Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication. Its use is now rare; 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. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported adverse reproductive 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. While most commonly taken by mouth, DES was available for use by other routes as well, such as vaginally, topically, and by injection.
DES is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic and nonsteroidal estrogen of the stilbestrol group, and differs from the natural estrogen estradiol. 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. These differences result in DES having an increased risk of blood clots, cardiovascular issues, and certain other adverse effects.
DES was discovered in 1938 and introduced for medical use in 1939. 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. 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. The United States Food and Drug Administration subsequently withdrew approval of DES as a treatment for pregnant women. 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 infertility.
The United States National Cancer Institute recommends 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". Since the discovery of the toxic effects of DES, it has largely been discontinued and is now mostly no longer marketed for human treatment.
Medical uses DES has been used in the past for the following indications: 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 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 men and women As an emergency postcoital contraceptive As a means of chemical castration for treating hypersexuality, paraphilias, and sex offenders Prevention of the testosterone flare at the start of gonadotropin-releasing hormone agonist (GnRH agonist) therapy Feminizing hormone therapy for transgender women
DES was used at a dosage of 0.2 to 0.5 mg/day in menopausal hormone therapy.
Interest in the use of DES to treat prostate cancer continues today. 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. In addition to prostate cancer, some interest in the use of DES to treat breast cancer continues today as well. However, similarly to the case of prostate cancer, arguments have been made for the use of bioidentical estrogens like estradiol instead of DES for breast cancer.
Oral DES at 0.25 to 0.5 mg/day has been found effective in the treatment of hot flashes in men undergoing androgen deprivation therapy for prostate cancer.
Side effects 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%).
Breast changes and feminization The pigmentation of the breast areolae are often very dark and almost black with DES therapy. This is because the pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as estradiol. The mechanism of the difference is unknown. Progestogens like hydroxyprogesterone caproate have been reported to reduce the nipple hyperpigmentation induced by high-dose estrogen therapy.
In men treated with it for prostate cancer, DES has been found to produce high rates of gynecomastia (breast development) of 41 to 77%.
Blood clots and cardiovascular issues 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. The risk is dose-dependent. A dosage of 5 mg/day DES has been associated with a 36% increase in non-cancer-related (mostly cardiovascular) deaths. In addition, there is an up to 15% incidence of venous thromboembolism. 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%. 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).
Other long-term effects
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: 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). 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. 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. Additionally, evidence also points to transgenerational effects in F2 sons, such as hypospadias. At this time however, the extent of DES transgenerational effects in humans is not fully understood.
Overdose 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.
Pharmacology
Pharmacodynamics
Estrogenic activity DES is an estrogen; specifically, it is a highly potent full agonist of both of the estrogen receptors (ERs). It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, respectively. 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. 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). DES produces all of the same biological effects attributed to natural estrogens like estradiol. This includes effects in the uterus, vagina, mammary glands, pituitary gland, and other tissues.
A dosage of 1 mg/day DES is approximately equivalent to a dosage of 50 μg/day ethinylestradiol in terms of systemic estrogenic potency. Similarly to ethinylestradiol, DES shows a marked and disproportionately strong effect on liver protein synthesis. 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).
DES has at least three mechanisms of action in the treatment of prostate cancer. 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. DES has also been found to decrease DNA synthesis at high doses.
DES is a long-acting estrogen, with a nuclear retention of around 24 hours.
Antigonadotropic effects
Due to its estrogenic activity, DES has antigonadotropic effects. 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. A study of ovulation inhibition found that 5 mg/day oral DES was 92% effective, with ovulation occurring in only a single cycle. 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. 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). However, it has also been reported that 1 mg/day DES results in approximately 50% suppression of testosterone levels, albeit with wide interindividual variability. It has been said that doses of DES of less than 1 mg/day have no effect on testosterone levels. 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. 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.
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