Follicle size by ultrasound versus cervical mucus quality: normal and abnormal patterns in spontaneous cycles*

Transcription

1 FERTILITY AND STERILITY Copyright <> 1989 The American Fertility Society Printed in U.S.A. Follicle size by ultrasound versus cervical mucus quality: normal and abnormal patterns in spontaneous cycles* Douglas C. Daly, M.D.t:j: Karen Reuter, M.D.t:j: Stephen Cohen, M.D.t Jennie Mastroianni, RN -C, M.S. t University of Massachusetts Medical School, Worcester, Massachusetts Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvent in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (lnsler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. The findings were: ( 1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation. Fertil Steril 51:598, 1989 The postcoital test (PCT) is generally accepted as an integral part of the infertility evaluation. 1 When the mucus is normal in quality with active forwardly motile sperm, both patient and physician are reassured. When the mucus is abnormal in quality, however, with increased viscosity, several questions arise: (1) Was the PCT adequately timed? (2) Is the mucus abnormal because follicular development is suboptional with depressed serum estradiol (E 2)? 2 or (3) Is the mucus abnormal because the cervix is hyporesponsive to E 2? 3 The initial question is traditionally addressed by repeat Received March 1, 1988; revised and accepted December 20, * Prize paper, presented in part at the prize paper meeting of the Obstetrical Society of Boston, February 20, 1986, Boston, Massachusetts. t Department of Obstetrics and Gynecology. :j: Department of Radiology. Reprint requests: Douglas C. Daly, M.D., Philadelphia Fertility Institute, 330 South Ninth Street, Philadelphia, Pennsylvania Daly et al. Follicle size versus cervical mucus PCTs in the same or subsequent cycles (possibly timed by luteinizing hormone [LH] monitoring). The couple may find this quite stressful, and frequently the adequacy of the mucus in relation to ovulation remains unresolved. 4 Therefore, a method to confirm that normal mucus is present 2 to 3 days before ovulation would be desirable for both physician and patient. The other questions are still harder to resolve. There is evidence to support both inadequate E 2 synthesis 2 and cervical resistence to estrogen action (receptor defect) 3 as causes of abnormal mucus. It has been reported that patients with abnormal mucus have an average peak E 2 lower than that of normal patients. 2 However, the overlap in values and the difficulty in timing and obtaining adequate serum samples to coincide with the serum E 2 peak often makes this approach impractical. Further, the relative success of timed intrauterine insemination with washed sperm in patients with inadequate mucus suggests that ovulation quality is adequate in many patients. 5 In these patients, the ab- Fertility and Sterility

2 normal cervical mucus is apparently secondary to a hyporesponsive cervix rather than to abnormal follicular development. 3 Unfortunately, no method has been developed to reasonably differentiate patients with abnormal cervical mucus due to a hyporesponsive cervix from those with abnormal follicular development. This inadequacy prevents the appropriate selection of therapy based on the cause of the abnormal mucus. Daly et al. 6 and Ying et al. 7 have demonstrated the usefulness of serial ultrasound (US) to document normal and abnormal follicular dynamics, including luteinized unruptured follicle syndrome (LUFS), in patients with unexplained infertility and luteal phase defect (LPD), respectively. Follicular growth as assessed by US has been shown to correlate with serum E 2 levels in several studies.8-10 Therefore, it was thought that US for follicular dynamics could be used to assure the adequacy of the timing of the PCT, to assess when mucus became normal in relation to ovulation, and to differentiate abnormal mucus patients with abnormal follicular development from those with hyporesponsive cervixes. In addition, if US were useful in diagnosing the precise abnormality in patients with abnormal cervical mucus, assessing follicular dynamics in patients with LPD, 7 and diagnosing abnormal follicular dynamics in patients with unexplained infertility6; then US might be cost-effective as part of a standard evaluation of couples with undefined infertility. This study was therefore designed to address three issues: (1) What is the pattern of cervical mucus maturation in relation to follicular growth in infertility patients with normal PCTs?, (2) Is US useful in defining the cause of abnormal cervical mucus? and (3) Is the routine use of US in the evaluation of the undiagnosed infertile couple cost-effective? Question 1 MATERIALS AND METHODS What is the pattern of cervical mucus maturation in relation to follicular growth? Fifty control patients presenting as undefined infertility patients were evaluated prospectively from March 1984 to March By history, they were not at risk for tubal disease. They had already demonstrated normal biphasic basal body temperature charts, and their partners had normal semen analyses. The patients then were evaluated prospectively as follows: (1) In the initial cycle, the patients underwent serial US for follicular dynamics with postcoital testing. The initial US and PCT were scheduled 3 to 4 days before anticipated ovulation. The US was repeated every 1 to 2 days depending on follicle size until rupture occurred. 6 The PCT was repeated every other day until normal or until ovulation had occurred, as assessed by US. The quality of mucus on PCTwas scored by a modified Insler score with viscosity assessment emphasized.u A score< 11 with a viscosity< 2 was considered abnormal (i.e., a score of 10 but a viscosity of 3 would be considered normal). If an abnormality was found, the US and PCTs were repeated in a second cycle. Two abnormal cycles were necessary to make a diagnosis. Three comparisons were made from the resulting data: (1) mean follicular size(± standard deviation [SD]) versus day before ovulation; (2) mean mucus score (±SD) versus day before ovulation; and (3) mean mucus score (±SD) versus follicle size. Based on the standard curves generated, a follicle was defined as having abnormal small size at rupture when the z was <0.01 (z < 0.01) on a one-sided critical ratio test. 12 All scans were performed on ADR 4000L/S at 3.5 ml{z (ATL, Tempe, AZ). The patients then had LPD exeluded by late luteal phase endometrial biopsy 13 followed by hysterosalpingogram and/or hysteroscopy /laparoscopy as indicated. Question2 Is US useful in defining the cause of abnormal cervical mucus? Eighteen patients were referred to the University of Massachusetts Reproductive Endocrinology Service for abnormal cervical mucus between March 1984 and December They were evaluated for the quality of ovulation based on US-determined follicular dynamics and forcervical mucus quality by PCT testing using the same protocol as the "control" patients. The resulting pattern of follicular growth versus mucus quality for each patient then was used to diagnose the patients as having one of three abnormal patterns: 1. Narrow mucus window: normal follicle dynamics but with normal cervical mucus present only within 24 hours of ovulation. 2. Hyporesponsive cervix: normal follicular dynamics but abnormal mucus. 3. Follicular dysfunction: abnormal follicular dynamics with abnormal mucus. These groups then were compared with the normal patients. Significant differences were defined as P or z values <0.05. Daly et al. Follicle size versus cervical mucus 599

3 Days Prior to Ovulation Figure 1 The follicular growth curve for the normal PCT patients is similar to previous studies, 6 although average size of rupture was slightly smaller, at 20.3 mm with an average growth velocity of 2.1 mm per day (control patients). A follicle at rupture with an average diameter smaller than normal (z < 0.01) from the mean is considered abnormal. In these patients, this was a follicle with a diameter less than 17 mm the day before rupture. Four patients with abnormal mucus (D) ruptured follicles below this size. The remainder of the patients with abnormal mucus demonstrated normal growth dynamics with rupture at a normal follicular diameter (X-X, abnormal mucus; 1::.-!::., delayed mucus maturation; all with a normal growth slope before rupture). Question3 Is the routine use of US in the evaluation of the undefined infertility couple cost-effective? The estimation of cost-effectiveness is imprecise even in a randomized comparison. This comparison is not randomized. We have attempted, however, to be conservative in our estimates and base them on the best available data. The cost-effectiveness of routine serial US for follicular dynamics was estimated from the diagnostic workup of the "control" patients and is based on prevailing fees. The cost of ultrasound is estimated at $250 per cycle. Based on the findings in these patients, 40% less PCTs would be required to assess adequacy of cervical mucus if PCTs were only performed when the follicle is 15 mm or larger. It also is assumed that the patients with abnormal follicular dynamics (but with normal endometrial biopsies) would not have been diagnosed as having a cause for their infertility if US had not been used. Patients with abnormal follicular dynamics would not require subsequent endometrial biopsy, as they would already be defined as abnormal. RESULTS Question 1 In the 50 undefined infertility patients prospectively examined, 16 initially were defined as having abnormalities based on US, PCT, and endometrial biopsy: LPD (6), LPD-LUFS (2), LUFS (2), and apparent pelvic pathology on US (7,1 with LPD). N ormograms for follicular size versus day before rupture (Fig. 1), cervical mucus score versus day before rupture (Fig. 2), and follicular size versus cervical mucus score (Fig. 3) then were constructed from the other 34 patients. Based on the Figure 1 normogram, 4 of the 50 patients were defined as rupturing small follicles; 2 of these patients already had been diagnosed as LPD on endometrial biopsy. Therefore, of the 8 patients with LUFS or small follicles, 4 also had LPD. The commonly accepted belief that the mucus becomes hospitable to sperm 3 to 4 days before rupture is confirmed in Figure 2. Figure 3 reveals that the cervical mucus progresses from viscous and inhospitable to sperm at a follicle diameter of 13 mm to thin and hospitable at 16 mm in the normal patient. For follicular dynamics to be normal in a cycle, the follicle must rupture at a minimum of 17 mm in size (Fig. 1). By these definitions, all cycles with normal follicular dynamics should also have normal cervical mucus. Four patients were diagnosed as having abnormal cervical mucus quality based on these definitions. These 4 patients with abnormal mucus are considered further with the patients referred for abnormal mucus. Q) 14 *pori.< **p or z < u 8 en "' :J u :J ~ n= Days Prior to Ovulation Figure 2 Cervical mucus becomes normal by the third day before physical ovulation (-3, mucus score > 11). Four patients demonstrated significantly delayed mucus maturation (!::. -!::.) and did not develop normal mucus until the day of, or the day before, physical ovulation. The remainder of patients demonstrated a significantly abnormal mucus score within 24 hours of ovulation (day 0 or day -1 or +1). Most of these patients rupture their follicles at a normal size (X-X), although four patients ruptured an unusually small follicle (D). 600 Daly et al. Follicle size versus cervical mucus Fertility and Sterility

4 abnormal mucus: follicular dysfunction. Eleven patients demonstrated normal follicular dynamics but persistently abnormal mucus. These patients were diagnosed as having hyporesponsive cervices. 01~.--r--.--r--r--o-,,--.-,--,-~----~~ Follcle Size nvn Figure 3 There is a strong relationship between follicle size and mucus quality in the normal PCT group. At a follicle diameter of 13 mm, the Insler score is low and progresses to ovulatory quality mucus by a follicle diameter of 16 mm. The patients (n = 11) with abnormal mucus (X-X) had significantly abnormal mucus scores when the follicle was larger than 15 mm. Four patients (D) never developed a follicle larger than 16 mm. While they never had normal mucus, the mucus quality was consistent with the follicle "size (P or z = not significant). Four patients (Ll. - Ll.) had delayed maturation of cervical mucus. There was a significant retardation in mucus quality with follicle diameters of17 mm to 19 mm. Thirty-eight patients underwent laparoscopy. Fifteen were found to have significant pathology, including all 7 suspected by US. The total number of patients with abnormalities was 30. Three patients conceived before laparoscopy. Therefore, 17 patients had unexplained infertility at the end of the evaluation. The distribution of diagnoses is summarized in Table 1. Question2 Using the standard curves (Figs. 1 to 3), each of the patients referred for abnormal mucus can be defined as normal or as having one of the three proposed abnormal patterns. Three patients were found to have entirely normal follicular growth and cervical mucus patterns. They had been misdiagnosed before referral. Therefore, a total of 19 patients actually had abnormal cervical mucus patterns (15 referred and 4 from the control group). Four of these patients developed normal mucus only on the day of ovulation, with rupture occurring within 24 hours of the cervical mucus becoming adequate. The follicle size, 17 to 21 mm, at which the mucus became hospitable to sperm in these patients was greater than in normal patients. These patients therefore were diagnosed as having a narrow mucus window. Four patients were found to have abnormal growth with rupture at small size, i.e., abnormal follicular dynamics and persistently Question3 Cost-effectiveness was estimated as the cost per diagnosis, the cost incurred in the workup of all of the patients divided by the number of diagnoses obtained. Twelve of the patients were diagnosed without ultrasound, 4 with abnormal mucus and 8 with LPD. Seven patients were believed on ultrasound to have pelvic pathology (including one with LPD). These patients were also diagnosed by laparoscopy, however. Therefore, they would not have been missed and are not included as a US diagnosis. Four of the 8 patients with L UFS or small follicle had no other abnormality and would not have been diagnosed without ultrasound. Therefore, the total abnormalities diagnosed by outpatient evaluation without ultrasound was 12: 8 LPDs and 4 abnormal mucus. Using ultrasound, the total diagnosed was 16: 4 LUFS or small follicles, 4 LUFS or small follicles with LPD, 4 LPDs with normal follicle dynamics, and 4 abnormal mucus. Based on these diagnoses and the cost of evaluation, the estimated cost per diagnosis is $2,100 with US testing versus $2,000 per diagnosis when ultrasound is not used. The early demonstration of pelvic pathology (7 of 15 patients with pelvic pathology; 47%) and the increased understanding of the cause of a patients LPD or abnormal mucus are additional benefits of the US approach that are not included in this calculation. Table 1 Diagnosis Distribution Percent of Percent of otherwise Number all patients unexplainedb Unexplained LPDonly LPD abnormal US Abnormal US Abnormal PCT Pelvic pathology 15 OnUS (1 with LPD) 7 (47%) Not on US 8 (53%) Pregnant before laparoscopy 3 The patients were preselected to exclude anovulation, abnormal semen, and history suggestive of tubal disease. b Percent of unexplained infertility patients not diagnosed if test had not been done (number abnormal on test/unexplained + number abnormal on test). Daly et al. Follicle size versus cervical mucus 601

5 DISCUSSION Three issues were addressed in this study: (1) the relation of follicular dynamics to quality of cervical mucus; (2) the cause of abnormal cervical mucus as defined by follicular dynamics; and (3) the costeffectiveness of routine US in the basic diagnostic evaluation of the undefined infertility couple. It is demonstrated that there is a predictable relationship in follicular growth compared with cervical mucus maturation. This correlation has two implications for physician and patient. By combining US with PCT there can be no confusion as to whether a poor PCT is truly abnormal or a result of poor timing. Also, by demonstrating that cervical mucus becomes normal2 or more days before physical ovulation, the couple can be instructed not to waste money or psychic energy 4 on urinary LH testing or any other technique designed to time intercourse. Instead, the couple can be confidently instructed to have intercourse approximately every other day, hopefully at their leisure, with the certainty that this will result in sperm being present at ovulation. For many couples, this is welcome relief from physician-imposed or self-imposed sexual rigidity! Second, serial US for follicular dynamics in conjunction with PCT testing defines three patterns of abnormality in patients with abnormal cervical mucus. In this study, a total of 19 patients actually had abnormal cervical mucus. Eleven (58%) had normal follicular growth, implicating a hyporesponsive cervix as the reason for the abnormal mucus. Four patients (21%) had abnormal follicular dynamics as the apparent cause of the abnormal mucus. Four patients (21 %) eventually developed normal mucus, but with a narrow mucus window of 24 hours or less. Each of these patterns may have treatment implications. Patients with a narrow mucus window can be treated by timed intercour!'le using urinary LH monitoring or some other method to predict the ovulatory day. The patients with abnormal follicular dynamics warrant treatment to improve the quality of ovulation. The patients with hyporesponsive cervixes have two available treatment options. Intrauterine insemination has been successful in treating abnormal mucus, presumably in this subset of patients, with a fecundibility of 0.08 to This technique, however, requires urinary LH timing and replaces normal intercourse in the conception process. Alternatively, the use of human menopausal gonadotropins to induce supraphysiologic ovarian estra- diol production can be used to stimulate the cervix into normal mucus production. This technique has the advantage of maintaining conjugal relations and has a higher fecundibility, f = It is more expensive per cycle, however, and does require close monitoring. The routine use of US at the time of PCT in the basic workup of undiagnosed infertility couples appears cost-effective. This is due in part to the potential to decrease the number of PCTs and endometrial biopsies (patients with abnormal US patterns do not require endometrial biopsies; those with normal patterns still do.) and in part to an increase in the diagnoses made. The improved understanding of the cause of abnormal cervical mucus and LPD obtained by serial US has implications for treatment of both of these conditions This increases the value of serial US beyond this simple cost per diagnosis evaluation. Further, the use of serial US detects unsuspected pelvic pathology. In this group of patients, 7 of 15 patients ( 4 7%) were detected by ultrasound. The US-detected patients tended to have the most significant pathology. The time to laparoscopy for some of these patients was shortened and unnecessary diagnostic tests was eliminated for others. In conclusion, serial US with PCT in the basic infertility workup is cost-effective because of the increase in diagnoses made. It allows the physician to determine the cause of abnormal cervical mucus and to select appropriate therapy. It is reassuring to the couple to have a normal mucus interval demonstrated. This may decrease the risk of sexual dysfunction being induced by attempts at the unnecessary timing of intercourse. We believe that serial US with PCT should be adopted as a routine component of the infertility evaluation. REFERENCES 1. Blasco L: Clinical approach to the evaluation of sperm-cervical mucus interactions. Fertil Steril 28:1133, Roumen F JME, Doesburg WH, Rolland R: Hormonal patterns in infertile women with a deficient postcoital test. Fertil Steril 38:42, Abuzeid MI, Wiebe RH, Aksel S, Shepherd J, Yeomen RR: Evidence for a possible cytosol estrogen receptor deficiency in endocervical glands of infertile women with poor cervical mucus. 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