Luteal Phase Defect Research Articles

P-156. Luteal phase defects in patients with first trimester habitual abortions

P-156. Luteal phase defects in patients with first trimester habitual abortions

The assessment of normal and abnormal luteal function by transvaginal color Doppler sonography

Objective: To evaluate intraovarian resistance index (RI) in 47 healthy fertile volunteers with ovulatory cycles, 28 patients with luteal phase defect (LPD) and four patients with luteinized unruptured follicle (LUF Sy). Study design: Transvaginal color Doppler assessment of the follicular and corpus luteum blood flow and plasma progesterone (P) levels were obtained in each patient. Results: Significantly higher intraovarian artery RI (< 0.001) was obtained for LPD group than for controls during the luteal phase. In the control group both follicular and corpus luteum RI were significantly lower ( P < 0.001) on the dominant side, while in LPD group no difference ( P > 0.05) between the sides occurred. Mean P levels were significantly lower ( P < 0.001) in the LPD group (6.9 ± 2.3 ng/ml) than in controls (24.1 ± 11.4 ng/ml). In all the LPD patients histopathology revealed delayed endometrial pattern, while normal endometrial dating was found in all the evaluated patients from the control group ( n = 15). In the patients with LUF Sy ( n = 4) similar RI values were obtained in the follicular and corpus luteum phase. There was no difference between the sides in terms of the intraovarian RI. while subnormal values of P were obtained in all the examined patients (14.1 ± 6.2 ng/ml). Conclusion: Transvaginal color Doppler may predict the functional capacity of the corpus luteum.

Luteal phase defect: comparison between Doppler velocimetry, histological and hormonal markers

The aim of this prospective study was to investigate the relationship between the ultrasonographic appearance of the endometrium, histological dating by biopsy, hormonal profile and impedance within the segmental uterine and ovarian circulation for assessment of luteal phase function. A total of 61 infertile patients undergoing endometrial biopsy were studied by transvaginal B-mode and color and pulsed Doppler ultrasound. Uterine, radial, spiral, ovarian and intraovarian artery impedance throughout the natural ovarian cycle were related to histological and hormonal markers of uterine receptivity. Plasma levels of follicle stimulating hormone, luteinizing hormone (LH) and estradiol were measured on cycle days 5 and 10 and measurements were continued daily until the detection of the LH surge. Endometrial biopsy was performed 7 days after ultrasonically and hormonally detected ovulation. Progesterone levels were evaluated on the day of endometrial biopsy and 3 days later. After all the data were collected, the patients were divided into two groups, according to the histopathology: 15 patients with normal endometrial dating and 43 patients with a delayed endometrial pattern (i.e. luteal phase defect). One patient with an asynchronous endometrium and two anovulatory subjects were excluded from further evaluation. A significant difference between patients with a luteal phase defect and the control group was obtained for impedance in the uterine (p < 0.05), radial (p < 0.05), spiral (p < 0.001), ovarian (p < 0.05) and intraovarian arteries (p < 0.001) during the luteal phase. The endometrium showed secretory transformation when serum levels of progesterone were higher than 15 ng/ml. Segmental uterine and ovarian artery perfusion demonstrates a significant correlation with histological and hormonal markers of uterine receptivity. Therefore, blood flow impedance in the corpus luteum and spiral arteries may aid in assessing luteal phase adequacy.

Sustained release double-layered progesterone suppository for luteal support therapy

A sustained release suppository containing progesterone with a double-layered structure was prepared for the treatment of the luteal phase defect. Hydroxypropylcellulose-H (HPC) and Carbopol-934P (CP) were used as bases of the inner layer and Witepsol W35 was used as a base of the outer layer. The strength of the inner layer (stick) decreased with the increase of the rate of content of HPC component. The strength of the stick which was prepared from a mixture of HPC and CP in a ratio of 1:1, was inverse by proportional to the rate of the addition of crystalline cellulose (CC) and the amount of released drug was proportional to the rate of the addition of CC. The area under the drug release curve of the stick containing 60% of CC in the base was about 12 times of the stick containing no CC (control stick). Furthermore, the mean release time of the stick containing 60% of CC became about a half of the control stick. It was suggested that the drug release of progesterone from the stick could be controlled by changing the rate of the addition of CC. Two types of suppository which containing progesterone in both phases (suppository A) and in the stick alone (suppository B) were prepared. Both suppositories showed a sustained release property and suppository B had a lag time of two hours. When the suppositories were administered in to the vagina of rabbits, they showed a sustained release property and a rapid rise in the serum concentration was more suppressed than an ordinary Witepsol suppository. One hour after the administration of the two layered suppository, some parts of the suppository was identified macroscopically to be remained in the vagina. The usefulness of the double-layered suppository as a hospital preparation should be suggested after the attainment of the optimization of the formulation.

Endocrinology: Midluteal immunoreactive -inhibin serum concentrations as markers of luteal phase deficiency

The present prospective clinical study was undertaken to determine the usefulness of midluteal phase serum immunoreactive alpha-inhibin concentrations as markers of luteal phase deficiency and whether they are better indicators of biopsy confirmed luteal phase defect than serum progesterone. Consecutive patients (n = 138) with regular menstrual cycles attending our Infertility Clinic (experimental group) and 15 fertile women who were requesting contraception and had regular menstrual patterns (control group) were included. In all women (patients and controls), basal body temperature, midluteal serum concentrations of oestradiol, prolactin, progesterone and immunoreactive alpha-inhibin, and premenstrual endometrial biopsy were used in the same cycle to assess luteal function. Out-of-phase secretory endometria were detected in 15 of the 138 patients. Thus, hormonal concentrations were compared between the following three groups of women: group 1 (n = 15), infertile patients with defective secretory endometria; group 2 (n = 123), infertile patients with normal secretory endometria; and controls (n = 15), fertile women with normal secretory endometria. Midluteal serum concentrations of progesterone, immunoreactive alpha-inhibin, oestradiol, and prolactin of the two groups studied were similar to those of the control group of fertile women. Our results indicate that midluteal serum inhibin determination does not accurately reflect histological maturation of the endometrium and it is not a better indicator of endometrial luteal phase deficiency than midluteal serum progesterone concentration.

Infertile women with and without endometriosis: a case control study of luteal phase and other infertility conditions.

To assess the relationship in infertile women between endometriosis and luteal phase defects and other infertility conditions. University Medical School. Case-control study. One hundred and seventy-four infertile women with endometriosis and 174 infertile women without endometriosis, all of them studied by laparoscopy. The inclusion criteria were failure of six cycles of ovulation stimulation or abnormal preliminary study (abnormal pelvic physical, hysterosalpingographic or ultrasound findings). The frequency of out-of-phase biopsies (16.1% vs 16.7%) as well as other endometrial abnormalities were similar in endometriosis associated infertility (EAI) and in non-endometriosis infertility (NEI). Mean progesterone and prolactin levels, as well as the proportion of abnormal progesterone levels (37.4% vs 44.3%) and of hyperprolactinemia (12.9% vs 13.2%) were similar in EAI and NEI. The frequency of uterine myomas was similar in both groups. Sperm characteristics were not better in EAI than in NEI. Higher endometriosis stages were not associated with a higher frequency of the aforementioned conditions. Luteal phase defects, sperm abnormalities and myomas are no more common in EAI than in NEI or in advanced stages of endometriosis.

Progesterone profiles in luteal-phase defects associated with recurrent spontaneous abortions.

Histologically documented luteal-phase defects (LPD) have been detected in 20-40% of women with recurrent spontaneous abortions. In 28 patients with recurrent spontaneous abortions, luteal-phase serum progesterone (P) levels (days 19, 21, 23, 25) and endometrial biopsies were evaluated. On the basis of endometrial biopsy findings, the patients were separated into two groups: Group 1, recurrent spontaneous abortions with LPDs (n = 18); and Group 2, recurrent spontaneous abortions with normal biopsies (n = 7). The data are shown in the table below. This study demonstrated that the P values found in Group 1 were significantly lower than those in Group 2, almost throughout the luteal phase. The results also indicate a close relationship between the P profile in the luteal phase and endometrial biopsy.

Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation

To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation. Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation. An academic teaching hospital. One hundred seventy-five endometrial biopsies from regularly cycling women with luteal phase defect (LPD; group 1; n = 80), medically treated LPD (group 2; n = 16), minimal and mild endometriosis with aberrant alpha v beta 3 expression (group 3; n = 21), fertile controls (group 4; n = 26), and infertile controls (group 5; n = 32). Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction. Among the five groups studied, nuclear PR expression was significantly elevated in glandular epithelial cells from tissue samples with histologic delay > or = 3 days consistent with luteal phase deficiency (LPD; group 1). Failure of PR down-regulation was associated with aberrant alpha v beta 3 integrin expression. Medical correction of LPD was associated with return of normal endometrial histology, normal integrin expression, and the loss of epithelial PR, similar to controls. The other two cycle-dependent integrin markers, alpha 1 beta 1 and alpha 4 beta 1, were not different between groups. In women with aberrant alpha v beta 3 and "in phase" endometrium, epithelial PR expression was not different from controls. The establishment of normal endometrial receptivity appears to be tightly associated with the down-regulation of epithelial PR. Histologic delay, consistent with LPD, is associated with a failure of PR down-regulation and the lack of normal markers of endometrial receptivity. Occult uterine receptivity defects (aberrant beta 3 expression in otherwise normal histology) are regulated differently, suggesting alternate mechanisms also exist which influence endometrial receptivity.

Serum Lipoperoxide Level Variations in Normal and Luteal Phase Defect Cycles

A luteal phase defect (LPD) is a clinical problem leading to infertility and is characterized by reduced progesterone levels during the luteal phase. Serum lipoperoxidation is an expression of cellular hypoxic damage occurring under all stress-oxidative conditions. Forty-eight consecutive infertility patients, according to the infertility class II of the WHO classification, underwent clinical observation. Twenty-five patients ovulated constantly with a normal luteal phase, while the other 23 had a LPD, hormonally and histologically assessed. The luteal phase was monitored biochemically by titration of progesterone, oestradiol, and serum lipid peroxides during the ovulatory period and 6-12 days after ovulation. The mean plasmatic concentration of oestradiol was not statistically different between the LPD and the normal-cycle groups, while a statistically significant difference was found for progesterone plasmatic concentrations between the LPD and the normal-cycle groups (p < 0.05); a greater statistical difference was also found in the mean serum lipoperoxide titration (p < 0.001). These findings suggest that serum lipoperoxidation titration may be a useful tool in the study of the interactions between hormonal milieu and sympathetic activity.

Stress and Amenorrhea

Advances in our understanding of the physiological mechanisms subserving reproduction and those mediating responses to stress now permit us to understand in detail at least one mechanism by which stress compromises fertility. In women, stress, as evidenced by an increase in cortisol secretion, suppresses hypothalamic gonadotropin-releasing hormone (GnRH) input to the pituitary-ovarian axis. If the decrement in GnRH drive is chronic, anovulation results. Episodic decrements in the GnRH pulse generator likely result in luteal inadequacy or oligo-ovulation. The more complete the suppression of GnRH, the more likely is the reproductive compromise to be clinically recognizable. Profound and persistent loss of GnRH input manifests as amenorrhea, whereas episodic or less profound interruptions in GnRH secretion can be clinically occult and present only as decrements in luteal phase progesterone secretion by the corpus luteum in the face of preserved menstrual cycle intervals, i.e., so-called luteal phase defects. Recognition of stress-induced compromise of ovarian function expands therapeutic options because, at least in theory, stress management and reduction will lead to return of GnRH drive, resumption of ovulation and menses, and restoration of fertility.

Decreased Expression of Endometrial Decay Accelerating Factor (DAF), a Complement Regulatory Protein, in Patients With Luteal Phase Defect

We investigated the level of decay accelerating factor (DAF) in the endometrium of luteal phase defect (LPD) patients, before and after treatment with progesterone. Endometrial samples from fourteen normal-cycling controls and six samples from infertility patients with LPD before and four samples after progesterone treatment were stained by anti-DAF IgG using immunohistochemistry. Mean DAF OD in LPD patients was 15% compared to 60% in the control group. The mean DAF OD was 88% after treatment with progesterone. Results support interpretation that progesterone upregulates DAF while decreased progesterone may be associated with reduced expression of the DAF in LPD patients.

Color flow pulsed Doppler ultrasound in diagnosing luteal phase defect

To determine whether color flow pulsed Doppler analysis of corpus luteum blood flow in normal cycles differs from cycles with a luteal phase defect. A prospective study of natural ovarian cycles. The University of Vermont Reproductive Endocrinology and Infertility Service. Ten women with regular menstrual cycles and at risk for luteal phase defect (LPD) four with unexplained infertility, two with recurrent abortion, and four with age > 35 years. All women were examined by transvaginal color flow pulsed Doppler during the early follicular, late follicular, early luteal, midluteal, and late luteal phase of the menstrual cycle. Venous blood for P concentration was drawn on each day of Doppler exam. Urine testing for LH surge and endometrial biopsy during the late luteal phase were performed on each patient. Lowest resistance index associated with the highest amplitude signal from intraovarian vessels of each ovary, dated endometrial biopsies, serum P. Mean resistance indexes in LPD patients (n = 3) were significantly higher compared with normal women (n = 6) throughout the follicular and luteal phases. One patient remained anovulatory and was excluded from statistical analysis. Although systolic and diastolic velocities generally were observed to be lower in LPD patients compared with normal women, these differences were not statistically significant. High correlations were observed between P and resistance index within each luteal time point, achieving its highest value during the midluteal phase. This initial study provides evidence that color flow pulsed Doppler analysis of blood flow impedance to the corpus luteum may aid in assessing luteal phase adequacy.

Endocrinology: Observations on the use of purified follicle-stimulating hormone in the treatment of luteal phase defects

We treated 18 infertile patients affected by histologically confirmed luteal phase deficiency with 75 IU of purified follicle-stimulating hormone (FSH) daily during the first 5 days of the cycle. Patients who were not pregnant after the first cycle of treatment underwent a second cycle. In the second cycle the daily doses of purified FSH were doubled if luteal phase deficiency had persisted during the first cycle. During the two cycles before treatment and during treatment, patients underwent an endometrial biopsy 1-3 days before the expected onset of menses. An assessment of progesterone serum concentrations was also performed on days 8, 6 and 4 before the expected onset of menses. Treatment was administered in a total of 33 cycles resulting in 30 ovulatory cycles. Six pregnancies were achieved. Among non-conception ovulatory cycles, 13 presented delayed endometrial dating and 11 normal endometrium. The mean +/- SD of the sum of the three progesterone determinations was 14.7 +/- 1.4 ng/ml in pretreatment cycles, 14.6 +/- 1.6 ng/ml in cycles with normalization of endometrial dating, 14.8 +/- 1.7 ng/ml in cycles with persistence of luteal phase deficiency and 30.4 +/- 3.0 ng/ml in conception cycles (P < 0.05 versus other groups). We conclude that purified FSH, if effective in the treatment of luteal phase deficiency, does not act through an increase in progesterone concentrations.

Habitual abortion is accompanied by low serum levels of placental protein 14 in the luteal phase of the fertile cycle

To study serum levels of placental protein 14 (PP14) in relation to endometrial function in women with a history of habitual abortion.Prospective study.Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland.Fifty patients (26 primary and 24 secondary habitual aborters) and 38 controls without a history of abortion studied during a regular cycle.Habitual aborters as a whole or when subgrouped into those with normal cycles (n = 40) or with a luteal phase defect (LPD; n = 10) and control women demonstrated a distinct increase in PP14 levels from late follicular to late luteal phases. In the luteal phase, serum PP14 levels were lower in the patients than in the controls (27.2 +/- 3.1 versus 48.5 +/- 10.1 micrograms/L), but the differences in PP14 levels between habitual aborters with or without LPD was not significant (16.3 +/- 4.3 versus 29.9 +/- 3.7 micrograms/L).Habitual aborters exhibit lower serum PP14 levels in the late luteal phase compared with normal fertile women.

Decreased expression of endometrial decay accelerating factor (DAF), a complement regulatory protein, in patients with luteal phase defect

Decreased expression of endometrial decay accelerating factor (DAF), a complement regulatory protein, in patients with luteal phase defect

Ovulation triggering in clomiphene citrate-stimulated cycles: Human chorionic gonadotropin versus a gonadotropin releasing hormone agonist

To compare the use of human chorionic gonadotropin (hCG) to a gonadotropin releasing hormone (GnRH) agonist, nafarelin, in initiating ovulation and supporting the luteal phase after priming with clomiphene. In 26 infertile women 50 mg clomiphene citrate produced a preovulatory-size follicle. Then, 11 women were randomized to receive two 400-micrograms doses of nafarelin intranasally 16 h apart, and 15 women were injected intramuscularly with 5000 IU of hCG (luteal day 0 = LD0). Starting on LD6, 7 more 400-micrograms doses of nafarelin were repeated on an every 16-h schedule or a single 2500 IU dose of hCG was given, respectively. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P), and hCG were measured. On LD13, endometrium was evaluated with ultrasonography and biopsy in 19 nonpregnant women. As judged by a threefold rise in serum LH, an LH surge was detected on LD1 in all 11 nafarelin patients, but in only 8 hCG patients (P = 0.01). LH and FSH levels were significantly higher on LD1, 7, and 8 and were significantly suppressed on LD13 in the nafarelin group. All patients had mid-luteal P levels greater than 10 ng/ml and luteal phases longer than 13 days. Significantly different luteal E2 or P levels were noted only on LD13, with lower values in the nafarelin group. Pregnancies were achieved in 3 of 11 nafarelin cycles and 2 of 15 hCG cycles. Luteal phase defects were also similar: 4 of 8 nafarelin patients and 7 of 11 hCG patients. Nafarelin or hCG in conjunction with clomiphene can result in viable pregnancies, but is associated with low pregnancy rates and a high incidence of luteal phase defects.

Luteal phase defects and ectopic pregnancy

To determine whether luteal phase defect (LPD) may be an etiologic factor in ectopic pregnancy (EP). All patients who were seen over a 6-year period with the chief complaint of infertility underwent an extensive infertility workup and were followed prospectively. The diagnoses of the causes of infertility were assigned retrospectively. Two hospital-based tertiary care reproductive endocrine-infertility units. A total of 1,077 infertility patients were evaluated. Of the 633 who became pregnant, the infertility had been due to LPD in 51 and to anovulation in 210. All the infertility patients who became pregnant were followed to determine whether they miscarried, developed an EP, or had a viable birth. The incidence of EP and miscarriage in the patients whose infertility was found to be due to LPD were compared with a control group in whom the infertility was due to anovulation. The EP rate in the patients with LPD was significantly higher than in a control group whose infertility was due to anovulation (6 of 51 pregnancies versus 6 of 210 pregnancies, respectively). The spontaneous abortion rate in LPD cases also was highly significantly greater than in the control group (19 of 51 pregnancies versus 12 of 210 pregnancies, respectively). The EP and spontaneous abortion rates also were higher in patients with LPD who were untreated than in those who were treated. This study suggests that there is a significantly increased incidence of tubal EP in patients with LPD and that when patients with LPD become pregnant early ultrasound should be performed to rule out EP. The study also indicated that spontaneous abortion occurs in a significantly high percentage of LPD cases.

Relationship of Endometrial Thickness and Echo Patterns on Pregnancy Rates in Patients with Luteal Phase Defects

The objective of this prospective comparative study was to investigate the relationship of sonographic measurements of the endometrium at the time of peak follicular maturation to conception outcome in patients treated for luteal phase defects (as determined by out-of-phase endometrial biopsies). Treatments for luteal phase defects included progesterone supplementation with or without follicle-maturing drugs, depending on whether the patient attained a follicle of at least 18 mm and a serum estradiol of > 200 pg/ml. No differences in pregnancy rates were found by the thickness of endometrium (< 10 vs. > or = 10 mm) or echo pattern in any of the treatment modalities. Thus, contrary to findings in stimulated cycles for in vitro fertilization, endometrial thickness at the time of peak follicular maturation is not predictive of outcome in patients treated for luteal phase defects in natural cycles.

プロゲステロン含有ウイテプゾール・エチレン‐酢酸ビニル共重合体混合系坐剤の処方最適化

For the purpose of replacement therapy using progesterone, the mixed suppository consisting of Witepsol and ethylene-vinyl acetate copolymer (EVA) was investigated using a computer optimization technique. Witepsol-W35, EVA40Y and EVA250 were employed as the suppository base. Nine formulations were prepared according to a composite experimental designfor two factors; the rate of Witepsol-W35 (X1) and the rate of EVA250 in the EVA phase (X2). Characteristics such as the penetration (Y1), the strength (Y2), DSC peak temperature (Y3), heat of fusion (Y4), the amount dissolved (ADT, Y5) and mean dissolution time (MDT, Y6) were measured. As absorption parameters of progesterone, AUC (Y7) and MRT (Y8) were estimated after vaginal administration of suppositories in rabbits.After application of multiple regression analysis for each of the characteristics, optimum regression equations were obtained. The best formulation to maximize AUC was sought under the restriction of experimental region. Experimental results obtained for the optimum formulation agreed well with the predictions.When the mixed suppository which contained 100mg progesterone was administered to voluntary patients, the efficient blood level was maintained for 24 hours.These results suggested that the progesterone-mixed suppository was quite useful for the treatment of the luteal phase defect.

Primary infertility: characteristics of women in North America according to pathological findings.

To determine, in women with primary infertility, whether specific characteristics or behavioural factors are associated with the various pathological conditions identified as contributing to the infertility. Case-control study. Seven institutions in the USA or Canada. Study subjects were 1750 women who presented with primary infertility, among whom the main pathological cause of infertility was male factor (417), tubal obstruction (231), endometriosis (194), luteal phase defects (153), other ovulatory problems (193), cervical abnormalities (92), and polycystic ovarian disease (84) and 1765 control women who delivered their first child at the same institution. Except for tubal obstruction and polycystic ovarian disease, the characteristics and behaviours of the women with infertility did not differ appreciably according to the pathological conditions recorded. Women with tubal obstruction had had more sexual partners, an earlier age at first intercourse, were more likely to have used an intrauterine device but less likely to have used a condom, and were more likely to have smoked cigarettes and to have used various recreational drugs than the other women. Women with polycystic ovarian disease were more obese, had had fewer sexual partners, and were less likely to have used cigarettes, contraceptives, and recreational drugs than the other women. Sexually transmitted infections seem to increase the risk of tubal obstruction but not other causes of infertility. Obesity is associated with polycystic ovarian disease. These data offer few clues to the aetiology of infertility attributed to endometriosis, cervical abnormalities, luteal phase defects, other ovulatory defects, or to male factors.