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.