigated in order to exclude possible pituitary, thyroid, or adrenal disease. Furthermore, each was assessed with respect to endogenous estrogen production by means of vaginal cytology, examination of the cervical mucus, and endometrial biopsy ; plasma concentrations of estradiol were measured by radioimmunoassay in most patients. The diagnosis of anovulation in 61 patients was made on the basis of monophasic basal body temperature and serial vaginal cytologies and endometrial biopsies; all of these patients were anovulatory for at least one year. The diagnosis of an inadequate luteal phase in 2 patients was based upon repeated endometrial biopsies on the first day of menses and upon hyperthermic plateaus
From the Infertility Center, Department of Obstetrics and Gynecology, and the Endocrine Research Laboratories, Department of Medicine, Notre Dame Hospital, University of Montreal.
Reprint requests: Dr. J, Van Campenhout, 1560 Sherbrooke
and
St., E.,
Canada.
*Cisclomiphene citrate was supplied by the Wm. S. Merrell Company, Canada.
321
322
Von
Compenhout
Table I. Clinical
February 1. 1973 Am. J. Obstet. Gynrcol.
et al
diagnoses Cisclomiphene
Clomiphene
17 (45.9%)
15 (57.6%)
13 (35.1%)
8 (30.7%)
Diagnosis Polycystic sclerotic ovaries Anovulatory oligomenorrhea Secondary amenorrhea Argonz-Del Castillo Oversuppression syndrome Postpartum Chiari-Frommel Hypothalamic Short luteal phase Anovulatory cycles Total No. of patients
2 1 1 1 1
2 3:
(100%)
26(100%)
of less than 10 days for a period of at least one year. Furthermore, all patients had been investigated to rule out other factors which might be contributing to the infertility. The husbands had normal semen analysis. The clinical diagnoses in the instances of patients selected for treatment with either clomiphene or cisclomiphene are given in Table I. The majority of patients had polycystic sclerotic ovaries or anovulatory oligomenorrhea. According to the diagnosis, the percentage of each type of disorder is approximately the same in the 2 groups treated with either clomiphene or cisclomiphene. The total number of patients who received clomiphene was 26, and 37 patients received cisclomiphene. Among these patients, 10 have been treated with the 2 compounds. There were totals of 129 treatments with cisclomiphene and 93 treatments with clomiphene. In all instances, medication was given for 5 days starting on the fifth day of spontaneous menses or induced withdrawal bleeding. The distribution of patients according to the dosage of cisclomiphene administered is shown in Fig. 1. Twenty-nine patients were started at the 10 mg. dosage, while 7 received initially 20 mg. daily and 1 patient received 40 mg. daily. Four patients responded transitorily to 10 mg. and were subsequently treated with 20 mg.; 11 patients who did not respond at a first treatment with 10 mg. received 20 mg. at the second treatment.
Thus, 22 patients received the 20 mg. dosage. If the response was not satisfactory, the next dosage was increased by 10 or 20 mg. Clomiphene was initially given in a dosage of 50 mg. to 19 patients and 100 mg. to 7 patients. If the response was inadequate, the dosage was progressively increased to 100, 150, and 200 mg. All patients were seen regularly during treatment. A postcoital test was performed 6 to 11 days after drug administration, and an endometrial biopsy was performed the first day of menstrual bleeding. Basal body temperature was continuously recorded. The cycle was considered ovulatory when followed by pregnancy or when endometrial biopsy disclosed a fully secretory differentiation with a hyperthermic plateau of 12 to 14 days. Results
Response to cisclomiphene. Results
according to dosage in 37 patients treated with cisclomiphene are shown in Fig. 1. Among the 29 patients treated with 10 mg., 16 (55 per cent) ovulated and 8 (28 per cent) became pregnant. Among the 22 patients who received 20 mg., 9 (41 per cent) ovulated and 3 (13.6 per cent) became pregnant. Eight pregnancies followed a dosage varying from 30 to 60 mg. Three patients were treated with a dosage varying from 80 to 140 mg., and none of them ovulated. Of the 37 patients (Table II) receiving cisclomiphene for 129 courses of treatment, 29 ovulated (78.1 per cent) and 19 became pregnant (51.3 per cent), with 85 (65.8 per cent) of the 129 treatments resulting in ovulation following the therapy. Table III lists the details of the 19 women who became pregnant following cisclomiphene administration. Of those 19 patients, there were only 2 abortions to date. Nine had an uneventful single pregnancy and were delivered at term of clinically normal children. Eight pregnancies are progressing well. Two pregnancies occurred during the first cycles off the drug and are not included in our results. As shown in Table IV, the ovulatory response to cisclomiphene varied markedly in
Volunle Number
115 3
Ovulation
induction
with
cisclomiphene
323
NUMBER OF PATIENTS I
Fig.
Table II. Summary
1. Results
according
of response to clomiphene No. of patients
Clomiphene, Cisclomiphene,
to dosage
50 to 200 mg. 10 to 140 mg.
26 37
in patients
k@!
No OF PATIENTS
m
No
=
No OF PREGNANCIES
treated
with
OF OVUl.ATlNG
PATIENTS
cisclomiphene.
and cisclomiphene
Treatments 93 129
relation to the adequacy of endogenous estrogens. When endogenous estrogens were assessed as poor or absent, 27.6 per cent ovulatory responses were obtained. When the endogenous estrogen secretion was estimated as good, 65.2 per cent of the responses were ovulatory. Although it must be kept in mind that the numbers are small, it seems that this difference in ovulatory response in relation to the adequacy of endogenous estrogens is encountered at the 10 to 20 mg. dosage level as well as at the 30 to 60 mg. dosage level. When the dose of cisclomiphene is raised to 60 mg. and over, ovulation does not seem to be induced in either group. The abundance and spinnbarkheit of the endocervical mucus was evaluated at the time of the postcoital test in 31 patients during 70 treatments after administration of amounts of cisclomiphene varying between 10 and 80 mg. per day. In each instance, the mucus was abundant with a spinnbarkheit of
Ovulatory cycles 57 (61%) 85 (65.8%)
Ovulating patients 18 (69.2%) 29 (78.1%)
over 10 cm. and numerous ozoa were present.
Pregnan&s 7 (27.0%) 19 (51.3%)
motile
spermat-
Comparative effectiveness of clomiphene and cisclomiphene. The over-all ovulation and pregnancy rates obtained with clomiphene were 69.2 and 27 per cent, respectively, whereas 78.1 and 51.3 per cent were obtained in the cisclomiphene group (Table II). The percentages of ovulating patients and of ovulatory cycles are only slightly higher in the group of women treated with cisclomiphene over those treated with clomiphene. The incidence of pregnancies, however, is significantly higher in the group treated with cisclomiphene (5 1.3 per cent) than in the group receiving clomiphene (27 per cent) . It should be noted that the mean number of treatments per patient was 3.3 for the clomiphene group and 3.4 for the cisclomiphene-treated group. Furthermore, 7 pregnancies resulted from 57 ovulatory cycles in-
324
Van
Campenhout
February 1, 1973 Am. J. Obstet. Gynecol.
et al
Table III. Pregnancies
during
cisclomiphene
Patient
Diagnosis
P. M. F. R. L. M.
Polycystic sclerotic ovaries Polycystic sclerotic ovaries Polycystic sclerotic ovaries Polycystic sclerotic ovaries Anovulatory oligomenorrhea Anovulatory oligomenorrhea Anovulatory cycles Short luteal phase Polycystic sclerotic ovaries Polycystic sclerotic ovaries Anovulatory oligomenorrhea Polycystic sclerotic ovaries Anovulatory oligomenorrhea Polycystic sclerotic ovaries Anovulatory oligomenorrhea Anovulatory cycles Short luteal phase Polycystic sclerotic ovaries Oversuppression syndrome
ii: G. D. D. P. V. B. R. F. D. N. M. T. S. G.
y. 0. J. P. s. J. G. M. G. L. L. P. T. T. R.
Table IV. Ovulatory
treatment 1
Dosage
Cycle
10 10 10 10 10 10 10 10 20 20 20 30 30 40 40 40 40 60 60
response to cisclomiphene
Outcome
1 12 6 1 5 1 2 1
Delivered at term Delivered at term Progressing well (4 months) Delivered at term Delivered at term Progressing well (2 months) Progressing well (5 months) Progressing well (8 months) Delivered at term Delivered at term Delivered at term Progressing well (6 weeks) Progressing well (2 months) Abortion (3 % months) Progressing well (9 months) Progressing well (6 weeks) Abortion (3 months) Delivered at term Delivered at term
: 1 3 4 I 1 3 1 1 2
related
to adequacy
of endogenous
estrogens Endogenous
estrogens
Good
Poor
or absent
Dosage cisclomiphene
of
10 to 30 to
20 60
68 20
44(64.7%) 16 (80%)
15 13
4 (26.6%) 4 (30.8%)
80 Total to 140
924
6:(65.2%)
291
i (27.6%)
(mg.)
No.
of cycles
Ovulations
duced by clomiphene, which represents an incidence of pregnancies of 12.2 per cent, whereas 19 pregnancies were obtained from 85 ovulatory cycles induced by cisclomiphene, which represents an incidence of pregnancies of 22.3 per cent. Moreover, if we consider only the pregnant patients, the mean number of ovulatory cycles which were necessary to obtain the pregnancy was 3.3 for the clomiphene group and 2.6 for the cisclomiphene group. Although these data are based on a restricted number of patients, it seems nevertheless that cisclomiphene is much more effective than clomiphene in regard to the pregnancy rate. If we compare the ovulatory response to the first course of therapy, at various dosages, it appears that dosages of 10 and 20 mg. of cisclomiphene, respectively, are as effective as the doses of 50 and 100 mg. of clomiphene (Table V) .
No.
of cycles
Ovulations
Table VI compares the responses of 10 patients treated successively with both medications; the first 8 patients received initially the isomeric mixture, and the last 2 patients were treated first with cisclomiphene. Four of the subjects did not respond to either clomiphene or cisclomiphene. Three women ovulated after clomiphene treatment (50 or 100 mg.) but became pregnant following 10 mg. courses of cisclomiphene. The remaining 3 patients exhibited a variety of reto 50 and 100 mg. sponses : not responding of clomiphene but ovulating after 40 mg. of cisclomiphene (L. S. ) , becoming pregnant with clomiphene therapy and not ovulating with the cis-isomer (P. L.) , or, as in the case of V. P., ovulating with 50 mg. clomiphene treatments and responding initially to a 10 mg. course of cisclomiphene followed by no response to 10 and 20 mg. dosages and then responding when the dosage of cisclomiphene
Volume Number
Ovulation
115 3
Table V. Response to first course of clomiphene
induction
and cisclomiphene
No.
50 100
Table VI. Comparison and with
cisclomiphene
325
therapy Cisclomiphene
Clomiphene Dosape
(w)
with
Dosape fmiJ 10 20
Ovulation
of patients
17 15
8 (47%) 7 (46.5%)
of ovulating
responses in 10 patients
No.
patients
of
Ovulation
29 22
treated
with
16 (55%) 9 (41%)
clomiphene
cisclomiphene -..Clomiphene Dosage Cm.1 50 100 200
Patient D. A.
No. of treatments 1 1 1
F. R. G. E.+
100 50
5 1
L.
P. M. P. R. S. H. v. P.
50 100 50 100 50 50
1 1 :
B. J.
100
1
P. L.
100
1
s.
“Pregnant
with
human
Ovulation -
5 6
menopausal
Cisclomiphene
gonadotropin
Pregnancy
+
+ + +
-
+ plus
+ human
was increased to 40 mg. These results indicate that a variety of responses can occur in patients being treated with clomiphene and its cis-isomer; Patient V. P. is particularly illustrative in this regard. Comment Few clinical studies concerning the effectiveness of cisclomiphene in the induction of ovulation have been reported to date. Charles and associates,’ administering cisclomiphene at 75 mg. daily dosages to 51 patients, obtained 8 pregnancies or a pregnancy rate of 15 per cent. No pregnancies occurred in the group reported by Murthy and co11eagues,5 but their study was limited to 13 patients. MacLeod and co-worker?’ 3 observed an ovulatory response of 78 per cent and a pregnancy rate of 50 per cent in patients treated
chorionic
Dosage (mg.1 10 30 50 100 10 10 30 50 20 40 10 20 10 10 10 20 40 10 20 10 20
No. of treatments 1 1 1 1 12 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Ovulation
Pregnancy
+ + + + + +
i
. * + _-.
-
gonadotropin.
with 20 mg. of cisclomiphene. In our present study in which the dosage was individualized, the ovulatory rate was 78.1 per cent with an over-all pregnancy rate of 51.3 per cent. If we exclude the 2 cases with short luteal phases which might represent anovulatory cycles with luteinization of follicles or ovulatory cycles with inadequate luteal function, the pregnancy rate is 48 per cent. It should be noted that, contrary to MacLeod and coworkers, we increased our dosage beyond 20 mg. ; 8 pregnancies, which represent 40 per cent of the total number of pregnancies obtained in this study, resulted from dosages of cisclomiphene of 30 to 60 mg. per day. In our experience, cisclomiphene has been shown to be as effective as clomiphene in the management of anovulation. Although the ovulatory response following treatment with
326
Van
Campenhout
February 1, 1973 Am. J. Obstet. Gynecol.
et al.
both compounds is approximately similar, the over-all pregnancy rate is higher following the administration of cisclomiphene than with clomiphene. Charles and associates’ and MacLeod and co-workers29 3 have also observed a higher incidence of pregnancy with cisclomiphene, the latter authors attributing their results to patient selection. The discrepancy between the relatively high rate of ovulation induced by clomiphene and the low pregnancy rate, as noted in our study, has been repeatedly reported.6l 7 MacGregor and associates,6 reviewing the clinical experience with clomiphene citrate, noted that since the initiation of clinical research with this drug the over-all ovulatory response has remained remarkably constant at about 70 per cent, while the over-all pregnancy rate was 31 per cent. This discrepancy has been attributed to the luteinization of developing follicles without ovulation,7 to abnormal corpus luteum function8 and to ovum entrapment.8 It is possible that with the use of cisclomiphene the occurrence of these abnormal ovarian responses may be reduced. Furthermore, an antiestrogenic effect of clomiphene citrate on the cervical mucus has been noted in many clinical studies.g-14 This local factor might interfere with conception and also explain to some extent the discrepancy between the ovulation and pregnancy rates. Contrary to the findings of Charles and associates,l an inhibitory effect of cisclomiphene on the abundance and spinnbarkheit of the endocervical mucus has not been observed in our present study. With regard to dosages, it appears from our study and from the data of MacLeod and co-worker? that 10 mg. of cisclomiphene
would elicit an equivalent ovulatory response to 50 mg. of clomiphene and that 20 mg. of cisclomiphene would equal 100 mg. of clomiphene in the induction of ovulation. As observed for clomiphene,” the ovulatory response to cisclomiphene varied markedly in relation to the adequacy of endogenous estrogen. Patients in whom the estrogen assessment was considered good generally responded well, whatever the dosages of cisclomiphene administered. If we consider the patients who became pregnant more than 6 months before the end of the present study, we note an abortion rate of 15.3 per cent. All delivered pregnancies were single, and no ovarian hyperstimulation syndrome was observed. Only 5 patients of the 37 (13.5 per cent) treated with cisclomiphene reported side effects; these 5 complained of mild vasomotor hot flushes. It seems thus that there is no contraindication to increase the dosage, provided it is adjusted to the individual response and progressively increased. In conclusion, although the data presented are based on a restricted number of patients and the homogeneity of the two groups of patients treated with cisclomiphene and with the isomeric mixture, respectively, is difficult to ascertain, it seems, nevertheless, that cisclomiphene is as effective as clomiphene in regard to apparent ovulation rate but has the decided advantage of being much more effective in terms of pregnancy rate. From our experience, it would seem worthwhile to increase progressively the dosage of cisclomiphene at least to 60 mg., the treatment being individualized according to the patient’s response.
REFERENCES
1. Charles, D., Klein, T., Lunn, S. T., and Lorraine, J. A.: J. Obstet. Gynaecol. Br. Commonw. 76: 1100, 1969. 2. MacLeod, S. Cl., Mitton, D. M., and Tupper, W. R. Cl.: AM. J. OBSTET. GYNECOL. 108: 814, 1970. 3. MacLeod, S. C., Mitton, D. M., and Parker, A. S.: Ann. R. COB. Physicians Surg. Can. 4: 52, 1971.
4.
Hotchkiss, J., Atkinson, L. E., and Knobil, E.: Endocrinology 89: 177, 1971. 5. Murthy, Y. S., Parekh, M. C., and Arronet, G. H.: Int. J. Fe&l. 16: 66, 1971. 6. MacGregor, A. H., Johnson, J. E., and Bund, C. A.: Fertil. Steril. 19: 616, 1968. 7. Van Hall, E. V., and Mastboom, J. L.: AM. J. OBSTET. GYNECOL. 103: 165, 1969. 8. Jones, G. S., Maffezzoli, R. D., Strott, C. A.,
Volume Numhrr
115 3
Ross,
Ovulation
G. T.,
and Kaplan, G.: AM. J. OBSTET. 1970. Van Campenhout, J., Simard, R., and Leduc, B.: Fertil. Steril. 19: 700, 1968. Graff, G.: Fertil. Steril. 22: 209, 1971. Cohen, M. R., and Perez-Pelaez, M.: Fertil. Steril. 16: 141, 1965. Figueroa-Casas, P. R., Archangeli, 0. A., GYNECOL.
9. 10. 1 I. 12.
induction
with
cisclomiphene
327
Gowland, C. M., Bodano, A. R., Berli, and Bonofiglio, E. C.: AM. J. OBSTET.
108: 847,
COL.
13. 14.
106:
R. R., GYNE-
828, 1970.
Shirai, E., Iizuka, R., and Notake, Steril. 23: 331, 1972. Lamb, E. J., and Guderian, A. Gynecol. 28: 505, 1966.
Y.: M.:
Fertil. Qhstet.