Induction of luteal phase defect with clomiphene citrate

The effect of clomiphene citrate and progesterone on luteal function in infertile women was studied. Endometrial biopsies were performed in 103 women immediately prior to menstruation. Group 1 (n = 62) had secretory endometrium with a histologic lag time of ≥48 hours with respect to the subsequent menses, that is, luteal phase defect. Group 2 (n = 10) had normal histologic characteristics of the secretory phase. Group 3 (n = 31) had anovulatory endometrium. The last group was subdivided into those with polycystic ovary syndrome (n = 9) and those without the characteristic gonadotropin pattern of polycystic ovary syndrome (n = 22). Clomiphene citrate at doses of 50 to 250 mg daily for 5 days was administered for induction of ovulation, timing of ovulation, or treatment of luteal phase defect. An endometrial biopsy was obtained after three ovulatory treatment cycles. Only one fourth of the women with prior luteal phase defect had normalization of the biopsy specimen with clomiphene citrate, while one half of those treated with progesterone had normal specimens. Half of the normally ovulating women had induction of a luteal phase defect with clomiphene citrate. Only women with polycystic ovary syndrome had consistently well-timed endometrial histologic features with clomiphene citrate therapy. Despite successful induction of ovulation, 16 of the other 22 previously anovulatory women had endometrial histologic findings compatible with luteal phase defect. Increasing the clomiphene citrate dosage was unsuccessful in improving endometrial maturation. These results suggest that the use of clomiphene citrate may be associated with a high rate of luteal phase defect induction, except among women with polycystic ovary syndrome. Clomiphene citrate, even at high doses, appears to be ineffective therapy for luteal phase defect.     

Effects of clomiphene citrate on cytosolic estradiol and progesterone receptor concentrations in secretory endometrium

Cytosolic estradiol and progesterone receptor concentrations were measured in luteal phase endometrial biopsy samples obtained from 12 anovulatory or oligoovulatory women on clomiphene citrate therapy and from 40 normal control subjects. Clomiphene citrate treatment (250 to 750 mg per cycle) decreased both endometrial estradiol and progesterone receptor concentrations. Estradiol receptor levels were nondetectable in seven tissue samples and progesterone receptor levels in four samples from the 12 subjects given clomiphene citrate compared to nondetectable estradiol receptor concentrations in one tissue sample and progesterone receptor concentrations in two samples from the 40 normal control subjects. In histologically dated endometrium, mean estradiol receptor concentrations on days 20 to 23 and progesterone receptor levels on days to 24 to 27 were lower than the values observed in the comparable dated endometrium of normal ovulatory women. Steroid receptor concentrations correlated negatively with the duration of clomiphene citrate therapy, which implies a time-dependent suppressive effect of clomiphene citrate on measurable cytosolic estradiol and progesterone receptor concentrations during the luteal phase of the cycle.     

Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles.

OBJECTIVE: To determine the histologic development of midluteal corpus luteum (CL) and endometrium in normal fertile women after induction of ovulation with clomiphene citrate (CC). DESIGN, PATIENTS, INTERVENTIONS: Twelve normally cycling women planning to undergo an elective tubal ligation were treated with 50 to 150 mg of CC daily on days 5 through 9 of the cycle. Luteectomy and endometrial biopsy were performed simultaneously 7 days after the urinary luteinizing hormone surge. RESULTS: Because polyovulation occurred in 10 of the 12 women, 22 CL and 12 endometrial biopsies were studied. Ten women had luteal and endometrial histology that were within 2 days of the ovulation to biopsy interval. The 2 remaining women had endometrial histology that lagged 3 days behind the chronological postovulatory date. In these women, out-of-phase endometrium occurred despite polyovulatory cycles in which two and three histologically normal CL lutea were present and associated with elevated progesterone concentrations. CONCLUSIONS: In CC-induced ovulatory cycles: (1) midluteal CL histology is normal and (2) apparently out-of-phase preimplantation endometrium occurs in midluteal phase.     

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women

A direct adverse effect of clomiphene citrate on the endometrium has been presumed, and interference with estrogen receptor-mediated endometrial estrogen receptor and progesterone receptor induction has been implicated as the mechanism responsible for an increased incidence of luteal phase deficiency in association with clomiphene citrate treatment. To clarify the net influence of clomiphene administration on endometrial steroid receptor induction, we studied five normal ovulatory women, in both a spontaneous and clomiphene-induced (150 mg/day, cycle days 5 to 9) ovulatory cycle. From cycle day 11 blood samples were obtained daily and urinary luteinizing hormone determinations were performed twice daily. Endometrial biopsy was performed on the day of the urinary luteinizing hormone surge and again 13 days after the surge. Serum levels of follicle-stimulating hormone and luteinizing hormone were determined by immunoradiometric assay, estradiol and progesterone by radioimmunoassay, and clomiphene citrate isomer concentrations in treatment cycles by reversed-phase high-performance liquid chromatography and fluorescence detection. Total, cytosolic, and salt-extracted nuclear endometrial estrogen receptor and progesterone receptor concentrations were determined by enzyme-linked immunoassay. Serum estradiol was threefold to fivefold higher (p less than 0.05) in clomiphene-induced than in spontaneous cycles 8 and 10 days before the luteinizing hormone surge, and progesterone was increased (p less than 0.05) from the day of the surge to end of the cycle. Serum enclomiphene rose to plateau between 12 and 6 days before the luteinizing hormone surge (4.1 +/- 0.8 ng/ml, mean +/- SE, n = 19) and fell thereafter to less than 1.0 ng/ml. Zuclomiphene levels increased rapidly between 14 and 8 days before the surge (53.9 +/- 2.8 ng/ml, mean +/- SE, n = 5) and then decreased gradually but remained elevated throughout the luteal phase (29.0 +/- 1.2 ng/ml, mean +/- SE, n = 33). Late luteal endometrial histology was abnormal in one of four available treatment cycle specimens, but the endocrine characteristics and number and subcellular distribution of estrogen receptor and progesterone receptor in the abnormal cycle were not different from those of normal, in-phase cycles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.

BACKGROUND: The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity. METHODS: Retrospective case-control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase. RESULTS: Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%). CONCLUSIONS: CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

自然及促排卵周期子宫内膜整合素α4β1的表达

目的 了解氯米芬（CC）、绝经期促性腺激素（hMG）对黄体中期子宫内膜整合素α4β1表达的影响。方法 应用单克隆抗体,采用免疫组织化学技术检测48例正常妇女自然周期以及48例正常妇女、30例多囊卵巢综合征患者应用CC／绒毛膜促性腺激素（hCG）及CC／hMG/hCG方案促卵治疗后黄体中期子宫内膜整合素α4β1的表达。结果 子宫内膜整合素α4β1在正常妇女自然周期着床窗口期呈现强阳性表达,而CC、hMG抑制整合率α4β1的表达,两者比较,差异有极显著性（P＜0．01）;妊娠者较妊娠者整合素α4β1表达强度高。结论 促排卵周期黄体中期整合素α4β1表达下降或缺失,子宫内膜容受性下降,妊娠率降低。     

Effect of clomiphene citrate on follicular and luteal phase luteinizing hormone concentrations in in vitro fertilization cycles stimulated with gonadotropins and gonadotropin-releasing hormone antagonist

OBJECTIVE: To investigate the effect that clomiphene citrate exerts on luteinizing hormone (LH) concentrations in gonadotropin/gonadotropin-releasing hormone (GnRH) antagonist cycles. DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENT(S): Two groups of patients undergoing in vitro fertilization (IVF) were compared. In group I, 20 patients were stimulated with clomiphene citrate (CC) in combination with gonadotropins and 0.25 mg of Cetrorelix (ASTA Medica AG; Frankfurt am Main, Germany) and in group II, 20 patients were stimulated with gonadotropins and 0.25 mg of Cetrorelix. INTERVENTION(S): Blood sampling was performed in the late follicular, periovulatory, early, mid, and late luteal phases. MAIN OUTCOME MEASURE(S): Luteinizing hormone (LH), estradiol, and progesterone. RESULT(S): LH levels were significantly higher in group I than in group II on all the days studied. Progesterone serum concentrations were significantly higher in group II in the early luteal phase, but not in the follicular or the middle and late luteal phases. CONCLUSION(S): LH concentrations are significantly higher in the follicular and luteal phases in cycles stimulated with CC, despite GnRH antagonist administration. This observation might have implications for the dose of GnRH antagonist needed to suppress LH in the follicular phase and questions the need for luteal-phase supplementation in cycles in which CC was used.     

Endometrial Evaluation Is Not Predictive for In Vitro Fertilization Treatment

Purpose: The main purpose of this study was to evaluate ovarian function by clomiphene citrate (CC) challenge test in a group of tubal infertile women and to study endometrial morphological maturation in the early luteal phase of CC-stimulated cycles as compared to in vitro fertilization (IVF) treatment outcome. Methods and Results: Four women presented with strongly retarded, proliferative endometrium in the luteal phase. Of these, three presented with impaired ovarian function, high basal follicle-stimulating hormone, and high follicle-stimulating hormone levels after clomiphene stimulation on cycle day 10. In the remaining 30 women, showing an in-phase endometrium after CC stimulation, a comparison of six morphological characteristics did not reveal any significant differences between the 14 women who did become pregnant and the 16 who did not. No significant differences in endometrial thickness were observed between the groups. Significant differences were found when comparing estradiol and progesterone area under the curve during the luteal phase (P < 0.001 and P < 0.01, respectively) between those who did and those who did not become pregnant. Conclusions: Luteal endometrium morphology was not a sharp instrument to detect differences between women who did and women who did not become pregnant following IVF treatment, while ovarian function, as measured by hormonal markers, seemed to be a more reliable prognostic factor for IVF treatment outcome.     

Osteopontin and αvβ3 integrin as markers of endometrial receptivity: the effect of different hormone therapies

The osteopontin: αvβ3 integrin complex has been proposed as a means of distinguishing receptive from non-receptive endometrium in clinical practice, thus offering new directions for the development of contraceptive approaches targeted to the endometrium as well as a better understanding of occult causes of infertility in women. Histological dating and immunohistochemical study were performed in control and study cycles in seven groups of women including 10 subjects per group and who received clomiphene citrate, ovarian stimulation for IVF, oral contraception, dehydrogesterone for endometrial luteal phase defect, two different regimens of hormone replacement therapy, or no treatment. Ten healthy fertile women served as a general control group. Osteopontin and αvβ3 integrin expression in the human endometrium was closely related to endometrial maturation and this was irrespective of the endometrium being in-phase or out-of-phase and the hormonal treatment (or no treatment) received. In conclusion, immunohistochemical assessment of the endometrium indicates that the use of osteopontin and αvβ3 integrin or the osteopontin: αvβ3 integrin complex as targets for the development of contraceptive approaches or the understanding of the pathogenesis of female infertility offer little benefit compared with simple histological dating.     

Luteal phase evaluation after clomiphene-chorionic gonadotrophin-induced ovulation

Fifty infertile patients treated with clomiphene and hCG for induction of ovulation were studied with plasma progesterone measurement and endometrial histology. Five patients (10%) presented defective endometria and low plasma progesterone in spite of biphasic BBT charts with normal luteal phase length. Forty-five patients (90%) had significantly higher plasma progesterone concentrations than those found in a control group of fertile women, but a defective endometrial secretory pattern occurred in 19 of these 45 patients (42.3%). These data suggest the need for monitoring the response to clomiphene by endometrial histology in addition to BBT and plasma progesterone, or for supplemental therapy to overcome the endometrial luteal phase deficiency in clomiphene-treated cycles.     

The primary treatment of luteal phase inadequacy: progesterone versus clomiphene citrate

This study was undertaken in order to evaluate the superiority, if any, of progesterone or clomiphene citrate in treatment of infertile women with luteal phase inadequacy. Eighty-two patients were randomly treated with progesterone or clomiphene citrate. Some patients with failure of progesterone were changed to clomiphene citrate treatment; some patients with failure of clomiphene citrate were changed to progesterone treatment. A life-table analysis was used for evaluation of the results. No statistical difference was noticed between the two treatments. Seventeen of 57 patients treated with progesterone and 13 of 62 patients treated with clomiphene citrate conceived. It is recommended that: patients with luteal phase inadequacy can be treated primarily with progesterone; an endometrial biopsy should be performed if the patients fail to conceive; if endometrial biopsy continues to be abnormal the patients can be treated again with clomiphene citrate. Some alternative treatments for luteal phase inadequacy are needed.     

Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation

OBJECTIVE: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for preventing premature luteinizing hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). DESIGN: Participants in the study formed two groups. Both groups received CC-hMG and Nal-Glu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. SETTING: Centre de Fecondation in Vitro, H?pital Antoine Béclère. PATIENTS: Eleven women 25 to 34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. INTERVENTION: Daily blood samples, pelvic ultrasound, and CC-hMG/Nal-Glu/hCG administration. MAIN OUTCOME MEASURES: (1) Spontaneous LH surge and P rise, follicular growth, and plasma E2 levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMG/Nal-Glu. RESULTS: Plasma E2 level increased from 983 +/- 80 pg/mL (mean +/- SEM) on the day of the first Nal-Glu administration to 1,159 +/- 102 and 1,610 +/- 114 pg/mL (mean +/- SEM) 24 and 48 hours later. In 10 women, LH and P remained low for at least 96 hours after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma E2 and P reached a maximum of 1,258 +/- 313 pg/mL and 50.3 +/- 12.8 ng/mL (mean +/- SEM), respectively, on the 6th day of the luteal phase. CONCLUSION: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 hours, in spite of increasing levels of plasma E2. Moreover, Nal-Glu had no adverse effect on the kinetic of E2 rise, the follicular growth, or on the post-hCG hormonal profile.     

Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat

OBJECTIVE: To compare the effects of letrozole and clomiphene citrate in the rat in terms of number of ovarian follicles; endometrial thickness; and serum levels of E2, FSH, LH, and T. DESIGN: Controlled prospective study. SETTING: University research laboratory. ANIMAL(S): Thirty sexually mature female Wistar-Albino rats that were 20 weeks of age. INTERVENTION(S): Letrozole, 5 mg/kg of body weight daily (10 rats); clomiphene citrate, 100 microg/kg daily (10 rats); or saline solution, 2 mL/d (10 rats). After 2 days, rats were euthanized and ovariectomized. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness, and serum levels of hormones. RESULT(S): Mean levels of FSH, LH, E2, and T; number of mature follicles; and ovary size differed among the groups, whereas the mean endometrial thickness did not differ. CONCLUSION(S): In rats, the effect of letrozole on follicular maturation is similar to that of clomiphene citrate.     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome

Background.?The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity.

Methods.?Retrospective case–control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase.

Results.?Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%).

Conclusions.?CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of metformin therapy on hyperandrogenism, insulin resistance, cervical scores, ovulation, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Infertility clinic of a tertiary referral center. PATIENT(S): Fifty-six women with clomiphene citrate-resistant PCOS. INTERVENTION(S): Two cycles of oral metformin therapy (850 mg, twice daily) in group I and placebo therapy (twice daily) in group II. Clomiphene citrate (100 mg/day) on cycle days 3-7 of the second cycle in both groups. MAIN OUTCOME MEASURE(S): Insulin, T, DHEAS, FSH, LH, body mass index (BMI), waist-to-hip ratio, endometrial thickness, cervical score, ovulation, and pregnancy rates in clomiphene-induced cycles after metformin therapy. Result(s): Metformin therapy resulted in a significant decrease in total T, LH level, LH/FSH ratio, insulin resistance, and mean BMI. No difference in waist-to-hip ratio, DHEAS level, and fasting insulin level was observed. Clomiphene citrate induction resulted in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group. There was higher cumulative pregnancy rate in the metformin group; however, there was no significant difference in the pregnancy rate between the two groups. CONCLUSION(S): Metformin therapy not only decreases hyperandrogenism and insulin resistance but also improves ovulation rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with PCOS.     

Enhanced pre-ovulatory progesterone levels in fertile cycles during clomiphene citrate treatment

We compared ovulatory changes in fertile and preceding infertile cycles in 21 patients with unexplained infertility conceiving after clomiphene citrate treatment. No significant differences were observed in follicular growth, cervical score and follicle stimulating hormone (FSH) levels. Progesterone was higher (P less than 0.05) in the 2 days preceding ovulation in fertile cycles, luteinizing hormone (LH) higher (P less than 0.05) the day before, and 17-beta-estradiol lower (P less than 0.05) 4 days before. Stimulating progesterone secretion by systematic LH administration before ovulation could improve secretory endometrial transformation and thus reproductive prognosis.     

Sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin in human in vitro fertilization. II. Study of luteal phase adequacy following aspiration of the preovulatory follicles

The 88 patients included in the in vitro fertilization program during 113 cycles were submitted to superovulation by sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin. No correlation was found between estradiol and progesterone levels during the luteal phase and estradiol on the days preceding administration of human chorionic gonadotropin. Nineteen biopsies of the endometrium were carried out. The importance of the increase of estradiol between the day before and the day of administration of human chorionic gonadotropin is positively correlated with the quality of the endometrium.     

Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential.

OBJECTIVE: To examine hormonal and endometrial responses to intermittent low-dose RU486 administration in the luteal phase of the menstrual cycle. DESIGN: Prospective open trial in which subjects serve as their own controls. PATIENTS/PARTICIPANTS: Eight normal cycling women. INTERVENTIONS: RU486 (10 mg, orally) was administered 5 and 8 days after urinary luteinizing hormone (LH) surge of treatment cycle. MAIN OUTCOME MEASURES: Daily serum concentrations of LH, follicle-stimulating hormone, estradiol (E2), and progesterone (P) were determined in control, treatment, and recovery cycles (n = 5) or treatment and recovery cycles (n = 3). Changes in endometrial morphology and immunohistochemical staining for P receptor (PR) and E2 receptor (ER) were determined during control (or recovery) and treatment cycles. RESULTS: Cycle length and hormonal patterns were unaltered after treatment with RU486. As demonstrated by reduced stromal edema and delayed glandular development, endometrial dyssynchrony occurred in all eight treatment cycles. In addition, seven of eight treatment cycle endometria demonstrated a decrease in PR staining without consistent change in ER staining. CONCLUSIONS: Two low doses of RU486 given 72 hours apart during the luteal phase of the cycle disrupted ongoing endometrial maturation without altering the hormonal and time course of the menstrual cycle. This study provides a basis for the development of a novel form of luteal contraception.     

Histological dating of timed endometrial biopsy tissue is not related to fertility status

OBJECTIVE: To assess the ability of histological dating to discriminate between women of fertile and infertile couples. The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain. DESIGN: Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years. SETTING: University-based infertility practices. PATIENT(S): Volunteer subjects (847) recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20-39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study. Fertile controls were excluded if they had a history of infertility, recurrent pregnancy loss, or recent breastfeeding. INTERVENTION(S): Subjects underwent daily urinary LH testing. After detection of the LH surge, subjects were randomized to biopsy in the mid (days 21-22) or the late (days 26-27) luteal phase. Pathologists at each site estimated the cycle day based on standard criteria. For the primary analysis, an out-of-phase biopsy was defined as a greater than 2-day delay in the histological maturation of the endometrium. MAIN OUTCOME MEASURE(S): The proportion of out-of-phase biopsies in fertile and infertile women was compared using logistic regression models with age at randomization as a covariate. Comparisons were also made between fertile vs. infertile at the midluteal or late luteal phase time points. RESULT(S): Biopsies were evaluated (301 mid and 318 late; N = 619). Out-of-phase biopsy results poorly discriminated between women from fertile and infertile couples in either the midluteal (fertile: 49.4%, infertile: 43.2%) or late luteal phase (fertile: 35.3%, infertile 23.0%). Results did not substantially differ using alternative definitions of "out-of-phase" or standardized cycle day. CONCLUSION(S): Histological dating of the endometrium does not discriminate between women of fertile and infertile couples and should not be used in the routine evaluation of infertility.