Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric complaints.

OBJECTIVE: Tibolone has been shown to alleviate climacteric symptoms. This study was designed to compare the effect of tibolone (Livial, 2.5 mg daily) on different climacteric complaints and its impact on the endometrium, determined by vaginal ultrasound, with that of conjugated estrogens (Premarin, 0.625 mg daily) continuously for 6 months in combination with the progestogen medrogestone (Colpron, 2 x 5 mg daily for 12 days each month). METHODS: One hundred and twenty-nine postmenopausal women were recruited and the severity of climacteric symptoms as well as endometrial thickness were recorded at the pre-trial examination and after 1, 3, and 6 months. RESULTS: With the exception of vertigo, mood depression, mood disorder, loss of libido, and dryness of skin, where tibolone was found to be more effective than conjugated estrogens/medrogestone, climacteric symptoms improved significantly in both groups over the 6-month study period. Endometrial thickness did not increase significantly in the tibolone group, whereas in the conjugated estrogens/medrogestone group there was a highly significant increase after 1 month and still a trend towards significance after 6 months. Recurrence of vaginal bleeding occurred significantly less frequently in the tibolone group than in the comparison group. CONCLUSION: Tibolone seems to offer a complete treatment of the climacteric complaints whilst avoiding some of the problems associated with classical hormone replacement therapy.

A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 20 micrograms ethinylestradiol/150 micrograms desogestrel, with respect to efficacy, cycle control and tolerance.

The aim of this study was to compare contraceptive reliability, cycle control and tolerance of an oral contraceptive containing 20 micrograms ethinylestradiol and 75 micrograms gestodene, with a reference preparation containing the same dose of estrogen combined with 150 micrograms desogestrel. This article presents interim data from centers in France and Austria, involving a total of 479 women and 4,991 cycles. Contraceptive reliability was good with both preparations. Two pregnancies occurred in the gestodene group, but neither were due to method failure. In the desogestrel group there were also two pregnancies, of which one was due to method failure. With respect to cycle control, there is a trend towards a lower incidence of intermenstrual bleeding in the gestodene group. The incidence of spotting (scanty bleeding) during the important first three cycles was 3.5% lower in the gestodene group, and over the first six cycles, it was 7.6% lower. Amenorrhea was similar in both groups, but the incidence of dysmenorrhea was significantly lower in the gestodene group (p=0.001). Adverse events were similar in both groups, with headache, breast tension and nausea the most frequently reported symptoms. Body weight remained relatively constant during treatment in both groups, and no hypertension was reported for any woman during the course of the study. In each treatment group, 19 women discontinued because of adverse events. It is concluded that both preparation are reliable and well tolerated oral contraceptives are reliable and well tolerated oral contraceptives; however, there is a more favourable effect on dysmenorrhea by the gestodene formulation.

The effect on blood pressure of a monophasic oral contraceptive containing ethinylestradiol and gestodene.

To obtain an overview of the effect of monophasic gestodene on blood pressure and to determine the frequency of "OC elevated BP/hypertension," the results of blood pressure monitoring from four clinical studies of contraceptive efficacy and safety have been retrospectively analyzed. A total of 1930 women took part in the studies, which recorded BP for up to 24 cycles. Analysis of results revealed that 97 women (5.0%) showed an increase in blood pressure from previously normal to elevated values while taking monophasic gestodene, with only 26 (1.35%) fulfilling the criteria of "OC elevated BP/hypertension." Only four women dropped out of the trials due to hypertensive blood pressure values, while 67 women (3.5%) experienced a normalization of previously elevated blood pressure measurements. In conclusion, this analysis has confirmed that gestodene has a negligible effect on blood pressure, with increased BP a relatively rare event.

PIP: Schering AG (manufacturer of a monophasic oral contraceptive [OC] containing 75 mcg gestodene plus 30 mcg ethinyl estradiol) in Berlin, Germany, conducted a retrospective analysis of blood pressure measurements from 4 clinical trials of the contraceptive efficacy and safety of monophasic gestodene to examine gestodene's effect on blood pressure and the incidence of OC-related blood pressure/ hypertension. (OC-related blood pressure/hypertension is defined as: women with neither history of hypertension nor elevated blood pressure before OC use develop increased blood pressure or hypertension that is reversible once OC use ceases.) The clinical trials recorded the blood pressure of 1930 women for up to 24 cycles. Most women (89.9%) experienced no change in their blood pressure during OC use. 97 women (5%) experienced an increase in blood pressure. 26 women (1.35%) had OC-elevated blood pressure/hypertension. Four women left the trials due to hypertension. 67 women (3.5%) who had elevated blood pressure before OC use attained normalization of blood pressure during OC use. These results show that the gestodene-containing OC had an insignificant effect on blood pressure and that elevated blood pressure rarely occurred.

Comparative evaluation of the androgenicity of four low-dose, fixed-combination oral contraceptives.

Changes in endogenous androgen metabolism were compared in healthy women taking one of four low-dose modern oral contraceptives (OCs). One hundred women were randomized to (1) 35 micrograms ethinyl estradiol (EE) + 250 micrograms norgestimate (Cilest); (2) 20 micrograms EE + 150 micrograms desogestrel (Mercilon); (3) 30 micrograms EE + 150 micrograms desogestrel (Marvelon); or (4) 30 micrograms EE + 75 micrograms gestodene (Femodene). During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded, and plasma levels of the following variables were recorded: sex-hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), testosterone, free testosterone, dihydrotestosterone, androstenedione, dihydroepiandrosterone sulfate (DHEAS), and hydroxyprogesterone. The free androgen index was also calculated. These variables were remeasured during the third week of OC intake and during the fourth and sixth cycles. There were no statistically significant differences in androgenic variables among the four OCs. The DHEAS concentration decreased less with the 20 micrograms EE + desogestrel formulation compared with either 30 micrograms EE + desogesterel or norgestimate-containing formulations (20% vs. 45%). Concentrations of SHBG and CBG increased significantly in all four groups (average 263 +/- 119% and 94 +/- 26%, respectively); CBG increased less in women taking 20 micrograms EE + desogestrel (about 75%) than in the other formulations (about 100%). The four modern, low-dose OCs tested had similar impacts on endogenous androgen metabolism, yielding significant decreases in testosterone, dihydrotestosterone, androstenedione, and DHEAS. All of these formulations may be beneficial in women with androgen-related syndromes such as acne and hirsutism. Large studies are under way to establish which of the third-generation OCs is the least androgenic. In vitro studies suggest that norgestimate has the least androgenic profile.

The acceptance of a 7-week cycle with a modern low-dose oral contraceptive (Minulet).

Cycle control and tolerance were studied in a group of 55 female volunteers, who took during 42 consecutive days a modern low-dose oral contraceptive: gestodene 75 micrograms/ethinylestradiol 30 micrograms (Minulet). During these 42 days, 96% of the women experienced no breakthrough bleeding and 81% of the women experienced no spotting or breakthrough bleeding. When the findings of this study are compared with the findings of an earlier study with also a seven-week cycle but with other oral contraceptives, it can be concluded that Minulet offered an excellent cycle control.

PIP: 55 women took the combined oral contraceptive Minulet (30 mcg ethinyl estradiol and 75 mcg gestodene) for 42 consecutive days, using 2 active pill strips, to lengthen the interval between withdrawal bleeding and assess acceptability. The study was an open multi-center trial in which 38 general practitioners each supervised 1 or 2 women. The women averaged 27 years old (range 18-40), and had used Minulet without problems for the previous 6 months. 10 women noted spotting, and 2 had breakthrough bleeding, both after Day 21 of pill intake. There was 1 dropout for unrelated medical reasons. Other minor side effects were breast tenderness (7%), nausea (4%), abdominal bloating (4%), headache (2%), and dysmenorrhea (2%). 92% of the women reported extreme to moderate satisfaction, but 4% were not satisfied because of breakthrough bleeding. Nevertheless, these data on breakthrough bleeding were much lower than published data from trials with other combined pills, especially those containing levonorgestrel.

Comparative review of third-generation progestins.

Desogestrel, gestodene, and norgestimate represent a new generation of progestins designed for use in oral contraceptives. A high degree of efficacy has been retained in these progestins, and the adverse metabolic impact exhibited by older progestins has been reduced considerably. The clinical profile of each progestin, as it is marketed in Europe in combination with ethinyl estradiol, is reviewed. Direct comparisons are made whenever applicable. The major advantages of these formulations over the older combined oral contraceptives are that they have less effect on lipid metabolism and on carbohydrate metabolism, and they are less androgenic. The clinical implications of these findings are discussed.

Clinical trial with 3-keto-desogestrel subdermal implants.

The study was done to assess the clinical performance and in vivo steroid release rate of 3-keto-desogestrel subdermal implants designed to deliver 5 different doses of the progestin. Volunteers were healthy women of proven fertility who provided blood samples at scheduled intervals during treatment. No pregnancy occurred in 514 woman-months in users of implants delivering 30 and 40 micrograms per day of 3-keto-desogestrel. Three pregnancies, one ectopic, were observed in 109 woman-months recorded with implants delivering 20 micrograms per day or less. Ovulation was inhibited, as judged by depressed progesterone levels, in 57 of 59 (97%) blood samplings in women whose 3-keto-desogestrel plasma levels were greater than 0.28 nmol/L and in 39 of 75 (52%) of cases with lower levels. Users of 4 cm implants manufactured by The Population Council, New York, showed mean levels above 0.28 nmol/L until 18 months of use. Levels achieved with 4.4 cm implants manufactured by Organon, Oss, Holland, were less consistent. No changes were observed in the plasma lipoprotein pattern or clinical chemistry during treatment. The main complaint was the occurrence of bleeding irregularities, particularly with the lower doses. Ovarian cysts found during pelvic examination in 11 (22%) subjects disappeared spontaneously within 7-90 days. 3-keto-desogestrel implants releasing around 40 ug/day and providing plasma levels around 0.28 nmol/L afford efficient contraceptive protection.

Desogestrel: using a selective progestogen in a combined oral contraceptive.

Desogestrel is the most selective progestogen used in oral contraceptives (OCs). The clinical characteristics of the monophasic combined OC containing 150 micrograms desogestrel and 30 micrograms EE per tablet (Marvelon) are in accordance with the strong progestogenic and minimal androgenic effects of desogestrel: a very high contraceptive efficacy is combined with minimal and, in the case of lipid metabolism, even potentially positive effects on metabolic parameters. Through increasing the plasma levels of sex hormone binding globulin, and thereby decreasing the plasma levels of free testosterone, the desogestrel-containing OC also has substantial beneficial effects on acne.

Clinical experience with a modern low-dose oral contraceptive in almost 100,000 users.

Efficacy, cycle control, tolerance, and adverse events were studied in a clinical Phase IV study using a new progestogen, gestodene, in an amount of 75 micrograms combined with 30 micrograms ethinylestradiol. The study was performed as a multicenter trial in 96,000 patients over a period of 6 cycles. Half of the patients taking the new preparation were first-time OC users, the other half switched from another OC. With regard to contraceptive efficacy, the life-table analysis showed a value of 0.032% for method failure and 0.114% for patient failure. The correspondent Pearl-Index is 0.062 and 0.22. The new drug was found acceptable by more than 90% of the women involved in the trial. Dysmenorrhea present in the "switchers" mostly disappeared on the new OC, while body weight and blood pressure remained virtually unchanged. Thus, it can be concluded that blood pressure and body weight behaviour is similar to that seen with other low-dose OCs. The new combined pill offers excellent cycle stability and has a very favourable effect on dysmenorrhea. The number of clinically diagnosed thrombotic events documented in this study was 0.65 per 1000 woman-years (TWY) and does not exceed the range of events seen in groups of women using non-hormonal methods of contraception (Oxford-FPA study 0.4/TWY and RCGP study 0.8/TWY).

PIP: Efficacy, cycle control, tolerance, and adverse events were studied in a clinical phase IV study using a new progestogen, gestodene, in an amount of 75 mcg combined with 30 mcg ethinyl estradiol. The study was performed as a multicenter trial in 96,000 patients over a period of 6 cycles. 1/2 of the patients taking the new preparation were 1st-time OC users, the other 1.2 switched from another OC. With regard to contraceptive efficacy, the life table analysis showed a value of 0.032% for method failure and 0.114% for patient failure. The correspondent Pearl Index is 0.062 and 0.22. The new drug was found acceptable by more than 90% of the women involved in this trial. Dysmenorrhea present in those who switched disappeared for the most part with this new OC, while body weight and blood pressure remained virtually unchanged. Thus, it can be concluded that blood pressure and body weight behavior is similar to that seen with other low-dose OCs. The new combined pill offers excellent cycle stability and has a very favorable effect on dysmenorrhea. The number of clinically diagnoses thrombotic events documented in this study was 0.65/1000 woman-years (TWY) and does not exceed the range of events seen in groups of women using nonhormonal methods of contraception (Oxford-FPA study 0.4/TWY and RCGP study 0.8/TWY).