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Diethylstilbestrol

Diethylstilbestrol

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Diethylstilbestrol is a synthetic nonsteroidal estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

 that was first synthesized in 1938. 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 subsequently withdrew DES from use in pregnant women. Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetime of those exposed. The United States National Cancer Institute recommends that 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
Dyson Perrins Laboratory
The Dyson Perrins Laboratory in the science area of the University of Oxford was the main centre for research into organic chemistry of the University from its foundation in 1916 until its closure as a laboratory in 2003...

 at the University of Oxford
University of Oxford
The University of Oxford is a university located in Oxford, United Kingdom. It is the second-oldest surviving university in the world and the oldest in the English-speaking world. Although its exact date of foundation is unclear, there is evidence of teaching as far back as 1096...

, based on a formulation of Wilfrid Lawson at the Courtand Institute of Biochemistry, led by Sir Edward Charles Dodds at Middlesex Hospital Medical School of the University College London
University College London
University College London is a public research university located in London, United Kingdom and the oldest and largest constituent college of the federal University of London...

 of the University of London
University of London
-20th century:Shortly after 6 Burlington Gardens was vacated, the University went through a period of rapid expansion. Bedford College, Royal Holloway and the London School of Economics all joined in 1900, Regent's Park College, which had affiliated in 1841 became an official divinity school of the...

, and a report of its synthesis was published in Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...

on February 5, 1938.

DES was first synthesized by English university research funded by the MRC
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...

 who had a policy against patenting drugs discovered using public funds.

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: gonorrhea
Gonorrhea
Gonorrhea is a common sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. The usual symptoms in men are burning with urination and penile discharge. Women, on the other hand, are asymptomatic half the time or have vaginal discharge and pelvic pain...

l vaginitis
Vaginitis
Vaginitis is an inflammation of the vagina. It can result in discharge, itching and pain, and is often associated with an irritation or infection of the vulva. It is usually due to infection. The three main kinds of vaginitis are bacterial vaginosis , vaginal candidiasis, and trichomoniasis. A...

, atrophic vaginitis
Atrophic vaginitis
Atrophic vaginitis is an inflammation of the vagina due to the thinning and shrinking of the tissues, as well as decreased lubrication...

, menopausal symptoms, and postpartum lactation
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...

 suppression to prevent breast engorgement. The gonorrheal vaginitis indication was dropped when the antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

 penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

 became available. From its very inception, the drug was highly controversial.

In 1941, Charles Huggins and Clarence Hodges at the University of Chicago
University of Chicago
The University of Chicago is a private research university in Chicago, Illinois, USA. It was founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller and incorporated in 1890...

 found DES to be the first effective drug for treatment of metastatic prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

. Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over forty years, until the GnRH agonist leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...

 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
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...

 for estrogen deficiency states such as ovarian dysgenesis
Gonadal dysgenesis
Gonadal dysgenesis is a term used to describe multiple reproductive system development disorders. They are conditions of genetic origin. It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo....

, premature ovarian failure
Premature ovarian failure
Premature Ovarian Failure , also known as premature ovarian insufficiency, primary ovarian insufficiency , premature menopause, hypergonadotropic hypogonadism, is the loss of function of the ovaries before age 40...

, and post-oophorectomy
Oophorectomy
Oophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...

.

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 7th and 8th week 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
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

 woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953.

In the early 1950s, a double-blind
Double-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....

 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
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

. 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
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 in postmenopausal women. DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...

, a selective estrogen receptor modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...

 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
Journal of the American Medical Association
The Journal of the American Medical Association is a weekly, peer-reviewed, medical journal, published by the American Medical Association. Beginning in July 2011, the editor in chief will be Howard C. Bauchner, vice chairman of pediatrics at Boston University’s School of Medicine, replacing ...

) 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
Yuzpe regimen
The Yuzpe Regimen is a method of emergency contraception using a combination of estrogen and progestogen hormones and started within 72 hours of sexual intercourse. It has been superseded by a progestogen-only hormonal regimen.-History:...

 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
Lactation suppression
Lactation suppression refers to the act of suppressing lactation in new mothers by chemical or other means.After birth some women may desire to stop the production of breast milk, for example when the mother wishes to bottlefeed from birth onwards, or in the case when the infant dies or is...

 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
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

, stopped making and marketing DES in 1997.

First generation


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
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...

published a report showing that 7 of 8 girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...

 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 is the only transplacental carcinogen known in humans. Daughters exposed to DES in utero may also have an increased risk of moderate/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, 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
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...

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.

In utero exposure to DES has been suggested to increase the likelihood of a girl being homosexual or bisexual.

Studies of DES daughters have so far failed to establish a link between in utero exposure to DES and autoimmune diseases.

DES sons


Initially, there were fewer studies documenting risks of prenatal exposure to diethylstilbestrol on males (referred to as "DES Sons"). 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
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...

 and hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...

.
. Research published by Palmer et. al in 2009 further confirmed evidence of these findings.
The U.S. Centers for Disease Control (CDC) has acknowledged the link between diethylstilbestrol exposure and non-cancerous epididymal cysts. It has also been suggested that exposed males may be more likely to be left-handed than unexposed males.

Recent 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 change, and also intersexuality. Dr. Scott Kerlin of the DES Sons International Research Network has documented for the past 15 years "the 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."

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 "feminisation of males"). Several published studies in the medical literature on psycho-neuro-endocrinology 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.

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
Digit ratio
The digit ratio is the ratio of the lengths of different digits or fingers typically measured from the bottom crease where the finger joins the hand to the tip of the finger. It has been suggested by some scientists that the ratio of two digits in particular, the 2nd and 4th , is affected by...

. Excessive in-utero estrogen exposure may have an impact on hemispheric brain specialization, and hinder connections to the prefrontal cortex (usually associated with impulse control and concentration). While exposure to DES might not specifically cause them, it may exacerbate a predisposition in individuals susceptible to schizophrenia, anxiety disorders, anorexia, psychopathy, paraphilic
Paraphilia
Paraphilia is a biomedical term used to describe sexual arousal to objects, situations, or individuals that are not part of normative stimulation and that may cause distress or serious problems for the paraphiliac or persons associated with him or her...

 (or fetish) sexual interest,and other neurological issues.

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
Supreme Court of California
The Supreme Court of California is the highest state court in California. It is headquartered in San Francisco and regularly holds sessions in Los Angeles and Sacramento. Its decisions are binding on all other California state courts.-Composition:...

, Sindell v. Abbott Laboratories, in which the court imposed a rebuttable presumption of market share liability
Market share liability
Market share liability is a legal doctrine unique to the law of the United States that allows plaintiffs injured by fungible products to apportion liability among the manufacturers according to their share of the market for the injurious product.-Origins:...

 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.

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
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...

 changes. Epigenetic changes 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) multi-center study of DES show that 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 that the sons of prenatally DES-exposed women might have an increased risk of hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...

 but other studies suggest a lower risk. A possible link with hypospadias in third generation sons was suggestive but inconclusive in the NCI study, which is the only study in which the mothers' prenatal DES exposure (or lack of exposure) is verified by the medical record.

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 five days and then once every 4 to 7 days as needed.

DES in food production


During the 1960s, DES was used as a growth hormone in the beef and poultry industry. It was later found to cause cancer and was "phased out in the late 1970s." Its alleged continued illegal use in the beef industry is depicted in the novel My Year of Meats
My Year of Meats
My Year of Meats by Ruth L. Ozeki was written as somewhat of a documentary. The book takes advantage of the differences between Japanese and American culture to comment on both.- Overview :...

, by Ruth L. Ozeki
Ruth Ozeki
Ruth Ozeki is a Canadian-American novelist, filmmaker and Zen Buddhist priest. She worked in commercial television and media production for over a decade and made several independent films before turning to writing fiction.-Life:...

.When it was discovered that DES was harmful to humans, it was moved to veterinarian use. DES was found to cause liver failure in cats.

Chemistry


See also


External links