Human Reproduction vol.6 no.4 pp.484-499, 1991

REVIEW

Evaluation of the luteal phase

T.C.Li1 and I.D.Cooke Department of Obstetrics and Gynaecology, University of Sheffield, Jessop Hospital for Women, Sheffield S3 7RE, UK 'To whom correspondence should be addressed

The values of various methods used to evaluate the luteal phase, including basal body temperature, measurement of progesterone (P), endometrial biopsy, ultrasonographic measurement of endometrial thickness, and measurement of endometrial proteins, are reviewed. Luteal phase defect (LPD) is a controversial entity. The diagnosis of this condition is best based on a histological study of the endometrium. Methods to improve the accuracy of the diagnosis are discussed. LPD is more likely to be a result of an abnormal response of the endometrium to P, than to a subnormal production of P by the corpus luteum. Many methods of treatment for LPD have been proposed but none is based on a properly controlled clinical trial. Treatment designed to improve the response of the endometrium to P may be more rewarding than P supplementation. Key words: luteal phase defect/endometrial biopsy/endometrial protein/progesterone

has occurred. It is commonly asked in infertility practice and is relatively easy to answer. In contrast, the second question is less often addressed, partly because it is more difficult to answer. It assumes that the luteal phase may be categorized as normal or abnormal (defective) and that the latter (luteal phase defect) may be a cause of infertility (Jones, 1949). However, the LPD is such a controversial issue that some gynaecologists question its existence. It is important to note that the two questions above are different, not only in terms of diagnosis, but also of treatment. For example, there are well established and effective treatments for anovulation, but the value of treatment of the defective luteal phase is less well proven (see Discussion). Methods of evaluation Various methods may be used to evaluate the luteal phase including the following: monitoring basal body temperature (BBT), measurement of progesterone, histological assessment of an endometrial biopsy (EB), ultrasonographic measurement of endometrial thickness and characterization of endometrial protein profiles. Has a luteal phase been produced?

Introduction

Basal body temperature

The luteal phase of the normal menstrual cycle starts at the time of ovulation and ends at the onset of menstruation. During this time progesterone (P) is secreted by the corpus luteum (CL). One of the most important functions of P is to produce secretory changes in the endometrium, in preparation for the reception of the fertilized ovum (implantation). Progesterone is also indispensable for the maintenance of early pregnancy (Csapo and Pulkkinen, 1978). The normal function of the CL has been recently reviewed (Hillier and Wickings, 1985; Cooke, 1988). In this article, an attempt is made to review the different methods used to evaluate the luteal phase, and the diagnosis, pathophysiology and treatment of luteal phase defect (LPD).

It has been recognized for many years that the BBT rises by —0.4-1.0°F in the luteal phase, probably resulting from a direct effect of P on the hypothalamic temperature regulation centre. BBT is commonly used to assess whether or not ovulation has occurred, because it is inexpensive, non-invasive and reasonably reliable. However, the interpretation of a BBT chart may sometimes be difficult and subjective (Lenton et ai, 1977).

Aims of evaluation of the luteal phase In the evaluation of the luteal phase, two questions may be asked: (i) given a particular stage of the menstrual cycle, whether or not a luteal phase has been produced; (ii) given that a luteal phase has been produced, whether or not it is functionally normal. The first question is equivalent to asking whether or not ovulation 484

Progesterone Like BBT, the measurement of P concentration in plasma samples has been a useful test for ovulation for many years. Most investigators collect a single blood sample in the presumed midluteal phase, e.g. day 21 of a 28 day cycle. As the plasma concentration of P in the follicular phase (including the late follicular phase) rarely exceeds 10 nmol/1 (Israel et al., 1972), this has been used as a threshold level by many investigators to indicate whether or not ovulation has occurred (Israel et al., 1972; Abraham et al., 1974; Shepard and Senturia, 1977; Wathen et ai, 1984). Some investigators even used a lower threshold of 6.4 nmol/1 (Nadji et ai, 1975; Rosenfeld and Garcia, 1976), whereas the World Health Organization (1984) recommended © Oxford University Press

Evaluation of the luteal phase

a higher level of 18 nmol/1. The threshold level used to distinguish between ovulation and anovulation should not be confused with one used to distinguish between a normal and a defective luteal phase. In the latter case, a much higher level of ~ 30 nmol/1 has been proposed (see Discussion). Such a high threshold level should not be used to distinguish between ovulation or anovulation, otherwise a large proportion of false negative results will be produced (Steele et al., 1985). The measurement of P in plasma is generally accepted to be more precise and objective than BBT.

unpublished data), the proliferative endometrium was found to vary from < 3 to 9 mm in thickness, whereas the secretory endometrium varied from 9 to 15 mm in thickness. Thus, a finding of endometrial thickness of 10 mm or more in a regularly cycling woman is a strong indication that the cycle has entered the luteal phase. Apart from being inexpensive and non-invasive, ultrasonographic measurement of endometrial thickness has the unique advantage that the result is immediately available, unlike P measurement or EB which may take several days before the results are available. It is possible that such a method will be more popular in the future.

Endometrial biopsy In the luteal phase, under the influence of P produced by the corpus luteum, the morphology of the endometrium is characterized by various secretory changes. Histological evidence of the latter almost always suggests that the menstrual cycle has entered into the luteal phase. In the 1950s and 1960s, EB was more commonly performed because P assays were then more expensive and not as precise. Nowadays, EB is performed less often. The two investigations most commonly performed to test for ovulation are BBT and the taking of a blood sample in the 'mid-luteal phase' for P assay. However, the value of EB should not be underestimated, especially when differentiating between a functionally normal or defective luteal phase. On the whole, the diagnosis of ovulation or anovulation based on endometrial histology is highly correlated with that based on plasma P assay in the 'mid-luteal phase'. Using a plasma P level of 6.4 nmol/1 (2 ng/ml) in the 'mid-luteal phase' as the threshold between ovulation and anovulation, Nadji et al. (1975) and Rosenfeld and Garcia (1976) found 90-93% correlation with that obtained by histological examination of EB. Using a higher threshold of 9.6 nmol/1 (3 ng/ml), Shepard and Senturia (1977) found agreement in 75% of cases. Ultrasonography of the endometrium A number of studies have shown that the thickness of the endometrium, as measured by ultrasonography, gradually increases throughout the menstrual cycle (Rabinowitz et al., 1986; Randall etal, 1989). In a recent study directly correlating endometrial thickness measured by ultrasonography and endometrial histology in 34 regularly cycling women (L.Nuttall, T.C.Li and I.D.Cooke,

Endometrial proteins In the luteal phase, the endometrium produces several types of secretory product. One of the principal proteins secreted by endometrial glands in the luteal phase is placental protein 14 (PP14), also known as progestogen-dependent protein (PEP) or pregnancy-associated endometrial alpha-2-globulin (a2 PEG). The concentration of this protein in the serum and in endometrial tissue has been found to increase from the early luteal phase to reach a maximum in the late luteal phase of normal cycles (Julkunen et al., 1986). In addition, PP14 has been found to possess immunosuppressant effects (Bolton et al., 1987; Pockley et al., 1988); hence it has been hypothesized that PP14 may play an important role in the process of human implantation by protecting the implanting embryo from rejection by the maternal immune response. Endometrial proteins such as PP14 may be measured directly in endometrial tissue extracts by radioimmunoassay (RIA) (expressed per unit weight of total protein or DNA), in histological tissue sections by immunohistochemical techniques or in plasma samples by RIA. As only insignificant levels of PP14 are detected in the plasma of the follicular phase, the presence of significant amounts of PP14 in a given plasma sample indicates that a luteal phase has been produced. In contrast to that of P, the best time to collect a plasma sample for measurement of PP14 is in the late luteal phase or at the onset of menstruation, when the plasma concentration of PP14 is highest in the menstrual cycle (Joshi et al., 1986; Julkunen et al., 1986; Wood et al., 1989). However, it is doubtful whether the measurement of plasma PP14 has any advantage over that of P, for simply determining whether or not ovulation has occurred.

Table I. Comparison of various methods to assess whether or not a luteal phase has been produced (BBT, basal body temperature, P, progesterone; EB, endometrial biopsy; USS, ultrasonographic measurement of endometnal thickness) BBT Cost

None

Invasiveness Precision How often used in current clinical practice Comment

Non-invasive Fair

EB

USS

Endometrial proteins

Inexpensive

Inexpensive

Inexpensive

Non-invasive

Slightly invasive Good Sometimes

Non-invasive Good Occasionally

Still a research tool Non-invasive Probably good

Also of value in evaluating whether the luteal phase is normal or defective

Likely to be used more often in the future

Very often

Good Very often

Interpretation of BBT chart not always easy

Also of value in evaluating whether the luteal phase is normal or defective

Still a research tool Advantage over P measurement yet to be established

485

T.C.Li and I.D.Cooke

Which one to choose? The merits of each of the various methods used to determine whether or not a luteal phase has been produced are summarized in Table I. Is the luteal phase normal or defective? Historical background In the 1950s and 1960s, the histological dating of endometrium was thought to be a superior method of evaluating corpus luteum function, as hormonal assays then had a multitude of technical difficulties. It was therefore proposed that the diagnosis of defective corpus luteum function (luteal phase defect) should be based primarily on histological dating of the endometrium (Jones and Madrigal-Castro, 1970; Wentz, 1982). However, as the quality of hormone assays improved, more and more reliance was placed on plasma progesterone assays to assess corpus luteum function (Hull et al., 1982; Abdulla et al., 1983). More recently, measurement of progesterone in the saliva has been found to correlate well with that in the plasma (Walker et al,, 1981; Zorn et al., 1984). It has since evolved as a simple, reliable and non-invasive alternative in the evaluation of corpus luteum function. Different names have been used by various investigators to refer to the defective luteal phase: e.g. luteal phase defect (Jones, 1976; Andrews, 1979; Daly, 1983; Lee, 1987; Crosignani, 1988), luteal phase deficiency (Balasch et al., 1986a; McNeely and Soules, 1988), luteal phase inadequacy (Murthy et al., 1970; Rosenfeld etal., 1980; Wentz, 1982) and luteal phase insufficiency (Taubert, 1978).

as an in-vivo bioassay of the entire function of the corpus luteum (Table II). However, some others preferred to obtain EB in the mid-luteal phase. An argument for the latter is that it is during this time that implantation starts to take place, so the morphology at this time is more likely to reflect normal or defective endometrial function than morphology at the end of the luteal phase, which is dominated by degenerative changes. In addition, it has been shown that the precision of histological dating by the traditional criteria in the first half of the luteal phase is better than that in the second half (Li etal., 1989a). Similarly, Johannisson et al. (1987) found that histological features of the endometrium have significantly less variance in the first half of the luteal phase than in the second half. Thus, it is possible that taking EB in different parts of the luteal phase may contribute to the controversy in the diagnosis of LPD. The different timings of EB by various investigators are summarized in Table II. At present, we collect most EBs in the mid-luteal phase, at about day LH + 5. What were the different criteria used to discriminate between a normal and a defective luteal phase? Nearly all previous investigators used the traditional dating criteria of Noyes et al. (1950) to perform histological dating of the endometrium. Most considered the endometrium to be abnormally retarded (or out of phase) if the histological dating was > 2 days behind the corresponding chronological date; however, some considered the endometrium to be abnormally retarded if the histological dating was 2 days or more behind the corresponding chronological data (Table HI). Such a difference is likely to have a significant impact on the results. Davies et al. (1989) found that among 35 EBs studied, the prevalence of retardation was 31 or 51 %, depending on whether the threshold point used for abnormality was > 2 days and > 2 days, respectively. They felt that the use of > 2 days

Luteal phase defect: a controversy The concept of a luteal phase defect (LPD) was first introduced by Jones (1949) and has been defined as 'corpus luteum defective in progesterone production' (Jones and Madrigal-Castro, 1970; Jones, 1976). However, controversy abounds in almost every aspect of this condition. Several investigators have recently attempted to review this condition (Wentz, 1979; Andrews, 1979; Balasch and Vanrell, 1987; McNeely and Soules, 1988). In our opinion, the basic problem is a lack of consensus in the diagnosis. Many investigators of LPD have used different diagnostic criteria; thus, comparison of results among various investigators is often difficult, if not impossible. In order to determine whether or not the results of different investigators may be directly compared, a number of questions have to be asked such as which method was used for the diagnosis (progesterone measurement, or endometrial biopsy?) and for a given method, when during the luteal phase was the diagnostic test performed? What was the threshold level used to distinguish between a normal and a defective luteal phase? How many cycles were studied before the diagnosis was established?

Table II. The different timing of endometrial biopsy in various studies of the defective luteal phase Mid-luteal phase

Noyes, 1959 Shepard and Sentuna. 1977 Gautray et al.. 1981

Late luteal phase

Jones, 1976 Soules et al.. 1977 Taubert, 1978 Wentz, 1980 Annos et al.. 1980 Rosenfeld et al., 1980 Mansuwan etal.. 1982 Shangold el al.. 1983 Downs and Gibson. 1983 Cumming et al., 1985 Balasch et al., 1985 Check and Adelson, 1987 Hague et al.. 1987 Davies et al.. 1989 Olive et al.. 1989

Mid- or late luteal phase

Gillam, 1955 Zorn et al.. 1984 Huang, 1986

Entire luteal phase

Cooke etal.. 1972 Driessen et al.. 1980 Li etal.. 1987

Diagnosis by EB When was the EB performed? The majority of previous investigators have performed EB in the late luteal phase on the assumption that endometrial histology at this time may be used 486

Evaluation of the luteal phase

as a discriminant would result in a significant over-estimation of the prevalence of LPD. How many cycles were studied to establish the diagnosis? Many investigators suggested that more than one cycle should be studied prior to establishing the diagnosis of LPD, on the grounds that if the abnormality was of clinical significance, it would persist in subsequent cycles. This may be particularly important as there is significant variation in the results of endometrial dating between cycles within the same subject (Balasch etai, 1985; Davies et al., 1989; Li et al., 1989a). Thus, the result in one cycle may not reliably predict that in another cycle. However, Wentz (1980) suggested that there was remarkable consistency in the results of endometrial dating from one cycle to another cycle. It has been postulated that in some subjects, retarded endometrial development is persistent in every cycle but in others it may be sporadic. Balasch et al. (1985) estimated that - 5 0 % belong to the first group and 50% belong to the latter. However, if two cycles are to be studied, what clinical significance should be attached to those with normal results in one cycle but abnormal results in another? It has been suggested that in situations like this, a third cycle should be studied to resolve the doubt (Balasch et al., 1985). However, such an approach is cumbersome, and unlikely to be acceptable to most clinicians and patients. The number of cycle(s) studied by various investigators in establishing a diagnosis of LPD are summarized in Table IV. Diagnosis by progesterone measurement When was the sample taken? In the past, most investigators took a single blood sample in the mid-luteal phase as a means of evaluating the luteal phase (Radwanska et al., 1976; Hull et al., 1982; Shangold et al., 1983; Glazener et al., 1988; Crosignani, 1988; Olive et al., 1989). However, there is no evidence to support the concept that the mid-luteal phase is in the optimal time to measure P concentrations in the plasma. In an analysis

of the relationship between endometrial development and daily saliva progesterone concentrations, Li et al. (1989b) found those with retarded endometrial development (« = 8) had significantly lower P concentrations between days LH + 3 and LH + 7, but not on other days of the luteal phase. Such an observation rather suggests that the early luteal phase may well be the optimal time to obtain samples for P measurement. Other investigators (Dodson etal., 1975; Shepard and Senturia, 1977) similarly observed that the rate of the post-ovulation rise of P in the first half of the luteal phase might be more important than the peak level of P achieved in the mid-luteal phase. On the other hand, Daya (1989) suggested that the optimal time for serum progesterone measurement to diagnose luteal phase defect was the late luteal phase.

Table FV. The number of cycles studied by different investigators in study of luteal phase defect, based on endometrial histology One cycle

Grant et al , 1959 Cooke etal, 1972 Rosenfeld and Garcia, 1976 Shepard and Senturia, 1977 Driessen etai, 1980 Mansuwan etai, 1981 Nash, 1982 Shangold el at., 1983 Cumming et al., 1985 Li etai, 1987

Two cycles

Noyes, 1959 Jones, 1976 Soules etai, 1977 Wentz, 1980 Witten and Martin, 1985 Balasch etai, 1986 Hague et at., 1987 Check and Adelson, 1987 Daya and Ward, 1988 Olive etai, 1989

Table III. The different criteria used by various investigators to define normal or retarded endometnum

Table V. The different timings of P measurement recommended by various investigators for evaluation of the luteal phase

> 2 days

Early luteal phase

Dodson etai, 1975 Shepard and Senturia, 1977 Li etai, 1989b

Mid-luteal phase

Radwanska el al., 1976 Hensleigh and Fainstat, 1979 Hull etal., 1982 Shangold etal., 1983 Glazener etai, 1983 Crosignani, 1988 Olive etai, 1989

Late luteal phase

Daya, 1989

Jones, 1976 Shepard and Senturia, 1977 Annos et al., 1980

Wentz, 1980 Nash, 1982 Shangold etai, 1983 Huang, 1986 Balasch et al., 1986b Hague etai, 1987 Olive et al., 1989 >2 days

Gillam, 1955 Noyes, 1959 Murthy etai., 1970 Di Paola et al., 1971 Cooke etai, 1972 Rosenfeld and Garcia, 1976 Soules et al., 1977 Mansuwan et al., 1981 Downs and Gibson, 1983 Zorn et al., 1984 Witten and Martin, 1985 Cumming etal., 1985 Check and Adelson, 1987 Daya and Ward, 1988 Crosignani, 1988

Table VI. The various minimum concentrations of a single mid-luteal plasma progesterone level used by different investigators to define normal or defective luteal phases Radwanska et al., 1976 Hensleigh and Fainstat. 1976 Hull etai, 1982 Shangold eiai, 1983 Crosignani, 1988 Olive et ai, 1989

32 32 30 32 28 32

nmol/1 nmol/l nmol/l nmol/l nmol/l nmol/l

487

T.C.Li and I.D.Cooke

The different times considered by various investigators to be optimal in obtaining samples for P measurement are summarized in Table V. One difficulty encountered in the measurement of P in a single sample is the relatively wide variation in the results between subjects (Lenton et al., 1983), partly due to the pulsatile release of P into the circulation (Steele et al., 1985). To overcome this problem, some investigators suggested the use of serial samples throughout the luteal phase. Abraham et al. (1974) proposed using the mean of three P measurements in the mid-luteal phase to calculate the P index as a means of evaluating the luteal phase. However, serial blood sampling is rather tedious and unpleasant and so is not widely used. The use of serial P measurements to evaluate the luteal phase will be further discussed later. What was the discriminant between a normal and a defective luteal phase? In defining a normal or defective luteal phase, many investigators used a threshold point of ~30nmol/l, in the mid-luteal phase (Table VI). Despite this, its clinical value has not been confirmed by controlled follow-up or treatment studies. Thus, it has been argued that the use of a single determination of plasma P to diagnose LPD remains an unverified concept (McNeely and Soules, 1988). How many cycles were studied to establish the diagnosis? As in the case of endometrial biopsy, it is unclear how many cycles should be studied in order to establish a diagnosis of LPD, based on P measurements. Lenton et al. (1983) found significant consistency in the results of mid-luteal concentrations of plasma progesterone between cycles of the same individual, but Glazener

Table VII. The results of progesterone (P) measurement in subjects with retarded endometrial development Authors

Number of subjects with retarded endometnum

Proportion with Normal P Subnormal P

Shangold et al , 1983 Zorn et al., 1984 Balasch and Vanrell. 1987 Li etal., 1989b Li etal., 1991b

20 37 42 8 15

45% 78% 86% 50% 87%

55% 22% 14% 50% 13%

et al. (1988) could not demonstrate similar results. The latter investigators suggested that as many as six cycles should be studied in order to establish the diagnosis! Correlation betwen EB and P Many investigators have attempted to correlate the results of endometrial dating with the plasma P concentration. Some of them (Gautray etal., 1981; Cook etal., 1983) found that in women with an endometrium retarded by >2 days, the mid-luteal phase P levels were significantly lower than in those with normal endometrial development. However, many other investigators found no difference in the luteal levels of plasma P between those with normal or with retarded endometrial biopsies (Rosenfeld et al., 1980; Balasch et al., 1982a; Haciski et al., 1983), or a lack of significant correlation between these two methods in the evaluation of corpus luteum function (Cooke etal., 1972; Shepard and Senturia, 1977; Annos et al., 1980; Shangold et al., 1983). More recently, Daya and Ward (1988) analysed the relationship between P level and the results of endometrial dating using Cohen's Kappa statistics: they found the positive predictive value of P for retarded endometrium was not greater than 71 %. Li et al. (1989b) recently hypothesized that the controversy was due to a lack of precision in the measurements of endometrial development, the progesterone assay or both. A prospective study was conducted to examine the relationship between endometrial development and progesterone concentrations using more precise methods of endometrial dating, using the luteinizing hormone surge for chronological dating (Li et al., 1987) and morphometric analysis for histological dating (Li et al., 1988a), as well as monitoring daily salivary P levels throughout the whole luteal phase, instead of a single measurement. Among 34 fertile women and 21 with unexplained infertility, it was found that those with retarded endometrium had significantly lower salivary P concentrations from days LH + 3 to LH + 7, but not before LH + 3 or after LH + 7 . In addition an overall, statistically significant correlation (P < 0.01) was found between normal or retarded endometrium, and normal or subnormal salivary P profile respectively. However, of particular clinical interest is the relationship between a retarded endometrium and a subnormal progesterone level. In a number of studies (Li et al., 1989b, 1990c, 1991b)

Table VIII. The preference of various investigators in choosing between endometrial biopsy (EB) or progesterone (P) measurement for evaluation of the luteal phase Authors

Choice

Comment

Jones and Madrigal-Castro, 1970 Abraham et al., 1974 Shepard and Senturia, 1977

EB P P

' . . the timed EB is the most practical . . .'

Rosenfeld et al., 1980 Hull etal., 1982 Wentz, 1982 Shangold etal., 1983

EB P EB Both

Balasch et al., 1985 Daya and Ward. 1988 McNeely and Soules, 1988 Nod et al., 1988 Crosignani, 1988

EB EB EB EB EB

488

' . . a single, well timed serum P determination is superior to a single EB luteal function' 'EB is essential for the diagnosis of luteal phase inadequacy'

. . for evaluation of

'EB would be best . . .' "Both mid luteal serum P levels and the late luteal endometrial histology should be assessed because neither can be used to predict the other' . . EB is the primary mode of diagnosis' ". . . the EB still remains the gold standard for the diagnosis of luteal phase defect' 'The EB remains the best current method for the diagnosis of luteal phase defect' The EB seems to be the most practical method for investigating luteal phase deficiency' 'EB remains the classical way to diagnose an inadequate luteal phase'

..

Evaluation of the luteal phase

we have consistently found that the majority (50% or more) of cases with retarded endometrial development were associated with normal salivary progesterone profiles, suggesting that an abnormal response of the endometrium to a normal concentration of P is a more common occurrence than is a subnormal P concentration resulting in abnormal endometrial development. Several other investigators reported similar findings (Table VII). The artificial cycle (one produced in women with nonfunctioning or absent ovaries by the administration of steroid hormones, oestrogen and progesterone, in a sequential manner so as to mimic the natural cycle) has produced a unique opportunity to study the precise relationship between the steroid hormones, oestrogen and progesterone, and endometrial morphology. Navot et al. (1989) studied the effect of a variable duration of oestrogen priming and reported that endometrial development in the artificial cycle was similar in those with a short duration of priming (6 days), a standard duration of priming (2 weeks), or a long duration of priming (3—5 weeks). Devroey et al. (1989) found that normal endometrial maturity in the midluteal phase of artificial cycles could be achieved with a rather wide range of serum progesterone concentrations (from levels slightly lower than 10 ng/ml to >30 ng/ml). The correlation between oestrogen and progesterone doses, and endometrial morphology in the artificial cycle has been reviewed (Li et al., 1991c). EB or P, which is better? It is a matter of debate which of the two methods, EB or P measurement, is to be preferred in establishing whether the luteal phase is normal or defective (Table VIII). Those who prefer P measurement may argue that the collection of samples (whether blood or saliva) is minimally invasive and the measurement, using radioimmunoassay, is precise. Although the latter is true, it is generally accepted that there is a rather wide variation in the comparably timed P concentrations between subjects (Lenton et al., 1983). This may in part be due to the pulsatile release of P into the circulation (Steele et al., 1985). In contrast, there appears to be a relatively low inter-subject variation of certain morphological features of the endometrium; e.g, the range of coefficient of inter-subject variation of the volume fraction of gland cell occupied by nucleus in the first half of the luteal phase was 4.1-10.7%, suggesting a tight biological control, and reflects the biological importance of the tissue studied (Dockery etai, 1988). EB has been criticized as an invasive procedure. The possible complications of EB are listed in Table IX. However, most investigators consider EB to be a safe procedure with a low

Table fX. Possible complications of endometrial biopsy Discomfort during the procedure** Delayed discomfort after the procedure** Perforation of the uterus* Pelvic infection* Endometrial biopsy taken in cycle of conception* Insufficient endometrial sample* **. common; *. rare.

complication rate (Burge and Morley, 1960; Hofmeister, 1974; Wild et al., 1986; Li and Cooke, 1990a). In addition, we have shown that the discomfort of out-patient EB could be reduced by avoiding the use of a vulsellum to hold the cervix during the procedure, putting the woman in the dorsal, rather than the lithotomy position and offering a simple analgesic as soon as the procedure is completed to reduce delayed abdominal discomfort (Li and Cooke, 1990b; Li etai, 1990a). Furthermore, it is possible that the use of a smaller plastic cannula could further reduce the discomfort associated with out-patient endometrial biopsy, although the quality and size of endometrial samples should also be an important consideration in the choice of instruments for EB. Those who favour the use of EB maintain that, functionally, the endometrium is directly involved in the process of implantation, which is the most important biological event occurring in the luteal phase and endocrinologically, the endometrium is the principal target organ to which P produced by the corpus luteum is directed. Endometrial morphology can therefore be used as an in-vivo bioassay of P, thus reflecting normal or defective function of the corpus luteum. Clinically, most cases with a retarded endometrium are associated with a normal level of P (Table VII) and so the reliance on P measurement for diagnosis will miss the majority of cases with an endometrial abnormality. Also, occasionally, EB may uncover other abnormalities such as endometrial polyp or hyperplasia. On balance, we tend to favour the use of EB to distinguish between normal and defective luteal phases provided that improved methods of dating are used (see Discussion). Other methods of diagnosis It is unlikely that the BBT chart could be used to assess whether the luteal phase is normal or defective. The reasons for this have been summarized by Jones (1976), namely a BBT chart does not reflect the levels of P produced, some patients may have a poor thermogenic response to P, giving the impression of a luteal phase defect that does not exist, and some patients are notoriously poor temperature-takers. In addition, McNeely and Soules (1988) commented that most women with luteal phase defect have an apparently normal BBT chart, which therefore cannot be used as the primary method of diagnosis. BBT may be used to assess the duration of the luteal phase, but its value is doubtful for two reasons. Firstly, several studies have challenged whether the day of ovulation can be reliably predicted from the BBT chart (Lenton et al., 1977; Hilger and Bailey, 1980; Templeton et al., 1982). Secondly, the clinical significance of the short luteal phase as a cause of infertility has been questioned by Smith et al. (1984) who found no difference in the prevalence of short luteal phases ( 2 days behind, or > 2 days behind, chronological dating Authors

Population studied (n)

When EB taken

Method of chronological dating

Definition of retarded endometrium

Number of cycle studied

Prevalence of luteal phase defect

Grant et al, 1959

(£2) Recurrent miscarriage (n = 175)

9

BBT

9

1

60%

Unspecified infertilty (n = 165)

9

BBT

9

1

20%

Jones and Pourmand, 1962

Unspecified infertility (n = 555)

Late luteal phase

NMP

> 2 days

2

Cooke et al., 1972

Unspecified infertility (n = 59)

Throughout luteal phase

NMP

> 2 days

1

27%

Rosenfeld and Garcia, 1976

Unspecified infertility (n = 95)

?

NMP

> 2 days

1

36%

Shepard and Sentuna, 1977

Unspecified infertility (n = 33)

Mid-luteal phase

BBT and NMP

> 2 days

1

36%

Driessen et al., 1980

Unspecified infertility (n = 176)

Throughout luteal phase

NMP

> 2 days

1

20.5%

> 2 days

1

14.8%

Unspecificed infertility (« = 149)

Late luteal phase

NMP

> 2 days

1

29.5%

2

1.9%

Mansuwan et al., 1981

Unspecified infertility (n = 1151)

Late luteal phase

NMP

> 2 days

1

12.4%

Shangold et al., 1983

Unspecificed infertility (n = 34)

Late luteal phase

NMP

>2 days

1

48%

Pittaway et al., 1983

Endometnosis (n = 68)

? Late luteal phase

?NMP

9

> 2 days

1

8.8%

Infertility without endometnosis (« = 75)

9

Late luteal phase

9

? > 2 days

1

5 3%

Zorn et al, 1984

Unspecified infertility {n = 121)

Mid- and late luteal phase

NMP

> 2 days

1

30%

Cumming et al.. 1975

Unexplained Infertility (n = 98)

Late Luteal phase

NMP

>2 days

1

44%

Witten and Martin. 1985

Unspecified infertility (n = 456)

NMP

>2 days

2

17%

Balasch and Vanrell. 1985

Endometriosis (" = 27)

NMP

> 2 days

2

18 5%

Wentz, 1980

492

Late

NMP

3.7%

Evaluation of the luteal phase

Table X. Continued Authors

Population studied («)

When EB taken

Method of chronological dating

Definition of retarded endometrium

Number of cycle studied

Prevalence of luteal phase defect

Huang, 1986

Unspecified infertility (n = 285)

Mid- and late luteal phase

NMP

> 2 days

1

65.3%

2

45.3%

Normal fertility (n = 25)

Late luteal phase

NMP

> 2 days

2

4%

Unspecified infertility (n = 355)

Late luteal phase

NMP

> 2 days

2

12.9%*

Recurrent (>2) miscarriage (n = 60)

Late luteal phase

NMP

> 2 days

2

31 7%**

Zhang el al., 1989

Endometnosis (n = 16)

Throughout luteal phase

LHS

> 2 days

1

61.5%

Li etal . 1991b

Normal fertility (n = 68)

Throughout luteal phase

LHS

> 2 days

1

4.4%

Unexplained infertility (n = 48)

Throughout luteal phase

LHS

> 2 days

1

2i%*»

Endometriosis (« = 21)

Throughout luteal phase

LHS

> 2 days

1

33%**

Tubal infertility (« = 34)

Throughout luteal phase

LHS

> 2 days

1

2.9%*

Male infertility (« = 39)

Throughout luteal phase

LHS

> 2 days

1

7.7%*

Balasch el al.. 1986a

BBT, basal body temperature; LHS, luteinizing hormone surge; NMP, onset of the next menstrual period, *, the prevalence was directly compared to a fertile population, but no significant difference was found, **, the prevalence was directly compared to a fertile population, and was significantly higher (P < 0.05) than the latter.

between luteal phase defect and hyperprolactinaemia (Balasch, 1987). Women with hyperprolactinaemia may of course be amenorrhoeic. As the function of the corpus luteum is under the control of the pituitary gland, it is possible that conditions associated with hypothalamo-pituitary dysfunction may also be associated with luteal phase defect, e.g. extremes of weight, extremes of reproductive life, strenuous exercise and stress (Wentz, 1979). However, data in support of these are lacking. Studies carried out in our department and by others have consistently demonstrated that the majority of cases with retarded endometrial development were associated with normal progesterone levels (see Table VII), suggesting that subnormal P production is not the commonest cause of luteal phase defect. The control of human corpus luteum function has been recently reviewed by Baird (1985) and Cooke (1988).

Abnormal response of the endometrium It is possible that the endometrium may fail to respond appropriately to stimulation by circulating progesterone (Cooke and Lambadarios, 1974). This may result from a deficiency in the number or function of P receptors. While the former has been established by Keller et al. (1979), the latter is more difficult to document and may be a consequence of increased levels of a physiological antagonist of P, such as oestrogen. Several studies have compared the cytosol concentrations of P receptor in endometrium with retarded morphology, to those found in endometrium with normal morphology. The results are conflicting. In some studies, the concentration of cytosol progesterone receptor was found to be lower in endometrium with retarded morphology (Laatikainen etal., 1983; Spirtos et al., 1985), but in others, it was found to be the same as (McRae 493

T.C.Li and I.D.Cooke

et al., 1984), or even higher than (Saracoglu et al., 1985) those with normal morphological development of the endometrium. Similarly, the concentration of the nuclear P receptor in the endometrium with retarded morphology has been found to be higher (Gravanis et al., 1984),or lower (Gautray et al., 1981), than in those with normal morphology. It is possible that these conflicting results are due to a lack of precision in the measurements of endometrial morphology, progesterone receptor, or both. The measurements related to endometrial dating have been discussed earlier. Problems related to the measurement of progesterone receptor have been addressed by Tsibris et al. (1981), who remarked that both corticosteroidbinding globulin and the endogenous P content had to be carefully considered during assay of the P receptor concentration in human endometrium. The difficulty of distinguishing progesterone binding to its receptor from binding to corticosteroid-binding globulin-like protein in the endometrium, which also has a high affinity for progesterone, and the possible techniques that may be used to overcome this difficulty, have been discussed by Milgrom (1978). In any case, it is of interest to note that the morphological features of endometrium of luteal phase defect in women with previously unexplained infertility (Li et al., 1990b) bear some similarity to the endometrium of normal, fertile subjects who were treated with a progesterone receptor antagonist (Li et al., 1988b).

Other causes In addition, luteal phase defect has been associated with the use of clomiphene citrate (for review see Birkenfeld et al., 1986), or gonadotrophins in association with gonadotrophin-releasing hormone agonist (Van Steirteghem et al., 1988) to induce ovulation, although Garcia et al. (1984) reported on the advancement of endometrial maturation after ovulation induction with human menopausal gonadotrophin and human chorionic gonadotrophin for IVF. Delayed ovulation has been reported to cause luteal phase defect (Balasch et al., 1986b). It is also possible that other ovulatory abnormalities such as luteinized unruptured follicle may be associated with defective luteal phase. The pathophysiology of luteal phase defect has been reviewed by Jones (1976), Wentz (1979), Balasch and Vanrell (1987) and McNeely and Soules (1988). The various conditions associated with luteal phase defect are listed in Table XI.

Luteal phase defect in artificial cycles In women with premature ovarian failure receiving a standard regime of hormone replacement therapy capable of supporting a pregnancy (Navot et al., 1986), we found that the endometrial response varied significantly between individuals. Preliminary data from our department (in preparation) suggest that the endometrial development of women whose premature ovarian failure is a result of Turner's Syndrome (XO) is retarded when compared to those whose premature ovarian failure is idiopathic. It is possible that the former group of subjects has some form of abnormal response or P receptor defect in the endometrium. 494

Table XI. Conditions associated with luteal phase defect See text for reference Probable

1. Unexplained infertility 2. Recurrent miscarriage 3. Treatment by clomiphene citrate

Possible/controversial

1. 2. 3. 4. 5. 6. 7. 8.

Endometriosis Follicle aspiration Hyperprolactinaemia Extremes of reproductive life Extremes of weight Ovulation induction by gonadotrophins Abnormal ovulation Short luteal phase?

Table XII. Possible treatments for luteal phase defect Methods

Investigators

Gonadotrophins

Huang etal , 1983, 1984 Daly et al., 1983

Clomiphene citrate

Downs and Gibson, 1983 Daly et al.. 1983 Witten and Martin, 1985 Balasch et al , 1985 Balasch et al., 1986a Huang, 1986 Murray et al., 1989

Cyclofenil

Sengupta, 1976

Progesterone, intramuscular

Soules et al., 1977

Progesterone, pessary

Jones and Pourmand, 1962 Soules et al., 1977 Rosenberg et al., 1980 Balasch el al., 1982b Daly et al., 1983 Wentz etal., 1984 Witten and Martin. 1985 Huang. 1986 Check and Adelson, 1987 Murray et al , 1989

Dydrogesterone (Duphaston)

Balasch era/., 1982b. 1983

Human chorionic gonadotrophin

Soules etal., 1977

Combined clomiphene and Progesterone

Daly et al., 1983 Wentz el al., 1984 Balasch et al.. 1986a

Combined clomiphene and human chorionic gonadotrophin

Nash, 1982

Treatment of luteal phase defect The various forms of treatment of luteal phase defect are listed in Table XII. In assessing the value of a particular treatment, one should remember that there is a lack of consensus in the diagnosis of luteal phase defect and that there is significant variation in the results of endometrial dating between cycles of

Evaluation of the luteal phase

the same subject (Li et al., 1989a). Some women with a luteal phase defect may become pregnant without treatment (Di Paola etai, 1971; Cooke etai, 1972; Driessen etai, 1980; Zorn et al., 1984; Balasch and Vanrell, 1987). In view of these factors, it is particularly important that any study on the treatment of luteal phase defect should be randomized and placebo-controlled. However, it is disapppointing that, among the various reports on the treatment of luteal phase defect summarized in Table XII, only one was randomized and controlled (Balasch et al., 1982b). In that study, 16 subjects with luteal phase defect received a P vaginal pessary, another 16 subjects with luteal phase defect received dydrogesterone (Duphaston), whereas 12 control subjects with luteal phase defect did not receive any treatment. The treatment was considered successful if pregnancy occurred or endometrial dating became normal during treatment. Of those who received a P vaginal pessary, 62.7% were successful; of those who received dydrogesterone, 68.7% were successful, the success rates in both groups being significantly higher than in the control group (16.6%). So far, none of the studies carried out on the treatment of luteal phase defect has been based on a randomized, double-blind, placebo-control design. In the prospective planning of any study on the method of treatment for luteal phase defect, there should be a number of considerations. Firstly, in view of the expected high proportion of placebo-response, large numbers of patients would be required to demonstrate a clinically significant difference between treatment and control groups. For example, if the placeboresponse rate is estimated to be - 2 0 % and the treatment response rate is estimated to be —50%, 36 patients would be required in each arm (alpha = 0.05, beta = 0.2; Pocock, 1983), i.e. 72 patients in the randomized trial, to demonstrate a significant difference. Assuming that the prevalence of luteal phase defect among an infertile population is 14% (Li et al., 1991b), the total number of infertile patients required in the study is 514. Secondly, the analysis of the pregnancy rate following treatment in an infertile population is often complicated by the fact that the subjects may sometimes have more than one underlying cause of their infertility, and may receive various other treatments during the study period. To obtain a more homogeneous group of subjects there will be a need to recruit an even larger number of patients. At present the value of any treatment for luteal phase defect should be considered unconfirmed, although many investigators believe that the treatment is of benefit (Soules et al., 1977; Rosenberg et al., 1980; Daly et al., 1983; Wentz et al., 1984). One may perhaps ask what treatment is most logical and worth further investigation? Although progesterone therapy may be the most widely used treatment, we believe that it is unlikely to help the majority of cases, for two reasons. Firstly, most cases with luteal phase defect are associated with normal levels of progesterone, suggesting that an abnormal endometrial response to P is the commonest cause of the defect. Secondly, we found that P treatment, given intramuscularly in high dose(s) did not advance the normally developing endometrium in either natural or artificial cycles (unpublished data). In contrast, the observation that the majority of cases with luteal phase defect are associated with an abnormal response of the endometrium to P indicates that the most logical treatment should be aimed at improving

(restoring) the responsiveness of the endometrium. This is likely to involve strategies capable of increasing either the number or function of P receptors in the endometrium. Is luteal phase defect a cause of infertility? To establish beyond doubt that luteal phase defect is a cause of infertility, the following requirements would have to be fulfilled: (a) luteal phase defect is associated with infertility; (b) the treatment of luteal phase defect successfully improves or restores fertility in previously infertile women, and (c) the induction of luteal phase defect in a previously fertile woman reduces her fertility. There is perhaps little doubt that luteal phase defect is associated with infertility. The infertile population has a significantly higher prevalence of luteal phase defect than the fertile, control population (Table X) and follow-up study suggests that women with luteal phase defect have reduced fertility compared to those without luteal phase defect (Klentzeris et al., 1990). As regards the treatment of luteal phase defect, there has been a randomized controlled study which demonstrated a significant improvement when the success of treatment was defined by either conception or normal endometrial dating during treatment (Balasch et al., 1982). However, the number of subjects in that study was too small to permit analysis based on conception alone. There has been no randomized, controlled study in the literature which addresses the question of whether or not treatment of luteal phase defect improves fertility. As for the induction of luteal phase defect in a previously fertile woman, preliminary data suggest that endometrial abnormalities not dissimilar to luteal phase defect may be induced by the administration of a progesterone receptor blocker (Li et al., 1988b) and that this is associated with reduced fertility (Lahteenmaki et al., 1988). On balance, the present evidence does suggest that the luteal phase defect is a cause of infertility. However, further work is required to establish beyond doubt the cause and the relationship. Summary In the evaluation of the luteal phase, the aims are to find out whether or not a luteal phase has been produced and whether or not the luteal phase is normal or defective. Although BBT and P are commonly used to evaluate the luteal phase, ultrasonographic measurement of endometrial thickness and EB each has its unique advantages and are likely to play an important role in the evaluation of the luteal phase. Further research is required to elucidate whether measurement of endometrial proteins has any advantage over existing methods. The precision of endometrial dating may be improved if chronological dating is based on the luteinizing hormone surge, rather than the onset of the next menstrual period, and histological dating is based on more objective, quantitative techniques. Similarly, the diagnostic value of P measurement may be improved if samples are timed by the luteinizing hormone surge, and serial samples, rather than a single sample, are collected in the luteal phase. Luteal phase defect is a controversial issue, mainly because of a lack of consensus in its diagnostic criteria. Luteal phase defect is more prevalent in women with infertility 495

T.C.Li and I.D.Cooke

(especially unexplained infertility and endometriosis) and recurrent miscarriages. It may also be associated with the various forms of ovulation induction therapy, follicle aspiration, hyperprolactinaemia, abnormal ovulation and possibly also extremes of weight. At least 50% of cases of luteal phase defect as defined by endometrial histology are associated with normal P, suggesting that a primary endometrial defect (end organ resistance) is a more common cause of luteal phase defect than subnormal production of P. The value of treatment of luteal phase defect has not been established. It is time that prospective, randomized, placebocontrolled studies were conducted to find out whether treatment of luteal phase defect is of benefit. Preliminary evidence suggests that P therapy is unlikely to be of use in the majority of cases with a luteal phase defect; strategies directed towards improving the number and function of P receptors in the endometrium may be more rewarding.

Acknowledgements The authors would like to thank the late Professor A.Rogers, Dr P.Dockery, Dr A.Hill, Dr E.A.Lenton, Dr A.Bolton, Dr S.Ramsewak, Dr L.Klentzeris and Dr L.Nuttall for their valuable help in some of the work mentioned in this review. We are also grateful to Mrs Gillian Burkinshaw and Mrs Marilyn Thorpe for typing the manuscript.

References Abraham,G.E., Maroulis,G.B. and Marshall,.!.R. (1974) Evaluation of ovulation and corpus luteum function using measurement of plasma progesterone. Obstet. Gynecol, 44, 522—525. Abdulla,U., Diver,M.J., Hipkin.L.J. and Davis,J.C. (1983) Plasma progesterone levels as an index of ovulation. Br. J. Obstet. Gynaecol., 90, 543-548. Andrews,W.C. (1979) Luteal phase defects. Fend. Steril., 32, 501-509. Annos,T., Thompson,I.E. and Taymor,M.L. (1980) Luteal phase deficiency and infertility: difficulties encountered in diagnosis and treatment. Obstet. Gynecol., 55, 705-710. Baird,D.T. (1985) Control of luteolysis. In Jeffcoate,S.L. (ed.), The Luteal Phase. John Wiley, Chichester, pp. 25-42. Balasch,J. and Vanrell.J.A. (1985) Mild endometriosis and luteal function. Int. J. Fertil., 30, 4—6. Balasch,J. and Vanrell.J.A. (1987) Corpus luteum insufficiency and fertility: a matter of controversy. Hum. Reprod., 2, 557-567. Balasch,J., Vanrell,J.A., Marquez.M., Rivera,F. and Gonzalez-Merlo,J. (1982a) Luteal phase in infertility: Problems of evaluation. Int. J. Fertil., 27, 60-62. Balasch.J., Vanrell.J.A., Marquez.M., Burzaco.I. and GonzalezMerlo.J. (1982b) Dydrogesterone versus vaginal progesterone in the treatment of the endometrial luteal phase deficiency. Fertil. Steril., 37, 751-754. Balasch.J., Vanrell.J.A., Marquez,M. and Gonzalez-Merlo.J. (1983) Dydrogesterone treatment of endometrial luteal phase deficiency after ovulation induced by clomiphene citrate and human chorionic gonadotropin. Fertil. Steril., 40, 469—471. Balasch,J., Vanrell.J., Creus.M., Marquez.M. and Gonzalez-Merlo.J. (1985) The endometrial biopsy for diagnosis of luteal phase deficiency. Fertil. Steril., 44, 699-701. Balasch,J., Creus.M., Marquez,M.. Burzaco.I. and Vanrell,J.A. (1986a) The significance of luteal phase deficiency on fertility: a diagnostic and therapeutic approach. Hum. Reprod., 1, 145-147. Balasch.J., Creus.M. and Vanrell.J.A. (1986b) Luteal function after delayed ovulation. Fertil. Steril., 45. 342-344. 496

Birkenfeld.A., Beier.H.M. and Schenker.J.G. (1986) The effect of clomiphene citrate on early embryonic development, endometrium and implantation. Hum. Reprod., 1, 387—395. Bolton.A.E., Pockley.A.G.. Clough.K.J., Mowles.E.A., Stoker,R.J., Westwood.O.M.R. and Chapman.M.G. (1987) Identification of placenta! protein 14 as an immunosuppressive factor in human reproduction. Lancet, i, 593-595. Burge.E.S. and Morley.B. (1960) Endometrial biopsies in the office; report of 400 cases. Am. J. Obstet. Gynecol., 80, 325-331. Chearskul.S., Ricon-Rodriquez.I., Sufi.S.B., Donaldson,A. and Jeffcoate.S.L. (1982) Simple direct assays for measuring oestradiol and progesterone in saliva. In Radioimmunoassay and Related Procedures. International Atomic Energy Authority, Vienna, pp. 265-274. CheckJ.H. and Adelson.H.G. (1987) The efficacy of progesterone in achieving successful pregnancy: II. In women with pure luteal phase defects. Int. J. Fertil., 32, 139-141. Choe,J.K., Khan-Dawood.F.S. and Dawood.M.Y. (1983) Progesterone and estradiol in the saliva and plasma during the menstrual cycle. Am. J. Obstet. Gynecol., 1476, 557-562. Cook.C.L., Rao.Ch.V. and Yussman.M.A. (1983) Plasma gonadotrophin and sex steroid hormone levels during early, mid follicular and mid luteal phases of women with luteal phase defects. Fertil. Steril., 40, 45-48. Cooke,I.D. (1988) The corpus luteum. Hum. Reprod., 3, 153-156. Cooke.I.D. and Lambadarios,C. (1974) The endometrium in the management of infertility. In Cooke,I.D. (ed.), Clinics in Obstetrics and Gynaecology. W.B. Saunders, i, pp. 369 — 393. Cooke.I.D., Morgan.C.A.and Parry.T.E. (1972) Correlation of endometrial biopsy and plasma progesterone levels in infertile women. J. Obstet. Gynaecol. Br. Commonw., 76, 647-650. Crosignani.P.G. (1988) The defective luteal phase. Hum. Reprod., 3, 157-160. Csapo.A.I. and Pulkkinen.M. (1978) Indispensability of the human corpus luteum in the maintenance of early pregnancy: lutectomy evidence. Obstet. Gynecol. Surv., 3, 69—81. Cumming.D.C, Honore.L.H., Scott.J.Z. and Williams.K.P. (1985) The late luteal phase in infertile women: Comparison of simultaneous endometrial biopsy and progesterone levels. Fertil. Steril., 43, 715-719. Daly.D.C. (1983) The endometrium and the luteal phase defect. In Speroff.L. (ed.), Seminars in Reproductive Endocrinology. Vol. 1, Thieme Medical Publishers, New York, pp. 237-247. Daly.D.C., Walters,C.A., Soto-Albors,C.E. and Riddick,D.H. (1983) Endometrial biopsy during treatment of luteal phase defects is predictive of therapeutic outcome. Fertil. Steril., 40, 305—310. Davies.O.K., Berkeley,A.S., Naus.G.J., Cholst,I.N. and Freedman.K.S. (1989) The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsies. Fertil. Steril., 51. 582-586. Daya.S. (1989) Optimal time in the menstrual cycle for serum progesterone measurement to diagnose luteal phase defects. Am. J Obstet. Gynecol., 161, 1009-1011. Daya,S. and Ward.S. (1988) Diagnostic test properties of serum progesterone in the evaluation of luteal phase defects. Fertil. Steril., 49. 168-170. Devroey.P.. Palermo,G., Bourgain.C, Van-Waesberghe.L., Smitz.J. and Van-Steirteghem.A.C. (1989) Progesterone administration in patients with absent ovaries. Int. J. Fertil., 34. 188-193. DiPaola.G.R.. Mendez Ribas.J.M. and Arrighi.L.A. (1971) Critical study of the retarded progestational phase. Int. J. Gvnecol. Obstet., 16. 189-194. Dockery.P., Li.T.C, Rogers,A.W., Cooke.I.D.. Lenton.E.A. and Warren.M.A. (1988) An examination of the variation in timed endometrial biopsies. Hum. Reprod., 3. 715-720.

Evaluation of the luteal phase Dockery,P., Warren,M.A., Li.T.C, Rogers,A.W., CookeJ.D. and Mundy.J. (1990) A morphometric study of the human endometrial stroma during the peri-implantation period. Hum. Reprod., 5, 494-498. Dodson,K.S., Macnaughton,M.C. and Coutts.J.R.T. (1975) Infertility in women with apparently ovulatory cycles. I. Comparison of their plasma sex steroid and gonadotrophin profiles with those in normal cycle. Br. J. Obstet. Gynaecoi, 82, 615-624. Downs,K.A. and Gibson.M. (1983) Clomiphene citrate therapy for luteal phase defect. Fertil. Sterii, 39, 34-38. Driessen.F., Holwerda,P.J., van den Putte,S.C.J. and Kremer,J. (1980a) The significance of dating an endometrial biopsy for the prognosis of the infertile couple. Int. J. Fertil., 25, 112-116. Driessen,F., Kremer,J., Alsbach.G.P.J. and Dekroon,R.A. (1980b) Serum progesterone and oestradiol concentrations in women with unexplained infertility. Br. J. Obstet. Gynaecoi., 87, 619—623. El Mahgoub,S. (1978) Galactorrhoea and the defective luteal phase of the menstrual cycle. Int. J. Gynecol. Obstet., 16, 124-128. Feichtinger.W., Kemeter.P., Szalay.S., Beck,A. and Janisch.H. (1982) Could aspiration of the Graafian collide cause luteal phase deficiency? Fertil. Sterii., 37, 205-208. Frydman,R., Testart,J., Giacomini,P., Imbert,M.C. Martin,E. and Nahoul,K. (1982) Hormonal and histological study of the luteal phase in women following aspiration of the preovulatory follicle. Fertil. Sterii., 38, 312-317. Garcia.J., Jones,G.S., Acosta,A.A. and Wright,G.L. (1981) Corpus luteum function after follicle aspiration for oocyte retrieval. Fertil. Sterii., 36, 565-572. Garcia,J.E., Acosta.A.A., Hsiu,J.-G. and Jones,H.W. (1984) Advanced endometrial maturation after ovulation induction with human menopausal gonadotropin/human chorionic gonadotropin for in vitro fertilization. Fertil. Sterii., 41, 31-35. Garcia,E., Bouchard,P., DeBrux,J., Berdah,J., Frydman,R., Schaison.G., Nilgrom.E. and Perrot-Applanat,M. (1988) Use of immunocytochemistry of progesterone and estrogen receptors for endometrial dating. J. Clin. Endocrinol. Metab., 67, 80-87. Gautray,J.P., DeBrux,J., Tajchner.G., Robel.P. and Mouren.M. (1981) Clinical investigations of the menstrua] cycle. III. Clinical, endometrial and endocrine aspects of luteal defect. Fertil. Sterii., 35, 296—303. Gillam,J.S. (1955) Study of the inadequate secretion phase endometrium. Fertil. Sterii., 6, 18-36. Glazener.C.M.A., Kelly.N.J. and Hull,M.G.R. (1988) Luteal deficiency not a persistent cause of infertility. Hum. Reprod., 2, 213—217. Grant,A. (1966) Additional sterility factors in endometriosis. Fertil. Sterii., 17, 514-519. Grant,A., McBride,W.G. and Moyes,J.M. (1959) Luteal phase defects in abortion. Int. J. Fertil., 4, 323-329. Gravanis,A., Zorn,J.-R., Tanguy.G., Nessmann.C, Cedard.L. and Robel,P. (1984) The 'dysharmonic luteal phase' syndrome: endometrial progesterone receptor and estradiol dehydrogenase. Fertil. Sterii., 42, 730-736. Grunfeld,L., Sandler,B., Fox.J., Boyd,C, Kaplan.P. and Navot.D. (1989) Luteal phase deficiency after completely normal follicular and periovulatory phases. Fertil. Sterii., 52, 919—923. Haciski,R., Maroulis,G.B., Blake,R., Hatch,R. and Holt,J. (1983) Inadequate luteal phase: decreased endometrial response to progesterone? Fertil. Sterii. (Abstr.), 39, 392. Hague,W.E., Maier,D.B., Schmidt,C.L. and Randolph.J.F. (1987) An evaluation of late luteal phase endometrium in women requesting reversal of tubal ligation. Obstet. Gynecol., 69, 926-928. Hensleigh,P.A. and Fainstat.T. (1979) Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion. Fertil. Sterii., 32, 396-400. Hilger,T.W. and Bailey,A.J. (1980) Basal body temperature and estimated time of ovulation. Obstet. Gynecol., 55, 333 — 339.

Hillier.S.G. and Wickings,E.J. (1985) Cellular aspects of corpus luteum function. In Jeffcoate.S.L. (ed.), The Luteal Phase. John Wiley & Sons Ltd., Chichester, pp. 1-23. Hofmeister.F.J. (1974) Endometrial biopsy: another look. Am. J. Obstet. Gynecol., 118, 773-777. Huang,K.-E. (1986) The primary treatment of luteal phase inadequacy: progesterone versus clomiphene citrate. Am. J. Obstet. Gynecol., 155, 824-828. Huang,K.-E.. Muechler.E.K. and Bonfiglio,T.A. (1983) Experience on treatment of luteal phase defect with pure FSH in infertile women. Fertil. Sterii., (Abstr.), 39, 393. Huang,K.E., Muechler,E.K. and Bonfiglio.T.A. (1984) Follicular phase treatment of luteal phase defect with follicle-stimulating hormone in infertile women. Obstet. Gynecol., 64, 32—36. Hull,M.G.R., Savage,P.E., Bromham.D.R., Isamail.A.A.A. and Morris, A.F. (1982) The value of a single progesterone measurement in the mid-luteal phase as a criterion of a potentially fertile cycle ('ovulation') derived from treated and untreated conception cycles. Fertil. Sterii., 37, 355-360. Israel,R., Mishell,D.R., Jr, Stone,S.C, Thorneycroft,I.H. and Moyer,D.L. (1972) Single luteal phase serum progesterone assay as an indicator of ovulation. Am. J. Obstet. Gynecol., 112, 1043-1046. Johannisson,E., Parker,R.A., Landgren.B.-M. and Diczfalusy.E. (1982) Morphometric analysis of the human endometrium in relation to peripheral hormone levels. Fertil. Sterii., 38, 564—571. Johannisson,E., Landgren,B.-M., Rohr,H.P. and Diczfalusy.E. (1987) Endometrial morphology and peripheral hormone levels in women with regular menstrual cycles. Fertil. Sterii., 48, 401—408. Jones,G.E.S. (1949) Some newer aspects of the management of infertility. J. Am. Med. Assoc, 1123-1129. Jones,G.S. (1976) The luteal phase defect. Fertil. Sterii., 27, 351-356. Jones,G.S. and Pourmand,K. (1962) An evaluation of etiologic factors and therapy in 555 private patients with primary infertility. Fertil. Sterii., 13, 398-410. Jones,G.S. and Madrigal-Castro,V. (1970) Hormonal findings in association with abnormal corpus luteum function in the human: the luteal phase defect. Fertil. Sterii., 21, 12-13. Joshi,S.G., Rao,R., Henriques,E.E., Raikar,R.S. andGordon.M. (1986) Luteal phase concentrations of a progestagen-associated endometrial protein (PEP) in the serum of cycling women with adequate or inadequate endometrium. J. Clin. Endocrinol. Metab., 63, 1247-1249. Julkunen,M., Apter.D., Seppala,M., Stenman,U.-H. and Bohn,H. (1986) Serum levels of placental protein 14 reflect ovulation in nonconceptional menstrual cycles. Fertil. Sterii., 45, 47-50. Julkunen,M., Seppala.M. and Janne.O.A. (1988) Complete amino acid sequence of human placental protein 14: a progesterone regulated uterine protein homologs to beta-lactoglobulins. Proc. Natl. Acad. Sci. USA, 85, 8845-8849. Keller,D.W., Wiest,W.G., Askin.F.B., Johnson,L.W. and Stickler,R.C. (1979) Pseudo-corpus luteum insufficiency: a local defect of progesterone action on endometrial stroma. J. Clin. Endocrinol. Metab., 48, 127-132. Kemeter,P., Feichtinger,W., Neumark.J., Szalay.S., Bieglmayer,Ch. and Janisch,H. (1982) Influence of laparoscopic follicular aspiration under general anaesthesia on corpus luteum progesterone secretion in normal and clomiphene-stimulated cycles. Br. J. Obstet. Gynaecoi., 89, 948-950. Kerin,J.F., Broom.T.J., Ralph,M.M., Edmonds,D.K., Wames,G.M., Jeffrey.R., Crocker,J.M., Godfrey.B., Cox.L.W., Seamark.R.F. and Matthews,CD. (1981) Human luteal phase function following oocyte aspiration from the immediately preovular Graafian follicle of spontaneous ovular cycles. Br. J. Obstet. Gynaecoi., 88, 1021 - 1028. Klentzeris.L.. Li,T.C, Dockery,P. and Cooke,I.D. (1990) Endometrial morphology: A predictive factor of pregnancy rate in infertile women.

497

T.C.Li and I.D.Cooke Abstract presented at the European Society of Human Reproduction and Embryology, August 29 to September 1, 1990, Italy. Kreitmann,O., Nixon,W.E. and Hodgen,G.D. (1981) Induced corpus luteum dysfunction after aspiration of the preovulatory follicle in monkeys. Fertil. Steril., 35, 671-675. Laatikainen,T., Anderson,B., Karkkainen,J. and Wahlstrom,T. (1983) Progestin receptor levels in endometna with delayed or incomplete secretory changes. Obstet. GynecoL, 62, 592-595. Lahteenmaki.P., Rapeli,T., Kaariainen,M., Alfthan.H. and Ylikorkala, O. (1988) Late postcoital treatment against pregnancy with antiprogesterone RU486. Fertil. Steril., 50, 36-38. Langley.F.A., BaakJ.P.A and Oort,J. (1983) Diagnosis making: Error sources. In Baak,J. P. A. and Oort.J. (eds), A Manual ofMorphometry in Diagnostic Pathology. Springer-Verlag, Berlin, pp. 6 — 14. Lee,C.S. (1987) Luteal phase defects. Obstet. Gynecol. Surv., 42, 267-274. Lenton.E.A., Weston.G.A. and Cooke.I.D. (1977) Problems in the use of basal body temperature recordings in an infertility clinic. Br. Med. J., 1, 803-805. Lenton,E.A., Lawrence.G.F., Coleman,R.A. and Cooke,I.D. (1983) Individual variation in gonadotrophin and steroid concentrations and in lengths of follicular and luteal phases in women with regular menstrual cycles. Clin. Reprod. Fertil., 2, 143-150. Lenton,E.A., Landgren,B.-M. and Sexton,L. (1984) Normal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase. Br. J. Obstet. Gynaecol., 91, 685-689. Li,T.C. and Cooke,I.D. (1990a) Outpatient endometrial biopsy: clinical, endocrinologic and histologic consequences. Int. J. Gynecol. Obstet., 31, 3 5 - 4 1 . Li,T.C. and Cooke,I,D. (1990b) Delayed abdominal pain after outpatient endometrial biopsy in the luteal phase. Int. J. Gynecol. Obstet., 32, 267-268. Li,T.C, Rogers,A.W., Lenton,E.A., Dockery,P. and Cooke.I.D. (1987) A comparison between two methods of chronological dating of human endometrial biopsies during the luteal phase and their correlation with histologic dating. Fertil. Steril, 48, 928-932. Li.T.C, Rogers,A.W., Dockery.P., Lenton.E.A. and Cooke,I.D. (1988a) A new method of histologic dating of human endometnum in the luteal phase. Fertil. Steril., 50, 52-60. Li,T.C, Dockery,P., Thomas,P., Rogers,A.W., Lenton.E.A. and Cooke.I.D. (1988b) The effects of progesterone receptor blockade in the luteal phase of normal fertile women. Fertil. Steril., 50, 732-742. Li.T.C, Dockery,P., Rogers,A.W. and Cooke.I.D. (1989a) How precise is histologic dating of endometrium using the standard dating criteria? Fertil. Steril., 51, 759-763. Li.T.C., Lenton.E.A., Dockery.P., Rogers.A.W. and Cooke.I.D. (1989b) The relation between daily salivary progesterone profile and endometrial development in the luteal phase of fertile and infertile women. Br. J. Obstet. Gynaecol., 96. 445-453. Li.T.C., King.H. and Cooke.I.D. (1990a) The discomfort of outpatient endometrial biopsy in relation to parity and techniques. J. Obstet. Gynecol., 10, 243-247. Li,T.C, Dockery,P., Rogers.A.W. and Cooke.I.D. (1990b) A quantitative study of endometrial development in the luteal phase: comparison between women with unexplained infertility and normal fertility. Br. J. Obstet. Gynaecol., 97, 576-582. Li.T.C., Lenton.E.A., Dockery,P. and Cooke,I.D. (1990c) A comparison of some clinical and endocrinological features between normal and defective luteal phases in women with unexplained infertility. Hum. Reprod., 5, 805-810. Li.T.C., Pockley.G.. Bolton.A.E. and Cooke,I.D. (1991a) The variation of endometrial protein PP14 in different parts of the human endometrium. Int. J. Gynecol. Obstet., 34. 257-260. Li.T.C, Dockery,P. and Cooke.I.D. (1991b) Endometrial development

498

in the luteal phase of women with various types of infertility: comparison with women of normal fertility. Hum. Reprod., 6, 325-330. Li,T.C, Warren,M.A., Dockery,P. and Cooke,I.D. (1991c) Endometrial morphology around the time of implantation in natural and artificial cycles. J. Reprod. Fertil., in press. Luisi.M., Franchi.F., Kicovic.P.M., Barletta.D. and Buver.V. (1982) Variation of salivary progesterone throughout the menstrual cycle. In: Read.G.F., Riad-Fahmy.D., Walker.R.F.and Griffiths.K. (eds), Immunoassays of the Steroids in Saliva. Alpha Omega Publishing Ltd, Cardiff, pp. 101-114. Lundy,L.E., Lee.S.G., Levy,W., Woodruff,J.D., Wu.C.H. and Abdalla.M. (1974) The ovulatory cycle: a histologic, thermal, steroid and gonadotrophin correlation. Obstet. Gynecol., 44, 14—25. McNatty,K.P., Sawers,R.S. and McNeilly.A.S. (1974) A possible role for prolactin in the steroid secretion by human Graafian follicles. Nature, 250, 635-655. McNeely,M.J. and Soules.M.R. (1988) The diagnosis of luteal phase deficiency: a critical review. Fertil. Steril., 50. 1 — 15. McRae.M.A., Blasco.L. and Lyttle.C.R. (1984) Serum hormones and their receptors in women with normal and inadequate corpus luteum function. Fertil. Steril., 42, 5 8 - 6 3 . Mansuwan.K., Chongwatana.V., Egkarntrong.P., Boonvisut.S. and Apichaisiri.P. (1982) Five years experiences with endometrial biopsy in infertile patients. Asia-Oceania J. Obstet. Gynecol, 8, 155 — 158. Milgrom,E. (1978) Progesterone-binding proteins in plasma and the reproductive tract. In O'Malley,B.W. and Birnbaumer.L. (eds), Receptor and Hormone Action, Vol. II. Academic Press, New York, pp. 474-490. Misrahi.M., Atger.M. and Milgrom.E. (1987) A novel progesteroneinduced messenger RNA in rabbit and human endometria. Cloning and sequence analysis of the complementary DNA. Biochemistry, 26, 3975-3982. Murray,D.L., Reich.L. and Adashi,E.Y. (1989) Oral clomiphene citrate and vaginal progesterone suppositories in the treatment of luteal phase dysfunction: a comparative study. Fertil. Steril., 51, 35—41. Murthy,Y.S., Arronet.G.H. and Parekh.M.C. (1970) Luteal phase inadequacy: its significance in infertility. Obstet. Gynecol., 36. 758-761. Nadji,P., Reyniak,J.V., Sedlis.A., Szariowski.D.H. and Bartosik.D (1975) Endometrial dating correlated with progesterone levels. Obstet. Gynaecol., 45, 193-194. Nash.L.D. (1982) The treatment of luteal phase dysfunction with clomiphene and human chorionic gonadotropin (HCG). Infertility, 5, 87-104. Navot.D.. Laufer.N.. Kopolovic.J., Rabinowitz,R., Birkenfeld.A., Lewin.A., Granat.M., Margalioth,E.J. and Schenker.J.G. (1986) Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. New Engl. J. Med., 314. 806-811. Navot,D., Anderson.T.L., Droesch,K., Scott,R.T , Kreiner.D. and Rosenwaks.Z. (1989) Hormonal manipulation of endometrial maturation. J. Clin. Endocrinol. Metab., 68. 801-807. Noci.L, Dubmi.V., Piacentini.R.. Colafraceschi.M.. Taddei.G. and Scarselli.G. (1988) Correlation between endometrial biopsy and luteal phase plasma progesterone in women complaining of couple infertility. J. Endocrinol. Invest., 11, 361—363. Noyes.R.W. (1959) The underdeveloped secretory endometrium. Am. J. Obstet. Gynecol.,11. 929-943. Noyes.R.W., Hertig.A.T. and Rock,J. (1950) Dating the endometrial biopsy. Fertil. Steril., 1, 3 — 25. Olive.D.L., Thomford.P.J.. Torres.S.E., Lambert.T.S. and Rosen.G.F. (1989) Twenty-four-hour progesterone and luteinizing hormone profiles in the midluteal phase of the infertile patient: correlation with

Evaluation of the luteal phase other indicators of luteal phase insufficiency. Fertil. Sterii, 51, 587-592. Oskowitz.S., Seibel,M., Smith,D. and Taymor,M.L. (1986) Luteal phase serum progesterone levels after follicle aspiration with and without clomiphene citrate treatment. Fertil. Sterii., 46, 461 -465. Pittaway.D.E., Maxson,W., Daniell.J., Herbert,C. and Wentz,A.C. (1983) Luteal phase defects in infertility patients with endometriosis. Fertil. Sterii., 39, 712-713. Pockley,A.G., Mowles.E.A., Stoker,R.J., Westwood,O.M.R., Chapman,M.G. and Bolton,A.E. (1988) Suppression of in vitro lymphocyte reactivity to phytohemagglutinin by placental protein 14. J. Rep. Immunol., 13, 31-39. Pocock.S.J. (1983) Clinical Trials: A Practical Approach. John Wiley and Sons. Chichester, pp. 229-230. del Pozo,E., Wyss,M., Tolis,G., Alcaniz,J., Campana.A. and Naftolin,F. (1979) Prolactin and deficient luteal function. Obstet. Gynecoi, 53, 282-286. Rabinowitz.R., Laufer.N., Lewin.A., Navot,D., Bar,L, Margalioth,E.J. and Schenker,J.J.G. (1986) The value of ultrasonographic endometrial measurement in the prediction of pregnancy following in vitro fertilization. Fertil. Sterii., 45, 824-828. Radwanska.E., McGarrigle.H.M.G. and Swyer,G.I.M. (1976) Plasma progesterone and oestradiol estimation in the diagnosis and treatment of luteal insufficiency in menstruating infertile women. Acta Europ. Fertil., 7, 39-47. Randall,J.M., Fisk,N.M, McTavish,A. and Templeton.A.A. (1989) Transvaginal ultrasonic assessment of endometrial growth in spontaneous and hyperstimulated menstrual cycles. Br. J. Obstet. Gynaecoi, 96, 954-959. Rosenberg,S.M., Luciano,A.A. and Riddick.D.H. (1980) The luteal phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone. Fertil. Sterii., 34, 17-20. Rosenfeld,D.L. and Garcia,C.R. (1976) A comparison of endometrial histology with simultaneous plasma progesterone determinations in infertile women. Fertil. Sterii, 27, 1256-1266. Rosenfeld.D.L., Chudow,S. and Bronson.R.A. (1980) Diagnosis of luteal phase inadequacy. Obstet. Gynecoi., 56, 193 — 196. Saracoglu.O.F., Aksel.S., Yeoman,R.R. and Wiebe,R.H. (1985) Endometrial estradiol and progesterone receptors in patients with luteal phase defects and endometriosis. Fertil. Sterii, 43, 851-855. Sengupta,B.S. (1976) Defective luteal phase—measurement and evaluation of the ovarian hormone before and during cyclofenil (Bisp-acetoxphenyl) cyclo-hexylidenemethane (compound 6066) treatment. W. Ind. Med. J., 25, 107-120. Shangold,M., Berkeley.A. and Gray.J. (1983) Both midluteal serum progesterone levels and late luteal endometrial histology should be assessed in all infertile women. Fertil. Sterii., 40, 627—630. Shepard.M.K. and Senturia,Y.D. (1977) Comparison of serum progesterone and endometrial biopsy for confirmation of ovulation and evaluation of luteal function. Fertil. Sterii., 28, 541-548. Shoupe,D., Mishell,D.R.Jr, Lacarra,M., Lobo,R.A., Horenstein,J., d'Ablaing,G. and Moyer.D. (1989) Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet. Gynecoi., 73, 88-92. Smith,S.K., Lenton,E.A., Landgren,B.-M. and Cooke,I.D. (1984) The short luteal phase and infertility. Br. J. Obstet. Gynaecoi., 91, 1120-1122. Soules,M.R., Wiebe.R.H., Aksel,S. and Hammond,C.B. (1977) The diagnosis and therapy of luteal phase deficiency. Fertil Sterii., 28, 1033-1037. Spirtos.N.J., Yurewicz,E.C, Moghissi,K.S., Magyar,D.M., Sundareson,A.S. and Bottoms,S.F. (1985) Pseudocorpus luteum insufficiency: A study of cytosol progesterone receptors in human endometrium. Obstet. Gynecoi., 65, 535-540. Steele,P.A., White.G.H. and Judd,S.J. (1985) Reliability of a single

serum progesterone determination as an indicator of ovulation. Clin. Reprod. Fertil., 3, 125-130. Van Steirteghem,A.C, Smitz.J., Camus,M., Van Waesberghe,L., Deschacht.J., Khan,I., Staessen.C, Wisanto.A., Bourgain,C. and Devroey.P. (1988) The luteal phase after in-vitro fertilization and related procedures. Hum. Reprod., 3, 161-164. Taubert,H.D. (1978) Luteal phase insufficiency. Contrib. Gynecoi. Obstet., 4, 78-113. Templeton.A.A., Penney,G.C. and Lees,M.M. (1982) Relation between the luteinizing hormone peak, the nadir of the basal body temperature and the cervical mucus score. Br. J. Obstet. Gynaecoi., 89, 985—988. Tsibris,J.C.M., Fort,F.L., Cazenave.C.R., Cantor.B., Bardawil,W.A., Notelovitz,M. and Spellacy,W.N. (1981) The uneven distribution of estrogen and progesterone receptors in human endometrium. J. Steroid Biochem., 14, 997-1003. Walker,S., Mustafa.A., Walker.R.F. and Riad-Fahmy,D. (1981) The role of salivary progesterone in studies of infertile women. Br. J. Obstet. Gynaecoi, 88, 1009-1015. Wathen,N.C, Perry,L., Lilford.R.J. and Chard,T. (1984) Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. Br. Med. J., 228, 7 - 9 . Wentz,A.C. (1979) Physiologic and clinical considerations in luteal phase defects. Clin. Obstet. Gynecoi, 22, 169-185. Wentz,A.C. (1980) Endometrial biopsy in the evaluation of infertility. Fertil. Sterii, 33, 121-124. Wentz.A.C. (1982) Editorial: Diagnosing luteal phase inadequacy. Fertil. Sterii, 37, 334-335. Wentz,A.C, Herbert.C.M., Maxson,W.S. and Garner.C.H. (1984) Outcome of progesterone treatment of luteal phase inadequacy. Fertil. Sterii, 41, 856-862. Wild,R.A., Sanfilippo,J.S. and Toledo,A.A. (1986) Endometrial biopsy in the infertility investigation. The experience at two institutions. J. Reprod. Med., 31, 954-957. Witten,B.I. and Martin,S. A. (1985) The endometrial biopsy as a guide to the management of luteal phase defect. Fertil. Sterii., 44, 460—465. Wood.P.L., Walker,R.A. and Bell.S.C. (1989) Serum levels of pregnancy-associated endometrial alpha 2-globulin (alpha-2-PEG) during normal menstrual and combined oral contraceptive cycles and relationship to immunohistological localization. Hum. Reprod., 4, 140-146. World Health Organisation (1984) Simplified management of the infertile couple (Draft). Study 84914. Geneva, World Health Organization. diZerega.G.S. and Hodgen,G.D. (1981) Luteal phase dysfunction in infertility: a sequel to aberrant folliculogenesis. Fertil. Sterii, 35, 489-499. Zhang,Y., Ji,H., Han.M., Tang,M., Sun,A. and Zhang,D. (1989) Luteal function in patients with endometriosis. Proc. Chin. Acad. Med. Sci. Peking-Union Med. Coll., 4, 96-101. Zorn,J.R., Cedard.L., Nessman,C. and Sevale.M. (1984) Delayed endometrial maturation in women with normal progesterone levels. The dysharmonic luteal phase syndrome. Gynecoi. Obstet. Invest., 17, 157-162. Received on August 15, 1990; accepted on January 14, 1991

499