Diethylstilbestrol

Diethylstilbestrol (DES, former BAN stilboestrol) is a synthetic nonsteroidal estrogen that was first synthesized in 1938. It is also classified as an endocrine disruptor. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers. From about 1940 to 1970, DES was given to pregnant women in the mistaken belief it would reduce the risk of pregnancy complications and losses. In 1971, DES was shown to cause a rare vaginal tumor in girls and women who had been exposed to this drug in utero. The United States Food and Drug Administration subsequently withdrew DES from use in pregnant women. Follow-up studies have indicated DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed. The United States National Cancer Institute recommends women born to mothers who took DES undergo special medical exams on a regular basis to screen for complications as a result of the drug. Individuals who were exposed to DES during their mothers' pregnancies are commonly referred to as "DES daughters" and "DES sons".

Synthesis
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, based on a formulation of 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, and a report of its synthesis was published in Nature on 5 February 1938.

DES was first synthesized by English university research funded by the 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.

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

In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found DES to be the first effective drug for treatment of metastatic prostate cancer. Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the GnRH agonist leuprolide was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.

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.

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-Meyers 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. 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. 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. 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.

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. On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975. The number of persons exposed to DES during pregnancy or in utero during 1940–1971 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".

In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women. 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.

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. 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. 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. 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.

In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens. 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.

First generation
An estimated 3 million pregnant women in the USA were prescribed DES between the early 1940s and the 1970s. DES was also widely prescribed to women in Canada, the UK, Europe, Australia, and New Zealand during a similar period. Women who were prescribed DES during pregnancy have been shown to have a modestly increased risk of breast cancer and breast cancer mortality.

DES daughters
DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in utero. In 1971, the New England Journal of Medicine published a report showing that seven of eight girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES. Subsequent studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in utero to DES. As a consequence of this evidence, DES is considered an established human carcinogen. DES was one of the first transplacental carcinogens discovered in humans, meaning a toxin could cross the placenta and harm the fetus. It had originally been believed that the placenta protected the developing fetus but we now know that is not true. Daughters exposed to DES in utero may also have an increased risk of moderate to severe cervical squamous cell dysplasia and an increased risk of breast cancer.

In addition to its carcinogenic properties, DES is a known teratogen, an agent capable of causing malformations in daughters and sons who were exposed in utero. DES-exposed daughters are at an increased risk of abnormalities of the reproductive tract, including vaginal epithelial changes (which as vaginal adenosis, means a type of tissue develops on the surface of the vagina that is not generally found there), an increased cervical transformation zone, and uterine abnormalities, such as T-shaped uterus. These anomalies contribute to an increased risk of infertility and adverse pregnancy outcomes in prenatally DES-exposed daughters. The most recent published research on DES daughters' adverse health outcomes documented by the U.S. National Cancer Institute (NCI) appears in the October 6, 2011 issue of the New England Journal of Medicine under the authorship of RN Hoover et al., and lists these adverse effects and risk factors: Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5%; spontaneous abortion, 50.3% vs. 38.6%; preterm delivery, 53.3% vs. 17.8%; loss of second-trimester pregnancy, 16.4% vs. 1.7%; ectopic pregnancy, 14.6% vs. 2.9%; preeclampsia, 26.4% vs. 13.7%; stillbirth, 8.9% vs. 2.6%; early menopause, 5.1% vs. 1.7%; grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4%; and breast cancer at 40 years of age or older, 3.9% vs. 2.2%. Daughters with prenatal exposure to DES may also have an increased risk of uterine fibroids, and incompetent cervix in adulthood.

At least one published study by researchers specializing in psycho-sexual development has determined there is a positive association between in-utero DES exposure among DES daughters and increased potential of a girl being homosexual or bisexual. However, later studies have concluded that "no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior," and another found that "DES Daughters were slightly more likely than unexposed women to have ever been married and were less likely to report having had a same-sex sexual partner." These studies contradict earlier studies indicating an inclination towards female attraction in DES daughters, as well as no indication for increased prevalence of gender-atypical behavior.

Studies of DES daughters have not found a link between in utero exposure to DES and autoimmune diseases.

In an animal model designed to study environmental estrogens, DES turned out to be an obesogen capable of causing adult weight gain in female mice which had been exposed to DES during neonatal development. The excess weight gain was not apparent at birth or in infancy, but occurred in adulthood.

DES sons
Initially, fewer studies documented risks of prenatal exposure to diethylstilbestrol on males (referred to as "DES sons"). The first documented case study of intersexuality occurring in a male prenatally exposed to DES was published in the New England Journal of Medicine in 1959 by Kaplan.

In the 1970s and early 1980s, studies published on prenatally DES-exposed males investigated increased risk of testicular cancer, infertility and urogenital abnormalities in development, such as cryptorchidism and hypospadias. Research published in the U.S. by Palmer et al. in 2009 further confirmed evidence of these findings. Additional research published in Finland in 2012 has further confirmed an increased risk of cryptorchidism among males exposed prenatally to DES.

The U.S. Centers for Disease Control (CDC) has acknowledged the link between diethylstilbestrol exposure and noncancerous epididymal cysts.

The American Association of Clinical Endocrinologists (AACE) has documented that prenatal DES exposure in males is positively linked to a condition known as hypogonadism (low testosterone levels) that may require treatment with testosterone replacement therapy.

Exposed males may have a greater likelihood of being left-handed than unexposed males.

Research on DES sons has explored the hypothesis that the range of effects of prenatal exposure to DES in males might include behavioral or neurological changes, and also intersexuality. Dr. Scott Kerlin, founder of the DES Sons International Research Network, has documented for the past 15 years a high prevalence of individuals with confirmed or strongly suspected prenatal DES exposure who self-identify as male-to-female transsexual, transgender, and intersexed, and many individuals who have reported experiencing difficulties with gender dysphoria. These findings in part arose from an online discussion and support group created for DES-exposed men with health concerns. Although such forums are useful, they tend to produce biased data, simply because they attract individuals who have both the exposure and a health concern, ensuring that the exposure and health concern will be seen as linked. A large US study, in which recruitment was not dependent on health concerns, and in which DES exposure (or lack of exposure) was confirmed for all participants, found no association between prenatal DES exposure and sexual orientation when the DES-exposed men were compared to unexposed men. However, no research into gender identity issues was explored in this study.

Various neurological changes occur after prenatal exposure of embryonic males to DES and other estrogenic endocrine disrupters. Animals that exhibited these structural neurological changes were also shown to demonstrate various gender-related behavioral changes (so-called "feminization of males"). Several published studies in the medical literature on psychoneuroendocrinology have examined the hypothesis that prenatal exposure to estrogens (including DES) may cause significant developmental impact on sexual differentiation of the brain, and on subsequent behavioral and gender identity development in exposed males and females. There is significant evidence linking prenatal hormonal influences on gender identity and transsexual development.

Psychological anomalies
Most of the initial research documenting the psychological effects of prenatal DES exposure was poorly conducted, often by mail card. Despite that, some more carefully conducted studies show a clear link to depression and lower visual-spatial reasoning skills. However, as noted above, this was not seen in a large, well-conducted US study involving a comparison of DES-exposed and unexposed individuals, in which DES exposure (or lack thereof) was confirmed by the medical record.

What has become more clear in recent years is the psychological disturbances caused by excessive prenatal estrogen exposure (regardless of source) as measured by the digit ratio. Excessive in utero estrogen exposure may have an impact on hemispheric brain specialization, and hinder connections to the prefrontal cortex. While exposure to DES might not specifically cause them, it may exacerbate a predisposition in individuals susceptible to schizophrenia, anxiety disorders, anorexia, psychopathy, paraphilic (or fetish) sexual interest, and other neurological issues.

Lastly, using DES as an "environmental estrogen", a 2009 animal study determined prenatal exposure disrupts specialized brain cells and their ability to regulate brain chemistry, specifically altering the way cells release and reabsorb dopamine, an important chemical messenger that governs movement and pleasure.

Research into the links between excessive prenatal estrogen exposure, gender identity and resultant psychiatric conditions continues, and professional opinions remain divided at this time.

Lawsuits
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.

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.

Researchers are still following the health of persons exposed to DES to determine whether other health problems occur as they grow older.

Third generation
Current research also looks at DES in the third generation. These are the children of men and women who were exposed to DES in utero; thus, they are also the grandchildren of women who were given DES during pregnancy. Studies of the third generation are important because DES might be associated with epigenetic changes, which involve changes to the way genes behave (not involving the DNA itself) that may be heritable from one generation to another. If epigenetic changes occur and are heritable, studies of the DES-exposed third generation have implications for the influence of environmental endocrine disruptors on human health and evolution.

Recent results from the US National Cancer Institute (NCI) multicenter study of DES show the daughters of DES prenatally exposed women may be less likely than the unexposed to have regular menstrual periods. A possible increased risk of infertility in the older, third generation daughters was also noted. The NCI study provides limited evidence of an increased risk of birth defects in the sons or daughters of women who were exposed prenatally to DES. An increased risk of ovarian cancer in the daughters of prenatally exposed women was seen, but it was based on three cases, so the finding is considered preliminary and requires confirmation.

Some evidence suggests the sons of prenatally DES-exposed women might have an increased risk of hypospadias, but other studies suggest the increase in risk might not be as great as once thought.

DES for canines
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. It is generally administered once a day for seven to ten days and then once every week as needed.

DES in food production
During the 1960s, DES was used as a growth hormone in the beef and poultry industries. It was later found to cause cancer and was "phased out in the late 1970s". When DES was discovered to be harmful to humans, it was moved to veterinarian use. DES was found to cause liver failure in cats.

Chemistry
Diethylstilbestrol can be synthesized from 4-propylanisole.
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In fiction
An account of DES's use in the beef industry is depicted in the novel My Year of Meats, by Ruth L. Ozeki.