Lack of binding of gestodene to estrogen receptor in human breast cancer tissue.

Competition studies with progesterone and estradiol receptors of human myometrial tissue as well as of mammary cancer tissue showed that gestodene bound with high affinity to the progesterone receptor, as did other synthetic and natural progestogens. However, gestodene did not bind to the estradiol receptor. The relative binding affinities of all tested synthetic and natural ligands showed no organ-specific differences and no differences between neoplastically transformed and normal tissues.

Comparison of two hormone replacement regimens--influence on lipoproteins and bone mineral content.

Two hormone replacement therapy regimens were tested in a double-blind clinical trial involving 49 patients. In both cases the oestrogen component was 2 mg oestradiol valerate. This was administered for 21 days and sequentially combined for 10 days with either 0.5 mg norgestrel + (Cyclo-Progynova) or 1 mg cyproterone acetate (SH D 461 A). Each treatment cycle was followed by a 7-day tablet-free period. Both regimens proved to be equally effective in alleviating climacteric complaints. However, the low-density-lipoprotein cholesterol lowering effect of SH D 461 A was found to be superior to that of Cyclo-Progynova. There were no changes in bone mineral content during the one-year treatment period with either combination.

Efficacy and acceptability of intravenously administered sulprostone, a tissue-selective prostaglandin-E2 derivative, for induction of first-trimester abortion.

The abortifacient effect of a new tissue-selective prostaglandin E2-derivative, sulprostone, administered intravenously, has been investigated in 166 women in the the first trimester of pregnancy. Four different dose schedules (1.7 mcg/min for 5 or 10 hour--total dose 500 mcg or 1000 mcg, 2.8 mcg/min and 4.1 mcg/min for 6 hours--total dose 1000 mcg and 1500 mcg) have been evaluated. No absolute failures occurred and no severe complications or side-effects were recorded. Best results (high abortifacient efficacy and low systemic side-effects) were obtained by infusing 1000 mcg sulprostone in appr. 10 h. Our study indicates that sulprostone appears to have a high degree of acceptability.

Influence of the LH-RH analogue buserelin on cyclic ovarian function and on endometrium. A new approach to fertility control?

The long-acting stimulatory luteinizing hormone - releasing hormone analogue D-Ser(TBU)6-EA10-LH-RH (buserelin) was administered intranasally once daily in a dose of 400 mcg to 24 normally ovulating women and to 4 women with pre-existing endocrine dysregulation. Ovulation was inhibited in 136 out of 156 treatment months. In 20 treatment months, progesterone values temporarily increased indicating luteinization of follicles or ovulation with defective corpus luteum function. Estradiol secretion showed a tendency to lower values as treatment progressed but individually indicated follicle maturation until the end of the observed medication period. Bleeding pattern ranged from menses-like bleeding in regular as well as irregular intervals to amenorrhea. The morphological findings of 31 endometrial biopsies of 20 volunteers ranged from atrophy (n = 4) to proliferation (n = 25) with early signs of hyperplasia as well as early secretory transformation (n = 2). The morphological alterations indicate that unopposed estrogen stimulation of the endometrium is the main problem of long-term contraception with the dose schedule of buserelin used.

Gestodene: a novel synthetic progestin--characterization of binding to receptor and serum proteins.

Gestodene, 17 alpha-ethinyl-13-ethyl-17 beta-hydroxy-4,15-gonadien-3-one, is a new orally active progestational agent, which is available for clinical use in oral contraceptives. The aim of the present study is to make a broad characterization of gestodene at the receptor level and to discuss the results in comparison to those of established progestogens. Kinetic studies of 3H-gestodene uptake show a rapid increase in the amount of specific binding during the first three hours. After saturation, the amount of specifically bound 3H-gestodene remained almost constant up to 24 hours at 4 degrees C. The dissociation of 3H-gestodene from the cytoplasmic myometrial progestone receptor, measured by displacement of labeled steroid with dextran-coated charcoal treatment at 4 degrees C at various times, showed a biphasic or two-component first order dissociation curve. As anticipated, sucrose gradient centrifugation analysis of the 3H-gestodene-labeled cytosol of human myometrial tissue showed that the gestodene binding components sedimented in the 4S and 8S region. A 200-fold molar excess of nonradioactive gestodene reduced only the 8S binding of 3H-gestodene. 4S binding of 3H-gestodene was not reduced, which indicate the existence of a second high capacity binding component. In biological test systems, such as the Clauberg test or Kaufmann test, gestodene has proved to be a very effective progestogen. Among nortestosterone derivatives it is one of the most potent and resembles progesterone biologically in its progestogenic effects. This biologically identical gestagenic activity of gestodene and progesterone is reflected by a very similar behavior in vitro in terms of binding to progesterone receptors of human uterus cytosol. Furthermore, competitive studies indicated that gestodene like other synthetic progestagens also displays some affinity for androgen and glucocorticoid receptors but no measurable affinity for the estrogen receptor. Remarkable is the high binding affinity of gestodene to the binding sites of the mineralocorticoid receptor of rat kidney with a RBA value of 350% compared to aldosterone.

3H-ZK 98,734, a new 11 beta-aryl substituted antigestagen: binding characteristics to receptor and serum proteins.

Recently, in the laboratories of Schering in Germany a competitive progesterone antagonist, ZK 98,734, was synthetized, which is characterized by a similar antigestagenic activity as RU 38,486, synthezised by Roussel-Uclaf in France, as assessed by inhibition of nidation tests in rats and guinea pigs. However, this compound has a substantially lower antiglucocorticoid activity measured in cell culture systems than RU 38,486. The purpose of this study was to present a comparison of biochemical and physical properties of the complexes formed by the human uterine progesterone receptor with 3H-ZK 98,734 on one hand and with other well-established progestins on the other hand. ZK 98,734 competed in the same order of magnitude as progesterone or RU 38,486 for the 3H-R5020 binding site of progestin receptor, whereas R5020, Org 2058 or progesterone were unable to compete against 3H-ZK 98,734. This apparent contradiction could be explained by means of FPLC-chromatography and sucrose density centrifugation technique. FPLC-chromatography with an anion exchange column (Mono Q, Pharmacia, Uppsala, Sweden) showed that 3H-ZK 98,734 forms at least two stable complexes with uterine cytosol, on one hand with serum albumin, which presents almost 90% of bound radioactivity, and on the other hand with the two native progestin receptor forms, corresponding to 4S and 8S receptor forms in sucrose density gradient analysis. Competition experiments in liver cytosol of adrenalectomized rats with increasing concentrations of unlabeled ligands other than dexamethasone showed that ZK 98,734, RU 38,486 and cortisol displaced 3H-dexamethasone efficiently from the binding sites in the cytosol. Furthermore, results concerning the specificity of 3H-cortisol binding to serum proteins in diluted pregnant serum demonstrated that ZK 98,734 did not compete with 3H-cortisol for serum binding.

[Aqueductal stenosis and hydrocephalus in a psychotic adolescent]. / Aquäduktstenose und Hydrocephalus bei einem psychotischen Jugendlichen.

Examination of a 14-year-old male who was admitted to an inpatient unit with an acute paranoid syndrome yielded serious organic findings: macroencephaly, head tilted to one side, strabismus, neurological deficits, hydroencephaly and an expressive speech disorder. The personal and family history revealed a disturbance of motor development since infancy and psychiatric illness in the immediate family. The medication and the surgical procedure selected--endoscopic third ventriculostomy--are described and the difficult differential diagnosis is discussed.

[Diagnostic and differential-diagnostic considerations regarding the assessment of children's reactions within the scope of psychosocial care in paediatric oncology and haematology]. / Diagnostische und differenzialdiagnostische Abwägungen zur Einschätzung kindlicher Reaktionsweisen im Rahmen der psychosozialen Versorgung in der pädiatrischen Onkologie und Hämatologie.

Oncological diseases in children and adolescents represent a considerable burden for the children themselves and for their families. In order to position such concomitants of a life-threatening disease appropriately among the diagnostic options of psychosocial cancer care one is repeatedly confronted with the issue of giving a diagnosis from the area of reactions to burdens and adaptive disturbances (ICD 10: F: 43 ff). This touches the question of whether or not confronting a life-threatening disease in and by itself suffices to fully justify establishing one of the psychiatric diagnoses mentioned, which would imply that the intensity of the burden experienced justified the assumption of a psychiatric disturbance in the person affected. Whereas considerable effort is regularly spent on taking action and giving support and care, and reactions occasionally exceed the appropriate degree, a fair majority show no pathological processes that would justify determining a psychiatric diagnosis as a rule. Ultimately, one would arrive at a false interpretation of actually altogether adequate reactions of the patient to the burden. The ICD and DSM classification systems, however, do not provide for diagnoses other than those allocated disease status; it must therefore be considered whether it may be better in these cases to speak not of a reaction to a burden or an adaptive disturbance in the sense of the ICD 10, Section F, but rather of a sustained reaction to a burden. This opinion is increasingly gaining acceptance in pediatric oncology.

Intrauterine death of a single fetus in twin pregnancies.

The paper reports on nine twin pregnancies in the years 1982-1987 with the intrauterine death of a single fetus. The incidence of 0.10% is consistent with that reported in other comparable studies. Evaluation of the causes of death shows a preponderance of asphyxia. A fetofetal transfusion syndrome occurred in 4 cases. Eight of the pregnancies were terminated by caesarean section. One of the surviving children died in the neonatal period. The course of the neonatal period in the other babies was determined mainly by the state of maturity. No increased maternal morbidity was observed. On the basis of this and other experience described in the literature, some general guidelines are proposed for the management of the further pregnancy and delivery in such high-risk cases.

Issues to debate on the Women's Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma?

In July 2002 the data of the prematurely stopped Estrogen plus Progestin study of the Women's Health Initiative (WHI) were presented in the Journal of the American Medical Association. The results of the Heart and Estrogen/Progestin Replacement Study (HERS/HERS II) were published in the same issue. The results of WHI for healthy postmenopausal women often are interpreted to be in analogy with the HERS/HERS II results for postmenopausal women with established coronary heart disease. As a result of HERS/HERS II and WHI, use of HRT in general became questionable. This is an unjustified judgement of HRT in general. This synoptic review and criticism of both studies will show the methodological weaknesses and their consequences and the reasons for limited generalizability of the study results from WHI and HERS/HERS II on normal HRT users.

[Experiences with intravenous sulprostone administration in massive postpartal hemorrhage]. / Erfahrungen mit intravenöser Sulproston-Applikation bei massiven postpartalen Blutungen.

Forty-three patients at the University Gynecology Clinic in Charlottenburg were given the prostaglandin E2 derivative sulprostone for severe postpartal hemorrhage. It was administered intravenously in a dose of 1.7 mcg/min (100 mcg/100 ml/h), with short-term increases to three times this amount in isolated cases. The drug proved highly efficacious (rapid onset and lasting effect). In 80% of the cases there were no side effects. Rises in body temperature occurred in six patients and in one patient a venous irritation developed in the arm into which the drug was infused. An RDS occurred, though it was considered that there was not necessarily a causal connection between this and the sulprostone infusion. In the authors' experience this drug has an established place in the treatment of atonic postpartal hemorrhage emergencies.

[Ovarian function and recurrence in adjuvant chemotherapy of breast cancer]. / Ovarialfunktion und Rezidiv bei adjuvanter Chemotherapie des Mammakarzinoms.

The present paper reports the results of a prospective study of the influence of adjuvant chemotherapy (1) on ovarian function and (2) on recurrence and the patient's endocrine function status. Observation criteria were the endocrine status before, during and after chemotherapy. The follow-up period ranged from 12 to 78 months. The patient population comprised 80 women, of whom 39 were treated with AC and 41 with CMF. Of the 80 women, 56 (70.0%) had hypergonadotropic function at the end of treatment; 31 of these had been treated with AC and 25 with CMF. Significantly more women (p less than 0.1) who had undergone AC therapy were hypergonadotropic than among those treated with CMF; 28 of the patients had recurrences during the follow-up period. Among women with undisturbed ovarian function under chemotherapy (eugonadotropinemia), recurrences occurred more frequently (50.0%) than among chemically castrated patients (28.6%). This effect was especially apparent among patients in the AC group with positive receptor status and chemotherapeutically induced ovarian suppression. CMF therapy produced no difference between eugonadotropic and hypergonadotropic patients with regard to frequency of recurrences, not even when there was a correlation with their receptor status.

A highly specific radioimmunological determination of sulprostone (1) using antisera against two different haptens.

A sensitive and specific radioimmunoassay for sulprostone in serum has been developed. The use of antisera raised against two different haptens allows the determination of sulprostone alone or together with its main metabolites. Radioactive tracers with high specific radioactivity were synthesized by coupling the haptens to [125I]-iodohistamine.

[Deliveries in patients with more than 1 cesarean section]. / Entbindungen bei Patientinnen mit mehr als einem Kaiserschnitt.

The mode of delivery in 49 women with two or more previous cesarean sections was examined. In 33 cases (67%) a primary re-cesarean section was performed, in 12 of 16 patients (75%) a vaginal birth was possible. Emphasis was given to the causes leading to the latest cesarean section to the maternal and infant conditions and complications and the relevant factors from earlier cesarean sections. The results were discussed by comparison to related publications. Some fundamental considerations about the mode of delivery in cases of repeated cesarean sections were presented. The justifications for a repeated primary cesarean section based on the previous record to two or more cesarean sections alone seems to be no longer given.

[Sulprostone, a new prostaglandin E2 derivative (author's transl)]. / Sulproston, ein neues Prostaglandin-E2-Derivat. Therapeutisches Spektrum bei der Abortinduktion.

Sulprostone, a new synthetic prostaglandin E2 derivative, was used for interruption of pregnancy in 479 patients with different lengths of pregnancy. Systemic forms of administration (i.v. and i.m.) were superior to non-systemic ones (intraamnial, extraamnial). In comparison with prostaglandins used up to now this substance is characterised by a higher rate of success and clearly reduced systemic side effects. As a consequence of these results a new clinical concept of artificial abortion with prostaglandins using sulprostone is presented: 1. i.m. application for induction of early abortion before the 6th week of pregnancy and for softening of the cervix up to the 12th week of pregnancy. 2. i.v. drip of termination of intact and disturbed pregnancies beyond the first trimenon.

[Clinical experiences in the treatment of endometriosis with the LH-RH analog buserelin with special reference to the post-therapy course]. / Klinische Erfahrungen der Endometriosebehandlung mit dem LH-RH-Analogon Buserelin unter besonderer Berücksichtigung des posttherapeutischen Verlaufs.

The current therapy study with 50 patients showed that a reversible down regulation of the ovaries is possible. Particularly in cases with severe endometriosis a rapid release of pain can usually be achieved. Further development of the disease could be prevented and in two third of the cases even a partial reduction of tumor size. Within 12 weeks after the therapy the cycle is normally stabilized. But in about 70% of the patients the typical complaints of endometriosis were recurrent. The advantage of this treatment is the high acceptance of the patients in comparison to steroid medication. In long term administration it is mandatory to control bone and lipid metabolism.

Radioimmunoassay of serum SP 1 and HPL in normal and abnormal pregnancies.

Serum concentrations of the pregnancy-specific beta 1-glycoprotein (SP 1) and human placental lactogen (HPL) were measured by radioimmunoassay in 372 blood samples obtained from 40 women in the second half of a normal singleton pregnancy. The mean level of SP 1 steadily increased from 40 micrograms/ml in the 22nd week of pregnancy to 168 micrograms/ml in the 36th week of gestation and thereafter reached a plateau. The half-life of SP 1 during the first week after delivery was about 39 h. The clinical value of SP 1 in comparison to HPL estimations was assessed in a prospective study of a few high risk pregnancies. There were no significant differences between serum SP 1 and HPL levels in pregnancies complicated by preeclampsia with or without intrauterine growth retardation and in twin pregnancies. Serum HPL and SP 1 levels were equally effective in predicting placental insufficiency with fetal growth retardation.