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Clomid therapy for anovulatory infertility
Clomid therapy for anovulatory infertility NATHAN
KASE,
ADNAN
MROUEH,
LOWELL New
Haoen,
E.
M.D. M.D.
OLSON,
M.D.
Connecticut
The results of Clomid treatment of 81 infertile patients seeking pregnant) are reported: 60.5 per cent of patients ovulated and 25.9 per cent became pregnant. unusual side eflects of therapy were noted. In general, patients who were oligoovulatory or amenorrheic with evidence of estrogen production had successful responses. These results are comparable to other series. The disparity between ovulation and pregnancy rates in all these studier is noted and a case indicating a Clomid-induced non-corpus luteum source of progesterone production is included.
1 N T H E past 5 years, several reviews have appeared describing the successful induction of ovulation by Clomid” therapy.le3, ‘9 ’ HOWever, because of the lack of uniformity of patient selection and uncertainty regarding the criteria for positive response, the true efficacy of this drug has not been clearly established. This report presents the results of treatment in a group of infertile patients in whom the sole purpose of drug administration was to achieve pregnancy.
Case
material
and
cause of infertility. Because the nature of the underlying pathology, could not be verified in each patient, the case material is classified in three symptomatic categories. Oligoamenorrhea. This group of 52 patients had irregular periods with prolonged intermenstrual intervals varying from one to 6 months. The reduced frequency of ovulation was considered incompatible with ease of conception. The purpose of therapy in this category was to increase ovulation rate and predictability with consequent enhancement of fertility potential. Amenorrhea. Twenty-two patients had absent menses for longer than 6 months prior to therapy. The range of duration of this symptom was 6 months to 8 years. A single instance of primary amenorrhea was included. Inappropriate lactation syndromes. Of the 7 amenorrheic patients in this category 6 had persistent lactation following pregnancy (Chiari-Frommel syndrome) and one spontaneous galactorrhea (de1 Castillo syndrome) . None of these had demonstrable central nervous system disease. All patients underwent thorough endocrine evaluation prior to initiation of therapy. None of the patients treated had thyroid, adrena cortica1, or organic central nervous system disease. Pituitary-ovarian axis dysfunction of varying severity was believed
methods
The 81 patients comprising this series were investigated and treated at the Yale-New Haven Hospital Infertility Clinic. They varied in age from 18 to 34 years with a median of 26.5 years. The average duration of infertility was 2.9 years and the range was 6 months to 10 years. After thorough diagnostic work-up, absence or insufficient frequency of ovulation was the only discernible
From the Department of Obstetrics Gynecology, Yale Uniuersit)l School Medicine.
No
and
of
This study was supported by United States Public Health Service Grant AM-06129. *2-(P-[2-Chloro-I-2-diphenyl vinyl] phenoxy) triethylamine dihydrogen citrate was generously supplied by William S. Merrell Combanv. Cincinnati, Ohio. 1 ”
1037
1038
Kase,
Mroueh,
and
August 15, 1967 :\m. .I. Oh. & Gyrrw.
Olson
to be the underlying defect in the majority of cases. Sixty-six patients had biologic evidence of estrogen production by cndometrial biopsy, vaginal smear maturation index, and cervical ~nucus changes. In the remaining 15 patients without estrogen, IO had undetectable urinary gonadotropin by the mouse uterine weight assay. No case of primary ovarian failure was included in this series. Most patients were referred after having been treated unsuccessfully with other modalities to achieve ovulation. Of 29 patients treated with cortisone or derivatives, 5 had temporary or infrequent ovulatory responses. Ovarian wedge resection had been performed in 19 patients resulting in ovulation in 5 and pregnancy in 2. Return of prewedge menstrual pattern necessitated treatment with Clomid. Thirty-eight had cyclic hormone therapy with a variety of estrogen-progestin combinations. Last, 16 had received empirical thyroid treatment without effect. Initial Clornid treatment consisted of 50 m,q. daily for 5 days. In the presence of preceding menses the drug \vas administered beginning day 5. Generally, if no ovulation was noted in the first three treatment cycles, dosage was increased to 100 mg. daily for 5 to 7 days. Prior to each course patients were questioned for side effects and a pelvic examination performed to detect residual ovarian enlargement. Accurate basal hod) temperature charts were kept throughout treatment. An ovulatory response \vas defined as a sustained elexration in temperature of 0.4’ or more of 11 to 16 days’ duration. Table I. Distribution of Clomid treatment No.
of patierzts 6 12 12 13 15 15 2 5 1
Total
81
It is acknowledged that this elevation need not indicate true ovulation, a point which will be discussed below. After a pattern of dose dependent ovulation \vas established. patients were instructed in appropriate tinring of coitus. Results Ovulation and pregnancy rates. Of 346 treatment cycles, 149 or 43.1 per cent were ovulatory: 60.5 per cent of patients ovulated at least once on medication. Twenty-three pregnancies occurred in 21 patients. In terms of patient success, 25.9 per cenf of patients became pregnant on therapy. The per cent of pregnancies per induced ovulatory cyclrs was 15.4 per cent. An additional 2 patients spontaneously conceived 4 and 5 months following conclusion of Clomid treatment hut are not included in these data. As seen in Table I, the peatest s~~cms occurred in the first three treatment cycles. With prolonged treatment, while the perccntage of ovulations did not diminish appreciably, pregnancy rates did decrease. Sig-nificantly. of the patients in whom conception occurred. all but three were from category one (oligoamenorrheic) . The frequency of ovulation induction in the amenorrheic ,yroup t\vo \\‘as 17 ovulations in I 11 courses or 15.3 per cent. T\vo pregnancies occurred in this group, and one in the lactational syndrome category. All but one prcgnanq oclx rrc,d irr ze~omen with biologic midrxcc of utrogm production j.vior to thrrapy. The single instance where estro,qen effect had not
of ovulation and pregnancy rates correlated with number cycles ____ / No. of treatment No. of wulatory 1 Per cent Of 1 cycles cvcles omlation 1 2 3 4 5 6 7 8 9 346
4 19 17 9 37 29 6 23 5 149
66.6 79.1 -17.8 17.3 49.3 32.2 42.9 57.5 55.5 43.1
PW,!pZ?l~j 3 5 3 2 6 3 1 1
Clomid
been manifest was a patient with ChiariFrommel syndrome with secondary amenorrhea of 3 years’ duration and undetectable urinary gonadotropins. Timing of ovulation following a Clomid course was consistent for each patient. Almost 90 per cent of ovulations occurred between 7 and 14 days after a course of the drug. However, the duration of this interval ranged from temperature elevations which began while on treatment to a delay as long as 3 weeks following completion of each course. Despite these variations among patients, the interval length remained reproducible within 1 to 3 days for each individual. Fate of induced pregnancies. No multiple births or congenital anomalies have appeared in this series to date. Two abortions at 6 and 8 lveeks have occurred. In one, following an interval of oligoamenorrhea similar to that noted prior to Clomid, a repeat series of treatment resulted in an intrauterine gestation which is progressing normally (at present 20 weeks) Side effects of treatment. Ovarian enlargement, either unilateral or bilateral was the most common side effect, appearing in 7 patients. In none was hospitalization for pain or rupture required. However, the presence of this reaction alerted the physician so that subsequent treatment dosage was either postponed or not increased. Other side effects were vasomotor symptoms, bloating, and breast tenderness. These were sporadic complaints and in no instance was dosage moditied by their presence. Effect of Clomid on previous treatment failure. Previous bilateral wedge resection, Of 19 patients having previous wedge resection, while 2 had had pregnancies subsequent to operation all had reverted to their prewedge menstrual pattern. A total of 83 treatment cycles were administered to this group resulting in 47 ovulatory cycles and 8 pregnancies. Prmious cortisone or dcrir?atit!e trcatnleut failure. Twenty-nine patients in this group either had received cortisone alone or had failed to ovulate following cortisone and
therapy
for
anovulation
1039
wedge resection. These patients received a total of 153 courses which resulted in 71 ovulatory cycles and three pregnancies. Follow-up of Clomid failures. Fifty-nine patients had not become pregnant on Clomid at the time this report was prepared. Twentytwo subsequently received human menopausal gonadotropin (HMG) therapy. Ten patients became pregnant on gonadotropins, while 7 are currently receiving this form of ovulation induction. Of the 5 remaining patients, 3 continued anovulatory despite multiple courses of HMG. Successful application of gonadotropin was found to be independent of previous responsiveness to Clomid. Six patients became pregnant on HMG despite being totally anovulatory on several courses of Clomid. Five patients received wedge resection after Clomid failure. Two have become pregnant and the remaining at present are ovulating regularly. An additional 5 patients have become pregnant spontaneously within 2 years after Clomid. Of the remaining 27 patients, 12 are continuing Clomid therapy at this writing, 5 have adopted, whereas 12 patients have become disinterested or left the area and are lost to follow-up. In the 47 patients where data is available, all but 5 retained pre-Clomid menstrual abnormalities. Comment
and
conclusions
On the basis of the results herein reported as well as data from numerous workers (Table II). Clomid appears to be a relatively safe, easily administered, and wclltolerated medication which in approximately 60 per cent of anovulatory patients may be expected to induce more frequent and predictable ovulatory cycles. About one quarter of patients treated will become pre
1040
Kase,
Table II. infertility
Mroueh,
and
Comparative
Inoestigators Beck and associates’ Roy and associate@ Rivo and Rocks Yale-New Haven
Olson
data
patients
-~
129 179 70 81
of major
series of Clomid
(%I 68 77.6 86 60.5
the biologic presence of estrogen. It must be emphasized that this virtue of Clomid cannot undermine the physician’s primary responsibility to rule out disorders of pituitary, adrenal, and thyroid origin requiring specific treatment before initiating ovulation induction therapy. Furthermore, cases of ovarian failure require exclusion as these are unreactive to any form of ovulation induction. Analysis of the comparative data depicted in Table II indicates that the ovulation rate in the Yale-New Haven series is somewhat lower than noted in other reports. Two explanations can be given for this difference. As stated above it has been the practice at this clinic to maintain Clomid dosage at minimum levels in the face of incipient signs of drug provoked ovarian enlargement. It is felt that this conservative approach in part accounts for not only the very low incidence of side effects in this series but also the diminished number of ovulatory cycles. Furthermore, there is evidence that strict adherence to the criteria for ovulation observed in this series? while depressing over-all rates, nevertheless produced the highest frequency of pregnancies per ovulations of the reports cited. Further assessment of the data brings into focus two areas of uncertainty concerning the effectiveness of Clomid therapy of infertility hitherto only suggested by studies confined to ovulation rates alone. Placebo effect. Whereas some of the pregnancies included in this series unquestionably were the result of Clomid induced ovulation, the majority occurred in women who were spontaneously, albeit irregularly, ovulating. It is difficult to prove that pregnancy was not associated with either an unrelated
treatment
CYGlt?S 17 15.1 35.7 25.9
299 956 287 346
for anovulatot)
(76)
cycle
53 60.2 86.9 43.1
14.01 5.73 11.25 154
spontaneous ovulation or a “placebo” enhancement of this inherent faculty rather than pharmacologically related to drug administration. While the length of infertility experienced prior to Clomid partially negates the former, the placebo effect is not easily dismissed. Both Johnson and associates” and Townsend’s’ work with a Clomid placebo indicate significant participation of psychological factors clinically well known in infertility practice. In these studies the incidence of placebo responders was reported to be 12 and 57 per cent, respectively. Five patients in our series spontaneously conceived at periods greater than 4 months following conclusion of Clomid treatment. Whereas others might consider these as drug related phenomena, we cannot agree with that assignment. These cases emphasize the difficulty of assessing drug efficacy in a group of oligoovulatory patients in whom a susceptible psychogenic component may be an important factor in ovulatory dysfunction. “Apparent ovulation.” According to Ki\To and Rock,” under normal circumstances pregnancy may be expected to occur within four ovulatory cycles. As seen in Table IT. a disparity exists between ovulation rate and pregnancy rate secondary to Clomid. While a portion of infertility admittedly remains idiopathic despite the presence of ovulation. the disproportion noted on Clomid requires further explanation. In all Clomid studies, the biologic effects of progesterone secretion have been taken as evidence of ovulation. However, these effects are known to occur in the absence of a corpus lutemn7 Luteinization of follicle tissue without ovum extrusion is the suggested source of this steroid. Similar difficulties were associated with preg-
Volume Numher
98 R
Clomid
Fig. larity
1. Section following
of ovarian administration
follicle exhibiting of Clomid.
Fig. 2. Clomid-induced progesterone
stromal luteinization in the absence of a true corpus
extensive
theta
suggested as the luteum (see text).
nant mare serum therapy for anovulation. The following case taken from this series illustrates this problem of “apparent ovulation.” B. P. is a 25-year-old white female with 3 years of primary infertility. History and physical examination were consistent with the polycystic ovary syndrome. Preliminary treatment with prednisone was ineffective. Five courses of Clo-
therapy
intcrna
source
for
luteinization
of ovarian
anovulation
and
1041
vasru-
secretion
of
other contributing factor. Bilateral ovarian wedge resection was performed within one month of Clomid-induced “ovulation.” However, the ovarics did not contain corpora lutea. Histologically, multiple sections of wedge tissue revealed polycystic ovaries displaying extensive thecal and stromal luteinization with formation of large cortical nests of lipoid-laden cells (Figs. 1 and 2). Three months following wedge resection pregnancy occurred.
mid were given and three were associated with typical nancy
thermogenic ovulatory did not occur despite
responses. absence
of
Pregany
It is felt that and progesterone
nonovulatory luteinization secretion accounts for the
1042
Kase,
Mroueh,
and
Olson
aforementioned disparity between “ovulation” and pregnancy rate. This is further expressed in the large number of patients in whom Clomid failed who subsequently conceived on HMG, the frequent though transient temperature elevations while taking the drug, and the increased plasma progesterone levels on Clomid prior to ovulation.4 Despite these qualifications, Clomid is an effective drug particularly when used in the treatment of oligoovulatory infertility. Because of the ease of administration and minimal side effects when carefully monitored it should be used as primary treatment certainly before resorting to admittedly more
effective HMG therapy. However, there appears to be negligible value in postponing the more aggressive modalities if Clomid success is not achieved within four cycles of treatment. At the moment Clomid has displaced but not eliminated cortisone and wedge resection in a program of therapeutic induction of ovulation. It is clear from the data that prior failure with either (Xomid or wedge does not rule out success with alternate therapy. Furthermore, its use in the single woman or in other gynecologic endocrine disorders seems unwarrante(1 in the face of the availability of orally acti\x. materials with known mechanism of action.
REFERENCES
1.
2.
3. 4. 5.
Beck, P., Grayzel, E. F., Young, I. S., and Kupperman, H. S.: Obst. & Gynec. 27: 54, 1966. Johnson, J. E., Bunde, C. A., and Hoekenga, M. T.: Presentation, Thirteenth Meeting Pacific Coast Fertility Society, Las Vegas, October, 1965. Kistner, R. W.: AM. J. OBST. & GYNEC. 92: 380. 1965. Lurie, A. O., Villee, C. A., and Reid, D.: J. Clin. Endocrinol. 26: 742, 1966. Rive. E., and Rock. J.: Pacific Med. & Surg. 73: 413. 1965.
6.
7.
8.
Roy, S., Greenblatt, R. B., Mahesh, V. B. and Jungck, E. C.: Fertil. & Steril. 14: 575, 1963. Staemmler, H. J.: Die gestijrte Regelung der Ovariel Funktion, Berlin, 1964, Springer Verlag, Fig. 72n. Townsend, L.: Proc. Fifteenth Meeting .4merican College of Obstetricians and Gynecologists, Chicago, May, 1966. 333 Cedar New Haven,
Street Connecticut
KASE,
ADNAN
MROUEH,
LOWELL New
Haoen,
E.
M.D. M.D.
OLSON,
M.D.
Connecticut
The results of Clomid treatment of 81 infertile patients seeking pregnant) are reported: 60.5 per cent of patients ovulated and 25.9 per cent became pregnant. unusual side eflects of therapy were noted. In general, patients who were oligoovulatory or amenorrheic with evidence of estrogen production had successful responses. These results are comparable to other series. The disparity between ovulation and pregnancy rates in all these studier is noted and a case indicating a Clomid-induced non-corpus luteum source of progesterone production is included.
1 N T H E past 5 years, several reviews have appeared describing the successful induction of ovulation by Clomid” therapy.le3, ‘9 ’ HOWever, because of the lack of uniformity of patient selection and uncertainty regarding the criteria for positive response, the true efficacy of this drug has not been clearly established. This report presents the results of treatment in a group of infertile patients in whom the sole purpose of drug administration was to achieve pregnancy.
Case
material
and
cause of infertility. Because the nature of the underlying pathology, could not be verified in each patient, the case material is classified in three symptomatic categories. Oligoamenorrhea. This group of 52 patients had irregular periods with prolonged intermenstrual intervals varying from one to 6 months. The reduced frequency of ovulation was considered incompatible with ease of conception. The purpose of therapy in this category was to increase ovulation rate and predictability with consequent enhancement of fertility potential. Amenorrhea. Twenty-two patients had absent menses for longer than 6 months prior to therapy. The range of duration of this symptom was 6 months to 8 years. A single instance of primary amenorrhea was included. Inappropriate lactation syndromes. Of the 7 amenorrheic patients in this category 6 had persistent lactation following pregnancy (Chiari-Frommel syndrome) and one spontaneous galactorrhea (de1 Castillo syndrome) . None of these had demonstrable central nervous system disease. All patients underwent thorough endocrine evaluation prior to initiation of therapy. None of the patients treated had thyroid, adrena cortica1, or organic central nervous system disease. Pituitary-ovarian axis dysfunction of varying severity was believed
methods
The 81 patients comprising this series were investigated and treated at the Yale-New Haven Hospital Infertility Clinic. They varied in age from 18 to 34 years with a median of 26.5 years. The average duration of infertility was 2.9 years and the range was 6 months to 10 years. After thorough diagnostic work-up, absence or insufficient frequency of ovulation was the only discernible
From the Department of Obstetrics Gynecology, Yale Uniuersit)l School Medicine.
No
and
of
This study was supported by United States Public Health Service Grant AM-06129. *2-(P-[2-Chloro-I-2-diphenyl vinyl] phenoxy) triethylamine dihydrogen citrate was generously supplied by William S. Merrell Combanv. Cincinnati, Ohio. 1 ”
1037
1038
Kase,
Mroueh,
and
August 15, 1967 :\m. .I. Oh. & Gyrrw.
Olson
to be the underlying defect in the majority of cases. Sixty-six patients had biologic evidence of estrogen production by cndometrial biopsy, vaginal smear maturation index, and cervical ~nucus changes. In the remaining 15 patients without estrogen, IO had undetectable urinary gonadotropin by the mouse uterine weight assay. No case of primary ovarian failure was included in this series. Most patients were referred after having been treated unsuccessfully with other modalities to achieve ovulation. Of 29 patients treated with cortisone or derivatives, 5 had temporary or infrequent ovulatory responses. Ovarian wedge resection had been performed in 19 patients resulting in ovulation in 5 and pregnancy in 2. Return of prewedge menstrual pattern necessitated treatment with Clomid. Thirty-eight had cyclic hormone therapy with a variety of estrogen-progestin combinations. Last, 16 had received empirical thyroid treatment without effect. Initial Clornid treatment consisted of 50 m,q. daily for 5 days. In the presence of preceding menses the drug \vas administered beginning day 5. Generally, if no ovulation was noted in the first three treatment cycles, dosage was increased to 100 mg. daily for 5 to 7 days. Prior to each course patients were questioned for side effects and a pelvic examination performed to detect residual ovarian enlargement. Accurate basal hod) temperature charts were kept throughout treatment. An ovulatory response \vas defined as a sustained elexration in temperature of 0.4’ or more of 11 to 16 days’ duration. Table I. Distribution of Clomid treatment No.
of patierzts 6 12 12 13 15 15 2 5 1
Total
81
It is acknowledged that this elevation need not indicate true ovulation, a point which will be discussed below. After a pattern of dose dependent ovulation \vas established. patients were instructed in appropriate tinring of coitus. Results Ovulation and pregnancy rates. Of 346 treatment cycles, 149 or 43.1 per cent were ovulatory: 60.5 per cent of patients ovulated at least once on medication. Twenty-three pregnancies occurred in 21 patients. In terms of patient success, 25.9 per cenf of patients became pregnant on therapy. The per cent of pregnancies per induced ovulatory cyclrs was 15.4 per cent. An additional 2 patients spontaneously conceived 4 and 5 months following conclusion of Clomid treatment hut are not included in these data. As seen in Table I, the peatest s~~cms occurred in the first three treatment cycles. With prolonged treatment, while the perccntage of ovulations did not diminish appreciably, pregnancy rates did decrease. Sig-nificantly. of the patients in whom conception occurred. all but three were from category one (oligoamenorrheic) . The frequency of ovulation induction in the amenorrheic ,yroup t\vo \\‘as 17 ovulations in I 11 courses or 15.3 per cent. T\vo pregnancies occurred in this group, and one in the lactational syndrome category. All but one prcgnanq oclx rrc,d irr ze~omen with biologic midrxcc of utrogm production j.vior to thrrapy. The single instance where estro,qen effect had not
of ovulation and pregnancy rates correlated with number cycles ____ / No. of treatment No. of wulatory 1 Per cent Of 1 cycles cvcles omlation 1 2 3 4 5 6 7 8 9 346
4 19 17 9 37 29 6 23 5 149
66.6 79.1 -17.8 17.3 49.3 32.2 42.9 57.5 55.5 43.1
PW,!pZ?l~j 3 5 3 2 6 3 1 1
Clomid
been manifest was a patient with ChiariFrommel syndrome with secondary amenorrhea of 3 years’ duration and undetectable urinary gonadotropins. Timing of ovulation following a Clomid course was consistent for each patient. Almost 90 per cent of ovulations occurred between 7 and 14 days after a course of the drug. However, the duration of this interval ranged from temperature elevations which began while on treatment to a delay as long as 3 weeks following completion of each course. Despite these variations among patients, the interval length remained reproducible within 1 to 3 days for each individual. Fate of induced pregnancies. No multiple births or congenital anomalies have appeared in this series to date. Two abortions at 6 and 8 lveeks have occurred. In one, following an interval of oligoamenorrhea similar to that noted prior to Clomid, a repeat series of treatment resulted in an intrauterine gestation which is progressing normally (at present 20 weeks) Side effects of treatment. Ovarian enlargement, either unilateral or bilateral was the most common side effect, appearing in 7 patients. In none was hospitalization for pain or rupture required. However, the presence of this reaction alerted the physician so that subsequent treatment dosage was either postponed or not increased. Other side effects were vasomotor symptoms, bloating, and breast tenderness. These were sporadic complaints and in no instance was dosage moditied by their presence. Effect of Clomid on previous treatment failure. Previous bilateral wedge resection, Of 19 patients having previous wedge resection, while 2 had had pregnancies subsequent to operation all had reverted to their prewedge menstrual pattern. A total of 83 treatment cycles were administered to this group resulting in 47 ovulatory cycles and 8 pregnancies. Prmious cortisone or dcrir?atit!e trcatnleut failure. Twenty-nine patients in this group either had received cortisone alone or had failed to ovulate following cortisone and
therapy
for
anovulation
1039
wedge resection. These patients received a total of 153 courses which resulted in 71 ovulatory cycles and three pregnancies. Follow-up of Clomid failures. Fifty-nine patients had not become pregnant on Clomid at the time this report was prepared. Twentytwo subsequently received human menopausal gonadotropin (HMG) therapy. Ten patients became pregnant on gonadotropins, while 7 are currently receiving this form of ovulation induction. Of the 5 remaining patients, 3 continued anovulatory despite multiple courses of HMG. Successful application of gonadotropin was found to be independent of previous responsiveness to Clomid. Six patients became pregnant on HMG despite being totally anovulatory on several courses of Clomid. Five patients received wedge resection after Clomid failure. Two have become pregnant and the remaining at present are ovulating regularly. An additional 5 patients have become pregnant spontaneously within 2 years after Clomid. Of the remaining 27 patients, 12 are continuing Clomid therapy at this writing, 5 have adopted, whereas 12 patients have become disinterested or left the area and are lost to follow-up. In the 47 patients where data is available, all but 5 retained pre-Clomid menstrual abnormalities. Comment
and
conclusions
On the basis of the results herein reported as well as data from numerous workers (Table II). Clomid appears to be a relatively safe, easily administered, and wclltolerated medication which in approximately 60 per cent of anovulatory patients may be expected to induce more frequent and predictable ovulatory cycles. About one quarter of patients treated will become pre
1040
Kase,
Table II. infertility
Mroueh,
and
Comparative
Inoestigators Beck and associates’ Roy and associate@ Rivo and Rocks Yale-New Haven
Olson
data
patients
-~
129 179 70 81
of major
series of Clomid
(%I 68 77.6 86 60.5
the biologic presence of estrogen. It must be emphasized that this virtue of Clomid cannot undermine the physician’s primary responsibility to rule out disorders of pituitary, adrenal, and thyroid origin requiring specific treatment before initiating ovulation induction therapy. Furthermore, cases of ovarian failure require exclusion as these are unreactive to any form of ovulation induction. Analysis of the comparative data depicted in Table II indicates that the ovulation rate in the Yale-New Haven series is somewhat lower than noted in other reports. Two explanations can be given for this difference. As stated above it has been the practice at this clinic to maintain Clomid dosage at minimum levels in the face of incipient signs of drug provoked ovarian enlargement. It is felt that this conservative approach in part accounts for not only the very low incidence of side effects in this series but also the diminished number of ovulatory cycles. Furthermore, there is evidence that strict adherence to the criteria for ovulation observed in this series? while depressing over-all rates, nevertheless produced the highest frequency of pregnancies per ovulations of the reports cited. Further assessment of the data brings into focus two areas of uncertainty concerning the effectiveness of Clomid therapy of infertility hitherto only suggested by studies confined to ovulation rates alone. Placebo effect. Whereas some of the pregnancies included in this series unquestionably were the result of Clomid induced ovulation, the majority occurred in women who were spontaneously, albeit irregularly, ovulating. It is difficult to prove that pregnancy was not associated with either an unrelated
treatment
CYGlt?S 17 15.1 35.7 25.9
299 956 287 346
for anovulatot)
(76)
cycle
53 60.2 86.9 43.1
14.01 5.73 11.25 154
spontaneous ovulation or a “placebo” enhancement of this inherent faculty rather than pharmacologically related to drug administration. While the length of infertility experienced prior to Clomid partially negates the former, the placebo effect is not easily dismissed. Both Johnson and associates” and Townsend’s’ work with a Clomid placebo indicate significant participation of psychological factors clinically well known in infertility practice. In these studies the incidence of placebo responders was reported to be 12 and 57 per cent, respectively. Five patients in our series spontaneously conceived at periods greater than 4 months following conclusion of Clomid treatment. Whereas others might consider these as drug related phenomena, we cannot agree with that assignment. These cases emphasize the difficulty of assessing drug efficacy in a group of oligoovulatory patients in whom a susceptible psychogenic component may be an important factor in ovulatory dysfunction. “Apparent ovulation.” According to Ki\To and Rock,” under normal circumstances pregnancy may be expected to occur within four ovulatory cycles. As seen in Table IT. a disparity exists between ovulation rate and pregnancy rate secondary to Clomid. While a portion of infertility admittedly remains idiopathic despite the presence of ovulation. the disproportion noted on Clomid requires further explanation. In all Clomid studies, the biologic effects of progesterone secretion have been taken as evidence of ovulation. However, these effects are known to occur in the absence of a corpus lutemn7 Luteinization of follicle tissue without ovum extrusion is the suggested source of this steroid. Similar difficulties were associated with preg-
Volume Numher
98 R
Clomid
Fig. larity
1. Section following
of ovarian administration
follicle exhibiting of Clomid.
Fig. 2. Clomid-induced progesterone
stromal luteinization in the absence of a true corpus
extensive
theta
suggested as the luteum (see text).
nant mare serum therapy for anovulation. The following case taken from this series illustrates this problem of “apparent ovulation.” B. P. is a 25-year-old white female with 3 years of primary infertility. History and physical examination were consistent with the polycystic ovary syndrome. Preliminary treatment with prednisone was ineffective. Five courses of Clo-
therapy
intcrna
source
for
luteinization
of ovarian
anovulation
and
1041
vasru-
secretion
of
other contributing factor. Bilateral ovarian wedge resection was performed within one month of Clomid-induced “ovulation.” However, the ovarics did not contain corpora lutea. Histologically, multiple sections of wedge tissue revealed polycystic ovaries displaying extensive thecal and stromal luteinization with formation of large cortical nests of lipoid-laden cells (Figs. 1 and 2). Three months following wedge resection pregnancy occurred.
mid were given and three were associated with typical nancy
thermogenic ovulatory did not occur despite
responses. absence
of
Pregany
It is felt that and progesterone
nonovulatory luteinization secretion accounts for the
1042
Kase,
Mroueh,
and
Olson
aforementioned disparity between “ovulation” and pregnancy rate. This is further expressed in the large number of patients in whom Clomid failed who subsequently conceived on HMG, the frequent though transient temperature elevations while taking the drug, and the increased plasma progesterone levels on Clomid prior to ovulation.4 Despite these qualifications, Clomid is an effective drug particularly when used in the treatment of oligoovulatory infertility. Because of the ease of administration and minimal side effects when carefully monitored it should be used as primary treatment certainly before resorting to admittedly more
effective HMG therapy. However, there appears to be negligible value in postponing the more aggressive modalities if Clomid success is not achieved within four cycles of treatment. At the moment Clomid has displaced but not eliminated cortisone and wedge resection in a program of therapeutic induction of ovulation. It is clear from the data that prior failure with either (Xomid or wedge does not rule out success with alternate therapy. Furthermore, its use in the single woman or in other gynecologic endocrine disorders seems unwarrante(1 in the face of the availability of orally acti\x. materials with known mechanism of action.
REFERENCES
1.
2.
3. 4. 5.
Beck, P., Grayzel, E. F., Young, I. S., and Kupperman, H. S.: Obst. & Gynec. 27: 54, 1966. Johnson, J. E., Bunde, C. A., and Hoekenga, M. T.: Presentation, Thirteenth Meeting Pacific Coast Fertility Society, Las Vegas, October, 1965. Kistner, R. W.: AM. J. OBST. & GYNEC. 92: 380. 1965. Lurie, A. O., Villee, C. A., and Reid, D.: J. Clin. Endocrinol. 26: 742, 1966. Rive. E., and Rock. J.: Pacific Med. & Surg. 73: 413. 1965.
6.
7.
8.
Roy, S., Greenblatt, R. B., Mahesh, V. B. and Jungck, E. C.: Fertil. & Steril. 14: 575, 1963. Staemmler, H. J.: Die gestijrte Regelung der Ovariel Funktion, Berlin, 1964, Springer Verlag, Fig. 72n. Townsend, L.: Proc. Fifteenth Meeting .4merican College of Obstetricians and Gynecologists, Chicago, May, 1966. 333 Cedar New Haven,
Street Connecticut