Examining the relationship between ovarian reserve, as measured by basal FSH levels, and the risk of poor obstetric outcome in singleton IVF gestations.

BACKGROUND: The higher prevalence of preterm birth (PTB) and low birthweight (LBW) following infertility treatment may relate to the treatment itself or indicate that subfertility predisposes to a higher risk. Our aim was to examine whether basal FSH levels are related to the risk for PTB and LBW among pregnancies resulting from IVF. METHODS: We studied a retrospective cohort in the 2008 National Society for Assisted Reproductive Technology Database, including all women who underwent a fresh non-donor IVF cycle resulting in a singleton live birth having a recorded basal serum FSH value (n = 14 262). The FSH value used was either the maximum basal or clomiphene-stimulated serum level. Log binomial models were created to assess the associations between FSH and PTB (<37 weeks), and between FSH and LBW (<2500 g), adjusting for maternal age, ethnicity, gravidity/parity, history of PTB, smoking, BMI and infant gender. RESULTS: Data for 14 086 patients were analyzed. FSH levels were inversely related to the risk of PTB and LBW. Women in the highest quartile of FSH levels (≥ 9 mIU/ml) had the longest adjusted mean gestational age (271.2 days), the lowest adjusted relative risk (RR) of PTB [0.87, 95% confidence interval (CI): 0.76-1.01], the highest adjusted mean birthweight (3249 g) and the lowest adjusted RR of LBW (0.89, 95% CI: 0.73-1.04). CONCLUSIONS: The inverse relationship between maximal basal FSH levels and the risk for PTB and LBW in singleton IVF gestations suggests that diminished ovarian reserve is not the primary mediator of the increased prevalence of PTB and LBW in IVF pregnancies.

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.

Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.

The effect of luteal phase estrogen antagonism on endometrial development and luteal function in women.

Previous studies of the role of estrogen in primate luteolysis, designed to investigate the effects of estrogen antagonism or selective inhibition of luteal phase estrogen production on luteal function, have ignored the impact of such treatments on secretory endometrial development. We examined the effect of luteal phase estrogen antagonism on endometrial maturation and luteal function in six women. In each of two menstrual cycles in each woman, blood samples were obtained on alternate days from cycle days 3-9, daily until 1 day after the urinary LH surge (day 0), and again on alternate days until the onset of menses. In the second of each pair of cycles, clomiphene citrate (100 mg) was administered daily from 2 days after the LH surge until menses. Endometrial biopsy was performed 13 days after the LH surge in each cycle. Serum FSH, LH, estradiol, and progesterone (P) were measured by RIA. The endometrial histological date and concentration of cytosolic (C) and nuclear (N) estrogen (ER) and P (PR) receptors were determined. We found significant (P less than 0.05) increases in luteal phase serum FSH, LH, estradiol, and P levels in the clomiphene cycle compared to those in the control cycle. Endometrial histology was significantly (P less than 0.002) different during estrogen antagonism; a maturation delay of more than 2 days was found in all six women during the clomiphene cycle. Luteal phase duration was unchanged by clomiphene (P = 0.29). Endometrial ER-C [7.38 +/- 2.52 (+/- SEM) vs. 38.75 +/- 10.17 fmol/mg protein], ER-N (248 +/- 84 vs. 685 +/- 80 fmol/mg DNA), and PR-C (97 +/- 38 vs. 189 +/- 38 fmol/mg protein) were significantly lower (P less than 0.03) in the clomiphene cycle than in the control cycle, whereas PR-N was not different (P greater than 0.10). These data suggest that luteal phase estrogen 1) modulates endometrial PR and 2) plays an important role in secretory endometrial development.

Epidermal growth factor and sex steroids dynamically regulate a marker of endometrial receptivity in Ishikawa cells.

The factors regulating human endometrial receptivity remain poorly understood. The alpha v beta 3 integrin cell adhesion molecule appears to be regulated in the human endometrium, appearing on postovulatory days 5-6, corresponding to the time of initial embryo attachment. This integrin has been extensively studied as a potential marker of endometrial receptivity and is aberrantly expressed in the endometrial epithelium of some infertile women. Ishikawa cells are a well differentiated endometrial adenocarcinoma cell line that maintain functional estrogen and progesterone receptors and are a useful model to study steroid-mediated events in human endometrial epithelium. This cell line expresses most of the normal endometrial epithelial integrins, including the alpha v beta 3 vitronectin receptor. The regulation of this integrin was studied with fluorescence immunocytochemistry, flow cytometry, and Northern blot analysis. Estrogen with or without progesterone treatment down-regulates alpha v beta 3 in this cell line. Several growth factors, including epidermal growth factor and the closely related transforming growth factor-alpha significantly increase the expression of this integrin. We conclude that endometrial differentiation is influenced by both steroid hormones and growth factors. The alpha v beta 3 integrin appears to be an excellent marker to study the molecular events leading to the establishment of uterine receptivity and successful implantation.

Relationship of uteroplacental blood flow to the placental clearance of maternal dehydroepiandrosterone through estradiol formation in the pregnant baboon.

The theory that maternal intervillous blood flow is a major determinant of the rate at which the placenta clears androgenic steroid precursors through estrogen formation has never been tested by direct experimentation. We studied the effects of graded reductions in maternal distal aortic blood flow (Qda) on the placental clearance (PC) of dehydroepiandrosterone (D) through estradiol (E2) formation in pregnant baboons near term. A continuous iv infusion of [7-3H]D and [4-14C]E2 was administered to four pregnant baboons (Papio anubis) at 155-165 days gestation (term, 184 days) for 270 min (t0-t270). Maternal Qda was continuously recorded by electromagnetic flow transducer at the aortic bifurcation and altered with an aortic snare device. A 50% reduction in Qda was imposed at t60 and released at t180. Blood samples were collected at 10-min intervals from t30-t60 (control interval), t120-t180 (occlusion interval), and t240-t270 (release interval). All four animals were later studied after pregnancy with an identical infusion for 90 min, with blood samples obtained at 10-min intervals from t30-t90. Equilibrium concentrations of [3H]D, [3H]E2, and [14C]E2 in plasma were determined and the MCR of D (MCR-D), the transfer constant of conversion of D to E2 (rho DE2), and the PC of D through E2 formation (PCDE2) were calculated for each of the three levels of Qda corresponding to the control, occlusion, and release intervals in pregnant animals and under conditions of existing Qda in the nonpregnant state. Control MCR-D during pregnancy (mean +/- SE, 740 +/- 74 liters/day) exceeded MCR-D after pregnancy (500 +/- 40 liters/day). MCR-D fell significantly during occlusion (P less than 0.05). Both rho DE2 and PCDE2 decreased uniformly when Qda was reduced by 50% and returned toward the control level with release of the aortic constriction. The mean rho DE2 in pregnant animals was 0.068 +/- 0.0073 (+/- SE), 0.039 +/- 0.0020, and 0.059 +/- 0.0063 during control, occlusion, and release intervals, respectively, all exceeding rho DE2 in the nonpregnant state (0.013 +/- 0.0004). Control mean PCDE2 was 46.3 +/- 8.24 (+/- SE) ml/min; it decreased to 18.9 +/- 2.68 with 50% reduction in Qda and was 35.6 +/- 5.43 when Qda was restored to 75% of the control value. PCDE2 was directly proportional to Qda (r2 = 0.98; P less than 0.01; n = 12) and remained a constant fraction (0.13 +/- 0.002) thereof in all four animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Onset and characteristics of the midcycle surge in bioactive and immunoactive luteinizing hormone secretion in normal women: influence of physiological variations in periovulatory ovarian steroid hormone secretion.

Limited studies in nonhuman primates suggest that the midcycle LH surge is characterized by distinctly different patterns of bioactive (LH-BIO) and immunoactive (LH-RIA) LH secretion. To further examine the patterns of midcycle LH-BIO and LH-RIA secretion and explore the influence of physiological variations in steroid hormone feedback on LH surge dimensions we studied seven normal ovulatory women over the periovulatory interval. In each, blood samples were obtained every 3 h and transvaginal ultrasonography was performed every 12 h over a 5-7 day interval at midcycle. Serum levels of LH-RIA, FSH, estradiol (E2), progesterone (P4), and 17-hydroxyprogesterone were determined by RIA; LH-BIO was estimated using a mouse leydig cell bioassay. Hormone data were standardized to the time of surge onset in LH-RIA (time zero), defined as a 100% increase above a 6-point running mean baseline value; surge cessation was defined as a decline to below baseline concentration. Mean LH-RIA surge duration was 54.0 +/- 4.0 h. LH-BIO surge onset was simultaneous with that of LH-RIA and coincident with the peak in E2 levels (mean data). Mean P4 and 17-hydroxyprogesterone rose in a parallel, phasic manner, an abrupt increase in slope occurred between -6 h and +30 h but an acute rise in P4 was not consistently observed among individuals. The surge onset to follicle rupture interval (mean 37.6 +/- 4.2 h) positively correlated with peak LH-RIA (r = 0.76, P less than 0.05), surge amplitude (r = 0.74, P less than 0.05) and surge onset to peak interval (r = 0.87, P less than 0.02), but not surge duration. There were no significant relationships between E2 or P4 (mean, peak, integrated, slope) and surge amplitude or duration (LH-RIA, FSH), peak value, or surge onset to peak interval (LH-RIA, LH-BIO, FSH). These data suggest that in women, 1) onset of the midcycle surge in LH-RIA and LH-BIO is simultaneous, and 2) surge characteristics are not influenced by physiological variations in steroid hormone secretion that occur beyond the thresholds required for surge initiation.

A prospective, randomized study of endometrial telomerase during the menstrual cycle.

The purpose of this study was to characterize telomerase activity during the menstrual cycle, focusing on the luteal phase. A total of 84 endometrial biopsy samples were obtained from 72 participants. Daily urinary LH testing (OvuQuick, Quidel) was used to establish the day of the LH rise, and participants were randomized to return during the secretory phase. Twelve women returned on the identical day during the luteal phase of a subsequent cycle to allow intercycle comparisons of telomerase activity. Telomerase activity was evaluated using a modified TRAP-eze (Intergen) detection protocol. At the time of each endometrial biopsy, serum estrogen and progesterone were measured. Proliferative phase endometrium showed high telomerase activity. At the onset of the luteal phase telomerase activity was high, but it decreased during the early luteal phase, disappeared by the midluteal phase (6 d after LH surge detected), and then rose to moderate levels in the late luteal phase beginning on luteal d 10. Serum progesterone levels were inversely related to telomerase activity. In conclusion, endometrial telomerase activity is dynamic: high during the proliferative phase but inhibited during the midsecretory phase of the menstrual cycle. The timing of expression coincides with the rise and fall of progesterone levels and the time period of maximal uterine receptivity for embryo implantation. This supports a relationship between sex steroid levels and telomerase regulation.

Osteopontin and its receptor alphavbeta(3) integrin are coexpressed in the human endometrium during the menstrual cycle but regulated differentially.

Osteopontin is an arginine-glycine-aspartic acid-containing acidic glycoprotein component of the extracellular matrix that is postulated to bind to integrin receptors at the cell surface to mediate cellular adhesion and migration during embryo implantation. The primary aim of this study was to examine the uterine expression of osteopontin throughout the menstrual cycle in normal fertile controls sampled prospectively based on urinary LH surge detection. Expression of osteopontin was documented using Northern blot analysis, in situ hybridization, and immunohistochemistry. Furthermore, the temporal pattern of osteopontin expression was compared with that of its receptor, the alphavbeta3 integrin. Using Ishikawa cells, a well differentiated endometrial adenocarcinoma cell line, the in vitro regulation of osteopontin and its receptor alphavbeta3 integrin was studied. By Northern blot analysis, osteopontin mRNA appears during the early secretory phase, with maximal expression occurring in mid to late secretory-phase endometrium. The in situ hybridization analyses showed that osteopontin mRNA specifically localized in epithelial cells within the endometrium. Immunostaining of osteopontin was detected in the glandular secretions and on the apical portions of surface (luminal) epithelium. The patterns of expression of osteopontin by Northern blotting, in situ hybridization, and immunohistochemistry are remarkably similar to the pattern for the alphavbeta3 integrin. Despite these similarities in distribution, in vitro studies demonstrate that osteopontin and beta3 integrin subunit expression are differentially regulated. The expression of osteopontin was primarily induced in response to progesterone, whereas the beta3 integrin subunit was up-regulated by epidermal growth factor or heparin-binding epidermal growth factor. The differential regulation of these two endometrial proteins suggests the existence of two separate pathways regulating epithelial gene expression in human endometrium during the window of implantation. In adhesion assays using Ishikawa cells, alphavbeta3 but not alphavbeta5 or beta1 integrins appear to be the primary receptors for osteopontin. These findings may better define the factors that favor the development of a receptive endometrium.

Combined abdominal-perineal sonography to assist in diagnosis of transverse vaginal septum.

BACKGROUND: Transperineal sonography has been used to detect incompetent cervices, placenta previa, cervical pregnancy, and vaginal and cervical atresia. CASE: Transperineal sonography was used to investigate primary amenorrhea in a 14-year-old girl. A mid-transverse septum was found and confirmed surgically. CONCLUSION: Transperineal or translabial sonography assisted in the differentiation of primary amenorrhea, when adequate vaginal access was prohibited.

Doubling time of human chorionic gonadotropin (hCG) in early normal pregnancy: relationship to hCG concentration and gestational age.

There is controversy regarding whether the doubling time of human chorionic gonadotropin (hCG) in early normal pregnancy is constant or rises with increasing gestational age (GA) and hCG concentration. To clarify the influence of these variables on hCG doubling time, we obtained serial blood specimens every 2 to 4 days between postovulatory day 12 and 70 from 16 women who conceived while monitoring basal body temperature. The serum concentration of beta-hCG was determined by radioimmunoassay. Serial doubling time of hCG was calculated in all subjects and correlated with GA and hCG concentration. Least-squares estimates of 95% confidence bands were established from regression analysis given the second hCG concentration for each pair of samples or GA. For elimination of the need for calculation and thus improvement of the clinical utility of doubling time determinations, a nomogram relating the concentrations of hCG in paired serum samples to doubling time was constructed. We observed a significant correlation of doubling time with hCG concentration and GA, both in the group overall and within each individual pregnancy. These data support the recommendation that doubling time determinations should be evaluated with reference to normal values for a given GA or hCG concentration and suggest that previously proposed normal values of doubling time in early normal pregnancy may be low.

The endocrinology of the menstrual cycle: the interaction of folliculogenesis and neuroendocrine mechanisms.

(1) The gonadotropins are secreted in a pulsatile fashion in response to the similar pulsatile release of GnRH from neurosecretory neurons centered in the arcuate nucleus of the medial basal hypothalamus. (2) The gonadal steroids appear to exert their feedback effects both directly on the pituitary and through modulation of the pulsatile pattern of GnRH secretion. They may also influence the degree of sialylation and subsequent biologic activity of the gonadotropins. (3) GnRH release is under the control of catecholaminergic neurotransmitters. Norepinephrine appears to act as an excitatory agent, whereas dopamine inhibits GnRH secretion. (4) Dopamine also directly inhibits PRL release and may be the prolactin-inhibiting factor. (5) The endorphins are endogeneous opiate peptides and are derived from a common ACTH/ beta-lipotropin precursor. Through modulation of neurotransmitter mechanisms, the endorphins may affect both PRL and gonadotropin secretion. (6) The catecholestrogens, by virtue of their structural similarity to the neurotransmitters, may mediate the central feedback actions of the gonadal steroids.

Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.

OBJECTIVE: To determine the serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate treatment in anovulatory infertile women. DESIGN: Prospective cohort. SETTING: Tertiary institutional infertility clinic. PATIENT(S): Fourteen consenting anovulatory infertile women receiving standardized, cyclic, incremental treatment with clomiphene citrate for ovulation induction. INTERVENTION(S): Clomiphene citrate treatment (50-150 mg/d, cycle days 5-9), titrated to the minimum effective ovulation-inducing dose, was administered for three to six total cycles. Blood samples were obtained on cycle days 3 and 10 in each treatment cycle. MAIN OUTCOME MEASURE(S): Serum concentrations of enclomiphene and zuclomiphene. RESULT(S): Cycle day 3 zuclomiphene levels were below assay limits in all initial cycles, increased progressively across three consecutive cycles, and thereafter plateaued. Cycle day 3 enclomiphene concentrations were uniformly undetectable. Cycle day 10 enclomiphene levels increased with dose administered, but these observations were not statistically significant. CONCLUSION(S): Clomiphene citrate induction of ovulation results in an isomer-specific systemic accumulation of zuclomiphene across consecutive cycles of treatment. The combined maximum concentration of enclomiphene and zuclomiphene attained in practice approximates 100 nmol/L and is generally well below levels previously demonstrated to have adverse effects in vitro.

The effect of oral contraceptive pills on markers of endometrial receptivity.

OBJECTIVE: To determine if oral contraceptive (OC) usage alters expression of integrins associated with endometrial receptivity. DESIGN: Immunohistochemical staining intensity for integrins was compared in frozen sections of endometrial tissue specimens obtained from women with normal ovulatory cycles (n = 23; cycle days 20 to 24 based on LH surge) and from those taking oral contraceptives pills (n = 23; cycle days 5 to 27). SETTING: University-based outpatient infertility clinic. RESULTS: Constitutive integrin expression in the endometrium (alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha 6 beta 1, and alpha 6 beta 4) was similar in OC users and normally cycling individuals, except for an increase in epithelial alpha 3 beta 1 in OC users. Oral contraceptive use was associated with significant alterations in cycle-dependent integrin expression (alpha 1 beta 1, alpha 4 beta 1, and alpha v beta 3). Specifically, we observed increased glandular alpha 4 beta 1, and decreased alpha v beta 3 expression. The P-regulated alpha 1 subunit was present in both groups. Increased stromal alpha v and beta 3 and decreased alpha 3 beta 1 and alpha 6 beta 1 staining was observed in OC users. CONCLUSIONS: Expression of those integrins most closely associated with endometrial receptivity, alpha v beta 3 and alpha 4 beta 1, is altered in the glandular epithelium of women taking OCs. Stromal integrin expression in OC users also differs from that in cycling women. These alterations in epithelial and stromal integrin expression suggest that impaired uterine receptivity is one mechanism whereby OCs exert their contraceptive actions.

Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment.

OBJECTIVE: To examine the patterns of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate (CC) treatment. DESIGN: Prospective analysis of cycle characteristics. SETTING: Academic tertiary medical center. PATIENTS: Nineteen consenting anovulatory infertile women receiving standardized, cyclic, incremental treatment with CC (50 to 150 mg/d, cycle days 5 to 9) for ovulation induction. INTERVENTIONS: In each of up to six consecutive treatment cycles, urinary LH was monitored twice daily from cycle day 10 until detection of the LH surge or day 21; blood samples and transvaginal ultrasound (US) examination were obtained on cycle days 3, 10, and every 1 to 3 days thereafter until collapse of the dominant follicle. Endometrial biopsy was performed 11 to 13 days after the LH surge in the first, third, and sixth ovulatory cycle. RESULTS: Follicular phase duration, peak follicular diameter, the number of preovulatory follicles, and peak endometrial thickness and echo pattern remained consistent across consecutive ovulatory (n = 55) and anovulatory (n = 23) treatment cycles. Endometrial dating was > or = 3 days out of phase in 2 of 31 (6%) cycles sampled. Peak serum E2 and P concentrations did not vary with cycle number or correlate with endometrial thickness or echo pattern. Cycle day 10 FSH levels were significantly higher in ovulatory subjects than in anovulatory subjects. CONCLUSIONS: Patterns of gonadotropin response, follicular development, and endometrial growth and maturation remain consistent across consecutive cycles of CC treatment.

Therapeutic cup insemination with cryopreserved donor sperm: prognostic value of cervical mucus score at insemination and the number of motile sperm in mucus at 24 hours.

OBJECTIVE: To examine the prognostic value of cervical mucus score at insemination and the number of motile sperm in mucus 24 hours after therapeutic cup insemination with cryopreserved donor sperm. DESIGN: Retrospective analysis. SETTING: Academic tertiary medical center. PATIENTS: One hundred thirty-eight women with confirmed bilateral tubal patency who received therapeutic cup inseminations with cryopreserved donor sperm between 1986 and 1993. INTERVENTIONS: All insemination cycles were monitored with serial daily urinary LH determinations with a single (n = 312) insemination or two inseminations (n = 212) performed on and/or 1 day after the day of LH surge detection. A single examiner assigned cervical mucus scores in all insemination cycles and recorded the number of motile sperm in mucus 24 hours after the first insemination in dual insemination cycles. MAIN OUTCOME MEASURE: Pregnancy rate during various cervical mucus and motile sperm scores. RESULTS: Ninety-one women conceived (66%) and seven of these achieved two pregnancies. The overall pregnancy rate per insemination cycle was 18.7%. Age and day of insemination were the only variables identified as having significant influence on cycle outcome. Pregnancy occurred with decreasing frequency as patient age increased and was nearly twice as likely after insemination on the day after the urinary LH surge as on the day of surge detection. CONCLUSIONS: Insemination the day after the urinary LH surge is superior to the day of surge detection. Cervical mucus score and the number of motile sperm in mucus 24 hours after therapeutic cup insemination with cryopreserved donor sperm do not correlate with cycle outcome.

Preoperative evaluation of intersex patients with pelvic magnetic resonance imaging in search of Y chromosome-bearing gonadal tissue.

OBJECTIVE: To illustrate the utility of preoperative magnetic resonance imaging in the evaluation of intersex patients who require gonadectomy. DESIGN: Case reports of two phenotypic females having karyotypes containing a Y chromosome whose preoperative evaluation included pelvic magnetic resonance imaging. SETTING: Tertiary academic referral center. MAIN OUTCOME MEASURE: Pelvic magnetic resonance imaging for gonadal localization. RESULTS: Preoperative evaluation with magnetic resonance imaging correctly identified the most appropriate surgical approach to gonadectomy. CONCLUSIONS: Pelvic magnetic resonance imaging can be useful in the preoperative evaluation of intersex patients having nonpalpable Y chromosome-bearing gonadal tissue.

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

OBJECTIVE: To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation. DESIGN: Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation. SETTING: An academic teaching hospital. PATIENTS: 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). MAIN OUTCOME MEASURE: Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction. RESULTS: 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. CONCLUSIONS: 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.

Use of integrins to date the endometrium.

OBJECTIVE: To compare traditional histologic dating criteria of the endometrium with immunohistochemical criteria based on epithelial integrin expression during the menstrual cycle. DESIGN: Prospective clinical study. SETTING: An academic teaching hospital. PATIENT(S): Fertile and infertile women undergoing endometrial biopsy. MAIN OUTCOME MEASURE(S): Immunohistochemical staining intensity and distribution (HSCORE) of three integrins and traditional histologic endometrial dating. RESULT(S): In 1,501 endometrial specimens, phase assignment-based integrin staining was 95% and 85% concordant with histology for the proliferative and early secretory phase, respectively, but only 54% and 49% concordant for the middle and late secretory phase, respectively. The greatest disagreement occurred during the midluteal phase. Of 1,090 patients who underwent sampling 6-10 days after detection of a urinary LH surge (corresponding to cycle days 20-24), multiple logistic regression analysis revealed that endometriosis was positively correlated and male factor infertility was negatively correlated with absent beta3 integrin subunit expression. Diagnosis and absent epithelial alpha4beta1 expression were not related. Patient age was not correlated with the incidence of abnormalities in integrin expression. CONCLUSION(S): Traditional histologic dating of the endometrium has remained the gold standard for nearly 50 years. Although the use of marker proteins provides additional information and may reflect endometrial function or receptivity, such markers cannot yet replace traditional methods of endometrial assessment.

Effect of exogenous gonadotropins on endometrial maturation in oocyte donors.

OBJECTIVE: To determine the effects of controlled ovarian hyperstimulation (COH) on endometrial maturation. DESIGN: Prospective, before and after evaluation of midluteal endometrial biopsies in oocyte donor's spontaneous and subsequent COH cycles. SETTING: Tertiary academic medical center assisted reproductive technologies clinic. PATIENT(S): Nineteen oocyte donors. INTERVENTION(S): Exogenous gonadotropins, endometrial biopsies. MAIN OUTCOME MEASURE(S): Endometrial histology and an immunohistochemical marker of uterine receptivity, the alphavbeta3 vitronectin. RESULT(S): Glandular and stromal dyssynchrony was more common after COH in 16 (80%) of 20 cycles than 6 (30%) of 20 spontaneous cycles (P <.05). Glandular lag was more frequent in COH cycles and unaffected by progesterone administration. The beta3 subunit of the alphavbeta3 vitronectin receptor was present in 9 (45%) of 20 spontaneous and 2 (10%) of 20 COH cycles (P <.05). CONCLUSION(S): Exogenous gonadotropin use in healthy reproductive age women did not result in endometrial evidence of a luteal phase defect. A greater incidence of glandular-stromal dyssynchrony resulted from the use of exogenous gonadotropins. The presence of alphavbeta3 was noted in most endometrial specimens demonstrating in phase glandular maturation. We conclude that endometrial dyssynchrony that results from delayed glandular development most likely represents a normal histologic variant.