Therapeutic activity of Physioquens in the treatment of certain gynecological conditions (author's transl)]

The new hormonal preparation Physioquens was administered during the study to 181 women during 1.634 cycles and has proved to be very effective in the treatment of various gynaecological disturbances. A definitive reduction has been observed in premenstrual and pre and postmenopausal complaints, dysmenorrhoea, amenorrhoea, intermenstrual pain and endometriosis. Physiquens is also a perfect regulatory device of the cycle in the case of menorrhagia, metrorrhagia and irregular menstrual cycles connected with a hormonal insufficiency. The normophasic treatment with Physioquens is made up of the cyclical administration of a tablet of 0.050 mg ethinyloestradiol for the first 7 days, followed by a tablet of 1 mg lynestrenol and 0.050 mg ethinyloestradiol for the next 15 days. Because of its effectiveness and good tolerance both clinically and biologically Physioquens can be considered an important new step in the treatment of gynaecological problems.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Male contraception: expanding reproductive choice

The development of steroid-based oral contraceptives had revolutionized the availability of contraceptive choice for women. In order to expand the contraceptive options for couples by developing an acceptable, safe and effective male contraceptive, scientists have been experimenting with various steroidal/non-steroidal regimens to suppress testicular sperm production. The non-availability of a long-acting androgen was a limiting factor in the development of a male contraceptive regimen since all currently tested anti-spermatogenic agents also concurrently decrease circulating testosterone levels. A combination regimen of long-acting progestogen and androgen would have advantage over an androgen-alone modality since the dose of androgen required would be much smaller in the combination regimen, thereby decreasing the adverse effects of high steroid load. The progestogen in the combination regimen would act as the primary anti-spermatogenic agent. Currently, a number of combination regimens using progestogen or GnRH analogues combined with androgen are undergoing trials. The side effects of long-term use of androgens and progestogens have also undergone evaluation in primate models and the results of these studies need to be kept in view, while considering steroidal regimens for contraceptive use in men. Efforts are also being made to popularize non-scalpel vasectomy and to develop condoms of greater acceptability. The development of contraceptive vaccines for men, using sperm surface epitopes not expressed in female reproductive tract as source, still requires considerable research efforts.     

Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-microgram oestrogen preparations.

Progestogens probably have metabolic effects that may contribute to the increased risk of cardiovascular reactions associated with combined oestrogen-progestogen oral contraceptives. This possibility was investigated by a study of nearly 2000 reports to the Committee on Safety of Medicines from 1964 to 1977. The reports concerned preparations in which norethisterone acetate in doses of 1.0, 2.5, 3.0, or 4.0 mg was combined with 50 microgram of ethinyloestradiol and those in which levonorgestrel in doses of 150 or 250 microgram was combined with 30 microgram of ethinyloestradiol. Observed and expected numbers of reports were compared, using retail pharmacy purchase figures as a measure of the use of different preparations. There was a significant positive association between the dose of norethisterone acetate and deaths from stroke and ischaemic heart disease (IHD); this association was also found for all cases of these two conditions, fatal plus non-fatal. There were no associations of dose of norethisterone acetate with hypertension or venous thrombosis. The higher dose of levonorgestrel was associated with a possible excess of deaths, non-venous plus venous, and an excess of strokes. There was no association between dose of levonorgestrel and hypertension or venous thrombosis. The reports were also used to assess the relative safety of 30-microgram and 50-microgram oestrogen preparations. Those with 30 microgram of oestrogen were associated with significantly fewer reports of death and IHD (both fatal, and fatal plus non-fatal) than those with 50 microgram of oestrogen. In view of the large-scale move towards preparations with progressively lower oestrogen doses, there are no grounds for major changes in oral contraceptive practice. Within the range of preparations currently in use, however, there is a case for minimising the dose of progestogen to reduce the chances of thromboembolism.     

Sequential Therapy to Achieve Anovulatory Cycles

Sequential oral contraceptive therapy was devised to inhibit ovulation by a potent estrogen alone. A progestational agent was added at the end of the course of therapy to prepare the endometrium for adequate withdrawal bleeding. The program consisted of giving 80 μg. of metranol daily for 15 days and then a combination of 80 μg. of mestranol and 2 mg. of chlormadinone acetate for five additional days. Such a regimen proved to be effective in 6070 patients carefully observed for 82,085 cycles of therapy at 25 medical centres.Increased cycle regularity was noted: 98.1% of the cycles were 25 to 31 days long. In 80.1% of cycles, the withdrawal interval was two to five days in length. Duration of flow was four to six days in 85.3% of the therapeutic cycles. The amount of flow decreased as compared with pretreatment values. The incidence and severity of dysmenorrhea during sequential therapy were significantly lower than before treatment. Side effects, usually infrequent, diminished as therapy was continued; the average incidence of breakthrough bleeding was 1.9% and nausea was 2.9%. Extensive laboratory studies showed no consistent abnormalities. For oral contraception, sequential therapy has proved to be virtually 100% effective when taken as directed.     

Effective suppression of ovarian cyclicity in the lowland gorilla with an oral contraceptive

To determine the effects of a human oral contraceptive on normal and abnormal reproductive endocrine patterns in two lowland gorillas (Gorilla gorilla), daily urine samples were analyzed by radioimmunoassay for estrone conjugates (EC) and pregnanediol-3-glucuronide (PdG). During a pre-treatment period one female (F1) demonstrated regular menstrual cycles averaging 27.6 ± 1.8 days, whereas ovarian cyclicity in female 2 (F2) was consistently prolonged, ranging from 37–51 days. A 56 day regimen of an oral contraceptive (Demulen 50®) was administered to both females beginning in the late luteal phase, and within 6 and 7 days of treatment onset (F1 and F2, respectively) urinary EC and PdG declined to and remained at concentrations consistent with amenorrhea throughout the administration period. Ten and twenty days after contraceptive withdrawal (F1 and F2, respectively) an EC peak was observed with subsequent PdG elevations 1–2 days later. Mean cycle length and luteal phase durations were not different (P > 0.05) before or after treatment for either female, while combined peak PdG concentrations were greater (P < 0.05) for the first 3 months after treatment compared to pre-treatment values. These results indicate that a human oral contraceptive rapidly suppresses ovarian activity in female lowland gorillas, but that the abnormal endocrine pattern observed in F2 could not be redirected into a normal profile after contraceptive withdrawal. © 1992 Wiley-Liss Inc.     

A model for evaluation of the peroral insulin therapy: short-term treatment of alloxan diabetic rats with oral water-in-oil-in-water insulin emulsions.

Alloxan diabetic rats with fasting blood glucose levels above 300 mg/100 ml were treated with oral administration of water-in-oil-in-water (W/O/W) insulin emulsions at a dose of 50 U/100 g body weight, three times daily for 10 to 14 days. The course of diabetes was followed by determinations of glucose levels in blood and urine. During treatment with oral W/O/W insulin emulsions, daily excretion of urinary glucose decreased by about 30 to 40% (2 to 3 g/day) in all of the five rats studied, and returned to the pre-treatment levels after the treatment being discontinued. During treatment, a significant reduction in fasting blood glucose levels was observed in 4 out of 5 rats, giving the decrease by 18 to 44%. Quantitative estimates suggested that the effectiveness of 50 U/100 g of oral W/O/W insulin emulsions was comparable to that after intramuscular regular insulin at a dose of 0.5 U/100 g. Although oral W/O/W insulin emulsions are still of low efficiency, these results would indicate that diabetes can be controlled by effective oral insulin preparations.     

Nomegestrol acetate, a novel progestogen for oral contraception

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5 mg and 17β-estradiol (E2) 1.5 mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3 mg/ethinyl estradiol (EE) 30 μg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 μg/EE 30 μg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending.     

Dose-dependent effect of galangin on fructose-mediated insulin resistance and oxidative events in rat kidney

Abstract

Galangin is an antioxidant flavonol present in high concentrations in the rhizome of Alpinia galanga. We investigated the effect of galangin on whole-body insulin resistance and kidney oxidative stress in a fructose-induced rat model of metabolic syndrome. Male albino Wistar rats were divided into 6 groups containing six animals each. Groups I and VI received a starch-based control diet, while groups II, III, IV and V were fed a high fructose diet (60 g/100 g). Groups III, IV and V additionally received galangin (50, 100 and 200 μg/kg body weight, respectively) while group VI received 200 μg galangin/kg body weight. At the end of 60 days, fructose-fed rats exhibited insulin resistance, increased levels of peroxidation end products and diminished antioxidant status. galangin, dose-dependently normalized blood glucose and insulin levels. The minimum effective dose was 100 μg galangin/kg body weight. At this dose, galangin also prevented the development of insulin resistance and the exaggerated the response to oral glucose challenge. The oxidant–antioxidant balance was maintained by galangin. Micro-albuminuria and tubular and glomerular changes observed in fructose-treated rats were significantly prevented by galangin (100 μg/kg body weight). These findings imply that galangin potentiates insulin sensitivity and antioxidant capacity and reduces renal damage in this dietary model of metabolic syndrome.     

Norethisterone contraceptive microspheres

Two formulations of polylactic and polyglycolic acid microcapsules containing 75 and 100 mg of NET respectively were studied for a 90-day period of anticipated contraceptive effect in two groups of five women. A 200 mg dose of NET preparation was also studied for a 180-day period of anticipated contraceptive effect in 19 women. Alteration in menstrual cycle, with tendency to short bleeding episodes, spotting days, and amenorrhea were the most important collateral effects. In the majority of cases, ovulation was inhibited. No cases of pregnancy were presented. The obtained NET circulating levels were very stable during the period of anticipated contraceptive effect.     

Doping in sport: 3. Metabolic conversion of oral norethisterone to urinary 19-norandrosterone

The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL. The contribution of norethisterone to urinary 19-NA with and without 19-norandrostenedione, a known norethisterone tablet impurity, requires evaluation. Preparations containing, either <2 ng or 1 μg 19-norandrostenedione impurity per 5 mg of norethisterone, administered to female volunteers (n = 10) in doses comparable to those used for menstrual disorders (5 mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63 ng/mL, respectively. The maximal concentration of 19-NA, 2 h post-administration of a single 1 μg dose of 19-norandrostenedione, was 2.4 ng/mL. These results prove unequivocally that norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n = 30) of a single contraceptive tablet containing norethisterone (1 mg) with one of the highest proportions of the impurity 19-norandrostenedione (∼0.5 μg, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1 ng/mL, with a maximum concentration ratio of 19-NA to the norethisterone metabolite 3α,5β-tetrahydronorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred.     

Venous effects of oral contraceptives

In a five-year analysis of an oral contraceptive trial by the Council for the Investigation of Fertility Control venous effects were the third most troublesome group of side-effects with both combined and sequential therapy. Vein complaints, leg cramps, and thrombophlebitis were significantly more frequent with the combined preparations that contained a relatively low dose of progestogen and a high dose of oestrogen than with the other groups tested. No cases of thrombophlebitis occurred in women taking the strongly oestrogenic sequential groups.Histological examination of uterine curettings showed that most progestogenic combined preparations were associated with a high incidence of dilated endometrial sinusoids, while the oestrogenic sequential regimens and low-dose progestogen-only regimens had a low incidence. The incidence of stromal condensation round the sinusoids correlated with the incidence of leg cramps, and these effects appeared to be specific for each preparation tested.     

Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen.

The frequency of menstruation was reduced to once every three months in 196 women by the continuous administration of the oral contraceptive pill, Minilyn, for 84 days (tri-cycle regimen). No pregnancies occurred. One hundred and sixty-one women (82%) welcomed the reduction in the number of periods with the associated freedom from menstrual and premenstrual symptoms, and many found the tri-cycle regimen easier to follow. Weight gain of more than 2 kg, irregular cycle control, especially in the first three months, breast tenderness, and headaches were the main side effects. Menstrual loss was unchanged or reduced in all but seven women. The doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves.     

Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study.

OBJECTIVE--To assess the risk of cerebral thromboembolism in women using low dose oral contraceptives. DESIGN--A retrospective case-control study. SETTING--All Danish medical, neurological, neurosurgical, and gynaecological departments. SUBJECTS--All 794 women in Denmark aged 15-44 who had suffered a cerebral thromboembolic attack during 1985-9 and 1588 age matched randomly selected controls. RESULTS--Of 692/1584 case/control questionnaires sent out, 590/1396 (85.3%/88.1%) were returned. Among the cases, 15 refused to participate, 69 had a revised or unreliable diagnosis, 40 had had thromboembolic disease previously, 13 were pregnant, and 152 had a disease predisposing to a cerebral thromboembolic attack. Of the 323 cases without a known predisposition, 320 reported use or non-use of oral contraception. Among the 1396 controls, eight refused to participate, were mentally retarded, or lived abroad; 18 returned an uncompleted questionnaire; 17 had had thromboembolic disease previously; 31 were pregnant; and 130 had a disease predisposing to a cerebral thromboembolic attack. Thus 1198 non-predisposed controls were available, among whom 1197 reported use or non-use of oral contraception. Among the 320 cases, 116 (36.3%) were oral contraceptive users at the time of the cerebral thromboembolic attack. By comparison there were 191 users (16.0%) among the 1197 controls, giving a crude odds ratio of 3.0. After multivariate analysis, including confounder control for age, smoking, years of schooling, and trend in use of different types of oral contraceptives during 1985-90, pills containing 50 micrograms oestrogen were associated with an odds ratio for cerebral thromboembolic attack of 2.9 (95% confidence interval 1.6 to 5.4), those containing 30-40 micrograms oestrogen an odds ratio of 1.8 (1.1 to 2.9), those containing progestogen only an odds ratio of 0.9 (0.4 to 2.4). The odds ratio did not change with increasing age or with duration of oral contraceptive use. A 50% increased risk of a cerebral thromboembolic attacks among cigarette smokers (after confounder control) was independent of oral contraception status and age. CONCLUSION--Low dose oral contraceptives are associated with an increased risk of cerebral thromboembolic attack. Combined or sequential pills containing 30-40 micrograms oestrogen are associated with a one third reduced risk compared with preparations containing 50 micrograms oestrogen. Progestogen only pills did not increase the risk of a cerebral thromboembolic attack.     

Chorea and the Oral Contraceptives

The case histories are reported of six women who developed chorea while taking oral contraceptive drugs. The chorea that results from taking compounds containing oestrogen and progestogen has many features in common with chorea gravidarum, and the pathogenesis is probably similar. In some of the patients, however, the sudden onset of symptoms suggests a vascular aetiology.     

Contraceptive Action of Continuous Low Doses of Norgestrel

Norgestrel in a dose of 50 μg. was administered daily to 188 women during 2,250 menstrual cycles. Only two pregnancies occurred because of failure of the method, giving a failure rate of 1.1 pregnancies per 100 woman-years. The method was acceptable to most of the subjects, and side-effects, other than menstrual irregularity, were minimal; 68% of the cycles were 28 ±5 days in length and 21% were less than 23 days. There did not appear to be any increased incidence of amenorrhoea. The antifertility action of continuous administration of low doses of progestogen may be due to an effect on corpus luteum function, in addition to the effects on cervical mucus, endometrium, and tubal transport of ova. The optimum dose of norgestrel appears to be in the range of 50–75 μg./day.     

Metabolic,Hormonal, and Vascular Changes after Synthetic Oestrogen Therapy in Oophorectomized Women

Mestranol, the three-methyl ether form of ethinyloestradiol and one of the two oestrogens used in oral contraceptive steroids, was administered in a dose of 0·02 mg daily for 120 days to 25 oophorectomized women.Urinary oestriol and pregnanediol excretions were unaffected by the mestranol treatment but there was a shift of the maturation index of the vaginal smear to the right, indicating a correction of the pretreatment oestrogen deficiency. No significant change in the blood pressure or electrocardiograph recordings occurred during this relatively short period of administration. A significant rise in the serum protein-bound iodine, which might be regarded as an undesirable effect of mestranol on a long-term basis, occurred. Hepatic function as measured by bromsulphthalein was not impaired by the treatment. Mestranol had no effect on the total body water or on the total exchangeable potassium of the women. Its two most serious adverse effects were impairment of glucose tolerance and a high incidence (16%) of venous thrombo-embolic disease.The gravity of the adverse effects far outweighs any beneficial ones and precludes the use of mestranol alone for long-term hormone replacement therapy in postmenopausal women.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

A New and Practical Oral Contraceptive Agent: Norethindrone with Mestranol

The usefulness of a new oral contraceptive compound containing norethindrone 5 mg. and mestranol 0.075 mg. (Ortho-Novum) was studied. One hundred and seventeen private patients used this preparation for a total of 998 menstrual cycles. There were no pregnancies. Side effects were minimal and caused few (11 patients) to discontinue use. The most significant of these was weight gain and a premenstrual tension syndrome including nausea, breakthrough bleeding and skin effects. Other symptoms were minor and easily controlled. Instruction in use of the preparation is easy. Patient acceptance is excellent. Possible masculinizing effects, liver damage, or harmful effects on the uterus were checked specifically by laboratory evaluation; no significant abnormal findings were noted.This appears to be an effective oral contraceptive which is well accepted by the patient and which produced no serious side effects as used in this study.     

Hormonal contraception

The combination hormonal contraceptive pill consisting of a fixed ratio of a progestational compound to an estrogenic compound administered from the 5th to 25th day of the cycle approaches 100% in efficacy. Cycle control is excellent and is related to the mechanism of action. The progestogen plus estrogen of the combination pill inhibit the hypothalamic-anterior pituitary-ovarian axis, thus insuring almost complete inhibition of ovulation and endogenous steroid hormone biosynthesis. The lack of endogeneous hormone is not critical since the pill replaces the lost hormones particularly as to uterine endometrial stimulation so that the tissue is prepared for a bleed on treatment withdrawal. The carefully timed hormonal replacement ensures excellent cyclicity. Although suppression of ovulation may be continued for years, cessation of treatment is followed by a return to normal hormonal function and fertility.Variants of the combination treatment include a once-a-month pill and a once-a-month injectable preparation. Both formulations are based on combinations of a progestogen plus estrogen.A high degree of efficacy approaching that seen for the combination pill has been achieved with a sequential regimen. In this procedure an estrogen alone is administered for 5 to 15 days while a mixture of estrogen plus a progestational agent is administered for the balance of the 20 days of treatment. Withdrawal of treatment brings on a bleed in 2 to 5 days. The mechanism of of antifertility is similar to that of the combination pill.Contraceptive efficiency of a high order may be attained with a small continuous dose of a progestational agent. The pregnancy rate and cyclicity are acceptable but not as good as that of the combination or sequential regimens. The pure progestogen treatment has been adapted to a pseudo post-coital therapy where one sexual contact requires one pill usually within 1 to 3 hours of the event. Thus far a reasonable efficacy has been established but as much as 33% of the cycles may be less than 20 days in length.A Single injection of a progestogen can produce effective antifertility for 90 days. This treatment is efficacious but the early treatment periods may involve considerable irregular bleeding and after repeated use ammenorrhea may be a problem.A true post-coital treatment has not been established. However, for emergency use 4 to 6 days of treatment with high doses of estrogen is highly effective in preventing pregnancy. The mechanism may involve speeding of ova transport thus preventing implantation.