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An investigation was carried out into the effectiveness of Ovostat E, a low dosage oral contraceptive. One hundred women, aged between 17 and 39 years, participated in the trial; 47 women completed 12 treatment cycles and 42 of these completed all 24 treatment cycles. The following results were obtained by computer analysis: Reliability was 100% and the Pearl Index therefore = 0; Cycle Control; length: an obvious regulating effect; 85-3% was the average percentage of women with a cycle length of 26 to 30 days; withdrawal bleeding occurred in 94-6% of cycles; duration of withdrawal bleeding: no change in 26-0%; 1--2 days shorter in 51-7%; 1--2 days longer in 5-6%; intensity of withdrawal bleeding: no change in 61-9%; decreased in 29-3%; increased in 3-4%; irregular bleedings occurred in 4-6% of cycles. The most common complaints were nervousness, headache and nausea, the last two virtually disappearing after the 3rd treatment cycle. Of the 49 women who continued the investigation for the further eighteen months, 2 dropped out because of intolerance, 1 because of objections to the periodic check-ups and 1 for reasons unknown.

A simulation model of the effects of hormone replacement therapy (HRT) on hip fractures and their consequences is based on a population of 100,000 post-menopausal women. This cohort is confronted with literature derived probabilities of cancers (endometrium or breast, which are contra-indications to HRT), hip fracture, disability requiring nursing home or home care, and death. Administration of HRT for life prevents 55.5% of hip fractures, 22.6% of years with home care and 4.4% of years in nursing homes. If HRT is administered for 15 years, these results are 15.5%, 10% and 2.2%, respectively. A slight gain in life expectancy is observed for both durations of HRT. The net financial loss in the simulated population is 222 million Swiss Francs (cost/benefit ratio 1.25) for lifelong administration of HRT, and 153 million Swiss Francs (cost/benefit ratio 1.42) if HRT is administered during 15 years.

Estrogen use in 119 women in whom breast cancer developed after surgically induced menopause was compared to use among an equal number of controls matched for age, date of bilateral oophorectomy, and duration of follow-up. No increased risk for estrogen use versus no use was evident (relative risk = 0.7). When the authors examined three measures of estrogen dose--number of chart notations of estrogen use, time since first use, and duration between first and last use--only those with greater than or equal to 5 notations had any significantly elevated risk (relative risk = 2.1; confidence limits 1.2-3.6), and there was a significant trend toward increasing risk with more notations (P = 0.03). Use specifically of conjugated estrogens was also associated with an increasing risk with more notation of estrogen use (P = 0.07). However, the other two measures of dose did not confirm this trend. Matched multiple logistic analysis suggested that number of notations of estrogen use conferred increased breast cancer risk (relative risk = 1.7), in dose-response relationships, but this result could have occurred by chance. Because of a lack of consistency, the generally low and statistically nonsignificant relative risks, and the lack of consistent effect modification in high-risk groups, the authors were unable to demonstrate a clear increased risk of breast cancer associated with replacement estrogen use.

Serum concentrations of testosterone (T) and estradiol-17 beta (E2) were analyzed in prostatic cancer patients treated with 160, 240, or 320 mg polyestradiol phosphate (PEP) i.m. every fourth week as single drug therapy during a 6 month period. Estrogen effects on the liver were studied by analyzing serum levels of sex hormone binding globulin (SHBG) in the 320 mg group and compared with values obtained in patients treated with 80 mg PEP i.m. every fourth week + oral ethinylestradiol (EE2) 150 micrograms daily, or by orchidectomy. Orchidectomy levels of T were reached within 3 weeks in the 320 and 3 months in the 240 mg group. In the 160 mg group, mean T levels reached the upper limit of orchidectomy values after 6 months. Accumulation of E2 occurred to mean levels 1,300-2,500 pmol/L at 6 months. At 6 months, SHBG levels had increased to 617% of pretreatment values in the oral EE2 group, to 166% in the 320 mg group, and were unaffected by orchidectomy. No cardiovascular side effects occurred during single-drug PEP treatment.

Evaluating previous findings and own experience, the author tries to develop new starting points for the prevention of systemic osteoporoses including disturbances in mineralisation. Here, a life-long physical activity for the establishment of a large bone mass is just as important as a sufficient isolation ensuring the satisfaction of an increased demand for vitamin D, sufficient supply of protein and minerals and the substitution of an estrogen deficiency.

The effects of oestrogen therapy and of orchidectomy on coronary status, as reflected by exercise ECG-testing before and after one year of treatment, were assessed in a randomized study of patients (N = 100) with prostatic cancer. Oestrogen was given as polyestradiol phosphate 80 mg i.m. per month in combination with 150 micrograms ethinylestradiol p.o. per day. There were no significant inter-group differences in conventional risk factors or in pre-treatment exercise test results. Twelve months after the start of therapy the oestrogen group showed a significantly greater depression of the ST-segment during maximal exercise in leads CH2 (P less than 0.0005) and CH5 (P less than 0.01) compared with the pre-treatment depression. Twenty-five per cent (N = 13) of the patients in the oestrogen group suffered cardiovascular complications during the year of therapy, whereas no such complications were observed in the orchidectomy group. However, even the patients in the oestrogen group who had not suffered cardiovascular complications had significantly greater depressions of the ST-segment during exercise both in lead CH2 (P less than 0.0005) and in CH5 (P less than 0.05). There was no significant change in the ST-segment level in the orchidectomy group twelve months after surgery. In summary, we found evidence of an induction of myocardial ischaemia during treatment with exogenous oestrogens at low dosage in patients with prostatic cancer. This deleterious effect of oestrogen on the coronary status argues against oestrogen therapy, since oestrogen has not been shown to be more beneficial than orchidectomy against prostatic carcinoma.

The new multiphasic oral contraceptives represent an attempt to maximize contraceptive efficacy while minimizing physical and metabolic side effects. By varying the dose of progestin during the cycle, the total steroid dose per month has been reduced as compared to most fixed-dose preparations. Lowering the progestin dose appears to reduce the incidence of certain cardiovascular complications. Different oral contraceptive formulations may selectively alter lipid and carbohydrate metabolism. Norethindrone-containing multiphasics appear to have the greatest efficacy and the smallest metabolic impact.

The effect of estrogen on prolactin (PRL) release and gonadotropin suppression was assessed in six experiments performed on four hypogonadal women. Ethinyl estradiol at a dose of 1 microgram/kg per day induced a significant elevation of serum PRL levels within the 1st wk of treatment. There was a further rise until a plateau was reached in about 3-4 wk to levels of more than 3 times the initial concentration. This was accompanied by a pattern of increased episodic fluctuation. The corresponding serum luteinizing hormone and follicle-stimulating hormone fell progressively during the study period. These data indicate that a positive feedback relationship between estrogen and PRL release exists in humans.

Within the last several years, previously rare liver tumors have been seen in young women using oral contraceptive steroids. The Registry for Liver Tumors Associated with Oral Contraceptives at the University of California, Irvine, has clearly identified 27 cases. The recent literature contains 44 case reports. Common to these 71 cases has been a histopathologic diagnosis of focal nodular hyperplasia, adenoma, hamartoma, and hepatoma. Significant statistical etiologic factors include prolonged uninterrupted usage of oral contraceptive steroids. Eight deaths and liver rupture in 18 patients attest to the seriousness of this new potentially lethal adverse phenomenon.

Menopausal women receiving 0.625 mg/day conjugated oestrogen continuously for 6 mth were also given either 10 mg/day dydrogesterone continuously or 20 mg/day for the first 12 days of each calendar month in order to evaluate both the efficacy and the tolerance of each regimen. The following parameters were assessed: subjective symptoms, bleeding patterns, lipid metabolism, glycaemia, weight and blood pressure. Of the 81 patients who entered the study, 60 opted for the continuous treatment and 21 for the cyclic treatment. Seven (7) patients dropped out, 6 for administrative reasons and 1 because of nausea. The two groups were comparable with regard to all parameters, with the exception of the duration of pretreatment amenorrhoea, which was longer in the continuous-treatment group (40.6 vs. 19.1 mth), and the initial lipid profile levels, which were higher in the same group. The subjective symptoms were influenced rapidly and positively by both treatments. The other parameters remained unchanged, except for a clinically insignificant rise in triglycerides in both groups. Both treatments were quite satisfactorily accepted by the patients, in spite of a 70% rate of withdrawal bleeding in the cyclic group and a 40% rate of spotting in the continuous-treatment group. Sixty-two (62) patients remained free of side effects, while mastodynia was reported in 9 cases.

The efficacy of chemotherapy for prostatic cancer is difficult to evaluate owing to the low incidence of measurable indicator lesions and the resulting need for indirect response criteria. Although complete regressions remain exceptional, a number of agents, eg, doxorubicin and cisplatin have been shown to be effective in the treatment of this disease. So far, combinations of effective agents with or without concomitant hormone therapy have not proven to be more effective than single agents. Androgen priming has considerable theoretical appeal and deserves further consideration. A higher effectiveness of chemotherapeutic agents might be obtained by linkage to various carriers. Estramustine phosphate is an example of such a complex that has a cytotoxic effect in test systems in which estrogen has no effect and in patients with hormone-refractory prostatic cancer. The use of hormonal and other carriers that could increase the specificity of chemotherapeutic agents deserves extensive exploration.

Long acting injectable hormonal contraceptives are among the most effective fertility regulating agents developed; yet they are also among the most controversial because of animal data indicating a possible carcinogenic potential in several species. A critical analysis of these animal findings has revealed, in all instances, the existence of specific mechanisms not occurring in the human. For this reason, most national and international scientific bodies who have reviewed this issue have concluded that there are no toxicological reasons for not using long acting hormonal contraceptives. Long acting agents can be divided into 2 separate groups: those having a duration of action of one month, which are composed of a long acting oestrogen and a progestagen, and those lasting for several months which consist of only a progestagen. Among the injectable progestagen-only contraceptives tested, only 2 have so far reached the international market: depot medroxyprogesterone acetate (DMPA), which has been administered at 3- or 6-month intervals and norethisterone enanthate, which has been injected at intervals ranging between 2 and 3 months. The most important side effect observed with these 2 agents is a complete disruption of the menstrual bleeding pattern, leading - in some cases - to total amenorrhoea, which is more frequent with depot medroxyprogesterone acetate than with norethisterone enanthate. The latter, however, has a shorter duration of action with a higher pregnancy rate than the former. Other adverse reactions are rare and of no real importance. Metabolic effects with progestagen-only injectable preparations are, in general, mild and less marked than with combined oestrogen-progestagen formulations. Recent investigations have shown that the return of fertility following their use is delayed but in no way impaired. Monthly injectable oestrogen-progestagen combinations have been tested to a more limited extent and these agents are available only in a very few countries. Their main advantage over progestagen-only preparations is that they allow a reasonable menstrual bleeding pattern in the majority of cases. Their obvious disadvantage is that they contain a long acting oestrogen.

Weekly intravenous doses of 20 mg Adriamycin were given to 22 patients with hormone-resistant metastatic cancer of the prostate. (Median duration treatment: 8 weeks; range 3-60 weeks.) Of 21 adequately treated patients, 6 achieved a subjective response (Median duration: 4 weeks; range 4-28 weeks). In 2 patients a more than 50% size reduction of measurable lymph node metastases was observed, while the disease progressed at other sites (mixed response). The median survival from treatment start (8.5 months) was unrelated to the achievement of subjective response. In 10 of 21 patients a reduction of serum alkaline phosphatase was observed and 7 of 21 patients showed a decrease of serum prostatic acid phosphatase. These biochemical changes were not related to response. Toxicity was generally mild, but one case with severe irreversible thrombocytopenia was observed after 3 weekly doses of 20 mg Adriamycin. Weekly low-dose Adriamycin has marginal subjective efficacy in progressing hormone resistant prostatic cancer, a condition where effective and feasible chemotherapy is lacking. The combination of weekly low-dose Adriamycin with other agents, preferably hormones, should be explored.

Oestro-Gynaedron or Kolpi-Gynaedron vaginal gel were applied by the authors to 53 patients for treatment of oestrogen deficit of differentiated aetiology. The patients were between 17 and 73 years old. The therapy resulted soon in mitigation of subjective complaints, that is perception of burning, stinging, and dryness. The majority of patients was entirely free of complaints, following treatment. The cytological condition of atrophic colpitis was visibly improved. The authors are in agreement with numerous data in the literature according to which colpitis vetularum complaints can be completely eliminated by application of Oestro-Gynaedron or Kolpi-Gynaedron, with the colpocytological pattern being improved. Oestro-Gynaedron and Kolpi-Gynaedron were found to be properly applicable. Both medicaments have added greatly to the therapeutic potential by which to get to grips with fluor vaginitis.

Osteoporosis is a major public health problem, particularly for the postmenopausal woman. With the withdrawal of estrogen at menopause, bone resorption begins to exceed formation in remodeling cycles and bone mass is inexorably lost. Clearly, preventing postmenopausal osteoporosis is the aim of management. Individuals with risk factors for developing this condition should have noninvasive bone density determination and should be considered for preventive regimens. Therapeutic options for prevention include calcium, estrogen, and exercise. Once osteoporosis is established, therapeutic options may include those listed previously as well as fluoride and other modalities currently under investigation.

Treatment of idiopathic osteoporosis in the elderly presupposes exact radiological diagnosis, the exclusion of a primary illness as the cause of the pathological process and exact differential diagnosis from other metabolic osteopathies. We consider possible means of prevention of the immobilization of old people, and appropriate hormonal substitution in cases of previous illnesses which coincide with a disturbance of the gonadal function, as important prophylactic measures. In the case of manifest osteoporosis, if possible, an assignment of the disease to a manifestation with high or low bone turnover should be made, by means of biochemical adjuvants. In high bone turnover, the substitution of sex hormones or the administration of calcitonin is indicated, particularly if symptoms of pain are distinct. In osteoporosis with low bone turnover, fluoride in long-term therapy is the preferred medication. The latest studies show that a combination of fluoride and active vitamin D metabolites is preferable to monotherapy. All therapy for this disease, independent of the age of the patient, should be supported by isometric exercises, analgesics and appropriate dietary measures. Orthopaedic supporting measures should be applied only if conservative measures in acute vertebral fractures fail.

The classification of estrogens based on chemical structure and origin is presented. The metabolism of endogenous estrogens and the postulated mechanism of action of steroid hormones are reviewed. Specific effects of estrogen on bone, kidney and coagulation are also discussed.

An attempt was made to programme ovulation in women on a predetermined day of the menstrual cycle by treatment used to induce ovulation in anovulatory sterility. At laparotomy for elective sterilization the ovaries were observed to assess the occurrence of ruptured follicles and ovulation. Histological analysis of ovaries and endometrium was performed, and ova were recovered from some women. Several regimens were tested but ovulation seldom occurred as planned. Clomiphene citrate, human chorionic gonadotrophin (HCG), synthetic luteinizing hormone releasing hormone (LH-RH), and ethinyloestradiol were ineffective. Human menopausal gonadotrophin followed by HCG was more effective, but multiple ovulations occurred. When one single injection of a potent long-acting LH-RH analogue was given on day 13 of the cycle to 10 women pretreated with ethinyloestradiol signs of recent ovulation were observed on day 15 in seven and on day 16 in two.

The benefits of hormone replacement therapy in alleviating climacteric symptoms, preventing osteoporosis and reducing the incidence of cardiovascular disease and stroke are now generally agreed. Nonetheless, perhaps only 5% of postmenopausal women currently receive adequate treatment often because of patient or clinician fears that such treatment may be associated with harmful side effects.

4112 women completed a retrospective questionnaire indicating when during their last menstrual cycle they felt their well-being and sexual interest to be at their best and worst. The commonest pattern was for well-being to be lowest during the premenstrual and highest during the postmenstrual week. Sexual interest was strongly associated with well-being, suggesting that variations of well-being have a powerful effect on sexuality in the majority of women. Oral contraceptive users, though broadly similar in their reported pattern, were less likely to show peaks and troughs of well-being and highs and lows of sexual interest. This was most evident in the subgroup of monophasic pill users who showed the least tendency to variations in both well-being and sexual interest, and a greater tendency to show either peaks or troughs of well-being during menstruation. Triphasic pill users were intermediate between monophasic and non-pill users.

The effect of estradiol on lipolysis in blood and in adipose tissue of female rat has been investigated. The hormone was administered to the studied animals subcutaneously during 20 days. The lipid mobilizing activity was determined in blood serum according to the four different experimental protocols: test serum--test tissue, test serum--control tissue, control serum--test tissue, and control serum--control tissue. Blood serum concentrations of triglycerides, free fatty acids and glucose, as well as lipolytic activity against exogenous substrate, were determined in addition. Estradiol administration was found to enhance the activity of factors potentiating lipolysis both in the blood and in adipose tissue of female rats, inasmuch as an increase in free fatty acids and triglyceride concentration, and a decrease in glucose concentration were observed during the period of administration of the hormone.