Ultrasonographic and clinical correlates of menotropin versus sequential clomiphene citrate: menotropin therapy for induction of ovulation

Vol. 44, No.3, September 1985 Printed in U.SA.

FERTILITY AND STERILITY Copyright c 1985 The American Fertility Society

Ultrasonographic and clinical correlates of menotropin versus sequential clomiphene citrate: menotropin therapy for induction of ovulation

Joseph Tal, M.D.*t Baram Paz, M.D.* Ichel Samberg, M.D.* Nissim Lazarov, M.D.:j: Mordechai Sharf, M.D.* Haifa Medical Center (Rothschild), Faculty of Medicine, Technion, Haifa, Israel

Forty-six women remaining infertile with clomiphene citrate (CC) with or without human chorionic gonadotropin (hCG) were treated by either human menopausal gonadotropin (hMG, 44 cycles) or CC + hMG (33 cycles) and monitored by serum estradiol (E2 ) and ultrasonography. Ovarian hyperstimulation syndrome (OHS) and pregnancy outcome were compared in both regimens. In the presence of dominant follicles (~ 18 mm) alone or with a single secondary follicle (14 to 16 mm) at hCG administration, OHS did not develop. A significant increase in OHS was noted when three or more secondary follicles were observed. Overall pregnancy rates were similar in both regimens but significantly higher when hCG was injected before rather than after the E2 peak. The results suggest (1) secondary follicles rather than dominant follicles are a valuable sign of possible OHS development; and (2) CC + hMG should be considered in CC-failure patients. Fertil Steril 44:342, 1985

The discrepancy between the rates of ovulation and pregnancy with clomiphene citrate (CC) is well documented and has been attributed, among other possibilities, to follicular maldevelopment. l Therefore, a rational approach to the induction of ovulation after CC failure would be menotropin treatment. 2 However, the two main complications involved, namely ovarian hyperstimulation syndrome (OHS) and multiple pregnancies, make the meno-

Received October 8, 1984; revised and accepted May 23, 1985. *Department of Obstetrics and Gynecology. tReprint requests: Joseph Tal, M.D., Department ofObstetrics and Gynecology, Haifa Medical Center (Rothschild), P.O. Box 4940, Haifa, Israel. :J:Department of Diagnostic Radiology. 342

Tal et al. Menotropins and sonography

tropin treatment risky. Furthermore, to reduce the rate of these complications, one must employ a monitoring system that uses estrogen measurements combined with biologic parameters, a method that raises the cost of the procedure significantly and entails considerable inconvenience for both patient and physician. Several studies have shown pregnancy rates on combined CC and human menopausal gonadotropin (hMG) (CC + hMG) to be comparable with hMG alone. 3 -5 Other reports have found a reduced incidence of OHS or multiple pregnancy rates with the combined regimen. 6 , 7 Recently, ultrasonographic imaging of follicular development has become a new modality for monitoring induction of ovulation, with the hope of further reduction of complications associated with treatment and perhaps improvement in timing of ovulation induction. Fertility and Sterility

In this study we deal with the following questions: (1) Are the ovarian follicular morphologic features, as observed in ultrasonography, of any significance regarding prediction of possible OHS development and multiple pregnancies? (2) Is the timing of human chorionic gonadotropin (hCG) administration in relation to the serum estradiol (E 2) pattern in the follicular phase important to the occurrence of these two complications of ovulation induction? (3) Are hMG and CC + hMG regimens different in respect to ovarian morphologic features and pregnancy outcome?

MATERIALS AND METHODS PATIENTS

From July 1983 to April 1984, 46 infertile women were treated for ovulation induction or enhancement in the Infertility Clinic of the Haifa Medical Center (Rothschild), Haifa, Israel. Forty-three of the patients included in the study had normal hysterosalpingographies and no abnormalities on laparoscopy. Three other patients had microsurgical adhesiolysis for bilateral periadnexal adhesions, with no evidence of tubal disease. Male infertility (severe oligospermia or azoospermia) was diagnosed in 12 of the 46 couples; these couples underwent artificial insemination by donor semen. In the other 34 couples, the man was considered to be fertile according to spermiogram results and postcoital tests. The 46 patients were normoprolactinemic and had not achieved pregnancy after 6 to 9 months of treatment with CC (lkapharm, Tel-Aviv, Israel); 100 to 150 mg/day, for 5 days, with or without hCG. They had a total of 361 cycles, 241 (68.1%) of which were ovulatory as judged by both biphasic basal body temperature (BBT) and a midluteal progesterone (P) level of > 5 ng/ml. The patients were randomly assigned to one of two treatment regimens: group A, hMG; group B, CC + hMG. Eventually, 19 patients had only hMG cycles, 16 only CC + hMG, and 11 both hMG and CC + hMG. ULTRASOUND

The equipment used was an SDR 7450 realtime sector scanner with a 3.5 MHz rotating head transducer (Phillips Rohe, Eindhoven, The NethVol. 44, No.3, September 1985

erlands). With the use of the full bladder technique,S the ovaries, uterus, and cul-de-sac were carefully scanned. Developing follicles of all sizes were measured, and the largest diameter of each follicle was serially followed. A dominant follicle was defined as a progressively growing follicle reaching a diameter of 18 to 25 mm on the day ofhCG administration (day -1) and later displaying ultrasonic signs of ovulation as will be described below; secondary follicles were those achieving a maximum diameter of14 to 16 mm (day -1) and lacking the criteria of ovulation in ultrasonography. TREATMENT AND MONITORING PROTOCOL

The ovaries were examined ultrasonographically before the start of treatment; whenever residual follicles or cysts from previous cycles were found, treatment was not begun. Patients were seen in the Infertility Clinic every other day during the treatment cycle for assessment of cervical mucus score, serum E2 measurement, and pelvic ultrasonographic examination. The treatment protocol for hMG has been described in detail previously. 9 According to this protocol in the hMG group, either 2 or 3 ampules (150 to 225 IU) ofhMG were injected intramuscularly daily, beginning on day 5 of a spontaneous cycle or induced withdrawal bleeding. Because the peak effect of an hMG dose takes 3 to 4 days to reach, changes in dosage were made (1 ampule) only if no change in E 2 level was observed within this time span. Once estrogen response was initiated, the dosage was held constant. In the combined treatment group (CC + hMG), CC of 50 mg/day was administered from days 5 to 9, followed by daily injections of hMG. This low CC dose was chosen in order to avoid hyperstimulation and antiestrogenic effects. The hMG dose on day 10 was based on the E 2 level on day 9: ifE2 was ~ 250 pg/ml, 1 ampule of hMG (75 IU) was prescribed, and if it was ~ 250 pg/ml, 2 ampules of hMG (150 IU) were given. The rest of the cycle was continued as described for the hMG group. When the largest developing follicle had reached a maximal diameter of 18 to 20 mm, 10,000 IU of hCG (lkapharm) was injected intramuscularly (day -1). An additional 10,000 IU of hCG was given on the following day (day 0) and 5000 IU on day + 1, for a total of 25,000 IU. Induction of ovulation was therefore based on ultrasonographTal et al. Menotropins and sonography

343

ic follicular development independent of the serum E2 levels. In order to study the relationship of hCG administration (day -1) and the serum E2 pattern, blood was also drawn on day O. On day + 1 (48 hours after the first hCG), ultrasonography was repeated so that we could look for signs of ovulation. Only if the diameter of the dominant follicle had regressed by > 30%, which was usually associated with appearance of intrafollicular echoes and in many cases free fluid in the cul-de-sac, was the cycle called "ovulatory." Seven to 8 days after the temperature rise, blood was drawn for serum P. Pregnancy was confirmed initially by a urine test and then by ultrasonography. All gestations in this study went beyond the eighth week.

Table 1. General Data on 46 Patients Group A (hMG)

Treatment cycles hMG ampules u Days of hMG treatmentU Day of biological shift (cervix)U No shift Ovulation Spontaneous b By BBTb By P (> 5)C By ultrasound b Day of temperature shiftd Luteal phase lengthd Midluteal phase P (ng/ml)d

44 17.3 ± 9.5 11.2 ± 1.6 -3.5 ± 1.5

Group B (CC + hMG)

36 7.9 ± 3.5 6.9 ± 1.2 -2.0 ± 1.06 5/36 (13.8%)

2/44 36/44 43/44 40/44

(4.5%) (82%) (97.7%) (90.9%)

+ 1.09 ± 0.4 12.5 ± 1.9 19.0 ± 7.7

4/36 32/36 36/36 33/36

(11%)

(89%) (100%) (91.6%) + 1.13 ± 0.3 12.7 ± 1.9 19.3 ± 4.1

UStudent's t-test: P < 0.00l. bChi-square with Yates' correction: not significant. CChi-square with Yates' correction: P < 0.001. dStudent's t-test: not significant.

OVARIAN HYPERSTIMULATION SYNDROME

In 41 patients before stimulation, mean ± standard error of the mean ovarian diameters on ultrasonography were 2.4 ± 0.9 cm over 3.4 ± 0.7 cm. In three patients with oligoovulation and two with anovulation, the diameters were 3.6 ± 1.1 cm over 3.9 ± 0.9 cm before treatment. In any cycle in which the ovary attained a diameter of at least 6 x 6 cm on ultrasonography 48 to 72 hours after the first hCG injection associated with abdominal discomfort, the cycle was called OHS grade I. In such cycles, only bed rest was recommended. In grade II OHS, ovaries were cystic (diameter 10 x 10 cm or larger), with abdominal distension. Nausea and vomiting were frequent. Patients with grade II OHS had been hospitalized and treated until symptoms and signs resolved. Patients with grade III OHS, i.e., symptoms and signs as in grade II with associated ascites, hydrothorax, and hemoconcentration, were not observed in our study. RADIOIMMUNOASSAY

Radioimmunoassays for serum E 2 , P, and prolactin were performed with a commercial kit purchased from International Cea-Ire-Sorin, St. Quentin Yvelines, France. STATISTICAL ANALYSIS

Statistical analysis with Student's t-test, chisquare with the Yates' correction, and linear regression analysis were performed when appropriate. 344

Tal et aI. Menotropins and sonography

RESULTS Forty-six patients had a total of 80 treatment cycles with either hMG (44 patients) or CC + hMG (36 patients), averaging 1.74 cycles per patient. Table 1 reveals a 50% reduction in the amount of hMG ampules in group B (CC + hMG), compared with group A (hMG only) (P < 0.001). As a result, the days of hMG treatment were significantly reduced from 11.2 ± 1.6 to 6.9 ± 1.2 (P < 0.001). This meant savings not only on the number of ampules but also on days of monitoring, blood tests, ultrasonographic examinations, injections, and physician's visits. The biological shift in cervical mucus, defined as a score of 8/12 or more according to Insler et aI.,10 occurred approximately 1.5 days earlier in group A than in group B (P < 0.001). Of more importance, perhaps, was the finding that despite the low CC dose (50 mg/day), in almost 14% of the treatment cycles the cervical score was < 8/12 on the day of ovulation induction. This was especially disturbing in three of the five cycles involving artificial insemination by donor procedures. Spontaneous ovulation, that is, sonographic disappearance of the follicle before hCG administration, occurred more frequently in group B (11%) than in group A (4.5%) but was not statistically different. Circumstantial evidence for ovulation by BBT (12 days or more of temperature rise), P (;;:: 5 ng/ml in the midluteal phase), and ultrasonogFertility and Sterility

, f

Table 2. Conceptions in the Two Treatment Modalities

Anovulation Oligoovulation Artificial insemination After microsurgery Total

Conceptions/ patient No. %

Conceptions/cycle" CC + hMG No. % No. %

5/8 9/23

62.5 39

3/9 5/19

33.3 26.3

2/2 4122

100 18.2

3/12

25

2/12

16.7

1110

10

3/3

100

114

25

2/2

100

20/46

43

11/44

25

9/36

25

hMG

·Chi-square with the Yates' correction: no statistically significant difference found between hMG and CC + hMG regimens in any of the diagnostic categories.

raphy (as defined above) were comparable between the two groups. No statistical difference was noted between the two groups as to the day of temperature shift, luteal phase length, and midluteal P. Table 2 summarizes the conceptions achieved with the two treatment modalities according to diagnosis. On the average, four treatment cycles were needed to achieve a pregnancy in both the hMG and ee + hMG groups. Three patients who did not achieve a pregnancy within 6 months after surgery became pregnant· after one or two treatment cycles. The numbers of conceptions in all diagnostic categorie.s were not statistically different. Figure 1 is a histogram of the mean ± standard error ofthe mean of serum E2 levels on the day of heG administration in the two treatment groups divided into subgroups according to the number of dominant follicles per cycle. The serum E2 levels on day - 1 for cycles with singleton pregnancies, multiple pregnancies, and OHS are also given. In the hMG regimen, the mean E2 levels were statistically different for the subgroups divided according to the number offollicles. However, it is obvious from looking at the histogram that the overlap in the serum E2 level is considerable for all subgroups, and therefore in the individual case it was not possible to predict the existence of a single follicle or multiple follicles without the aid of ultrasonography. In the ee + hMG regimen, no such statistical difference was found. Because serum E2 is not predictive of the number of dominant follicles or the chance for OHS, we asked the following question: Are the ovarian follicular morphologic features, namely, the presVol. 44, No.3, September 1985

ence of preovulatory follicles and/or secondary size follicles, of any advantage for the prediction of possible development of hyperstimulation and multiple pregnancies? Accordingly, we divided the cycles into those with dominant follicles only and those with mixed morphologic features. Table 3 shows that in cycles in which only dominant follicles were present, hyperstimulation never developed; this was true for both treatment regimens even if there were three preovulatory follicles. OHS occurred only when both preovulatory and secondary follicles coexisted. In this situation, when two dominant follicles in addition to secondary size follicles were present, OHS occurred in 3 of 12 cycles of the hMG-treated patients (25%) and 1 of 7 cycles of the ee + hMG group (14%). However, when three dominant follicles coexisted with secondary follicles, the rate of OHS increased: two of two cycles in the hMG group (100%) and one of two cycles in the ee + hMG. group (50%). With four dominant follicles, the number of secondary follicles was always more than three and OHS always ensued (three cycles). Thus, OHS occurred in 8 of the 44 hMG-treatment cycles (18.2%), whereas only 2 of 36 cycles were complicated with OHS in the ee + hMG group (5.5%). Although this difference did not attain statistical significance, it is 3.3 times greater. Some indication for the overall chance of OHS development is therefore possible (last row in Table 3). With two dominant follicles it is roughly 20% in group A and 10% in group B, and it increases to 50% in group A and 30% in group B with three dominant follicles. Of interest also is the finding that the mean levels of serum E2 on day -1 in the hMG group were significantly different in OHS cycles with • p-0.01

NS- Dlff.rence Not Stellatlce"y Slgnlflcent

HMO

7

21

11

..

17

3

§

o

8

§

SP

MP

10

cc·_

Figure 1 Serum E2 levels on day of hCG administration; dominant follicles, conceptions, and OHS. Open circles in bars, number of dominant follicles per cycle; SP, single pregnancy; MP, multiple pregnancies; OHS, ovarian hyperstimulation syndrome. Tal et al. Menotropins and sonography

345

Table 3. OHS per Cycle and Follicular Size hMG (group

Treatment modality No. of dominant follicles Dominant follicle(s) only Dominant and secondary follicles ORS rate a Overall chance of ORS (%)

CC + hMG (group B)

A)

1 0112 0/9

2 0/4 3/12

3 0/2 2/2

0/21 0

3/16 18.7

2/4 50

4 3/3

1 0/10 0/11

2 0/5 117

3 0/1 112

3/3 100

0/21 0

1112 8.3

113 33.3

aEight of 44 cycles in group A and 2 of 36 cycles in group B; difference is not statistically significant.

mixed pattern follicular morphologic features compared with cycles in which only dominant follicles were present, 804 ± 217 pg/ml and 418 ± 119 pg/ml, respectively (P < 0.05). In the CC + hMG group, no such difference was found; 589 ± 108 pg/ml and 671 ± 217 pg/ml, respectively, P > 0.5. Regarding the appearance of secondary follicles, three patterns emerged (Table 4): (1) when there was only a single secondary size follicle in both ovaries, no hyperstimulation occurred; (2) if the number of the secondary size follicles was three or more (average, 4.2), hyperstimulation of either grade I or grade II always developed (9 of 9 cycles); (3) with two secondary follicles, ORS occurred only once in 16 such cycles (6.25%). Furthermore, the two treatment regimens differed mainly in the development of three or more secondary follicles per cycle. As Table 4 reveals, in the hMG group there were 2.7 times more cycles in which this phenomenon occurred,compared with CC + hMG cycles (7 of26 = 27% versus 2 of 20 = 10%, respectively). Aside from ovarian follicular morphologic features, we asked if there was any correlation between the timing of hCG administration during the rising serum E2 wave in the late follicular phase and the chance for ORS and multiple pregnancies. Figure 2 shows that in the hMG group, in 19 cycles ovulation was induced before the E2 peak and eight pregnancies (42%) resulted: one triplet, one twin, and six singleton. Six of these pregnancies (75%) were associated with ORS (five grade I and one grade II). Two other cycles ended in grade II hyperstimulation but were not conceptual. On the other hand, when hCG was injected at or after the E2 peak, only 3 of 23 such cycles (13%) were conceptual (all singleton); none of these 23 cycles was complicated by ORS. In the second group (CC + hMG), a similar pattern was noted. When hCG was given before the E2 peak, 6 of 15 cycles (40%) were conceptual 346

Tal et aI. Menotropins and sonography

(one twin, five singleton), twice as much as the subgroup in which ovulation was induced at or after the E2 peak (3 of 15, i.e., 20%, all singleton). Two cycles were complicated by ORS with the combination treatment regimen, one in each of the above subgroups. Considering together both regimens, conception rates were significantly higher if ovulation was induced before rather than after the E2 peak (P < 0.05). Furthermore, nine often cycles were complicated by ORS when hCG was given before the serum E2 peak, and only one ORS cycle occurred if hCG was given after the E2 peak (P < 0.01). Figure 2 reveals an association of early administration ofhCG with a high pregnancy rate and a considerable number of hyperstimulated cycles in the hMG group. On the other hand, in the CC + hMG cycles, early hCG administration resulted in a high pregnancy rate, with only a small percentage of ORS. We have performed linear regression analysis on the correlation between E 2 1evels (day -1) and the number of dominant follicles or secondary follicles for all cycles combining both study groups and separately for the ORS cycles. Statistical significance (0.005 < P < 0.05) was found in the correlations of the whole study group but not in the OHS cycles. In the patients with grade I ORS, symptoms and signs resolved rather quickly within days.

Table 4. Secondary Follicles and OHS OH8/cycle

Secondary fOllicles/ _ _ _ _G_ro_u...:.p_a_ _ __ A B A+B cycle (n

1

2 3-8

= 26)

0/9 1110 717

(n

p

= 20) (n = 46)

0/12 0/6 2/2

0/21 1116 9/9

NS b

< O.Ol c

aGroup A = hMG; group B = CC + hMG. bNot significant. cDifference between 1116 and 9/9 is statistically significant (Fisher's exact probability test).

Fertility and Sterility

HCG:Before E,Peak

At E,Peak Before E,Peak

HMG

CC HMG

e

1000

'"

600 400

"-

IL

W

AA

800

200

-7 -5 -3 -10 Conceptions 8/19 Cycle OHS _Cycle

8/19

-7 -5 -3 -1 0 Day

3/23

6/15

3/17

0/23

1/15

1/17

Figure 2 Conceptions and OHS in relation to E2 level and day of hCG administration. Arrow, day in cycle when first hCG was injected. Conception and OHS rates were significantly higher if hCG had been injected before rather than after E2 peak: X2 = 5.12, 0.01 < P < 0.05 and X2 = 7.10, 0.001 < P < 0.01, respectively (treatment regimens considered together).

The four patients with grade II OHS were hospitalized and treated by bed rest, fluids, and careful monitoring of their electrolytes and .hematocrit. In one of these four .patients, who achieved a twin pregnancy during the treatment cycle, symptoms lasted 24 days. The other three patients were discharged after 10 to 14 days. It is noteworthy that the triplet pregnancy in the hMG group and the twin pregnancy in the CC + hMG group were not associated with hyperstimulation. In the triplet pregnancy, the right ovary contained three dominant follicles and the left ovary one secondary size follicle. In the twin pregnancy in group B there were three dominant follicles in the left ovary without any secondary size follicles. In the twin pregnancy associated with OHS, two preovulatory follicles developed in the right ovary in addition to four secondary size follicles. Is there any predictive value for the chance of multiple pregnancies by ultrasonic observation of the number of dominant follicles? We had 27 cycles with two dominant follicles, but only one twin gestation resulted (3.7%; Table 5). However, with three or four dominant follicles in 11 cycles, two multiple pregnancies occurred (18.2%). At the time of submission of this article, the patients with twin gestations delivered normal newborns. The gravida patient with the triplet pregnancy is in her 28th week of gestation. She had cervical cerclage in the 12th week, and since the 25th week we recommended complete bed rest. Vol. 44, No.3, September 1985

DISCUSSION

At E,Peak

Ovulation has been induced in 46 infertile patients with either an hMG or CC + hMG regimen. The dose ofhCG used was 25,000 IV because of our experience l l (unpublished data), short luteal phases occur less frequently with 25,000 IV than with 10,000 IV. In a previous communication9 we have shown that the incidence ofOHS is not increased with the use of the higher dose. Our working hypothesis in this study was that differences in rates of OHS and multiple gestations between the two treatment modalities (hMG versus CC + hMG) may correlate with ultrasonographic and hormonal (E 2) results. We decided to inject hCG only when the largest follicle(s) attained a diameter of 18 to 20 mm, disregarding the serum E2 level. This was based on our measurements in spontaneous ovulatory cycles in which we found the dominant follicle to be of a diameter of 21 ± 1.7 mm before disappearance and also according to data from Sallam et a1.,12 who found a 95% ovulation rate with hMG when hCG was given when the mean leading follicular diameter was 21.3 mm. Our data confirm findings by others5 , 6 who also noted a reduction in the number of hMG ampules used per cycle in the combined treatment regimen, compared with hMG treatment only. The implications for the reduction in expenses are obvious. One of the clinical problems encountered with the' combined regimen was reduced cervical mucus quality (14% of the cycles). A similar effect was noted by Kemmann and Jones. 5 Therefore, we no longer use CC + hMG in patients with inadequate cervical mucus, especially if they are on an artificial insemination program. Parameters expressing circumstantial evidence for ovulation, such as luteal phase length and P levels, were comparable in the two regimens. The high incidence of spontaneous premature ovulation seen in the combined group may be attributed to relatively high levels of endogenous luteinizing hormone induced by CC. The cycles in -Pregnancies Singleton Twin Triplet

No. of dominant

Cycles

1 2 3 or 4

42 27 11

8 4 5

1 1

1

80

17

2

1

follicle~

Total

Tal et al. Menotropins and sonography

347

which this phenomenon occurred were short (23 + 2 days), and the luteal phase length was always under 11 days. No difference in the overall pregnancy rate per cycle was noted between the two treatments (Table 2). That estrogen levels alone are non predictive of follicular development (number, different sizes, and growth rate) was confirmed here and was found also by Sallam et al. 12 and O'Herlihy et al. 13 It is here that ultrasonography is needed. Our data clearly show two main patterns of follicular development with these potent drugs used for induction of ovulation (Table 3). In one line of cycles, only dominant follicles developed, sometimes with an occasional secondary follicle. We have never encountered ovarian hyperstimulation in these cycles, even when three preovulatory dominant follicles were present. This is of course a desirable result of such treatments and was found in 28 of36 (77.7%) cyclesofCC + hMG and in 27 of 44 (61.4%) cycles of hMG. Can one safely induce ovulation with such a picture on ultrasonography? Based on the data of this study no OHS should be expected here, but there is an 18% chance of multiple pregnancies if three or four dominantfollicles are found. Therefore, if the couple is willing to take this chance (in our experience many will), they should be so advised. We found a very low incidence of multiple pregnancies when two dominant follicles were present at the time of ovulation induction (3.7%). Thus we always induce ovulation in such patients unless multiple secondary follicles also coexist. The second line of cycles (Table 4) included cases with both dominant and two or more secondary follicles. There were nine cycles in which the number of secondary follicles ranged from three to eight (average, 4.2) per cycle, and all ended with OHS. These secondary follicles usually developed in both ovaries, although the distribution was in favor of the ovary bearing the dominant follicles. In 16 cycles in which two secondary folhc.t:s existed, OHS occurred only once in a case with three dominant follicles iIi the same ovary. Because we had no case of OHS when only dominant follicles or dominant follicles with a single secondary follicle were present, we assume that the process of recruitment and selection is more successful here and similar to spontaneous cycles. In cycles with multiple secondary follicles, the process was probably abnormal from the beginning. 348

Tal et al. Menotropins and sonography

This is consistent with the difference we have noticed in this study between the two treatment regimens in regard to OHS. The increase of 2.7 times in incidence of cycles with more than three secondary follicles in the hMG group, compared with the CC + hMG group, is compatible with the 3.3 times increase in the rate of OHS. We suggest that the phenomenon of hyperstimulation is correlated more with the number of follicles in the ovaries that have a diameter of 14 to 16mm than with the number of dominant follicles. The explanation for that is not clear. However, we speculate that although these multiple secondary follicles reach a limited diameter, they do not undergo atresia, whereas the dominant . follicles achieve full maturation and thus contribute to the hyperstimulation process. We have found a statistically significant correlation (using linear regression analysis) between follicular number (dominant or secondary) and E2 levels (day -1), testing the whole study group cycles. On the other hand, the lack of correlation between these two parameters in the OHS cycles suggests that the morphologic landmark of three or more secondary follicles stands for itself unrelated to any particular E2 level. Our relatively high rate of OHS (7.5%, grade I; 5.0%, grade II) is not surprising. McArdle et al.,14 using ultrasonography to monitor hMG treatment, found sonographically hyperstimulated ovaries in 44% of the cycles. It is expected that the use of that technique would increase the detection of grade I OHS. Multiple pregnancies, especially twins, although many times well accepted by the couple, are looked upon as a complication mainly because of the increased fetal wastage. We had a 3 of 46 (6.5%) multiple pregnancy rate/patient and 3 of 80 (3.7%)/cycle. This is a low rate, compared with most reports,15 but in a previous report 9 with a larger number of patients, we noticed a 15.5% multiple pregnancy rate, which is probably more representative in our population. The combination of hyperstimulated ovaries with multiple gestation is a worrisome factor. During the first trimester the ovarian cysts grow significantly under the stimulation of high levels of hCG, and the patient is frequently symptomatic. This occurred in one of our patients. In that regard our finding that the existence of only dominant follicles may lead to multiple gestation but not to hyperstimulation is important. For the Fertility and Sterility

treating physician, this early knowledge enabling him to avoid OHS is extremely valuable. An interesting finding was the high rate of pregnancy when hCG was administered before rather than at or after the serum E2 peak (Fig. 2). It is possible that maturational processes are more adequate with early hCG administration. In that respect it is noteworthy that Lopata 16 found a higher pregnancy rate in his in vitro fertilization and embryo transfer program when hCGwas administered before the E2 peak. That this phenomenon is not necessarily associated with multiple ovarian follicles and OHS emerged from our study; the same pattern was observed in the CC + hMG group, in which only a small percentage of OHS was found, compared with the hMG group. In conclusion, our findings in this study point toward a predictive value for ultrasonography in regard to the development of OHS in hMG- and CC + hMG-induced cycles, dependent upon the existence of multiple secondary size follicles, whereas dominant follicles are more significant for multiple gestations. The combined treatment with CC + hMG was associated with a reduced incidence of OHS, compared with the hMG regimen, without a noticeable difference in the pregnancy rate. Acknowledgment. We are grateful to Mrs. Neomi Porat for her assistance. . REFERENCES 1. Jones GS, Maffezoli RD, Rose GT, Kaplan G: Pathophysiology of reproductive failure after clomiphene-induced ovulation. Am J Obstet Gynecol108:847, 1970 2. Brown JB, Evans JH, Adey FD, Taft HP, Townsend SL: Factors involved in clinical induction of fertile ovulation with human gonadotropins. J Obstet Gynaecol Br Commonw 76:289, 1969

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3. Goldfarb AG, Groll M, Rakoff AE: Experience in the induction of ovulation with sequential Clomid-menotropin therapy. In Gonadotropin Therapy in Female Infertility: Proceedings of the Meeting held at Worcester, Massachusetts, 1972, Edited by E Rosenberg. New York, American Elsevier Publishing Co., 1973, Excerpta Medica International Congress Series 266, p 157 4. Jarrell J, Mcinnes R, Cooke R, Arronet G: Observations on the combination of clomiphene citrate-human menopausal gonadotropin-human chorionic gonadotropin in the management of anovulation. Fertil Steril 35:634, 1981 5. Kemmann E, Jones JR: Sequential clomiphene citratemenotropin therapy for induction or enhancement ofovulation. Fertil Steril 39:772, 1983 6. Kistner RW: Sequential use of clomiphene citrate and human menopausal gonadotropin in ovulation induction. Fertil Steril 27:72, 1976 7. March CM, Tredway DR, Mishell DR Jr: Effect of clomiphene citrate upon amount and duration of gonadotropin therapy. Am J Obstet Gynecol 125:699, 1976 8. Donald I: Use of ultrasonics in diagnosis of abdominal swellings. Br Med J 2:1154, 1963 9. Samberg I, Tal J, Zilberman A, Oettinger M, Sharf M: Experience with combined individualized method of hMGIhCG therapy. Int J Fertil 28:85, 1983 10. Insler V, Melmed H, Eichenbrenner I, Serr DM, Lunenfeld B: The cervical score-a simple semiquantitative method for monitoring of the menstrual cycle. Int J Gynaecol Obstet 10:223, 1972 11. Tal J, Samberg I, Paz B, Sharf M: Unpublished data 12. Sallam HN, Marinho AO, Collins WP, Rodeck CH, Campbell S: Monitoring gonadotropin therapy by real-time ultrasonic scanning of ovarian follicles. Br J Obstet Gynaecol 89:155, 1982 13. O'Herlihy C, Evans JH, Brown JB, de Crespigny LT, Robinson HP: Use of ultrasound in monitoring ovulation induction with human pituitary gonadotropins. Obstet Gynecol 60:577, 1982 14. McArdle C, Seibel M, Hann LE, Weinstein F, Taymor M: The diagnosis of ovarian hyperstimulation (OHS): the impact of ultrasound. Fertil Steril 39:464. 1983 15. Lunenfeld B, Insler V: Diagnosis and Treatment of Functional Infertility. Berlin, Grosse Verlag, 1978, p 80 16. Lopata A: Concepts in human in vitro fertilization and embryo transfer. Fertil Steril 40:289, 1983

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