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.

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.

Laser treatment of recurrent vulvar angiokeratoma associated with Noonan syndrome.

BACKGROUND: Vulvar angiokeratoma is often confused with other, more common perineal lesions. Chronically elevated venous pressures may contribute to this rare disorder. Laser treatment may lend palliation for several years. CASE: A woman with the characteristic cardiac abnormalities of Noonan syndrome initially responded to Argon laser treatment of vulvar angiokeratoma. Excessive recurrent disease was treated satisfactorily with the Nd:YAG laser. CONCLUSION: Recurrent vulvar angiokeratoma in Noonan syndrome supports the premise that increased persistent central venous pressure may be involved in the disease process.

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.

Impaired glucose tolerance in pregnant women with polycystic ovary syndrome.

OBJECTIVE: To determine whether women with polycystic ovary syndrome (PCOS) are more likely to develop gestational diabetes mellitus compared with age- and weight-matched controls. METHODS: This retrospective cohort study compared reproductive-age women with and without PCOS who received prenatal care at the University of North Carolina Hospitals between April 1989 and June 1998. We reviewed the medical charts of 22 women with PCOS diagnosis before pregnancy based on menstrual histories, elevated androgen levels, and LH-FSH ratios greater than 2. These women were compared with 66 women without PCOS matched for age and weight. Gestational diabetes mellitus (GDM) was diagnosed in women if they had abnormal results on a 50-g glucose screening test and at least two abnormal plasma glucose values during a 100-g glucose tolerance test. Medical complications of pregnancy, pregnancy complications, and birth outcomes were compared between women with and without PCOS. RESULTS: Nine of 22 women with PCOS also had GDM diagnosis, compared with two of 66 controls (odds ratio [OR] 22.2; 95% confidence interval [CI] 3.8, 170.0), and these women exhibited increased plasma glucose values for all measurements except fasting. Five of 22 women with PCOS developed preeclampsia compared with one of 66 controls (OR 15.0; 95% CI 1.9, 121.5). CONCLUSION: Women with PCOS are at increased risk of glucose intolerance and preeclampsia during pregnancy.

Advanced maternal age and perinatal outcome: oocyte recipiency versus natural conception.

OBJECTIVE: To compare perinatal outcome in older oocyte recipients with that in women of advanced maternal age who conceived without assisted reproductive technologies. METHODS: We performed a retrospective cohort study of 46 oocyte recipients and 49 women who conceived without assisted reproductive technologies. The obstetric courses in singleton and multiple gestations in the two groups of women were compared. RESULTS: Among singleton pregnancies, a comparable obstetric course was noted between the groups. Fifty percent of the oocyte recipients experienced multiple gestations, resulting in an increased risk for placenta previa, premature rupture of membranes, preterm labor and delivery, glucose intolerance of pregnancy, pregnancy-induced hypertension, and cesarean delivery. However, only the risks for pregnancy-induced hypertension and cesarean delivery were significantly increased in the pregnancies of oocyte recipients with multiple gestations. CONCLUSIONS: Perinatal complications in women receiving oocyte donation may be related to their higher incidence of multiple gestation.

Evidence of gonadal and gonadotropin antibodies in women with a suboptimal ovarian response to exogenous gonadotropin.

Failure to respond to human menopausal gonadotropin (hMG) with adequate ovarian stimulation is associated with a poor prognosis in subsequent cycles in women participating in an in vitro fertilization/embryo transfer program. Sera from 26 menstruating women (mean age 38 +/- 4.3 years) identified as "low responders" with either tubal or male factor infertility, mean baseline FSH values of 11 mIU/mL, and peak serum estradiol levels lower than 300 pg/mL were assessed for specific antibodies to human ovary and gonadotropins. Twenty-five infertile women with tubal or male factor infertility with a good response to hMG served as controls. Ninety-two percent of low responders had antibodies to FSH and 65% had antibodies to LH when assessed by enzyme-linked immunosorbent assay. Similarly, 77% of low responders had ovarian antibodies. No hepatic antibodies were found in the sera of low responders, indicating that the positivity was not a general interaction with cell components. None of the "good responders" had antibodies to gonadotropins or to ovarian or liver tissue. The significant differences in antibodies between the groups supports a possible immunologic cause for low ovarian stimulation response to gonadotropin.

Thermal balloon and rollerball ablation to treat menorrhagia: a multicenter comparison.

OBJECTIVE: To compare the clinical efficacy and safety of a thermal uterine balloon system with hysteroscopic rollerball ablation in the treatment of dysfunctional uterine bleeding. METHODS: Two hundred fifty-five premenopausal women were treated in a randomized multicenter study comparing thermal uterine balloon therapy with hysteroscopic rollerball ablation for the treatment of menorrhagia. Preprocedural and postprocedural menstrual diary scores and quality-of-life questionnaires were obtained. Twelve-month follow-up data are presented on 239 women. RESULTS: Twelve-month results indicated that both techniques significantly reduced menstrual blood flow with no clinically significant difference between the two groups as reflected by return to normal bleeding or less (balloon 80.2% and rollerball ablation 84.3%). Multiple quality-of-life questionnaire results were also similar, including percent of patients highly satisfied with their results (balloon 85.6% compared with rollerball 86.7%). A 90% decrease in diary scores was seen in more than 60% of patients in both groups. Procedural time was reduced significantly in the uterine balloon therapy group. Intraoperative complications occurred in 3.2% of the hysteroscopic rollerball patients, whereas no intraoperative complications occurred in the thermal balloon group. CONCLUSION: In the treatment of dysfunctional uterine bleeding, uterine balloon therapy is as efficacious as hysteroscopic rollerball ablation and may be safer.

Unsuspected leiomyosarcoma: treatment with a gonadotropin-releasing hormone analogue.

We present a case of a 46-year-old woman evaluated for abnormal uterine bleeding and an enlarged uterus, with normal endometrial sampling. Three months of leuprolide acetate injections resulted in a nonenlarging uterus and resolution of iron deficiency anemia and menorrhagia. Intraoperative examination suggested leiomyosarcoma, which was confirmed by postoperative permanent histologic sections. Residual uterine sarcomatous disease was confirmed on reexploration. Similar cases will continue to raise arguments against conservative hormonal intervention in the perimenopausal woman with an enlarged uterus. As the gynecologist gains familiarity with the use of gonadotropin-releasing hormone analogue therapy in the treatment of myomatous uteri, the criteria for hysterectomy will become less rigid and the potential for delay in the diagnosis and treatment of sarcomatous disease will become more common. Physicians must be cognizant of this potential complication of conservative therapy of leiomyomata uteri.

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.

Effect of low-dose estrogen on hemodynamic response to stress.

OBJECTIVE: To determine the effect of low-dose esterified estrogen on hemodynamic responses at rest and during stress in postmenopausal women, and to compare the changes with those seen with conjugated equine estrogen. DESIGN: Open-label study of esterified estrogen compared with a double-blind, placebo-controlled investigation of conjugated equine estrogen. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Postmenopausal women with normal endometrium, not currently using hormones. INTERVENTION(S): Cardiovascular parameters at rest and in response to stressors were assessed in 11 postmenopausal women before and 6 months after receiving 0.3 mg esterified estrogen. Responses were compared with 42 postmenopausal women randomized to 0.625 mg conjugated equine estrogen or placebo. MAIN OUTCOME MEASURE(S): Changes in mean arterial pressure (MAP) and vascular resistance index from before to after treatment. RESULT(S): At rest, MAP increased 3.3 +/- 1.5 mm Hg (+/-SD) in the placebo group, while declining 2.3 +/- 1.5 mm Hg and 4.8 +/- 1.4 mm Hg, respectively, in the esterified estrogen and conjugated equine estrogen groups after treatment. During mental stressors, MAP dropped significantly in both treatment groups. At rest and during mental stressors, vascular resistance index decreased with estrogen treatment. CONCLUSION(S): Low-dose esterified estrogen improved hemodynamic patterns similar to standard doses of conjugated equine estrogen in postmenopausal women.

Diagnostic value of cervical fetal fibronectin in detecting extrauterine pregnancy.

OBJECTIVE: To determine whether fetal fibronectin (FFN) might serve as a marker to distinguish intrauterine versus extrauterine pregnancy. DESIGN: Prospective cohort study. SETTING: Academic research center. PATIENT(S): Cervicovaginal FFN samples were obtained from 46 women who were at high risk for or presented with signs and/or symptoms of extrauterine pregnancy. INTERVENTION(S): Samples of blood were analyzed for FFN with use of an enzyme-linked immunoabsorbent assay (ELISA). MAIN OUTCOME MEASURE(S): Fetal fibronectin level. RESULT(S): The rate of extrauterine pregnancy in our study was 26.1%, with 12 extrauterine and 34 intrauterine pregnancies identified by ultrasonography or at time of surgery. Seventeen samples had FFN levels of > 50 ng/mL and were considered positive (range, 0-1,000 ng/mL). Positive FFN levels were observed in 41.7% (5 of 12) of women with extrauterine pregnancies versus 35.3%) (12 of 34) of women with intrauterine pregnancies. The sensitivity, specificity, and positive and negative predictive values for extrauterine pregnancy were 41.7%, 64.7%, 29.4%, and 75.9%, respectively. CONCLUSION(S): The use of FFN does not appear to alter significantly the likelihood of identifying extrauterine pregnancy over current laboratory or ultrasonographic methods.

Secondary hypogonadism in hemochromatosis.

Hemochromatosis is a rare disorder of iron storage. This report illustrates a case of hypogonadotropic-hypogonadism in a female with biopsy-proven hemochromatosis. Dynamic pituitary and gonadal testing revealed subnormal gonadotropin responses to gonadotropin-releasing hormone (GnRH) but normal ovarian reserve, as shown by normal follicular stimulation with hMG. Thus, abnormalities of ovulation and menstruation in patients with hemochromatosis are most likely because of inadequate pituitary responsiveness to GnRH.

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.

Value of estradiol response after human chorionic gonadotropin administration in predicting in vitro fertilization success.

OBJECTIVE: To determine whether the serum E2 response after the administration of exogenous hCG is predictive of outcome during IVF. DESIGN: Prospective, noncomparative cohort. SETTING: Two academic centers and one private-practice IVF program. PATIENT(S): Two hundred twenty-two couples undergoing IVF for infertility arising from ovarian dysfunction, asthenoteratospermia, endometriosis, tubal disease, or unexplained infertility. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and miscarriage rates were compared in cycles that demonstrated an increase, decrease, or plateau in the serum E2 level on the day after hCG administration. The effects of age, cause of infertility, and maximum E2 value on outcome were evaluated. RESULT(S): Ninety-two cycles resulted in a clinical pregnancy and 130 cycles failed. Of 115 cycles in which the E2 level rose, 42 (37%) resulted in an ongoing pregnancy; among cycles with plateauing E2 responses, 20 of 69 (29%) resulted in a pregnancy. Fifteen of 38 (39%) of cycles exhibiting a drop in serum E2 resulted in an ongoing pregnancy. No statistically significant differences in ongoing pregnancy rates were noted in the increasing, plateauing, or decreasing E2 response groups. CONCLUSION(S): E2 values obtained on the day after hCG administration are not predictive of outcome in women undergoing IVF.

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.

New techniques in the diagnosis of ectopic pregnancy.

Pulse and color Doppler studies have provided a potent method for the investigation of functional changes and pathologic conditions in the female pelvis, both in the gravid and nongravid state. Combined with transvaginal sonography, which optimizes the imaging capability, the transvaginal color Doppler ultrasonography provides a new major modality for reproductive flow studies that have hitherto been possible only in animal models because of the invasiveness of the technique. Apart from these potential applications of the technique for research purposes, however, transvaginal imaging and the Doppler technique have become major modalities in all patients suspected of ectopic pregnancy at our institution.

The Effect of sex steroid hormones on substrate oxidation during prolonged submaximal exercise in women.

In animals, female sex steroid hormones (SS, estrogens-progesterone) influence the energy substrate that is metabolized. Human research on this issue is controversial. This study examined whether changes in circulating SS hormone levels affected the carbohydrate-lipid metabolism during submaximal prolonged (60 min) exercise. Young, physically active females were studied. Four were classified as anovulatory-oligomenorrheic and four were classified as ovulatory-eumenorrheic. Subject responses were pooled to form one group (n = 8) and then their responses under low (L) and high (H) pharmaceutically manipulated SS hormone conditions were examined. During exercise, the mean oxygen consumption levels were 1.70 +/- 0.10/ x min(-1) for L-SS and 1.75 +/- 0.11/ x min(-1) for H-SS (p = 0.07), respectively. The respiratory exchange ratio (RER) responses were significantly different during exercise between the conditions: 0.93 +/- 0.04 for L-SS and 0.90 +/- 0.04 for H-SS (p < 0.05), respectively. RER responses were utilized to calculate substrate oxidation. Significantly less carbohydrate oxidation was found in the H-SS condition as compared to the L-SS condition (p < 0.05). Lipid oxidation was also significantly different, but for this measure, the levels of oxidation were greater in the H-SS than in the L-SS condition (p < 0.05). Finally, total energy expenditure for the 60 min of exercise was not significantly different between the hormonal conditions. Results suggest that sex steroid hormones have an impact upon substrate oxidation in women during exercise. Specifically, high circulating concentrations of the SS hormones result in an enhanced reliance upon the oxidation of lipid as an energy substrate and consequently induce a reduction in carbohydrate oxidation. The mechanism inducing this "metabolism shift" appears due to sex steroid hormones directly and indirectly increasing lipid mobilization and lipolysis.

Hysteroscopic removal of an interstitial ectopic gestation. A case report.

A 31-year-old woman with plauteauing quantitative serial beta-human chorionic gonadotropin levels, suspect pelvic sonography and the absence of products of conception on uterine curettage was suspected of having an interstitial ectopic pregnancy. Confirmation was by endoscopy. Cornual uterine wedge resection was avoided with laparoscopically guided hysteroscopic removal of the products of conception.

Nifedipine versus ritodrine for suppressing preterm labor.

Fifty-eight women in preterm labor were selected randomly to receive either oral nifedipine or intravenous ritodrine hydrochloride. In comparison to ritodrine, nifedipine had similar tocolytic efficacy with fewer adverse maternal and fetal side effects. On Doppler studies nifedipine had an insignificant effect on umbilical blood flow. Preliminary data suggest that nifedipine is a safe, effective and well-tolerated tocolytic agent. It may prove to be a suitable alternative to ritodrine hydrochloride, especially for women in whom beta-sympathomimetics are contraindicated.