Disease relevance of diethylstilbestrol

• This possibility was supported by the observations that DES, in contrast to most other carcinogens, failed to induce mutations in the Salmonella/microsome test or malignant transformations of eukaryotic cells in culture [1].
• Previous results have shown that when compared to male Syrian hamsters, female Syrian hamsters have a distinct predisposition to acquire amyloidosis either normally with aging or experimentally with sodium caseinate or diethylstilbestrol (DES) treatments [2].
• The mean weight of the pituitary tumors in the groups treated with 1 mg EE2 was approximately 1.5 times that of the groups treated with DES [3].
• The MCA-induced suppression of NK activity was discussed in relation to the earlier reported difference in incidence of MCA-induced sarcomas between DES-treated and control females after they were given 20 micrograms MCA in adult life, as well as in relation to the same incidence in the 2 groups treated with 100 micrograms MCA [4].
• Premenopausal breast cancer after in-utero exposure to stilboestrol [5].

Psychiatry related information on diethylstilbestrol

• The latency period was shortest in the DES-treated group irradiated during late lactation [6].
• When given on PND 10-14 (the critical period of gland genesis), 10 micrograms and 100 micrograms of coumestrol and 10 micrograms DES greatly increased uterine weight, while no effect was elicited by equol [7].
• Finally, to better evaluate the potential role of p63 in human development of DES-induced cervical/vaginal adenosis, we describe the ontogeny of p63 in human female fetuses [8].
• Focus group participants reported that learning about their DES exposure was devastating; they experienced strains in their family relationships, emotional shock, a feeling that their health concerns were not appreciated by others and, to some degree, a sense of social isolation [9].
• Prenatal exposure to diethylstilbestrol (DES): childhood play behavior and adult gender-role behavior in women [10].

High impact information on diethylstilbestrol

• We now report that DES is positive in sister chromatid exchange (SCE) induction, a short-term test for which a high correlation with the carcinogenicity of the compounds tested has been observed [1].
• Also, the amyloidogenic effect of DES in male Syrian hamsters was inhibited by concomitant injections of testosterone, indicating that estrogens induce amyloid in male hamsters by inhibiting testosterone synthesis [2].
• Stilboestrol exposure in utero and risk of pre-eclampsia [11].
• Stilboestrol and stuttering priapism in homozygous sickle-cell disease [12].
• The excess risk of ovarian cancer in this group occurred primarily among 21 women who had also used stilboestrol (diethylstilbestrol) [13].

Chemical compound and disease context of diethylstilbestrol

• The concordance rate in simultaneous ER assays was 85%; however, we found a considerable high discordance rate for PgR in primary tumor and lymph node metastasis (25%) [14].
• Although preliminary, these observations suggest that the cancers that arise in the DES model bear similarities to human endometrial cancers and provide insights into transcriptional alterations that accompany estrogen-driven endometrial carcinogenesis [15].
• We examined multiple samples of 65 primary breast carcinomas larger than 1 cm in diameter for thymidine labelling index (TLI), DNA index (DNAI, a measure of cellular DNA content by flow cytometry), and estrogen (ER) and progesterone (PgR) receptors by radioligand-binding [16].
• Re: Diethylstilbesterol revised: androgen deprivation, osteoporosis and prostate cancer [17].
• While DES appears more effective in suppressing testosterone it is also associated with a higher incidence of toxicity [18].

Biological context of diethylstilbestrol

• The theory postulates that diethylstilbestrol (DES), an inducer of stalk cell differentiation and a plasma membrane proton translocating ATPase inhibitor, should cause acidification of the cytosol [19].
• The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbesterol (DES) [20].
• Inhibition of cellular proliferation was seen with the synthetic estrogen diethylstilbestrol (DES) at concentrations greater than 10 microM in each of the three cell lines [21].
• These data indicate that E induces TPH gene expression in nonhuman primates and that the addition of P has little additive effect on TPH gene expression [22].
• The correlation between the altered hormonal level during pregnancy and the expression of galactose binding sites was examined in hepatocytes and Kupffer cells isolated from virgin rats treated with the synthetic estrogen diethylstilbesterol [23].

Anatomical context of diethylstilbestrol

• This effect is consistent with the pharmacological action of DES and with the proposal that DES, a stalk cell inducer, should acidify the cytosol [19].
• We observed that E-induced proliferation of uterine epithelial cells is markedly compromised in the absence of C/EBPbeta [24].
• However, when cytochrome P-450-mediated oxidation was analyzed by product formation assays, the oxidation of E-diethylstilbestrol to diethylstilbestrol-4',4"-quinone by tumor microsomes was 10-20% of the rate found in control microsomes [25].
• Significant (p less than 0.05) suppression from the reactivity obtained with untreated patients' leukocytes to allogeneic extracts of malignant prostatic tissue ranging from 19 to 80% was observed in all patients following preincubation of their leukocytes with diethylstilbesterol diphosphate [26].
• Follitropin (FSH) has been shown in previous studies to stimulate the induction of the LH/CG receptor (LHR) and LHR mRNA in the granulosa cells of diethylstilbesterol-primed immature rats [27].

Associations of diethylstilbestrol with other chemical compounds

• Using pyranine as the pH indicator, we find that the median cytoplasmic pH in cells treated with 10 microM DES dropped from 7.19 to pH 6.02 [19].
• Strongly carcinogenic estrogens such as estrone had a maximal renal cell proliferation response (2.4-fold above untreated control levels) between 0.1 and 10 nM, DES and 17 beta-estradiol responded at 1.0 nM, and 4-hydroxyestradiol responded at 10 nM [28].
• Also examined were acute changes that occur in oviduct RNA from animals stimulated with estrogen, withdrawn from hormone and then injected for 1, 2, and 4 days with synthetic estrogen [diethylstilbestrol (DES)], progesterone (P), or testosterone (T) [29].
• In addition, E and E+P treatment increased serotonin uptake in the basal ganglia [30].
• PR but not ER immunoreactivity was significantly reduced in both leiomyomata and myometrium after RU 486 treatment compared with tissues from untreated patients, suggesting that regression of tumors may be attained through a direct antiprogesterone effect [31].

Gene context of diethylstilbestrol

• Pten was down regulated in the majority of the DES-promoted carcinomas, which is analogous to the frequent loss of PTEN expression in human endometrial tumors [15].
• Both total ir-FS and free basal FS production increased up to 4-fold with the degree of differentiation of GC, produced by treating rats in vivo with DES (undifferentiated), DES plus FSH (partially differentiated), or DES plus FSH plus hCG (fully differentiated) [32].
• We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy [33].
• Besides that, the presence of ER and PR in carcinoma cells is considered to provide a growth advantage as shown by the positive association between the phenotype (ER+/PR+) and high proliferative activity [34].
• CONCLUSION(S): This study supports the possibility of a transition of androgen action from being an enhancer of follicular differentiation (through the AR) to being a substrate of E synthesis (through aromatase) at the time of oocyte retrieval [35].

Analytical, diagnostic and therapeutic context of diethylstilbestrol

• Under a wide range of other assumptions, the cost-effectiveness of orchiectomy relative to DES was consistently less than $20 000/QALY [36].
• The expression of mRNA for tryptophan hydroxylase (TPH) was examined in ovariectomized (spayed) control, E-treated (28 d), and E+P-treated monkeys (14 d E and 14 d E+P) using in situ hybridization and a 249 bp TPH cRNA probe generated with RT-PCR (n = 5 animals/group) [22].
• Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy [37].
• S-100 positive cells were absent in both MtT/W15 and MtT/F4 transplantable tumors even after treatment with DES [38].
• In this regard, ovariectomy of Ad9-infected female rats prevented tumor development, while subsequent diethylstilbestrol (DES) treatment elicited tumor formation [39].

References