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Home , Corpus luteum, Endometrium, Luteal phase

■ OBGMANAGEMENT BY LAWRENCE ENGMAN, MD, and ANTHONY A. LUCIANO, MD

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.

espite scanty and controversial sup- difficult to definitively diagnose the deficien- porting evidence, evaluation of cy or determine its incidence. Further, while Dpatients with or recurrent reasonable consensus exists that endometrial loss for possible defi- biopsy is the most reliable diagnostic tool, ciency (LPD) is firmly established in clinical concerns remain about its timing, repetition, practice. In this article, we examine the data and interpretation. and offer our perspective on the role of LPD in assessing and managing couples with A defect of reproductive disorders (FIGURE 1). output? PD is defined as endometrial histology Many areas of controversy Linconsistent with the chronological date of lthough observational and retrospective the , based on the woman’s Astudies have reported a higher incidence of LPD in women with infertility and recurrent KEY POINTS 1-4 pregnancy losses than in fertile controls, no ■ Luteal phase deficiency (LPD), defined as prospective study has confirmed these find- endometrial histology inconsistent with the ings. Furthermore, studies have failed to con- chronological date of the menstrual cycle, may be firm the superiority of any particular therapy. caused by deficient progesterone secretion from the corpus luteum or failure of the Once considered an important cause of to respond appropriately to ovarian . infertility, LPD has become the subject of

debate, with some experts questioning its very ■ Wide variation in the reported incidence of LPD— existence. Unclear terminology describing 3.7% to 20% in infertile women—reflects lack of this disorder is part of the problem, making it agreement about its diagnostic criteria.

■ Dr. Engman is a fellow in reproductive and ■ Histologic dating of an endometrial sample is the infertility, University of Connecticut School of Medicine, gold standard for evaluation of the corpus luteum. Farmington, Conn. Dr. Luciano is professor of and gynecology, University of Connecticut School of Medicine, ■ Two main treatment strategies have been and director, Center for and Women’s Health, New suggested: improving follicular dynamics using Britain General Hospital, New Britain, Conn. follicle-maturing drugs such as clomiphene, and use of supplemental progesterone during the

August 2003 • OBG MANAGEMENT 41 luteal phase and first trimester of pregnancy. Luteal phase deficiency: What we now know

FIGURE 1 of the corpus luteum steroidogenic function. Diagnosis and treatment of luteal phase deficiency Normal embryonic implantation depends on a Infertility properly functioning luteal phase, which, in turn, Luteal phase length* requires optimal secretion of follicle-stimulating hor-

<12 days 12 to 16 days mone (FSH) and adequate follicular development dur- ing the . Measurement of midluteal serum progesterone levels and endometrial stripe by transvaginal Other requirements are a ultrasound satisfactory luteinizing hor- mone (LH) surge during and continuous Progesterone >9 Progesterone tonic LH pulses during the ng/mL, endometrial <10 ng/mL and/or stripe ≥8 mm with endometrial stripe luteal phase of the cycle. diffuse pattern <8 mm LH secretion from the pituitary occurs in a pul- 7 satile fashion, which is between cycle days essential for corpus 24 and 27 luteum function.8 During the follicular phase the

Normal Abnormal in pulse frequency is high, 3 consecutive cycles occurring at a rate of Clomiphene approximately 1 pulse per or No luteal phase defect 90 minutes. However, dur- ing the luteal phase and under the influence of * In 3 consecutive cycles progesterone, the pulse frequency is significantly next menses. It was first described by Jones in diminished, occurring approximately every 1949.5 One year later, Noyes et al6 published 3 to 6 hours, depending on the age of the criteria on endometrial dating that became corpus luteum.7,9 The corpus luteum is the gold standard for LPD diagnosis. unresponsive to LH pulses during the early Pathophysiology. LPD may be caused by luteal phase; sensitivity develops about 4 to deficient progesterone secretion from the 6 days after ovulation.7,9 corpus luteum or failure of the endometri- The luteal phase thus involves creation of um to respond appropriately to ovarian an optimal hormonal environment as well as steroids (TABLE). Most experts believe LPD adequate endometrial transformation. Alter- is a defect of corpus luteum progesterone ation of any of the factors that contribute to a output—both in amount and duration— normally functioning corpus luteum may resulting in inadequate stimulation of the thus deleteriously affect the endometrium endometrium for implantation of the blas- and embryonic implantation. tocyst (FIGURE 2).5 Thus, the endometrial Epidemiology. The reported prevalence of histologic pattern is an important bioassay LPD ranges from 3.7% to 20% among patients

42 OBG MANAGEMENT • August 2003 Luteal phase deficiency: What we now know

with infertility.10,11 When an out-of-phase TABLE endometrium is the diagnostic criterion, Etiology of luteal phase deficiency prevalence estimates range from 3.5% to 12,13 31%. A short luteal phase is thought to FOLLICULAR PHASE EVENTS 14 occur in 5% of ovulatory cycles. Some reports Trophic alterations suggest that LPD accounts for 25% to 40% of • Inadequate FSH stimulation 15 recurrent pregnancy losses. – Increased inhibin The wide variation in reported incidence • Alterations in LH secretion of LPD reflects the lack of agreement about its Intrinsic ovarian defects definition and diagnostic criteria. Further, • Defective granulosa cells some studies evaluating prevalence have not – Decreased inhibin levels concurrently tested controls—an important – Decreased follicular phase diameter omission since endometrial histology sugges- – Decreased primordial follicles tive of LPD occurs in up to 50% of single men- Intrinsic endometrial defects strual cycles and 25% of sequential cycles.16 • Inadequate priming

Thus, the true incidence of the defect may LUTEAL PHASE EVENTS never be known. Trophic alterations • Alterations in LH secretion Seeking a reliable diagnostic tool – Decreased LH surge and luteal levels lthough significant progress has been – Systemic factors Amade in recent years, LPD diagnosis is • Factors acting upon corpus luteum neither straightforward nor completely accu- rate. Approaches include measuring the luteal Intrinsic corpus luteum defects phase duration, taking • Specific cellular defects – Large and small cell abnormalities (BBT), and assessing single or multiple serum progesterone levels, as well as using sono- Intrinsic secretory endometrial defect graphic imaging and endometrial biopsy. • Deficient number of progesterone receptors Luteal phase duration. An abnormally LUTEAL RESCUE EVENTS short luteal phase—defined as less than 10 Trophic alterations days17,18—occurs in approximately 5% of ovu- • Defective hCG stimulus 19 latory cycles. Research has shown such Intrinsic corpus luteum defects in early pregnancy cycles to have low peak serum progesterone • Defective progesterone synthesis levels, suggestive of poor corpus luteum func- Intrinsic endometrial defects tion.18 The relationship between an abnor- FSH = follicle-stimulating , hCG = human chorionic , mally short luteal phase and infertility is LH = unclear, however. Smith and colleagues,20 for example, evaluated women with known fer- tility and women with unexplained infertility increases at midcycle. A rise of approximately and found the prevalence of a short luteal 2.5 ng/mL of progesterone will result in a phase to be the same in both groups. temperature elevation of nearly 1ºF. Our own practice is to measure luteal Interpretation of the BBT is based on this phase parameters in infertile patients. When thermogenic shift. Unfortunately, although the luteal phase is shorter than 12 days, we BBT may be a sensitive indicator of ovula- usually treat it. tion, it is a poor indicator of the quality of the Basal body temperature. A rise in BBT luteal phase. Neither the rate nor the magni- occurs when progesterone production tude of rise of the postovulatory temperature

August 2003 • OBG MANAGEMENT 45 Luteal phase deficiency: What we now know

curve correlates with endometrial histology. and conception cycles. However, as men- Overall correlation varies between 25%21 and tioned earlier, the cutoff level for normal 81%.22 Further, an abnormal BBT may occur progesterone is not standard in the literature. in 12% of women with normal endometrial Single midluteal serum values between 2.5 histologic dating.23 Because of this lack of ng/mL and 15 ng/mL have been used by var- specificity and sensitivity, BBT is not an ade- ious investigators to distinguish normal from quate diagnostic tool. abnormal luteal phase levels.14,29 Measuring progesterone and its Using 95% confidence intervals, metabolites. Because progesterone is the Landgren et al30 and Olive11 considered prog- principal product of the corpus luteum, its esterone levels abnormal when they were less measurement is clinically indicated to evalu- than 5 ng/mL for 5 or more days. In contrast, ate luteal phase abnormalities. For this rea- Wuttke and colleagues15 chose a cutoff of son, serum, urine, and salivary progesterone 8 ng/mL, based on the bimodal distribution determinations are utilized. of serum progesterone levels in normally ovu- lating women. In a prospective study evaluat- Histologic dating of an endometrial ing midluteal progesterone levels in the cycle of conception, Hull et al31 found values of biopsy is considered the gold standard 10 ng/mL or more in 21 successful singleton for corpus luteum evaluation. conceptions; as a result, they proposed that such levels in the midluteal phase be consid- Although serum progesterone is widely ered indicative of normal luteal function. used in the diagnosis of LPD, there is no A range of sampling intervals proposed. agreement in the cutoff level for abnormal To reduce the false-positive rate of a single assays, the number of assays required for measurement, Wuttke et al15 suggested 2 or 3 diagnosis, or the timing of the test. A number blood samples within 3 hours, since low prog- of studies have demonstrated lower proges- esterone levels are often observed prior to the terone levels in women with “out-of-phase” occurrence of an LH pulse. Thus, the proba- endometrial biopsies,24,25 but others have bility is high that within 3 consecutive hours noted normal progesterone levels in the pres- an LH episode will have stimulated luteal ence of abnormal biopsies.26-28 progesterone secretion into the normal range. These contradictory findings may be This approach has not been evaluated clini- explained by the episodic release of proges- cally. Moreover, it is likely to be time-con- terone in response to the slow pulsing of LH suming and inconvenient for the patient. during the luteal phase of the cycle. Other investigators have proposed using Consequently, there are wide and frequent abnormal progesterone levels in 3 successive fluctuations and diurnal variations in proges- cycles as indicative of LPD. The sum of 3 terone secretion. This makes the use of a sin- progesterone levels measured every other day gle serum progesterone determination—or during the midluteal phase also has been sug- even a series of single serum measure- gested, with totals of less than 15 ng/mL ments—unreliable. indicative of LPD.32 Integrated progesterone No standard for ‘normal’ progesterone levels. measurement based on daily levels, utilizing Researchers generally have determined nor- area under the curve and representing the mal levels based on the 95% confidence limits cumulative amount of progesterone in the of midluteal progesterone determinations in 2 circulation, may be the most reliable criterion groups of women: those with unexplained for evaluation of LPD.33 Unfortunately, it is infertility and those with normal ovulatory impractical and time-consuming, and thus

46 OBG MANAGEMENT • August 2003 Luteal phase deficiency: What we now know

FIGURE 2 Luteal phase deficiency

FSH LH Corpus luteum

Ovary Deficient progestrone output from corpus luteum—resulting in inadequate stimulation of endometrium for blastocyst implantation. FSH = follicle-stimulating hormone; LH = luteinizing hormone

cannot be used for clinical purposes. Biopsy: The ‘gold standard’ Without urinary LH determination, istologic dating of an endometrial biopsy appropriate timing for a midluteal phase His the gold standard for corpus luteum serum progesterone assay may be difficult to evaluation because it assesses both quantita- ascertain. The length of the luteal phase tive progesterone secretion and the morpho- ranges from 11 to 16 days in 95% of normal- logic transformation of the endometrium in ly ovulating women. Therefore, even with a preparation for implantation. well-defined LH surge, the midluteal phase The histologic features characteristic of may vary considerably.32 For this reason, it specific days of the menstrual cycle—first has been suggested that measurement of described by Noyes and colleagues in 19506— progesterone in the late luteal phase has have remained the cornerstone of endometri- greater sensitivity and specificity than mid- al dating. The endometrium is considered out luteal levels.34 of phase when the histologic and chronologi- In our practice, we seldom rely on serum cal dating differ by 3 or more days, provided progesterone alone. Indeed, if luteal phase this difference is present in 2 or more succes- deficiency is strongly suspected, we perform sive cycles. Using these criteria, Noyes and endometrial biopsy during the late luteal Haman35 showed endometrial biopsy to be phase of the cycle—about day 10 to 13 after accurate, with an interobserver agreement ovulation. Ultrasound measurement of the rate of 82% within the 2-day range. Hence, endometrial stripe is useful in assessing both the 3-day out-of-phase criterion. endometrial response and adequate luteal Variations in results. Recently, the accura- phase. If the midluteal-phase progesterone cy and reproducibility of endometrial histol- levels are normal (more than 10 ng/mL) and ogy in the diagnosis of LPD have been ques- the vaginal-probe ultrasound shows a thick tioned because of considerable intraobserver and diffuse stripe of 8 mm or more, we feel and interobserver variation in sample read-

that we have ruled out LPD. ings, as well as variation between cycles of the Maura Flynn IMAGE:

48 OBG MANAGEMENT • August 2003 Luteal phase deficiency: What we now know

same patient and timing of the biopsy. Before we consider it clinically Evaluation also can depend on which section significant, we require any LPD to be of the endometrium is sampled.36 Gibson and colleagues36 showed that 65% of the observed present in repeated cycles. variability in endometrium dating was due to inconsistencies between evaluators, 27% was questionable. Previous studies have docu- due to lack of concordance by the same eval- mented abnormal endometrial biopsy results uator, and 8% was due to regional differences in the range of 31% to 35% in fertile in the . women13,44—rates almost comparable to those In view of these variations, the theoretical of women with infertility. Earlier investigators probability of changing clinical management also demonstrated no significant differences is 15% to 28% after the same evaluator in pregnancy rates between infertile couples reviews a slide37 and 22% to 39% after anoth- with normal biopsy results, compared with er observer evaluates the same slide.38 those with abnormal findings.45 Refresher training fails to improve Clinical recommendations. Before we con- accuracy. To increase the accuracy and sider it clinically significant, we require any interobserver reproducibility of endometrial LPD to be present in repeated cycles, since dating, Duggan and colleagues39 offered approximately 20% to 80% of women with an refresher training in histologic criteria after abnormal biopsy have an “in-phase” initial endometrial dating. However, they endometrium on a repeat biopsy.13,46 found no improvement in accuracy or inter- The dating of endometrial biopsies observer reproducibility after this training. should only be done by experienced Timing of the endometrial biopsy also is histopathologists. We perform endometrial important.40 Traditionally, endometrial biop- biopsies after cycle day 24, and confirm any sies have been performed a few days before out-of-phase abnormality in 2 consecutive the presumed onset of to reflect biopsies. Further, before we diagnose the the maximal influence of progesterone on the endometrium as “out of phase,” histologic dat- endometrium. This practice recently has been ing must lag by at least 3 days. questioned, with some researchers favoring In our practice, all endometrial biopsies biopsies performed in the midluteal phase.40,41 are read by the senior author, who has had The method of determining the date extensive experience with Noyes’ criteria for of ovulation also varies considerably. endometrial dating. Traditionally, next-menstrual-period dating is used, whereby the day of menses after the Is there a proven treatment? biopsy is labeled day 28 and presumed to have ot surprisingly—given the disagreement occurred 14 days after ovulation. The use of Nabout its incidence and diagnosis—LPD urine LH to determine the preovulatory LH treatment also is controversial. Several case surge and—15 days later—menstruation, has series, observational trials, and retrospective been suggested as a more precise method.42 studies have explored whether treatment Significant intercycle variation may occur improves the chances of conception, but few within the same individual. Li and col- randomized trials have taken up the issue. leagues43 reported that within-subject, Two main strategies have been suggested: between-cycle variation of more than 2 days • Improving follicular dynamics using drugs occurred in about 41% of patients. such as clomiphene or gonadotropins, which Uncertain link to infertility. The link not only produce a follicle but increase prog- between an abnormal biopsy and infertility is esterone secretion during the luteal phase. CONTINUED

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• Administering supplemental progesterone treatment benefit, but may reflect natural during the luteal phase and first trimester of intercycle or biologic variation or sponta- pregnancy. neous conception independent of treatment. Clomiphene and other follicle-maturing Randomized trials. Most of the studies drugs. Clomiphene increases FSH secretion published to date are case series and observa- and induces development of multiple or larg- tional studies, which are subject to method- er follicles. As a result, LH receptivity is ologic bias. To the best of our knowledge, enhanced. In addition, higher estrogen con- only a few randomized studies of treatment centrations in the follicular phase increase efficacy have been published.51-53 All included receptor content in the endometrium. only a few patients and lacked adequate Although some studies support the use of power to detect any differences.50 clomiphene to treat LPD, in certain cases the drug may actually induce luteal phase defects that occur after therapy do in 30% to 50% of cycles.47 By its anti-estro- genic activity, clomiphene may suppress prog- not necessarily imply treatment benefit, esterone receptor levels, rendering the but may reflect natural intercycle variation. endometrium out of phase and less respon- sive to progesterone. Supplemental progesterone use is sup- For example, Balasch and colleagues52 ported by research from Lassey and col- evaluated treatment with vaginal progesterone leagues,48 who demonstrated an association suppositories, dehydrogesterone, and no treat- between LPD and abnormal expression of ment. Although there was a higher pregnancy alpha-v-beta-3-integrin, the biomarker of rate in the treatment groups, it was not statis- uterine receptivity, which is likely responsible tically significant. However, the power of this for the window of implantation. The trial to detect any differences in pregnancy endometrium of women with delayed matu- rates was very low. ration—that is, LPD—fails to express the Investigating recurrent pregnancy loss. alpha-v-beta-3-integrin when biopsied dur- We also lack properly designed studies assess- ing the window of implantation (days 20 and ing the role of luteal phase support in women 21). When given supplemental progesterone, with recurrent due to LPD. Two the vast majority of these patients return to meta-analyses reached different conclusions normal histologic status and alpha-v-beta-3- on the role of progesterone supplementation integrin expression.48,49 in patients with recurrent miscarriages.34,54 Progesterone versus clomiphene. Clin- Studies included in these analyses used vari- ical trials have not established whether prog- ous inclusion criteria. Moreover, diagnosis esterone treatment is more effective than was not based on currently accepted criteria, treatment with clomiphene or gonadotropin and the treatment of choice was either 17-OH or no treatment. Problems with design and progesterone or medroxyprogesterone. The methodology in trials that do exist make it trials also included patients at more than 8 impossible to draw any firm conclusions from weeks’ gestation. reports published thus far. One multicenter randomized study eval- The literature includes numerous uating with human chorionic descriptive studies, most of which involved gonadotropin (hCG) or placebo found no assessment of pregnancy rates before and significant difference in pregnancy rates.55 after treatment.50 However, pregnancies that Targeting the underlying cause. Steroid- occur after therapy do not necessarily imply ogenic cells consist of 2 main types: large and

August 2003 • OBG MANAGEMENT 55 Luteal phase deficiency: What we now know

small luteal cells. Large luteal cells derive from levels between LH pulses.15 The follicular- follicular granulosa cells and secrete autocrine- phase LH pulsatility, follicular development, acting and paracrine-acting peptides and and serum were all normal.15 eicosanoids but are not LH-receptive.56 They Theoretically, stimulation of luteal prog- ensure basal progesterone and estradiol produc- esterone secretion by hCG administration tion from the corpus luteum. Small luteal cells should be an effective therapy for hypothala- derive from follicular thecal cells and acquire mic LPD as well as a defect of large luteal LH receptivity; thus, they respond to regularly cells. If the defect involves the small luteal occurring LH pulses, leading to increased cells, however, hCG therapy will be ineffec- progesterone and estradiol production.15 tive, since the corpus luteum is unresponsive to gonadotropins.15 In such patients, proges- terone may be the treatment of choice. This Only expert histopathologists or may explain, at least in part, the differences reproductive endocrinologists with special in outcomes in the literature, since the training should evaluate samples. underlying causative category has not been identified. A well-designed, multicenter trial is In a series of excellent experiments, essential to address remaining questions Wuttke and colleagues15 studied corpus about LPD, not to mention a clear and uni- luteum function by measuring serial LH, form definition. progesterone, and estradiol levels. They sug- gested that, if the underlying cause of LPD Clinical management can be determined, therapy can be appropri- or those who believe, as we do, that LPD is ately directed, depending on whether the Fa real and potential cause of reproductive deficiency is hypothalamic LPD or a defect of disorders, we recommend that: small luteal cells or large luteal cells. • its diagnosis be standardized, In hypothalamic LPD, LH pulses are • only expert histopathologists or reproduc- absent and the hypothalamic gonadotropin- tive endocrinologists with special training releasing hormone pulse generator appears to and skills in endometrial dating evaluate his- be oversuppressed, even though serum proges- tologic samples, and terone levels are lower than normal. However, • once a “proper” diagnosis is made, treat- during the follicular phase, the pulse genera- ment be multifold and as minimally invasive tor functions normally.15 as possible. When there is a defect of small luteal cells, Our practice generally is to give patients the corpus luteum responds poorly to normal gonadotropins or clomiphene to improve fol- LH pulses during the luteal phase, resulting liculogenesis and corpus luteum function, and in subnormal basal progesterone. Wuttke et al to induce multiple ovulations, which increase postulated that a defect of small luteal cells serum progesterone levels as well as the chance occurs because the cells do not differentiate of pregnancy. well or fail to acquire LH receptivity.15 In patients at high risk for multiple gesta- A defect of large luteal cells—which tion, progesterone supplementation as oral ensure the release of basal LH and unstimu- tablets or vaginal cream is relatively safe, inex- lated progesterone—occurred in 21% of cases pensive, and well tolerated. There is no need studied. In these cases there was normal cor- to monitor effects of progesterone treatment, pus luteum response to normal LH pulses, but since this natural substance has no known progesterone secretion decreased to very low side effects or teratogenicity. ■ CONTINUED

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REFERENCES 31. Hull MGR, Savage PE, Bromham DR, et al. The value of a single serum proges- terone measurement in the midluteal phase as a criterion of a potentially fertile cycle 1. Stephenson MD. Frequency of factors associated with habitual in 197 (“ovulation”) derived from treated and untreated conception cycles. Fertil Steril. couples. Fertil Steril. 1996;66:24-29. 1982;37:355-360. 2. Rosemberg SM, Luciano AA, Riddick DH. The luteal phase defect: the relative fre- 32. Abraham GE, Maroulis GB, Marshall JR. Evaluation of ovulation and corpus quency of, and encouraging response to treatment with vaginal progesterone. Fertil luteum function using measurements of plasma progesterone. Obstet Gynecol. Steril. 1980;34:17-20. 1974;44:522-525. 3. Davidson BJ, Thrasher TV, Seraj IM. An analysis of endometrial biopsies per- 33. Wu CH, Minassian SS. The integrated luteal progesterone: an assessment of luteal formed for infertility. Fertil Steril. 1987;48:770-774. function. Fertil Steril. 1987;48:937-940. 4. Li TC, Dockery P, Cook ID. Endometrial development in the luteal phase of 34. Daya S. Efficacy of progesterone support for pregnancy in women with recurrent mis- women with various types of infertility: comparison with women of normal fertility. carriage. A meta-analysis of controlled trials. Br J Obstet Gynaecol. 1989;96:275-280. Hum Reprod. 1991;6:325-330. 35. Noyes RW, Haman JO. Accuracy of endometrial dating. Fertil Steril. 1953;4:504. 5. Jones GS. Some newer aspects of management of infertility. JAMA. 1949;141:1123- 1129. 36. Gibson M, Badger GJ, Byrn F, Lee KR, Korson R, Trainer TD. Error in histolog- ic dating of secretory endometrium: variance component analysis. Fertil Steril. 6. Noyes RW, Hertig AI, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3-25. 1991;56:242-247. 7. Jones GS, Pourmand K. An evaluation of etiologic factors and therapy in 555 pri- 37. Scott RT, Snyder RR, Bagnall JW, Reed KD, Adair CF, Hensley SD. Evaluation of vate patients with primary infertility. Fertil Steril. 1962;13:398-410. the impact of intraobserver variability on endometrial dating and the diagnosis of 8. Nash LD. The treatment of luteal phase dysfunction with clomiphene citrate and luteal phase defects. Fertil Steril. 1993;60:652-657. human chorionic gonadotropin. Infertility. 1982;5:87-104. 38. Scott RT, Snyder RR, Strickland DM, et al. The effect of interobserver variation in 9. McNeely MJ, Soules MR. The diagnosis of luteal phase deficiency: a critical review. dating endometrial histology on the diagnosis of luteal phase defects. Fertil Steril. Fertil Steril. 1988;50:1-15. 1988;50:888-892. 10. Balasch J, Vanrell JA. Luteal phase deficiency: an inadequate endometrial response 39. Duggan MA, Brashert P, Ostor A, et al. The accuracy and interobserver repro- to normal hormonal stimulation. Intern J Fertil. 1986;31:368-371. ducibility of endometrial dating. Pathology. 2001;33:292-297. 11. Olive DL. The prevalence and epidemiology of luteal phase deficiency in normal 40. Castelbaum AJ, Wheeler J, Coutifaris CB, Mastroianni L Jr, Lessey BA. Timing of and infertile women. Clin Obstet Gynecol. 1991;34:157-166. the endometrial biopsy may be critical for the accurate diagnosis of luteal phase 12. Andrews WC. Luteal phase defects. Fertil Steril. 1979;32:501. deficiency. Fertil Steril. 1994;61:443-447. 13. Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freeman KS. The incidence of luteal 41. Johannisson E, Landgren BM, Rohr HP, Diczfalusy E. Endometrial morphology phase defect in normal, fertile women, determined by endometrial biopsies. Fertil and peripheral hormone levels in women with regular menstrual cycles. Fertil Steril. 1989;51:582-586. Steril. 1987;48:401-408. 14. Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine regulation of the corpus 42. Li TC, Rogers AW, Lenton EA, et al. A comparison between two methods of luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. chronological dating of human endometrial biopsies during the luteal phase and 1984;73:1638-1647. their correlation with histologic dating. Fertil Steril. 1987;48:928-932. 15. Wuttke W, Pitzel L, Seidlova-Wuttke D, Hinney B. LH pulses and the corpus 43. Li TC, Dockery P, Rogers AW, Cooke ID. How precise is histologic dating of luteum: the luteal phase deficiency (LPD). Vitam Horm. 2001;63:131-158. endometrium using the standard dating criteria? Fertil Steril. 1989;51:759-763. 16. Hinney B, Henze C, Wuttke W. Regulation of luteal function by luteinizing hor- 44. Shoupe D, Mishell DR Jr, Lacarra M, et al. Correlation of endometrial maturation mone and at different times of the luteal phase. Eur J Endocrinol. 1995 with four methods of estimating day of ovulation. Obstet Gynecol. 1989;73:88-92. 133:701-717. 45. Driessen F, Holwerda PJ, vd Putte SC, Kremer J. The significance of dating on 17. Sherman BM, Korenman SG. Measurement of plasma LH, FSH, estradiol and endometrial biopsy for the prognosis of the infertile couple. Int J Fertil. 1980;25:112-116. progesterone in disorders of the human menstrual cycle: the short luteal phase. J 46. Wentz AC. Endometrial biopsy in the evaluation of infertility. Fertil Steril. Clin Endocrinol Metab. 1974;38:89. 1980;33:121-124. 18. Strott CA, Cargille CM, Ross GT, Lipsett MD. The short luteal phase. J Clin 47. Keenan JW, Herbert CM, Bush JR, Wentz AC. Diagnosis and management of out- Endocrinol Metab. 1970;30:246. of-phase endometrial biopsies among patients receiving clomiphene citrate for 19. Lenton EA, Landgren BM, Sexton L. Normal variation in the length of the luteal . Fertil Steril. 1989;51:964. phase of the menstrual cycle: identification of the short luteal phase. Br J Obstet 48. Lassey BA, Castlebaum AJ, Sawin SJ, Sun J. Integrins as markers of uterine recep- Gynaecol. 1984;91:685-689. tivity in women with primary unexplained infertility. Fertil Steril. 1995;63:535-542. 20. Smith SK, Lenton EA, Landgren BM, Cooke ID. The short luteal phase and infer- 49. Lassey BA, Damjanovich L, Coutifaris C, et al. Integrin molecules in the tility. Br J Obstet Gynaecol. 1984;91:1120-1122. human endometrium. Correlation with the normal and abnormal menstrual cycle. 21. Downs KA, Gibson M. Basal body temperature graph and the luteal phase defect. J Clin Invest. 1992;90:188-195. Fertil Steril. 1983;40:466-468. 50. Karamardian LM, Grimes DA. Luteal phase deficiency: effect of treatment on 22. Soules MR, Wiebe RH, Aksel S, Hammond CB. The diagnosis and therapy of pregnancy rates. Am J Obstet Gynecol. 1992;167:1391-1398. luteal phase deficiency. Fertil Steril. 1977;28:1033. 51. Echt CR, Romberger FT, Goodman JA. Clomiphene citrate in the treatment of 23. Johansson EAB, Larsson-Cohn U, Gemzell C. Monophasic basal body tempera- luteal phase defects. Fertil Steril. 1969;20:564-571. ture in ovulatory menstrual cycles. Am J Obstet Gynecol. 1972;113:933. 52. Balasch J, Vanrell JA, Marquez M, Burzaco I, Gonzalez-Merlo J. Dehydrogesterone 24. Cummings DC, Honore LH, Scott JC, Williams KP. The late luteal phase in infer- versus vaginal progesterone in the treatment of the endometrial luteal phase tile women: comparison of simultaneous endometrial biopsy and progesterone lev- deficiency. Fertil Steril. 1982;37:751-754. els. Fertil Steril. 1985;43:715-719. 53. Huang KE. The primary treatment of luteal phase inadequacy: progesterone versus 25. Daya S, Ward S. Diagnostic test properties of serum progesterone in the evaluation clomiphene citrate. Am J Obstet Gynecol. 1986;155:824-828. of luteal phase defects. Fertil Steril. 1988;49:168-170. 54. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of ran- 26. Batista MC, Carteledge TP, Merino MJ, et al. Midluteal phase endometrial biopsy domized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol. does not accurately predict luteal function. Fertil Steril. 1993;59:294-300. 1989;96:265-274. 27. Rosenfeld DL, Garcia CR. A comparison of endometrial histology with simultaneous 55. Harrison RF. Human chorionic gonadotrophin (hCG) in the management of plasma progesterone determinations in infertile women. Fertil Steril. 1976;27:1256-1261. recurrent abortion; results of a multi-centre placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 1992;47:175-179. 28. Shangold M, Berkeley A, Gray J. Both midluteal serum progesterone levels and late luteal endometrial histology should be assessed in all infertile women. Fertil Steril. 56. Ohara A, Mori T, Taii S, Ban C, Narimoto K. Functional differentiation in 1983;40:627-630. steroidogenesis of two types of luteal cells isolated from mature human corpora lutea of menstrual cycle. J Clin Endocrinol Metab. 1987;65:1192-1200. 29. Hensleigh PA, Fainstat T. Corpus luteum dysfunction: serum progesterone levels in diagnosis and assessment of therapy for recurrent and threatened abortion. Fertil Dr. Engman reports no financial relationship with any companies whose products Steril. 1979;32:396-400. are mentioned in this article. Dr. Luciano reports that he serves on the speakers 30. Landgren BM, Unden AL, Diczfalusy E. Hormonal profile of the cycle in 68 nor- bureau and as a consultant for Eli Lilly, and receives research grants from mally menstruating women. Acta Endocrinol. 1980;94:89-98. Chitogenics, ML Laboratories, Proctor & Gamble, and Tap Pharmaceuticals.

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