The diagnosis of luteal phase defect using different diagnostic criteria.

Gynecol. Endocrinol. 4 (1990) 193-204

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The diagnosis of luteal phase defect using different diagnostic criteria A. Chryssikopoulos, 0. Gregoriou, N. Vitoratos and A. Liapis

2nd Department of Obstetrics and Gynecology, University of Athens (Aretaiion Hospital), Athens, Greece Abstract We evaluated the real incidence of the luteal phase defect (LPD) syndrome in 149 women who previously had been diagnosed by four independent researchers as having it, by the use of a combination of 3 criteria: basal body temperature (BBt), the histological appearance of the endometrium (EB) and the serum level of progesterone (P). The women had been divided according to etiological factors of the LPD syndrome into 4 groups (A, B, C and D). When the 3 criteria were used simultaneously (category 11), the incidence of LPD among the patients was 41%; when P and EB (category 111) and P and BBt (category V) criteria were used, the incidence was the same in each case (45%). O n the contrary, with the use of BBt and EB (category IV) criteria the incidence was 65%. Furthermore, when the above-mentioned categories were used in each of the groups separately, the smallest deviation between the initial and final diagnosis of LPD was found in groups A and B, whereas the largest deviation was found in groups C and D. We conclude that the highest incidence of patients who remained with the diagnosis of LPD was observed after utilization of category IV (EB and BBt) criteria and we recommend that, in cases where LPD is diagnosed based on P levels, only higher serum levels be accepted as indicative of the syndrome.

Introduction The luteal phase defect (LPD) syndrome appears to be the most subtle of the known abnormalities of ovarian function but it remains underdiagnosed in the vast majority of women who are not attempting to conceive. It has been reported that 10% of all cases of infertility and 25% of all cases of habitual Correspondence to: A. Chryssikopoulos, Korai str. %lo, GR-145 61 Kifisia-Athens, Greece

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Chryssikopoulos, Gregoriou, Vitoratos and Liapis

abortions are due to the LPD syndrome','. 'Physiological' LPD seems to occur in p r e m e n ~ p a u s a l ~and . ~ postpartal5 periods of life and, furthermore, psychological LPD appears in women after stress or strenuous exercise6. There is controversy among investigators with regard to the estimation of different methods and criteria for the diagnosis of the LPD syndrome. This has led to it being diagnosed less frequently than it is generally believed to occur and explains why the comparison of different therapeutic schemes is difficult. The purpose of this retrospective study was to evaluate the incidence of the LPD syndrome in 149 women who previously had been diagnosed by four independent researchers as suffering from it, by the simultaneous use of 3 characteristic criteria and various combinations of these.

Materials and methods One hundred and forty-nine women with primary or secondary infertility were diagnosed as having the LPD syndrome by four investigators working independently. The diagnostic criteria, used separately or in various combinations, for the diagnosis of this syndrome were the following: 1. The duration of the hyperthermic phase of the cycle by the use of basal body temperature (BBt criterion). The day of ovulation was identified as the last day on the BBt charts before the sustained rise of temperature. The length of the luteal phase was defined as the number of days of temperature elevation between ovulation and menses. All patients whose hyperthermic phase lasted less than 11 days were considered as having the LPD syndrome'. 2. The histological appearance of the endometrium by Novac procedure. The procedure was performed 1-3 days before the expected day of menstruation. The histological criteria were based on those suggested by Noyes et a/.'. The diagnosis of LPD was established in those cases in which endometrial maturation was delayed for more than 2 days (endometrial biopsy (EB) criterion). 3. The plasma progesterone (P) level during the 2nd phase of the cycle. The P level was determined either from a single blood sample taken between days 4 and 7 of the 2nd phase of the cycle or from 3 blood samples taken on days 4, 6 and 8 of the hyperthermic phase of the cycle. In the case of determinations from a single blood sample, the LPD syndrome was considered t o be present in those women whose P level in blood was less than or equal to 10 ng/m19. When 3 blood samples were used, we considered as suffering from the syndrome those patients whose mean value of P was less than or equal to 15 ng/ml" (P criterion).

All the patients had a normal hysterosalpingogram and the semen analysis of their male partners was also normal. All the women were screened for thyroid diseases and hyperprolactinemia, and their serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone and dehydroepiandrosterone sulfate (DHEA-S) were determined.

T h e diagnosis of luteal phase defect using different diagnostic criteria

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Table 1 The incidence of patients with the luteal phase defect syndrome in categories


and etiological groups

Category I

Caregory 11

Category I l l

Category IV

Category L'

Patients

n = 149

41% ( n = 61)

45% ( n = 67)

65% ( n = 97)

45% (ti = 67)

Group A GroupB Group C Group D

n = 79

41.77% 40.0% 45.0% 30.0%

45.57% 48.57% 45.0% 30.0%

64.55% 65.71o/' 70.0% 60.0°/0

45.57% 45.7% 50.0% 30.0%

n=35 n = 20 n = 15

Category I = various combinations of the criteria; category 11 = BBt, E B and P criteria; category 111 = EB and P criteria; category IV = EB and BBt criteria; category V = P and BBt criteria

Depending on the cause of the LPD syndrome the patients were divided into 4 groups:

G r o u p A : 79 patients with unknown etiology of LPD. C r o u p B: 35 patients with LPD due to hyperprolactinemia (mean value of prolactin (PRL) 37.18 f 8.7 ng/ml). G r o u p C : 20 patients with oligonienorrhea or secondary amenorrhea who developed LPD after treatment with clomiphene citrate (CC). C r o u p D: 15 patients with monophasic cycles who developed LPD secondary to CC treatment. The 149 women were divided into different categories according to the criteria used in the diagnosis of the LPD syndrome:

Category I: This category included all 149 women who initially had been diagnosed by four independent investigators as having the LPD syndrome, based on various combinations of the diagnostic criteria. Category II: This category included 61 (41%) of the 149 women, who were diagnosed as having the LPD syndrome by the simultaneous use of 3 characteristic criteria (BBt, EB and P). Category 111: This included 67 (45%) of the 149 women, who were diagnosed as having the syndrome by the use of 2 criteria (P and EB). Category IV: This category included 97 (65%) of the 149 women, who were diagnosed as having the syndrome when the BBt and EB criteria were used. Category V : This included 67 (45%) of the 149 women, who were found to have the LPD syndrome when the diagnostic criteria P and BBt were used (Table 1). The statistical analysis was performed using the Student t test.


196 Clzrysrikopoulos, Cregoriou, Vitoratos arid Liapis

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Figure 2 Mean (kSD) duration of the hyperthermic phase on BBt charts in patients with LPD according to etiological factors (groups) and to criteria (tests) (*p < 0.1, **p < 0.05, ***p < 0.01, ****p < 0.001)

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Results O f the 149 patients considered to have the LPD syndrome only 41% presented with it with simultaneous use of the BBt, EB and P (category 11) diagnostic criteria. When P and EB (category 111) or P and BBt (category V) diagnostic criteria were used, the incidence of patients who were found to have LPD was the same (45%). O n the contrary, the incidence was higher (65%) when BBt and EB (category IV) diagnostic criteria were used. When the above-mentioned categories were used in each of the groups separately, the smallest deviation between the initial and final diagnoses of LPD syndrome was found in groups A and B, whereas the largest deviation was found in groups C and D. Furthermore, in each of the groups the highest incidence of patients who remained with the diagnosis of LPD was observed in category IV (Table 1). Age: There was no statistically significant difference in the mean age between the 4 groups of women. The only significant difference (p < 0.05) was found in group B patients in categories I and I1 (Figure 1). Basal body temperature: The mean duration of the luteal phase (BBt criterion) was 9.46, 8.39, 8.63, 8.56 and 8.51 days in categories I-V, respectively. There was a statistically significant difference (p < 0.0001) in the mean duration of the luteal phase between category I and the others (Table 2). When the BBt criterion was used in different groups, the mean duration of the hyperthermic phase was significantly higher among the patients who were initially diagnosed as having LPD than in the patients in categories 11-V. This observation was relevant to each group of our population (Figure 2). Furthermore, as is indicated in this diagram, the fluctuations were greatest in groups A and D and smallest in groups B and C. Endometrial biopsy: The mean number of the days out of phase with the late luteal endometrial biopsy was 4.37, 5.03, 4.95, 4.91 and 4.80 in categories I-V, respectively. There was a statistically significant difference (p < 0.0001) for the mean number of days out of phase between category I and the others. O n the contrary, no statistically significant difference was found among categories 11, 111, IV and V (Table 2). When the EB criterion was used in each of the 4 groups, the mean number of days out of phase was statistically significantly higher among the patients who remained with the initial diagnosis than in patients belonging to categories 11-V. This finding was indicated in each group of our population, with the highest difference in group A (Figure 3). Progesterone: The mean value of the P serum level among the various categories of patients was 10.77, 8.35, 8.42, 9.87 and 8.27 ng/ml in categories I-V, respectively. There was a statistically significant difference in the mean value of P between category I and categories 11,111 and V as well as between category IV and categories 11, 111 and V (Table 2).


The diagnosis of luted phase defect using diflerent diagnostic criteria

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Table 2 The mean (+ SD) values and the statistical analysis of 3 criteria in the 5 categories of our patients Category 1

Category I1

Category I l l

Category 1V

Category V

149

61

67

97

67

9.46(la) 1.80

8.39(1b) 1.02

8.63(1b) 1.40

8.56(1b) 1.20

8.51 (lb) 1.22

EB (days) Mean SD

4.37(la) 1.07

5.03(lb) 0.77

4.95(1b) 0.76

4.91 (lb) 0.75

4.80(lb) 0.92

P (ng/ml) Mean SD

10.77(la) 2.99 (3a)

8.35(1b) 1.22 (2b)

8.42(1b) 1.24(2b)

9.87(1b) 5.54(2a) (3b)

8.27(2b) 1.36

No. ofpatients


Criteria BBt (days) Mean

SD

Category I = various combinations of the 3 criteria; category 11 = BBt, EB and P criteria; category 111 = EB and P criteria; category IV = EB and BBt criteria; category V = P and BBt criteria la/lb, p < O.OOO1; 2a/2b, p < 0.0001; 3a/3b, p < 0.0001

When the P criterion was used in each of the 4 different groups, the mean value of the P level was statistically significantly higher among the patients who were initially diagnosed as having the LPD syndrome than in those who remained with the diagnosis of LPD in categories 11-V. This statistically significant difference was obvious in every group, but was higher in groups A and D and lower in groups B and C. There was also a statistically significant difference in groups A, B and D among the patients who were diagnosed as having the LPD syndrome in category I1 and those in category IV (Figure 4).

Discussion The diagnosis of LPD in the clinical setting remains difficult and controversial; first of all, because no practical diagnostic method has been validated, and secondly because different forms of the syndrome have been reported, 'such as: (a) the 'inadequate luteal phase', in which P output is lower than expected but the interval from ovulation to menses is normal", (b) the short luteal phase"~'2, and (c) the 'dysharmonic luteal phase', which is characterized by delayed endometrial maturation despite normal P ~ u t p u t ' ~ . ' ~ . It is obvious that, due to the existence of many variants of the syndrome, the use of the proper criterion in diagnosing the LPD syndrome is of primary importance. In our study, the lowest incidence (41%) of women who were finally considered as presenting it was found in category 11 (all 3 criteria), whereas the highest incidence (65%) was found in category IV (EB and BBt criteria). When the P criterion was involved, as in categories 111 and V, the incidence of patients who finally remained with this diagnosis was 45%.


T h e diagnosis of h e a l phase defect usirig different diagriostic criteria

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Using the BBt criterion as well as the EB criterion, we found no statistically significant difference among categories 11,111, IV and V. On the contrary, when the P criterion was used, a statistically significant difference was observed among the above categories; i.e., this was observed whether or not the P criterion was involved in the categories for the diagnosis of the LPD syndrome (Table 2). The disadvantage of the BBt criterion is the fact that the temperature charts are reliable for the diagnosis of LPD only when there are persistent short luteal phases, so this criterion is not adequate for the diagnosis of all cases of LPD. O n the contrary, when the P criterion is involved, the discrepancies in the diagnosis of the LPD syndrome are even higher's'8, with the discrepancies often surpassing 55y0'~.The most likely cause of this difference lies in the pulsatile secretion of P in the mid-luteal and late luteal phases's20. The average range of P is 260% in the mid-luteal phase and an even higher range (425%) has been observed in the late luteal phase". These frequent and rather wide fluctuations of serum P levels over 24 hours therefore make the accurate diagnosis of the LPD syndrome problematic when a single or a few serum P determinations are used. Furthermore, in cases where the LPD syndrome has developed secondary to treatment with CC, the serum P level has been reported to be higher than 10-15 ng/m12'. This phenomenon was observed in groups C and D of our patients. O f the 3 diagnostic criteria (BBt, EB and P), in our opinion the most reliable is that of endometrial biopsy, due to its being a bioassay criterion, independent of the fluctuations of hormone levels. The incidence of LPD as diagnosed by EB in women with infertility has been reported to range between 18.6% and 30.6%. It has been reported, however, that false positive and false negative results with the use of this criterion are obtained in between 15% and 30% of patient^^'-*^. Furthermore, most authors have reported good correlation between the BBt and EB criteria due to the fact that the discrepancies between the above criteria in diagnosing the LPD syndrome range from 20% to 27°/~8*'5*'6. As far as regards a therapeutic approach, in cases where the LPD syndrome is due to hyperprolactinemia (group B) we suggest that treatment should consist of bromocriptine in low doses24,provided that the presence of pituitary tumors has been appropriately excluded. In cases where the syndrome has developed secondary to treatment with CC (groups C and D) we, like many other authors, suggest that CC be replaced with human menopausal gonadotropins or a combination of purified FSH and human chorionic gonadotropin (hCG). Finally, where the cause of the LPD syndrome is unknown (group A patients) we recommend either a more sophisticated endocrine evaluation be made or the use of progesterone supplementation with vaginal suppositories, in doses as reported by many authors'^^^. We conclude that the combined use of BBt and EB diagnostic criteria is quite reliable in diagnosing the LPD syndrome, despite the fact that BBt alone is not a very sensitive criterion. We also recommend, in cases where the LPD syndrome is diagnosed based on the P level, that only higher serum levels should be accepted as indicative of the syndrome or that routine daily evaluation of serum P during the luteal phase of the cycle should be performed.

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