MEASUREMENT OF THE OVARIAN FOLLICLE BY ULTRASOUND IN OVULATION INDUCTION

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1 FRTLTY AND STRLTY Copyright 1979 The American Fertility Society Vol. 31, No.6, June 1979 Prinl d in U.SA. MASURMNT OF TH OVARAN FOLLCL BY ULTRASOUND N OVULATON NDUCTON PKKA YLOSTALO, M.D.* LARS RONNBRG, M.D. PNTT JOUPPLA, M.D. Department of Obstetrics and Gynaecology, University of Oulu, Oulu, Finland Ultrasonic monitoring of ovarian follicles and estimation of serum estradiol were carried out in 12 patients with clomiphene therapy, in patients with gonadotropin therapy, and in 7 normal controls. The average diameter of preovulatory follicles in normal controls was 12.8 mm; in ovulation induction groups it was 2 to 4 mm greater. The level of serum estradiol was also higher in ovulation induction groups than in normal controls. The combined use of these two methods is recommended: ultrasonic monitoring to minimize the risk of multiple pregnancies and estrogen level monitoring to minimize the risk of hyperstimulation. Ultrasound is also safe and practical in following the size of hyperstimulated ovaries. Fertil Steri31:61, 1979 Urinary or serum estrogen assays have generally been used to monitor the ovarian response to ovulation induction treatment with human menopausal gonadotropin (HMG) or clomiphene. During gonadotropin therapy it is possible by estrogen monitoring to minimize the risk of hyperstimulation syndrome l but not to exclude the risk of multiple pregnancies. Recently HackelOer et a1. 2 have reported the use of ultrasound in monitoring the size and number of follicles during gonadotropin therapy and in preventing multiple pregnancies. t has also proved possible to follow follicular size during the normal menstrual cycle.3 n the present study we report our experience with ultrasonic monitoring in ovulation induction during clomiphene or gonadotropin therapy. PATNTS AND MTHODS The gonadotropin (HMG) therapy group consisted of patients on whom 29 successful ultra- Received September 11, 1978; revised November 13, 1978, and January 12, 1979; accepted January 12, *Reprint requests: Pekka Yliistalo, M.D., Department of Obstetrics and Gynaecology, University of Oulu, SF-922 Oulu 22, Finland. sonic measurements of follicular size were carried out. n the clomiphene therapy group of 12 patients, 14 measurements were performed. The control group consisted of 7 volunteers with normal menstrual cycles, and 9 successful measurements were performed. All menstrual cycles tested in this study were ovulatory, and ovulation was confirmed by basal body temperature measurements, subjective sensations, and serum progesterone estimations.4 The ultrasonic equiment was a gray-scale B scanning apparatus, Kretztechnik's Combison, together with a special transducer of 2 MHz which focused at a depth of 1 cm; in some cases a real time scanner (Axiscan, Roche Laboratories, Nutley, N. J.) was used in the follow-up of pregnancy. n the ultrasonic examination an exacting technique with a full bladder was used as described by Hackeloer et a1. 2,3 Both longitudinal and transverse scannings were performed every. cm. The ultrasound velocity was calibrated to 14 msec. Serum estradiol levels were tested by radioimmunoassay4 in connection with ultrasonic examination. Student's t-test was used for statistical analyses. 61

2 June 1979 YLOSTALO T AL o c 1....J o is «:: tn 1. ::> ::.,,! 1 1 DAMTR OF FOLLCL 2mm FG. 2. Linear regression of serum estradiol values and diameter of follicles in normal control, clomiphene, and HMG groups. FG. 1. Longitudinal ultrasonic scan. B, Bladder; F, follicle. RSULTS n Figure 1 is presented a typical ultrasonic picture of a normal follicle just before ovulation. When only those ultrasonic measurements made no more than 2 days before ovulation were considered, the average diameter of the follicles was 2 to 4 mm larger in ovulation induction groups than in normal controls (Table 1). The differences in the diameter of the follicles were statistically significant when the clomiphene (P <.1) and HMG (P <.1) groups were compared with normal controls. The average serum estradiol level was higher in the ovulation induction groups than in normal controls; however, these differences. were not statistically significant. By taking into account all of the successful measurements, we calculated line regressions between follicular diameter and serum estradiol values (Fig. 2). The value r in normal controls was.9; in the clomiphene group,.62; and in the HMG group,.23. A case report of HMG ovulation induction is presented in which it was possible to follow the growth of two follicles (Fig. 3) during the 9 days before ovulation (Fig. 4). The patient had polycystic ovary syndrome. She was treated first with clomiphene and later with three courses ofhmghuman chorionic gonadotropin (HCG) without success, although during HMG treatment the serum estradiol level rose to a sufficiently high level (.4 to 1.7 nmoleslliter) according to our ref- TABL 1. Diameter of Follicles before Ovulation, and Serum stradiol Values Serum estradiol Diameter of follicles Group studied No. Mean± SD Range Mean± SD ± ±.8 2.9± 2.76 nmoleslliter mm Normal controls Clomiphene-treated Gonadotropin (HMGJ-treated ± ± ±. Range

3 MASURMNT OF OVARAN FOLLCLS BY ULTRASOUND Vol. 31, No.6 63 FG. 3. Two follicles in the right ovary (transverse ultrasonic scan). F, Follicle; B, bladder; U, uterus. erence values. We first used ultrasonic monitoring during HMG therapy, and when the diameters of two follicles were 1 and 16 mm, the serum estradiol was at a high level (7. nmoles/liter). After discussing the high risk of hyperstimulation with the patient and the possibility of a twin pregnancy we decided to give HCG, U, and to recommend sexual intercourse. As a result, after 1 week, the left ovary showed signs of moderate hyperstimulation (more than 1 mm) (Fig. ); the size later diminished. The size of each ovary was monitored only by ultrasound, and bimanual examination was avoided to minimize the risk of ovarian rupture. Three weeks after the HCG injection, a twin pregnancy was suspected following the detec7.s7.7lj x x 3. HMG (-=71U P 2.? 2 1. ::::. c U 1 u.. u.. 1 a.. Q 1;: - <!? 6 2 (!) 2 z <! Our study confirms the results of Hackeloer et a1. 2,3 that it is possible by the full bladder technique to find and measure the ovarian follicle when its diameter is at least 1 mm. n our experience this is often possible when its diameter is only DSCUSSON Q.3 tion by ultrasound of two amniotic sacs in the uterus; 2 weeks and 3 days later (Fig. 6) embryonal echoes in both sacs could be seen. C P ::J FG.. Longitudinal ultrasonic scan of enlarged, polycystic right ovary during hyperstimulation after HMG-HCG treatment. C, Cysts..1 1 ::::> DAYS FG. 4. A patient with two ripening follicles during HMGHCG therapy, and serum estradiol and progesterone levels. FG. 6. mbryonal echoes in two amniotic sacs (A ) (longitudinal scan).

4 64 YLOSTALO T AL. June 1979 to 6 mm. We strongly emphasize the need for a very full bladder to make possible visualization of both ovaries. The growth ofthe follicle seems to be 1 to 4 mm/day, and is greatest just before ovulation. n the study by Hackeloer et al. 3 the diameter of the follicle in normal women immediately prior to ovulation was 18 to 24 mm but in our study it was 11 to 16 mm. The reasons for this difference, first, may reflect the difference in calibration of apparatus. We used an ultrasound velocity value of 14 msec instead of 16 msec. Second, in some cases the measurements had been made 1 to 2 days before ovulation. However, our results do not disagree with statements that "a ripe follicle is -8 mm in diameter and may reach 1-2 mm immediately before rupture" and "the fully developed Graafian follicle is 1 mm or more in diameter."6 n a previous study by Hackeloer et av the average diameter of follicles just before ovulation in women with normal menstrual cycles was 12 to 14 mm; after successful ovulation induction with HMG-HCG it was at least 18 mm. n the present study the average diameter offollicles in ovulation induction patients was also 2 to 4 mm greater than in normal control subjects, and serum estradiol levels were likewise higher. t has been found that in normal, ovulatory responses to clomiphene, peak levels of serum estradiol were higher than those in spontaneous cycles 3 ; treatment with clomiphene also appears to produce increased follicular growth and more active corpora lutea. 9 n their response to HMG, patients vary greatly. An adequate response is considered when the estradiollevels are within or just above the range of values in the preovulatory phase of normal, spontaneous cycles.! The regression lines demonstrating different slopes of estradiollevellfollicular size for these ovulation induction groups lay above the line of normal controls. The obvious explanation for this finding is that, in ovulation induction groups, several follicles may be producing estradiol, but only the largest follicle is big enough for visualization by ultrasound. n our case report of twin pregnancy, two follicles were found during HMG treatment, thereby predicting the possibility the simultaneous fertilization of two ova. After administration of an HCG bolus, more than two (approximately six) cysts were found in the enlarged ovary. Only two corpora lutea should have been developed. There may have been very small follicles before ovulation, from which the many corpora lutea may have developed, or it is possible that not all of the cysts were corpora lutea, but four of them follicular cysts. Crooke,1O in connection with gonadotropin treatment of a patient with Stein-Leventhal (polycystic ovarian) syndrome, found at laparotomy 6 days after the injection ofhcg large hemorrhagic follicles, numerous cysts, and a corpus luteum. n our patient with an enlarged ovary, unfortunately, we did not try to differentiate by ultrasound the corpora lutea from other cysts, and we cannot be sure at this point whether it is possible to do this by ultrasound in hyperstimulation cases. n any event, Terinde and his co-workersll likewise found a correlation between the visualization of two follicles and subsequent twin pregnancy after ovulation induction with gonadotropins. t may be also possible that if two or more follicles of different sizes have developed during HMG treatment, only those follicles big enough have the capacity to ovulate; the others simply change to corpus luteum. n our experience to date, ultrasonic monitoring is in practice often more useful than monitoring serum estradiol. nformation about the growth of the follicle is immediate by ultrasound. On the other hand, many causes may delay the daily results of serum estradiol measurement, thereby impairing the practical value of its estimation. n our practice the decision to administer HCG at the right time was made in some cases on the basis of ultrasonic monitoring alone, without knowledge of serum estradiol level. We consider tha t a diameter of 1 to 16 mm is suitable for HCG injection. The ultrasonic monitoring of ovaries also seems to be very useful in cases of hyper stimulation because it is thus possible to follow the size of enlarged ovaries without risk of rupture, which is increased in bimanual examination. Serum estradiol estimations are very useful in preventing hyperstimulation by gonadotropin therapy. n preventing multiple pregnancies, ultrasonic monitoring seems to be a promising method by which it is possible to predict how many simultaneous pregnancies may result from ovulation induction. Further comparative studies, however, are needed to determine which method is superior in the diagnosis of the simultaneous development of multiple Graafian follicles. n conclusion, we consider that in medical centers in which gonadotropin therapy is given for ovulation induction the simultaneous use of ultrasonic and estrogen monitoring of ovarian follicles is of great practical value. RFRNCS 1. Shaaban MM, Klopper A: A study on the monitoring of

5 Vol. 31, No.6 MASURMNT OF OVARAN FOCLS BY ULTRASOUND 6 gonadotrophin therapy by the assay of plasma oestradiol and progesterone. J Obstet Gynaecol Br Commonw 8:783, Hackel<ier BJ, Nitschke S, Daume, Sturm G, Buchholz R: Ultraschalldarstellung von Ovarveranderungen. Geburtshilfe Frauenheilkd 37:18, Hackel6er BJ, Robinson HP: Ultraschalldarstellung des wachsenden Follikels und Corpus luteum im normalen physiologischen Zyklus. Geburtshilfe Frauenheilkd 38: Hammond GL, Viinikka L, Vihko R: Automation of steroid radioimmunoassays employing both iodinated and tritiated ligans. Clin Chem 23:12,1977. Jeffcoate N: Principles of Gynaecology, Fourth dition. London, Butterworths, 197, p 6. Hall R, Anderson J, Smart GA, Besser M: Fundamentals of Clinical ndocrinology. London, Pitman Medical, 1974, p Hackeliier BJ, Nitschke S, Buchholz R: Beobachtungen des Follikel-wachstums am normalen und HMG-stimulierten Ovar durch Ultraschall. n Gynakologie und Geburtshilfe, Forschungen-rkenntnisse, dited by H Husslein. Vienna, H germann, 1977, p 1 8. Kjeld JM, Harsoulis P, Nader S, Kuku SF, Fraser TR: Hormonal responses to a first course of clomiphene citrate in women with amenorrhoea. Br J Obstet Gynaeco82:397, Dodson KS, Macnaughton MC, Coutts JRT: nfertiity in women with apparently ovulatory cycles. ll. The effects of clomiphene treatment on the profiles of gonadotrophin and sex steroid hormones in peripheral plasma. Br J Obstet Gynaecol 82:62, Crooke AC: n Fertility and Sterility. Proceedings of the Fifth World Congress, June 16-22, 1966, Stockholm, dited by B Westin, N Wiqvist. Amsterdam, xcerpta Medica nt Congr Ser 133, 1967, p Terinde R, Schmidt-lmendorff H, Tigges J: Ultraschallkontrollierte ovarielle Stimulation mit Gonadotropinen und nachfolgenden Zwillingsschwangerschaften. Geburtshilfe Frauenheilkd 38:28, 1978