Intra- and interobserver variability of intrapartum cardiotocography: a multicenter study comparing the FIGO classification with computer analysis software.

OBJECTIVE: To evaluate and compare the computer analyzing software system with subjective interpretation using the FIGO classification of intrapartum cardiotocograms. METHODS: Twenty-four obstetricians and 19 midwives from 3 hospitals [19 junior (≤3 years) and 24 senior (>3 years) experience] participated in this study. Forty-three doctors and midwives interpreted intrapartum cardiotocographic (CTG) readings from 12 parturients without knowing the clinical outcome. Two CTG readings were repeated for evaluation of the intraobserver variability. Inter- and intraobserver agreement in CTG interpretation using the FIGO score and the computer analyzing software was assessed via proportions of agreement (Pa), with 95% confidence intervals. The level of inter- and intraobserver agreement was analyzed by calculating Pa values for CTG baseline, variability, accelerations and decelerations. RESULTS: In total, for all parameters of the FIGO classification, Pa was very low. The highest 95% confidence level of Pa was found for the baseline parameter (0.49-1.01), and the lowest for the parameter acceleration. No significant difference was seen between obstetricians and midwives as well as between junior and senior experience. In assessments of normal cases, the Pa were significantly higher than in pathological readings. CONCLUSION: Computer analyzing software can reduce the high inter- and intraobserver variability; however, further studies are needed to find out whether this can improve fetal outcome and reduce the number of Cesarean sections.

[The significance of electronic CTG for intrauterine volvulus in the 32nd week of gestation]. / Die bedeutung der elektronischen CTG-analyse bei einem fetalen Volvulus in der 32. SSW.

Intrauterine intestinal volvulus is a difficult diagnosis to make, but has life-threatening implications for the fetus. We present a case of vulvulus without malrotation in a single fetus revealed in the 32nd gestation week in a 44-year-old woman. The presenting complaint of this patient was reduced fetal movements. Ultrasound examination showed a normal result except for a dilated stomach. Doppler ultrasound results were within the normal range. Computed cardiotocography (CTG) showed pathological results for acceleration and suspect values for variability. Short-term variability (STV) was at 2.80 ms. Due to the pathological computed CTG results a Caesarian section was carried out. The newborn received prompt postnatal surgical treatment and continues to be in good overall condition.

[Short time variation of foetal heart rate: therapeutic management and effect on heart rate variation in the context of chronic hypotension in the 27th week of gestation]. / Die Kurzzeitvariabilität der fetalen Herzfrequenz - Therapeutisches Management und Auswirkungen auf die Herzfrequenzvariabilität bei einer drohenden Entgleisung einer chronischen Hypertonie in der 27. SSW.

The non-stress test is the most commonly used method in prepartal surveillance. Due to the high intra- and interobserver variability involved in subjective evaluation, the computer-assisted analysis is gaining in importance. Some studies have shown that low foetal STV may be associated with higher rates of acidosis and intrauterine mortality. Other factors influencing STV are largely not known. Low STV has been found as an effect of cortisone. In this case report, we illustrate the relevance of haemodilation therapy in the context of essential hypertension in the 27 (th) week of gestation and its effect on SVT. The treatment led to a prolongation of pregnancy to the 32 (nd) week. At the start of treatment STV increased to 4.5 ms and dropped back below this value concurrently with centralisation as documented by Doppler sonography. STV correlated clearly with the foetal condition. However, STV is dependent on numerous factors which should be investigated in further studies in order to determine appropriate reference values.

Does texture analysis improve breast ultrasound precision?

OBJECTIVE: To evaluate the possibility of distinguishing between benign and malignant breast tumors using a computer-aided evaluation of echogenicity and echostructure of ultrasound findings at certain focal points. STUDY DESIGN: The ultrasound images from 89 cases of breast tumor were documented under standardized conditions using a linear array machine and 7.5 MHz transducer. In each sonographic image, the maximum area of the 'region of interest' of the tumor was marked and then subjected to consecutive statistical analysis and correlation with the histological findings. For evaluation of tumor status eight parameters of first and second order texture statistics (gray level histogram, Fourier analysis, co-occurrence matrix) were applied. RESULTS: Benign tumors were clearly distinguished from carcinomas in the evaluation of the co-occurrence matrix and the Fourier analysis on the basis of Wilcoxon and Student t-test (P < 0.05) but not in the gray level histogram. Using logistic regression a sensitivity of 73.8% and a specificity of 54.2% were obtained. A statistically significant difference between benign tumors and moderately differentiated together with poorly differentiated carcinomas could be demonstrated. CONCLUSION: This study concludes that texture analysis appears to distinguish between benign and most malignant tumors. A computer texture analyzing system is able to improve the subjective assessment of ultrasound images of the breast but can not replace it. Where the limits of subjective assessment of a given tumor are reached, computerized texture analysis will provide additional information in the differentiation of benign from malignant findings.

Comparison of cytosolic p53 protein levels in the female genital tract and breast, and their tumors.

Under normal conditions, p53 protein is thought to maintain genomic stability. We measured this parameter in healthy tissues from female breast and genital tract using a quantitative, highly sensitive luminometric assay. An organ-specific pattern of p53 expression became evident: breast parenchyma (n = 40, median p53: 0.0346 ng/mg protein) and ovarian tissue (n = 12, 0.063 ng/mg) demonstrated markedly higher p53 levels than endometrium (n = 24, 0.0065 ng/mg), myometrium (n = 31, 0.005 ng/mg) or uterine cervix tissue (n = 25, 0. 002 ng/mg). Malignant tumors derived from these organs maintained the pattern of p53 expression with ovarian cancers (n = 14, median: 0.84 ng/mg) exceeding all other tissue types examined. Generally, p53 concentrations in malignant tumors, but also in uterine myomas were significantly higher than those in healthy controls. Breast cancer tissues, subgrouped according to prognostic parameters, demonstrated the highest p53 concentrations in samples with atypical histology, grading II-III, negative steroid receptors, and in cases of positive axillary lymph nodes. The frequency of elevated p53 concentrations in cancer cytosols, based on organ-specific normal concentrations, varied between 62% in breast cancers and 100% in cervical carcinomas. Uterine myomas showed 6% of elevated values. Grade II-III breast carcinomas overexpressed p53 more often than those with grading I (p < 0.05). In all carcinomas, the frequencies of overexpressed p53 protein markedly exceeded the frequencies of mutated p53 gene mutations reported in the literature. In conclusion, our data indicate that the extent of p53 expression and overexpression is organ dependent. When data of other studies on primary breast cancers are included, elevated levels of p53 protein in malignant tumors to some extent may indicate p53 gene mutations and worse prognosis if they exceed a higher threshold.

Differential steroid and gonadotropin response by individual tertiary porcine follicles in vitro. Possible physiologic role of atretic follicles.

Since atretic follicles contain significant amounts of androgen and/or progesterone in their follicular fluid, we examined whether they also contribute to ovarian steroid secretion. Steroid secretion by atretic porcine follicles and their responsiveness to FSH was assessed by a perifusion system that allows for separate dynamic incubation of whole follicles in vitro. Identically treated nonatretic follicles of comparable size served as a reference group. The extent of granulosal pyknosis, on which the staging of atresia was based, was inversely related to follicular estradiol (E2) secretion and its responsiveness to FSH. Both basal and FSH-stimulated secretion of testosterone (T), androstenedione (A), and progesterone (P) were maintained by follicles in all stages of atresia. Secretion of A by late atretic follicles was greater than that in earlier stages or by nonatretic follicles. Atretic follicles may therefore release comparable or larger amounts of androgen and P into their intraovarian environment than do nonatretic follicles. We examined whether steroids secreted by atretic follicles in vitro could be utilized by nonatretic follicles. A static incubation system was used that allows for simultaneous incubation of a number of individual follicles. When nonatretic follicles were exposed to A, T, or P in physiologic concentrations (10(-7)-10(-5) M), their secretion of E2 increased 2-8-fold. Doses of FSH or LH that stimulated follicular steroid in vitro had no additional stimulatory effect when combined with A or P treatment, respectively. In conclusion, atretic follicles may contribute significantly to intraovarian levels of androgen and P.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibin secretion by individual porcine follicles perifused in vitro.

To examine the relative contribution of dominant and nondominant follicles to ovarian inhibin secretion, individual porcine follicles (n = 69, diameter 4 to 9 mm) were perifused in vitro for 12 hours and then histologically examined via light microscopy. Follicle-stimulating hormone (FSH, 1 microgram/mL) was added during the second half of the perifusion period. Levels of 32 kD inhibin, estradiol (E2), and progesterone (P) in perifusion media were determined by radioimmunoassay. Viable and atretic follicles of medium size (4 to 7 mm) secreted negligible amounts of inhibin. Significant levels of inhibin (2 to 5 ng/mL) were only found in media from large viable follicles. In contrast to media concentrations of E2 and P, inhibin levels did not rise during FSH stimulation. Levels of inhibin correlated with those of P (P less than 0.01) but not with those of E2. In conclusion, mature dominant follicles may be the principal source of peripheral inhibin during the follicular phase.

Follicular size and steroid secretion of dominant bovine follicles.

Twenty one estrogen-active bovine follicles obtained in the preovulatory period prior to the endogenous LH peak were superfused for 10h. Follicular diameter and superfusate estradiol (E2), testosterone (T) and progesterone (P4) were measured. A close correlation between follicle size and E2 secreted into the superfusate was found (r = 0.77; p less than 0.01). There was no correlation between superfusate T or P4 and follicular diameter. These data indicate that within certain limits the amount of E2 secreted can be predicted by follicle size in an in vitro superfusion system. As follicle size correlates closely with granulosa cell number in estrogen-active follicles, one can speculate that the rise in estrogen secretion is a reflection of an increase in granulosa cell number of the dominant bovine follicle. The application of these in vitro findings to the in vivo situation might help in the interpretation of the quality of ovarian stimulation with hMG/hCG.

Alteration of follicular steroid secretion and thecal morphology after in-vitro exposure of individual pig follicles to follicle regulatory protein.

Medium-sized (4-6 mm) pig follicles were incubated for 10 h and then examined via light microscopy. Treatment with pig FSH resulted in significantly increased concentrations of oestradiol, testosterone, androstenedione and progesterone in the medium. Follicle regulatory protein (FRP) alone (1 micrograms/ml) decreased follicular secretion of oestradiol (56%) and progesterone (53%) but stimulated the secretion of testosterone (226%) and androstenedione (139%). In the presence of 1 ng FSH/ml, the inhibitory effect of FRP on oestradiol secretion was enhanced (74%), progesterone values were unaffected and secretion of testosterone and androstenedione were reduced by 66% and 53%, respectively. All effects of FRP were fully overcome by 1 micrograms FSH/ml. The incidence of atresia, as defined by granulosa cell pycnosis, was similar in all treatment groups (1-3 of 10 follicles per group). The remaining follicles had intact granulosa cells. However, follicles treated with FRP (1 micrograms/ml) + FSH (1 ng/ml) had pycnotic nuclei in the theca interna cells, in the presence of an intact stratum granulosum. External exposure of follicles to FRP may not reflect physiological conditions since, in vivo, thecal pycnosis is never observed before granulosa cell pycnosis. However, the present results indicate that FRP is potentially capable of altering both follicular morphology and steroidogenesis. We suggest that FSH and FRP interact to affect follicular development.

Is follicular fluid steroid content representative of follicular steroid secretion?

Nine oestrogen-active (E-A) and seven oestrogen-inactive (E-I) bovine follicles were superfused for 10 h. Levels of oestradiol (E2), testosterone (T) and progesterone (P4) were measured in superfusate and follicular fluid. No correlation between intrafollicular steroid concentrations of E2, T and P4 and the amount of these steroids detected in the superfusate was found in oestrogen-active follicles, i.e. follicular fluid E2, T or P4 levels did not allow for any prediction of superfusate E2, T and P4 concentrations and vice versa. In contrast, E-I follicles showed a close correlation between intrafollicular and superfusate T and P, but not E2 levels. It is speculated that an alteration in intrafollicular regulatory mechanisms might explain the different findings for these two classes of follicles.

Determination of follicle regulatory protein levels in urine during the normal menstrual cycle using an enzyme-linked immunosorbant assay.

A protein from follicular fluid [referred to as follicle regulatory protein (FRP)] which inhibits aromatase activity in granulosa cells was recently isolated and partially characterized. The purified FRP was used to produce a monoclonal antibody which was used to develop an enzyme-linked immunosorbant assay suitable for quantitation of FRP in urine. Twelve normal premenopausal women underwent daily collection of blood and first morning urine samples, beginning on the 1st day of menses, as well as daily ultrasonographic evaluation of follicular diameter, beginning on the 10th day of the menstrual cycle, until the onset of the next menses. Serum estradiol, progesterone, LH, and FSH levels were determined by RIA. Urinary FRP levels increased in the midfollicular phase, reached their zenith in the midluteal phase [mean, 0.38 +/- 0.03 (+/- SE) immunoreactive units; 1 immunoreactive unit = approximately 1 ng FRP/mL.mg creatinine], and then declined to reach their nadir (not detectable) during the early follicular phase. Immunohistochemical evaluation of ovarian tissue demonstrated that anti-FRP localized to mural granulosa cells in viable follicles, to all follicular epithelial cells in atretic follicles, and to the large cells of the corpus luteum. These findings indicate that immunoreactive FRP levels in urine change during the menstrual cycle and suggest a relationship among FRP, follicular maturation, and corpus luteum formation.

Endocrine parameters of human follicular fluid and fertilization capacity of oocytes.

The induction of multiple follicular growth during ovarian stimulation for in vitro fertilization (IVF) implies follicular asynchrony. As a consequence oocytes of different quality are obtained. The maturity and fertilizability of oocytes cannot sufficiently be predicted by their morphological appearance under the light microscope. Looking for additional parameters of oocyte quality, FSH, hCG, estradiol (E2), progesterone (P), testosterone (T), prolactin (PRL) and cAMP were analysed in human follicular fluid (FF) containing a morphologically mature oocyte. The evaluation of the relationship between FF values and oocyte fertilization showed the following results: no differences of FSH, hCG, E2, P and T concentrations in FF between the group of fertilized and not fertilized ova. However, significant differences were detected for PRL and cAMP. In FF of fertilized oocytes PRL content was higher (38.8 +/- 2.2 vs 29.7 +/- 2.3 ng/ml, P less than 0.01) and cAMP level was lower (32.7 +/- 1.9 vs 59.8 +/- 7.4 pmol/ml, P less than 0.01) as compared with FF of unfertilizable oocytes. In conclusion PRL- and cAMP concentration of FF might be additional parameters of oocyte maturation and fertilizability.

In-vitro steroid secretion of tertiary atretic bovine follicles in a superfusion system correlated to their histological features.

In monotocus mammals most of the tertiary follicles are atretic. The experimental design of a blind study was used to evaluate the steroid secretion pattern and histological features of atretic bovine follicles. Steroidogenesis of the vesicles was studied with the aid of a superfusion system, and the superfused follicles were evaluated independently using the histological classification elaborated by Marion et al. Twelve single atretic follicles removed during the follicular and luteal phases of twelve cows were superfused for 10 h and then histologically processed. Follicles in early and definite contracting atresia secreted predominantly testosterone, whereas follicles in definite cystic, advanced contracting and late atresia secreted predominantly progesterone. Such secretion was independent of the stage of the oestrus cycle of the animal, so that follicles with the same histological pattern had a characteristic steroid secretion pattern, which was not influenced by the stage of the oestrus cycle at the time of follicular removal. In conclusion, atretic follicles should be considered significant endocrine organs.

A postulated role for naturally occurring aromatase inhibitors in follicle selection.

The studies reviewed here indicate that follicle regulatory protein (FRP) alters aromatase and 3B-hydroxysteroid dehydrogenase activity in porcine, human, and rat granulosa cells. The inhibitory effect of FRP on granulosal aromatase activity depend upon the response of the cell to FSH: large amounts of FSH can partially overcome FRP inhibition while relatively small amounts of FSH sensitize the granulosal aromatase system to FRP. Although androgens potentiate FSH-mediated granulosal functions, they also sensitize granulosa cell steroidogenic enzymes to inhibition by FRP. The demonstration that FRP acts primarily on granulosa cells of less mature antral follicles to inhibit aromatase supports the hypothesis that FRP may facilitate follicle selection and suggests a role for FRP in atresia. Most of the effects of FRP on granulosal activities reflect an interplay between the systemic endocrine and local paracrine systems. That FRP functions, at least in part, by modulating follicular response to FSH is consistent with the hypothesis that paracrine effectors are important mediators of folliculogenesis in the presence of gonadotropins.

[A clinical study of the treatment of sterility in hyperandrogenic ovarian insufficiency]. / Eine klinische Studie zur Sterilitätstherapie bei der hyperandrogenämischen Ovarialinsuffizienz.

The therapeutic effect of glucocorticoid therapy in infertile patients with hyperandrogenemic ovarian insufficiency was verified in a clinical study and compared with the results of other forms of therapy. Of 40 patients treated with 0.5 mg/d dexamethasone only one conceived. Of 47 patients treated with 7.5 mg/d prednisone 6 became pregnant. A combination therapy of dexamethasone and clomiphene resulted in 3 pregnancies among 20 patients; a combination of prednisone and clomiphene in 18 patients led to one pregnancy. In the majority of these patients previous treatment with clomiphene only had been unsuccessful. In the patient in whom both clomiphene and glucocorticoid therapy was unsuccessful, hMG/hCG therapy was applied. The pregnancy rate, 24% in the dexamethasone group and 36% in the prednisone group, was much higher. Plasma testosterone concentrations were not significantly suppressed under corticoid therapy. Neither at the beginning of a cycle nor at the time of ovulation were FSH and LH levels changed by the administration of corticoids. There was no significant correlation between the plasma testosterone values and the length of the cycle, the duration of the follicular phase, the duration of the rise in basal temperature or the length thereof. There was a significant correlation between testosterone and the LH/FSH quotient at the beginning of the cycle both in the spontaneous cycles and under corticoid therapy, though not under clomiphene therapy. In the control cycles there was a significant correlation between testosterone and LH; in the corticoid cycles it was not significant, and under corticoid therapy there was no correlation. A negatively significant correlation between testosterone and FSH was found in the control cycles. This correlation was not significant under glucocorticoid therapy and there was no correlation under clomiphene therapy. As testosterone concentrations increased a decrease in the percentage of biphasic cycles was observed in all groups. Regardless of the testosterone concentration, the pregnancy rate in patients showing signs of androgenization, at 22%, was higher than in patients without these symptoms. In patients who conceived under corticoid therapy there was no uniform correlation either to the pretherapeutic testosterone levels or to the degree of testosterone suppression. Neither the initial testosterone level nor the degree of its suppression is of any prognostic value for corticoid therapy. The more pronounced the clinical symptoms in hyperandrogenemic patients, the more effective a corticoid therapy will be; this applies both to signs of androgenization as well as to the degree of ovarian insufficiency.