O. Watkins Smith

DIETHYLSTILBESTROL IN THE PREVENTION AND TREATMENT OF COMPLICATIONS OF PREGNANCY

In 1948, Olive Watkins Smith published “Diethylstilbestrol in the Prevention and Treatment of Complications of Pregnancy” in the American Journal of Obstetrics and Gynecology. In 632 women treated with diethylstilbestrol, Smith demonstrated that the drug stimulated the production of progesterone [4], a hormone [5] that regulates the uterine condition during pregnancy [6]. On the basis of her article, and several follow up articles authored by Smith and her husband, George Van Siclen Smith, physicians around the world began prescribing DES to women at risk for pregnancy [6] complications like miscarriage [7] and premature delivery. However, in 1953, researchers found that DES did not prevent pregnancy [6] complications. In 1970, researchers linked fetal exposure to DES to rare and severe cancers later in life. Researchers labeled DES as an endocrine disruptor, a substance that disrupts the hormone [5] system of the body across multiple generations.

Prolan and estrin in the serum and urine of diabetic and nondiabetic women during pregnancy, with especial reference to late pregnancy toxemia

Abstract Analyses on 12 nondiabetic women throughout normal pregnancies indicate that the peak in prolan of both urine and serum occurs at approximately two months and that by the beginning of the fourth month this hormone reaches a lower and fairly constant level coincident with an increase in estrin. The most rapid rise in estrin of both urine and serum takes place during the last trimester. The data on 6 cases of late pregnancy toxemia (4 of them diabetics) confirm the previously reported finding of high prolan and low estrin in this condition and demonstrate that the abnormal rise in serum prolan precedes the clinical manifestations by at least six weeks . The curves on 5 diabetic women throughout normal pregnancies are essentially similar to those of the normal nondiabetics. A somewhat later rise in estrin and a less marked plateau of prolan suggests, however, that the high incidence of toxemia in diabetic pregnancies may be linked with a prolan-estrin imbalance which approaches the toxemic borderline. In 4 cases, two diabetic patients, high serum prolan at five to seven months led to the prediction of late pregnancy toxemia. One of these women (diabetic) had a premature delivery at seven and one-half months. The other 3 showed a very marked rise in estrin during the last trimester coincident with a drop in prolan to within the limits of normal and the appearance of only very mild toxic symptoms. Of the 11 diabetic patients followed, 4 had either stillbirths or edematous giant infants. All 4 of these women showed the prolan-estrin imbalance typical of toxemia at five to seven months. The diabetic patients with normal curves for prolan and estrin delivered normal, living infants. Two of the diabetic patients, on the other hand, whose prolan was excessive and who developed severe toxemia, were delivered by cesarean section at seven and one-half months of normal, living infants. Although it might be argued that in these two cases early delivery had preceded abnormal growth of the fetus, the data at hand are too limited to permit the establishment of any connection between the endocrine findings and the type of infant in diabetic pregnancies.

Further Studies on Pituitary Responses to an Oxidative Inactivation Product of Estrone

Summary Westerfelds lactone, an oxidative inactivation product of crystalline estrone, stimulates the release of luteinizing hormone from the pituitaries of immature female rats, eliciting this response in smaller dosages than does estrone. Unlike estrone, it does not, upon prolonged administration, prevent the secretory or cytological changes in the pituitary which follow removal of the ovaries. Therapeutic implications are discussed.

Pituitary Stimulating Property of Stilbestrol as Compared with That of Estrone.

Summary Stilbestrol is about 100 times as active as estrone in causing the stimulation and release of adrenotropic and gonadotropic factors from the pituitaries of intact mature male rats. In castrated animals it is only about twice as active as estrone. Unlike estrone, the pituitary responses to stilbestrol are not influenced by the presence of the testes or the administration of progesterone, both of which depress the rate of inactivation of estrone as well as its pituitary stimulating activity. It would appear that the mechanism of stil-bestrols action upon the pituitary differs from that of the naturally-occurring estrogens.

Menstrual Discharge of Women. I. Its Toxicity in Rats.

Conclusion The menstrual discharge of women with normal cycles is highly toxic to rats through the production of vascular damage. The possibility that this toxicity is accountable to protein decomposition has not been conclusively ruled out, although the marked effect of hormonal conditions upon resistance appears to argue against this. The greatest susceptibility requires the presence of the ovaries. Functional corpora lutea afford partial protection, but the administration of estrogen overrides this action. Protection may be rendered by pretreatment with large amounts of progesterone, adrenal cortical extract or “immune” rabbit serum. The toxin appears to be intimately associated with a large moleculed protein material.

Evidence that Menstrual “Toxin” and Canine “Necrosin” are Identical:

Conclusion Physical, chemical, and biological similarities, cross precipitin tests and experiments on transferable immunity indicate that Menkins so-called necrosin of canine pleural exudates and the toxin of human menstrual discharge are identical.

Further Studies on the Menstrual Discharge of Women.

Conclusion The toxicity of the menstrual discharge of normal women appears to be due to a specific product of the endometrium formed in vivo.

Evidence for Circulating Menstrual “Toxin” During Menstruation and Toxemia of Late Pregnancy

Conclusion Serum from the circulating blood of women during menstruation and toxemia of late pregnancy differs from that of normal non-menstruating and normally pregnant women and resembles menstrual “toxin” in that it is pyrogenic and fibrinolytic, gives positive precipitin tests with the serum of rabbits immunized against cannie “necrosin,” and contains a pseudoglobulin capable of prolonging the survival time of rats after a lethal dose of menstrual toxin. It is concluded that a factor identical to menstrual “toxin” is present in the circulating blood of menstruating and toxemic women. The protective factor is being further investigated as to its possible therapeutic applications.

Clinical experiments in relation to the excretion of the estrogens

Abstract Urinary studies in a patient with severe pre-eclampsia during a fourday period when veratrum viride was given have shown that the excretion of estrogen metabolites is markedly affected by the temporary vasodilatation caused by this drug. The findings indicate a sudden decrease in degradation and increased metabolic conversion of the estrogens. The hormonal effects are of as short duration as are the clinical. There is reason to suppose that the relationship between sex steroid production and metabolism and genital vascular supply is reciprocal. The etiologic and therapeutic implications of this finding are discussed.

Menstrual Discharge of Women. II. Its Progesterone-Stimulating Effect in Mature Rats.

Conclusion The menstrual discharge of normally menstruating women contains a heatstable factor, insoluble in lipoid solvents, which stimulates increased luteal activity in mature rats. This factor has also been found in venous blood and urine at the time of menstruation. Its progesterone-stimulating effect is not accountable to any free or combined estrogen or to any known gonadotropic hormone. So far as this work has progressed, the progesterone-stimulating factor of menstrual discharge resembles the substance reported by Astwood and Greep as occurring in the rat placenta. 4 Our material has not yet been tested upon hypophysectomized rats but the fact that alcohol precipitation destroys toxicity without decreasing progesterone-stimulating activity makes it appear that the progesterone stimulation is not a non-specific toxic effect.