Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol.

Naringenin, quercetin and kaempferol, which may be found in glycoside form in natural compounds such as grapefruit, are potent inhibitors of cytochrome P-450 metabolism. The influence of these flavonoids on the metabolism of 17 beta-estradiol was investigated in a microsome preparation from human liver. The flavonoids were added in concentrations of 10, 50, 100, 250 and 500 mumol/l to the microsome preparation. The metabolism of 17 beta-estradiol was concentration dependently inhibited by all the flavonoids tested. Addition of the flavonoids to the microsome preparation did not influence estrone formation, while a potent inhibition of estriol formation was observed. At the highest concentrations tested of the respective flavonoid, there was approximately 75-85% inhibition of estriol formation. However, naringenin was a less potent inhibitor of 17 beta-estradiol metabolism as compared to quercetin and kaempferol. The most likely mechanism of action of the flavonoids on 17 beta-estradiol metabolism is inhibition of the cytochrome P-450 IIIA4 enzyme, which catalyzes the reversible hydroxylation of 17 beta-estradiol into estrone and further into estriol. These hydroxylation processes represent the predominant steps of the hepatic metabolic conversion of endogenous as well as exogenous 17 beta-estradiol. This interaction would be expected to inhibit the first-pass metabolism of 17 beta-estradiol, and this has recently been demonstrated after oral administration of 17 beta-estradiol to women.

Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women.

In an open, randomized, cross-over study the concentrations of 17 beta-estradiol and estrone in serum were measured over 192 hours in 8 ovariectomized women after a single oral dose intake of 2 mg micronized 17 beta-estradiol. The subjects were studied with and without grapefruit juice intake containing the three natural flavonoids, naringenin, quercetin and kaempherol, which are found as glycosides in citrus fruit. These flavonoids interact with the metabolism of drugs such as 17 beta-estradiol and other steroids that are extensively metabolised through the P-450NF (P-450 IIIA4) enzyme or closely related P-450 systems. After administration of grapefruit juice, peak estrone (between 2-6 hours after tablet intake) concentrations increased significantly. The AUC0-48 and AUC0-192 for estrone but not 17 beta-estradiol, resulting from a single administration of micronized 17 beta-estradiol, were significantly altered. Combined measured estrogens (i.e. 17 beta-estradiol and estrone) also increased significantly. The relationship between the AUCs for 17 beta-estradiol and estrone was not altered by juice intake indicating that a metabolic step after estrone, i.e. further A and/or D ring conversion was inhibited. This study demonstrates that grapefruit juice may alter the metabolic degradation of estrogens, and increase the bioavailable amounts of 17 beta-estradiol and its metabolite estrone, presumably by affecting the oxidative degradation of estrogens. This food interaction may be one factor behind the interindividual variability in 17 beta-estradiol, estrone and estriol serum concentrations after exogenous administration of 17 beta-estradiol to patients.

Pharmacokinetic evaluation of oral 17 beta-oestradiol and two different fat soluble analogues in ovariectomized women.

A randomised, single-blind comparative study was carried out in 9 ovariectomized women to evaluate the kinetics of single doses of three different steroid combinations: 0.150 mg desogestrel + 2.0 mg micronized 17 beta-oestradiol, 0.150 mg desogestrel + 0.500 mg 17 beta-oestradiol cyclo-octyl acetate and 0.150 mg desogestrel + 1.0 mg 17 beta-oestradiol decanoate. Serum levels of 17 beta-oestradiol and oestrone were measured, as well as the excretion of 17 beta-oestradiol and its metabolites (oestrone and oestriol) in urine. In relation to the doses given, higher peak serum concentrations of 17 beta-oestradiol were obtained after the two fat soluble analogues, while the AUCs were similar to that after micronised 17 beta-oestradiol. However, there was more extensive conversion of the micronised 17 beta-oestradiol preparation into oestrone compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. The oestrone/17 beta-oestradiol serum concentration ratio was approximately 2.6 before tablet intake and remained essentially unchanged after intake of 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. After micronized 17 beta-oestradiol however, there was a 2-3-fold increase in the ratio at Cmax and slower elimination of 17 beta-oestradiol from plasma, which may be due to the fact that high serum oestrone levels may serve as a reservoir, since both a metabolite and also a precursor of 17 beta-oestradiol. The urinary excretion of 17 beta-oestradiol, oestrone and oestriol was highest after oral administration of micronized 17 beta-oestradiol compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancies with growth-retarded twins in breech-vertex presentation at increased risk for entanglement during delivery.

The purpose of this population based study on twins born in Sweden between 1961 and 1987 was to estimate the risk to the fetuses of becoming entangled during birth, and to identify those pregnancies with an increased risk for this rare complication. By using 3 separate questionnaires, 41 of 26,428 twin pregnancies with entanglement were identified. Twins in breech-vertex presentation (group A; 29 cases) were at significantly greater risk of entanglement (chi 2 = 168.3, p less than 0.001) than twins not in breech-vertex presentation (group B; 8 in vertex-vertex, 3 in breech-breech, and 1 in vertex-breech presentation). Known risk factors for entanglement in group A were intra-uterine growth retardation, a birth weight less than 2000 g, and antenatal fetal death. Intrapartum-neonatal mortality reached 38.9% in group A (median gestational week 36); and for group B, 8.3% (median gestational week 38). Entanglement during the study period occurred in 1 of 645 twin deliveries, on average. A vaginal delivery is proposed for women with twins in breech-vertex presentation, unless other risk factors leading to an increased risk for entanglement warrant abdominal delivery.

Vaginal administration of low-dose oestradiol--effects on the endometrium and vaginal cytology.

Twenty (20) post-menopausal women, mean age 62.4 yr, presenting with symptoms associated with urogenital atrophy were treated intravaginally with daily doses of 25 and 50 micrograms oestradiol (E2) in a double-blind, cross-over study. After randomization, the patients started daily treatment with pessaries containing either 25 or 50 micrograms E2 for 3 wk, followed by a maintenance period of 6 wk during which the pessaries were used only twice a week. A 4-wk wash-out period was followed by another treatment period of 9 wk. The effects on the karyopyknotic index (KPI) and on endometrial histopathology were assessed before and after 3, 9, 16 and 22 wk of treatment. In the case of the 25 micrograms dose the mean KPI values were 34.7 and 20.9% after 3 and 9 weeks of treatment, respectively, the corresponding figures after treatment with 50 micrograms E2 being 39.2 and 22.7%. No dose-effect relationship was apparent from the vaginal cytology findings. Endometrial biopsies could not be taken systematically in all patients. Weak proliferation of the endometrium was observed in 1 woman after 3 wk of daily treatment with the 50 micrograms dose. No endometrial stimulation was detected in any of the patients after treatment with 25 micrograms daily. Beneficial clinical and cytological effects were obtained with both dosage regimens. Daily intravaginal administration of 25 micrograms E2 can accordingly be advocated for the treatment of urogenital symptoms attributable to oestrogen deficiency in post-menopausal women.

Anthropometric variables and metabolism in polycystic ovarian disease.

Anthropometric, endocrine and metabolic variables, were examined in women with polycystic ovarian syndrome (PCO), and in normal control women. Obese women with PCO had higher plasma insulin values than non obese women with PCO, but lean body mass, glucose tolerance, plasma triglycerides and blood pressure were not different in spite of almost twice the body fat mass in the obese PCO women. However, in comparisons between non-obese PCO and control women, with equal body fat mass, the PCO women had higher blood pressure, plasma triglycerides and insulin, as well as a tendency to increased lean body mass. Both PCO groups had a high waist/hip ratio and larger abdominal fat cells than controls, indicating a preferential abdominal accumulation of adipose tissue. In comparison with abdominal adipocytes, femoral adipocytes were larger and had higher lipoprotein lipase activity in the control women, while in the PCO women these regional differences were not found. Basal and norepinephrine stimulated lipolysis were higher in the abdominal than femoral adipocytes in all groups. Substitution of the PCO women with ethinyl estradiol plus desogestrel during 6 months resulted in a regression of clinical androgenic symptoms as well as a normalization of plasma concentrations of free testosterone and sex hormone binding globulin. However, neither body composition nor metabolism were normalized. It was concluded that body fat distribution is more closely related to hypertension and metabolic derangements than total fat mass in the PCO syndrome. It is suggested that the relative paucity of femoral adipose tissue is due to a lack of specific effects of progesterone on adipocytes in this region.

Ethinylestradiol and desogestrel, alone or in combination with two doses of estriol. Effects on plasma proteins.

Nineteen fertile women were treated with three differently composed oral contraceptives in a cross-over study and were randomly allocated to begin with one of the three preparations. The tablets contained 0.030 mg ethinylestradiol +0.15 mg desogestrel alone (A) or in combination with either 0.5 mg estriol (B) or 2 mg estriol (C). After two treatment cycles on each preparation, blood samples were obtained and analysed for ceruloplasmin, SHBG, prealbumin, transcortin and thyroxine-binding globulin. No differences were found in the induction of liver protein synthesis. It was concluded that the addition of estriol in doses of 0.5 or 2 mg did not influence the effects induced by ethinylestradiol.

Fat-soluble 17 beta-estradiol: a way of reducing dosage in steroid hormonal substitution?

Eight ovariectomized women were given 0.5 mg 17 beta-estradiol cyclo-octyl acetate (E2COA) dissolved in arachis oil + 0.15 mg desogestrel, and 2 mg micronized 17 beta-estradiol (mE2) + 0.15 mg desogestrel orally in a crossover fashion for 20 days each. The preparations were taken on 10 days together with a meal, on 10 days 3 hours after a meal. Blood samplings were performed 3 h after capsule ingestion for analysis of serum estradiol (S-E2), estrone (S-E1) and sex hormone binding globulin (SHBG). Before treatment, all women had climacteric complaints. During treatment these symptoms were alleviated and no discomfort was reported. No differences in serum levels of estrogens were found in either of the preparations when capsules were taken with or without food. However, serum levels of E2 were found to be 100% higher per mg substance given after E2COA vis-à-vis mE2. This indicates either a delayed breakdown and/or a better resorption. The E1/E2 ratio after E2COA was only half that after mE2 intake. This hints at another route of resorption. SHBG concentrations were somewhat elevated following mE2 administration, whereas a slight decrease was found after E2COA. The resulting post-treatment difference was significant, suggesting a less estrogenic liver effect by E2COA. No accumulation of E2 or E1 was seen after either of the preparations. Our findings support the hypothesis that E2COA, being fat soluble, is resorbed via the lymphatic system. By avoiding the first liver pass the dosage of estrogen can be halved.

Ovulation inhibition with 17 beta-estradiol cyclo-octyl acetate and desogestrel.

Ovulation inhibition and bleeding control with a combination of 0.5 mg 17 beta-estradiol cyclo-octyl acetate (E2COA) and 0.15 mg desogestrel was investigated in 10 regularly menstruating women for 21 days. In half the group the treatment was extended for 7 days (days 22-28) with 0.03 mg desogestrel in order to evaluate any posttreatment influence on the gonadotropin levels. E2COA, beeing a long-chain fatty ester dissolved in oil, was expected to be resorbed from the intestinal wall via the lymphatic system. By incorporating it in the chylomicrons, E2COA would thereby avoid the unfavourable first liver pass. The serum levels of progesterone were suppressed during treatment. No increase in 17 beta-estradiol (E2) concentration was found; levels remained low and even during medication. No peak values of gonadotropins were seen. Thus follicular hormonal activity and ovulation was inhibited by this combination. Bleeding control was, however unacceptable in all volunteers. The addition of desogestrel during the fourth investigation week apparently did not induce any hormonal differences. The estrogenic activity is shown by the low, even S-E2 levels, but the dosage of E2COA seems to be too low in relation to progestogen dosage. Further studies will have to be performed in order to find the ideal combination.

Second trimester abortion by rivanol with or without cervical dilatators. A randomized comparison.

Fifty women undergoing second trimester legal abortion were randomly assigned to one of three groups: 1. given Rivanol and left with balloon catheter in the cervical canal with addition of oxytocin infusion. 2. same treatment as above but catheter removed and replaced by a Lamicel cervical dilatator, 5 mm in diameter; 3. as group 2, but with a 6 mm Laminaria tent inserted. Induction-abortion interval and need for analgesics were recorded, as well as possible side effects and complications. No statistical differences were found between the three groups for any of the parameters. We have thus not been able to show any advantages of using Laminaria or Lamicel osmotic cervix dilatators in second trimester abortions.

The relative fatty acid composition of serum lecithin and cholesterol ester: influence of an estrogen-progestogen regimen in climacteric women.

The relative fatty acid compositions of serum lecithin and cholesterol ester were studied during continuous treatment with an estrogen/progestogen combination. All 26 women who participated suffered from climacteric complaints and were given one tablet daily containing 2 mg of 17 beta-estradiol, 1 mg of estriol, and 1 mg of norethindrone acetate. Blood samples were taken before treatment and after 3 and 12 months of treatment. In serum lecithin, a decrease (p less than 0.01) in stearic acid concomitant with an increase of linoleic (p less than 0.05) and arachidonic (p less than 0.01) acids was recorded. The most evident changes noted in cholesterol ester were decreased levels of stearic (p less than 0.01), oleic (p less than 0.05), and arachidonic (p less than 0.001) acids. Polyunsaturated acids of the n-6 series are precursors for prostaglandins and leukotrienes. In the present study an increase of dihomo-gamma-linolenic, linoleic, and arachidonic acids in serum lecithin was found after treatment, and theoretically this finding may have an impact on the prostacyclin-thromboxane balance.

Effects of a low-dose desogestrel-ethinylestradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome.

Twenty women suffering from a polycystic ovary syndrome (PCO) accompanied by hirsutism were given a low-dose oral contraceptive combination containing 0.150 mg desogestrel plus 0.030 mg ethinylestradiol for 8 months. The pretreatment situation regarding hair and hormone profiles in the PCO group was compared with that in 22 regularly menstruating women. Serum levels of free and total testosterone and androstenedione were significantly elevated in PCO women, as were body weight, blood pressure, hair diameter and depilation frequency. Sex hormone binding globulin (SHBG) binding capacity was lower. Following treatment of the PCO group for 8 months, total and free testosterone levels were depressed, but androstenedione had not changed significantly. SHBG binding capacity was increased five-fold. Body weight decreased in the obese women. Hair growth was significantly suppressed and the hair itself was less coarse. Depilation intervals were longer. Acne, present before the treatment had now disappeared. Blood pressure did not change. Few and mild side effects were recorded. After treatment, 3 women succeeded in becoming pregnant and in 8 others spontaneous menstruations had recurred.

Lipid metabolic studies in women with a polycystic ovary syndrome during treatment with a low-dose desogestrel-ethinylestradiol combination.

Twenty women with the polycystic ovary syndrome (PCO) were treated with a combination of desogestrel and ethinylestradiol (EE) and the effects on lipids and lipoproteins were compared with those induced in a group of 13 regularly menstruating, healthy women. All women were examined before and after 3 months of treatment. Compared with the regularly menstruating women, the PCO women had significantly higher body weights and blood pressure as well as elevated levels of triglycerides in serum and VLDL. During treatment, 14 out of 20 women affected by PCO lost weight. No significant change in blood pressure was observed. In the PCO group, moderate increments were encountered in serum cholesterol, phospholipids and triglycerides. No significant changes were seen in LDL-cholesterol or HDL-cholesterol. The ratio LDL-cholesterol/HDL-cholesterol did not alter. The level of total cholesterol in VLDL rose during treatment. These changes in serum and lipoprotein lipids in PCO patients were of the same type and magnitude as those found in the control group, apart from an increase in HDL-cholesterol in the latter. The only remaining difference after treatment was a slightly higher level of VLDL triglycerides in the PCO women. Thus only moderate changes were induced in lipid and lipoprotein patterns by the combination of desogestrel and EE. A "positive" influence on lipids and lipoproteins cannot be considered as a further advantage, added to the list of indications when hormonal treatment is used in PCO-affected women. The clinical implications of elevated triglycerides remain to be clarified.

PIP: 20 women with the polycystic ovary syndrome (PCO) were treated with a combination of desogestrel and ethinylestradiol (EE) and the effects on lipids and lipoproteins were compared with those induced in a group of 13 regularly menstruating, healthy women. All women were examined before and after 3 months of treatment. Compared with the regularly menstruating women, the PCO women had significantly higher body weights and blood pressure as well as elevated levels of triglycerides in serum and VLDL. During treatment, 14 out of 20 women affected by PCO lost weight. No significant change in blood pressure was observed. In the PCO group, moderate increments were encountered in serum cholesterol, phospholipids, and trigylcerides. No significant changes were seen in LDL-cholesterol or HDL-cholesterol. The ratio LDL-cholesterol/HDL-cholesterol did not alter. The level of total cholesterol in VLDL rose during treatment. These changes in serum and lipoprotein lipis in PCO patients were of the same type and magnitude as those found in the control group, apart from an increase in HDL-cholesterol in the latter. The only remaining difference after treatment was a slightly level of VLDL triglycerides in the PCO women. Thus only moderate changes were induced in lipid and lipoprotein patterns by the combination of desogestrel and EE. A "positive" influence on lipids and lipoproteins cannot be considered as a further advantage, added to the list indications when hormonal treatment is used in PCO-affected women. The clinical implications of elevated triglycerides remain to be clarified.

Pharmacodynamic studies on desogestrel administered alone and in combination with ethinylestradiol.

Most progestogens in oral contraceptives are testosterone derivatives and have androgenic side effects such as weight increase, acne and hirsutism. They pose a problem to many women just like the clinical picture of the polycystic ovary syndrome (PCO) with obesity, hirsutism, acne and amenorrhea. The aim of this study was to evaluate androgenicity of the most used progestogens with special reference to desogestrel which is a new progestogen. Radioimmunoassay was used for hormone determination while serum proteins were determined with electroimmunoassay or in some studies for sex hormone binding globulin (SHBG) with capacity assays. Serum lipids and lipoproteins were determined in serum and after ultracentrifugation in HDL, LDL and VLDL fractions. In a comparative study on levonorgestrel/ethinylestradiol (EE) (n = 10) versus desogestrel/ethinylestradiol (n = 10) the latter combination gave increases in SHBG capacity while the former did not. Similar increases in estrogen-sensitive proteins cortisol binding globulin (CBG) and ceruloplasmin indicated that the estrogenicity and "antiestrogenicity" was the same for the two combinations whereas the androgenicity of levonorgestrel was greater giving a reduction in the EE-induced increase in SHBG (SHBG is increased by estrogens and suppressed by androgens). When giving desogestrel 0.125-0.500 mg and lynestrenol 5 mg alone in daily doses to a group of regularly menstruating women (n = 8) strong suppression of SHBG was achieved while ceruloplasmin, CBG and thyroxine binding globulin (TBG) did not change. TBG is decreased and prealbumin increased by androgenic/anabolic activity but only a moderate increase in prealbumin was found during lynestrenol treatment. The changes in SHBG are probably the result of a dose-dependent receptor interaction related to 17 alpha-alkylation in 19-norsteroids. Twenty women with PCO were treated for 8 months with 0.150 mg desogestrel/0.030 mg EE. Evaluation was done before treatment and after 3 and 8 "pill" cycles regarding androgens, estradiol, SHBG, hirsutism and body weight. Spontaneous menstrual cycles were assessed after treatment. Serum lipids and lipoproteins were studied before treatment and at the end of the third "cycle". In PCO the suppression of increased total and free testosterone levels (in comparison to 22 healthy women) was evident during treatment, concordant with increases in SHBG capacity. Hirsutism was suppressed and body weight was reduced in obese women.(ABSTRACT TRUNCATED AT 400 WORDS)

Lipid metabolism in women with polycystic ovary syndrome: possible implications for an increased risk of coronary heart disease.

This study reports values of serum lipids, lipoproteins, and the relative fatty acid composition of lecithin and cholesterol ester in 20 women with typical polycystic ovary syndrome (PCO). These values were compared with values of 22 regularly menstruating women without clinical evidence of androgen excess. Higher levels of triglycerides in serum (P less than 0.05) and very low-density lipoproteins (P less than 0.01) and lower concentrations of free cholesterol in low-density lipoproteins (P less than 0.05) were found in the PCO women. In serum lecithin the PCO patients had higher palmitic and lower stearic acid levels compared with those of the normal women. This finding was interpreted as a reduction of the excretory capacity of the liver in the PCO group. No correlations between lipids and sex hormones were found. Body weights and blood pressures were higher in the PCO group. The results indicate that PCO women could be at increased risk for coronary heart disease, because an increased serum triglyceride level, body weight, and blood pressure are considered to be risk factors of coronary heart disease.

A new combination of conjugated equine oestrogens and medroxyprogesterone for treatment of climacteric complaints.

Thirty-four post-menopausal women with climacteric complaints were given conjugated equine oestrogens (1.25 mg/day) for 21 days followed by 2 days without hormones and then 5 mg medroxyprogesteroneacetate daily for 5 days. The present trial was designed to study effects on vasomotor symptoms, bleeding patterns and endometrial histopathology. Vasomotor disturbances were completely relieved. No recurrence of symptoms was recorded in the oestrogen-free week. Withdrawal bleedings were regular and slight, which was a positive experience for those women who had previously been treated with other oestrogen-progestogen regimens. In most patients inactive or weak secretory endometrial epithelium was found during treatment. Two women developed differing degrees of hyperplasia after 2.5 and 3 yr, respectively. This fact emphasizes the necessity of adding progestogens for at least 10 days each month even if the oestrogens and progestogens are administered separately. It may also be wise to perform an endometrial biopsy when sex hormones are administered on a long-term basis.

Androgenic, anabolic, estrogenic and antiestrogenic effects of desogestrel and lynestrenol: effects on serum proteins and vaginal cytology.

Eight healthy (apart from pelvic endometriosis) women were given daily doses of 0.125, 0.250 and 0.500 mg of desogestrel or 5 mg of lynestrenol orally in a randomized order. Duration of each treatment was 6 weeks. Serum was analyzed for sex hormone binding globulin (SHBG), ceruloplasmin, cortisol binding globulin (CBG), thyroxine binding globulin (TBG) and prealbumin using an electroimmunoassay. Serum 17 beta-estradiol (E2) and testosterone (T) were analyzed by radioimmunoassay. Vaginal cytology was studied using the maturation value (MV). E2 levels were depressed by desogestrel and lynestrenol apart from values in two women after 0.125 mg desogestrel. T concentration was suppressed by desogestrel but not by lynestrenol. SHBG concentration and MV were dose-dependently suppressed indicating an antiestrogenic or possibly androgenic effect of desogestrel and lynestrenol. No androgenic or anabolic effects of desogestrel were however seen, e.g. suppression of TBG content or increase in prealbumin levels. For lynestrenol, however, a small but significant increase in prealbumin concentration indicated a weak androgenic/anabolic effect. No estrogenic effects were seen, e.g. increases in ceruloplasmin, CBG levels or in elevations of MV. A depressed SHBG production ability in the hepatocytes during treatment with 19-nortestosterone derivatives is postulated, possibly due to competitive receptor binding.

PIP: 8 healthy (apart from pelvic endometriosis) women were given daily doses of 0.125, 0.250, and 0.500 mg of desogestrel or 5 mg of lynestrenol orally in a randomized order. Duration of each treatment was 6 weeks. Serum was analyzed for sex hormone binding globulin (SHBG) ceruloplasmin, cortisol binding globulin (CBG), thyroxine binding globulin (TBG) and prealbumin using an electroimmunoassay. Serum 17Beta-estradiol (E2) and testosterone (T) were analyzed by radioimmunoassay. Vaginal cytology was studied using the maturation value (MV). E2 levels were depressed by desogestrel and lynestrenol apart from values in 2 women after 0.125 mg desogestrel. T concentration was suppressed by desogestrel but not by lynestrenol. SHBG concentration and MV were dose-dependently suppressed indicating an antiestrogenic or possibly androgenic effect of desogestrel and lynestrenol. No androgenic or anabolic effects of desogestrel were however seen, e.g., suppression of TBG content or increase in prealbumin levels. For lynestrenol, however, a small but significant increase in prealbumin concentration indicated a weak and androgenic/anabolic effect. No estrogenic effects were seen, e.g. increases in ceruloplasmin, CBG levels or in elevation of MV. A depressed SHBG production ability in the hepatocytes during treatment with 19-nortesterone derivatives is postulated, possibly due to competitive receptor binding.

Restovar--new low-dose, combined, oral contraceptive. Effects on serum proteins, free testosterone and clinical efficacy.

PIP: A combined oral contraceptive (OC, Restovar, Organon) containing 0.0375 mg ethinyl estradiol and 0.75 mg lynestrenol was investigated. Various clinical and laboratory variables were studied in 164 women over 1376 treatment cycles. No pregnancies occurred. In common with other low-dose combined preparations, Restovar also caused some intermenstrual bleeding but acceptability was good in the majority of women. The frequency of general complaints was low. The estrogen-sensitive proteins, ceruloplasmin and transcortin, increased in proportion to the estrogen content of the preparation. The estrogen-androgen-sensitive proteins, sex hormone binding globulin, and thyroxin binding globulin, increased to a rather high level. Free testosterone decreased significantly. The elevation of sex hormone binding globulin level was accompanied by a decrease in free testosterone. The strong increases in sex hormone binding globulin and thyroxin binding globulin indicate that the preparation has a very low androgenic activity. The latter was confirmed in 2 women with initially low sex hormone binding globulin levels who showed a marked improvement in hirsutism and acne during treatment; this improvement was correlated with an increase in sex hormone binding globulin and decreased free testosterone levels.^ieng

A continuous estrogen-progestogen regimen for climacteric complaints. Effects on lipid and lipoprotein metabolism.

The lipid composition of serum and the lipoprotein fractions, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) were determined in 26 peri- and postmenopausal women treated with a daily dose of 2 mg 17-beta-estradiol, 1 mg estriol and 1 mg norethisteroneacetate in a continuous regimen for 12 months. A decrease was noted in all serum lipids, triglycerides, cholesterol and phospholipids during treatment. When comparing the lipid values after 3 and 12 months of treatment a tendency was found to approach pretreatment values with time. A reduction of triglycerides in VLDL after 3 months, concomitant with a decrease in HDL-cholesterol, was interpreted as an effect mainly of the progestogen component. A decrease of free cholesterol in LDL was found during treatment. The ratio of LDL-cholesterol/HDL-cholesterol was unaltered when comparing values before vs. after 3 and 12 months of treatment. Decreased levels of HDL-cholesterol and elevated levels of LDL-cholesterol are considered to be risk factors for coronary heart disease. The significance of lipid metabolic effects induced by treatment in the present study on a longterm basis is hard to evaluate in terms of atherogenicity.