Luteal phase deficiency: What we now know
Disagreement about the cause, true incidence, and diagnostic criteria of this condition makes evaluation and management difficult. Here, 2 physicians dissect the data and offer an algorithm of assessment and treatment.
- Luteal phase deficiency (LPD), defined as endometrial histology inconsistent with the chronological date of the menstrual cycle, may be caused by deficient progesterone secretion from the corpus luteum or failure of the endometrium to respond appropriately to ovarian steroids.
- Wide variation in the reported incidence of LPD—3.7% to 20% in infertile women—reflects lack of agreement about its diagnostic criteria.
- Histologic dating of an endometrial sample is the gold standard for evaluation of the corpus luteum.
- Two main treatment strategies have been suggested: improving follicular dynamics using follicle-maturing drugs such as clomiphene, and use of supplemental progesterone during the luteal phase and first trimester of pregnancy.
Despite scanty and controversial supporting evidence, evaluation of patients with infertility or recurrent pregnancy loss for possible luteal phase deficiency (LPD) is firmly established in clinical practice. In this article, we examine the data and offer our perspective on the role of LPD in assessing and managing couples with reproductive disorders (FIGURE 1).
FIGURE 1 Diagnosis and treatment of luteal phase deficiency
Many areas of controversy
Although observational and retrospective studies have reported a higher incidence of LPD in women with infertility and recurrent pregnancy losses than in fertile controls,1-4 no prospective study has confirmed these findings. Furthermore, studies have failed to confirm the superiority of any particular therapy.
Once considered an important cause of infertility, LPD has become the subject of debate, with some experts questioning its very existence. Unclear terminology describing this disorder is part of the problem, making it difficult to definitively diagnose the deficiency or determine its incidence. Further, while reasonable consensus exists that endometrial biopsy is the most reliable diagnostic tool, concerns remain about its timing, repetition, and interpretation.
A defect of corpus luteum progesterone output?
LPD is defined as endometrial histology inconsistent with the chronological date of the menstrual cycle, based on the woman’s next menses. It was first described by Jones in 1949.5 One year later, Noyes et al6 published criteria on endometrial dating that became the gold standard for LPD diagnosis.
Pathophysiology. LPD may be caused by deficient progesterone secretion from the corpus luteum or failure of the endometrium to respond appropriately to ovarian steroids (TABLE). Most experts believe LPD is a defect of corpus luteum progesterone output—both in amount and duration—resulting in inadequate stimulation of the endometrium for implantation of the blastocyst (FIGURE 2).5 Thus, the endometrial histologic pattern is an important bioassay of the corpus luteum steroidogenic function.
Normal embryonic implantation depends on a properly functioning luteal phase, which, in turn, requires optimal secretion of follicle-stimulating hormone (FSH) and adequate follicular development during the follicular phase. Other requirements are a satisfactory luteinizing hormone (LH) surge during ovulation and continuous tonic LH pulses during the luteal phase of the cycle.
LH secretion from the pituitary occurs in a pulsatile fashion,7 which is essential for corpus luteum function.8 During the follicular phase the pulse frequency is high, occurring at a rate of approximately 1 pulse per 90 minutes. However, during the luteal phase and under the influence of progesterone, the pulse frequency is significantly diminished, occurring approximately every 3 to 6 hours, depending on the age of the corpus luteum.7,9 The corpus luteum is unresponsive to LH pulses during the early luteal phase; sensitivity develops about 4 to 6 days after ovulation.7,9
The luteal phase thus involves creation of an optimal hormonal environment as well as adequate endometrial transformation. Alteration of any of the factors that contribute to a normally functioning corpus luteum may thus deleteriously affect the endometrium and embryonic implantation.
Epidemiology. The reported prevalence of LPD ranges from 3.7% to 20% among patients with infertility.10,11 When an out-of-phase endometrium is the diagnostic criterion, prevalence estimates range from 3.5% to 31%.12,13 A short luteal phase is thought to occur in 5% of ovulatory cycles.14Some reports suggest that LPD accounts for 25% to 40% of recurrent pregnancy losses.15
The wide variation in reported incidence of LPD reflects the lack of agreement about its definition and diagnostic criteria. Further, some studies evaluating prevalence have not concurrently tested controls—an important omission since endometrial histology suggestive of LPD occurs in up to 50% of single menstrual cycles and 25% of sequential cycles. 16 Thus, the true incidence of the defect may never be known.
Etiology of luteal phase deficiency
FOLLICULAR PHASE EVENTS
Intrinsic ovarian defects
Intrinsic endometrial defects
LUTEAL PHASE EVENTS
Intrinsic corpus luteum defects
Intrinsic secretory endometrial defect
LUTEAL RESCUE EVENTS
Intrinsic corpus luteum defects in early pregnancy
Intrinsic endometrial defects
FSH = follicle-stimulating hormone, hCG = human chorionic gonadotropin,
LH = luteinizing hormone
Seeking a reliable diagnostic tool
Although significant progress has been made in recent years, LPD diagnosis is neither straightforward nor completely accurate. Approaches include measuring the luteal phase duration, taking basal body temperature (BBT), and assessing single or multiple serum progesterone levels, as well as using sonographic imaging and endometrial biopsy.
Luteal phase duration. An abnormally short luteal phase—defined as less than 10 days17,18—occurs in approximately 5% of ovulatory cycles. 19 Research has shown such cycles to have low peak serum progesterone levels, suggestive of poor corpus luteum function.18 The relationship between an abnormally short luteal phase and infertility is unclear, however. Smith and colleagues,20 for example, evaluated women with known fertility and women with unexplained infertility and found the prevalence of a short luteal phase to be the same in both groups.
Our own practice is to measure luteal phase parameters in infertile patients. When the luteal phase is shorter than 12 days, we usually treat it.
Basal body temperature. A rise in BBT occurs when progesterone production increases at midcycle. A rise of approximately 2.5 ng/mL of progesterone will result in a temperature elevation of nearly 1°F. Interpretation of the BBT is based on this thermogenic shift. Unfortunately, although BBT may be a sensitive indicator of ovulation, it is a poor indicator of the quality of the luteal phase. Neither the rate nor the magnitude of rise of the postovulatory temperature curve correlates with endometrial histology. Overall correlation varies between 25%21 and 81%.22 Further, an abnormal BBT may occur in 12% of women with normal endometrial histologic dating.23 Because of this lack of specificity and sensitivity, BBT is not an adequate diagnostic tool.
Measuring progesterone and its metabolites. Because progesterone is the principal product of the corpus luteum, its measurement is clinically indicated to evaluate luteal phase abnormalities. For this reason, serum, urine, and salivary progesterone determinations are utilized.
Histologic dating of an endometrial biopsy is considered the gold standard for corpus luteum evaluation.
Although serum progesterone is widely used in the diagnosis of LPD, there is no agreement in the cutoff level for abnormal assays, the number of assays required for diagnosis, or the timing of the test. A number of studies have demonstrated lower progesterone levels in women with “out-of-phase” endometrial biopsies,24,25 but others have noted normal progesterone levels in the presence of abnormal biopsies.26-28
These contradictory findings may be explained by the episodic release of progesterone in response to the slow pulsing of LH during the luteal phase of the cycle. Consequently, there are wide and frequent fluctuations and diurnal variations in progesterone secretion. This makes the use of a single serum progesterone determination—or even a series of single serum measurements—unreliable.
- No standard for ‘normal’ progesterone levels.
- A range of sampling intervals proposed. To reduce the false-positive rate of a single measurement, Wuttke et al15 suggested 2 or 3 blood samples within 3 hours, since low progesterone levels are often observed prior to the occurrence of an LH pulse. Thus, the probability is high that within 3 consecutive hours an LH episode will have stimulated luteal progesterone secretion into the normal range. This approach has not been evaluated clinically. Moreover, it is likely to be time-consuming and inconvenient for the patient.
Biopsy: The ‘gold standard’
Histologic dating of an endometrial biopsy is the gold standard for corpus luteum evaluation because it assesses both quantitative progesterone secretion and the morphologic transformation of the endometrium in preparation for embryo implantation.
The histologic features characteristic of specific days of the menstrual cycle—first described by Noyes and colleagues in 19506—have remained the cornerstone of endometrial dating. The endometrium is considered out of phase when the histologic and chronological dating differ by 3 or more days, provided this difference is present in 2 or more successive cycles. Using these criteria, Noyes and Haman35 showed endometrial biopsy to be accurate, with an interobserver agreement rate of 82% within the 2-day range. Hence, the 3-day out-of-phase criterion.
Variations in results. Recently, the accuracy and reproducibility of endometrial histology in the diagnosis of LPD have been questioned because of considerable intraobserver and interobserver variation in sample readings, as well as variation between cycles of the same patient and timing of the biopsy. Evaluation also can depend on which section of the endometrium is sampled.36 Gibson and colleagues36 showed that 65% of the observed variability in endometrium dating was due to inconsistencies between evaluators, 27% was due to lack of concordance by the same evaluator, and 8% was due to regional differences in the uterus.
In view of these variations, the theoretical probability of changing clinical management is 15% to 28% after the same evaluator reviews a slide37 and 22% to 39% after another observer evaluates the same slide.38
Refresher training fails to improve accuracy. To increase the accuracy and interobserver reproducibility of endometrial dating, Duggan and colleagues39 offered refresher training in histologic criteria after initial endometrial dating. However, they found no improvement in accuracy or inter-observer reproducibility after this training.
Timing of the endometrial biopsy also is important.40 Traditionally, endometrial biopsies have been performed a few days before the presumed onset of menstruation to reflect the maximal influence of progesterone on the endometrium. This practice recently has been questioned, with some researchers favoring biopsies performed in the midluteal phase.40,41
The method of determining the date of ovulation also varies considerably. Traditionally, next-menstrual-period dating is used, whereby the day of menses after the biopsy is labeled day 28 and presumed to have occurred 14 days after ovulation. The use of urine LH to determine the preovulatory LH surge and—15 days later—menstruation, has been suggested as a more precise method.42
Significant intercycle variation may occur within the same individual. Li and colleagues43 reported that within-subject, between-cycle variation of more than 2 days occurred in about 41% of patients.
Uncertain link to infertility. The link between an abnormal biopsy and infertility is questionable. Previous studies have documented abnormal endometrial biopsy results in the range of 31% to 35% in fertile women13,44 —rates almost comparable to those of women with infertility. Earlier investigators also demonstrated no significant differences in pregnancy rates between infertile couples with normal biopsy results, compared with those with abnormal findings.45
Before we consider it clinically significant, we require any LPD to be present in repeated cycles.
Clinical recommendations. Before we consider it clinically significant, we require any LPD to be present in repeated cycles, since approximately 20% to 80% of women with an abnormal biopsy have an “in-phase” endometrium on a repeat biopsy.13,46
The dating of endometrial biopsies should only be done by experienced histopathologists. We perform endometrial biopsies after cycle day 24, and confirm any out-of-phase abnormality in 2 consecutive biopsies. Further, before we diagnose the endometrium as “out of phase,” histologic dating must lag by at least 3 days.