Dose-dependent stimulation of melatonin secretion after administration of Agnus castus.

The circadian rhythm of melatonin secretion was measured in 20 healthy males (20 - 32 yrs.) after intake of placebo or various doses of a special extract of Agnus castus (AC: 120 - 480 mg/die) for 14 days. A significant (p < 0.05) dose-dependent increase of the area under the melatonin secretion curve (AUC) was found. The pattern of circadian rhythm of melatonin secretion was, however, not influenced. It remains to be elucidated whether the AC-stimulated increase of melatonin secretion is suitable for treatment of sleep disturbances.

Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women.

BACKGROUND AND OBJECTIVES: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP 1A2 activity is not clear. METHODS: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean +/- SD) 27.8 +/- 3.8 years, body mass index 23.8 +/- 3.8 kg x m-2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 +/- 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. RESULTS: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day -9 to -4 prior to onset of the next menses) to the follicular phase (days 5-10) was (n = 13, point estimate) 1.03 (90% CI 0.95-1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. CONCLUSIONS: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.

[Value of fetal lung maturity assessment in maternal diabetes]. / Wert der fetalen Lungenreifebestimmung bei mütterlichem Diabetes.

OBJECTIVE: Results of antepartal fetal lung maturity (FLM) testing in diabetics were compared to control patients. We analysed 274 patients by phospholipid profile and 219 by phosphatidylglycerol (PG), consisting of 73, respectively 54 diabetic and 201, resp. 165 normal control subjects. MATERIAL AND METHODS: Phospholipid concentration increased exponentially with gestational age (rreg = 0.44 for diabetic and 0.57 for normal control patients). There was no significant difference between both groups. Measurement of PG showed a trend towards lung immaturity in diabetic infants for preterm and term gestations, which did not reach significance (chi-square [chi 2] test 0.07, resp. 0.06). RESULTS: Diabetic and non-diabetic pregnancies did not differ significantly in FLM and RDS frequency. Both methods show a high rate of falsely immature results. Antepartal FLM testing by measurement of phospholipids and PG does not play a role in clinical management of diabetic patients.

Lamellar body counts in amniotic fluid for prediction of fetal lung maturity.

OBJECTIVE: Comparison of three different methods of fetal lung maturity (FLM) testing in amniotic fluid (AF) to predict fetal respiratory distress syndrome (RDS): phospholipid concentration, phosphatidylglycerol (PG) and lamellar body count (LBC). STUDY DESIGN: 315 amniotic fluid (AF) samples were tested, 291 by determination of phospholipid, 237 by PG and 68 by LBC. Eighty one patients (26%) delivered within 3 days, incidence of RDS was 7% (n = 6). Correlation of phospholipids and LBC to gestational age was analyzed as well as correlation of LBC and PG versus phospholipid concentration. Sensitivity and specificity for all three methods were calculated. RESULTS: Phospholipids and LBC increased exponentially with gestational age (rregr = 0.54, p < 0.01, rregr = 0.76, p < 0.01) showing a curvilinear function. There was a linear correlation between both methods (rcorr = 0.51, p < 0.01, n = 47). Sensitivity for prediction of RDS was 80% for phospholipids compared to 83% for LBC and 67% for PG. Specificity was best for PG (92%) followed by phospholipids (85%). While positive predictive value was low (27% for phospholipids and 50% for LBC), negative predictive value varied between 97% and 100%. CONCLUSIONS: LBC is a simple and reliable method for FLM testing, with a sensitivity comparable to phospholipid testing and a somewhat lower specificity (67% vs. 85%). It may be useful for screening of FLM in a cascade approach.

The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects.

The effects of three doses of a special Agnus castus extract (BP1095E1)--extracts from 120 mg, 240 mg and 480 mg of drug per day--were examined within the framework of a placebo-controlled clinical study of tolerance and prolactin secretion in 20 healthy male subjects during a period of 14 days. There was good tolerance during the study as regards the following: adverse effects, the effects on blood pressure and heart rate, blood count, Quick's test, clinical chemistry as well as testosterone, FSH and LH values. During each study phase the 24-hour prolactin secretion profile was measured from the penultimate to the final day, and the amount of prolactin release was monitored an hour after TRH stimulation on the last day. A significant increase in the 24-hour profile was registered with the lowest dose in comparison to placebo, the opposite being the case with the higher doses, i.e. a slight reduction. In contrast to the administration of placebo, the 1-hour AUC after TRH stimulation resulted in a significant increase with the lowest dose and a significant reduction with the highest dose. The results suggest effects of the special Agnus castus extract which are dependent on the dose administered and the initial level of prolactin concentration.

Differences in the nyctohemeral secretion of TSH and PRL in healthy euthyroid men.

The circadian rhythm of TSH, PRL and cortisol was studied in 21 healthy euthyroid men in a normal sleep/wake cycle. Higher nyctohemeral (22.00 h till 6.00 h) levels of TSH as compared to diurnal (8.00 h till 22.00 h) levels were observed in 14 out of 21 men (Group A). In the remaining 7 volunteers the nyctohemeral and diurnal TSH-levels (Group B) were the same. In Group A, the nyctohemeral PRL-surge was also higher than in Group B (p < 0.01). The nyctohemeral area under the curve (AUC) of both TSH and PRL were significantly higher in Group A than in Group B (p < 0.05 and p < 0.001 respectively). The mean diurnal concentrations of TSH and PRL were, however, similar in both groups. Therefore, an impairment of the nyctohemeral TSH-surge can occur in healthy men usually combined with a reduced nyctohemeral PRL-surge. An impairment of nyctohemeral TSH-surge is thus not confined to patients with thyroid diseases.

[The diagnostic value of routine prolactin determination in sterility patients]. / Uber die diagnostische Aussagekraft der routinemässigen Prolaktinbestimmung bei Sterilitätspatientinnen.

In the year 1976 an expert group of the WHO recommended to determine serum-prolactin routinely at the beginning of any infertility work-up. We investigated whether this recommendation is still tenable. Serum-prolactin was determined in 292 patients of an infertility clinic. In 33 women serum-prolactin exceeded the upper limit of the norm (600 microIE/ml). In 11/33 cases only, hyperprolactinemia was found to persist. This shows that the routine determination of prolactin in such cases appears to be of questionable value.

Influence of oral contraceptives on integrated secretion of gonadotropins.

The mechanism of action of various oral contraceptives has not yet been satisfactorily resolved, as to how gonadotropins affect ovarian function. Alterations of the pulsatile release of LH might be a common denominator. As methodological difficulties for the evaluation of LH pulse pattern with low basal levels exist, we elected to determine the area under the curve (AUC) for LH and FSH for 6 hours before and during treatment with oral contraceptives. LH and FSH were determined every 15 min for 6 hours on day 4 and day 20 of a control cycle and a treatment cycle in 22 women with ovulatory cycles. They received either a combined preparation containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, a sequential preparation containing 50 micrograms of ethinyl estradiol and 125 g of desogestrel or only 125 micrograms desogestrel. There was no difference between the sum of LH pulses on day 4 and day 20 of the control cycle. The AUC for FSH was lower on day 20. When the combined preparation was taken, FSH was suppressed on day 4, and FSH and LH on day 20 of treatment. The degree of suppression was even more pronounced when the sequential OC was taken. Ethinyl estradiol alone was as effective as the combination with desogestrel. Desogestrel alone inhibited ovulation without affecting serum LH and FSH in a comparable manner, suggesting a direct effect on the ovary. The determination of the AUC seems to be a sensitive tool for the evaluation of OC-induced changes in gonadotropin output.

PIP: The inhibition of ovulation by oral contraceptives (OCs) is mainly due to the alteration in the production and secretion of pituitary gonadotropins in a time- and dose-dependent manner. This study examined the influence of OCs on integrated secretion of gonadotropins. Respondents included 22 women aged 18-28 years with normal ovulatory cycles. Results indicate that the determination of the area under the curve (AUC) of serum luteinizing hormone (LH) seems to be a suitable quantitative method for studying the impact of oral contraceptives on gonadotropin release. There were no significant differences on the curve of LH starting from day 4 until day 20 in the control cycles. The AUC for follicle stimulating hormone (FSH) was lower in day 20. Treatment with the combined and sequential preparation, the LH and the FSH concentrations on both day 4 and day 20 were significantly lower than on the days of control cycles. Ethinyl estradiol alone was as effective as the combination with desogestrel, while desogestrel alone inhibits ovulation without affecting the serum LH and FSH. Lastly, determination of the AUC serves as an important tool for the evaluation of OC-induced changes in the output of gonadotropin.

Is 3 alpha, 17 beta-androstanediol-glucuronide a diagnostic marker in women with androgenic manifestations?

3 alpha, 17 beta-androstanediol-glucuronide (Adiol-G) has been described as a marker of local androgen excess due to the increased activity of 5 alpha-reductase in the cells of the hair follicles. In order to test the diagnostic value of Adiol-G, the serum level was compared to that of testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione and to the body mass index in 44 women with androgenic symptoms (Group I), 27 women with menstrual disturbances but no androgenic symptoms (Group II), and 48 healthy women (Group III) who served as controls. Adiol-G was significantly higher (7.8 +/- 5.1 nmol/l) in women with androgenic symptoms than in the other groups, but there was a considerable overlap. Serum testosterone was also found to be higher in Group I than in Groups II and III, respectively. There was a significant correlation between Adiol-G and testosterone, and Adiol-G and DHEA-S. No significant correlation could be shown to exist between androstenedione and Adiol-G. When Adiol-G and testosterone were simply classified as 'normal' or 'increased' (Adiol-G 9.4 nmol/l; testosterone greater than 2.4 nmol/l), higher than normal values of the former were found in the presence of normal testosterone in only 4% of the cases. It is concluded that the level of Adiol-G generally parallels that of testosterone. Consequently, it does not seem to be an effective marker of peripheral androgen excess.

[The behavior of serum hCG level in normal and disordered pregnancy--a prognostic factor]. / Das Verhalten des Serum-hCG-Spiegels bei normalen und gestörten Schwangerschaften--ein prognostischer Faktor.

The increase of serum hCG was determined in 305 pregnant women at least twice in the first 10 to 12 weeks of pregnancy. In a large number of cases this was done to rule out a disturbance of pregnancy. The results were evaluated by means of a comparison to the time-dependent changes of the normal range. They were classified in the following manner: 1 = Normally increasing values, 2 = Values lower than normal, but normal increase, 3 = values to low and increasing too slowly, 4 = Serum hCG too low or declining, 5 = initially normal values failing to rise. A type 4 secretion pattern was invariably followed by a demise of pregnancy. In about one half of the cases showing a type 2 pattern, the pregnancy either miscarried or was found to be in an ectopic location. In normal pregnancies, type 2 pattern was found in 29% and type 1 in 71%. A comparison of the results of the first and second hCG determination revealed close agreement in more than 90% of the cases, and in 84% when the comparison was extended to a third sample.

The ovary-suppression test in the evaluation of hyperandrogenemia.

Forty hyperandrogenemic women were investigated in order to determine whether the source of androgen excess could be attached to a dysfunction of the ovary or the adrenal cortex with a higher degree of accuracy when both steroid-producing organs were subjected to a supposedly specific suppression test. Dexamethasone (DXM) was administered at a dose of 2 mg for 2 days. The ovary-suppression test (OST) was carried out after a combined preparation containing 35 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate (EE-CPA) had been taken for 2-3 weeks. Before and after the tests, the serum levels of testosterone (T), free testosterone (fT), DHEA-S and SHBG were determined. Serum T was lowered by DXM and EE-CPA to the same degree: the latter was more effective with respect to fT. DHEA-S responded much better to DXM than to EE-CPA. The basal level of SHBG was below the lower limit of the norm in 45% of the women. This indicates that hyperandrogenemia can be associated with normal and subnormal levels of SHBG. T and/or fT were elevated in all 40 women. DHEA-S was higher than normal in only 22 of the 40. DXM normalized the DHEA-S level in all but 1 case. In another 18 women, serum T and fT remained unaffected by DXM. This indicates an ovarian source of androgen excess in these cases. The number of cases was reduced from 18 to 4 when the OST was carried out. Even though DXM and EE-CPA are not completely organ-specific in action, the combination of both suppression tests seems to allow a higher degree of discrimination to be made between an ovarian and an adrenal component of hyperandrogenemia than is possible with either test alone.

[Secretion of beta-hCG in pregnancy: an artefact?]. / Sekretion von hCG-beta in der Schwangerschaft: Ein Artefakt?

The concentration of beta-subunit (hCG beta) cannot be exactly quantified by means of competitive immunoassay in the presence of high levels of hCG, e.g. during normal pregnancy. Although the specificity and sensitivity of immunometric assay with mixed monoclonal antibodies was much improved, false positive results of hCG beta can, however, be obtained, if a high concentration of hCG is present in the hCG beta-IRMA (Ozturk et al. 1987). In this study hCG beta was therefore measured by subtraction of the values obtained by 2 immunometric assays for hCG + hCG beta and hCG in 174 serum samples of normal pregnant women during the 4th and 20th week of pregnancy. As both values did not differ, no hCG beta activity could be confirmed. Serum samples from pregnant women or authentic substances (hCG and hCG beta) were analyzed qualitatively by means of gel filtration (Sephadex-G100 column) and measurement of hCG and hCG + hCG beta activity in the fractions. In the chromatograms of pregnant serum, only one fraction with a hCG activity was observed. No additional fraction corresponding to the hCG beta activity could be identified in these chromatograms. It is concluded that, the secretion of hCG beta in serum during pregnancy is very low (less than 1%) and that the hCG beta activity measured by means of radioimmunoassay may possibly be due to an artifact.

Human chorionic gonadotropin levels in various compartments in disturbed early pregnancy.

The hCG level in the uterine cavity was higher than in peripheral blood in a case of choriocarcinoma and in patients with spontaneous expulsion of the conceptus. In two patients with missed abortion, the hCG concentrations in peripheral blood and in serum from the uterine cavity did not differ. In contrast, the hCG concentrations in PF in these patients were lower than in peripheral blood. The measurement of hCG in these compartments may provide evidence concerning the location of the trophoblast.

[Alpha fetoprotein in maternal serum in pregnancies with trisomy 18]. / Alpha-Fetoprotein im mütterlichen Serum bei Schwangerschaften mit Trisomie 18.

Maternal serum alpha-fetoprotein (MS-AFP) was assayed before amniocentesis in 2441 pregnancies of women age 35 or over and of women with prior birth of a child with a chromosome anomaly. Ten cases of trisomy 18 and 25 cases of trisomy 21 were detected. In trisomy 18 without neural tube defect we found MS-AFP levels significantly lower than in trisomy 21.

[Quantitative hCG spot test of the serum and peritoneal fluid in intrauterine and tubal pregnancy]. / Quantitativer hCG-Spot-Test im Serum und in der Peritonealflüssigkeit bei intrauteriner und tubarer Gravidität.

The concentration of hCG was measured in serum and peritoneal fluid (PF) of women with normal intrauterine pregnancy (34), extrauterine pregnancy (21), and intrauterine abortion (12) by two different methods. A new rapid, quantitative method (Spot-Test; ICON-QSR) which provides the results within 10 minutes was compared to an immunofluorometric method requiring 90 minutes (IFMA). The serum concentration of hCG and the ratio of hCG in serum and in the PF correlated well when determined by both methods (p less than 0.001). Comparable results were also obtained when hCG was measured in the serum of 4 patients with extrauterine pregnancy for a period of 2 to 3 weeks before and after surgery. When hCG was measured by means of the spot test in samples of undiluted serum containing less than 30 IU/l, lower values were obtained as compared to the IFMA. In samples containing more than 200 IU/l, the relationship was reversed. In all cases of intact intrauterine pregnancy, the level of hCG in serum exceeded that in PF, whereas the converse was observed in 19 out of 21 tubal pregnancies. These results show the spot test to be suitable for the rapid and quantitative determination of hCG in serum and the PF, provided that there is no strong hemolysis in the samples. When the concentration of hCG exceeds 300 IU/l, the measurement has to be repeated with diluted samples. Differences in concentrations of less than 20% cannot always be distinguished. Even though the results of the present study are promising, the usefulness of the spot test for routine clinical practise has to be examined in further studies.