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Diethylstilbestrol

May 02, 2024

Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used.[5][6][7] In the past, it was widely used for a variety of indications, including pregnancy support for those with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency, treatment of prostate cancer and breast cancer, and other uses.[5] By 2007, it was only used in the treatment of prostate cancer and breast cancer.[8] In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer.[9] While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.

Diethylstilbestrol
Clinical data
Other namesDES; Stilboestrol; Stilbestrol; (E)-11,12-Diethyl-4,13-stilbenediol
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • X
Routes of
administration		By mouth, vaginal, topical, intravenous, intramuscular injection (as an ester)
Drug classNonsteroidal estrogen
ATC code
Pharmacokinetic data
BioavailabilityWell-absorbed[1]
Protein binding>95%[2]
MetabolismHydroxylation, oxidation, glucuronidation[1][2][3]
Metabolites• (Z,Z)-Dienestrol[1]
• Paroxypropione[1]
• Glucuronides[2][3]
Elimination half-life24 hours[1][4]
ExcretionUrine, feces[2][3]
Identifiers
  • 4,4'-[(3E)-Hex-3-ene-3,4-diyl]diphenol
CAS Number
  • 56-53-1 Y
PubChem CID
  • 448537
IUPHAR/BPS
  • 2801
DrugBank
  • DB00255 Y
ChemSpider
  • 395306 Y
UNII
  • 731DCA35BT
KEGG
  • D00577 Y
ChEBI
  • CHEBI:41922 Y
ChEMBL
  • ChEMBL411 Y
CompTox Dashboard (EPA)
  • DTXSID3020465
ECHA InfoCard100.000.253
Chemical and physical data
FormulaC18H20O2
Molar mass268.356 g·mol−1
3D model (JSmol)
  • Interactive image
  • Oc2ccc(/C(=C(/c1ccc(O)cc1)CC)CC)cc2
  • InChI=1S/C18H20O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,19-20H,3-4H2,1-2H3/b18-17+ Y
  • Key:RGLYKWWBQGJZGM-ISLYRVAYSA-N Y
  (verify)

DES is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[7] It is a synthetic and nonsteroidal estrogen of the stilbestrol group, and differs from the natural estrogen estradiol in various ways.[7] Compared to estradiol, DES has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus.[7] These differences result in DES having an increased risk of blood clots, cardiovascular issues, and certain other adverse effects.[7]

DES was discovered in 1938 and introduced for medical use in 1939.[10][11] From about 1940 to 1971, the medication was given to pregnant women in the incorrect belief that it would reduce the risk of pregnancy complications and losses.[10] In 1971, DES was shown to cause clear-cell carcinoma, a rare vaginal tumor, in those who had been exposed to this medication in utero.[10][5] The United States Food and Drug Administration subsequently withdrew approval of DES as a treatment for pregnant women.[10][5] Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed, including XY genital undermasculinization.[10][12]

The United States National Cancer Institute recommends[13] children born to mothers who took DES to undergo special medical exams on a regular basis to screen for complications as a result of the medication. Individuals who were exposed to DES during their mothers' pregnancies are commonly referred to as "DES daughters" and "DES sons".[10][14] Since the discovery of the toxic effects of DES, it has largely been discontinued and is now mostly no longer marketed.[10][15]

Medical uses edit

DES has been used in the past for the following indications:[5][additional citation(s) needed]

DES was used at a dosage of 0.2 to 0.5 mg/day in menopausal hormone therapy.[27][5]

Interest in the use of DES to treat prostate cancer continues today.[28][29][30][31][32][33][34] However, use of bioidentical parenteral estrogens like polyestradiol phosphate has been advocated in favor of oral synthetic estrogens like DES due to their much lower risk of cardiovascular toxicity.[35][32][34] In addition to prostate cancer, some interest in the use of DES to treat breast cancer continues today as well.[36][37] However, similarly to the case of prostate cancer, arguments have been made[38] for the use of bioidentical estrogens like estradiol instead of DES for breast cancer.[36][38]

Oral DES at 0.25 to 0.5 mg/day is effective in the treatment of hot flashes in men undergoing androgen deprivation therapy for prostate cancer.[39]

Although DES was used to support pregnancy, it was later found not to be effective for this use and to actually be harmful.[40][41][42][43]

Side effects edit

At more than 1 mg/day, DES is associated with high rates of side effects including nausea, vomiting, abdominal discomfort, headache, and bloating (incidence of 15–50%).[44]

Breast changes and feminization edit

The pigmentation of the breast areolae are often very dark and almost black with DES therapy.[5][45][46][47][48][49][50][51] The pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as estradiol.[5][45] The mechanism of the difference is unknown.[5] Progestogens like hydroxyprogesterone caproate have been reported to reduce the nipple hyperpigmentation induced by high-dose estrogen therapy.[52]

In men treated with it for prostate cancer, DES has been found to produce high rates of gynecomastia (breast development) of 41 to 77%.[53]

Blood clots and cardiovascular issues edit

In studies of DES as a form of high-dose estrogen therapy for those with prostate cancer, it has been associated with considerable cardiovascular morbidity and mortality.[29][5] The risk is dose-dependent.[29] A dosage of 5 mg/day DES has been associated with a 36% increase in non-cancer-related (mostly cardiovascular) deaths.[29] In addition, there is an up to 15% incidence of venous thromboembolism.[54] A 3 mg/day dosage of DES has been associated with an incidence of thromboembolism of 9.6 to 17%, with an incidence of cardiovascular complications of 33.3%.[29] A lower dosage of 1 mg/day DES has been associated with a rate of death due to cardiovascular events of 14.8% (relative to 8.3% for orchiectomy alone).[29]

Other long-term effects edit

See also: Birth defects of diethylstilbestrol

DES has been linked to a variety of long-term adverse effects in women who were treated with it during pregnancy, and/or in their offspring, including increased risk of the following:[40]

A comprehensive animal study in 1993 found a plethora of adverse effects from DES such as (but not limited to)

Rodent studies reveal female reproductive tract cancers and abnormalities reaching to the F2 generation, and there is evidence of adverse effects such as irregular menstrual cycles intersexual in grandchildren of DES mothers.[57] Additionally, evidence also points to transgenerational effects in F2 sons, such as hypospadias.[58] At this time however, the extent of DES transgenerational effects in humans is not fully understood.[citation needed]

Overdose edit

DES has been assessed in the past in clinical studies at extremely high doses of as much as 1,500 to 5,000 mg/day.[36][59][60]

Pharmacology edit

Pharmacodynamics edit

Estrogenic activity edit

DES is an estrogen; specifically, it is a highly potent full agonist of both of the estrogen receptors (ERs).[61][62] It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, respectively.[63] However, EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, have been reported, suggesting, in spite of its binding affinity for the two receptors, several-fold preference for activation of the ERβ over the ERα.[64] In addition to the nuclear ERs, DES is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (~1,000 nM).[65] DES produces all of the same biological effects attributed to natural estrogens like estradiol.[66][67] This includes effects in the uterus, vagina, mammary glands, pituitary gland, and other tissues.[66][67][68][69]

A dosage of 1 mg/day DES is approximately equivalent to a dosage of 50 µg/day ethinylestradiol in terms of systemic estrogenic potency.[1][4] Similarly to ethinylestradiol, DES shows a marked and disproportionately strong effect on liver protein synthesis.[7] Whereas its systemic estrogenic potency was about 3.8-fold of that of estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, the hepatic estrogenic potency of DES was 28-fold that of estropipate (or about 7.5-fold stronger potency for a dosage with equivalent systemic estrogenic effect).[1]

DES has at least three mechanisms of action in the treatment of prostate cancer.[70] It suppresses gonadal androgen production and hence circulating androgen levels due to its antigonadotropic effects; it stimulates hepatic sex hormone-binding globulin (SHBG) production, thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and dihydrotestosterone (DHT) in the circulation; and it may have direct cytotoxic effects in the testes and prostate gland.[70] DES has also been found to decrease DNA synthesis at high doses.[70]

DES is a long-acting estrogen, with a nuclear retention of around 24 hours.[71][72]

Relative oral potencies of estrogens
Estrogen HFTooltip Hot flashes VETooltip Vaginal epithelium UCaTooltip Urinary calcium FSHTooltip Follicle-stimulating hormone LHTooltip Luteinizing hormone HDLTooltip High-density lipoprotein-CTooltip Cholesterol SHBGTooltip Sex hormone-binding globulin CBGTooltip Corticosteroid-binding globulin AGTTooltip Angiotensinogen Liver
Estradiol 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Estrone ? ? ? 0.3 0.3 ? ? ? ? ?
Estriol 0.3 0.3 0.1 0.3 0.3 0.2 ? ? ? 0.67
Estrone sulfate ? 0.9 0.9 0.8–0.9 0.9 0.5 0.9 0.5–0.7 1.4–1.5 0.56–1.7
Conjugated estrogens 1.2 1.5 2.0 1.1–1.3 1.0 1.5 3.0–3.2 1.3–1.5 5.0 1.3–4.5
Equilin sulfate ? ? 1.0 ? ? 6.0 7.5 6.0 7.5 ?
Ethinylestradiol 120 150 400 60–150 100 400 500–600 500–600 350 2.9–5.0
Diethylstilbestrol ? ? ? 2.9–3.4 ? ? 26–28 25–37 20 5.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations: HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCaTooltip urinary calcium. FSH = Suppression of FSHTooltip follicle-stimulating hormone levels. LH = Suppression of LHTooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
Potencies of oral estrogens[data sources 1]
Compound Dosage for specific uses (mg usually)[a]
ETD[b] EPD[b] MSD[b] MSD[c] OID[c] TSD[c]
Estradiol (non-micronized) 30 ≥120–300 120 6 - -
Estradiol (micronized) 6–12 60–80 14–42 1–2 >5 >8
Estradiol valerate 6–12 60–80 14–42 1–2 - >8
Estradiol benzoate - 60–140 - - - -
Estriol ≥20 120–150[d] 28–126 1–6 >5 -
Estriol succinate - 140–150[d] 28–126 2–6 - -
Estrone sulfate 12 60 42 2 - -
Conjugated estrogens 5–12 60–80 8.4–25 0.625–1.25 >3.75 7.5
Ethinylestradiol 200 μg 1–2 280 μg 20–40 μg 100 μg 100 μg
Mestranol 300 μg 1.5–3.0 300–600 μg 25–30 μg >80 μg -
Quinestrol 300 μg 2–4 500 μg 25–50 μg - -
Methylestradiol - 2 - - - -
Diethylstilbestrol 2.5 20–30 11 0.5–2.0 >5 3
DES dipropionate - 15–30 - - - -
Dienestrol 5 30–40 42 0.5–4.0 - -
Dienestrol diacetate 3–5 30–60 - - - -
Hexestrol - 70–110 - - - -
Chlorotrianisene - >100 - - >48 -
Methallenestril - 400 - - - -
Sources and footnotes:
  1. ^ [73][74][75][76][77][78] [79][80][81][82] [83][84][85][86][87][88][89][90][91]
  1. ^ Dosages are given in milligrams unless otherwise noted.
  2. ^ a b c Dosed every 2 to 3 weeks
  3. ^ a b c Dosed daily
  4. ^ a b In divided doses, 3x/day; irregular and atypical proliferation.
Parenteral potencies and durations of nonsteroidal estrogens
Estrogen Form Major brand name(s) EPD (14 days) Duration
Diethylstilbestrol (DES) Oil solution Metestrol 20 mg 1 mg ≈ 2–3 days; 3 mg ≈ 3 days
Diethylstilbestrol dipropionate Oil solution Cyren B 12.5–15 mg 2.5 mg ≈ 5 days
Aqueous suspension ? 5 mg ? mg = 21–28 days
Dimestrol (DES dimethyl ether) Oil solution Depot-Cyren, Depot-Oestromon, Retalon Retard 20–40 mg ?
Fosfestrol (DES diphosphate)a Aqueous solution Honvan ? <1 day
Dienestrol diacetate Aqueous suspension Farmacyrol-Kristallsuspension 50 mg ?
Hexestrol dipropionate Oil solution Hormoestrol, Retalon Oleosum 25 mg ?
Hexestrol diphosphatea Aqueous solution Cytostesin, Pharmestrin, Retalon Aquosum ? Very short
Note: All by intramuscular injection unless otherwise noted. Footnotes: a = By intravenous injection. Sources: See template.

Antigonadotropic effects edit

 
Testosterone levels with no treatment and with various estrogens in men with prostate cancer.[92] Determinations were made with an early radioimmunoassay (RIA).[92] Source was Shearer et al. (1973).[92]
 
Testosterone levels with placebo and 0.2 to 5 mg/day diethylstilbestrol (DES) for 6 months in men with prostate cancer.[93] Determinations were made with a radioimmunoassay (RIA).[93] Source was Kent et al. (1973).[93]

Due to its estrogenic activity, DES has antigonadotropic effects.[83][70][94][95] That is, it exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), suppresses the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses sex hormone production as well as gamete production or maturation in the gonads.[83][70][94][95] A study of ovulation inhibition found that 5 mg/day oral DES was 92% effective, with ovulation occurring in only a single cycle.[96][90] DES consistently suppresses testosterone levels in men into the castrate range (<50 ng/dL) within 1 to 2 weeks at doses of 3 mg/day and above.[83][95][97] Conversely, a dosage of 1 mg/day DES is unable to fully suppress testosterone levels into the castrate range in men, which instead often stabilize at just above castrate levels (>50 ng/dL).[29][70][94] However, it has also been reported that 1 mg/day DES results in approximately 50% suppression of testosterone levels, albeit with wide interindividual variability.[83][98] It has been said that doses of DES of less than 1 mg/day have no effect on testosterone levels.[83] However, the addition of an "extremely low" dosage of 0.1 mg/day DES to cyproterone acetate has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men.[99][100][101] DES at 3 mg/day has similar testosterone suppression to a dose of 300 mg/day, suggesting that suppression of testosterone levels is maximal by 3 mg/day.[102]

Other activities edit

In addition to the ERs, an in vitro study found that DES also possesses activity, albeit relatively weak, at a variety of other steroid hormone receptors.[64] Whereas the study found EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, the medication showed significant glucocorticoid activity at a concentration of 1 μM that surpassed that of 0.1 nM dexamethasone, as well as significant antagonism of the androgen, progesterone, and mineralocorticoid receptors (75%, 85%, and 50% inhibition of positive control stimulation, respectively, all at a concentration of 1 μM).[64] It also showed approximately 25% inhibition of the activation of PPARγ and LXRα at a concentration of 10 μM.[64] The researchers stated that, to the best of their knowledge, they were the first to report such actions of DES, and hypothesized that these actions could be involved in the clinical effects of DES, for instance, in prostate cancer (notably in which particularly high dosages of DES are employed).[64] However, they also noted that the importance of the activities requires further study in animal models at pharmacologically relevant doses.[64]

DES has been identified as an antagonist of all three isotypes of the estrogen-related receptors (ERRs), the ERRα, ERRβ, and ERRγ.[103][104] Half-maximal inhibition occurs at a concentration of about 1 μM.[104]

Pharmacokinetics edit

DES is well-absorbed with oral administration.[1] With an oral dosage of 1 mg/day DES, plasma levels of DES at 20 hours following the last dose ranged between 0.9 and 1.9 ng/mL (3.4 to 7.1 nmol/L).[1] Sublingual administration of DES appears to have about the same estrogenic potency of oral DES in women.[105] Intrauterine DES has been studied for the treatment of uterine hypoplasia.[106] Oral DES is thought to have about 17 to 50% of the clinical estrogenic potency of DES by injection.[107]

The distribution half-life of DES is 80 minutes.[1] It has no affinity for SHBG or corticosteroid-binding globulin, and hence is not bound to these proteins in the circulation.[108] The plasma protein binding of DES is greater than 95%.[2]

Hydroxylation of the aromatic rings of DES and subsequent conjugation of the ethyl side chains accounts for 80 to 90% of DES metabolism, while oxidation accounts for the remaining 10 to 20% and is dominated by conjugation reactions.[2][3] Conjugation of DES consists of glucuronidation, while oxidation includes dehydrogenation into (Z,Z)-dienestrol.[1][2][3] The medication is also known to produce paroxypropione as a metabolite.[109] DES produces transient quinone-like reactive intermediates that cause cellular and genetic damage, which may help to explain the known carcinogenic effects of DES in humans.[1] However, other research indicates that the toxic effects of DES may simply be due to overactivation of the ERs.[110] In contrast to estradiol, the hydroxyl groups of DES do not undergo oxidation into an estrone-like equivalent.[111]

The elimination half-life of DES is 24 hours.[1] The metabolites of DES are excreted in urine and feces.[2][3]

Chemistry edit

 
Chemical structures of estradiol and DES.[112] Note the preservation of the two hydroxyl groups in DES and the similar distance between them relative to estradiol, which is notable when it is considered that DES was discovered serendipitously.[112][113][114]

DES belongs to the stilbestrol (4,4'-dihydroxystilbene) group of compounds.[115] It is a nonsteroidal open-ring analogue of the steroidal estrogen estradiol.[112] DES can be prepared from anethole, which also happens to be weakly estrogenic.[115][116][114][113] Anethole was demethylated to form anol and anol then spontaneously dimerized into dianol and hexestrol, with DES subsequently being synthesized via structural modification of hexestrol.[115][116][114][113] As shown by X-ray crystallography, the molecular dimensions of DES are almost identical to those of estradiol, particularly in regards to the distance between the terminal hydroxyl groups.[113]

History edit

Synthesis edit

DES was first synthesized in early 1938 by Leon Golberg, then a graduate student of Sir Robert Robinson at the Dyson Perrins Laboratory at the University of Oxford. Golberg's research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by Sir Edward Charles Dodds at Middlesex Hospital Medical School now part of University College London). A report of its synthesis was published in Nature on 5 February 1938.[117][118][119]

DES research was funded by the UK Medical Research Council (MRC), which had a policy against patenting drugs discovered using public funds. Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.[citation needed]

Clinical use edit

DES was first marketed for medical use in 1939.[11] It was approved by the United States Food and Drug Administration (FDA) on September 19, 1941, in tablets up to 5 mg for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement.[119] The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available. From its very inception, the drug was highly controversial.[120][121]

In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found estradiol benzoate and DES to be the first effective drugs for the treatment of metastatic prostate cancer.[122][123] DES was the first cancer drug.[124]

Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the GnRH agonist leuprorelin was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.[97]

From the 1940s until the late 1980s, DES was FDA-approved as estrogen replacement therapy for estrogen deficiency states such as ovarian dysgenesis, premature ovarian failure, and after oophorectomy.[citation needed]

In the 1940s, DES was used off-label to prevent adverse pregnancy outcomes in women with a history of miscarriage. On July 1, 1947, the FDA approved the use of DES for this indication. The first such approval was granted to Bristol-Myers Squibb, allowing use of 25 mg (and later 100 mg) tablets of DES during pregnancy. Approvals were granted to other pharmaceutical companies later in the same year.[125] The recommended regimen started at 5 mg per day in the seventh and eighth weeks of pregnancy (from first day of last menstrual period), increased every other week by 5 mg per day through the 14th week, and then increased every week by 5 mg per day from 25 mg per day in the 15th week to 125 mg per day in the 35th week of pregnancy.[126] DES was originally considered effective and safe for both the pregnant woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953.

In the early 1950s, a double-blind clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES.[127] The study showed no benefit of taking DES during pregnancy; adverse pregnancy outcomes were not reduced in the women who were given DES. By the late 1960s, six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage.[125][128]

Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes, DES continued to be given to pregnant women through the 1960s. In 1971, a report published in the New England Journal of Medicine showed a probable link between DES and vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug in utero. Later in the same year, the FDA sent an FDA Drug Bulletin to all U.S. physicians advising against the use of DES in pregnant women. The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use.[129] On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975.[130] The number of persons exposed to DES during pregnancy or in utero during the period of 1940 to 1971 is unknown, but may be as high as 2 million in the United States. DES was also used in other countries, most notably France, the Netherlands, and Great Britain.

From the 1950s through the beginning of the 1970s, DES was prescribed to prepubescent girls to begin puberty and thus stop growth by closing growth plates in the bones. Despite its clear link to cancer, doctors continued to recommend the hormone for "excess height".[131]

In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women.[132] DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved tamoxifen, a selective estrogen receptor modulator with efficacy similar to DES but fewer side effects.[133]

Several sources from medical literature in the 1970s and 1980s indicate that DES was used as a component of hormone therapy for transgender women.[134][135][136]

In 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive (which had become prevalent at many university health services following publication of an influential study in 1971 in JAMA) to emergency situations such as rape, an FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES.[137]

In 1975, the FDA said it had not actually given (and never did give) approval to any manufacturer to market DES as a postcoital contraceptive, but would approve that indication for emergency situations such as rape or incest if a manufacturer provided patient labeling and special packaging as set out in a FDA final rule published in 1975.[138] To discourage off-label use of DES as a postcoital contraceptive, the FDA in 1975 removed DES 25 mg tablets from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications changed to state: "This drug product should not be used as a postcoital contraceptive" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label.[130][139] In the 1980s, off-label use of the Yuzpe regimen of certain regular combined oral contraceptive pills superseded off-label use of DES as a postcoital contraceptive.[140]

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens.[141] In the 1990s, the only approved indications for DES were treatment of advanced prostate cancer and treatment of advanced breast cancer in postmenopausal women. The last remaining U.S. manufacturer of DES, Eli Lilly, stopped making and marketing it in 1997.[citation needed]

Trials edit

Diethylstilbestrol has been used countless times in studies on rats. Once it was discovered that DES was causing vaginal cancer, experiments began on both male and female rats.[142] Many of these male rats were injected with DES while other male rats were injected with olive oil, and they were considered the control group.[142] Each group received the same dosage on the same days, and the researchers performed light microscopy, electron microscopy, and confocal laser microscopy. With both the electron and confocal laser microscopy, it was prevalent that the Sertoli cells, which are somatic cells where spermatids develop in the testes, were formed 35 days later in the rats who were injected with Diethylstilbestrol compared to the rats in the control group.[142] Proceeding the completion of the trial, it was understood that rats of older age who were injected with DES experienced delay in sertoli cell maturation, underdeveloped epididymides, and drastic decrease in weight compared to its counterparts.[142]

The female rats used were inbred and most of them were given DES combined in their food. These rats were divided into three groups, one group who received no diethylstilbestrol, one group who had DES mixed into their diet, and the third group who had DES administered into their diet after day 13 of being pregnant.[143] Some rats who were given DES unfortunately died before delivering their pup.[143] The group that received DES in their food for 13 days while being pregnant resulted in early abortion and delivery failure.[143] These outcomes showed that DES had a detrimental effect on pregnancy when administered as often as it was. Providing the dosing of diethylstilbestrol later in the pregnancy term also made visible the occurrence of abortions among the rats.[143] Overall, any interaction with DES in female rats concluded in the rats' experiencing abortions, improper fetal growth, and the increase in sterility.[143]

A review of people who had been treated or exposed to DES was done to find out what long-term effects would show.[144] People for a long time had been treated during their pregnancy with DES, and there have been known to be toxic and adverse effects to the hormone therapy. "Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, <2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10 000."[144] Side effects of DES are proving to be long-term as it can cause increased risks of cancer after use.[144] There will be continued work to see how far the adverse effects of DES go after previous therapy and how it will affect offspring and the mothers longer-term.[144]

Regulations edit

In 1938, the ability to test the safety of DES on animals was first obtained by the FDA. The results from the preliminary tests showed that DES harmed the reproductive systems of animals. The application of these results to humans could not be determined, so the FDA could not act in a regulatory manner.[145]

New Drug Applications for DES approval were withdrawn in 1940 in a decision made by the FDA based on scientific uncertainty. However, this decision resulted in significant political pressure, so the FDA came to a compromise. The compromise meant that DES would be available only by prescription and would have to have warnings about its effects on the bottle, but the warning was dropped in 1945. In 1947, DES finally gained FDA approval for prescription to pregnant women who had diabetes as a method of preventing miscarriages. This led to the widespread prescription of DES to all pregnant women.[145]

In 1971, the FDA recommended against the prescription of DES to pregnant women.[146] As a result, DES then began to see a withdraw from the US market starting in 1972 and in the European market starting in 1978, but the FDA still did not withdraw its approval for the use of DES in humans.[147]

DES was classified as a Group 1 carcinogen by the International Agency for Research on Cancer. After classification as a carcinogen, DES had its FDA approval withdrawn in 2000.[146] DES is currently only in use for veterinary practices and in research trials as allowed by the FDA.[148]

Medical ethics edit

Medical Ethics in regard to the approval and use of Diethylstilbestrol have been dismissed because of the actions of the FDA and pharmaceutical companies that were making DES at the time of its use. The Vice President of the American Drug Manufacturers Association, Carson Frailey, was employed by drug companies creating DES in order to help get it approved by the Food and Drug Administration (FDA). Nancy Langston, the author of The Retreat from Precaution: Regulating Diethylstilbestrol (DES), Endocrine Disruptors, and Environmental Health, states that "Frailey persuaded fifty-four doctors from around the country to write to the FDA, describing their clinical experiences with a total of more than five thousand patients. Only four of these fifty-four doctors felt that DES should not be approved, and the result was that, against the concerns of many of the FDA medical staff, the FDA's drug chief Theodore Klumpp recommended that the FDA approve DES."[149] This excerpt describes how DES was unethically approved and shows that the motivation behind its approval was for the benefit of drug companies rather than the people who were going to use the drug. This approval of DES violates the values of medical ethics, autonomy, non-maleficence, beneficence, and justice as there was little thought put into how DES would affect its users.[150] The decisions made by the FDA leaders to approve DES without further study and convince doctors to dissimulate their opinions on the use of DES is unethical. Once DES was approved for public consumption the "warnings [for DES were] made available only on a separate circular that patients would not see. Doctors could get this warning circular only by writing to the drug companies and requesting it. Letters between companies and FDA regulators reveal that both groups feared that if a woman ever saw how many potential risks DES might present, she might refuse to take the drug—or else she might sue the company and the prescribing doctors if she did get cancer or liver damage after taking the drug."[149] Women were not informed about the possible effects of DES because doctors and FDA regulators were afraid DES would fail and never be approved costing the drug companies millions of dollars. The act of distributing potentially dangerous medicine to patients regardless of the effect and harm it may do solely for monetary gain is unethical.[citation needed]

Lawsuits edit

In the 1970s, the negative publicity surrounding the discovery of DES's long-term effects resulted in a huge wave of lawsuits in the United States against its manufacturers. These culminated in a landmark 1980 decision of the Supreme Court of California, Sindell v. Abbott Laboratories, in which the court imposed a rebuttable presumption of market share liability upon all DES manufacturers, proportional to their share of the market at the time the drug was consumed by the mother of a particular plaintiff.[citation needed]

Eli Lilly, a pharmaceutical company manufacturing DES, and the University of Chicago, had an action filed against them in regard to clinical trials from the 1950s. Three women filed the claim that their daughters had developments of abnormal cervical cellular formations as well as reproductive abnormalities in themselves and their sons.[151] The plaintiffs had asked the courts to certify their case as a class action but were declined by the courts. However, the courts issued an opinion that their case had merit. The court held that Eli Lilly had a duty to notify about the risks of DES once they became aware of them or should have become aware of them.[151] Under Illinois tort law, for the plaintiffs to recover under theories of breach of duty to warn and strict liability, the plaintiffs must have alleged injury to themselves. Ultimately, under their claims of breach of duty to warn and strict liability due to the plaintiffs citing risk of physical injury to others, not physical injury to themselves, the case was dismissed by the courts.[151] Although the case was not certified as class action and their claims of breach of duty to warn and strict liability was dismissed, the courts did not dismiss the battery allegations.[151] The issue was then to determine whether the University of Chicago had committed battery against these women but the case was settled before trial.[151] Part of the settlement agreement for this case, Mink v. University of Chicago, attorneys for the plaintiffs negotiated for the university to provide free medical exams for all offspring exposed to DES in utero during the 1950 experiments as well as treat the daughters of any women involved who develop DES-associated vaginal or cervical cancer.[151]

As of February 1991, there were over a thousand pending legal actions against DES manufacturers.[151] There are over 300 companies that manufactured DES according to the same formula and the largest barrier to recovery is determining which manufacturer supplied the drug in each particular case.[151] Many of the successful cases have relied on joint or several parties holding liability.

A lawsuit was filed in Boston Federal Court by 53 DES daughters who say their breast cancers were the result of DES being prescribed to their mothers while pregnant with them. Their cases survived a Daubert hearing. In 2013, the Fecho sisters who initiated the breast cancer/DES link litigation agreed to an undisclosed settlement amount on the second day of trial. The remaining litigants have received various settlements.[152]

The advocacy group DES Action USA helped provide information and support for DES-exposed persons engaged in lawsuits.[153]

Society and culture edit

Alan Turing, the ground-breaking cryptographer, founder of computing science and programmable computers, who also proposed the actual theoretical model of biological morphogenesis, was forcefully given this drug to induce chemical castration as a punitive and discredited "treatment" for homosexual behaviour, shortly before he died in ambiguous circumstances.[154]

At least on one occasion in New Zealand in the early 1960s, diethylstilbestrol was prescribed for the "treatment" of homosexuality.[155]

James Herriot describes a case regarding treating a small dog's testicular Sertoli cell tumor in his 1974 book All Things Bright and Beautiful. Herriot decided to prescribe a high dose of stilboestrol for the recurring tumor, with the amusing side effect that the male dog became "attractive to other male dogs", who followed the terrier around the village for a few weeks. Herriot comments in the story that he knew "The new drug was said to have a feminising effect, but surely not to that extent."

Veterinary use edit

Canine incontinence edit

DES has been very successful in treating female canine incontinence stemming from poor sphincter control. It is still available from compounding pharmacies, and at the low (1 mg) dose, does not have the carcinogenic properties that were so problematic in humans.[156] It is generally administered once a day for seven to ten days and then once every week as needed.[citation needed]

Livestock growth promotion edit

The greatest usage of DES was in the livestock industry, used to improve feed conversion in beef and poultry. During the 1960s, DES was used as a growth hormone in the beef and poultry industries. It was later found to cause cancer by 1971, but was not phased out until 1979.[157][158] Although DES was discovered to be harmful to humans, its veterinary use was not immediately halted. As of 2011, DES was still being used as a growth promoter in terrestrial livestock or fish in some parts of the world including China.[159]

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  67. ^ a b Jacobsen E, Christensen SS (1939). "Comparison of the effects of stilboestrol and oestrone on the mammary tissue of castrated female rats". Acta Pathologica et Microbiologica Scandinavica. 16 (4): 359–364. doi:10.1111/j.1600-0463.1939.tb06045.x. ISSN 0365-5555. After it was shown by Dodds, Goldberg, Lawson, and Robinson that stilboestrol (4.4' dioxy-α-β-diethylstilbene had the same effects as the natural oestrones on the vaginal mucosa of castrated female rats, a great number of works have appeared, which show that this substance, despite its very great chemical difference from the natural female sexual hormones has practically the same effect as these in all respects. The most important of these investigations have been made by Dodds, Lawson and Noble, by Noble, by Bishop, Boycott and Zuckermann, by Erik Guldberg, by Engelhardt, by Winterton and MacGregor, by Erik Jacobsen and most recently by Kreitmair and Sickman, by Buschbeck and Hausknecht, by Cobet, Ratschow and Stechner. The previous experiments have been made on hens, mice, rats, guineapigs, rabbits, monkeys, and human subjects.
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Further reading edit

External links edit

  • Diethylstilbestrol (DES) and Cancer National Cancer Institute
  • DES Update from the U.S. Centers for Disease Control and Prevention
  • DES Action USA national consumer organization providing comprehensive information for DES-exposed individuals
  • from the U.S. National Institutes of Health (c. 1980)
  • DES Follow-up Study 2011-09-29 at the Wayback Machine National Cancer Institute's longterm study of DES-exposed persons (including the DES-AD Project)
  • University of Chicago DES Registry of patients with CCA (clear cell adenocarcinoma) of the vagina and/or cervix
  • DES Diethylstilbestrol Provides resources and social media links for general DES awareness

May 02, 2024
diethylstilbestrol, also, known, stilbestrol, stilboestrol, nonsteroidal, estrogen, medication, which, presently, rarely, used, past, widely, used, variety, indications, including, pregnancy, support, those, with, history, recurrent, miscarriage, hormone, ther. Diethylstilbestrol DES also known as stilbestrol or stilboestrol is a nonsteroidal estrogen medication which is presently rarely used 5 6 7 In the past it was widely used for a variety of indications including pregnancy support for those with a history of recurrent miscarriage hormone therapy for menopausal symptoms and estrogen deficiency treatment of prostate cancer and breast cancer and other uses 5 By 2007 it was only used in the treatment of prostate cancer and breast cancer 8 In 2011 Hoover and colleagues reported on adverse health outcomes linked to DES including infertility miscarriage ectopic pregnancy preeclampsia preterm birth stillbirth infant death menopause prior to age 45 breast cancer cervical cancer and vaginal cancer 9 While most commonly taken by mouth DES was available for use by other routes as well for instance vaginal topical and by injection DiethylstilbestrolClinical dataOther namesDES Stilboestrol Stilbestrol E 11 12 Diethyl 4 13 stilbenediolAHFS Drugs comMicromedex Detailed Consumer InformationPregnancycategoryXRoutes ofadministrationBy mouth vaginal topical intravenous intramuscular injection as an ester Drug classNonsteroidal estrogenATC codeG03CB02 WHO G03CC05 WHO L02AA01 WHO Pharmacokinetic dataBioavailabilityWell absorbed 1 Protein binding gt 95 2 MetabolismHydroxylation oxidation glucuronidation 1 2 3 Metabolites Z Z Dienestrol 1 Paroxypropione 1 Glucuronides 2 3 Elimination half life24 hours 1 4 ExcretionUrine feces 2 3 IdentifiersIUPAC name 4 4 3E Hex 3 ene 3 4 diyl diphenolCAS Number56 53 1 YPubChem CID448537IUPHAR BPS2801DrugBankDB00255 YChemSpider395306 YUNII731DCA35BTKEGGD00577 YChEBICHEBI 41922 YChEMBLChEMBL411 YCompTox Dashboard EPA DTXSID3020465ECHA InfoCard100 000 253Chemical and physical dataFormulaC 18H 20O 2Molar mass268 356 g mol 13D model JSmol Interactive imageSMILES Oc2ccc C C c1ccc O cc1 CC CC cc2InChI InChI 1S C18H20O2 c1 3 17 13 5 9 15 19 10 6 13 18 4 2 14 7 11 16 20 12 8 14 h5 12 19 20H 3 4H2 1 2H3 b18 17 YKey RGLYKWWBQGJZGM ISLYRVAYSA N Y verify DES is an estrogen or an agonist of the estrogen receptors the biological target of estrogens like estradiol 7 It is a synthetic and nonsteroidal estrogen of the stilbestrol group and differs from the natural estrogen estradiol in various ways 7 Compared to estradiol DES has greatly improved bioavailability when taken by mouth is more resistant to metabolism and shows relatively increased effects in certain parts of the body like the liver and uterus 7 These differences result in DES having an increased risk of blood clots cardiovascular issues and certain other adverse effects 7 DES was discovered in 1938 and introduced for medical use in 1939 10 11 From about 1940 to 1971 the medication was given to pregnant women in the incorrect belief that it would reduce the risk of pregnancy complications and losses 10 In 1971 DES was shown to cause clear cell carcinoma a rare vaginal tumor in those who had been exposed to this medication in utero 10 5 The United States Food and Drug Administration subsequently withdrew approval of DES as a treatment for pregnant women 10 5 Follow up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed including XY genital undermasculinization 10 12 The United States National Cancer Institute recommends 13 children born to mothers who took DES to undergo special medical exams on a regular basis to screen for complications as a result of the medication Individuals who were exposed to DES during their mothers pregnancies are commonly referred to as DES daughters and DES sons 10 14 Since the discovery of the toxic effects of DES it has largely been discontinued and is now mostly no longer marketed 10 15 Contents 1 Medical uses 2 Side effects 2 1 Breast changes and feminization 2 2 Blood clots and cardiovascular issues 2 3 Other long term effects 3 Overdose 4 Pharmacology 4 1 Pharmacodynamics 4 1 1 Estrogenic activity 4 1 2 Antigonadotropic effects 4 1 3 Other activities 4 2 Pharmacokinetics 5 Chemistry 6 History 6 1 Synthesis 6 2 Clinical use 6 3 Trials 6 4 Regulations 6 5 Medical ethics 6 6 Lawsuits 7 Society and culture 8 Veterinary use 8 1 Canine incontinence 8 2 Livestock growth promotion 9 References 10 Further reading 11 External linksMedical uses editThis section needs additional citations for verification Please help improve this article by adding citations to reliable sources in this section Unsourced material may be challenged and removed September 2017 Learn how and when to remove this message DES has been used in the past for the following indications 5 additional citation s needed Recurrent miscarriage in pregnancy Menopausal hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy Hormone therapy for hypoestrogenism e g gonadal dysgenesis premature ovarian failure and after oophorectomy Postpartum lactation suppression to prevent or reverse breast engorgement 16 Gonorrheal vaginitis discontinued following the introduction of the antibiotic penicillin Prostate cancer and breast cancer Prevention of tall stature in tall adolescent girls Treatment of acne in girls and women As an emergency postcoital contraceptive As a means of chemical castration for treating hypersexuality and paraphilias and sex offenders 17 additional citation s needed Prevention of the testosterone flare at the start of gonadotropin releasing hormone agonist GnRH agonist therapy 18 19 20 21 22 23 24 Feminizing hormone therapy for transgender women 25 26 DES was used at a dosage of 0 2 to 0 5 mg day in menopausal hormone therapy 27 5 Interest in the use of DES to treat prostate cancer continues today 28 29 30 31 32 33 34 However use of bioidentical parenteral estrogens like polyestradiol phosphate has been advocated in favor of oral synthetic estrogens like DES due to their much lower risk of cardiovascular toxicity 35 32 34 In addition to prostate cancer some interest in the use of DES to treat breast cancer continues today as well 36 37 However similarly to the case of prostate cancer arguments have been made 38 for the use of bioidentical estrogens like estradiol instead of DES for breast cancer 36 38 Oral DES at 0 25 to 0 5 mg day is effective in the treatment of hot flashes in men undergoing androgen deprivation therapy for prostate cancer 39 Although DES was used to support pregnancy it was later found not to be effective for this use and to actually be harmful 40 41 42 43 Side effects editAt more than 1 mg day DES is associated with high rates of side effects including nausea vomiting abdominal discomfort headache and bloating incidence of 15 50 44 Breast changes and feminization edit The pigmentation of the breast areolae are often very dark and almost black with DES therapy 5 45 46 47 48 49 50 51 The pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as estradiol 5 45 The mechanism of the difference is unknown 5 Progestogens like hydroxyprogesterone caproate have been reported to reduce the nipple hyperpigmentation induced by high dose estrogen therapy 52 In men treated with it for prostate cancer DES has been found to produce high rates of gynecomastia breast development of 41 to 77 53 Blood clots and cardiovascular issues edit In studies of DES as a form of high dose estrogen therapy for those with prostate cancer it has been associated with considerable cardiovascular morbidity and mortality 29 5 The risk is dose dependent 29 A dosage of 5 mg day DES has been associated with a 36 increase in non cancer related mostly cardiovascular deaths 29 In addition there is an up to 15 incidence of venous thromboembolism 54 A 3 mg day dosage of DES has been associated with an incidence of thromboembolism of 9 6 to 17 with an incidence of cardiovascular complications of 33 3 29 A lower dosage of 1 mg day DES has been associated with a rate of death due to cardiovascular events of 14 8 relative to 8 3 for orchiectomy alone 29 Other long term effects edit See also Birth defects of diethylstilbestrol DES has been linked to a variety of long term adverse effects in women who were treated with it during pregnancy and or in their offspring including increased risk of the following 40 vaginal clear cell adenocarcinoma vaginal adenosis T shaped uterus uterine fibroids cervical weakness breast cancer infertility hypogonadism intersexual gestational defects depression A comprehensive animal study in 1993 found a plethora of adverse effects from DES such as but not limited to genotoxicity due to quinone metabolite teratogenicity penile and testicular hypoplasia cryptorchidism in rats and rhesus monkeys liver and renal cancer in hamsters ovarian papillary carcinoma in canines and malignant uterine mesothelioma in squirrel monkeys 55 Evidence was also found linking ADHD to F2 generations demonstrating that there is at least some neurological and transgenerational effects in addition to the carcinogenic 56 Rodent studies reveal female reproductive tract cancers and abnormalities reaching to the F2 generation and there is evidence of adverse effects such as irregular menstrual cycles intersexual in grandchildren of DES mothers 57 Additionally evidence also points to transgenerational effects in F2 sons such as hypospadias 58 At this time however the extent of DES transgenerational effects in humans is not fully understood citation needed Overdose editDES has been assessed in the past in clinical studies at extremely high doses of as much as 1 500 to 5 000 mg day 36 59 60 Pharmacology editPharmacodynamics edit Estrogenic activity edit DES is an estrogen specifically it is a highly potent full agonist of both of the estrogen receptors ERs 61 62 It has approximately 468 and 295 of the affinity of estradiol at the ERa and ERb respectively 63 However EC50 values of 0 18 nM and 0 06 nM of DES for the ERa and ERb respectively have been reported suggesting in spite of its binding affinity for the two receptors several fold preference for activation of the ERb over the ERa 64 In addition to the nuclear ERs DES is an agonist of the G protein coupled estrogen receptor GPER albeit with relatively low affinity 1 000 nM 65 DES produces all of the same biological effects attributed to natural estrogens like estradiol 66 67 This includes effects in the uterus vagina mammary glands pituitary gland and other tissues 66 67 68 69 A dosage of 1 mg day DES is approximately equivalent to a dosage of 50 µg day ethinylestradiol in terms of systemic estrogenic potency 1 4 Similarly to ethinylestradiol DES shows a marked and disproportionately strong effect on liver protein synthesis 7 Whereas its systemic estrogenic potency was about 3 8 fold of that of estropipate piperazine estrone sulfate which has similar potency to micronized estradiol the hepatic estrogenic potency of DES was 28 fold that of estropipate or about 7 5 fold stronger potency for a dosage with equivalent systemic estrogenic effect 1 DES has at least three mechanisms of action in the treatment of prostate cancer 70 It suppresses gonadal androgen production and hence circulating androgen levels due to its antigonadotropic effects it stimulates hepatic sex hormone binding globulin SHBG production thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and dihydrotestosterone DHT in the circulation and it may have direct cytotoxic effects in the testes and prostate gland 70 DES has also been found to decrease DNA synthesis at high doses 70 DES is a long acting estrogen with a nuclear retention of around 24 hours 71 72 vte Relative oral potencies of estrogens Estrogen HFTooltip Hot flashes VETooltip Vaginal epithelium UCaTooltip Urinary calcium FSHTooltip Follicle stimulating hormone LHTooltip Luteinizing hormone HDLTooltip High density lipoprotein CTooltip Cholesterol SHBGTooltip Sex hormone binding globulin CBGTooltip Corticosteroid binding globulin AGTTooltip Angiotensinogen Liver Estradiol 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 Estrone 0 3 0 3 Estriol 0 3 0 3 0 1 0 3 0 3 0 2 0 67 Estrone sulfate 0 9 0 9 0 8 0 9 0 9 0 5 0 9 0 5 0 7 1 4 1 5 0 56 1 7 Conjugated estrogens 1 2 1 5 2 0 1 1 1 3 1 0 1 5 3 0 3 2 1 3 1 5 5 0 1 3 4 5 Equilin sulfate 1 0 6 0 7 5 6 0 7 5 Ethinylestradiol 120 150 400 60 150 100 400 500 600 500 600 350 2 9 5 0 Diethylstilbestrol 2 9 3 4 26 28 25 37 20 5 7 7 5 Sources and footnotesNotes Values are ratios with estradiol as standard i e 1 0 Abbreviations HF Clinical relief of hot flashes VE Increased proliferation of vaginal epithelium UCa Decrease in UCaTooltip urinary calcium FSH Suppression of FSHTooltip follicle stimulating hormone levels LH Suppression of LHTooltip luteinizing hormone levels HDL C SHBG CBG and AGT Increase in the serum levels of these liver proteins Liver Ratio of liver estrogenic effects to general systemic estrogenic effects hot flashes gonadotropins Sources See template vte Potencies of oral estrogens data sources 1 Compound Dosage for specific uses mg usually a ETD b EPD b MSD b MSD c OID c TSD c Estradiol non micronized 30 120 300 120 6 Estradiol micronized 6 12 60 80 14 42 1 2 gt 5 gt 8 Estradiol valerate 6 12 60 80 14 42 1 2 gt 8 Estradiol benzoate 60 140 Estriol 20 120 150 d 28 126 1 6 gt 5 Estriol succinate 140 150 d 28 126 2 6 Estrone sulfate 12 60 42 2 Conjugated estrogens 5 12 60 80 8 4 25 0 625 1 25 gt 3 75 7 5 Ethinylestradiol 200 mg 1 2 280 mg 20 40 mg 100 mg 100 mg Mestranol 300 mg 1 5 3 0 300 600 mg 25 30 mg gt 80 mg Quinestrol 300 mg 2 4 500 mg 25 50 mg Methylestradiol 2 Diethylstilbestrol 2 5 20 30 11 0 5 2 0 gt 5 3 DES dipropionate 15 30 Dienestrol 5 30 40 42 0 5 4 0 Dienestrol diacetate 3 5 30 60 Hexestrol 70 110 Chlorotrianisene gt 100 gt 48 Methallenestril 400 Sources and footnotes 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 Dosages are given in milligrams unless otherwise noted a b c Dosed every 2 to 3 weeks a b c Dosed daily a b In divided doses 3x day irregular and atypical proliferation vte Parenteral potencies and durations of nonsteroidal estrogens Estrogen Form Major brand name s EPD 14 days Duration Diethylstilbestrol DES Oil solution Metestrol 20 mg 1 mg 2 3 days 3 mg 3 days Diethylstilbestrol dipropionate Oil solution Cyren B 12 5 15 mg 2 5 mg 5 days Aqueous suspension 5 mg mg 21 28 days Dimestrol DES dimethyl ether Oil solution Depot Cyren Depot Oestromon Retalon Retard 20 40 mg Fosfestrol DES diphosphate a Aqueous solution Honvan lt 1 day Dienestrol diacetate Aqueous suspension Farmacyrol Kristallsuspension 50 mg Hexestrol dipropionate Oil solution Hormoestrol Retalon Oleosum 25 mg Hexestrol diphosphatea Aqueous solution Cytostesin Pharmestrin Retalon Aquosum Very short Note All by intramuscular injection unless otherwise noted Footnotes a By intravenous injection Sources See template Antigonadotropic effects edit nbsp Testosterone levels with no treatment and with various estrogens in men with prostate cancer 92 Determinations were made with an early radioimmunoassay RIA 92 Source was Shearer et al 1973 92 nbsp Testosterone levels with placebo and 0 2 to 5 mg day diethylstilbestrol DES for 6 months in men with prostate cancer 93 Determinations were made with a radioimmunoassay RIA 93 Source was Kent et al 1973 93 Due to its estrogenic activity DES has antigonadotropic effects 83 70 94 95 That is it exerts negative feedback on the hypothalamic pituitary gonadal axis HPG axis suppresses the secretion of the gonadotropins luteinizing hormone LH and follicle stimulating hormone FSH and suppresses sex hormone production as well as gamete production or maturation in the gonads 83 70 94 95 A study of ovulation inhibition found that 5 mg day oral DES was 92 effective with ovulation occurring in only a single cycle 96 90 DES consistently suppresses testosterone levels in men into the castrate range lt 50 ng dL within 1 to 2 weeks at doses of 3 mg day and above 83 95 97 Conversely a dosage of 1 mg day DES is unable to fully suppress testosterone levels into the castrate range in men which instead often stabilize at just above castrate levels gt 50 ng dL 29 70 94 However it has also been reported that 1 mg day DES results in approximately 50 suppression of testosterone levels albeit with wide interindividual variability 83 98 It has been said that doses of DES of less than 1 mg day have no effect on testosterone levels 83 However the addition of an extremely low dosage of 0 1 mg day DES to cyproterone acetate has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men 99 100 101 DES at 3 mg day has similar testosterone suppression to a dose of 300 mg day suggesting that suppression of testosterone levels is maximal by 3 mg day 102 Other activities edit In addition to the ERs an in vitro study found that DES also possesses activity albeit relatively weak at a variety of other steroid hormone receptors 64 Whereas the study found EC50 values of 0 18 nM and 0 06 nM of DES for the ERa and ERb respectively the medication showed significant glucocorticoid activity at a concentration of 1 mM that surpassed that of 0 1 nM dexamethasone as well as significant antagonism of the androgen progesterone and mineralocorticoid receptors 75 85 and 50 inhibition of positive control stimulation respectively all at a concentration of 1 mM 64 It also showed approximately 25 inhibition of the activation of PPARg and LXRa at a concentration of 10 mM 64 The researchers stated that to the best of their knowledge they were the first to report such actions of DES and hypothesized that these actions could be involved in the clinical effects of DES for instance in prostate cancer notably in which particularly high dosages of DES are employed 64 However they also noted that the importance of the activities requires further study in animal models at pharmacologically relevant doses 64 DES has been identified as an antagonist of all three isotypes of the estrogen related receptors ERRs the ERRa ERRb and ERRg 103 104 Half maximal inhibition occurs at a concentration of about 1 mM 104 Pharmacokinetics edit DES is well absorbed with oral administration 1 With an oral dosage of 1 mg day DES plasma levels of DES at 20 hours following the last dose ranged between 0 9 and 1 9 ng mL 3 4 to 7 1 nmol L 1 Sublingual administration of DES appears to have about the same estrogenic potency of oral DES in women 105 Intrauterine DES has been studied for the treatment of uterine hypoplasia 106 Oral DES is thought to have about 17 to 50 of the clinical estrogenic potency of DES by injection 107 The distribution half life of DES is 80 minutes 1 It has no affinity for SHBG or corticosteroid binding globulin and hence is not bound to these proteins in the circulation 108 The plasma protein binding of DES is greater than 95 2 Hydroxylation of the aromatic rings of DES and subsequent conjugation of the ethyl side chains accounts for 80 to 90 of DES metabolism while oxidation accounts for the remaining 10 to 20 and is dominated by conjugation reactions 2 3 Conjugation of DES consists of glucuronidation while oxidation includes dehydrogenation into Z Z dienestrol 1 2 3 The medication is also known to produce paroxypropione as a metabolite 109 DES produces transient quinone like reactive intermediates that cause cellular and genetic damage which may help to explain the known carcinogenic effects of DES in humans 1 However other research indicates that the toxic effects of DES may simply be due to overactivation of the ERs 110 In contrast to estradiol the hydroxyl groups of DES do not undergo oxidation into an estrone like equivalent 111 The elimination half life of DES is 24 hours 1 The metabolites of DES are excreted in urine and feces 2 3 Chemistry edit nbsp Chemical structures of estradiol and DES 112 Note the preservation of the two hydroxyl groups in DES and the similar distance between them relative to estradiol which is notable when it is considered that DES was discovered serendipitously 112 113 114 DES belongs to the stilbestrol 4 4 dihydroxystilbene group of compounds 115 It is a nonsteroidal open ring analogue of the steroidal estrogen estradiol 112 DES can be prepared from anethole which also happens to be weakly estrogenic 115 116 114 113 Anethole was demethylated to form anol and anol then spontaneously dimerized into dianol and hexestrol with DES subsequently being synthesized via structural modification of hexestrol 115 116 114 113 As shown by X ray crystallography the molecular dimensions of DES are almost identical to those of estradiol particularly in regards to the distance between the terminal hydroxyl groups 113 History editSynthesis edit DES was first synthesized in early 1938 by Leon Golberg then a graduate student of Sir Robert Robinson at the Dyson Perrins Laboratory at the University of Oxford Golberg s research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry led by Sir Edward Charles Dodds at Middlesex Hospital Medical School now part of University College London A report of its synthesis was published in Nature on 5 February 1938 117 118 119 DES research was funded by the UK Medical Research Council MRC which had a policy against patenting drugs discovered using public funds Because it was not patented DES was produced by more than 200 pharmaceutical and chemical companies worldwide citation needed Clinical use edit DES was first marketed for medical use in 1939 11 It was approved by the United States Food and Drug Administration FDA on September 19 1941 in tablets up to 5 mg for four indications gonorrheal vaginitis atrophic vaginitis menopausal symptoms and postpartum lactation suppression to prevent breast engorgement 119 The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available From its very inception the drug was highly controversial 120 121 In 1941 Charles Huggins and Clarence Hodges at the University of Chicago found estradiol benzoate and DES to be the first effective drugs for the treatment of metastatic prostate cancer 122 123 DES was the first cancer drug 124 Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years until the GnRH agonist leuprorelin was found to have efficacy similar to DES without estrogenic effects and was approved in 1985 97 From the 1940s until the late 1980s DES was FDA approved as estrogen replacement therapy for estrogen deficiency states such as ovarian dysgenesis premature ovarian failure and after oophorectomy citation needed In the 1940s DES was used off label to prevent adverse pregnancy outcomes in women with a history of miscarriage On July 1 1947 the FDA approved the use of DES for this indication The first such approval was granted to Bristol Myers Squibb allowing use of 25 mg and later 100 mg tablets of DES during pregnancy Approvals were granted to other pharmaceutical companies later in the same year 125 The recommended regimen started at 5 mg per day in the seventh and eighth weeks of pregnancy from first day of last menstrual period increased every other week by 5 mg per day through the 14th week and then increased every week by 5 mg per day from 25 mg per day in the 15th week to 125 mg per day in the 35th week of pregnancy 126 DES was originally considered effective and safe for both the pregnant woman and the developing baby It was aggressively marketed and routinely prescribed Sales peaked in 1953 In the early 1950s a double blind clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES 127 The study showed no benefit of taking DES during pregnancy adverse pregnancy outcomes were not reduced in the women who were given DES By the late 1960s six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage 125 128 Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes DES continued to be given to pregnant women through the 1960s In 1971 a report published in the New England Journal of Medicine showed a probable link between DES and vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug in utero Later in the same year the FDA sent an FDA Drug Bulletin to all U S physicians advising against the use of DES in pregnant women The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use 129 On February 5 1975 the FDA ordered 25 mg and 100 mg tablets of DES withdrawn effective February 18 1975 130 The number of persons exposed to DES during pregnancy or in utero during the period of 1940 to 1971 is unknown but may be as high as 2 million in the United States DES was also used in other countries most notably France the Netherlands and Great Britain From the 1950s through the beginning of the 1970s DES was prescribed to prepubescent girls to begin puberty and thus stop growth by closing growth plates in the bones Despite its clear link to cancer doctors continued to recommend the hormone for excess height 131 In 1960 DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women 132 DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977 when the FDA approved tamoxifen a selective estrogen receptor modulator with efficacy similar to DES but fewer side effects 133 Several sources from medical literature in the 1970s and 1980s indicate that DES was used as a component of hormone therapy for transgender women 134 135 136 In 1973 in an attempt to restrict off label use of DES as a postcoital contraceptive which had become prevalent at many university health services following publication of an influential study in 1971 in JAMA to emergency situations such as rape an FDA Drug Bulletin was sent to all U S physicians and pharmacists that said the FDA had approved under restricted conditions postcoital contraceptive use of DES 137 In 1975 the FDA said it had not actually given and never did give approval to any manufacturer to market DES as a postcoital contraceptive but would approve that indication for emergency situations such as rape or incest if a manufacturer provided patient labeling and special packaging as set out in a FDA final rule published in 1975 138 To discourage off label use of DES as a postcoital contraceptive the FDA in 1975 removed DES 25 mg tablets from the market and ordered the labeling of lower doses 5 mg and lower of DES still approved for other indications changed to state This drug product should not be used as a postcoital contraceptive in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label 130 139 In the 1980s off label use of the Yuzpe regimen of certain regular combined oral contraceptive pills superseded off label use of DES as a postcoital contraceptive 140 In 1978 the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens 141 In the 1990s the only approved indications for DES were treatment of advanced prostate cancer and treatment of advanced breast cancer in postmenopausal women The last remaining U S manufacturer of DES Eli Lilly stopped making and marketing it in 1997 citation needed Trials edit Diethylstilbestrol has been used countless times in studies on rats Once it was discovered that DES was causing vaginal cancer experiments began on both male and female rats 142 Many of these male rats were injected with DES while other male rats were injected with olive oil and they were considered the control group 142 Each group received the same dosage on the same days and the researchers performed light microscopy electron microscopy and confocal laser microscopy With both the electron and confocal laser microscopy it was prevalent that the Sertoli cells which are somatic cells where spermatids develop in the testes were formed 35 days later in the rats who were injected with Diethylstilbestrol compared to the rats in the control group 142 Proceeding the completion of the trial it was understood that rats of older age who were injected with DES experienced delay in sertoli cell maturation underdeveloped epididymides and drastic decrease in weight compared to its counterparts 142 The female rats used were inbred and most of them were given DES combined in their food These rats were divided into three groups one group who received no diethylstilbestrol one group who had DES mixed into their diet and the third group who had DES administered into their diet after day 13 of being pregnant 143 Some rats who were given DES unfortunately died before delivering their pup 143 The group that received DES in their food for 13 days while being pregnant resulted in early abortion and delivery failure 143 These outcomes showed that DES had a detrimental effect on pregnancy when administered as often as it was Providing the dosing of diethylstilbestrol later in the pregnancy term also made visible the occurrence of abortions among the rats 143 Overall any interaction with DES in female rats concluded in the rats experiencing abortions improper fetal growth and the increase in sterility 143 A review of people who had been treated or exposed to DES was done to find out what long term effects would show 144 People for a long time had been treated during their pregnancy with DES and there have been known to be toxic and adverse effects to the hormone therapy Exposure to DES has been associated with an increased risk for breast cancer in DES mothers relative risk lt 2 0 and with a lifetime risk of clear cell cervicovaginal cancer in DES daughters of 1 1000 to 1 10 000 144 Side effects of DES are proving to be long term as it can cause increased risks of cancer after use 144 There will be continued work to see how far the adverse effects of DES go after previous therapy and how it will affect offspring and the mothers longer term 144 Regulations edit In 1938 the ability to test the safety of DES on animals was first obtained by the FDA The results from the preliminary tests showed that DES harmed the reproductive systems of animals The application of these results to humans could not be determined so the FDA could not act in a regulatory manner 145 New Drug Applications for DES approval were withdrawn in 1940 in a decision made by the FDA based on scientific uncertainty However this decision resulted in significant political pressure so the FDA came to a compromise The compromise meant that DES would be available only by prescription and would have to have warnings about its effects on the bottle but the warning was dropped in 1945 In 1947 DES finally gained FDA approval for prescription to pregnant women who had diabetes as a method of preventing miscarriages This led to the widespread prescription of DES to all pregnant women 145 In 1971 the FDA recommended against the prescription of DES to pregnant women 146 As a result DES then began to see a withdraw from the US market starting in 1972 and in the European market starting in 1978 but the FDA still did not withdraw its approval for the use of DES in humans 147 DES was classified as a Group 1 carcinogen by the International Agency for Research on Cancer After classification as a carcinogen DES had its FDA approval withdrawn in 2000 146 DES is currently only in use for veterinary practices and in research trials as allowed by the FDA 148 Medical ethics edit Medical Ethics in regard to the approval and use of Diethylstilbestrol have been dismissed because of the actions of the FDA and pharmaceutical companies that were making DES at the time of its use The Vice President of the American Drug Manufacturers Association Carson Frailey was employed by drug companies creating DES in order to help get it approved by the Food and Drug Administration FDA Nancy Langston the author of The Retreat from Precaution Regulating Diethylstilbestrol DES Endocrine Disruptors and Environmental Health states that Frailey persuaded fifty four doctors from around the country to write to the FDA describing their clinical experiences with a total of more than five thousand patients Only four of these fifty four doctors felt that DES should not be approved and the result was that against the concerns of many of the FDA medical staff the FDA s drug chief Theodore Klumpp recommended that the FDA approve DES 149 This excerpt describes how DES was unethically approved and shows that the motivation behind its approval was for the benefit of drug companies rather than the people who were going to use the drug This approval of DES violates the values of medical ethics autonomy non maleficence beneficence and justice as there was little thought put into how DES would affect its users 150 The decisions made by the FDA leaders to approve DES without further study and convince doctors to dissimulate their opinions on the use of DES is unethical Once DES was approved for public consumption the warnings for DES were made available only on a separate circular that patients would not see Doctors could get this warning circular only by writing to the drug companies and requesting it Letters between companies and FDA regulators reveal that both groups feared that if a woman ever saw how many potential risks DES might present she might refuse to take the drug or else she might sue the company and the prescribing doctors if she did get cancer or liver damage after taking the drug 149 Women were not informed about the possible effects of DES because doctors and FDA regulators were afraid DES would fail and never be approved costing the drug companies millions of dollars The act of distributing potentially dangerous medicine to patients regardless of the effect and harm it may do solely for monetary gain is unethical citation needed Lawsuits edit In the 1970s the negative publicity surrounding the discovery of DES s long term effects resulted in a huge wave of lawsuits in the United States against its manufacturers These culminated in a landmark 1980 decision of the Supreme Court of California Sindell v Abbott Laboratories in which the court imposed a rebuttable presumption of market share liability upon all DES manufacturers proportional to their share of the market at the time the drug was consumed by the mother of a particular plaintiff citation needed Eli Lilly a pharmaceutical company manufacturing DES and the University of Chicago had an action filed against them in regard to clinical trials from the 1950s Three women filed the claim that their daughters had developments of abnormal cervical cellular formations as well as reproductive abnormalities in themselves and their sons 151 The plaintiffs had asked the courts to certify their case as a class action but were declined by the courts However the courts issued an opinion that their case had merit The court held that Eli Lilly had a duty to notify about the risks of DES once they became aware of them or should have become aware of them 151 Under Illinois tort law for the plaintiffs to recover under theories of breach of duty to warn and strict liability the plaintiffs must have alleged injury to themselves Ultimately under their claims of breach of duty to warn and strict liability due to the plaintiffs citing risk of physical injury to others not physical injury to themselves the case was dismissed by the courts 151 Although the case was not certified as class action and their claims of breach of duty to warn and strict liability was dismissed the courts did not dismiss the battery allegations 151 The issue was then to determine whether the University of Chicago had committed battery against these women but the case was settled before trial 151 Part of the settlement agreement for this case Mink v University of Chicago attorneys for the plaintiffs negotiated for the university to provide free medical exams for all offspring exposed to DES in utero during the 1950 experiments as well as treat the daughters of any women involved who develop DES associated vaginal or cervical cancer 151 As of February 1991 there were over a thousand pending legal actions against DES manufacturers 151 There are over 300 companies that manufactured DES according to the same formula and the largest barrier to recovery is determining which manufacturer supplied the drug in each particular case 151 Many of the successful cases have relied on joint or several parties holding liability A lawsuit was filed in Boston Federal Court by 53 DES daughters who say their breast cancers were the result of DES being prescribed to their mothers while pregnant with them Their cases survived a Daubert hearing In 2013 the Fecho sisters who initiated the breast cancer DES link litigation agreed to an undisclosed settlement amount on the second day of trial The remaining litigants have received various settlements 152 The advocacy group DES Action USA helped provide information and support for DES exposed persons engaged in lawsuits 153 Society and culture editAlan Turing the ground breaking cryptographer founder of computing science and programmable computers who also proposed the actual theoretical model of biological morphogenesis was forcefully given this drug to induce chemical castration as a punitive and discredited treatment for homosexual behaviour shortly before he died in ambiguous circumstances 154 At least on one occasion in New Zealand in the early 1960s diethylstilbestrol was prescribed for the treatment of homosexuality 155 James Herriot describes a case regarding treating a small dog s testicular Sertoli cell tumor in his 1974 book All Things Bright and Beautiful Herriot decided to prescribe a high dose of stilboestrol for the recurring tumor with the amusing side effect that the male dog became attractive to other male dogs who followed the terrier around the village for a few weeks Herriot comments in the story that he knew The new drug was said to have a feminising effect but surely not to that extent Veterinary use editCanine incontinence edit DES has been very successful in treating female canine incontinence stemming from poor sphincter control It is still available from compounding pharmacies and at the low 1 mg dose does not have the carcinogenic properties that were so problematic in humans 156 It is generally administered once a day for seven to ten days and then once every week as needed citation needed Livestock growth promotion edit The greatest usage of DES was in the livestock industry used to improve feed conversion in beef and poultry During the 1960s DES was used as a growth hormone in the beef and poultry industries It was later found to cause cancer by 1971 but was not phased out until 1979 157 158 Although DES was discovered to be harmful to humans its veterinary use was not immediately halted As of 2011 DES was still being used as a growth promoter in terrestrial livestock or fish in some parts of the world including China 159 References edit a b c d e f g h i j k l m Chabner B Longo DL 1996 Cancer Chemotherapy and Biotherapy Principles and Practice Lippincott Raven Publishers p 186 ISBN 978 0 397 51418 2 Piperazine estrone sulfate and micronized estradiol were equipotent with respect to increases in SHBG whereas DES was 28 4 fold more potent With respect to decreased FSH DES was 3 8 fold and ethinyl estradiol was 80 to 200 fold more potent than was piperazine estrone sulfate The dose equivalents for ethinyl estradiol 50 µg and DES 1 mg reflect these relative potencies 220 DES a potent synthetic estrogen Fig 6 12 is absorbed well after an oral dosage Patients given 1 mg of DES daily had plasma concentrations at 20 hours ranging from 0 9 to 1 9 ng per mL The initial half life of DES is 80 minutes with a secondary half life of 24 hours 223 The principal pathways of metabolism are conversion to the glucuronide and oxidation The oxidative pathways include aromatic hydroxylation of the ethyl side chains and dehydrogenation to Z Z dienestrol producing transient quinone like intermediates that react with cellular macromolecules and cause genetic damage in eukaryotic cells 223 Metabolic activation of DES may explain its well established carcinogenic properties 224 a b c d e f g h Oelschlager H Rothley D Dunzendorfer U 1988 New Results on the Pharmacokinetics of Fosfestrol Urologia Internationalis 43 1 15 23 doi 10 1159 000281427 ISSN 1423 0399 a b c d e f Droz JP Kattan J Bonnay M Chraibi Y Bekradda M Culine S February 1993 High dose continuous infusion fosfestrol in hormone resistant prostate cancer Cancer 71 3 Suppl 1123 30 doi 10 1002 1097 0142 19930201 71 3 lt 1123 AID CNCR2820711434 gt 3 0 CO 2 T PMID 8428334 S2CID 23078614 a b Abramson FP Miller HC December 1982 Bioavailability distribution and pharmacokinetics of diethystilbestrol produced from stilphostrol J Urol 128 6 1336 9 doi 10 1016 s0022 5347 17 53502 8 PMID 7154205 a b c d e f g h i j Noller KL Fish CR July 1974 Diethylstilbestrol usage Its interesting past important present and questionable future Med Clin North Am 58 4 793 810 doi 10 1016 S0025 7125 16 32122 8 PMID 4276416 Elks J 14 November 2014 The Dictionary of Drugs Chemical Data Chemical Data Structures and Bibliographies Springer pp 396 ISBN 978 1 4757 2085 3 a b c d e f Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration PDF Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 Watkins ES 16 April 2007 The Estrogen Elixir A History of Hormone Replacement Therapy in America JHU Press pp 26 ISBN 978 0 8018 8602 7 Effects of Diethylstilbestrol DES a Trans placental Carcinogen dceg cancer gov 20 November 2012 Retrieved 3 September 2020 a b c d e f g Veurink M Koster M Berg LT June 2005 The history of DES lessons to be learned Pharm World Sci 27 3 139 43 doi 10 1007 s11096 005 3663 z PMID 16096877 S2CID 12630813 a b Feldberg GD Ladd Taylor M Li A 2003 Women Health and Nation Canada and the United States Since 1945 McGill Queen s Press MQUP pp 103 ISBN 978 0 7735 2501 6 DES Update For Consumers United States Department of Health and Human Services Centers for Disease Control and Prevention Retrieved 2011 06 30 Diethylstilbestrol DES and Cancer National Cancer Institute Retrieved 2011 06 30 Arnold A January 5 2017 The Devastating Effects of a 1940s Wonder Pill Haunt Women Generations Later Broadly Coelingh Bennink HJ April 2004 Are all estrogens the same Maturitas 47 4 269 275 doi 10 1016 j 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from a variety of problems attributed to the drug Swyer GI April 1959 The oestrogens Br Med J 1 5128 1029 31 doi 10 1136 bmj 1 5128 1029 PMC 1993181 PMID 13638626 Diethylstilbestrol suffers from the serious drawback that in doses above 1 mg a day it is likely to produce nausea vomiting abdominal discomfort headache and bloating in a proportion of patients varyingly estimated from 15 to 50 a b Dell Castillo EB Argonz J April 1954 Oestrogen treatment in cases of rudimentary ovary syndrome Acta Endocrinologica 15 4 299 312 doi 10 1530 acta 0 0150299 PMID 13157878 Labhart A 6 December 2012 Clinical Endocrinology Theory and Practice Springer Science amp Business Media pp 720 ISBN 978 3 642 96158 8 Davis ME Boynton MW 1941 Indications clinical use and toxicity of 4 4 dihydroxy diethyl stilbene The Journal of Clinical Endocrinology amp Metabolism 1 4 339 345 doi 10 1210 jcem 1 4 339 ISSN 0021 972X Davis ME Boynton MW Ferguson JH Rothman S 1945 Studies on Pigmentation of Endocrine Origin The 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Wise LA Palmer J Hyer M et al August 2006 Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol DES International Journal of Epidemiology 35 4 862 868 doi 10 1093 ije dyl106 PMID 16723367 Kalfa N Paris F Soyer Gobillard MO Daures JP Sultan C June 2011 Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy a multigenerational national cohort study Fertility and Sterility 95 8 2574 2577 doi 10 1016 j fertnstert 2011 02 047 PMID 21458804 Carter AC Sedransk N Kelley RM Ansfield FJ Ravdin RG Talley RW Potter NR May 1977 Diethylstilbestrol recommended dosages for different categories of breast cancer patients Report of the Cooperative Breast Cancer Group JAMA 237 19 2079 8 doi 10 1001 jama 1977 03270460065023 PMID 576887 Karnaky KJ December 1952 Micronized stilbestrol for dysfunctional uterine bleeding and endometriosis South Med J 45 12 1166 72 doi 10 1097 00007611 195212000 00009 PMID 13005120 Jordan VC 2013 Estrogen Action Selective Estrogen Receptor Modulators and Women s Health Progress and Promise World Scientific pp 143 ISBN 978 1 84816 958 6 Seiler JP Autrup JL Autrup H 6 December 2012 Diversification in Toxicology Man and Environment Proceedings of the 1997 EUROTOX Congress Meeting Held in Arhus Denmark June 25 28 1997 Springer Science amp Business Media pp 23 ISBN 978 3 642 46856 8 Kuiper GG Carlsson B Grandien K Enmark E Haggblad J Nilsson S Gustafsson JA March 1997 Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta Endocrinology 138 3 863 870 doi 10 1210 endo 138 3 4979 PMID 9048584 a b c d e f Coss CC Jones A Parke DN Narayanan R Barrett CM Kearbey JD Veverka KA Miller DD Morton RA Steiner MS Dalton JT March 2012 Preclinical characterization of a novel diphenyl benzamide selective ERa agonist for hormone therapy in prostate cancer Endocrinology 153 3 1070 81 doi 10 1210 en 2011 1608 PMID 22294742 Prossnitz ER Arterburn JB July 2015 International Union of Basic and Clinical Pharmacology XCVII G Protein Coupled Estrogen Receptor and Its Pharmacologic Modulators Pharmacological Reviews 67 3 505 540 doi 10 1124 pr 114 009712 PMC 4485017 PMID 26023144 a b Lackner JE Tulsky AS 1941 Effect of stilbestrol on the myometrial and endometrial activity of the human castrate uterus The Journal of Clinical Endocrinology amp Metabolism 1 5 415 418 doi 10 1210 jcem 1 5 415 ISSN 0021 972X Diethylstilbestrol differing distinctly in chemical structure from the previously known estrogens has been shown to produce all the biologic effects attributed to them such as suppression of the antuitary 2 inhibition of body growth 2 proliferation of the ductile system of the breast 3 suppression of engorgement incident to lactation 4 hyperemia edema and distention of the uterus 5 proliferation of the endometrium 6 vaginal cornification 7 and swelling of the sexual skin 8 It likewise presumably has the supposed carcinogenic propensities of the true estrogens 9 a b Jacobsen E Christensen SS 1939 Comparison of the effects of stilboestrol and oestrone on the mammary tissue of castrated female rats Acta Pathologica et Microbiologica Scandinavica 16 4 359 364 doi 10 1111 j 1600 0463 1939 tb06045 x ISSN 0365 5555 After it was shown by Dodds Goldberg Lawson and Robinson that stilboestrol 4 4 dioxy a b diethylstilbene had the same effects as the natural oestrones on the vaginal mucosa of castrated female rats a great number of works have appeared which show that this substance despite its very great chemical difference from the natural female sexual hormones has practically the same effect as these in all respects The most important of these investigations have been made by Dodds Lawson and Noble by Noble by Bishop Boycott and Zuckermann by Erik Guldberg by Engelhardt by Winterton and MacGregor by Erik Jacobsen and most recently by Kreitmair and Sickman by Buschbeck and Hausknecht by Cobet Ratschow and Stechner The previous experiments have been made on hens mice rats guineapigs rabbits monkeys and human subjects Lewis AA Turner CW 1941 Effect of Stilbestrol on the Mammary Gland of the Mouse Rat Rabbit and Goat Journal of Dairy Science 24 10 845 860 doi 10 3168 jds S0022 0302 41 95467 X ISSN 0022 0302 Lewis AA Turner CW 1942 Effect of Diethylstilbestrol on Mammary Gland Development in Dairy Animals1 Endocrinology 31 5 520 528 doi 10 1210 endo 31 5 520 ISSN 0013 7227 a b c d e f Denis LJ Griffiths E Kaisary AV Murphy GP 1 March 1999 Textbook of Prostate Cancer Pathology Diagnosis and Treatment Pathology Diagnosis and Treatment CRC Press pp 294 297 ISBN 978 1 85317 422 3 Runnebaum B Rabe T 17 April 2013 Gynakologische Endokrinologie und Fortpflanzungsmedizin Band 1 Gynakologische Endokrinologie Springer Verlag pp 88 ISBN 978 3 662 07635 4 Hammond CB Maxson WS January 1982 Current status of estrogen therapy for the menopause Fertility and Sterility 37 1 5 25 doi 10 1016 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90 of the folliculin taken up in the blood of the vena portae is inactivated in the liver Neither KAUFMANN 1933 1935 RAUSCHER 1939 1942 nor HERRNBERGER 1941 succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol Other results are reported by NEUSTAEDTER 1939 LAUTERWEIN 1940 and FERIN 1941 they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120 300 oestradiol or with 380 oestrone Rietbrock N Staib AH Loew D 11 March 2013 Klinische Pharmakologie Arzneitherapie Springer Verlag pp 426 ISBN 978 3 642 57636 2 Martinez Manautou J Rudel HW 1966 Antiovulatory Activity of Several Synthetic and Natural Estrogens In Robert Benjamin Greenblatt ed Ovulation Stimulation Suppression and Detection Lippincott pp 243 253 a b Herr F Revesz C Manson AJ Jewell JB 1970 Biological Properties of Estrogen Sulfates Chemical and Biological Aspects of Steroid Conjugation pp 368 408 doi 10 1007 978 3 642 49793 3 8 ISBN 978 3 642 49506 9 Duncan CJ Kistner RW Mansell H October 1956 Suppression of ovulation by trip anisyl chloroethylene TACE Obstetrics and Gynecology 8 4 399 407 PMID 13370006 a b c Shearer RJ Hendry WF Sommerville IF Fergusson JD December 1973 Plasma testosterone an accurate monitor of hormone treatment in prostatic cancer Br J Urol 45 6 668 77 doi 10 1111 j 1464 410x 1973 tb12238 x PMID 4359746 a b c Kent JR Bischoff AJ Arduino LJ Mellinger GT Byar DP Hill M Kozbur X May 1973 Estrogen dosage and suppression of testosterone levels in patients with prostatic carcinoma J Urol 109 5 858 60 doi 10 1016 s0022 5347 17 60564 0 PMID 4699685 a b c Salam MA 2003 Principles amp Practice of Urology A Comprehensive Text Universal Publishers pp 684 ISBN 978 1 58112 412 5 a b c Lam JS Leppert JT Vemulapalli SN Shvarts O Belldegrun AS January 2006 Secondary hormonal therapy for advanced prostate cancer J Urol 175 1 27 34 doi 10 1016 S0022 5347 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effects of estrogen on the prostate in an aging male to female transsexual The Journal of Urology 131 3 553 4 doi 10 1016 s0022 5347 17 50493 0 PMID 6199525 Lehrman KL February 1976 Pulmonary embolism in a transsexual man taking diethylstilbestrol JAMA 235 5 532 3 doi 10 1001 jama 1976 03260310046024 PMID 946104 Seyler LE Canalis E Spare S Reichlin S July 1978 Abnormal gonadotropin secretory responses to LRH in transsexual women after diethylstilbestrol priming The Journal of Clinical Endocrinology and Metabolism 47 1 176 83 doi 10 1210 jcem 47 1 176 PMID 122396 Kuchera LK October 1971 Postcoital contraception with diethylstilbestrol JAMA 218 4 562 3 doi 10 1001 jama 218 4 562 PMID 5171004 FDA 1975 Diethylstilbestrol as posticoital oral contraceptive patient labeling Fed Regist 40 25 5451 5 40 FR 5451 FDA 1975 Estrogens for oral or parenteral use Drugs for human use drug efficacy study amended notice Fed Regist 40 39 8242 39 FR 8242 Hatcher RA Stewart GK Stewart F Guest F Josephs N Dale J 1982 Contraceptive Technology 1982 1983 New York Irvington Publishers pp 152 7 ISBN 0 8290 0705 9 FDA 1978 Estrogens for postpartum breast engorgement Fed Regist 43 206 49564 7 43 FR 49564 a b c d Toyama Y Ohkawa M Oku R Maekawa M Yuasa S May 2001 Neonatally administered diethylstilbestrol retards the development of the blood testis barrier in the rat Journal of Andrology 22 3 413 423 doi 10 1002 j 1939 4640 2001 tb02197 x PMID 11330641 S2CID 14127534 a b c d e Kawaguchi H Miyoshi N Miyamoto Y Souda M Umekita Y Yasuda N Yoshida H October 2009 Effects of exposure period and dose of diethylstilbestrol on pregnancy in rats The Journal of Veterinary Medical Science 71 10 1309 1315 doi 10 1292 jvms 001309 PMID 19887736 a b c d Giusti RM Iwamoto K Hatch EE May 1995 Diethylstilbestrol revisited a review of the long term health effects Annals of Internal Medicine 122 10 778 788 doi 10 7326 0003 4819 122 10 199505150 00008 PMID 7717601 S2CID 25131834 a b Langston N 2008 The Retreat from Precaution Regulating Diethylstilbestrol Des Endocrine Disruptors and Environmental Health Environmental History 13 1 41 65 doi 10 1093 envhis 13 1 41 ISSN 1084 5453 JSTOR 25473193 a b Zamora Leon P September 2021 Are the Effects of DES Over A Tragic Lesson from the Past International Journal of Environmental Research and Public Health 18 19 10309 doi 10 3390 ijerph181910309 PMC 8507770 PMID 34639609 Eve L Fervers B Le Romancer M Etienne Selloum N November 2020 Exposure to Endocrine Disrupting Chemicals and Risk of Breast Cancer International Journal of Molecular Sciences 21 23 9139 doi 10 3390 ijms21239139 PMC 7731339 PMID 33266302 Carey JL Nader N Chai PR Carreiro S Griswold MK Boyle KL January 2017 Drugs and Medical Devices Adverse Events and the Impact on Women s Health Clinical Therapeutics 39 1 10 22 doi 10 1016 j clinthera 2016 12 009 PMC 5779632 PMID 28069260 a b Langston N January 2008 The retreat from precaution Regulating diethylstilbestrol DES endocrine disruptors and environmental health Environmental History 13 1 41 65 doi 10 1093 envhis 13 1 41 Beauchamp TL 2018 The principles of biomedical ethics as universal principles Islamic Perspectives on the Principles of Biomedical Ethics Muslim Religious Scholars and Biomedical Scientists in Face to Face Dialogue with Western Bioethicists Intercultural Dialogue in Bioethics Vol 1 pp 91 119 doi 10 1142 9781786340481 0004 ISBN 978 1 78634 047 4 a b c d e f g h Mastroianni AC Faden R Federman D March 1994 Women and health research a report from the Institute of Medicine Kennedy Institute of Ethics Journal 4 1 55 62 doi 10 1353 ken 0 0121 PMID 10132589 S2CID 31494934 Lavoie D 9 January 2013 DES Pregnancy Drug Lawsuit Settlement Reached Between Melnick Sisters And Eli Lilly And Co Huffington Post Archived from the original on 10 January 2013 Retrieved 19 March 2014 Collection DES Action USA records Smith College Finding Aids Retrieved 2020 06 09 West Taylor Z 24 September 2016 The Alan Turing Law a Formal Pardon for Unpardonable Homophobia Affinity magazine Archived from the original on 3 December 2016 Retrieved 3 December 2016 Kilgallon Steve 22 January 2023 How gay conversion drugs ruined this man s life Stuff Retrieved 22 January 2023 Urinary Incontinence Merck Veterinary Manual Merck Veterinary Manual Retrieved 30 November 2012 Harris RM Waring RH June 2012 Diethylstilboestrol a long term legacy Maturitas 72 2 108 12 doi 10 1016 j maturitas 2012 03 002 PMID 22464649 Gandhi R Snedeker S 2000 06 01 Consumer Concerns About Hormones in Food PDF Fact Sheet 37 June 2000 Program on Breast Cancer and Environmental Risk Factors Cornell University Archived from the original on 2011 07 19 Retrieved 2011 07 20 Liu WJ et al 2018 Removal and Biodegradation of 17b Estradiol and Diethylstilbestrol by the Freshwater Microalgae Raphidocelis subcapitata International Journal of Environmental Research and Public Health 15 3 452 doi 10 3390 ijerph15030452 PMC 5876997 PMID 29510598 S2CID 4711788 Further reading editJohnston E 2017 Poisoned subjects life writing of DES daughters Frontiers A Journal of Women Studies 38 1 University of Nebraska Press 31 63 doi 10 5250 fronjwomestud 38 1 0031 JSTOR 10 5250 fronjwomestud 38 1 0031 S2CID 152010855 External links editDiethylstilbestrol DES and Cancer National Cancer Institute DES Update from the U S Centers for Disease Control and Prevention DES Action USA national consumer organization providing comprehensive information for DES exposed individuals DES Booklets from the U S National Institutes of Health c 1980 DES Follow up Study Archived 2011 09 29 at the Wayback Machine National Cancer Institute s longterm study of DES exposed persons including the DES AD Project University of Chicago DES Registry of patients with CCA clear cell adenocarcinoma of the vagina and or cervix DES Diethylstilbestrol Provides resources and social media links for general DES awareness Retrieved from https en wikipedia org w index php title Diethylstilbestrol amp 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