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The twentieth century
Published in Michael J. O’Dowd, The History of Medications for Women, 2020
Estrogenic preparations became commercially available during the 1930s, but the efforts to purify and standardize these products led to many errors. The first artificial estrogen was synthesized by Cook and associates (1933). At that time E.C. Dodds, who was involved in that first synthesis, was the Courtauld professor of biochemistry at the Middlesex Hospital, London. Following the 1933 publication there were many papers on synthetic estrogens from his unit. In 1938 Dodds, and Robinson of Oxford, prepared various combinations of substituted stilbenes and found that the diethyl derivative was the most effective. Unlike some other hormonal drugs, diethylstilbestrol (DES) was found to be effective when administered orally. The potency of the compound was five times that of estradiol. DES was easy to prepare in pure form and was cheap to produce. Dienestrol and hexestrol were two other compounds which showed only minor structural and therapeutic differences from DES and they also became available through the work of Dodds and co-workers (Dodds et al., 1938a-d).
Effects on Human Males of In Utero Exposure to Exogenous Sex Hormones
Published in Takao Mori, Hiroshi Nagasawa, Toxicity of Hormones in Perinatal Life, 2020
McLachlan and Shah and McLachlan62 have quantitated 3H-DES distribution in pregnant mice and found that free and conjugated DES were of approximately equal concentrations in fetal plasma 30 min after injection of the pregnant mothers and that the levels in the fetal plasma exceeded that in the maternal plasma. Most importantly, free DES was ten times greater than conjugated DES in the fetal genital tract and the level of free DES was two times greater than in the fetal liver. The P-dienestrol metabolites of DES found in mouse, rat, monkey, and human urine have been found to have estrogenic activity in both the in vivo mouse uterine weight bioassay and the in vitro with E2 receptor binding assay.68
Cancers of the Vulva and Vagina
Published in Jennifer L. Kelsey, Nancy G. Hildreth, Breast and Gynecologic Cancer Epidemiology, 2019
Jennifer L. Kelsey, Nancy G. Hildreth
From the Adenocarcinoma Registry it has been found that among the cases of clear cell carcinoma of the vagina and cervix in which a maternal history of drug exposure could be obtained, about 65% had documented exposure to DES or to the chemically related compounds dienestrol and hexestrol. About 10% had exposure to an unidentified medication to prevent abortion, and about 25% had no exposure to medication to maintain pregnancy.58 Although many of those without known exposure to DES or a related compound may have had faulty memories or inadequate records, Herbst et al.58 believe that other etiologic factors are probably involved in some of these cases since some mothers had no history of miscarriage or difficulties with the pregnancy. On the other hand, DES may sometimes have been administered without a particular medical indication.
Hormone replacement therapy and cervical cancer: a systematic review of the literature
Published in Climacteric, 2021
V. Vargiu, I. D. Amar, A. Rosati, G. Dinoi, L. C. Turco, V. A. Capozzi, G. Scambia, P. Villa
The study by Ploch31 is the only study with the influence of HRT on the CC recurrence rate and overall survival as the primary outcome, and showed that HRT does not affect oncologic outcomes. One hundred and twenty patients with CC (FIGO stage I–II) treated surgically or by radiation therapy were enrolled. After excluding patients with contraindications to HRT, 80 patients were randomly assigned to two groups: 40 patients were treated with triphasic estrogen/gestagen preparations, and 40 patients were assigned to the control group. Given the promising results after the first 2 years of the study, a further 40 patients were enrolled and treated with a non-steroid synthetic estrogen (dienestrol) and synthetic progestagen (chlormadinon). Finally, 80 patients received HRT while 40 patients had their menopausal symptoms treated with non-hormonal therapies. The observation period was at least 5 years. Primary outcomes were the influence of HRT on the oncological treatment at 5-year follow-up and its effect on patients’ QoL. The analysis of the association between HRT and oncological outcomes showed no significant difference in 5-year survival and recurrence rate between the two groups (HRT vs. control group: OS 80% vs. 65%, recurrence rate 20% vs. 32%, p > 0.05). Regarding the incidence of post-radiation therapy complications, the hormonally treated group showed a much lower incidence rate than the control group. Moreover, complications were milder and of shorter duration (post-radiation complications lasting more than 3 years: 17% vs. 45%, p < 0.01). Therefore, the authors concluded that controlled HRT seems not to worsen the oncological outcome of CC and, besides, is effective in controlling climacteric symptoms.
Sex steroid hormone receptor expression in the vaginal wall in cervical cancer survivors after radiotherapy
Published in Acta Oncologica, 2019
Alexandra Hofsjö, Nina Bohm-Starke, Karin Bergmark, Britt Masironi, Lena Sahlin
Another interesting finding was that the survivors with high radiation dose at biopsy site showed lower expression of ERα in both epithelium and stroma, compared to survivors with minimal radiation dose. One may speculate if the radiation hampers the normal tissue response to estrogen therapy. To our knowledge, there are no studies evaluating modern hormonal therapy on vaginal changes in cervical cancer survivors treated with radiotherapy. In the only double-blind, placebo-controlled study on topical estrogen therapy after radiotherapy for cervical cancer, 0.01% dienestrol cream was used. In the evaluation with clinical examinations after 5–8 months, the results from the study showed less vaginal bleeding and the vaginal epithelium was considered normal in appearance in 43% compared to 10% in control women using cream without estrogen. Frequency of intercourse was equal in the groups, but the estrogen-treated group reported less dyspareunia [9]. Dienestrol is a synthetic non-steroid estrogen with high binding affinity for ERα, two times as great compared to estradiol, the substance typically used in topical estrogen therapy today. Estriol, used in estrogen cream and gel in postmenopausal vaginal atrophy, has less affinity for ERα than estradiol. In one study on systemic estrogen therapy evaluating the effect on vaginal cytology in women treated with radiotherapy for cervical cancer, no benefits from treatment were seen. It must be pointed out though, that the women in the study were examined after just one week of systemic conjugated estrogen treatment [10]. In our study, most cancer survivors started systemic estrogen therapy at the end of the oncological treatment, but regarding topical estrogen therapy the majority started after vaginal symptoms of atrophy had already occurred. Early start and accurate dosage, formula and type of local estrogen therapy might be of importance for normal tissue function, including preservation of receptor expression.