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Serum concentrations of hormones show typical time-dependent patterns. The diurnal course of the serum concentrations of the luteinizing hormone (LH) was assessed in 35 healthy females monitoring individual concentrations every ten minutes for 24 hours during the follicular phase of their menstrual cycle. Based on these in vivo data, a mathematical procedure was developed for calculation of the momentary hormone secretion rate of an endocrine gland from the time course of the hormone serum concentrations. By means of this procedure, we were able to define the complete 24 hours secretion pattern of LH, including the fact, that basal and pulsatile secretion could be separated from each other in an objective manner. It is possible to calculate the total amount of LH which is secreted per LH-pulse and the basal LH-secretion rate. Two methods were developed to define the time of the onset of an LH-pulse with a preselected probability. Describing the hormonal secretion pattern with a mathematical model provides the basis for therapeutic application of these methods to program implantable hormone-pumps for the therapy of glandular insufficiency.

In an overall study population (3 different study designs) of n = 285 patients the role of laparoscopic resp. laser-assisted techniques was evaluated on the basis of the results of distal tubal reconstruction. An interventional comparison of a laparoscopic (n = 150) with a retrospective microsurgical (n = 135) group of patients with distal tubal pathology showed a significantly higher baby-take-home rate in the laparoscopically treated patients (38% vs. 22.2%, p < 0.05), but detailed critical analysis of indication revealed a certain selection effect in the laparoscopic group. A prospective study on laser (n = 100) and non-laser techniques for salpingostomy showed in no significant differences between the two groups, as results were concerned (delivery 35% in the laser, 44% in the non-laser cohort). In a prospective randomized subgroup laparoscopic fimbrial eversion with the laser was compared to suture eversion (n = 20). In both groups the reocclusion rate was of 20%. On may thus conclude, that the most important surgical approaches for treatment of a tuboperitoneal sterility: micro-surgery and endoscopy, resp. the various surgical techniques: laser and non-laser, should not be regarded as competing procedures, but as components of a multimodal strategy. The indication, however, must be critically viewed in every particular case. Of major importance being strict scientific evaluation criteria to prevent misinterpretations, e.g. based on indication-specific selection.

Objective: On the basis of the evaluation of 300 patients who underwent myoma surgery with the desire for uterus preservation at the Department of Obstetrics and Gynaecology of Heidelberg University, a management scheme including endoscopic techniques was developed., Method: Despite the patients' wish for organ preservation, in 12 cases (family planning complete, therapy-resistant sterility, no desire for a child) with an extremely large uterus (20th-24th week of gestation) or a degenerated, intramural myoma (a sarcoma not being excluded), a primary hysterectomy had to be performed. Overall, 37.9% of patients underwent conventional, 42% laparoscopic and 20.1% hysteroscopic surgery. Additionally, to objectify the role of a pretreatment with GnRH analogues (GnRHa), the following control parameters were examined in 128 patients with and 160 patients without pretreatment: rate of primary laparotomies, conversion, secondary hysterectomy, intraoperative bleedings, amount of distension medium and percentage of repeat interventions., Results: No significant differences in the study parameters between study and control groups could be found in the patients treated by laparoscopy. In the hysteroscopy group, conversion rate (13.3 vs. 7%), operation time (35 vs. 21.9 min), rate of severe intraoperative bleeding (33.3 vs. 9.3%), amount of distension medium necessary (difference 2.1 litres) and rate of repeat interventions (40.4 vs. 16.3%) differed significantly between study and control groups., Conclusion: In the operative management, the key question is when to perform an invasive procedure. The second question should be which access route is the most convenient. The decision whether to give GnRHa pretreatment is also an individual one, especially in cases of a conventional or laparoscopic operative procedure. A preoperative GnRHa therapy is mandatory before hysteroscopy for submucous myoma.

The preclinical safety assessment of cyproterone acetate (CPA) with regard to liver tumorigenesis was based on tumorigenicity studies, which revealed no mutagenic potential. Recently, in vitro studies on the formation of adducts and the enhancement of DNA repair synthesis with CPA have been published. These results are not unique to CPA, and the role of adducts and increased DNA synthesis in mutagenesis is still not clear. Dose-related hepatic toxicity has been reported with the prolonged use of CPA. An active surveillance study of patients taking long term CPA treatment has shown no correlation between the duration of CPA treatment and the prevalence of liver enzyme elevations. In a multicentre surveillance study of long term CPA use in 2506 patients included so far, not a single case of hepatocellular carcinoma has been observed. These findings do not support the theory of an elevated risk of hepatocellular carcinoma as a result of CPA treatment. In conclusion, there have been no observations which could point to an increased risk of proliferative liver change as a result of CPA treatment.

We have shown that ethanol in concentrations of 0.0001%-10% significantly enhances 3H-thymidine uptake in cultured human mammary carcinoma cell line MCF-7. Methanol only enhances 3H-thymidine uptake in a concentration of 0.01%.

Leukotriene B4 directly enhanced progesterone release from superfused human granulosa cells. This secretory effect was observed in concentrations from 10(-12) to 10(-10) M. Lower and higher concentrations failed to affect progesterone release. When we analysed the high performance liquid chromatography profile of supernatant from human granulosa cell cultures, we detected a leukotriene B4 peak. In conclusion, these data support the hypothesis that leukotriene B4 may participate in the intracellular mechanism of progesterone release in human granulosa cells.

With transdermal estradiol substitution the so called "primary liver passage" is avoided. Taking into account also the low dose of estradiol the risk of hepatic side effects can be reduced. On the other hand, it was assumed that for the same reason desirable lipid effects regarding cardiovascular protection may also not be possible, in contrast to oral estrogen treatment. Treating 26 postmenopausal women with the estradiol patch releasing 0.05 mg daily and with 1 mg oral norethisterone acetate, added at least during 10 days in each cycle, a significant reduction was observed in total cholesterol as well as in LDL- and VLDL-cholesterol of about 15-20%. HDL-cholesterol first showed a decrease and thereafter it increased again to basic level. It is supposed that the reason for this may be different effects on subfractions of HDL-cholesterol. The triglycerides were lowered to about 20%. This result is thought to be important because oral estrogens have been associated with increases in triglycerides. By lowering LDL-cholesterol as well as triglycerides, both serum lipids, most important with respect to cardiovascular protection, are shown to be influenced positively.

The association between the use of oral contraceptives and the induction of liver tumors was first discussed by Baum et al. in 1973 [4]. Since the introduction of the pill a slight increase in the incidence of benign liver tumors has been found. In recent studies this could not be shown for liver cell carcinomas. In the world literature (1971-1994) 637 cases of patients with liver tumors who had taken oral contraceptives at any time of their lives have been reported. 233 liver cell adenomas, 210 focal nodular hyperplasia and 194 liver carcinomas were found. The incidence of liver tumors was not influenced by the type of progestin used.

The effect of cyproterone acetate (CPA) and spironolactone (SPL) on the serum androgen concentrations of premenopausal women with symptoms of hyperandrogenism were investigated in a total of 39 women. The observation period was 12 months. CPA was administered according to the Hammerstein regimen: cyproterone acetate (CPA) [Androcur] 100 mg/die 5.-14. day of the cycle; ethinylestradiol (EE) [Progynon C]: 40 mg/die 5.-25. day of the cycle; Spironolactone (SPL) was given in a dosage of 100 mg/die from day 1.-21. of the cycle. During the therapy with CPA a significant decrease of total testosterone (61%), free testosterone (78%), LH (48%) and 17 alpha-Hydroxyprogesterone (72%) was observed; during the medication with spironolacton only a significant decrease of 5 alpha-dihydrotestosterone (81%), which could not be seen during CPA use, was observed. Serum concentrations of total testosterone, free testosterone, LH and 17 alpha-Hydroxyprogesterone remained unchanged. DHA and DHAS did not change during neither medication. Since peripheral androgens were not suppressed by SPL the positive therapeutical effect of SPL can be explained by the antiandrogenic effect at the level of the receptor. A disadvantage of spironolacton is the lack of contraceptive efficacy. In cases where contraindication for oral contraceptives are present SPL can be considered as a good alternative to CPA. The suppressive effect of CPA/EE on total testosterone, LH addition to the antivulatory effect makes it the preferable medication for hyperandrogenemic patients with polycystic changes of the ovaries (PCOD).

The physiological role of inhibin and its relation to other sex hormones (estradiol, progesterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH)) has been investigated during gonadotropin-stimulated cycles of 38 in vitro fertilization-embryo transfer/gamete intrafallopian transfer (IVF-ET/GIFT) patients. Human menopausal gonadotropin (hMG) was given from day 3 of the cycle until 1 day before ovulation induction with human chorionic gonadotropin (hCG). Blood samples were taken twice daily and hormone measurements performed by radioimmunoassay or enzyme immunoassay. Patients were divided into two groups: Group A comprised patients < 35 years of age (n = 20) and Group B included patients > or = 35 years of age (n = 18). The pregnancy rate was significantly higher in Group A. During the follicular phase, serum inhibin level rose gradually in both groups but the values were higher in Group A (significantly between days -2 and 0). During the early luteal phase serum inhibin concentrations were similar in both groups. Estradiol pattern did not differ in the two groups. Estradiol pattern did not differ in the two groups. Whilst serum estradiol level did not increase significantly after day 0, serum inhibin concentration reached its peak value 1 day later, on day +1. Serum progesterone was higher in Group A between days +1 and +4 (significantly on days +1, +3 and +4). Serum FSH increased slowly in both groups and did not correlate with serum inhibin concentration. Basal LH concentrations were similar between days -6 and -2 in both groups. Around the time of ovulation induction (day -1, 0 and +1) serum LH was lower in Group A (significantly on day 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum inhibin concentrations of 64 cycles of in-vitro fertilization--embryo transfer (IVF-ET) or gamete intra-Fallopian transfer (GIFT) have been analysed retrospectively. No significant difference was observed in serum inhibin levels of cycles stimulated with buserelin and human menopausal gonadotrophin (HMG) or HMG alone. During the late follicular phase, serum inhibin was higher in cycles resulting in pregnancy than in cycles without a pregnancy (peak values on day +1: 8.3 versus 6.4 IU/ml, respectively). The same difference was found between stimulation cycles resulting in a viable or a non-viable pregnancy (peak values on day +1: 8.3 versus 7.5 IU/ml). However, these differences were not significant. During the early luteal phase, serum inhibin values were similar in these groups of patients. Our results indicate that the use of the gonadotrophin-releasing hormone (GnRH) analogue buserelin, in combination with HMG, for ovarian stimulation does not affect inhibin production by granulosa cells in vivo. The late follicular and early luteal concentrations of serum inhibin have to be considered unsuitable as predictors in IVF/GIFT cycles with respect to pregnancy and pregnancy outcome.

The efficacy and tolerability of a new oral contraceptive, norgestimate/ethinyl estradiol (250 micrograms of norgestimate/35 micrograms of ethinyl estradiol; Cilag GmbH Research, Sulzbach, Germany) were examined in an open-label study of 59,701 women who were evaluated during 342,348 menstrual cycles; 42,022 women completed the planned treatment regimen of six cycles. A use-efficacy (overall) Pearl index of 0.25 pregnancies per 100 woman-years was calculated based on 342,348 cycles. Tolerability was assessed for all women who completed six treatment cycles. Reductions in mean cycle length and duration of bleeding were noted; 32% of the women experienced reductions in the intensity of bleeding by the end of cycle 6. After six cycles of use, amenorrhea occurred in 1%, spotting in 4%, and breakthrough bleeding in 3% of the participating women. Treatment with norgestimate/ethinyl estradiol had minimal effects on weight, blood pressure, pulse, lipid metabolism, and blood glucose. Adverse effects (acne, nausea, or headaches) occurred at low frequencies and in many cases, were reduced compared with pretreatment levels. The results of this large-scale open trial were comparable with results from two other multicenter trials of the same formulation.

2,373 mothers and their newborn were studied during two years with respect to B streptococci colonisation or contamination. Bacteriological, vaginal and anal smears were taken from mothers at the beginning of parturition, as well as the amnion and the aspirated stomach contents of the newborn, employing, in each case, conventional culture methods and a latex agglutination test as a rapid testing method. Smears from the ears were also taken from the newborn for bacteriological examination. The vertical transmission and its possible influencing variables were examined in 1,328 mother/child pairs of the first observation year. Surface contamination of the newborn was confirmed in 10% in at least one smear. In the group of mothers with B streptococci colonisation, the amnion showed the highest rate of contamination (43%), followed by the aspirated stomach contents (26%) and the ear smears (taken from each side separately) with 28% and 30% respectively. Vertical transmission was decisively influenced by vaginal maternal colonisation (50% of the cases resulting in contamination of newborn), whereas anal colonisation, if it was the only site of colonisation, resulted in contamination of newborn in only 32% of the cases. The rate of contamination of newborn dropped significantly from 50% to 20% after intrapartal antibiotic prophylaxis, the latter appearing to be meaningful only after at least 6 hours of exposure. In this group, the surface contamination could be reduced from 61% to 8%. A group of newborn suffering from early onset of sepsis (0.4%), was compared with a group of 13 newborn at risk of infection (0.9%) with established surface contamination and clinical or laboratory chemistry confirmation of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in lipid metabolism in 25 healthy female volunteers during a 24-month application of Norplant-2 were evaluated in an open clinical trial. Total serum cholesterol decreased significantly (p less than 0.05/p less than 0.05) by 10%/9% after 12 months and by 3%/7% (n.s./n.s.) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). Serum triglycerides decreased by 34%/28% (n.s./p less than 0.05) after 12 months and by 29%/25% (p less than 0.05/p less than 0.05) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). HDL-cholesterol decreased significantly by 18%/12% (p less than 0.01/p less than 0.05) after 12 months and by 12%/12% (p less than 0.05/p less than 0.05) after 24 months of Norplant-2 use (all subjects/subjects completing 24 cycles). No statistically significant difference between serum levels of LDL-cholesterol prior to and after 12 and 24 months of Norplant-2 use could be found. VLDL-cholesterol levels decreased significantly by 38%/38% (p less than 0.05) after 12 and by 25%/25% after 24 months of Norplant-2 application (p less than 0.01) (all subjects/subjects completing 24 cycles). Apolipoprotein Al decreased significantly by 23%/23% (p less than 0.001/p less than 0.01) after 12 and by 21%/22% after 24 months of Norplant-2 application (p less than 0.01/p less than 0.01) (all subjects/subjects completing 24 cycles). No statistically significant difference between apolipoprotein All levels prior to and after 12 and 24 months of Norplant-2 implantation could be found. Apolipoprotein B decreased significantly by 27%/17% (p less than 0.05/p less than 0.05) after 12 months of Norplant-2 application (all subjects/subjects completing 24 cycles). The decline after 24 months of Norplant-2 use was not significant. Changes in lipid metabolism caused by oral hormonal contraceptives differ in the various clinical trials; however, most investigators found that serum levels of total cholesterol and triglycerides increase under the application of OCs. Contrary to this, a decrease of total cholesterol and triglycerides under Norplant-2 use was noted. Furthermore, we found a significant decrease of lipoproteins and apolipoproteins--with the exception of LDL-cholesterol and apolipoprotein All, which did not show any significant modifications. Thus, Norplant-2 seems to be non-contributory to cardiovascular risk and might even provide protection against such risks.

Serum estradiol, progesterone and luteinizing hormone (LH) levels of 16 pregnant and 58 non-pregnant stimulated in vitro fertilization-embryo transfer (IVF-ET) or gamete intrafallopian transfer (GIFT) cycles have been compared with regard to their predictive value for achievement of pregnancy. Serum estradiol and progesterone pattern of the pregnant and non-pregnant group did not show any significant difference. Around the time of ovulation induction by human chorionic gonadotropin (hCG) the serum LH values proved to be higher in the non-pregnant group than in the pregnant one. In spite of having a permissive function, preovulatory serum estradiol and progesterone seem not to have a predictive value with regard to pregnancy. Elevated preovulatory serum LH is detrimental for pregnancy, therefore the measurement of serum LH beyond hCG administration also, and the cancellation of cycles with high serum LH levels shortly before oocyte retrieval is recommended.

Changes of serum estradiol, progesterone, LH, FSH, prolactin, testosterone, androstendione, DHEA and DHEAS levels during a GnRH-analogue (buserelin) treatment have been analysed retrospectively taking account of effectiveness of treatment and its relation to the beginning and duration of treatment. 1200 micrograms/day buserelin were administered intranasally from the first day of the menstrual cycle (n = 30) or the 7th hyperthermic day of the cycle (n = 22). The results proved, that the administration of buserelin to sterile women inhibits the ovarian (estradiol, progesterone) and pituitary (LH, FSH) hormone secretion during the first 10-14 days of treatment. The adrenal hormone secretion (DHEA, DHEAS) remained unaffected, whereas the androgens of ovarian origin (testosterone, androstendione) were suppressed during the GnRH analogue treatment. The serum prolactin level increased during the first two weeks of treatment and returned to pretreatment values within the following two weeks. On the basis of the faster suppression of estradiol secretion with buserelin treatment, beginning in the middle of the luteal phase, this therapy is recommended for ovarian suppression.

Clinical results of a combined GnRH-analogue (buserelin, long protocol) + HMG stimulation of 44 IVF-ET or GIFT patients with previously failed pure HMG stimulation have been analysed. The cancellation rate and the incidence of premature LH surge was found to be lower in the buserelin + HMG group than in the control HMG group (30% vs. 40% and 16% vs. 51%). There was no significant difference between the buserelin + HMG and the control HMG group, neither in the number of retrieved and fertilized oocytes and transferred embryos nor in the fertilization and pregnancy rate. The combined GnRH-analogue and gonadotropin therapy led to a decrease of the cancellation rate and of premature LH surge in patients with previously failed pure HMG stimulation. In this group of patients the use of buserelin leads to treatment results comparable to results of pure HMG stimulated patients without previously failed stimulation cycles. Thus the GnRH-analogue + HMG stimulation is recommended for patients with previously unsuccessful pure HMG stimulation.

With an increasing frequency patients complaining problems with their hair show up in gynecologic office practices. We observe cases with alopecia androgenetica; both alopecia climacterica and postpartualis, being subgroups of alopecia androgenetica. From symptomatic as well as from pathogenetic point of view two other forms can be subdivided, to be named alopecia diffusa and alopecia areata. At the Department of Obstetrics and Gynecology of the University of Heidelberg an outpatients consulting programme for women with androgenetic symptoms was established some years before. The diagnostic procedures for a possible classification of the alopecia was intensified. The search for underlying internal diseases and/or endocrinopathies will be the first step towards a pathogenetically correct diagnosis, and if there is no plausible explanation reached by that, the investigation will be extended for heavy metal tracing or for the detection of other ecological damaging influences. A local treatment with thymus gland preparations (Thymu-Skin) was examined by following the conditions of a protocol. After treatment with the preparation (Thymu-Skin) 73% of all cases show improvement of the alopecia. The formula seems to be an effective alternative to the hormonal therapy. It is easy to administer and has no side-effects or contraindications. It proved also to be advisable for prophylactic use in combination with chemotherapy.

Normal values in endocrine testing are the most important precondition for the recognition of disorders of the endocrine system. To establish a reference range for adrenocorticotropic hormone (ACTH) stimulation tests, an intravenous and intramuscular ACTH stimulation test was conducted in 29 female volunteers without hyperandrogenism. A total of 25 IU of ACTH were administered intravenously or intramuscularly and blood sampling was performed before, 1 h and 2 h after ACTH injection. The test was performed on days 3-5 of the menstrual cycle. The following steroid hormones were assessed in the serum: 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone, dehydroepiandrosterone, testosterone, free testosterone and 5 alpha-dihydrotestosterone. The normal range was defined by the interval between the 5th and 95th percentiles; additionally the 1st, 25th, 50th, 75th and 99th percentiles are reported. A significant increase of serum hormone levels after ACTH administration could be observed for the following hormones: cortisol, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and dehydroepiandrosterone. There was no rise after ACTH application for testosterone, 5 alpha-dihydrotestosterone and free testosterone. It could be shown for all hormones that there was no significant difference between the serum levels that were reached after intravenous and intramuscular ACTH injection. Neither could we find a significant difference in the relative increase of the serum hormones when stimulation values were related to basal values. Since in most studies with ACTH stimulation tests, only the serum values 1 h after ACTH application are measured, we investigated whether the measurement of steroid hormones 2 h after ACTH application gave further information. We could demonstrate that for most measured serum hormones the majority of the volunteers had the maximal response 2 h after ACTH application, no matter whether ACTH was injected intramuscularly or intravenously. As a conclusion, we recommend the measurement of the respective hormones not only 1 h but also 2 h after ACTH stimulation. Since there is no increase after ACTH stimulation for total testosterone, free testosterone and 5 alpha-dihydrotestosterone, it is sufficient to assess the basal values of these hormones. Excessive adrenal response is reflected by dehydroepiandrosterone, 17 alpha-hydroxyprogesterone, 17 alpha-hydroxypregnenolone and cortisol.

Changes of serum oestradiol, LH and progesterone have been analysed in view of the effect of the GnRH analogue buserelin on the late follicular and early luteal phase of cycles stimulated with combined buserelin/HMG (n = 31) in an IVF-ET/GIFT programme. Patients undergoing cycles with HMG only (n = 57) served as the control group. With the use of the GnRH analogue buserelin, a significantly higher amount of HMG (25 versus 20 ampoules; P less than 0.001) for a significantly longer stimulation period (10 versus 8 days; P less than 0.001) was necessary to achieve the same oestradiol response as seen in HMG cycles. Serum progesterone levels during a three day period before ovulation induction tended to be lower in the combined buserelin/HMG cycles than in cycles with HMG stimulation only. We did not observe any significant difference in the luteal phase progesterone levels of the buserelin/HMG and the HMG group. On the other hand, we found that an inadequate luteal phase in buserelin/HMG cycles could be avoided by HCG administration during the luteal phase. Both the elevation of basal serum LH and a premature LH rise could also be avoided by the use of buserelin.

In this study we analysed the prevalence and the clinical relevance of premature (related to the day of ovulation induction with HCG) LH rise (LH greater than or equal to 180%, but less than 300% of the mean of all previous values) or peak (LH greater than or equal to 300% of the mean of all previous values): 12% (2/16) of the conception cycles showed a premature LH peak, 44% (7/16) a premature LH rise and 44% (7/17) showed neither a premature LH rise nor a premature LH peak. The pregnancy rate of cycles with premature LH peak was found to be 10% (2/21), without premature LH peak 37% (7/19). These results indicate, that the premature LH peak represents an unfavourable condition for achievement of pregnancy; the cancellation of such stimulations before oocyte retrieval is recommended. On the other hand, cycles with premature LH rise need not be cancelled. The fertilisation rate was independent of an LH rise/peak (no LH rise/peak: 55%, LH rise: 62%, LH peak: 46%): it is supposed, that the premature LH peak causes submicroscopical injury of the oocyte and although fertilisation is possible, further embryonic development will be hindered. The use of the GnRH analogue Buserelin in combination with HMG leads to a significantly (p less than 0.001) lower prevalence of the premature LH peak (16%; 7/44 versus 51%; 48/95); the combined Buserelin + HMG stimulation is recommended for treatment of premature LH peak.

At the Hospital of the Department of Gynaecology of the University of Heidelberg, a latex agglutination test (Strep B Patho Dx Test) was applied after extraction of antigens from amniotic fluid and gastric aspirate, parallel to the routine screening programme (vaginal and anal swabs) for maternal colonization with B streptococci. The latex agglutination test was applied in 1336 cases. Maternal vaginal colonization was detected in 14%, anal colonization in 17% of the cases. A comparison of the results obtained with the latex agglutination test and with conventional bacteriological procedures (no gradual bacteriology, incubation 48 hours) showed antigen identification in amniotic fluid in 54%, respectively 24%. In gastric aspirates a B streptococcal contamination was detected by bacteriology in 40% of cases, by the rapid latex agglutination test in 22%. If no streptococci were found in the mother, amniotic fluid or gastric aspirates were contaminated in 4% or 6%, respectively (agglutination test or bacteriology, respectively). With a sensitivity of approximately 50% and a specificity of 98%, the latex agglutination test proved superior to routine bacteriology. All clinically contaminated newborn (positive blood specimens) were clearly identified by this test. With this new latex agglutination test, a procedure is now available to detect B streptococcal contamination in newborns within less than half an hour, thus an intra- or postpartal antibiotic therapy can be applied early.

The cholesterol side chain cleavage enzyme (EC 1.14.15x) in mitochondria of a human term placenta was partially characterized. Enzyme activity was determined by separation of [26-14C]-cholesterol and [5-14C]-isocaproic acid formed by side chain cleavage. Since the amounts of unlabeled cholesterol were too large, a KM of cholesterol could not be determined. The apparent KM value of NADPH is 6.25 x 10(-4) M. A pH optimum was found at pH 9.5 (Tris buffer) and a temperature optimum at 40 C. The metal ions Sr2+ and Ba2+ showed no inhibition at 1 and 10 mM and a moderate inhibition at 100 mM. In low concentrations (1 mM), Mg2+ and Ca2+ slightly stimulated the enzyme whereas in higher concentrations (100 mM) an inhibitory effect was observed. A strong inhibition was achieved with 1 mM Zn2+, Cd2+, Cu2+ and by 10 and 100 mM Fe2+, Mn2+, Co2+ and Ni2+. During preincubation of the enzyme without radioactive substrate, a rapid loss in enzyme activity in relation to enzyme concentration was observed (initial activity = 100%) (preincubation time in hours): 0.5 h (97%), 1 h (55%) and 1.5 h (34%). A dose-dependent inhibition of the enzyme by the following proteins was achieved: bovine serum protein, human serum protein, human immunoglobulin G and ovalbumin. Furthermore, a dose-dependent inhibition was found with the membrane lipids lecithin and sphingosine.

Human placental 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) interconverts progesterone and 20 alpha-dihydroprogesterone (20 alpha-DHP). In this study, an endogenous inhibitor of the cytoplasmic 20 alpha-HSDH isolated from human term placenta is demonstrated. Characterization of the endogenous inhibitor was carried out by adding heat-denatured fractions of the 20 alpha-HSDH enzyme stock solution to the incubations. The aqueous phase of the 20 alpha-HSDH (after diethylether extraction) using 8-fold concentration of the enzyme inhibited the 20 alpha-HSDH activity by 50%. After ultrafiltration of the aqueous phase, this inhibitory effect (50%) was found in the aqueous fraction with a molecular weight above 12,800. No inhibition of the 20 alpha-HSDH was shown using the ether phase or the aqueous ultrafiltrate with a molecular weight below 12,800. The 20 alpha-HSDH was stimulated by human and bovine serum albumins up to 290% and 420% respectively. Bovine serum albumin showed a higher stimulatory effect on the oxidative (420%) than on the reductive (190%) pathway of the 20 alpha-HSDH. Ovalbumin and immunoglobulin G had no effect. The endogenous inhibitor of the cytoplasmic 20 alpha-HSDH isolated from the human term placenta is heat stable (100 degrees C), water soluble, not soluble in diethylether and has a molecular weight above 12,800. The stimulatory effect of serum albumins in 20 alpha-HSDH may be caused by binding and inactivation of the endogenous inhibitor.

Cholesterol side chain cleavage is determined by means of separation of (26-C14)-cholesterol and its radioactively labeled side chain (1-C14)k-isocaproic acid. Alumina minicolumn assay (AMCA): adsorption of cholesterol from an aqueous phase by aluminium oxide, while isocaproic acid can percolate through the column. In modification of a previously described technique (1), cholesterol is quantitatively eluted by ethanol. Filter assay (FA): retention of cholesterol by a membrane filter (pore size less than or equal to 0.1 um) while isocaproic acid can pass the filter. Two-phase scintillation assay (TPSA): pH-dependent partition of isocaproic acid between an organic scintillation mixture and an aqueous phase. The TPSA can be applied for all enzymatic reaction in which the polarity of the radioactive residue which is split off depends on pH values or when the total charge of a polar molecule is changed to an apolar state by cleaving one non-radioactive group (e.g. steroid sulfates) and vice versa. The criteria or reliability of the test systems are described. Bovine adrenal mitochondria were incubated and the side chain cleavage of (26-C14)-cholesterol was studied by the new tests systems and compared to the conversion rates of (4-C14)-cholesterol to its metabolites are determined by thin layer chromatography. A good agreement of all tests was found.

Two cases of carcinomatous meningeosis are reported. One occurred during cis-platinum combination treatment (PAC-scheme) for advanced ovarian carcinoma and one during the same treatment for a carcinoma of the cervix. Both patients showed no neurological problems prior to chemotherapy. The central nervous symptoms developed rapidly following the administration of small doses of cis-platinum (total dose 160 or 300 mg) and could not be controlled. In one case tumour cells were found in the cerebral spinal fluid. The cause of death could have been an unusually toxic reaction to cis-platinum. A thorough neurological examination prior and during chemotherapy with cis-platinum is necessary in order to recognize toxic side effects of the drug as soon as possible.

Sulfatase and aromatase are the key enzymes of estrogen biosynthesis in the human placenta. A total of 76 pregnancies with sulfatase deficiency have been reported. Reduced sulfatase activity occurs in 1:2000 of 1:6000 pregnancies. It can be suspected in patients with low urinary excretion or low serum estriol levels. The sulfatase deficiency can be detected during pregnancy by a prolongation of the half-life of dehydroepiandrosterone sulfate (DHAS) after venous DHAS loading (50 or 100 mg). Post partum the placental sulfatase deficiency can be demonstrated in vitro by nonconversion of radioactive DHAS to DHA. Only 7 of the 76 pregnancies described ended with an uncomplicated vaginal delivery after spontaneous onset of labor. A cesarian section was required in 18 cases. The other case reports mostly concern patients associated with a prolonged pregnancy, lack of cervical dilatation, or absent induction of labor. All 76 newborns were male. Sulfatase deficiency is probably a congenital, sex-specific, X-linked placental enzyme defect. A special therapy is not necessary but the antepartum diagnosis is important because this benign disorder has to be discriminated from the more serious fetal adrenal hypoplasia.

After preincubation of term placental tissue in organ culture for 24 h, progesterone synthesis is 2-3 fold lower than without preincubation. By adding human male serum proteins (MW less than 12,400), we obtained 2-3.5 fold lower tissue levels of progesterone. Serum proteins with high molecular weight (MW greater than 12,400) are postulated to facilitate progesterone release by binding free medium progesterone. In test series without preincubation, there are no significant (p less than 0.05) differences in progesterone formation in the presence of cholesterol (C), cholesteryl linoleate (CL), and LDL. In test series with preincubation, LDL causes a twofold increase in medium progesterone with C (0.1 and 1 mM) and CL (0.1 mM) in the presence of the low molecular weight serum protein (MW less than 12,400) solution. A decrease of 50% was obtained by 1 mM CL with/and without LDL. In culture medium containing high molecular weight serum proteins (MW greater than 12,400), 0.1 and 1 mM C and CL induce a twofold increase in progesterone production without any significant (p less than 0.05) differences between the single values. No further stimulation could be observed by LDL because there was sufficient LDL for maximal progesterone formation. In conclusion, LDL enhances the utilization of cholesterol and cholesteryl linoleate for progesterone production in term placenta. A lipoprotein cholesterol receptor is suspected.

Lipoxygenase metabolites of arachidonic acid were shown to stimulate gonadotrophin release dose-dependently in rat pituitary cells. The secretory activity of the arachidonate metabolite leukotriene C4 (LTC4) was biphasic and 10-fold more potent than that of the physiological stimulus gonadotrophin-releasing hormone (GnRH). In pre-labelled, superfused pituitary cells, GnRH dose-dependently enhanced the release of [3H]arachidonic acid, which occurred simultaneously with the secretion of luteinizing hormone (LH). When cells were pre-treated with GnRH for 24 h no response to a further stimulus by GnRH (10(-7) M) could be observed for either [3H]arachidonate nor LH, demonstrating that also in desensitized cells these two mechanisms react similarly. In addition, a GnRH antagonist did not affect the release of arachidonate or LH. These results suggest that arachidonic acid may be involved in the mechanism of GnRH action on gonadotrophins via its lipoxygenase metabolites and LTC4 could act as a very potent intracellular stimulus of LH secretion.

Oral hormonal contraception is a low risk and safe form of contraception for women between 15 and 35 years of age without risk factors in the history (smoking, obesity, diabetes mellitus, hypertension, hypercholesterinemia). Women over 35 years should take the pill only when risk factors have been excluded previously. In general, low dose pills with less than 50 micrograms ethinylestradiol should be used, because they have the lowest impact on the metabolism. There should be an additional indication even after exclusion of risk factors, if women over 40 years take the pill. Besides that it could be shown that using the pill has many positive effects on health, as for example benign mamma tumors more seldomly occur, in most of the cases the dysmenorrhoea improves, anaemia and inflammatory adnex diseases are significantly more seldom, and it could be shown that there is a clearly protective effect concerning the morbidity of endometrium and ovarian cancer.

In organ cultures the regulation of beta-hCG formation in human placentas of early gestation (EG) and at term (T) was analyzed using the following test substances: dibutyryl cAMP (dbcAMP), theophylline, and by two drugs used to treat patients with premature labor, fenoterol hydrobromide and verapamil hydrochloride. The rapid increase in beta-hCG in culture medium beginning at 24-48 h corresponds to morphologic changes (proliferation of the cytotrophoblast). Beta-hCG synthesis of human placenta is related to an adenylate cyclase as could be shown by dose-dependent stimulation by dbcAMP (T) (after 72 h) (controls = 100%): 2 nM = 125%; 70 nM = 200%; 2 microM = 300%. Similar results were obtained using EG. First stimulation by dbcAMP was found after 2 h and may be caused by a release of intracellular beta-CG or by a direct stimulation of beta-hCG synthesis; late effects (after 48-72 h) are suspected to be due to changes in morphologic differentiation of the placenta in organ culture. Theophylline (0.1 and 1 mM) did not influence beta-hCG formation in EG, whereas in T a dose-dependent stimulation could be achieved (controls = 100%): 0.1 mM = 110%; 1 mM = 300%; and 10 mM = 160%. Fenoterol hydrobromide, a tocolytic beta 2-receptor stimulating agent showed a slight (130-160%) beta-hCG stimulation (after 72 h) (EG and T). The stimulatory effect of a high dose (1 microgram/ml) of fenoterol hydrobromide could be due to a stimulation of beta 2 receptors related to an adenylate cyclase. Dose-related changes in beta-hCG in T were found for the calcium antagonist verapamil hydrochloride (controls = 100%): 0.01 microgram/ml = 125% stimulation; 0.33 microgram/ml = 200% stimulation; 10 micrograms/ml = 100%. As indicated by verapamil tests, calcium ions may play a role in the regulation of beta-hCG production.

Chronic placental insufficiency results in intrauterine fetal growth retardation (IUGR). The IUGR can be diagnosed by clinical signs (follow-up of maternal weight, fundus height, abdominal circumference), ultrasound examination (biparietal and thoracic diameters, circumferences of the head and the trunk), and by endocrinologic tests (estrogen determination in serum and urine without and after performance of a DHAS loading test). The different ways of performing the DHAS loading test reported in the literature are reviewed. The DHAS loading test measures the aromatization capacity of the human placenta and indirectly its metabolic exchange capacities. After DHAS loading, estrogens (estrone, estradiol, estriol), DHAS and DHA can be determined in blood and urine; furthermore, changes in urine total estrogen excretion can be evaluated. In conclusion, the best parameter for diagnosing IUGR seems to be the determination of the DHAS half-life after DHAS loading. A prolongation of DHAS half-life (greater than 4.7 h) after DHAS loading (50 mg i.v.) is a good index of IUGR.

The inhibitory effect of d,l-aminoglutethimide (AG) on the synthesis of progesterone and estradiol in early human pregnancy (8th-12th week of gestation) was investigated in volunteers; control group (n = 11), AG group [1000 mg AG orally at test begin (n = 6)]. Venous blood samples were taken at the beginning of the test and 0.5, 1, 2, 4, 8 and 24 h thereafter. In controls, no significant changes in serum progesterone and estradiol could be observed during 24 h. In the AG group, a decrease in progesterone and estradiol could be observed within 1 h after the test began; lowest serum steroid concentrations were reached after 4 h. Relative to the initial values taken as 100%, the greatest decrease in progesterone ranged between 37 and 83%, 62 +/- 15% (means +/- SD)(n = 6); the greatest decrease in estradiol ranged between 32 and 78%, 51 +/- 17% (means +/- SD)(n = 6). Twenty four hours after AG treatment, both steroids reached similar concentrations to those found at test begin. No clinical signs (e.g. uterine bleeding, contractions) for the abortifacient action of AG were observed. In conclusion, a single dose of AG (1000 mg given orally) cannot induce a therapeutic abortion in early pregnancy. In accordance with in vitro studies, the inhibitory effect of AG on placental progesterone formation is due to an inhibition of mitochondrial cholesterol side chain cleavage. The decrease in estradiol is thought to be related to an inhibition of placental aromatase.

Gonadotropin release in rat pituitary monolayer cultures was stimulated by phospholipase A2, as well as by its activator melittin. A dose-dependent stimulation of luteinizing hormone secretion by melittin was observed in a dose range of 10(-8) to 10(-4) M. A higher dose (1 mM) melittin had a sub-optimal effect. The stimulatory action of melittin was calcium-dependent and blocked by phospholipase A2 inhibitors, chloroquine and quinacrine. Similar to melittin, phospholipase A2 enhanced the effect of LH release in a dose range of 0.1-100 units/ml. The effect of this enzyme was also calcium-dependent with optimal calcium concentrations at 1.5 mM, as obtained also for melittin. In superfusion experiments, the stimulatory action of melittin and phospholipase A2 was reproducible in their effects on LH release in gonadotrophs. In addition, melittin (10(-7) M) stimulated LH and 3H-arachidonic acid efflux in superfused pituicytes following prelabelling with radiolabelled arachidonate. These data suggest that phospholipase A2, which releases arachidonic acid from phospholipids, may participate in controlling gonadotropin secretion in gonadotrophs, since arachidonic acid and its metabolites have previously been found to enhance gonadotropin release.

Addition of gonadotropin releasing hormone to myo-[2-3H]inositol-prelabeled rat pituitary cells in primary culture evoked a dose-dependent increase of the accumulation of [3H]inositol phosphates with a rise of inositol triphosphate within 30 sec of stimulation, followed by a rise in inositol diphosphate and inositol monophosphate. Inositol phosphate accumulation was enhanced up to 5-to-8-fold and was time-dependent between up to 15 min incubation without further increase beyond this time period. Without preincubation with LiCl2, there was no measurable increase of GnRH-induced inositol phosphate accumulation compared to controls. The presence of calcium in the incubation medium did not affect the increase of inositol phosphates. These data give evidence, that polyphosphoinositide breakdown may be an early step in the action of gonadotropin releasing hormone on gonadotropin secretion.

A new, simple, fast and highly practicable aromatase assay and its application is described. This test depends on the release of tritiated water after aromatization of [1 beta,2 beta-3H]- or [1,2-3H]-androstendione or testosterone. In tests with [1 beta,2 beta-3H]-androstendione, nonradioactivity labeled estrogens are formed whereas in tests using [1,2-3H]-androstendione as substrate both estrogens and water contain tritium atoms. Tritiated water is determined by a two-phase scintillation technique depending on the limited emulsifying capacity of dioxane-based scintillation solution for water. A small volume (0.1 ml) of water is completely emulsified by the scintillation solution (10 ml) and all tritium-labeled substances can be measured. After addition of 2 ml distilled water 95% of the tritiated water is partitioned in the aqueous phase and only (1 beta,2 beta-3H]-androstendione or [1,2-3H]-androstendione and tritium labeled estrogens can be counted. The amount of tritiated water in each test can be calculated by impulse differences before and after addition of 2 ml distilled water. This aromatase assay using [1,2-3H]-androstendione was compared to a method described by Thompson and Siiteri [1] depending on extraction of steroids prior to scintillation counting. A good agreement of both methods was found. In tests with human term placenta aromatase in microsomes the apparent Km of androstendione was determined to be 8.9 nM. Aminoglutethimide showed a 50% inhibition of the placental microsomal aromatase at 0.6 microM.

Endometrium morphology has been analysed by means of light microscopy, scanning and transmission microscopy in patients before and during treatment with a norgestimate containing low dose combined pill (Cilest). Endometrium biopsies were taken after 1 (N = 3), 2 (N = 3), 3 (N = 7), 5 (N = 1) and 6 (N = 4) OC cycles. Light microscopy of the endometrium obtained during the OC-free pretreatment cycles shows a regular secretory transformed endometrium. During the first OC cycles of Cilest treatment slight growth retardation of endometrial glands was observed. Endometrium after 3 to 6 OC cycles showed an increasing delay of the growth of endometrial glands in terms of an abortive secretion. Morphometric studies revealed a retardation of the development of endometrial glands and an "arrest of secretion". The degree of proliferation varied slightly; a general delay between the date of the menstrual cycle and endometrial dating was evident. Using scanning electron microscopy the endometrium presented mostly a regular surface corresponding to the midcycle or a late proliferative phase up to the early secretory phase. Infiltrative dysplasia or inflammatory changes as well as local proliferations could not be detected. In transmission electron microscopy with semi-thin and ultrathin slices, stroma, structure of glands and surface appeared to be normal. Furthermore, no time delay between the endometrium and the day of menstrual cycle was observed. During treatment with a norgestimate containing low dose combined pill, only slight changes of the endometrium in terms of a growth retardation of endometrial glands were seen in the first 6 treatment cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

The steroid hormone progesterone is necessary for the maintenance of human pregnancy. It protects the uterus against the labour-inducing effect of prostaglandins and oxytocine. Before the 8.-9th week of gestation progesterone is produced by the corpus luteum and thereafter by the human placenta. The progesterone production of the human placenta is widely independent of endocrine organs of the mother and the foetus and controlled by autoregulation. Progesterone is formed from cholesterol taken up from the maternal circulation in the form of lipoprotein complexes. After side-chain cleavage of cholesterol pregnenolone is formed, which is converted by a 3 beat-hydroxysteroid dehydrogenase, delta 4-5 isomerase to progesterone. Progesterone is released partly to the mother and via the umbilical cord to the foetus. In the foetus a high conversion to 20 alpha-dihydroprogesterone takes place and this compound is transported to the placenta and recycled to progesterone. The steroidogenic enzymes of the progesterone pathway are controlled by various feedback inhibitions; activators could not be isolated so far.

269 patients were interviewed in a private abortion clinic in Lindenfels, Hessen, West Germany on aspects of contraception and abortion. The results indicated three crucial points, which influence contraceptive behaviour: social barriers, which affect indirectly the access to and the handling of contraceptives; psychic, mainly unconscious barriers, which counteract contraception; an increasing distrust and rejection of modern medical contraception, especially in highly educated women. These barriers are evident in lack of information, differing in the various social groups; partly irrational and exaggerated fear of side effects, and lack of success of factual information. Furthermore, poor co-operation is evident on the part of the husband or partner together with considerable shortcomings in medical counselling.

In vitro, danazol showed a slight dose-dependent inhibition of the mitochondrial cholesterol side chain cleavage enzyme isolated from early gestational (8th to 12th week of gestation) placenta. In the presence of 100 microM danazol, the enzyme activity was 65% of controls. Danazol inhibits dose-dependently the mitochondrial 3 beta-hydroxysteroid dehydrogenase (I50 = 3.1 microM; Ki = 1 microM) (noncompetitive inhibition) and the cytoplasmic 20 alpha-hydroxysteroid dehydrogenase (I50 = 1.4 microM; Ki = 2.6 microM) (competitive inhibition). The inhibition of human placental progesterone synthesis by danazol in vitro is a further example for the direct interference of danazol with steroidogenesis.

The inhibitory effect in vitro of four synthetic steroids on enzyme systems of placental progesterone synthesis at term was analyzed. Cholesterol side chain cleavage enzyme (CSCC) was not influenced by azastene, trilostane, and WIN 32,729. A 50% inhibition of CSCC was found by 10 microM cyanoketone. The 3 beta-hydroxysteroid dehydrogenase was dose-dependently inhibited by azastene (I50 = 1 microM, trilostane (I50 = 4 nM), cyanoketone (I50 = 3 nM), and WIN 32,729 (I50 = 5 nM). A competitive inhibition of the 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) by azastene (I50 = 0.6 microM), trilostane (I50 = 4.1 microM), cyanoketone (I50 = 0.6 microM), and WIN 32,729 (I50 = 1.5 microM) was observed. No difference in the effect of steroids on the 20 alpha-HSDH of early gestational and term placenta was found. The four steroidogenic inhibitors did not affect the activity of placental aromatase in vitro. Our results allow a comparison of inhibitory potencies of four steroidogenic inhibitors on different steroidogenic enzymes in vitro.