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The effects of estrogen therapy on calcium metabolism was studied in postmenopausal women. Ethinyl estradiol gradually decreases plasma and urinary calcium and phosphate levels reaching a maximum at about 6 months. This decline is partially reversed by the end of 1 year though values consistently and indefinitely remain lower than control values. Tubular reabsorption of phosphate also shows a similar pattern. Urine calcium levels fall earlier than urine hydroxyproline though bo th appear to remain within the premonpausal range indefinitely. The hyp ophosphatalmic effect of estrogens is in part due to an inhibition of bone resorption but appears primarily due to parathyroid stimulation. The rise in calcium absorption may be explained by the rise in parathyroid hormone. Since the reduction in the rate of new bone formation is not as great as the degree of inhibition of bone resorption the net long-term effect is an enhancement of bone calcium balance. However there is no evidence that estrogens directly stimulate new bone formation. It is not certain to what extent the incidence of forearm fracture spinal osteoporosis and fractured femur of the neck might be reduced by the inhibition of bone resorption nor is it known how estrogens inhibit bone resorption. The comparative doses of estrogen needed to significantly reduce urine calcium excretion at 1 month are 6 mg estriol succinate .025 mg ethinyl estradiol .1 mg estrone sulphate and .65 mg conjugated estrogens. The results indicate that estrogens are capable of inhibiting bone resorption in postmenopausal women for most likely an indefinite period of time.

Objective: To evaluate the use of estriol in the treatment of experimental autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. Background: Experimental autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. Methods: Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examined. Results: Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the immunoglobulin (Ig) G1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased production of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. Conclusions: Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy.

In a prospective study 911 patients were treated over a period of 5 years (M = 2.2) or a total of 2007 treatment years with estriol succinate oral (Synapause, 2-12 mg per day). The treatment was very effective in the removal of all typical climacteric complaints and of the atrophic genital changes caused by estrogen deficiency. Subjective side effects were seldom seen and without practical importance for the treatment. Objective, grave side effects were only few: one superficial phlebo-thrombosis, 2 cases of thrombophlebitis, one carcinoma in situ of the portio vaginalis uteri and 2 mammary cancers were seen. The carcinoma had probably no causal relationship to the treatment. Embolies, myocardial infarctions, cerebrovascular and liver-gall bladder complications did not occur during treatment. The rate of uterine bleedings was low. The incidence of all complications was not increased by estriol succinate; but was even lower than expected. Endometrial and ovarian cancers were not seen. Estriol succinate is accordingly a very effective and well tolerated preparation against climacteric complaints, exerting no significant side effects. It is remarkable that it does not proliferate the endometrium when given in one dose a day. Estriol succinate can therefore be characterized as the estrogen to be favoured for the treatment of postclimacteric women, who do not want to have uterine bleedings any longer.(ABSTRACT TRUNCATED AT 250 WORDS)

A PREVIOUS PAPER (1) we reported that mushroom laccase oxidized estrogens in a 20 to 26.6‰ alcohol solution, whereas both mushroom and potato tyrosinase failed to do so. We employed alcoholic solutions because of the relative insolu-bility in water of estradiol, estrone, and estriol. The ineffectiveness of the tyrosinases used might be attributable to their great sensitivity to alcohol (2), although control experiments with catechol in alcoholic solution showed no marked inactivation of the tyrosinase. The estrogenic substrates are, however, oxidized much more slowly than catechol. This difference in oxidation rate, and the presence of an induction period, might allow for an alcohol effect upon the tyrosinases sufficient to block a possible oxidation. Accordingly Dr. William H. Pearlman prepared for us 4 completely watersoluble estrogen derivatives: estriol succinate, estrone carboxymethoxime, estradiol succinate and estradiol phthalate3. All of these could be dissolved stoichometrically by 0.01 M NaOH an...

Estrogen substitution for 50 castrated women consisted of estriol succinate and for another 50 women of estradiol valerate. The daily dose in both groups was 2 mg, given for six months starting one month after castration. The patients generally developed strong vegetative symptoms after oophorectomy. Five patients failed to respond to estriol succinate and one to estradiol valerate. The effect of estrogen therapy on the vaginal smear and the skin was also studied in these six cases. An estrogen effect, though often fairly weak, in the vaginal smear was observed. Total urinary estrogens were high in all the cases after three and six months of estrogen therapy. The epidermis was significantly thickened after three months of estrogen except in one case. There was generally no significant difference between the 3-month and 6-month skin specimens. Ostensibly ineffective estrogen subsitution may thus play a role in the prevention of postmenopausal degenerative changes. The effect of estrogen therapy on the vege...

The effect of estriol-16, 17-dihemisuccinate, an estrogen without significant feminizing side-effects, on the healing of duodenal ulcer was studied, using a double-blind method. Of 43 patients 18 received 10 mg of the drug daily and 25 received placebo tablets during 2 months. There was no statistical difference in the disappearance of subjective complaints. However, roentgenologically improvement of the ulcer was noted in 13 out of 16 treated and in 12 out of 25 controls, the difference being statistically significant (P = 0.01-0.02).

Postmenopausal women were given estriol succinate orally in a daily dose of 4 mg X 2 for 14 days or 4 mg X 2, 8 mg X 1 and 2 mg in the morning + 2 mg at noon + 4 mg in the evening for 4 wk. Each group consisted of 4 women. The effect of the estrogen treatment was estimated by the endometrial curettage samples taken both before and after the hormone treatment. The curettage samples were studied by both light and electron microscopy. The results showed that a treatment period of 4 wk was necessary to obtain any effect. When 8 mg of estriol succinate was given in a single dose only a slight effect was obtained on the endometrium but when the same dose was divided in 2 daily 4 mg parts, the endometrium showed clearly proliferative changes. Thus estriol is able to produce the same endometrial effect as estradiol. Ultrastructurally the hormone treatment caused an increase in the cytoplasm of the endometrial epithelial cells. Also, whorls of cytoplasmic microfilaments often appeared near the nucleus of the cells.

The occurence of high affinity and limited capacity estrogen receptors in skin specimens was investigated and the concentrations of cytoplasmic and nuclear receptors were studied in 14 normal and 22 castrated women. The skin estrogen receptor levels were low in all cases examined, although they usually exceeded the limit value used for estrogen receptor levels in breast cancer tissue. The cytoplasmic and nuclear receptor concentrations in normal women varied from 2.4 to 9.0 and from 1.5 to 7.0 fmol/mg cytosol protein, respectively. The receptor was present as a very high affinity binding component (KD = 0.2- 1.6 x 10(-9)M). The estrogen receptor concentrations in the skin during estriol succinate and estriol valerate therapy were at roughly the same level as during the normal menstrual cycle. The patients who received no replacement therapy after castration displayed the lowest skin estrogen receptor levels. The share of nuclear receptors seemed to be smaller on average during the normal menstrual cycle and in castrated patients not given estrogen therapy than in women treated with estriol succinate or estradiol valerate.

The effects of estrogens on plasma vasopressin and renin activity were investigated in 18 postmenopausal women. After an oral estrogen therapy (1 mg estradiol valerate + 2mg estriol succinate/day) of three weeks duration the plasma vasopressin level was decreased (p

The serum cholesterol level in pre-menopausal women is lower than in men of the same age. A correlation between the serum cholesterol level and coronary disease has been demonstrated, and before the age of 40 years coronary disease is also distinctly less common in women than in men. After the menopause these differences between the sexes soon become less pronounced and disappear. It was hoped that estrogen therapy would prevent the increase of serum lipids and possibly prevent and slow down the development of coronary disease. The effects of long term estrogen therapy are therefore of particular interest. The purpose of the present study was to clarify the effects of castration and oral estriol succinate and estradiol valerate therapy on serum cholesterol, triglyceride and phospholipid levels.

The effects of estriol succinate (Synapause®, 2 mg daily) ∗ on the renin-aldosterone system and blood pressure (RR) were studied in 14 postmenopausal women after bilateral oophorectomy. Plasma renin activity (PRA) and daily urinary aldosterone excretion (dU-Ald) were determined 1 mth after the operation and before estrogen treatment, at the end of 2 mth therapy, and, for the third time, 2 mth after the termination of treatment with the drug. No changes in PRA, dU-Ald or RR were found in normotensive women, or in 3 women with hypertension in this group. Another group of 11 postmenopausal women was investigated after long-term estriol succinate therrpy, which had lasted for 5–8 yr after oophorectomy. PRA, dU-Ald and RR were measured during treatment and 2 mth after terminating the therapy. No changes were found either in hormone or RR levels. This group also included 5 women with hypertension. Between the groups there were no differences in the mean levels of PRA or dU-Ald. The results suggest that estriol succinate is devoid of general harmful effects on the renin-aldosterone system during postmenopausal therapy for climacteric symptoms.

The effect of estrogens on the skin has been studied in numerous animal experiments. The results have been extremely diversified. In general, the studies have shown increased mitotic activity in the epidermis, even though some scientists have also established obstruction of mitosis. The effect of local estrogen therapy on the human skin has also been studied and has been found to have a generally stimulating effect on the ageing skin1. Today, peroral estrogen therapy has become important to an increasing extent in the treatment of post-climacteric women. Nevertheless there exist very few publications about the effects of this type of estrogen therapy on the skin besides a few studies published during the last few years2–5.

The vascular haemorrhagic action of cobra venom depends on the presence of a heparin precipitable material, the latter being possibly the so called Direct Lytic Factor, which apparently renders the phospholipase of the venom capable of causing bleeding. The haemorrhagic action of Agkistrodon piscivorus venom is independent of a heparin precipitable factor and it is also unlikely that the phospholipase activity of the venom is responsible for the haemorrhages. Estriol succinate counteracts the bleedings caused by cobra venom, but not the haemorrhages produced by the snake venom lacking the heparin precipitable factor.

To the Editor:— In the Department of Medicine of the University Hospital Gottingen, we have for 3 years now been employing estriol succinate with great success in the treatment of hemorrhagic diatheses of varying pathogenesis. The most important indications have proved to be thrombocytopenic bleeding, hemorrhagic diatheses resulting from isolated vascular damage, and postoperative capillary hemorrhage. Estriol succinate has also proved to be of value in the prophylaxis of hemorrhagic complications during long-term anticoagulant therapy. The daily dose amounts to 20-30 mg. of estriol succinate administered intravenously. However, even with daily doses as high as 60 mg., no side effects were encountered. Nevertheless, it is inadvisable to exceed the 30 mg. daily dose in women in the menopause when the therapy continues for more than 8 days; otherwise, a proliferation of the endometrium may occur, which can give rise to mild vaginal bleeding. Investigations have been carried out in collaboration