Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles

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1 FERTILITY AND STERILITY Copyright The American Fertility Society Vol. 39, No.3, March 1983 rinted in U.8A. Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles Franz Geisthovel, M.D. * Ulrike Skubsch, Cando Med. t Gabriele Zabel, Cando Med. t Helmut Schillinger, M.D. Meinert Breckwoldt, M.D. Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, West Germany Intraovarian morphologic alterations in 6 physiologic menstrual cycles were studied by sonography and compared with 13 inadequate cycles with a short or missing luteal phase. In addition, basal body temperature, 17~-estradiol, luteinizing hormone, progesterone, testosterone, and dehydroepiandrosterone sulfate levels in serum were measured. The maximal follicle was significantly smaller in insufficient cycles (17.7 ± 2.9 mm) than in physiologic cycles (23.0 ± 2.3 mm). Corpus luteum structure was visualized in five of the six physiologic cycles but was not detected in insufficient cycles. ersistent polyfollicular reaction (> 3 follicles per ovary) without a dominant follicle larger than 10 mm was detected in the ovaries of three patients with clinical and hormonal signs of polycystic ovarian disease. Ultrasonography can be regarded as a useful additional tool in the evaluation and management of insufficient ovarian cycles. Fertil Steril 39:277, 1983 In 1977 Hackeloer et al. 1 described the intraovarian morphologic dynamics of gonadotropinstimulated cycles by sonography. Since then, further sonographic criteria of spontaneous and stimulated cycles were investigated by HackelOer et al. I - 5 and Nitschke-Dabelstein et al.6, 7 and various other groups.8-16 Only limited information on the sonographic criteria of insufficient cycles is available. In 1980 HackelOer et al. 5 mentioned insufficient follicular Received May 5, 1982; revised and accepted November 16, *Reprint requests: Dr. Franz Geisthovel, Department ofobstetrics and Gynecology, University of Freiburg, 7800 Freiburg, West Germany. tmedical candidate. growth in a monophasic cycle. In another publication they observed two waves of follicular growth in a cycle with a short luteal phase; and in another cycle no hormonal evidence for ovulation, despite normal follicular growth, was detected. 3 Nitschke-Dabelstein et al.7 observed an enlargement of a follicle accompanied by a progesterone () increase, suggesting a luteinized unruptured follicle. 17 However, there is no consequent comparable sonographic study of the morphologic variations between spontaneous and various insufficient cycles in correlation with hormonal parameters. The objective of the present study was to compare ovarian morphologic characteristics monitored by ultrasonographic studies of normal and insufficient cycles and to correlate these findings with endocrine parameters. Vol. 39, No.3, March 1983 Geisthovel et ai. Ultrasonographic studies of menstrual cycles 277

2 Table 1. Sonographic Criteria of Ovarian Morphologic Characteristics in hysiologic (A) and Various Insufficient Cycles (B Db) Group First day of cycles on which a dominant follicle (> 8 mm) is visible a Diameter of the initial follicle a mm Day ofcycle on which the maximal follicle is visible a Diameter of the maximal follicle a mm Form of the maximal follicle A (n = 6) 8.2 ± ± ± ± 2.3 All follicles round 5/6 and sharply defined B (n = 4) 10.0 ± ± ± ± 2.5 2/2 deformed and! or poorly defined C (n = 3) 14.0 ± ± ± ± 0.5 2/3 deformed and! Da (n = 2) 13.5 (1l-16)b 14.5 (1l-18)b 15.0 (12-18)b 15.5 (12-1W or poorly defined 2/2 deformed and poorly defined Db (n = 1) 15mmj1l Round, sharply de- During two uncoordinated cycles (breakthrough fined bleeding) visible amean ± SD. b Range. CL ATIENTS MATERIALS AND METHODS Six physiologic menstrual cycles of 5 volunteers between 22 and 30 years of age (group A) and 13 cycles of 13 patients between 21 and 38 years of age with evidence of normogonadotropic ovarian insufficiency (group II of the classification of the World Health Organization [WHO]) were investigated. These 13 cycles were classified by their basal body temperature () curves into the following groups: (B) (n = 4) those with biphasic with a hyperthermic phase more than 10 days and retarded increase of the over 3 days; (C) (n = 3) those with biphasic with a hyperthermic phase less than 9 days; (Da) (n = 2) those with monophasic ; (Db) (n = 1) that with monophasic with a persisting follicle; and (E) (n = 3) those with monophasic with clinical symptoms of polycystic ovarian disease (COD). TREATMENT Echography was performed with the full urinary bladder technique, beginning on the second day of the cycle. After reaching a follicular diameter of 12 mm, follicular growth was monitored daily and in 2- to 3-day intervals after the disappearance of the follicle. We measured the intraovarian structures by longitudinal and transversal B-scan sections, employing a compound scanner (Combison 200, Kretztechnik, Zipf, Austria) with a 3.5 MHz transducer. An intraovarian cystic structure having a diameter of 5 mm or 6 mm and being reproducibly observed was identified as a follicle. Corresponding to the literature,6,11 a corpus luteum (CL) was defined as a solid or cystic structure developing some days after the disappearance of the maximal follicle. Simultaneously, 20-ml blood samples were drawn, and serum was separated within 30 minutes and stored at - 20 C until hormone assays 0 were performed. Serum levels of 1713-estradiol (E 2 ),, luteinizing hormone (), testosterone (T), and dehydroepiandrosterone sulfate CDHEA S) were determined by commercially available radioimmunoassays (Serono, Freiburg, West Germany; Institut National des Radioelements [IRE] Diagnostics, Frechen, West Germany). Validity criteria were assessed and fulfilled all requirements. levels were determined daily during the Form of Cycle FOllicular hase I CL hysiological 18 (A).., c: '"-18 Insufficient (8-Da) ~F. - Follicle ~ 18.-' C DO -.. fa 18 (E).. ~ hase I Follicular h":. ~,~\/.:;:~\ L\ ersistence 0" -If---" (Db) l!!"5 - - ' Days of Cycl. Figure 1 Sonographic criteria of ovarian morphologic characteristics in physi~logic and various insufficient cycles, showing diameters of follicle and CL (-) and disappearance of these structures (- - -). Shadings are menstrual bleeding. 278 Geisthovel et ai. Ultrasonographic studies of menstrual cycles Fertility and Sterility

3 Figure 2 reovulatoryfollicle.b, bladder. U, uterus. ro, right ovary. CO, cumulus oophorus (?). C, cyst. time of maximal follicular development (days -3 to 0) and on a pool of blood from days I , day 0 being defined as the day of maximal follicular diameter. As proposed by the WHO report, 18 the initial increase in levels was the first value that was 1.5 times the mean of the preceding baseline values. Results are expressed as mean ± standard deviation (SD). Student's t-test for unpaired data was used for statistical analysis, comparing group A with groups B to C (AlB-C) and groups B to Da (A/ B-Da). RESULTS The echographic criteria of all cycles are demonstrated in Table 1 and Figure 1. The physiologic cycles (group A) began with a homolateral transient polymicrofollicular reaction (> 3 follicles < 10 mm) in three of the six cases. The first ultrasonic observation of a dominant follicle exceeding 8 mm ± 2.6 mm in size was on day 8 ± 1.0 of the cycle. The dominant follicle steadily increased until a diameter of 23 mm ± 2.3 mm on day 13 ± 0.9 was reached (Fig. 2). Accompanying follicles were not observed. The preovulatory follicle appeared as a circular, distinctly defined cyst in all cases and disappeared within 1 day. Thereafter, a CL was identified in five of the six cases within 2.6 ± 0.5 days. A CL with a diameter of 26 mm ± 3.8 mm was recognized as a solid structure in three of the five cases or as a cystic structure in the remaining two cases (Fig. 3). In one case, the CL-like cyst persisted until day 7 of the subsequent cycle. In six of the nine insufficient cycles (groups B to Da) a polymicrofollicular reaction was observed in the homolateral ovary, beginning on day 8.5 ± 1.0 of the cycle. A dominant follicle occurred later (day 12 ± 3.0) than in group A (AIB-Da: < 0.01; A/B-C: < 0.05). On the average, 2.9 ± 2.0 days were required for follicular growth to a maximal diameter of 17.7 mm ± 2.9 mm, which is smaller than the diameter of the maximal follicle in group A (A/B-Da: < 0.01; A/B-C: < 0.01). The maximal follicle showed irregularities and/or poorly defined outlines in six of the nine cycles (Fig. 4). In one cycle of group C, in which the maximum was measured on day - 3, a follicle with a 19-mm diameter disappeared within 1 day, followed by a hyperthermic phase for only 4 days. In two of the nine insufficient cycles a second polymicrofollicular reaction occurred after the Figure 3 (A), CL hemorrhagicum (CLh). (B), CL cysticum (CLc). (C), CL graviditate (CLg) after human menopausal gonadotropin/ human chorionic gonadotropin stimulation. B, bladder. U, uterus. ro, right ovary. ZO, left ovary. Vol. 39, No. 3, March 1983 Geisthovel et al. Ultrasonographic studies of menstrual cycles 279

4 maximums occurred in seven of the nine cycles between day 0 and day + 3; maximums were in one of the six cycles on day - 3 and in two of the six cycles on days + 1 and + 2. increases followed on days + 1 to + 5, coinciding with the rise in. The hormonal pattern of a persisting follicle (no peak, no peak, no increase, monophasic ) was associated with a 15-mm follicle disappearing after two menstrual bleedings (breakthrough bleeding) (group Db). ersistent polymicrofollicular reaction without a dominant follicle was observed in the three patients of group E (Figs. 1 and 6) associated with elevated T levels (1.01 ± 0.23 ng/ml) and normal DHEA-S levels (2.6 ± 1.3 J.1g/ml). In our laboratory the normal values oft and DHEA-S are up to 0.8 ng/ml and 3.6 J.1g/ml, respectively. DISCUSSION Figure 4 Maximal follicle in an insufficient cycle. B, bladder. U, uterus. lo, left ovary. C, cyst. disappearance of the follicle in the contralateral ovary. In two monophasic cycles (group Da) a second follicle developed in the contralateral ovary shortly after the disappearance of the first follicle. This second follicle did not correspond to any hormonal peak. No CL formation could be identified in the insufficient cycles. A summary of the hormonal parameters in groups A to D is presented in Table 2. eaks or maximal concentrations of and were not significantly different between group A and groups B to Da. A marked increase in pooled levels was only seen in groups A to C with a significant difference between group A and groups B-C ( < 0.05). Table 3 and Figure 5 demonstrate that in group A the peak occurred in four of the six cycles on day 0 preceded by the peak in four of the six cycles on day - 1. The peak coincided with a increase, followed by the disappearance of the follicle and a subsequent rise in. In groups B to Da 280 Geisthovel et al. The transient polymicrofollicular reaction in the early follicular phase in three of six physiologic cycles is in agreement with the in vitro investigations of McNatty et al. 19 These authors showed that the majority of antral follicles reaching a diameter of 4 mm do not mature to ovulatory follicles but undergo atresia. From these, only one or two follicles contained sufficient granulosa cells consistent with subsequent ovulation. Our findings concerning the sonographic criteria of the follicular maturation correspond to those of other authors. 2-5, 9-13,16 Renaud et a1. 9 observed the peak-2 days before the disappearance of the follicle (day - 2) in seven of the ten cases, the peak on day - 1 in seven of the ten cycles, the lowest point of on day - 1 in five of the ten cycles, and the first increase on day - 1 in four of the eight cycles. These findings agree with our investigations regarding the physiologic cycles. After the disappearance of the follitable 2. Serum eaks of and and the ool Value of on Days +5/ + 7/ +9/ + 11 in hysiologic (A) and Insufficient (B-Da) Cyclesa Group A(n = 6) B (n = 4) C (n = 3) Da (n = 2) b b pb pg/ml ng/ml ng/ml 282 ± ± ± (90-210)C 11.4 ± ± ± ± ± ± ( )C 1.25 ( )C aday 0 is the day of the maximal follicle. bmean ± SD. CRange. Ultrasonographic studies of menstrual cycles Fertility and Sterility T

5 Table 3. Correlation of the Day of Maximal Follicle (O) to the Days of eaks ofe 2 and and the Increase of and in Every hysiologic (A) and Insufficient (B-Da) Cycles Group No. of patients A Day of cycle B C Da cle we found a solid CL in three of the six cycles and a cystic structure of the CL in two of the six cycles. The failure to identify a CL-like structure in one cycle could probably be due to technical failure, because the endocrine data were consistent with a normal ovulatory cycle. The differences in CL structures could be explained by the studies of Schillinger et ai.,20 who found that a concentration of red blood cells produced a remarkable attenuation of the echo, which was almost completely reduced following hemolysis. Since the enhancement of the echo is similar in hemolized blood, in urine, and in other low-molecular-weight fluids, the sonographic cystic CL structure could be related to a CL hemorrhagicum filled with serum or hemolized blood. A clearly defined CL cyst can be detected in early pregnancy (Fig. 3). The transient polymicrofollicular reaction and the "priming" of the dominant follicle are observed later in the insufficient cycle than in the physiologic cycle. This delayed follicular priming is followed by an inadequate follicular maturation, leading to significantly smaller diameters and irregularities of the maximal follicle. Impaired follicular development is gradually associated with inadequate luteal function, as reflected by the and the reduced levels. The maximums of and levels in the insufficient cycles are within the normal range; however, they do not correlate in most cases with the intraovar- E hysiological CycLes(A) 4 n=6 1/1 L ~ ~~~---J~~ '5 4 ~ ~r----j~~l---~ z T Insufficient CycLE (B - Da) 4 n= Day of Cycle Figure 5 Correlation of the day of the maximal follicle (0) to the days of peaks of (E) and (L) and the increase of () and (T) in all physiologic and insufficient cycles. 4 Vol. 39, No.3, March 1983 Geisthovel et al. Ultrasonographic studies of menstrual cycles 281

6 REFERENCES Figure 6 olymicrofollicular reaction in the two ovaries from a woman with COD. B, bladder. U, uterus. ro, right ovary. 10, left ovary. C, follicle cyst. ian morphologic processes. The pituitary response seems quantitatively normal, but ovulation fails to occur because the dominant follicle is either immature or undergoing atresia. The distinct rise and the biphasic temperature curves in groups Band C without sonographic evidence of CL formation suggest luteinization of regressing follicles. A luteinized unruptured follicle as described by Nitschke-Dabelstein et a1. 7 was not observed. In such cases the term "follicular phase insufficiency" would be more suitable than "CL insufficiency," which presumes CL formation. In 1973 Kun and Bosze21 described the diagnosis of COD by sonographic means. To avoid misinterpretations of the initial polymicrofollicular reaction in physiologic and insufficient cycles, one should repeat sonographic investigations at different stages of the cycle. Further studies from a greater number of patients with COD and hyperandrogenemic ovarian insufficiency should be conducted. The data of the present study indicate that ultrasonography provides useful information on the morphologic characteristics of the ovaries that can be helpful in interpreting the pathophysiologic features of ovarian insufficiency. 282 Geisthovel et al. 1. Hackeliier BJ, Nitschke S, Daume E, Sturm G, Buchholz R: Ultraschalldarstellung von Ovarveranderungen bei Gonadotropinstimulierungen. Geburtshilfe Frauenheilkd 37:185, Hackeliier BJ, Robinson H: Ultraschalldarstellung des wachsenden Follikels und Corpus Luteum im normalen physiologischen Zyklus. Geburtshilfe Frauenheilkd 38:163, Hackeliier BJ, Flemming R, Robinson H, Adam AH, Coutts JRT: Correlation of ultrasonic and endocrinologic assessment of human follicular development. Am J Obstet Gynecol 135:122, Hackeliier BJ, Nitschke-Dabelstein S: Ultrasonographic monitoring of ovarian structural changes. rog Med Ultrasound 1:141, Hackeliier BJ, Diirfler R, Nitschke S, Buchholz R: Ultraschalldarstellung des Follikelwachstums und Basaltemperaturmessung. Ultraschall1:133, Nitschke-Dabelstein S, Hackeliier BJ: Ultrasonic monitoring of ovarian-stimulating therapy. rog Med Ultrasound 1:155, Nitschke-Dabelstein S, Hackeliier BJ, Sturm G: Ovulation and corpus luteum formation observed by ultrasonography. Ultrasound Med Bioi 7:33, Terinde R, Schmidt-Elmendorff H, Tigges J: Ultraschallkontrollierte ovarialle Stimulation mit Gonadotropinen und nachfolgenden Zwillingsschwangerschaften. Geburtshilfe Frauenheilkd 38:208, Renaud RL, Macler J, Dervain I, Ehret M-C, Aron C, las-roser S, Spira A, ollack H: Echographic study of follicular maturation and ovulation during the normal menstrual cycle. Fertil Steril 33:272, O'Herlihy C, de Crespigny LJCh: Monitoring ovarian follicular development with real-time ultrasound. Br J Obstet Gynaecol 87:613, Queenan JT, O'Brien GD, Bains LM, Simpson J, Collins W, Campbell S: Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 34:99, de Crespigny LJCh, O'Herlihy C, Hoult IJ, Robinson H: Ultrasound in an in vitro fertilization program. Fertil Steril 35:25, Smith DH, icker RH, Sinosich M, Saunders DM: Assessment of ovulation by ultrasound and estradiol levels during spontaneous and induced cycles. Fertil Steril 33:387, Cabau A, Bessis R: Monitoring of ovulation induction with human menopausal gonadotropin and human chorionic gonadotropin by ultrasound. Fertil Steril 36:178, Seibel MM, McArdle CR, Thompson IE, Berger MJ, Taymor ML: The role of ultrasound in ovulation induction: a critical appraisal. Fertil Steril 36:573, Bryce RL, Shuter B, Sinosich MJ, Stiel IN, icker RH, Saunders DM: The value of ultrasound, gonadotropin, and estradiol measurements for precise ovulation prediction. Fertil Steril 37:42, Marik J, Hulka JF: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, WHO Report: Temporal relationships between ovulation and defined changes in the concentration of plasma estradiol-17[3, luteinizing hormone, follicle-stimulating hor- Ultrasonographic studies of menstrual cycles Fertility and Sterility

7 mone and progesterone. I. robit analysis. Am J Obstet Gynecol 138:383, McNatty K, Smith DM, Makris A, Osathanondh R, Ryan KJ: The microenvironment of the human antral follicle: interrelationship among the steroid levels in antral fluid, the population of granulosa cells, and status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab 49:851, Schillinger H, Mallien J, Kodweis G: Untersuchungen zur Schallschwachung von Flussigkeiten und Tumorgewebe in vitro. Ultraschall 1:255, Kun L, Bosze : Die Bedeutung der Ultraschalluntersuchung fur die Diagnosestellung des polycystischen Ovars. Geburtshilfe Frauenheilkd 33:452, 1973 Vol. 39, No.3, March 1983 Geisthovel et al. Ultrasonographic studies of menstrual cycles 283