The effect of D-ser (TBU)6-LH-RH-EA10 upon gonadotropin release in normally cyclic women.

D-Ser (TBU)6-LH-RH-EA10 (HOE 766) was found to be approximately 40-times as effective as LH-RH in stimulating LH and FSH release in normally cyclic women. The most pronounced reaction was seen in the late follicular phase, the least one in the early follicular phase. Maximal serum gonadotropin levels were found 4 h after the injection of HOE 766. When 5 microgram was injected every 8 h for 3 days, the initially high release of LH and FSH declined progressively to almost nil.

Synthesis and release of gonadotropins: effect of an oral contraceptive.

A double-stimulation test with 100 micrograms gonadotropin-releasing hormone per dose given twice within two hours was carried out in eight normally cyclic women before and during treatment with a combined oral contraceptive (30 micrograms ethinyl-estradiol + 150 micrograms desogestrel). The test was performed on days 8 to 11, 19 to 22, and 24 to 27 of a control cycle, and during the first and third treatment cycles. This oral contraceptive was found to diminish the capacity of the gonadotropes for the synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to a higher degree than that for the acute release in each treatment cycle. During the treatment-free interval, the reaction of LH differed from that of FSH: while the release of the former remained suppressed, that of FSH did not differ from the control cycle.

High doses of estrogens do not interfere with the ovulation-inducing effect of clomiphene citrate.

A sequential regimen of 100mg of clomiphene citrate (days 5 to 9) and 180 mug of ethynyl estradiol or 7.5 mg of conjugated estrogens (days 10 to 16 or 17) was given to 29 infertile patients. Eleven patients conceived. Four pregnancies terminated as early abortions; the remaining seven went to term. In four cases an ovarian hyperstimulation syndrome developed.

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.

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.

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 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.

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.

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.

Spontaneous recovery of ectopic pregnancy: a preliminary report.

Twelve patients with silent (occult) ectopic pregnancy were clinically managed by a non-surgical conservative approach. The laparoscopic findings in 4 patients were not conclusive enough to justify laparotomy, and there was only minimal clinical symptomatology. The serum hCG level in these cases did not exceed 2000 IU/l and no typical rise was found. Serum hCG was measured serially under careful clinical observation until it reached non-pregnant levels over a period of 20-45 days. Tubal patency could be demonstrated 6 months later in 2 patients who desired to become pregnant.

Inverse ratio of hCG in peritoneal fluid to that in serum in normal and tubal pregnancies.

The ratio of hCG in peritoneal fluid (PF) to that in serum (S) was studied in 60 patients with normal pregnancies (5th-15th wk of gestation = control group) and in 12 tubal pregnancies, 7 tubal abortions (5th-10th wk of amenorrhea) and one case of an early interstitial pregnancy (8th wk). The PF level in the control group was in every patient lower than in S independent of the gestational age. The ratio PF to S ranged from 0.24 to 0.87 (mean +/- S.E.: 0.51 +/- 0.02). In contrast to this, the patients with tubal pregnancy and tubal abortion showed in each case higher PF levels than in S. The ratio in the group with tubal pregnancy ranged from 1.1 to 374 (54 +/- 30) and in the group with tubal abortion from 1.2 to 162 (33 +/- 23). The difference in the ratio between the control group and both tubal pregnancy and tubal abortion was highly significant (P less than 0.001). The ratio of PF to S in the patient with interstitial pregnancy (0.73) did not differ from the control group. At the time of investigation, the S levels in all but 2 patients with ectopic pregnancy were below the range for normal pregnancy of the same gestational age. These findings indicate that the hCG ratio of PF to S may be dependent on the location of the gestational product.

[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.

[The maternal and fetal levels of human chorionic gonadotropin, human placental lactogen and prolactin during the perinatal period (author's transl)]. / Feto-maternale HCG-, HCS- und PRL-Konzentrationen in der perinatalen Periode

The levels of human chorionic gonadotropin (HCG), human placental lactogen (human choriosomatomamotropin HCS) and prolactin (PRL) were determined in the serum of 72 maternity patients and the serum of the newborn infants. The determinations were done with radioimmunologic tests (RIA). These three protein hormones were also determined in the amniotic fluid and in the maternal serum from 4-6 days prior to the delivery of the infant. The concentration of HCG or HCS in the serum of the newborn infants was a mean 0.43 or 0.37% of the level in the maternal serum. The concentration of PRL in the serum of the newborn was 118% and slightly higher than in the serum of the mothers. The concentration in the amniotic fluid was 1.5% for HCG, 5.8% for HCS, and 252% for PRL, compared to the corresponding levels in the maternal serum. The fact that the hormone concentrations in the amniotic fluid are significantly higher than in the serum of the newborn suggests excretion of the hormones from the fetal circulation via the fetal liver and the fetal kidney. The high levels of PRL in the maternal and the newborn serum may be caused by the high concentrations of estrogen or progesterone. Increased during the course of the pregnancy there was a significant sex linked difference in the level of HCG in the maternal serum correlated to the sex of the newborn infant.

[HCG in serum and peritoneal fluid in suspected ectopic pregnancy]. / HCG in Serum und Peritonealflüssigkeit bei Verdacht auf ektopische Schwangerschaft.

HCG was measured in peripheral serum and peritoneal fluid (PF), obtained by punction of the Douglas pouch (n = 12) or by laparoscopy (n = 14) in 26 patients with suspected ectopic pregnancy. In 10 patients with tubal pregnancy, the hCG-concentration in the PF was in every case higher than in serum. Contrary to this, in 11 disturbed and 2 normal intrauterine pregnancies the PF-hCG was lower than in serum. No hCG-gradient could be observed in 1 patient with an interstitial pregnancy. Moreover, in 2 patients with inconclusive laparoscopic findings, the PF-hCG was higher than in serum; this pointed to a probable harbouring of a suspected missed ectopic pregnancy, and treatment was therefore conservative. The PF-hCG level 35 h after i. m. application of 5000 IU hCG to non-pregnant women varied between 11 and 42% as compared to that of the serum. It is concluded that the gradient of hCG between PF and serum can be used for the verification of a suspected ectopic pregnancy in addition to other diagnostic methods.

[AFP and HbF determination in maternal blood as a parameter of fetomaternal microtransfusion in interventions of the pregnant uterus]. / Die AFP- und HbF-Bestimmung im mütterlichen Blut als Parameter der fetomaternalen Mikrotransfusion bei Eingriffen am schwangeren Uterus.

The applicability of AFP assay (radioimmunologic) and of erythrocytes containing Hb-F (Kleihauer et al. 1957) in maternal blood as a means of detecting fetomaternal microtransfusion was examined in 57 cases of abruptio and 65 women in whom genetically indicated amniocentesis was performed. There was a significant increase in AFP postoperatively in 40% of the abruptiones; after amniocenteses such behavior was far less pronounced (18.5%). The count of cells containing Hb-F in maternal blood smears revealed no significant increase in any of the cases examined. A correlation on the basis of these examination results is therefore unlikely. However, an evaluation of them demands that the assay methods used for AFP and Hb-F cells and, above all, their physiology, be taken into account. The diaplacental passage rates of the two substances are probably different, and under certain conditions they may also be produced by the maternal organism to a varying extent. It could be concluded from this that even though the AFP assay involves a simpler method and is more sensitive, neither parameter can replace the other, and therefore neither can be made the basis for a decision against anti-D immunoglobulin prophylaxis.