About DES

Uses of DES

Use in Medicine

During Pregnancy

The use of DES in medicine was always experimental. Starting from the year that DES was synthesised in 1938, laboratory studies showed animals administered DES developed mammary cancer, with high rates of foetal death, sterility and cancer in the offspring. Despite this, DES was approved for use in humans in 1940. Initially used to treat late pregnancy complications, by the mid 1940s the use was widened to include the prevention of miscarriage, i.e. for prophylactic use by women who had a history of miscarriage. However by 1949 DES was seen as making "a normal gestation more normal". By the early 1950s DES was being prescribed and marketed as a general pregnancy "tonic", mixed with vitamins and recommended for all pregnant women to ensure healthier pregnancies with "bigger and stronger" babies.

Its use was always controversial and a number of clinical trials were held worldwide (including in Australia) to test its efficacy. The largest of these studies was published in 1953 and is thought to be the first large-scale clinical trial carried out on humans. Undertaken by Dr William Dieckmann and colleagues at the University of Chicago, it involved 2,000 pregnant women. Half were given DES and the other half received a placebo. The Dieckmann study has taken on added significance in recent years as it has been "reconstituted" and forms the basis of current research with its cohorts of DES mothers, daughters and sons, together with the control groups of unexposed mothers, daughters and sons.

The findings of this 1953 study showed, to the surprise of the researchers, that the DES-treated group experienced higher rates of miscarriage, premature labour and neonatal death than the control group. They concluded that DES was not effective at preventing miscarriage.

Unfortunately this study was not influential as DES was already entrenched as standard obstetric clinical practice. Also by this stage DES was being aggressively promoted by the drug companies for use in all pregnancies.

We don't know how many women in Australia were prescribed DES during pregnancy. We do know it was prescribed by both obstetricians and GPs throughout the country from the early 1940s to the 1970s. The last instance that we know of DES being prescribed during pregnancy occurred 1987 in QLD. DES was administered as both tablets and injections, and sometimes as an implant. It was often mixed with vitamins (as with 'Diesavite', a popular Australian brand) and many women thought they were taking vitamins only.

In 1971 it was discovered that DES caused clear cell cancer of the vagina/cervix in DES daughters. DES was thus proven to be carcinogenic in humans.

Further reading:
DES Brand Names, 1983 (4)
DES: The Wonder Drug... , 1985 (5)

As Treatment to Suppress Lactation

Many women were prescribed stilboestrol to dry up breast milk. The use of DES as a lactation suppressant treatment was widespread throughout Australia. One nurse reported that during the 1970s the hospitals "were awash with stilboestrol." Its safety and efficacy for this purpose have never been proven.

As Treatment for Acne

Other women report having DES prescribed as a treatment of acne when they were teenagers and young women. Treatment was often prolonged, lasting 1-2 years or longer. Its safety and efficacy for this purpose have never been proven.

As the "Morning-After" Pill

Ironically DES was used for many years as a contraceptive, as the post-coital "morning-after" pill. Its safety and efficacy for this purpose have never been proven.

As Treatment for "Tall Girls"

From the 1960s onwards DES was used as a treatment of tall young girls to stunt their adult height. This use was experimental and, again, the efficacy and safety of this treatment was never proven. After initial media coverage of the issue in July 1997, a support and advocacy group, Tall Girls Inc., was established. Successful political lobbying lead to the group achieving their main goal of having the NH&MRC fund a study into the long-term bio-psycho-social effects of administration of oestrogen to young girls to inhibit their adult height. The Tall Girls group can be contacted via their web site: www.users.bigpond.com/jadetg/index.html

Further reading:
Tall Girls: Why the Silence? 1997 (11)
Tall Girls: Research Needed, 1997 (12)
Double Exposure: DES Daughter & Tall Girl, 2000 (13)

The DES experience is part of the widespread use of synthetic sex hormones in medicine over the past 60 years.

As Hormone Replacement Therapy (HRT) during Menopause

Running parallel to the use of DES during pregnancy is the use of oestrogen to treat menopausal symptoms. In the early 1940s, oestrogen was prescribed for short term use in alleviating severe menopausal symptoms, such as hot flushes and night sweats. Menopause was seen as an often difficult but transitory stage of life, but not as a disease. In the following decades this was to change and menopause became a "disease" of aging. Oestrogen was seen as the "fountain of youth" and, by the mid-1960s, it was being recommended that all women go on oestrogen for the rest of their lives. Cancer rates among middle aged women soared and, in 1975, it was shown that oestrogen replacement therapy (ORT) was associated with increased rates of uterine cancer. Sales plummeted. However by the early 1980s "unopposed oestrogen" was touted as the culprit. It was maintained that the risk of cancer could be reduced by combining oestrogen with progesterone. This combined hormone replacement therapy (HRT) was heavily promoted, not only as a treatment of menopausal symptoms such as hot flushes and night sweats; but also as a treatment to prevent osteoporosis; to reduce the risk of heart disease; and to improve cognitive function and a general sense of well being.

Surprisingly there had never been any large-scale scientific studies to evaluate the efficacy and safety of HRT until the 1990s. And then, in July 2002 , the largest of these scientific trials was abruptly and prematurely stopped when it was found that those women taking combined HRT had an increased risk of invasive breast cancer, ovarian cancer, heart attacks, blood clots and strokes.

As the Oral Contraceptive Pill

Developed during the 1950s, the oral contraceptive pill was approved by the ( US) FDA in 1960. This early pill consisted of 10 mg progesterone to suppress ovulation, with a smaller amount of oestrogen added to ease discomfort. Sales were prodigious: in the USA over one million women were taking the pill within a year of it coming on the market. However by the late 1960s there were many reports of serious adverse side effects, including fatal blood clots and strokes, depression, migraines and nausea. A book published in 1969, 'The Doctor's Case Against the Pill' by Barbara Seaman, prompted Senate hearings. These, in turn, lead to hormone levels in the oral contraceptive pill being slashed and the introduction of patient information leaflets in prescription drug packets. It has been estimated that over 80% of all American women born since 1945 have taken the oral contraceptive pill. The percentage would be the same, if not higher, for Australian women.

As Fertility Treatments

Less is known about the cocktail of hormones given to women on fertility and IVF programs. We are unaware of any long-term, large-scale follow-up studies of these women or their children. Based on the DES experience, any such follow-up would need to be ongoing for at least 20-30 years.

Further reading:
Dangers of 'Wonder Drugs', 2002 (23)
Need for DES Education Campaign letter, 2004 (29)

The outrage that erupted in the late 1960s over the health dangers of the oral contraceptive pill and HRT saw the rise of the women's health advocacy movement in the USA. And, if it hadn't been for the advocacy work of women such as Barbara Seaman, The National Women's Health Network, The Boston Women's Health Collective and Pat Cody of DES Action/USA, the DES story would never have been told.

The Dieckmann study is recognised as the first large-scale clinical trial ever undertaken in modern medicine. It is now being realised that the widespread use of hormones, such as with DES, HRT, and the oral contraceptive pill, constitutes the largest worldwide drug experiment ever carried out. The history and politics of this experiment are clearly and comprehensively set out in Barbara Seaman's book, 'The Greatest Experiment Ever Performed on Women: The Estrogen Myth Exploded', published in 2003.

Use in Veterinary Science

Parallel to the use of DES in medicine is its use in veterinary practice, both for domestic pets and breeding stock. One of the first "patients" may have been Tricky Woo of the 'All Creatures Great and Small' books and TV series. In the late 1930s kindly Dr Herriot prescribed the new "wonder drug" stilboestrol for Tricky Woo's embarrassing problem with incontinence.

Any drug which was thought to prevented miscarriage and result in bigger, healthier babies was of obvious interest to veterinary science. However, as in the earlier laboratory animal experiments, DES was soon shown to be deleterious to the health of the mother animal, to the DES exposed offspring and, interestingly, to subsequent litters.

The recommended use of DES in veterinary practice was thus limited to old animals, and animals that were never going to breed. Unfortunately there doesn't appear to have been any "cross over" of this information into human medicine.

Use of the Food Chain

For many years DES was used to fatten and "plump" poultry, pigs and cattle. DES was found to stimulate weight gain in animals - they gained weight faster and on less feed. In 1947 the use of DES to fatten and caponise chickens was approved in the USA. For over 30 years DES was fed to or injected into millions of livestock animals to fatten them up before slaughter. What is particularly significant about this is that residues of DES remained in the carcasses, and remained biologically potent when eaten by humans.

Both in the USA and Australia, this use of DES as an animal growth promotant appears to be widespread and only ceased, not because of any public health concerns, but to protect the meat trade with Europe.

As with human medicine, when DES use was stopped, it was simply replaced with other synthetic hormones.

Further reading:
DES & the Meat Industry, 1981 (2)
Oestrogens & Male Fertility, 1993 (9)

The Politics of Funding

Before we look at the health outcomes of DES exposure that have emerged so far, it is necessary to spell out just how little research has been done over the years. In fact, it was a struggle to have any research carried out. It was only after consumer advocacy groups, including the newly formed DES Action USA, put pressure of the US government that a FDA DES Task Force was established in 1978.

It is depressing to note that, right from these early days, it was a fight to get any funding for DES research. In the USA the relatively limited research funds available to study the DES population were constantly under threat. By the early 1980s research funding was more or less restricted to studies of DES daughters. DES sons were ignored, as were DES mothers.

Equally depressing is the realisation of just how much of the funding for medical research and ongoing drug education is linked directly or indirectly to the pharmaceutical industry. And no drug company is going to fund research into DES.

Both in Australia and the USA, and elsewhere in the world, it was only after DES Action groups organised that any attempt was made to alert the population at risk and provide accurate and accessible information. That is, it was done for consumers, by consumers.

Further reading:
DES: The Wonder Drug... , 1985 (5)
Education Panel, Colloquium, 2001 (18)

The Effects of DES

Latent, Invisible, Unexpected... & Deadly

In 1971 it was discovered that DES caused clear cell cancer of the vagina/cervix in DES daughters. Although rare (incidence is estimated as 1 in 1000 DES daughters), all DES daughters have a life time risk of the cancer and require annual screening. This involves a specific screening test, as a normal Pap smear will not detect the cancer.

This finding sent shock waves through the medical science community. Up until this time, based on the thalidomide tragedy, it was believed that any adverse outcomes to a drug would be evident soon after the exposure, as in "birth defects". With DES and clear cell cancer, the adverse outcome was expressed decades after the exposure.

Timing rather than Dose

It was found that the timing of the DES exposure was more important than the dose.

The "dose" of DES is impossible to measure, as there was great diversity in both the strength of dose and duration. Many women were prescribed DES in large, increasing doses over the pregnancy. Others, due to nausea, only took it for two or three days. DES daughters who develop clear cell cancer cover the full gamut of exposures - from only two or three days of exposure to huge doses for the whole pregnancy. What is critical is the timing of exposure, i.e. exposure that started in the first trimester.

Further reading:
Science & Discovery Panels, Colloquium, 2001 (18)

Multiple Adverse Effects

During the following years, more and more adverse health outcomes emerged. It can be compared to a stone thrown into a pond, with the ripples slowly moving out in ever-widening circles.

Many DES daughters have tissue and structural changes to the reproductive tract because of their DES exposure. They have increased rates of a range of conditions such as dysplasia, endometriosis, ovarian cysts, and early menopause. In addition many daughters experience infertility and pregnancy complications, such as ectopic pregnancy, first and second trimester miscarriage and pregnancy loss, and premature birth.

Many DES sons also have cellular and structural abnormalities of the reproductive tract, an increased risk of reproductive tract cancers, and impaired fertility. As with DES daughters, the severity and incidence of these adverse health effects appear to be related to the timing of the initial exposure.

A 1984 medical journal article published the finding that DES mothers have an increased risk of breast cancer, and noted that they tended to develop the disease at a younger age than the non-exposed control group.

Animal Studies & Animal Modelling

Whereas human research into the effects of DES exposure was essentially "reactive" and severely restricted due to funding constraints, animal studies have allowed proactive research into DES. Using mice, researchers were able to examine more precisely the effect of timing and dose. The mouse is a valid model as the differentiation stages of the reproductive tract is similar and comparable to that of a human. By correlating both dose and time of exposure, researchers were able to replicate in mice the adverse health outcomes found in the human DES population. That is, DES daughter mice developed clear cell cancer, had structural damage to the reproductive tract, and had high rates of infertility and adverse pregnancy outcomes. Similarly, DES son mice experienced structural damage to the reproductive tract, cancer, sterility and impaired fertility.

A 1981 landmark publication, 'Developmental Effects of DES in Pregnancy' edited by Arthur L Herbst and Howard A. Bern, brought together leading experimental researchers and expert clinicians on DES and this close collaboration between the two disciplines has continued.

Immune System Compromised

Another benefit of animal research is that, as the mouse has a much shorter life span, researchers can "look into the future" and predict what may emerge as the DES population ages. One such study reported in Herbst & Bern showed that, in later life, the immune system of DES exposed mice was suddenly compromised.

Preliminary studies of DES daughters in the early 1980s indicated that DES exposure is linked with immune system problems, including a higher incidence of autoimmune disease, such as asthma, arthritis, diabetes, systemic lupus and thyroid dysfunction.

Taking the initiative, DES Action USA collaborated in a Health Survey of its members, surveying a wide range of health conditions. The findings indicated that the DES population has a higher than expected incidence of depression, stress-related conditions, thyroid dysfunction and metabolic disorders

It appears that DES exposure affects not only the reproductive system but other body systems such as the immune, muscular-skeletal, and cardio-vascular systems; as well as the nervous system, including the brain.

Unfortunately at this time (late 1980s) all medical research funding into DES was stopped.

Further reading:
Autoimmune Disease, 1988 (7)
Education & Science Panels, Colloquium, 2001 (18)

The Endocrine Disruptor Model

Environmental Oestrogens

During the 1980s, just as DES researchers were becoming aware of the widening range of DES-related effects, environmental scientists were trying to make sense of apparent chaos being seen in wildlife populations throughout the world. Across species and in all parts of the world, scientists were seeing wildlife populations under threat due to sterility, reproductive problems, aberrant development and behaviours.

It was hypothesised that a number of man-made chemicals released into the environment, although not oestrogens, act as oestrogens-mimics. For the past 60 years a large number of these man-made chemicals have been released into the environment. These compounds are pervasive and persistent in the environment. Australians bear a high body burden of these chemicals, due to the widespread use of pesticides. Many of the pesticides end up in our water supply as well as our food chain.

In July 1991 a multidisciplinary group of experts gathered at a retreat at Wingspread, Racine, Wisconsin to discuss the issue of environmental oestrogens. The Wingspread consensus concluded that many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife and humans. The consequences of such disruption can be profound because of the crucial role hormones play in controlling development.

The Wingspread Conference and the development of the endocrine disruptor model was a landmark breakthrough. 'Our Stolen Future' by T Colborn, D Dumanoski & JP Myers, published in 1996, made this model accessible to the general public.

Further reading:
Oestrogens & Male Fertility, 1993 (9)
Boys will by Girls, 1994 (10)
DDT: Devil in the Details, 2004 (28)

What is an Endocrine Disruptor?

Put very simply, "chemical messengers" (hormones) are produced and released into the bloodstream by the various endocrine glands. These chemical messengers travel back and forth and they activate, regulate and control how the body develops and functions. The body's three great integrating networks - the reproductive, immune and endocrine systems - are closely interconnected. Changes in one part of this complex system can have profound and totally unexpected consequences elsewhere because everything is so interconnected.

It used to be thought that this signalling was "infiltration proof", with oestrogenic chemicals locking on to specific receptor cells, rather like a lock and key. DES is now recognised as an endocrine disruptor. That is, the body confuses DES with its own oestrogenic signalling messengers. Recent laboratory research shows DES can lock onto the receptor cell, fuse with the nucleus, and reprogram the cell. It is now thought that DES actually alters the DNA and changes the genetic blueprint.

Any oestrogenic agent has the potential to cause endocrine disruption by breaching the body's chemical defence systems at a vulnerable time of development, such as when the body normally uses natural oestrogen signals to guide development. By changing the intensity of the signal, these "ring-in" oestrogen-mimics can change development.

So this explains why DES exposure affects not just the reproductive system but also the immune and nervous systems. In fact DES exposure has the potential to affect all aspects of how the body functions.

The DES-exposed population has thus taken on added importance as leading indicators of the effects of endocrine disruptors. We are very clear-cut examples of this: DES daughters and sons are examples of exposure to an endocrine disruptor during foetal development; DES mothers are examples of exposure during pregnancy; while DES tall girls were exposed during puberty. And these are times when the body is undergoing change, and so the body's defence systems are potentially vulnerable to disruption.

Further reading:
Science Panel, Colloquium, 2001 (18)
Oestrogens in Plants, 2001 (26)
Soy as an Endocrine Disruptor, 2001 (27)
DDT: Devil in the Details, 2004 (28)

3rd Generation Effects

The suspicion, coming from wildlife research, that the effects of endocrine disruption passes down through the generations was supported with the 1998 finding of DES "grand daughter" mice developing clear cell cancer of the reproductive tract. That is, the mice developed cancer because their maternal grandmother was administered DES. Subsequent research went on to duplicate this finding in DES "grand son" mice. No cancer developed in the "control" groups.

There is no evidence of this 3rd generation effect showing up in humans, but it is of great concern that very little research is being carried out. "Absence of evidence isn't evidence of absence." We, more than anyone else, want this intergenerational link to be wrong. However, the mouse modelling has been an accurate predictor in the past, and there is an urgent need that DES "grandchildren" be closely monitored.

To carry the water analogy further, these endocrine disruption effects have been compared to a cascade. That is, the effects of exposure to an endocrine disruptor cascades down through the subsequent generations. An example of this can be seen with the Agent Orange experience. Dioxin, present in Agent Orange, is a known endocrine disruptor. The cascade effects of dioxin can be seen in the experiences of Vietnam veterans and their children. It can also be clearly seen in the devastating effects of Agent Orange on the civilian population of Vietnam, on those directly exposed and on the following generations.

Further reading:
3rd Generation Effects, 1998 (14)
Science Panel, Colloquium, 2001 (18)

The Modern Epidemics

As mentioned above, the DES population has taken on added importance as leading indicators of the effects of endocrine disruption. We are a very specific and early example of this.

Public health authorities have noted a gradual increase in the incidence of certain cancers, infertility, endometriosis, and autoimmune diseases, such as asthma, arthritis, diabetes and thyroid dysfunction, that echo our experiences.

Many of the bewildering, vague and distressing conditions we are currently experiencing can be explained by the endocrine disruptor model. We appear to have increased rates depression, chronic fatigue, severe mood swings, anxiety attacks, stress related conditions and attention deficit problems. We are very concerned that our children are also experiencing many of these conditions, but at a much earlier age.

Could these "modern epidemics" in the population be linked to endocrine disruption from environmental oestrogens? That this could happen seems incredible, but no more incredible than in utero exposure to a drug for just 3 days resulting in a healthy 19 year old woman suddenly developing a virulent cancer usually only seen in post menopausal women.

We are neither doctors nor medical scientists. We are certainly not saying the endocrine disruptor theory is "proven", rather that research is urgently needed. The endocrine disruptor model has allowed us to make sense of our experiences, and can explain the experiences of others, such as those exposed to Agent Orange.

The DES population provides an avenue to research these possible effects. DES was a medical experiment that went horribly wrong. But it is important to learn from mistakes and the cohorts of DES mothers, daughters, sons, grandchildren and 'tall girls' provide the perfect vehicle to study endocrine disruption. That is why the funding of the Tall Girls study is so important. This epidemiological study, funded by the NH&MRC in 2000, is looking at both the long-term physiological and psycho-social effects of oestrogen exposure on this distinct cohort - young girls exposed at or before puberty.

Further reading:
Need for DES Education Campaign letter, 2004 (29)
DES & Other Endocrine Disruptors letter, 2004 (31)