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In the fifties and sixties pregnant women with a history of habitual abortions or premature deliveries were treated with DES (diethylstilboestrol). This treatment can lead to certain pathognomonic uterine changes in the daughters, that are recognizable on hysterosalpingographs. Because of the obstetric consequences, it is important to interpret these changes correctly. The findings in 7 patients are described. As most of the DES-daughters are now coming into reproductive age, gynecologists and radiologists will be confronted more frequently with their specific problems.

The displacement of the phenolic OH-group of diethylstilbestrol into the 3,3'-position (trans-3,3'-dihydroxy-alpha, beta-diethylstilbene, compd. III) leads to a strong decrease of the estrogenic effect under conservation of the receptor affinity. In vitro, III inhibits the estradiol-receptor-interaction competitively and, in vivo, antagonises the uterotropic effect of estrone in the mouse. In tests with the DMBA-induces, hormone-dependent mammary carcinoma of the rat a dose-dependent strong decrease of tumor size and yield is achieved under the influence of III, due to the antiestrogenic properties of III. The replacement of the alpha, beta-bound ethyl groups in III by other alkyl chains leads to no further increase of the antiestrogenic and antitumor activity.

Direct Determination of Diethylstilbestrol and its Monoconjugates in Plasma After "homogeneous ion pair extraction" with CH3OH from plasma of patients suffering from metastatic prostate cancer and subsequent partitioning on a C18-phase diethylstilbestrol (E-DES) and its monoconjugates (glucuronide, sulfate) as well as its glucuronide-sulfate conjugate may be detected quantitatively by HPLC/UV (236 nm) or HPLC/ED (+1.0 V). Working electrode is a special home-made carbon paste electrode. The range of detection is in the low ng range (2-5 ng/ml plasma); standard deviation is less than 5%. It is the first time that plasma levels of these metabolites of fosfestrol (Honvan) could be measured directly without prior hydrolysis.

Endocrine findings of hypophyseal, testicular and adrenal function in the hormonal treatment of advanced prostatic carcinoma are described. Diethylstilbestrol (DES) reduces significantly the plasma levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In contrast, those of prolactin, dehydoepiandrosterone (DHEA), and cortisol as well as sexual hormone binding globulin (SHBG) are elevated. The additional administration of bromocriptine decreases prolactin to normal levels and further decreases the testosterone levels. The adrenal steroids are influenced differently: DHEA decreases as compared to the DES-treated group, while the cortisol levels rise significantly. The addition of cyproterone acetate to the therapeutic regimen decreases the cortisol levels, and all other values, including SHBG, are not altered significantly compared to the group treated with DES plus bromocriptine. What is of interest is that the estradiol levels are not altered by any treatment schedule. In a group of patients, orchiectomized prior to our study, the endocrine values are compared to those mentioned above. Following orchiectomy FSH and LH levels rise significantly, but not prolactin and SHBG. The testosterone levels were as low as under treatment with DES. From our results it is concluded that the combination of DES plus bromocriptine plus cyproterone acetate best achieves the inhibition of androgenic influence onto the prostatic carcinoma.

Vaginal adenosis is a rare kind of disease without specific symptoms and does not represent a very serious disorder from the beginning. Concerning the etiology teratogenetic dependencies are known which still are interpreted in different ways in the recent literature. The increased number of cases, including those with clear-cell-carcinoma of the vagina, in juveniles after exposition to DES during the early embryonal development shows in particular (Central index for the stilbestrol-adenosis-carcinoma-syndrome in the USA, since 1971) a wrong pathway in the organogenesis of cervix and vagina. This occurs at the interference zone between the epithelium of the Müllerian ducts and the epithelium of the sinus urogenitalis of the female fetus and in so far constitutes the origin of vaginal adenosis. The basics of the possibility of the development of such irregular differentiation and heterotopic dissemination are proven again by the case report of a vaginal adenosis showing the highly differentiated endocervical type. Not every case of vaginal adenosis does signify a precancerous lesion. The separation of the most frequently endocervical manifestation observed from endometrial and intermediate forms might be difficult. A positive distinction is prognostically essential, however, since clear-cell-carcinomas of the vagina are known in occurence with the endometrial type of vaginal adenosis only. Scanning electron microscopy as a method to follow tissue organization reveals the way of differentiation between the various types via ultrastructural analysis for vaginal adenosis is an example for failures of developmental organization. The same analysis is feasible in cytological smears also. The therapeutic requirements of vaginal adenosis depend on the tissular differentiation and the given local extent of the adenomatous lesions.

Testosterone, FSH and LH were measured in serum of patients suffering from prostatic carcinoma. The efficacy of treatment with 1 mg diethylstilbestrol/d (Cyren A) was shown by suppressed serum levels of testosterone, FSH and LH comparable to castration in a follow-up until 560 weeks after beginning of therapy. Prolactin was raised in all patients under treatment.

Apart from their antigonadotropic effect oestrogens also directly inhibit the androgen secretion of the testicles. Thus, on the 20th day of treatment the LH-level after 12 g diethylstilbestrol diphosphate (DSDP) decreases only to approximately 50% of the initial value, while the whole testosterone (T), however, is reduced to less than 5%. The sexual hormone binding globulin is significantly more increased (p less than 0.001) by the estrogen treatment than after orchidectomy only. Therefore, the free, biologically active T-level in the plasma consists of more than one third of the level after exclusive orchidectomy. The treatment with the depot estrogen Turisteron is clarly superior to the usual treatment Oestrasid implants. Both with and without orchidectomy the free testosterone level is significantly lower than after Oestrasid implants plus orchidectomy. Therefore, this therapy can successfully be used in the treatment of the carcinoma of the prostate also without orchidectomy.

Drugs undergoing presystemic elimination, enterohepatic recycling and multiple biotransformation show atypical plasma level curves with considerable deviations. The data are approximated by modified exponential functions, whose "intrinsic" properties anticipate the overall behaviour of the experimental data, even in complicated cases. The initial parameter estimates can be calculated directly from the experimental data.

After intravenous injection the distribution of iodine-labelled diethylstilbestral-diphosphate (cytonal) was investigated in various organs of the rat. For this purpose the concentration of activity in the organs of the animals were established by measurements of specimens in the bore-hole counter and scintigrams were made by means of a small animal scanner. The result was an unequivocal temporary dependence of the enrichment of the substance in the organs. The greatest enrichment was found 10 minutes after injection in the liver, then followed blood, kidneys, adrenal glands, seminal vesicles, prostate, abdominal wall and the fatty tissue surrounding the prostate. The blood activity relatively decreased. 7 days after injection an unambiguously higher activity was to be proved in the liver, kidney, adrenal gland than in the blood, whereas the enrichment of iodine-labelled diethylstilbestraldiphosphate in prostate, seminal vesicle, fatty and muscular tissue was always below the enrichment of the blood. But in every case the relation of organ activity to blood activity changed in favour of the organ activity, also with regard to the prostate. 10 minutes after injection the concentration of the activity of the seminal vesicle was somewhat higher than that one of the prostate, but in the further course it was below the concentration of the activity of the prostate. During the first two hours the fatty tissue surrounding the prostate showed a clearly and after the third day a slightly lower activity concentration than the prostate. On the basis of this distribution of the activity for the scintigraphy of the prostate above all a temporary interval of about 10 minutes to 3 hours after the injection of labelled cytonal is involved. The results cause us to perform investigations in men concerning the pharmacokinetics and the possibility of using radioactively labelled cytonal.

By well organized preventive examinations early tumour stages can be recognized. The diagnosis of prostatic cancer has to be secured by biopsy. The primary reliability of aspiration biopsies (cytology) was 94% compared with punch biopsies (histology) amounting to 73%. Indications and results of aspiration biopsies, radiological and nuclear medical techniques in diagnosing prostatic cancer are described. The combined anti-androgenic hormonal therapy (infusions of cytonal, subcapsular orchiectomy, permanent administration of oestrogen) is considered to be the unchanged basis of treatment. Comparative cytologic investigations in therapy indicate that high-voltage treatment connected with hormonal therapy seems to be superior to exclusive hormonal treatment. Observations after additional therapy by a radionuclid (89-Strontium) for affecting metastases are encouraging. Indications of a therapy by cytostatica in progressive prostatic cancer are explained.

Demonstrating a case of juvenile angiofibroma penetrating the base of the scull and growing mainly endocranially we refer to Honvan (Fostestrolum) treatment of this kind of tumor. The effect of this treatment can be shown histologically as a distinct sclerosis of the tumor tissue. Even in long term application of this drug only very few side effects are found.

For the elucidation of the age-dependent reduction of the avidin induction in the ovidict of quails, studies on the level of the post-transcriptional events were performed. In estrogen-treated young animals, the extractable activity of DNA dependent RNA polymerase II increases by 145% after progesterone treatment, while in old animals no increase is observed. In the presence of actinomycin D the incorporation ratio [3H] Ado/[3H] Urd into mRNA increases by about 80% in the case of mature animals; this value is drastically lower (15%) using old animals. The activities of the poly(A)-degrading enzymes in oviducts of mature animals are lower than those in old ones. After progesterone treatment the activities of these enzymes increase in oviducts from old animals, while in young quails no alteration is observed. The possible consequence of these findings on the chain length of the poly(A) segment of mRNA is discussed with regard to its translation capacity.

Due to an advanced prostatic carcinoma 166 patients were given a massive dose of oestrogen over a period of 10 days (6 g Honvan i.v.). A retrospective comparison of a control group of 94 patients without prophylaxis against thrombosis and a control group of 36 patients having received Heparin-Dihydergot did not show a significant difference of cardiovascular complications. Therefore, further 36 patients received a thrombocyte aggregation inhibitor (Godamed) as prophylaxis against embolic thrombosis. At the same time lung perfusion scintigraphy (99m Tc-Microspheres) was made directly before and after oestrogen therapy. Clinically and lung scintigraphically there was no different thromboembolic incidence compared to the patients given a Heparin-Dihydergot prophylaxis.

Prostata cancer is one of the most dangerous tumours occurring in the older man. No general accepted therapy has existed up to now. In this study we were engaged on the pharmacokinetics of fosfestrol (Honvan) after oral administration. Its active principle is E-diethylstilbestrol (E-DES), the main metabolite. 250-1600 ng/ml E-DES are measurable after 60-110 min in the plasma of 11 patients suffering from metastatic prostata cancer who have been administered 360 mg fosfestrol orally. This range is equivalent to E-DES concentrations in plasma of 1-4 x 10(-6) mol/l. Thus that E-DES concentration range (5 x 10(-6) mol/l) is nearly attained for a short time to the concentration which hinders the mitosis of human breast cancer cells. Surprisingly similar but not higher concentration - time courses may be measured after a bolus infusion of 360 mg fosfestrol (lasting 45 min). Furthermore, E-DES-glucuronide, E-DES-sulphate and the mixed E-DES-glucuronide-sulphate could be observed in plasma after oral administration. In spite of the high sensitivity of the analytical method (limit of detection for fosfestrol 0.1 micrograms/ml and for E-DES and its mono-conjugates 2-5 ng/ml) neither fosfestrol nor E-DES-monophosphate are detectable in plasma due to the biotransformation of fosfestrol, which is already metabolized by the enzymes of the gut wall. Both phosphates only exist in plasma after intravenous infusion. Further investigations are linked with the question if phase II-conjugates of E-DES can eventually be prodrugs delivering E-DES by cleavage of the ester bonds.

Lymphocytes of mothers and their newborn infants were treated with varying concentrations of diethylstilbestrol (10(-6) M, 10(-5) M and 10(-4) M) and mitomycin C (0.003, 0.009 and 0.03 microgram/ml), and the incidence of sister chromatid exchanges (SCE) was determined. The results showed that the spontaneous SCE rate in the newborns is less than that of their mothers. A dose-related increase in SCEs was observed in cells exposed to the alkylating chemical mitomycin C, while increases in SCEs were not noted in cultures exposed to diethylstilbestrol. No different susceptibilities of lymphocytes from mothers and newborns to the chemical induction were observed.

Symptoms and objective parameters of gynecomastia are analysed in 113 patients, who received prophylactic irradiation of the breast (12 Gy in 3 fractions) prior to estrogen therapy of prostatic carcinoma. Another 10 patients were treated equally after estrogens had caused severe complaints. Symptoms increased from 10% to 100% in relation to 4 classes of gynecomastia. They were mild in 27.5%, moderate in 23.9% and severe in 8.8%. A correlation between metric classification and graded symptoms became more evident when only 2 groups were distinguished. With a maximum diameter of 3.5 cm only 17% of the patients had mostly slight discomfort in contrast to 70% of the patients with a gland of more than 3.5 cm in diameter; they revealed moderate or serious complaints. These results indicate that prophylactic radiotherapy may reduce severe complications to less than 10% as compared to 70-80% without irradiation. If gynecomastia has developed, regression by subsequent radiotherapy seems to be impossible; but the intensity of complaints could be reduced in our ten patients. Provided that irradiation precedes estrogen application, this sequence may be considered as a reasonable alternative to expensive antiandrogen therapy.

From 1946 to 1971, diethylstilbestrol, a nonsteroid synthetic estrogen, came in for widespread use in the USA, and in other countries only occasional use, for the treatment of high-risk pregnancies. In 1971 a retrospective epidemiologic study showed a close association of this therapy with occurrence of vaginal and cervical adenocarcinoma in young women (mean age 19 years). Up to 1981 63% of 429 clear cell carcinomas of the vagina and cervix were related to DES exposure in utero in the USA. Following reports on a few cases in other countries, the present report is the first in a Swiss female, aged 23, with stage III DES-induced adenocarcinoma of the vagina. The risk of DES-related adenocarcinoma is estimated at about 1%, but benign teratogenic lesions are present in over 50% of patients. Vaginal adenosis is the most frequent finding, but other malformations of vagina (septa), cervix, uterus and fallopian tube may be found. Malformations of the genital tract have also been described in DES-exposed male offspring.

Clinical aspects of postconception fertility control are reviewed. Estrogens (ethinyl estradiol and diethylstilbestrol) have been used for this purpose. In addition to their undesirable side effects, they must be administered within a strictly defined time period. Several progestagens have been used as postcoital contraceptives, but they too are effective only when administered a few days after ovulation. A number of nonsteroidal substances appear promising, as inhibitors of implantation and as abortifacient agents. Prostaglandins also appear promising because of similar properties. Oral administration is not feasible, but vaginal administration is an attractive possibility. But the high incidence of side effects and somewhat unreliable effects are p roblems. The mechanisms of action of all these substances have not been explained.

Trends in hormonal contraception of all types are discussed. In spite of the disadvantages of their side effects, combined preparations are still the most popular. The tendency toward individualized prescription will become more widespread, and more preparations will be available. Sequential preparations will probably be more used, as will the "once a month" pill. Low-dose progestins will prove useful for women for whom estrogens of IUDs are contraindicated. Parenteral injections of depot preparations are limited by their side effects on the menstrual cycle. Hormonal suppression of implantation (estrogens or progestins) will be indicated for relatively few patients. Hormonal contraception for men is still experimental.

Four juvenile angiofibromas were examined with the electron microscope. Preceding the operation a hormonal therapy with stilbestrol disphosphate (Cytonal, Honvan) was carried out in the cases. The therapeutical effect after application of this drug is clearly correlated to especial changes in histology and cytology. The changes comprise reactions of the vascular component and of the stromal fibroblasts. Endothelial cells and pericytes show a markedly diminished cellular activity, a proliferation of vascular wall cells is not to be proved. The stromal fibroblasts may predominantly be classified as fibroblasts with histiocyte-like features, at which the organelle equipment speaks for a high activity of their metabolism. Furthermore an increased number of myofibroblasts and smooth muscle-like elements are encountered in the stroma. The striking diminution of lesion size and the reduction of disposition to bleeding from the beginning of the hormone therapy is suggested as a direct consequence of cellular contraction. Additionally alterations of synthesis of collagen fibers and ground substance by fibroblasts with histiocyte-like features contribute to a further gradual decrease of the growths.

To protect consumers against estrogen residues in foodstuffs, German law requires biological testing of randomly sampled livestock products. The conventional biological (mouse uterus) test is relatively sensitive, but gives no indication of the chemical structure of the residue, although different estrogen substances present varying degrees of risk. Whereas physiological (biogenic) estrogens have a short biological half-life (about 1 hour) and their absorption by the body is limited, stilbestrol derivatives break down slowly, remaining in the body for several weeks. The mouse test is also slow and costly, and chemical tests are being developed as substitutes. A method using high-speed liquid chromatography is described in detail. Because corticosterone is used as an internal standard, quantification of the stilbestrol derivatives is independent of the sample size and the occasions for error are reduced. This method, which uses urine, blood, or tissue samples, is faster than the biological test (4-6 hours vs. 3-5 days) and detects residues in the ng range. Parallel tests to determine applicability of this method under practical conditions are suggested.