Di-ethyl-stilboestrol (DES) is a synthetic oestrogen. Known as DES in the United States, it is more commonly known as stilboestrol in the UK and Australia.
Discovering DES
Stilboestrol was the first synthetic oestrogen produced, developed by Sir E. Charles Dodds and colleagues in the UK in 1938. Constructed from a chemical base, it produced the same feminising effect as oestrogens derived from animals (e.g. Premarin) but was more powerful and cheaper to produce Never patented, the DES formula was published in the magazine Nature on 15 February 1938, giving the world the first cheap and powerful oestrogen. As it was never patented, within months drug companies around the world were working with this formula, vying to market this lucrative new product straight out of the laboratory.
Warnings and Controversy
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. Dodds was aware of what a powerful and potentially carcinogenic drug he had synthesised. In the months following the discovery he became increasingly concerned about the carcinogenicity of the newly synthesised drug. In his laboratory he noticed that men on his staff who handled and inhaled the stilboestrol powder were growing breasts, suggesting to him stilboestrol might cause breast cancer in men. He suggested that animal studies be carried out looking at the carcinogenicity of stilboestrol in male rodents. In 1940 a paper was published showing that stilboestrol caused mammary cancers in both male and female mice.
In December 1939 the Journal of the American Medical Association (JAMA) published a strong editorial entitled Estrogen Therapy – A Warning
“Regarding conflicting reports about DES… a thorough investigation of this compound is in order before it can be prescribed for routine therapy. The possibility of carcinoma cannot be ignored…”
Many studies of a variety of experimental, agricultural and domestic animals were conducted and showed serious adverse effects of the drug including cancer, foetal death, and sterility of offspring. The risk of cancer was well known and documented. In fact Dodds himself spent many years thereafter warning that these drugs put women at serious risk of endometrial and breast cancer.
Dodds never envisaged that stilboestrol would be given to healthy women and was against the automatic and “promiscuous” prescribing of oestrogen. He maintained that the human female reproductive cycle was too delicate to introduce foreign substances into it.
Manufactured and marketed immediately
Despite the warnings and controversy, drug companies worldwide were marketing and promoting the drug within months.
Less than 2 years from the drug being synthesised, the Australian publication, THE PHYSICIAN’S INDEX 1940, lists 7 brands of stilboestrol, available in both tablet and injection form.
Stilboestrol
It has been shown by Dodds, Lawson and others that a series of synthetic substances of comparatively simple structure are capable of replacing oestrone in all its actions. Of these the simplest is stilboestrol, or 4 :4'-dihydroxy-diethlystilbene. It is between two and three times as potent as oestrone when given orally and equally active when injected. There is no international standard for it, but as it is of known constitution and definite chemical purity there is no need for such standard, since all doses can be referred directly to weight. Its value lies in the fact that it is fully effective when given orally, and is more effective than oestrone or oestradiol given by the same route.
Preparations of Stilboestrol
The following preparations of stilboestrol are listed in the General Section of this Index:
Neo-Oestranol I (Crookes): Tabs. of 1 and 5 and amps. of 1/2, 1 and 5 mgms.
Oestrogenine (F. & M.): Tabs. of 1/2 mgm.
Oestrornone (Merck): Tabs. of 1 and 3 mgms. Amps. of 1 and 3 mgms.
Ovendosyn (M. & J.): Tabs. of 5 mgms. plus 227 mgms. of calc. phos.
Stilboestrol (B.D.H.): Tabs. of 0.1, 1/2, 1 and 5 mgms., and amps. of 1 and 5 mgms.
Stilboestrol (B.W. & Co.): Tabloids of 1/2, 1 and 5 mgms. and hypoloids of 1 and 5 mgms.
Stilboestrol (G.L.): Tabs. of 1/2 and 1 mgm. and amps. of 1 and 5 mgm.
Dosage of Stilboestrol
MacBryde, Freedman, and Loeffel give in Jnl. Am. Med. Assoc., Dec. 23, 1939, a preliminary report of their studies of stilboestrol in 37 patients with total or partial ovariectomy, or hypogonadism and amenorrhoea. Symptoms of hypogonadism were relieved, marked oestrous changes produced (tested by vaginal smears and endometrial biopsies) and "withdrawal bleeding" produced at will. Breast growth was produced. The doses necessary for these effects were from 0.1 mg. to 5 mg. daily, orally and by injection. Nausea was the only toxic symptom, and complete blood studies, etc., were made without disclosing damage to any organ.
In the same number of the journal, Buxton and Eagle give a report of 17 cases, with menopausal symptoms, senile vaginitis, ovarian insufficiency, and secondary amenorrhoea. They found that the dosage varied greatly with individuals-from 1 mgm. daily for one week up to 30 mgm. daily for 14-21 days. Improvement of symptoms bore no relation to size of dose.
The Physician’s Index 1940, p. 475-476