The impact of luteal phase inadequacy in an infertile population Anne Colston Wentz, MD, Liliana R. Kossoy, MD, and Robert A. Parker, DSc Nashville, Tennessee A retrospective analysis of patients evaluated and treated for infertility was performed. Luteal phase inadequacy was diagnosed when the late luteal endometrial biopsy pattern was greater than 2 days out of phase in two cycles; in patients treated with clomiphene citrate therapy was changed if one biopsy was out of phase. One hundred ninety-seven patients underwent 242 biopsies. Among 137 women not treated with clomiphene citrate, 24 (17.5%) had out-of-phase biopsy specimens; 7 of 24 (29.2%) repeat biopsies were out of phase, with luteal phase inadequacy in 7 of 137 (5.1%) women. The probability of an out-of-phase biopsy occurring by chance alone was 4.2 of 137 or 3.1 %. No woman was diagnosed to have luteal phase inadequacy as the single infertility factor. Fifty-three pregnancies (41%) occurred in 130 women without luteal phase inadequacy and in 2 of 7 (28.6%) diagnosed to have luteal phase inadequacy with other infertility factors. In clomiphene citrate-treated patients, pregnancy occurred in 15 of 26 (57.7%) with corrected luteal phase inadequacy and in 21 of 34 (61.8%) without luteal phase inadequacy. In this population the diagnosis of luteal phase inadequacy was not made more frequently than by chance alone. Moreover, fecundity in patients with treated luteal phase inadequacy is comparable to that in patients without this diagnosis. (AM J OBSTET GYNECOL1990;162:937-45.)

Key words: Luteal phase inadequacy, endometrial biopsy, fecundity, pregnancy rates, female infertility The impact of luteal phase inadequacy on fecundity has seldom been addressed. Most studies have focused on the diagnosis and prevalence of luteal phase inadequacy and have analyzed correlations between luteal variables such as plasma progesterone levels, estradiol/progesterone ratios, decidual prolactin production, endometrial protein levels, endometrial histologic features, and other parameters. Few studies have attempted to ascertain if the diagnosis and treatment of luteal phase inadequacy have altered the outcome for infertile couples. The purpose of this retrospective study was to analyze fecundity in an infertile population with and without luteal phase inadequacy. Four questions were proposed: (1) In what percentage of infertile couples is luteal phase inadequacy the sole diagnosis? (2) Does the diagnosis of luteal phase inadequacy represent only a chance event? (3) Does the chance of conception vary between those women with clomiphene citrateinduced luteal phase inadequacy and those treated with From the Department of Obstetrics and Gynecology and the Department of Preventive Medicine, Vanderbilt University Medical Center. Presented by invitation at the Eighth Annual Meeting of the American Gynecological and Obstetrical Society, Hot Springs, Virginia, September 7-9, 1989. Reprint requests: Anne Colston Wentz, MD, Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Northwestern University School of Medicine, Prentice Women's Hospital, 333 East Superior St., Chicago, IL 60611. 616118254

clomiphene citrate without induced luteal phase inadequacy? (4) Does the diagnosis of luteal phase inadequacy further affect fecundity when fecundity is already impaired by other infertility factors?

Material and methods Diagnostic classification. A retrospective review of the charts of patients with infertility first seen between January 1981 and January 1988 was performed. Patients with recurrent spontaneous fetal wastage were excluded. Charts were examined to determine the factor(s) responsible for the couple's infertility. Patients were excluded from the analysis if an adequate infertility investigation had not been completed. An adequate infertility investigation included semen analysis of the male partner, evaluation of a basal body temperature chart for documentation of menstrual cyclicity, postcoital test, hysterosalpingogram, and late luteal phase endometrial biopsy. A laparoscopy was required if the patient had not achieved pregnancy within 6 months of diagnosis and the institution of treatment. Charts were reviewed by a single observer, using a scoring system that relied primarily on the presence or absence of a factor. Criteria for these factors are as follows: 1. Ovulatory factor. Ovulatory factor was diagnosed if menstrual cycles were oligomenorrheic (ordinarily >40 days), if the patient had secondary amenorrhea for;;;.3 months, or if, in thejudgment 937

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April 1990 Am J Obstet Gynecol

Table I. Results of endometrial biopsy First endometrial biopsy In phase Clomiphene citrate

Yes No TOTAL

n

n

60 137 197

34 113 147

I

Second endometrial biopsy (clomiphene citrate patients" treated"*) Out of phase

Out of phase

%

n

(56.7) (82.5) (74.6)

26 24 50

I

Third endometrial biopsy (all patients treatedt)

%

No biopsy

In phase

n

(43.3) (17.5) (25.4)

17 0 17

5 17* 22*

4 7 11

I

%

No biopsy

In phase

Out of phase

(44.4) (29.2) (33.3)

1 1 2

1 6 7

2 0 2

*"Treatment" in clomiphene citrate patients was a change in clomiphene citrate dose. tExcludes three women whose initial and second biopsy were both in phase.

of the physician, ovulation induction using either clomiphene citrate or human menopausal gonadotropin was indicated. Patients undergoing empiric ovulation stimulation were not included in this classification. 2. Male factor. World Health Organization criteria for normality, which specify a sperm concentration of ;;;.20 million/ ml, motility ;;;'50%, or normal morphologic features ;;;'50%, were used. ' Male factor infertility was also diagnosed if, in the presence of a normal semen analysis, a sperm penetration assay2 was 0% in the presence of a positive control. 3. Tubal factor. Incontrovertible evidence of morphologic tubal abnormality on hysterosalpingogram or unilateral-bilateral distal occlusion was required. Unilateral cornual occlusion was not graded as positive; bilateral cornual occlusion was considered a tubal infertility factor. 4. Peritoneal factor. Endometriosis, pelvic adhesions, or other mechanical-physical factors that, in the judgment of the operator, could impair fertility were diagnosed at laparoscopy. Most patients undergoing laparoscopy were treated by laser vaporization of endometriosis, lysis of adhesions, or another operative procedure. 5. Other. Uterine factor, defined as an abnormality of the uterine cavity or myometrium sufficient to induce infertility; cervical factor, defined as in- . adequate or hostile cervical mucus on repeated postcoital tests; unexplained infertility; and "not unexplained infertility" were included in this group. The final category of "not unexplained infertility" was used as a check, requiring the reviewer to indicate that a decision had been made concerning diagnostic classification. Endometrial dating. All endometrial biopsy specimens were reviewed by the A. C. W. and read for the medical record by faculty of the Department of Pathology. The biopsy readings were compared for interobserver variation. Criteria for the diagnosis of luteal phase inadequacy have been previously established.' The endometrial bi-

opsy was performed on ideal cycle day 25 or later (defined in some women as at least 11 days of elevated temperature judged from the basal temperature chart), and a histologic lag of >2 days was required in at least two different cycles. Because of the repetition of endometrial inadequacy in clomiphene citrate-treated patients,. therapy was instituted if one out-of-phase biopsy specimen was obtained. Endometrial dating was accomplished according to the criteria of Noyes et al. 5 The next menstrual period, the onset of full menstrual flow (not spotting), was assigned as day 28, and the expected endometrial date was determined by counting backward from the day of menstruation. Charts were reviewed for the presence or absence of out-of-phase biopsy specimens, for the diagnosis for luteal phase inadequacy, for whether luteal phase inadequacy was the only factor identified, for whether it was associated with clomiphene citrate ovulation induction, and for whether it was diagnosed in the presence of other infertility factors. All charts were further reviewed for the number of treatment cycles, the number of untreated cycles, the number of spontaneous or untreated conceptions, the number of cycles after hysterosalpingography if pregnancy occurred within 3 months of the hysterosalpingography and no other treatment was instituted, and the number of cycles after surgery if the patient had a tubal and/or peritoneal factor, up to 24 cycles. The end result was determined. This included pregnancy, patient still under treatment, treatment terminated because of adoption, voluntary termination of treatment, or patient lost to follow-up. The outcome of pregnancy was also determined and was recorded as ongoing if there was no chart documentation of delivery or abortion. Statistical analysis. A life-table analysis was used to determine the expected conception rate. Significance was determined by the log-rank test. The starting point in the life-table analysis was the first cycle of treatment, the first cycle after surgery, the first ovulatory cycle in patients treated with clomiphene citrate, or the first cycle after hysterosalpingography in patients who conceived in the three cycles after this procedure. The end

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Table II. Analysis of pregnancy results in 60 clomiphene citrate-treated patients Luteal phase inadequacy

No Yes TOTAL

Pregnant No.

%

No.

34 26 60

57.6 43.3 100

21 15 36

I

Table III. Probability of conception in patients with only ovulatory factor infertility: Effect of clomiphene citrate-induced luteal phase inadequacy on pregnancy rate

%

61.8 57.7 60.0

point in the life-table analysis was conception, the end of the study, or patient lost to follow-up. A one-sided Fisher's exact test was used to compare the results of first and second endometrial biopsies. A K statistic was used to compare interobserver variation of endometrial biopsy readings, and a t test was used to determine a difference in endometrial dates. Results

Endometrial biopsy specimens. Two hundred fortytwo endometrial biopsies were performed. Among 197 women, 161 underwent one endometrial biopsy, 27 underwent two endometrial biopsies, and 9 patients had three endometrial biopsies. The 242 endometrial biopsy specimens were analyzed for interobserver variation. The mean of the secretory data read by the Department of Pathology was 25.492 ± 1.059 days and by A. C. W. 25.731 ± 1.05 days, significantly different at p < 0.02. Concordance or identical biopsy reading was reached in 108 cases, disagreement by 1 day in 77, by 2 days in 55, and by >2 days in 2 cases. A. C. W. read ~2 days later than Pathology in 33 cases, and Pathology was ~2 days later in 22 cases. With a K statistic, the expected value of concordance is 0.2046, the observed proportion concordant is 38/108 (0.3519), and the K value is 0.1852. This confirms the results of the paired t test. Comparison of abnormality rates in first and second biopsy specimens. In the analysis of first and second biopsy results, we found, of 197 initial endometrial biopsies done, 50 were out of phase and 147 were in phase (Table I). Of the 147 in-phase biopsy specimens, repeat biopsies were performed in subsequent cycles in three women, and these biopsies were in phase. A total of 36 second endometrial biopsy specimens were taken, of which three were in women with a previous in-phase biopsy specimen. Of the remaining 33 biopsy specimens taken in women in whom the previous sample had been out of phase, 4 of 9 (44.4%) in clomiphene-treated women and 7 of 24 (29.2%) in untreated women were out of phase. One hundred sixtyone women did not undergo second biopsy. Statistical analysis was done to see if there was a difference between the results for the first and second biopsy specimens in women not receiving clomiphene

939

Cycle

2

3 6 7 8 9

Clomiphene citrate-induced luteal phase inadequacy (n = 4)

Clomiphene citrate, no luteal phase inadequacy

0.000 0.333 0.333 0.333 0.333 0.333

0.200 0.200 0.200 0.200 0.600 0.600

(n = 7)

*Log-rank test, p > 0.5. citrate. This difference was not statistically significant (p = 0.14, Fisher's exact test, one-sided since the second biopsy specimen would be expected to have a higher abnormal proportion than the first biopsy). Stated differently, 29.2% of second endometrial biopsy specimens were out of phase compared with an initial expectation of 17.5% out of phase for women not treated with clomiphene citrate. Luteal phase inadequacy. Fifty of 197 (25.4%) first biopsy specimens were out of phase (Table I). Thirtysix women underwent a second biopsy; of these, three initial biopsy specimens that had been in phase were again in phase, and of the remaining 33 specimens, 11 were out of phase. One hundred thirty-seven women were not undergoing ovulation induction, and 24 (17.5%) of them had out-of-phase first biopsy specimens. All patients underwent a second endometrial biopsy, with seven (29.2%) again out of phase. Seven of 137 patients (5.1 %) were diagnosed to have luteal phase inadequacy by the two-biopsy criteria. Among the 7 patients diagnosed to have luteal phase inadequacy in the absence of ovulation induction, 6 underwent rebiopsy on treatment and all repeat specimens were in phase. Sixty of the 197 women were undergoing ovulation induction with clomiphene citrate. In these 60 women, 26 (43.3%) first biopsy specimens were out of phase, and a change in the clomiphene citrate dosage was instituted on the basis of a single out-of-phase specimen. Nine women underwent rebiopsy, with 4 (44.4%) specimens persistently out of phase on therapy; 3 of these women underwent a further additional biopsy with changed therapy, and 2 (one diethylstilbestrol-exposed patient and another on high-dose clomiphene citrate for obesity-associated anovulation) had persistently outof-phase specimens. Infertility diagnosis and pregnancy rate. An ovulatory factor was diagnosed in 98 women, 26 of whom developed luteal phase inadequacy, and a tubal factor was found in 24. A peritoneal factor was present in 77, absent in 37, and not evaluated in 83 women. Male

940 Wentz, Kossoy, and Parker

April 1990 Am J Obstet Gynecol

Table IV. Probability of conception in clomiphene citrate-treated patients with and without luteal phase inadequacy

Cycle

2

3

4

5 6 7 8 9 10

With clomiphene citrate-induced luteal phase inadequacy* (n = 12)

Without luteal phase inadequacy* (n = 26)

0.250 0.344 0.344 0.475 0.475 0.475 0.475 0.475 1.000

0.231 0.352 0.352 0.514 0.514 0.514 0.676 0.838 0.838

*Log-rank test, p > 0.5. factor infertility was an additional diagnosis in 55 couples. Luteal phase inadequacy was not diagnosed as the sole infertility factor in any couple. One hundred twenty-five patients had one or more infertility factors other than anovulation; fifty-four of 125 (43.2%) conceived. Among 17 couples, a cause was not found to explain the infertility. Eight of these couples did not have evaluation for a peritoneal factor, 6 because pregnancy occurred and 2 because the evaluation was ongoing at the close of the study. Three of the 9 couples with unexplained infertility achieved pregnancy. Endometrial inadequacy in one biopsy specimen was diagnosed in association with clomiphene citrate administration in 26 women; 15 (57.7%) achieved pregnancy (Table II). Thirty-four patients taking clomiphene citrate for ovulation induction had in-phase endometrial biopsy specimens; 21 of 34 (61.8%) achieved pregnancy. Luteal phase inadequacy was unassociated with clomiphene citrate administration in 7 women, all of whom had other infertility factors; 2 (28.6%) achieved pregnancy with treatment. Chance of conception. A life-table analysis was performed, limited to patients with ovulatory factor infertility analyzed from the second treatment month. Of the initial 197 charts reviewed, 98 had an ovulatory factor. Fifty-one charts were excluded from the analysis since one or more other factors also were identified, and 36 were excluded since a potential cause of infertility (luteal phase inadequacy) was not excluded. Among the remaining 11 charts with only ovulatory dysfunction, there was one pregnancy among four women with clomiphene citrate-induced luteal phase inadequacy and two pregnancies among seven women with in-phase endometrial biopsy specimens. The pregnancy rate in patients with only ovulatory function infertility, whether with or without clomiphene citrateinduced luteal phase inadequacy, was not significantly

different by the log-rank test (p > 0.5). The probability of conception by month is shown in Table III. Among the initial 47 women with only ovulatory factor identified as a cause of infertility, nine women had results for no or only one treated cycle. When these nine women are excluded, there are 38 women treated with clomiphene citrate for ovulation induction, with no other identified infertility factors. Six of 12 women with clomiphene citrate-induced luteal phase inadequacy achieved pregnancy, and 14 of 26 without clomiphene citrate-induced luteal phase inadequacy achieved pregnancy. The difference between the two groups is not statistically significant by the log-rank test (p > 0.5). The probability of conception by month is shown in Table IV. To ascertain if the diagnosis of luteal phase inadequacy has an impact on fecundity, 67 charts were analyzed in which there was no ovulatory or male factor identified. Forty-four women had no treated cycles, so that 23 charts were available for analysis. Two of 7 women with luteal phase inadequacy plus other factors achieved pregnancy; two of 16 patients without luteal phase inadequacy and one or more infertility factors achieved pregnancy. This difference was not statistically significant by the log-rank test (p > 0.4). The probability of conception by month is shown in Table V. Comment

Murthy et al. 6 diagnosed luteal phase inadequacy in 37 of 335 infertile patients, none of whom had habitual abortion and in whom the luteal phase inadequacy was repetitive in only 13 women (3.9%). When treated and untreated groups were compared, the data indicate that treatment had no effect on either the incidence or the outcome of pregnancy. Driessen et al'> compared pregnancy rates among 232 women divided according to the single endometrial biopsy results and found that the cumulative pregnancy rate of all patients was 53% within 2 years. Balasch et al. 8 compared the incidence of luteal phase deficiency among fertile women (4.0%), infertile patients (12.9%), and women with early recurrent miscarriage (28.3%); their data showed that the outcome of pregnancy in infertility patients not receiving treatment is similar to that observed in treated women and that the incidence of luteal phase inadequacy does not differ between fertile and control groups. DiPaola et al 9 studied 41 cases of retardation of progestational phase endometrium among 620 infertile patients and found no difference in the incidence and outcome of pregnancy between couples in whom luteal phase inadequacy was the sole fertility factor and those with other causes for infertility. These authors state that this entity does not constitute an infertility factor. Davidson et al. 10 analyzed 774 endo-

Impact of luteal phase inadequacy on infertility

Volume 162 Number 4

metrial biopsies performed because of infertility, diagnosed luteal phase inadequacy in 5.7%, and concluded that endometrial biopsies may be useful only if performed in cases of habitual abortion or ovulation induction with clomiphene citrate. The conclusions of these five studies, which analyzed the impact of the diagnosis on the incidence and outcome of pregnancy, have not been generally recognized or accepted. Most studies emphasize only the frequency of diagnosis, and the incidence of luteal phase inadequacy has been reported as high as 65%" and 86%12 of an infertile population. The implication in the literature is that luteal phase inadequacy must be identified and treated to improve the incidence and outcome of pregnancy, which we challenge. Analysis of the predictability of biopsy results. A major discrepancy between this and other recent studies " · 12 is in the incidence of endometrial inadequacy and thus in the diagnosis of luteal phase inadequacy. Among our criteria for adequacy of the endometrial biopsy, we require that the biopsy be done as close to the expected menses as possible, no earlier than ideal day 25; Balasch and Vanrell 13 also use these criteria. The diagnosis of luteal phase inadequacy requires consistently out-of-phase biopsy specimens in at least two cycles. We 4 . 11 and others II. 15. 16 have shown that biopsy material obtained in the midluteal phase and earlier does not predict the onset of menses and has a wide interobserver error. Li et al. '7 have reported that an in-phase biopsy specimen would have a 5% chance of being read as out of phase in the early luteal phase compared with an 18% chance in the late luteal phase and that intraobserver variation of histologic dating was greater in the late luteal phase. However, these authors assign dates from the luteinizing hormone surge and not from next menses and assign a single day (i.e., luteinizing hormone day + 10 compared with secretory day 23 to 24). We were therefore startled to find a significant difference in endometrial dating between Pathology (25.452 ± l.059 days) and A. C. W. (25.731 ± l.05 days). In our experience interobserver and intraobserver variation in dating endometrium in the late luteal phase is not clinically different; despite the statistical difference, clinically, the readings are identical. Further, an endometrial pattern dated secretory day 25 to 26 and taken the day before (secretory day 27) the onset of menstruation (secretory day 28) is in phase, so only real asynchrony in endometrial development is diagnosed as significant. One might then argue that the criteria described above will "miss" patients with luteal phase inadequacy requiring treatment. However, the incidence of pregnancy in our group of patients with unexplained infertility (9/ 17, 52.9%) is consistent with that in the

941

Table V. Probability of conception in infertile couples with and without luteal phase inadequacy

Cycle

1

2 3 5 6 8 10 12 16

Patients with luteal phase inadequacy and other infertility factors* (n = 7)

/ nfertile couples without luteal phase inadequacy* (n = /6)

0.000 0.000 0.200 0.200 0.200 0.200 0.200 1.000 1.000

0.0625 0.0625 0.0625 0.0625 0.0625 0.0625 0.0625 0.0625 1.0000

*Log-rank test, p > 0.4 literature. '" Furthermore, Navot et aLI" have shown that consistent glandular-stromal disparity and asynchronous early biopsy readings are compatible with successful implantation. In what percentage of couples is luteal phase inadequacy the sole diagnosis? A reason sufficient to explain the infertility was diagnosed in 180 couples and the infertility remained unexplained in 17 couples. Two or more factors other than an ovulatory factor were diagnosed in 125 couples. No patient was found to have luteal phase inadequacy as the only infertility factor identified. Does the diagnosis of luteal phase inadequacy represent only a chance event? One hundred thirty-seven women did not undergo treatment with clomiphene citrate. Twenty-four endometrial biopsy specimens were out of phase on initial sampling (17.5%), and on repeat biopsy 7 (5.1 %) patients were again found to have out-of-phase endometrial biopsy specimens. To assess whether the 7 cases of luteal phase inadequacy are more than would be expected solely on the basis of chance, probability calculations can be used. With a baseline rate of 24 of 137 biopsy specimens being out of phase, the chance of a randomly selected sample being out of phase is 24 of 137. If the results of two consecutive specimens are random, then we would expect two consecutive specimens to be out of phase by chance with a probability: (241137) x (241137) = 0.1751824 x 0.1751824 = 0.0306880. Of 137 women, we would expect 137 x 0.0306880 or 4.204256 women with luteal phase inadequacy by chance. We observed 7 women with luteal phase inadequacy; the chance of observing ~7 women when the expected number is 4.2 is P = 0.133, using a Poisson distribution. As such, there is no evidence that the diagnosis of luteal phase inadequacy is more than a chance event in the population studied. Davidson et aI., 10 finding that 5.7% of their infertility population

942

Wentz, Kossoy, and Parker

had two consecutive out-of-phase biopsy specimens, arrived at the same conclusion. Driessen et aU in their discussion note that the 3.5% incidence reported by Katayama et al. 20 is not different from the 3.6% chance occurrence found in their own study. Does the chance of conception vary between those women with and those without clomiphene citrateinduced luteal phase inadequacy? This analysis required limitation to those women with an ovulatory factor who were analyzed from the second treatment month on. For the first month only, the probability of conception could be analyzed between women with luteal phase inadequacy in the presence of other factors and women with only ovulatory dysfunction. The chance of conception could be analyzed between women with luteal phase inadequacy and other factors against all women without other identified factors, and the pregnancy rate was not significantly different. There was also no difference found in the probability of conception in clomiphene citrate-treated patients with and without luteal phase inadequacy. Luteal phase inadequacy did not influence fecundity in this population. Does the diagnosis of luteal phase inadequacy further affect fecundity when fecundity is already impaired by other infertility factors? There are three major flaws inherent in this investigation. These include: (1) the problem of multiple variables, (2) the inability to achieve adequate statistical power, and (3) a lack of untreated controls. One can deal with multiple variables only by defining each of these variables in a consistent manner. For inclusion into and exclusion from a particular category, all charts were reviewed with the same definition, and a decision made whether the particular subject should be included or excluded from the classification and whether there were sufficient data to allow judgment. If data were insufficient, the chart was not included in the analysis. All charts included in the analysis were from one physician'S practice and were reviewed by one physician. The statistical analysis was carried out by an independent unbiased observer. These analyses were done on the basis of "yes" or "no" or "not evaluated," and infertility factors were not graded as to degree or severity. The second problem is that of inadequate statistical power, a problem of numbers. That no charts were included in which luteal phase inadequacy was the sole diagnosis is unusual, considering that approximately 3% of charts should have this diagnosis by chance. However, there were seven charts reviewed in which luteal phase inadequacy was found in the presence of other infertility factors but in the absence of clomiphene citrate administration. The observed occurrences are low but conform to those reported in the

April 1990 Am J Obstet Gynecol

context of pregnancy outcome; the occurrences are very low when compared to reports of incidence in the literature. Finally, to an infertile population, participation in a blinded study, in which a no-treatment arm is compared with a treatment arm, is not viewed as a positive opportunity. This is one explanation why the suggestion by Andrews 2l of a double-blind controlled study of luteal phase inadequacy has never been implemented. Data presented here suggest that the incidence ofluteal phase inadequacy is low and so confounded by other infertility variables that an appropriate study design would be elusive. In conclusion, the salient observations from this investigation are that the incidence of luteal phase inadequacy is low, about 5% in an infertile population, and that there were no differences observed in fecundity in patients diagnosed to have or not to have luteal phase inadequacy. Although clomiphene citrate administration resulted in a higher incidence of luteal phase inadequacy, pregnancy rates did not differ if treatment was instituted. By the use of a life-table approach to analysis, we show that couples in whom luteal phase inadequacy was identified (first cycle) and treated (second cycle) did not show a delay, or an increased number of cycles, until conception. In the population studied the diagnosis of luteal phase inadequacy did not have a negative impact on fecundity. We thank Dr. Carl M. Herbert and Dr. George A. Hill for their critical review of the manuscript and Beverly Steele and Karen Bernabei for their editorial assistance. REFERENCES 1. World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. Cambridge: Cambridge University Press, 1987. 2. Rogers BJ. The sperm penetration assay: its usefulness reevaluated. Fertil Steril 1985;43:821-40. 3. Jones GS. The luteal phase defect. Fertil Steril 1976; 27:351-6. 4. Wentz AC. Endometrial biopsy in the evaluation of infertility. Fertil Steril 1980;33:121-4. 5. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950; 1:3-25. 6. Murthy YS, Arronet GH, Parekh MC. Luteal phase inadequacy. Its significance in infertility. Obstet Gynecol 1970;36:758-61. 7. Driessen F, Holwerda PJ, Putte SCJ, Kremer J. The significance of dating an endometrial biopsy for the prognosis of the infertile couple. Int J Fertil 1980;25: 112-6. 8. Balasch J, Creus M, Marquez M, Burzaco I, Vanrell JA. The significance of luteal phase deficiency on fertility: a diagnostic and therapeutic approach. Hum Reprod 1986; 1:145-7. 9. DiPaola GR, Mendez Ribas JM, Arrighi LA. Critical study of the retarded progestational phase. Int J Fertil 1971; 16: 189-94. 10. Davidson BJ, Thrasher TV, Seraj 1M. An analysis of endometrial biopsies performed for infertility. Fertil Steril 1987;48:770-4.

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II. Cumming DC, Honore LH, Scott JZ, Williams KP. The late luteal phase in infertile women: comparison of simultaneous endometrial biopsy and progesterone levels. Ferti! Steril 1985;43:715-9. 12. CheckJH, Nowroozi K, Wu CH, Adelson HG, Lauer C. The importance of luteal phase deficiency as a cause of infertility in private practice-a preliminary report. Infertility 1987; 10: 111-20. 13. Balasch J, Vanrell JA. Corpus luteum insufficiency and fertility: a matter of controversy. Hum Reprod 1987; 2:557-67. 14. Wentz AC, Herbert CM, Maxson WS, Garner CH. Outcome of progesterone treatment of luteal phase inadequacy. Fertil Steril 1984;41 :856-62. 15. Huang KE. The primary treatment of luteal phase inadequacy: progesterone versus clomiphene citrate. AM J OBSTET GYNECOL 1986; 155:824-8. 16. Rosenfeld DL, Chudow S, Bronson RA. Diagnosis of luteal phase inadequacy. Obstet Gynecol 1980;56: 193-6. 17. Li TC, Dockery P, Rogers AW, Cooke rD. How precise is histologic dating of endometrium using the standard dating criteria? Ferti! Steril 1989;51 :759-63. 18. Rousseau S, Lord J, Lepage Y, Van Campenhout J. The expectancy of pregnancy for "normal" infertile couples. Fertil Steril 1983;40:768-72. 19. Navot D, Anderson TL, Droesch K, Scott RT, Kreiner D, Rosenwaks Z. Hormonal manipulation of endometrial maturation. J Clin Endocrinol Metab 1989;68:801-7. 20. Katayama KP, Ju K-S, Manuel M, Jones GS, Jones HW Jr. Computer analysis of etiology and pregnancy rate in 636 cases of primary infertility. AM J OBS1'ET GY:>JECOI. 1979;135:207-10. 21. Andrews WC. Luteal phase defects. Ferti! Steril 1979; 32:501-9.

Editors' note: This manuscript was revised after these discussions were presented.

Discussion DR. VAL DAVAjAN, Los Angeles, California. Dr. Wentz, I commend you and your co-workers for the enormous amount of work you did in preparing this manuscript. My first question has to do with the definition of luteal phase inadequacy as diagnosed by an endometrial biopsy. Some authors make the diagnosis of luteal phase inadequacy only when the luteal phase endometrial biopsy pattern is >2 days (therefore at least 3 days) out of phase in two cycles as calculated by subtracting 14 days from the date of onset of subsequent menses. In this manuscript you used the definition of "lag of ",,2 days." Davis et al. I reported the incidence of single and sequential out-of-phase endometrial biopsy specimens (using the count-back method) to be 51.4% and 26.7%, respectively, in five fertile women studied. Using a lag of ",,3 days to define luteal phase inadequacy, the incidence of single and sequential outof-phase biopsy specimens was 31.4% and 6.6%, respectively. These incidences in normal fertile women are as high as the rates quoted for the infertile population. I Dr. Wentz, does the I-day difference in definition make a significant difference? Would you also comment as to how and why two out-of-phase cycles are required-why not only one or three? If the incidence of out-of-phase biopsy specimens decreases with

Impact of luteal phase inadequacy on infertility 943

sequential biopsies, could a requirement of four outof-phase specimens essentially eliminate luteal phase inadequacy as a cause of infertility? My next question has to do with dating of the endometrium on the basis of subtracting 14 days from the date of subsequent menses to assign the presumptive day of ovulation to the cycle. In two recent publications this method proved to be inaccurate. Li et aJ.2 in 1987 reported that 42% of endometrial biopsy specimens were ",,2 days out of phase when onset of next menstrual period was used and only 10% were found to be out of phase when luteinizing hormone peak was used to establish dates for the endometrium! More recently, Shoupe et aI.' reported the results of dating of maturity of endometrium by histologic examination as correlated with four methods of ovulation detection in 13 cycling, parous women. The histologic date was assigned and correlated with the postovulatory duration as determined by daily transvaginal ultrasonographic scanning, serum luteinizing hormone measurements, basal body temperatures, and subtraction of 14 days from onset of menses. These authors reported that dating of endometrium was highly correlated (p < 0.002) with day of ovulation as determined by ultrasonography and found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1 %) of the interpretations. With the use of luteinizing hormone surge, there was an 84.6% correlation and with the use of a basal body temperature there was a 76.9% correlation. However, dating of endometrium was within 2 days of correct day in only 17 of 26 interpretations (65%) as determined by subtracting 14 days from the onset of subsequent menses. In other words, with this latter method of dating a biopsy specimen, 35% of fertile cycling women were found to be out of phase.' My third question has to do with the so-called clomiphene-induced luteal phase inadequacy. Did all 26 women with luteal phase inadequacy who received clomiphene have an in-phase biopsy specimen before starting clomiphene therapy? Would you also discuss how clomiphene causes luteal phase inadequacy? It has been shown that women treated with clomiphene have higher preovulatory serum 17~-estradiol levels (and larger follicles) when compared with those of spontaneously ovulating women. 4 How can higher levels of 17~-estradiol result in luteal phase inadequacy? On the other hand, if you accept the fact that clomiphene is one of the causes of luteal phase inadequacy, how can increasing the dose in an effort to correct the defect be considered a rational approach? My next question has to do with the finding that there was a statistically significant difference (p < 0.01) in the number of in-phase biopsy specimens obtained from patients not taking clomiphene as compared with the number obtained from patients taking clomiphene. The critical test requires that all 197 women undergo an initial endometrial biopsy before entering into this study. The clomiphene group could very well be the patients with ovarian dysfunctions who could be ex-

944 Wentz, Kossoy, and Parker

pected to have a higher incidence of luteal phase inadequacy before initiating clomiphene therapy. My last question has to do with the use of probability calculations to assess whether the seven cases of luteal phase inadequacy were more than would be expected solely on the basis of chance. The probability of two out-of-phase biopsy specimens is the product of individual probabilities only if the probability of two events is independent. The probability of two out-of-phase biopsy specimens may in fact not be independent events since the cause of luteal phase inadequacy may be persistent follicular dysfunction. REFERENCES 1. Davis OK, Berkeley AS, Naus Cj, Cholst IN, Freedman KS. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Ferti! Steril 1989;51 :582. 2. Li T, Rogers AW, Lenton AW, Dockery P, Cooke I. A comparison between two methods of chronological dating of human endometrial biopsies during the luteal phase, and their correlation with histologic dating. Ferti! Steril 1987; 48:928. 3. Shoupe D, Mishell DRJr, Lacarra M, et al. Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Cynecol 1989;73:88. 4. Vermesh M, Kletzky OA, Davajan V, Israel R. Monitoring techniques to predict and detect ovulation. Ferti! Steril 1987;47:259.

DR. EDWARD E. WALLACH, Baltimore, Maryland. Thank you very much for a very stimulating article. You have had a great deal of experience with this entity and have continually enlightened us with regard to it. My question will be a lot simpler than Dr. Davajan's, namely, are we diagnosing the syndrome, if there is such a syndrome or entity, on the basis of all or none criteria thereby using a 2-day or >2-day lag in all patients? Would there not be a better rationale in looking at data regarding treatment and fecundity after treatment for luteal phase defect by categorizing the condition as mild, moderate, or severe as we do with other entities such as endometriosis? In so doing, we would be considering in separate categories patients whose discrepancy in dating is brief or long and not including the patient with a discrepancy of 6 days in the same category as a patient whose endometrium is only 2 or 3 days out of phase. DR. MICHAEL SOULES, Seattle, Washington. If 1 understand correctly, you are questioning the clinical relevance of luteal phase deficiency as a cause of infertility. I think the whole matter of luteal phase deficiency is based on a "bed of sand" in the sense that it all comes down to the diagnostic method used. The endometrial biopsy is the method that you discussed. What we need is a gold standard for the diagnosis of luteal phase deficiency. The biopsy, as such, is an unproved diagnostic method. We have recently looked at the diagnostic methods used in diagnosing luteal phase deficiency. The women we studied underwent endometrial biopsies and daily

April 1990 Am J Obstet Gynecol

blood sampling throughout a complete menstrual cycle. We used a low integrated serum progesterone level over the course of the luteal phase as the gold standard for luteal phase deficiency. Obviously, daily progesterone measurements are not practical in the clinical setting but do serve as a definite indication that the problem is present. The endometrial biopsy, in comparison to this gold standard, had a 25% false-positive rate and a 30% false-negative rate. Therefore I think we are jumping ahead to get into the clinical relevance of luteal phase deficiency when we don't have a good method for diagnosis. Personally, I believe that luteal phase deficiency is relevant and occurs in 5% to 10% of chronically infertile women. However, in the context of your presentation, I would appeal to everyone to come up with a better method to diagnose luteal phase deficiency. DR. WENTZ (Closing). Dr. Davajan asked first about the definition of luteal phase inadequacy. By convention, we have consistently defined endometrial inadequacy as a biopsy;;=:2 days out of phase. In 1949, Dr. Georgeanna Jones initially described luteal phase inadequacy. During the 1960s, she showed that it could be experimentally induced by the administration of clomiphene citrate. 1 At that time, she validated a definition that was based on dating for 2 days, for example, secretory day 26 to 27 or 22 to 23. She also made a very important point that has been ignored; that point is that the biopsy must be done as closely as possible to the next menstrual period. That biopsy specimen then reflects a bioassay of the totality of estrogen and progesterone stimulation during the luteal phase. If one performs an endometrial biopsy as close as feasible to menses and it is read by 2-day dating to be secretory day 25 to 26 or even 27 to 28, it cannot be out of phase. In answer then to Dr. Wallach's question, "Should we have a mild, moderate, or severe defect," one cannot have a defect that is mild, moderate, or severe. The biopsy specimen is either in phase or out of phase, and no grading is possible. In addressing Dr. Davajan's second question about the number of cycles, our data showed that the ability of a first out-of-phase biopsy specimen to predict a second out-of-phase specimen is not statistically significant, although the significance fails by very little. There is a trend, but for the diagnosis to be made, two cycles would be needed. In reference to the article by Dr. Shoupe et al.,2 which, of course, was read with great interest, it is impossible to compare their data to those presented in our article. Since 1949, we have used the same criteria for the diagnosis of endometrial inadequacy and thus the diagnosis of luteal phase inadequacy. Shoupe et al. have used different criteria. Most endometrial biopsies in their study were done earlier, closer to secretory day 22 to 23 of the luteal phase and not close to menses. Their findings confirm the data of Cumming et al.' showing that the earlier the biopsy, toward secretory day 20 to 21, 21 to 22, or even 24 to 25, the more often the endometrial biopsy specimen will be out of phase.

Impact of luteal phase inadequacy on infertility

Volume 162 lI:umber 4

In reference to Dr. Davajan's question about the induction of endometrial inadequacy by the administration of clomiphene citrate, I was delighted to see a slide from his group confirming the previous work of Taubert and Dericks-Tan: showing that estradiol is indeed markedly increased in the midcycle in clomiphenetreated patients. The estradiol level correlates with the number of follicles, perhaps 500 pg/ml of estradiol. What Dr. Davajan failed to show us were the midluteal phase estradiol levels in those same patients; indeed, reflective of the midcycle estradiol increases, estradiol levels in the midluteal phase in these patients are also three to four times those anticipated during the normal menstrual cycle. However, in these patients progesterone levels are not increased three or four times and, in fact, are closer to normal. Therefore there is an abnormal estradiol-to-progesterone ratio induced by the increased amount of estrogen, and this then is reflected at the level of the endometrium. Dr. Davajan, there is no paradox that clomiphene citrate can be used to treat luteal phase inadequacy and that it also causes endometrial inadequacy. There is a dose-response relationship between the dosage of clomiphene administered and the follicle-stimulating hormone increase. If clomiphene citrate is administered to patients with, for example, a long follicular phase, one will correct the luteal phase inadequacy by inducing a follicle-stimulating hormone increase. However, if one gives clomiphene citrate to a normally ovulating woman, one will then induce an inadequacy of gonadotropin output and the other inadequacies of ratio that I have already discussed. There is therefore no paradox. In response to Dr. Soules, indeed, yes, we need a better mousetrap. If Dr. Soules measured daily pro-

945

gesterone levels during the luteal phase to diagnose luteal inadequacy, I would question even daily levels if these were from serum. Salivary progesterone measured on a daily basis may be the only way that we can find that the area under the progesterone curve does indeed decrease in patients with endometrial inadequacy. This correlation with the endometrium is almost perfect. I conclude that if criteria are used that are consistent, if endometrial dating that reflects the totality of estrogen-progesterone stimulation is used, and if those biopsies are done as close to menses as possible, then indeed the endometrial biopsy can be used as a means of diagnosing endometrial inadequacy. What our data were meant to show was that in a routine infertile population, among whom hyperprolactinemia and low body weight and other conditions were rare, the diagnosis and treatment of luteal phase inadequacy did not benefit the population in terms of pregnancy and its outcome. REFERENCES I. Jones GS, Maffezzoli RD, Strott CA, Ross GT, Kaplan G. Pathophysiology of reproductive failure after clomipheneinduced ovulation. AM J OSSTF.T GVNECOL 1970;108:847. 2. Shoupe D, Mishell DR, Lacarra M, et al. Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Gynecol 1989;73:88. 3. Cumming DC, Honore LH, ScottJZ, Williams KP. The late luteal phase in infertile women: comparison of simultaneous endometrial biopsy and progesterone levels. Ferti! SteriI1985;43:715. 4. Taubert HD, Dericks-Tan JSE. High doses of estrogens do not interfere with the ovulation-inducing effect of clomiphene citrate. Fertil Steril 1976;27:375.

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