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PubMed1992

Preparation of the N-(4'-hydroxy-[3'-125I]iodophenethyl)-6-(4-O-diethylstilbestryl)hexanam ide for diethylstilbestrol radioimmunoassays.

The synthesis of a radioiodinated diethylstilbestrol (DES) derivative is described. This derivative was prepared by coupling the previously synthesized active ester of 6-(4-O-diethylstilbestryl)hexanoic acid with mono-[125I]iodotyramine in dry tetrahydrofuran (20 to 22 C, 16 hours). The mono-[125I]iodotyramine was prepared using a chloramine-T method and purified by paper electrophoresis. The final product, N-(4'-hydroxy-[3'-125I]iodophenethyl)-6-(4-O- diethylstilbestryl)hexanamide, was separated by thin-layer chromatography (cyclohexane/ethanol/NH4OH 2.5 N/acetone; 40:50:5:20, v/v/v/v); it was stable for 2 months in ethanol at 4 C and had a specific activity higher than 540 Ci/mmol. The [125I]DES amide synthesized was found to retain the immunoreactivity of DES, since it competed with [3H]DES or DES in an in vitro radioimmunoassay system for the binding sites of a rabbit anti-DES antibody; thus, it seems to be capable of replacing the tritiated tracer used so far in DES radioimmunoassays.

Binding, Competitive↗
PubMed1995

A molecular modeling analysis of diethylstilbestrol conformations and their similarity to estradiol-17 beta.

Crystallographic and computer modeling studies throughout the last 25 years have shown the structure of diethylstilbestrol (DES) to exist in two symmetrical or one asymmetrical conformation. As a result of specific comparisons to estradiol-17 beta (E2), the asymmetrical DES conformer has been suggested as the geometry possessing estrogenic activity. In the present study, a more complete set of DES conformations has been elucidated through the use of computer modeling. All previously defined DES geometries were found within this new set of ten structural forms. Differences between the molecular mechanics heat of formation energies of the ten conformers, as well as the transition energies separating them from each other, were found to be less than 1 kcal/mol. Additionally, a computer-based molecular alignment method was employed to quantitatively compare the steric and electrostatic molecular features of each DES conformer relative to E2. All ten DES structures were found to have shape relationships similar to E2. Thus, a model for the estrogen action of DES is presented whereby this stilbene can favorably interact with the estrogen receptor regardless of the conformation or orientation of the initial ligand-receptor association.

Chemical Phenomena↗
PubMed1980

Effect of estradiol-17 alpha and diethylstilbestrol on adrenal cortex and anterior pituitary gland of the Mongolian gerbil.

Injection of diethylstilbestrol (DES) for 7 days in female gerbils significantly increased the number of vacuolar and membranous intranuclear inclusions with in mammotrophs of the anterior pituitary gland. The presence of multiple inclusions adjacent to the nuclear membrane suggests that vacuolar inclusions arise from the inner nuclear membrane. DES also increased significantly the number of lipid droplets in adrenocortical parenchymal cells and in macrophages of the zona reticularis. In contrast, estradiol-17 alpha induced only a few intranuclear inclusions in mammotrophs of castrated male gerbils after 14 days of injection. Estradiol-17 alpha injection was totally ineffective in causing accumulation of lipid droplets in macrophages or parenchymal cells of the zona reticularis, emphasizing the importance of stereo-specificity for inducing ultrastructural changes in the anterior pituitary and adrenal cortex of the Mongolian gerbil.

Adrenal Cortex↗
PubMed1987

Reduction of irreversible binding of diethylstilbestrol in hamster renal cortex by inhibitors of cytochrome P-450.

Hamster renal cortical slices metabolized [3H]diethylstilbestrol (DES) to reactive intermediates that irreversibly bound to macromolecules. Protein isolated from cortical slices following incubation with 50 nM [3H]DES for 90 min at 37 degrees C had 0.160 pmol [3H]DES eq/mg protein irreversibly bound. Samples of protein analyzed by gel electrophoresis revealed several radioactive peaks, indicating that specific adduct formation had occurred. No radioactivity was associated with DNA isolated from the same tissue slices. Incubation of the slices with [3H]DES under an atmosphere enriched in carbon monoxide decreased the nonextractable binding of [3H]DES metabolites to protein. The cytochrome P-450 inhibitors diethylaminoethyl 2,2-diphenylpentanoate HCl (SKF 525-A), metyrapone, butylated hydroxytoluene (BHT), and dicumarol decreased the irreversible binding of [3H]DES by 38 to 72%. Analysis of metabolites isolated from the incubation medium by high-pressure liquid chromatography indicated that carbon monoxide, BHT, and dicumarol inhibited the hydroxylation of [3H]DES. Arachidonic acid and indomethacin did not alter the irreversible binding of [3H]DES, indicating a lack of involvement of prostaglandin H synthetase in the metabolism of DES to reactive intermediates. These findings suggest that cytochrome P-450 isozymes in the hamster renal cortex metabolize DES to reactive species that covalently bind to macromolecules.

Animals↗
PubMed1992

The effects of diethylstilbestrol, tamoxifen, and toremifene on estrogen-inducible hepatic proteins and estrogen receptor proteins in female rats.

Alterations of estrogen-inducible hepatic proteins and estrogen receptor proteins were studied in female rats after daily oral administration of vehicle control (0.5% carboxymethylcellulose), the nonsteroidal antiestrogens tamoxifen (TAM; 3, 11, or 45 mg/kg body weight), toremifene (TOR; 3, 12, or 48 mg/kg body weight), or the potent synthetic estrogen diethylstilbestrol (DES; 10 mg/kg body weight) for 1 and 3 months. Serum corticosterone levels were significantly reduced by TAM 11, TOR 12, and DES at 1 month and by TOR 48 and DES at 3 months. Serum ceruloplasmin levels were unchanged at 1 month except for a significant reduction with TOR 48 and a significant increase in the DES-treated group. After 3 months, all doses of TAM and TOR had significant reductions whereas DES had elevations even greater than those at 1 month. The activity of the enzyme alanine aminotransferase in the liver was increased by TAM, TOR, and DES at 1 and 3 months of treatment. Both TAM and TOR caused a slight reduction in cytosolic estrogen receptor protein after 1 month and significant reductions at 3 months. The nuclear estrogen receptor (nER) protein levels were significantly increased at 1 and 3 months for TAM and TOR; whereas DES treatment resulted in nER levels no different than controls. In summary, chronic (up to 3 months) administration of TAM and TOR results in qualitatively and quantitatively similar hormone-related effects on the female rat liver. Thus, other mechanisms must be investigated to ascertain the hepatoproliferative differences seen with TAM administration but not with TOR.

Alanine Transaminase↗
PubMed1992

Differential effects of diethylstilbestrol and estradiol-17 beta in combination with testosterone on rat prostate lobes.

Treatment of Noble rats with separate silastic implants containing testosterone (T) and estradiol-17 beta (E2) for 16 weeks has previously been shown to induce multifocal epithelial dysplasia, a putative preneoplastic lesion, consistently in the dorsolateral prostate (DLP) but not in the ventral prostate (VP). We now studied effects of diethylstilbestrol (DES) substituted for E2 on these prostate lobes under the same conditions of exogenous androgen support. Three-week treatments with one 1-cm-long silastic implant of E2 or DES were approximately equipotent in changing target-organ weights and plasma prolactin. Accordingly, rats received for 16 weeks one 1-cm-long E2 or DES implant and two 2-cm-long T implants. In contrast to T + E2, T + DES induced widespread multifocal VP dysplasia and less or no DLP dysplasia. A serum-free explant-culture assay was used to determine uptake and metabolic disposition of 3H-labeled 5 alpha-dihydrotestosterone (DHT), T, and E2. Dysplastic VP explants incubated with 1.7 microM 1 beta-3H-labeled DHT and T accumulated more 3H-labeled steroid, metabolized 69 and 50% less substrate to terminal hydroxylated metabolites, and thereby formed and retained up to eight times as much estrogenic metabolite 5 alpha-androstane-3 beta,17 beta-diol (3 beta-androstanediol) and its lipoidal derivative than control VP. Experimental DLP explants did not form or retain more 3 beta-[3H]androstanediol than control DLP irrespective of treatments. Control VP metabolized [2-3H]E2 more actively to estrone than DLP. Dysplastic VP, however, metabolized one-half and accumulated five times as much E2 as VP and did not release more 3H as a marker of the 2,3-catechol estrogen pathway. These data suggest that differential target-tissue bioavailability of the estrogen component of the protracted dual-hormone stimulus determines in which prostate lobe dysplasia develops.

Animals↗
PubMed1975

Prostatic carcinoma: treatment of liver metastases with intravenous diethylstilbestrol diphosphate.

A patient with Stage B adenocarcinoma of prostate treated with radical prostatectomy and interstitial radioactive gold presented ten years later with liver metastases without evidence of local recurrence. This patient was treated only with massive doses of intravenous diethylstilbestrol diphosphate, with regression of metastases and marked decline of the acid and alkaline phosphatase levels.

Acid Phosphatase↗
PubMed1976

Endocrine changes after diethylstilbestrol therapy. Effects on prostatic neoplasm and pituitary-gonadal axis.

This study was undertaken to determine the effects of DES (diethylstilbestrol) on prostatic neoplasms and of different dosage levels on the pituitary-gonadal axis. It is recommended that when DES is chosen for treatment plasma testosterone be monitored carefully and for long periods of time to evaluate the ability of the dose to achieve levels comparable to castration in each patient.

Diethylstilbestrol↗
PubMed1978

Plasma testosterone in patients receiving diethylstilbestrol.

With accurate, inexpensive plasma testosterone assays now available it is possible to monitor the efficacy of hormonal manipulation in the patient with adenocarcinoma of the prostate. We monitored plasma testosterone in our patients receiving diethylstilbestrol (DES) 1 mg. per day. We found no statistical difference in mean plasma testosterone between patients with adenocarcinoma of the prostate and castrated patients with prostatic carcinoma, all receiving DES, 1 mg. per day. We recommend that plasma testosterone be closely monitored in patients receiving hormonal therapy for adenocarcinoma of the prostate.

Adenocarcinoma↗
PubMed1979

Transplacental exposure to diethylstilbestrol in men.

Diethylstilbestrol (DES) was widely prescribed during the late 1940s and early 1950s for complications of pregnancy. Twenty-four men exposed to DES in utero were examined and compared with twenty-four age-matched controls; contrary to previous reports, we found no difference between the two groups in their psychosexual history, medical history, genital examination, or semen analysis.

Adult↗
PubMed1985

Comparison of leuprolide and diethylstilbestrol for stage D2 adenocarcinoma of prostate.

In a controlled, prospective, randomized clinical trial, we evaluated the safety and efficacy of leuprolide, a superactive analog of luteinizing hormone releasing hormone, given in a single subcutaneous injection dose of 1 mg per day, versus diethylstilbestrol (DES) 3 mg per day by mouth in patients with previously untreated Stage D2 prostatic adenocarcinoma. Eleven leuprolide patients and 10 DES patients were evaluated for therapeutic response. Eighty per cent of patients in each group experienced subjective improvement in bone pain and urinary obstructive signs and symptoms. Although the pooled percentages of complete, partial, and stable objective responses were greater for the leuprolide group than the DES group, the sums of the percentages of complete and partial objective responses were comparable for both treatment groups during the first forty-eight and sixty weeks of the study, respectively. In addition, patients not responding to leuprolide generally experienced no benefit with crossover to DES, and vice versa. Serious adverse reactions were more common in the DES group and included fatal myocardial infarction, arrhythmia, deep venous thrombosis, and gynecomastia. Vasomotor flushing, disease flare, and injection site irritation occurred most often in leuprolide patients, but did not require modification or discontinuation of treatment.

Acid Phosphatase↗
PubMed1985

Clinical relevance of plasma testosterone and prolactin changes in advanced cancer of prostate treated with diethylstilbestrol or estramustine phosphate.

We have investigated a group of 30 patients with newly diagnosed metastatic carcinoma of the prostate who were randomly assigned to receive, as primary treatment, either diethylstilbestrol (DES) or estramustine phosphate (Emcyt). Clinical response was assessed following the guidelines of the National Prostatic Cancer Project and the Eastern Cooperative Oncology Group. Effective reduction in the levels of androgens was noted in all patients in both groups regardless of response. During the follow-up period (ranging between 2-5 years) relapses were noted despite the presence of androgen levels at or below castrate values. The most relevant endocrine observation was the detection of early elevations in serum prolactin in a majority of patients. It was noted, however, that those patients in whom hyperprolactinemia did not occur or appeared only briefly at the beginning of therapy, experienced a prolonged, symptom-free survival. Persistent hyperprolactinemia, on the other hand, carried an ominous prognosis. The differences in survival between normoprolactinemic and hyperprolactinemic groups carried statistical significance.

Carcinoma↗
PubMed1986

Influence of treatment with diethylstilbestrol for carcinoma of prostate on platelet aggregation and plasma lipoproteins.

Treatment of prostatic carcinoma with estrogens is accompanied by an increased risk for thromboembolic and cardiovascular complications. The underlying mechanisms are still unknown. Patients treated with diethylstilbestrol (DES) were compared with patients given no estrogen treatment regarding factors (platelet aggregation in vitro and plasma lipoproteins) that have been suggested to contribute to increased thrombogenesis and cardiovascular risk. The results do not show any increase in in vitro platelet aggregation in patients treated with DES compared with those given no treatment. This indicates that hyperaggregability does not contribute to the increased incidence in thromboembolic events seen in DES-treated patients. This is in contrast to the increased platelet aggregation previously described in patients treated with polyestradiolphosphate + etinylestradiol. The changes in plasma lipoproteins observed during DES-treatment are generally considered beneficial from an atherogenic point of view and do not appear to cause the elevated incidence of cardiovascular disease in these patients.

Aged↗
PubMed1989

Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma.

Two multicenter, open, randomized phase III clinical trials were conducted in the United Kingdom to compare the effectiveness and safety of the depot formulation of the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex, ICI Pharma, Wilmington, Delaware), 3.6 mg sc/28 d, with orchiectomy and with diethylstilbestrol (DES), 1 mg tid, in the treatment of advanced prostatic cancer. In the Zoladex versus orchiectomy trial, there was no significant difference between the treatment groups with regard to subjective and objective responses (British Prostate Group criteria), endocrine responses, clinical effects and side effects, time to treatment failure and death, or survival after similar median follow-up periods. It was concluded that depot Zoladex had behaved as a truly medical alternative to orchiectomy. In the Zoladex versus DES trial, subjective and objective responses (British Prostate Group and National Prostatic Cancer Project criteria), response duration and survival were similar. However, there was a more rapid response to treatment in the depot Zoladex group. Side effects from Zoladex such as flare symptoms during the initial stages of treatment required no discontinuation of therapy; in contrast, 15 percent of patients receiving DES required cessation of therapy during the first three months because of side effects. It was concluded that depot Zoladex was superior to DES in its attainment of an early objective response and in its absence of side effects, and that Zoladex was comparable with DES in terms of response rates and survival.

Antineoplastic Agents↗
PubMed1992

Diethylstilbestrol in treatment of postorchiectomy vasomotor symptoms and its relationship with serum follicle-stimulating hormone, luteinizing hormone, and testosterone.

Vasomotor symptoms such as hot flushes and profuse sweating have been described after bilateral orchiectomy. We evaluated 26 patients who had undergone bilateral orchiectomy for prostatic carcinoma to determine the incidence of vasomotor symptoms and the efficacy of low-dose diethylstilbestrol (DES) in the treatment of those symptoms. Measurements of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were performed to look for endocrine patterns which may be related to the presence of vasomotor symptoms. Fourteen patients (54%) reported the presence of vasomotor symptoms beginning one to four weeks after surgery. These patients were treated with DES or placebo in a double-blind crossover trial. The frequency and severity of hot flushes were significantly reduced during the time DES was given. This was accomplished with a low dose of 1 mg daily of DES which avoids the cardiovascular complications of higher doses. We found no correlation between the presence, severity, or frequency of hot flushes and serum gonadotropin or testosterone concentrations.

Climacteric↗
PubMed1985

Pathology of colposcopic findings in 2635 diethylstilbestrol-exposed young women.

An analysis of 6055 colposcopically directed biopsy specimens from 2635 diethylstilbestrol (DES)-exposed women and 445 biopsy specimens from 277 nonexposed women was undertaken to correlate microscopic findings with colposcopic patterns. All examinations were performed using a standardized protocol which required that each participant have colposcopy, cytologic smears, and biopsy of abnormal colposcopic lesions. The findings of colposcopic "columnar epithelium, gland openings, and Nabothian cysts" correlated most often with glandular epithelium in the biopsy specimen. "White epithelium," which includes three related colposcopic patterns, mosaicism, punctation, and white epithelium, was associated most frequently (82-93% of cases) with squamous metaplasia, but occasionally with dysplasia and carcinoma in situ (CIS)(0-6%). The presence of dysplasia or CIS in any individual biopsy specimen occurred most frequently with the observation of higher graded lesions by colposcopy or a prior diagnosis of dysplasia.

Carcinoma in Situ↗
PubMed1989

Stage II papillary clear cell adenocarcinoma of the vagina during observation in a diethylstilbestrol-exposed daughter.

Although many cases of Diethylstilbestrol (DES)-associated clear cell adenocarcinoma (CCA) of the cervix and vagina have occurred, few have arisen in patients whose initial gynecologic evaluation has revealed only nonmalignant DES-related changes. We report a case of a 32-year-old lady who developed a stage II CCA after 8 years of thorough gynecologic examinations. This case substantiates the need for long-term gynecologic assessment in DES daughters.

Adenocarcinoma, Papillary↗