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The structure-activity relationships of various natural and synthetic oestrogens, anti-oestrogens and some other steroid hormones with respect to early uterine albumin accumulation (EAV) was studied in spayed mice. The results were compared with the activity of these agents to produce a late anabolic response (LAR). The potency ranking order among the oestrogens with respect to EAV was found to be oestradiol-17β, > oestriol, > meso-hexoestrol, > erythro-deoxyhexoestrol, > ent-oestradiol-17β, > (-)methallenestril phenol. Generally the oestrogens were much more potent with respect to EAV than LAR. No correlation was found when the ability to promote EAV and LAR was compared. Among other agents tested for effect on the EAV, progesterone, the synthetic progestogen, DU-41165 and the anti-hormones MER-25 and U-11100A (nafoxidine) showed no effect. However, hydrocortisone diminished EAV, while dihydrotestosterone increased EAV substantially.

25 women aged 53–78 years with at least two vears menopause were divided in three groups receiving one of the following oral treatments for three weeks: 2 mg oestradiol-17β plus 1 mg oestriol, 4 mg oestradiol-17β plus 2 mg oestriol or 50 μg ethinyloestradiol daily. Blood samples were collected before, during and after the treatment and the effect on the serum concentration of prolactin, oestradiol-17β, follicle-stimulating hormone and luteinizing hormone was evaluated. During treatment with natural human oestrogens serum oestradiol-17β levels were significantly higher than before treatment. The serum concentration of prolactin was unchanged in patients receiving 2 mg oestradiol-17β plus 1 mg oestriol but increased in patients receiving 4 mg oestradiol-17β plus 2 mg oestriol or 50 μg ethinyloestradiol, thus indicating dose-dependence for natural human oestrogens. However, the increase was moderate, and these higher levels were not significantly different from levels of prolactin in serum found in 16 younger women. Concentrations of follicle-stimulating hormone and luteinizing hormon were depressed during treatment, the former to significantly lower levels when higher doses of oestrogens were used.

A routine method for the determination of urinary oestrone, oestradiol, and oestriol has been developed. After acid hydrolysis, extraction, and purification of the extracted material oestrogens are separated into oestrone, oestradiol, and oestriol fractions, using paper chromatography in formamide/chlorbenzene. Following the elution of single fractions from paper by means of a special extractor the Ittrich modification of the Kober reaction is applied for fluorimetric quantitation. Recovery of oestrone, oestradiol, and oestriol, added to urine was found to be 86 ± 13.6% for oestrone, 81 ± 6.4 % for oestradiol, and 80 ± 7.5 % for oestriol.

The contents of adrenaline and noradrenaline in the uterus of the rat have been investigated. A spectrofluorometric determination of the amines, converted into their lutines, has been used. The level of adrenaline, if present at all, was much lower than that of noradrenaline. The total amount of noradrenaline in the uterus did not vary significantly during oestrus, dioestrus and pregnancy. Treatment of spayed rats with ovarian hormones did not influence their uterine catecholamines. In partially denervated uteri the level was about half the normal value.

Methods are described for the in situ characterisation of 32 steroid oestrogens on thin-layer chromatograms. The methods are suitable for the detection of a) phenols, b) benzene rings, c) o-dihydroxyphenols, d) unsaturated bonds, e) ketones, f) α,β-diketones and g) individual oestrogens. The sensitivity of the different methods varies with various oestrogens and is between 0.2 and 15.0 μg.

The effects of ovariectomy and exogenous gonadal hormones on uterine enzymes have been examined for several laboratory mammals. Qualitative and quantitative measurement of uterine and placental enzymes involve histochemical, cytochemical and biochemical techniques. Enzymes have a wide and characteristic distribution in the female reproductive tract. The pattern of distribution varies showing peculiar species – specific differences in the anatomical localization of the enzyme and its relationship to the reproductive cycle. Progestational responses involve major endometrial growth and striking change in the enzyme system. The amount and biochemical composition of endometrial secretions vary with the stage of reproductive cycle. The placenta contains a complex enzyme system which has been classified into five major groups: hydrases, transferases, oxidoreductases, lyases and isomerases. The passage of many substances across the placental barrier is chemically regulated; the cytoplasm of barrier contains several enzymes and organelles. Carbonic anhydrase activity of the endometrium increases markedly during the luteal phase of the cycle and during pregnancy in the rabbit but not in some other species. Alkaline phosphatase is widely distributed in all types of placenta, in maximal concentration in species producing no fructose. Several hydrolytic enzymes are associated with the small cytoplasmic particles, the lysosomes, β-glucuronidase of the endometrial and glandular epithelia shows cyclical changes with the oestrus cycle. The activity of the succinic dehydrogenase may be an index of the functional status of the epithelial cells. Some enzymes e. g. acid and alkaline phosphatase, 5-nucleotidase and adenosinetriphosphate show a typical »secretion cycle«. The role of certain uterine enzymes in implantation of blastocyst deserves investigation.

By means of ion-exchange chromatography acid soluble nucleotides have been determined in the rabbit vagina in different hormonal conditions: i. e. normal mature rabbits, untreated castrated rabbits, and castrated rabbits treated with oestradiol for different periods of time (4–8 hours, 14–24 hours, 38–48 hours, 7–11 days, 18–28 days), as well as castrated rabbits, treated with oestradiol + progesterone. Castration results in a marked decrease in the NAD, ATP and uridine nucleotide-fractions and inorganic phosphorus but an increase in the AMP-fraction. As early as 4–8 hours after oestrogen treatment the nucleotides begin to return towards normal. Before 48 hours a normal nucleotide content (related to the amount of nitrogen) is obtained. The maximum oestrogen effect on acid soluble nucleotides is obtained after 7–11 days of oestrogen treatment. After oestrogen stimulation a marked and early increase is observed of NAD- and uridine nucleotide-fractions, a somewhat smaller increase in ATP- and ADP-fractions and an insignificant increase in AMP-fraction. The results indicate that castration induces dephosphorylation of ATP whereas oestrogen stimulation induces phosphorylation of AMP to ATP. The significance of these results is discussed.

The distribution in mice of 14C- and 3H-diethylstilboestrol has been investigated autoradiographically. The results have been compared with those which have been previously reported for natural oestrogens. Many similarities have been demonstrated between the synthetic and natural compounds. Thus a specific accumulation has been observed in the endometrium, the granulosa layer of large ovarian follicles, the adrenal cortex. the interstitial tissue of the testes, and the hypophysis. Natural and synthetic oestrogens differ widely concerning the penetration into and the distribution within the foetus.

1 case of primary 9 cases of secondary amenorrhea and 1 case of oligomenorrhea and anovulation were treated with 17-alpha-ethynyl-17-beta-hydroxy-estr-4-ene (ethinyl estrenol) and the progestational effects were studied. Ethinyl estrenol was administered orally in a daily dose of 5 mg for 7 days after 14 days of estrogen priming with ethinyl estradiol. The patients with oligomenorrhea received ethinyl estrenol only (5 mg/day) at such times that the bleeding interval was about 28 days. Withdrawal bleeding occurred within 1-4 days in all of the 34 cycles studied. In all the cases of amenorrhea the endometrium showed the characteristics of the secretory phase after a total dose of 35 mg/cycle. The appearance of the endometrium during the secretory phase was normal in all respects. In the patient with oligomenorrhea the secretory phase was doubtful. The basal body temperature was biphasic in 24 of the cycles (8 cases) and doubtful though probably biphasic in a further 7 (2 cases). No side effects were observed. It was concluded that this progestational steroid when administered orally may be of therapeutic value in certain conditions.

The urinary excretion of oestriol has been investigated in 30 cases of diabetic pregnancy. The mean excretion was low, although most of the values found were within the range of excretion in normal pregnancies. No correlation was found between the severity of the diabetes and the amounts of excretion oestriol.

A comparison of the effects of various oestrogenic substances on coronary and aortic atheroma in cholesterol-fed birds has been made. In general, oestrogenic activity paralleled the ability to regress coronary atherosclerosis but there were exceptions. Doisynolic acid, in a dose which produced side-effects comparable with oestradiol, did not significantly alter the incidence of coronary atherosclerosis. Epi-oestradiol, in an experiment of longer duration, and given in a dose which made it a potent oestrogenic substance with typical effects on serum lipids, gonads and sex characters, did not significantly reduce the incidence of coronary atherosclerosis.

Determination of the total α-ketolic fraction in separate 24-hour urine samples, as well as chromatographic identification of 16α-hydroxy-oestrone and 16-oxo-17β-oestradiol in pooled urine from newborn infants, has been carried out. The results obtained are a corroboration of the conclusions drawn from previous investigations on the oestrogen metabolism of the foetus and the newborn.

Median effective doses and relative potencies have been determined in vaginal smear tests in the rat and mouse for dimethylstilboestrol (DMS) and diethylstilboestrol (DES). These were done by injection or orally, and the relative potency of DMS in terms of DES varied from 0.0004 to 0.0165 according to species and route of administration. Comparison with the antifertility effects of these compounds in the same species by the same routes of administration lends support to the conclusion. also indicated in other studies, that in both cases the antifertility action is due to oestrogenic activity.

Parotid fluid, which can be collected in continuous fashion, was previously shown to possess free 17-hydroxycorticosteroid (17-OH-CS) levels which paralleled those in serum and reached a maximum two hours after corticotrophin or cortisol administration to normal men. The present study demonstrates that intravenously administered cortisol rapidly appears in parotid fluid, and that, thus, parotid fluid 17-OH-CS levels would serve as reliable indicators of plasma corticosteroid levels. This was borne out by ACTH stimulation studies in patients with Cushing's Syndrome as well as adrenal hyporesponsiveness. In the third trimester of pregnancy, despite the large rise in plasma 17-OH-CS, there was only a small, though significant, increase in parotid fluid 17-OH-CS. Conjugated 17-OH-CS were not found in appreciable quantity in parotid fluid. Chemical and radioisotopic techniques indicated cortisol and cortisone to be the major human parotid fluid 17-OH-CS. Parotid tissue from the dog converted cortisol to cortisone. Radioactive aldosterone, oestrogen and androgen also appeared in parotid fluid after intravenous injection.

In 32 subjects with histologically and/or cytologically verified prostatic cancer the hormonal pattern was studied by assaying 18 plasma and urinary hormones or groups of hormones and relating the values to the response to endocrine treatment. Total orchidectomy (orchiepididymectomy) was performed on 9 patients, subcapsular orchidectomy on 13 patients and oestrogen therapy with Estradurin was given in 4 patients. Six patients had total orchidectomy followed by estrogen therapy. With few exceptions all values were within the normal range. The only significant exceptions were the high urinary oestrogen values and the low urinary oestrone + oestradiol/oestriol ratio observed as compared to healthy males working in a factory. No urinary hormone values or ratios of hormone values could be used for the prediction of prognosis in prostatic carcinoma patients. However, the ratios of plasma testosterone/oestradiol (T/Oe2) and testosterone/prolactin (T/Prl) were found to give good information with regard to the response to endocrine treatment. High values for one or both of these ratios meant a good response to treatment in all subjects without exception in this material. Subjects with both ratios low had a good response to endocrine treatment in 50% of the cases. No other plasma hormones measured were of any help prognostically. It is concluded that by measuring the T/Oe2 and T/Prl ratios it seems possible to select a group of patients with favourable primary response to endocrine treatment.

Increases in serum triglycerides, cholesterol and pre-beta- and beta-lipoproteins have been considered as significant pathogenic factors regarding the possible thrombotic side effect of treatment with oral contraceptives (OCs) of the combined type containing synthetic estrogen. To investigate the influence of natural estrogen (estradiol-17beta + estriolnorethisterone acetate) vs. synthetic oestrogen (ethinyl estradiol-norethisterone acetate) on serum lipids and lipoproteins in young women compared with independent and individual controls, as controlled doubleblind investigation was performed in 33 women in a total material and 18 women in a selected group. The significant changes were: quantitative increases in serum triglycerides (p , .001) and beta-lipoproteins (p , .01) during treatment with synthetic oestrogen; no such change was observed in subjects on natural oestrogen, which was found to decrease serum cholesterol (p , .05), phospholipids (p , .05), and alpha-lipoprotein (p , .05). Quantitative estimation of serum lipoproteins was found to be more valuable than the relative estimation by electrophoresis. It is concluded that OCs containing natural estrogens induce less significant and, qualitatively, more benign changes in serum lipids and lipoproteins than preparations containing a synthetic estrogen do.

A description is given of experimental investigations and preliminary clinical experience with the long-acting oestriol compound polyoestriol phosphate – a water-soluble polymere of oestriol and phosphoric acid. The compound seems to exert all the physiologically important effects of oestriol. Even with high doses the hormone causes no proliferation of the endometrium and no withdrawal bleeding. It has no untoward effect on metabolism. It decreases slightly the cholesterol concentration (to the extent of ⅓–⅕ of the effect produced by long-acting oestradiol esters). The compound has a wide therapeutic range. No side-effects have been observed. Doses of 10 mg or more have a prolonged duration. Additional prolongation of the effect is largely dependent on dosage. To ensure an effect lasting for 4 weeks 40 mg polyoestriol phosphate (corresponding with 30 mg oestriol) is required – an amount which roughly corresponds with physiological quantitative data. The compound, which involves an interesting new principle of prolongation, was most effectively used in the treatment of menopausal symptoms and genital organic disorders. For these indications it can be recommended without reservation.

Groups of starved rats of both sexes were treated with three daily injections of either oestradiol benzoate (OB) alone or in combination with testosterone propionate (TP). The effect of these hormones on the concentration of the plasma unesterified fatty acids (UFA) was studied by withdrawing blood daily from the heart. For control conditions, groups of rats were treated with either olive oil, the vehicle of the above hormones, or no injection at all. It was found that oestradiol benzoate, 5 mg per dose, caused a mean rise of plasma UFA up to 1376 ± 209 μeq/litre; 10 mg OB per dose elevated the mean plasma UFA concentration to 3492 ± 246 μeq/litre; and a combination of 5 mg OB + 10 mg TP per dose resulted in a mean plasma UFA concentration of 2379 ± 236 μeq/litre. It is concluded that oestrogens possess a fat mobilising property similar to and possibly stronger than that of androgens.

The effective level of oestrogen in the body is followed by means of serial vaginal smears, stained according to Papanicolaou (1942) before and after hypophysectomy. This was done in 50 patients suffering from metastasizing mammary cancer. In 32 cases a positive oestrogen effect was apparent before the operation. 2–3 weeks after the operation, a decrease in the oestrogen effect was observed in 8 cases and two months after hypophysectomy, in 20 cases. The decrease was observed even later in one case. The oestrogen effect that had disappeared after hypophysectomy reappeared in 5 cases and at a time when the cancer disease showed a relapse. When a comparison was made between the effect of the hypophysectomy on the oestrogens and on the thyroid function as measured by the basal metabolic rate and the serum protein-bound iodine, it was found that the thyroid function was reduced earlier than the oestrogens. In 14 cases, both the oestrogen effect and the thyroid function were depressed. This was thought to indicate that the pituitary function was completely or virtually abolished, at least when compared with other cases in whom both these parameters did not follow a similar course. A favourable clinical effect was seen in 6 of these 14 cases, whereas no effect on the clinical course was observed in the other 8 cases.