Ultrasound-controlled gonadotropin therapy of anovulatory infertility

FERTILITY AND STERILITY Copyright 1986 The American Fertility Society

Vol. 46, No.5, November 1986 Printed in U.8A.

Ultrasound-controlled gonadotropin therapy of anovulatory infertility

Joachim Bordt, M.D. * Jftrgen P. Hanker, M.D. Hermann P. G. Schneider, M.D. Women's University Hospital, Munster, Federal Republic of Germany

Real-time ultrasound scanning of follicular development was performed during 45 cycles of 15 patients receiving gonadotropin therapy for treatment of anovulatory infertility. The amount of gonadotropins administered was based exclusively on the results of the ultrasound examinations. Fourteen pregnancies were obtained, with 10 singletons, 2 sets of twins, and 1 set of triplets, resulting in a cumulative pregnancy rate of> 93%. Mild hyperstimulation occurred in two cases. Ultrasound alone can be used effectively to control gonadotropin therapy in the majority of cases. Fertil Steril 46:818, 1986

The induction of follicular development with human menopausal gonadotropin (hMG) and ovulation with human chorionic gonadotropin (hCG) to establish pregnancies has become a well-established method in the treatment of anovulatory infertility.1-3 Traditionally, indirect measures have been used to assess the ovarian response to gonadotropin stimulation, such as serial vaginal smears, cervical scoring measurement of total urinary estrogens, and of 1713-estradiol (E 2 ) in peripheral venous plasma. However, these procedures have considerable shortcomings, such as being costly, time-consuming, unreliable, and less specific. Ultrasound, on the contrary, has the distinct advantage of providing direct investigation offollicular development, ovulation, and corpus luteum formation in both spontaneous and induced

cycles. 4 , 5 The results of the procedure are in realtime, and diagnostic evaluation and/or therapeutic action can be performed at the same time. Hence sonography has been used increasingly to augment endocrine monitoring of follicular development during gonadotropin therapy, providing more accurate information on follicular number and size than can be obtained using estrogen determinations alone, and has become a generally accepted procedure. 6-8 In this study we investigated whether pelvic ultrasound alone suffices to control ovarian response to gonadotropin stimulation and to time the application ofhCG to induce ovulation. Areas of particular interest included pregnancy rate, number of cycles required to achieve conception, and the incidence of multiple pregnancies and other complications. MATERIALS AND METHODS

Received October 11, 1985; revised and accepted July 10, 1986. *Reprint requests: Joachim Hordt, M.D., Women's University Hospital, Albert-Schweitzer-Strasse 33, 4400 Munster, Federal Republic of Germany. 818

Bordt et al.

Gonadotropin therapy and ultrasound

Fifteen patients, with a mean age of 27.3 years (range, 25 to 31 years) received gonadotropin therapy for treatment of chronic anovulatory infertility of> 2 years' duration (Table 1). Fertility and Sterility

Table 1. Clinical and Ultrasound Data During 14 Conception Cycles After Gonadotropin Therapy Patient

1 2 3 4 5 6 7 8 9 10 11

12 13 14

Age

Infertility

Treatment cycles

hMG

yr.

yr.

no.

ampule.

27 25 25 26 28 28 25 27 31 30 30 26 26 26

2 3 3 4 5 7 5

3 3 2 1 2 8 3 4 3 2 1

10

8 9 6 4 6 4

10

2 1

3 3 2 2 3 5 3 4 4 3 3 3 2 1

No./size of preovulatory follicles 19,17a 20,19 b 20,20,19 b 20,20 b 18,17a 20,20 b 22,21 b 21,18 b 20,20,17 b 19,19a 21,20,19 b 21,20,20 b 19,19,18b 20 b

Result

Singleton, spontaneous abortion at 5 months Singleton, spontaneous abortion at 9 weeks Twins, spontaneous abortion at 25 weeks Triplets, spontaneous abortion at 25 weeks Singleton, term delivery Singleton, term delivery Singleton, term delivery Singleton, term delivery Singleton, term delivery Singleton, cesarean-section at 36 weeks Singleton, ongoing at 30 weeks Singleton, ongoing at 28 weeks Twins, ongoing at 20 weeks Singleton, ongoing at 15 weeks

ahCG administered on the next day. bhCG administered on the same day.

Previous unsuccessful attempts to induce fertile ovulations included intravenous administration of clomiphene citrate and pulsatile infusion of gonadotropin-releasing hormone, if applicable. The patient couples were assessed, including a full history, serum measurements of prolactin (mean, 197 mUll; range, 60 to 645 mUll), folliclestimulating hormone (mean, 1.9 nmol/l; range 0.5 to 3.3 nmolll), E2 (mean, 130 nmolll; range, 48 to 248 nmolll), and thyroxine, with the use of radioimmunoassay. In addition, in some patients the functional state of hypothalamopituitary-ovarian axis was classified by measuring its response to gonadotropin-releasing hormone. 9 A withdrawal bleeding following a progestational challenge with medroxyprogesterone acetate, 10 mg daily for 10 days, occurred in 5 of 15 cases. Positive tests of tubal patency were obtained, preferably by laparoscopy (8 of 15) and hysterosalpingography (2 of 15), if applicable. In all male partners, a complete semen analysis was obtained on two separate occasions. Also, in some patient couples (7 of 15), a Sims test was performed, with positive results. Ultrasonographic examination was performed with the use of a real-time mechanical sector scanner with a 3.5-Mhz general purpose probe (Siemens RA-1, Erlangen, FRG). The patients were examined immediately before each injection, according to the full-bladder technique.lO On the initial scan, the pelvis, uterus, and ovaries were examined in detail. Any abnormalities were noted for consideration during subsequent examinations. Vol. 46, No.5, November 1986

During gonadotropin therapy, transverse and longitudinal measurements of any active follicles were obtained and the mean geometric diameter calculated. This average diameter of the leading follicle was used to estimate the dosage of hMG necessary to maintain follicle growth and to time the injection of heG to induce final oocyte maturation. For treatment, patients received sequential intramuscular injections of hMG (Humegon, Organon, Oberschleissheim, FRG; Pergonal, Serono, Freiburg, FRG), each ampule containing an average of 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone. Pretreatment, such as with progestins, was not used. In the initial treatment cycle, an average dosage of 4 ampules of hMG was used to induce adequate ovarian response. The first three infections were administered on days 1, 3, and 5 of the treatment cycle. 11 On cycle day 6 or 7, ovarian response was investigated with the use of ultrasound and the number and size of detected follicles recorded. Adjustments of the treatment regimen were made in the following manner: if one or two active follicles 7 to 8 mm in diameter were observed, the previ0us average hMG dosage was continued (Fig. 1). If active follicles were not detected, the hMG dosage was increased by approximately 50% and ultrasound scanning repeated after 3 to 4 days. If a cohort of active follicles was imaged, a hMG overdosage was suspected and the cycle abandoned. One to two active follicles were selected and their daily growth rate controlled to 2 to 3 mm with either incremental or decremental changes of Bordt et al. Gonadotropin therapy and ultrasound

819

RESULTS

Figure 1 Sonogram, transverse scan. Typical ovarian response after initial gonadotropin stimulation for 7 days. Many small follicles, the largest with a mean diameter of 7 mm, indicating selection of active follicle (x 1.5).

The clinical data are summarized in Table 1. A total of 45 treatment cycles were monitored. Pregnancy occurred after an average of three treatment cycles (range, one to ten). Fourteen patients conceived, resulting in a cumulative pregnancy rate of93.3%. In the remaining patient, the reason for the failure to conceive was suspected to be subfertility of the husband. In 11 patients, singletons were obtained; in the remainder there were two sets of twins and one set of triplets. Four pregnancies ended prematurely. There were three spontaneous abortions, including one twin and the triplet pregnancy. One right tubal pregnancy was treated with salpingectomy. Four pregnancies are ongoing. Six patients were delivered of normal babies, one by cesarean section in the 36th week of gestation because of premature rupture of the membranes and amnion infection syndrome. There were two cases of mild hyperstimulation, but no cases of moderate or severe hyperstimulation. 12

DISCUSSION

hMG doses. Further management of cases was individualized on a cycle-to-cycle basis. The follicles were considered preovulatory when they reached a mean diameter of 20 ± 1 mm. Ovulation was then induced by intramuscular administration of 5000 IU of hCG (Choragon, Ferring, Kiel, FRG). The hCG was withheld, though, if more than three preovulatory follicles were detected. If two or three preovulatory follicles were present, thus increasing the likelihood of multiple gestation, the patient couples were required to give informed consent before hCG was administered. Sexual intercourse was recommended on the day of hCG administration and on the following day. Further follow-up examination was not an integral part of the study. The patients would report either after menstrual bleeding for another treatment cycle or with secondary amenorrhea to have their pregnancy confirmed. However, follicle rupture was confirmed infrequently with the use of repeated ultrasound investigation, and in some patients blood was drawn 8 to 10 days after hCG injection for measurement of luteal phase progesterone levels. Data were available 4 to 6 weeks later. 820

Bordt et a!. Gonadotropin therapy and ultrasound

In this study, the ovarian response to gonadotropin stimulation was monitored exclusively with the use of ultrasound. The dosage of hMG required to stimulate and to maintain follicle growth as well as the timing of hCG administration for induction of ovulation were determined solely on the respective ultrasound findings. Ultrasound measurements provide a direct method of following follicle growth, in both spontaneous and induced cycles. 4 - B Consequently, sonography has been used increasingly to augment other methods of monitoring gonadotropin therapy (Table 2). Our aim in this study was to assess the value of ultrasound alone to control gonadotropin therapy. The results demonstrate that in the study group ovarian response to both hMG stimulation and hCG timing of ovulation could be predicted accurately using ultrasound measurements of number and size of follicles induced. The procedure resulted in a cumulative conception rate of > 93% after ten treatment cycles. Thus ultrasound alone can be used successfully to monitor gonadotropin induction of ovulation, without the use of additional monitoring measures, such as E2 level. Fertility and Sterility

Table 2. Results of Different Monitoring Methods of Gonadotropin Therapy Authors

Kurachi et aI., 198413 Zimmennann et aI., 1982 14 Pittaway and Wentz, 198315 West and Baird, 198416 Cabau and Bessis, 1981 17 Fink et aI., 198218 Marrs et aI., 198319 Haning et al., 1983 20 Lunenfeld, 19858 SaHam et aI., 198211

Method

Pregnancies! patient

%

Twins

%

Triplets -

Cervical score Plasma E2 Plasma E2 Plasma E2 Plasma E~u1trasound Plasma E~u1trasound Plasma E 2/ultrasound Plasma E~ultrasound Plasma E 2/ultrasound Ultrasound

498/2166 119/392 12/25 33/46 6/27 21 6118 22128 38411000 12/22

23 30 48 72 22

931361 261119 3114 10/46 216 2/21 0 3/22 115/384 0

26 22 21 22 33 10

34/361 5/392 0 0 0 3/21 0 1/22 35/384 0

The problem of gonadotropin therapy is its relatively small margin of safety between successful induction of ovulation and ovarian hyperstimulation, the latter being a complication frequently associated with multiple gestation (Table 2). In this study, there were two cases of mild ovarian hyperstimulation and three cases of multiple gestation (two sets of twins and one set of triplets), two of which terminated as midtrimester abortions. For safe management of gonadotropin therapy, the use of accurate predictors of exaggerated ovarian response to gonadotropin stimulation is mandatory. A comparison of the effectiveness of various predictors of ovarian hyperstimulation, such as urinary estriol glucuronide, plasma, E 2 , and ultrasound, showed E2 to be the best predictor of ovarian hyperstimulation, far superior to both urinary estriol glucuronide and the number of follicles. Thus management of gonadotropin therapy with ultrasound alone was insufficient to prevent severe ovarian hyperstimulation. 2o Because of the small number of cases in this study, no other conclusion can be drawn. To prove the efficacy of ultrasound alone to effectively prevent ovarian hyperstimulation during gonadotropin therapy, a much larger number of treatment cycles is required to demonstrate a difference to other single or combined monitoring measures. Three cases of multiple gestation occurred in this study. In any case, heG was given in the presence of two or three mature follicles, as determined by size. S ,21 Therefore, it appears that ultrasound monitoring could predict multiple ovulation and gestation by accurately assessing the number of leading follicles during gonadotropin therapy.7 A treatment modality restricting the number of preovulatory follicles to one should Vol. 46, No.5, November 1986

33 79 38 55

14 30

%

9 1

14 5 9

render multiple gestation an exception to the rule, as in the normal cycle. Another complication associated with gonadotropin therapy is increased fetal wastage and perinatal risk following multiple gestation. 16 , 22 In the study group, two of the three multiple pregnancies were lost to spontaneous midtrimester abortions. The increased fetal loss rate following induction of multiple ovulation and conception results in an unfavorable low term pregnancy rate, compromising the overall success of gonadotropin therapy. A treatment regimen approaching the normal cycle as closely as possible should in tum reduce the incidence of abortions and prematurity to approximately that following spontaneous conceptions. Whether this can be accomplished remains to be seen, because ultrasound imaging of ovaries during gonadotropin therapy has not been predictive of multiple pregnancies. IS, 23 Because there was no control group, the results of this study can be compared only with the results of other investigators, using other or additional parameters to predict ovarian response to gonadotropin therapy. Although it appears from this study that ultrasound alone is as effective as other monitoring measures in controlling gonadotropin therapy, definite evidence that ultrasound alone could replace other monitoring methods of gonadotropin therapy would require a study with a large control group. Also, a study should be done to randomize the patients treated (e.g., ultrasound only versus ultrasound plus E2 combined monitoring) for comparative evaluation. Ultrasound alone can be used effectively to control gonadotropin induction of ovulation in the majority of cases. However, additional monitoring, such as measuring serum E2 levels, may be Bordt et aI. Gonadotropin therapy and ultrasound

821

required in cases of dubious findings during ultrasound assessment of ovarian response to gonadotropin therapy. REFERENCES 1. Gemzell CA, Diszfalusy E, Tillinger KG: Clinical effect of human pituitary follicle stimulating hormone. J Clin Endocrinol Metab 18:1333, 1958 2. Lunenfeld B, Menzi A, Volet B: Clinical effects of human postmenopausal gonadotropin. Rass Clin Ter Sci Affini 59:213, 1960 3. Gemzell P, Roos P: Pregnancies following treatment with human gonadotropins. Am J Obstet Gynecol 94:490, 1966 4. HackelOer BJ, Robinson HG: Correlation of ultrasonic and endocrinologic assessment of human follicular development. Geburtshilfe Frauenheilkd 38:163, 1968 5. Hackeliier BJ, Nitschke S, Daume E, Sturm G, Buchholz R: Ultraschalldarstellung von Ovarveranderungen bei Gonadotropinstimulierung. Geburtshilfe Frauenheilkd 37:185, 1977 6. Yliistalo P,Riinnberg L, Jouppila P: Measurement of the ovarian follicle by ultrasound in ovulation induction. Fertil Steril 31:651, 1979 7. Haning RV Jr, Austin CW, Kuzma CL, Shapiro SS, Zweibel WJ: Ultrasound evaluation of estrogen monitoring of ovulation with menotropins. Fertil Steril 37:627, 1982 8. Lunenfeld B: Medikamentiis gesteigerte Fertilitat. Teil II: Ultraschall terminiert die Ovulationsausliisung. Sexualmedizin 14:200, 1985 9. Hanker JP, Bohnet HG, Leyendecker G, Schneider HPG: LH-RH-therapy in functional amenorrhea based on clinical subclassification. Int J Fertil 25:222, 1980 10. Donald I: Use of ultrasonics in diagnosis of abdominal swellings. Br Med J 11:1154, 1963 11. Sallam HN, Marinho AO, Collins WP, Rodeck CH, Campbell S: Monitoring gonadotropin therapy by real-time ultrasound scanning of ovarian follicles. Bri J Obstet Gynaecol 89:155, 1982 12. Schwartz M, Jewelewicz R: The use of gonadotropins for induction of ovulation. Fertil Steril 35:3, 1981

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13. Kurachi K, Aono T, Suzuki M, Hirano M, Kobayashi T, Kaibara M: Results of HMG (Humegon)-HCG therapy in 6096 treatment cycles of 2166 Japanese women with anovulatory infertility. Eur J Gynecol Reprod BioI 19:43, 1985 14. Zimmermann R, Soor B, Brandle W, Lehmann F, Weise HC, Bettendorf G: Gonadotropin therapy of female infertility. Obstet Gynecol Invest 14:1, 1982 15. Pittaway DE, Wentz AC: Evaluation of the exponential rise of serum estradiol concentrations in human menopausal gonadotropin-induced cycles. Fertil Steril 40:763, 1983 16. West CP, Baird DT: Induction of ovulation with gonadotropins: a ten year review. Scot Med J 29:212, 1984 17. Cabau A, Bessis R: Monitoring of ovulation induction with human menopausal gonadotropin and human chorionic gonadotropin by ultrasound. Fertil Steril 36:178, 1981 18. Fink RS, Bowes LP, Macintosh CE, Smith WI, Georgiades E, Ginsburg J: The value of ultrasound for monitoring ovarian responses to gonadotropin stimulant therapy. Br J Obstet Gynaecol 89:856, 1982 19. Marrs RP, March CM, Vargyas JM: Monitoring human menopausal gonadotropin ovulation induction with realtime ultrasound (Abstr). Fertil Steril 37:314, 1982 20. Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ: Plasma estradiol is superior to ultrasound as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 40:31,1983 21. Bryce RL, Shuter B, Sinisich MJ, Stiel IN, Picker RH, Saunders DM: The value of ultrasound, gonadotropin and estradiol measurements for precise ovulation prediction. Fertil Steril 37:42, 1982 22. Ben-Rafael Z, Dor J, Mashiach S, Blankstein J, Lunenfeld B, Serr DM: Abortion rate in pregnancies following ovulation induced by human menopausal gonadotropinihuman chorionic gonadotropin. Fertil Steril 39:157,1983 23. Bryce RL, Picker RH, Saunders DM: Ultrasound in gonadotropin therapy: a better predictor of ovarian hyperstimulation. Aust NZ J Obstet Gynaecol 21:237,1981

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